effects of early clozapine treatment on remission rates in

EARLY- Protocol final Version 5.0 AM 3.0 - Date: 30.11.2020 EudraCT-No.: 2018-001514-15 Confidential 1 of 71

BEZIRKSKLINIKEN SCHWABEN

STUDY PROTOCOL

Effects of early clozapine treatment on remission

rates in acute schizophrenia (EARLY)

Sponsor:

Bezirkskliniken Schwaben

Dr.-Mack-Straße 4 - D – 86156 Augsburg

Sponsor Delegated Person (SDP):

Prof. Dr. med. Alkomiet Hasan

Bezirkskrankenhaus Augsburg, Klinik für Psychiatrie, Psychotherapie und Psychosomatik der Universität Augsburg


EudraCT Number: 2018-001514-15 Study Code: EARLY_KUM_PSY

Version: Final 5.0 - AM 3.0

Date 30.11.2020

Confidential

This document is confidential and should serve as a source of information for Investigators and

other personnel involved in this clinical study, consultants and ethics committees and

regulatory authorities. The contents of this document shall only be disclosed to others in

agreement with the coordinating investigator and/or sponsor.

EARLY- Protocol final Version 5.0 AM3.0 – 30.11.2020 EudraCT-No.: 2018-001514-15 Confidential 3 of 71

Table of Contents

Inhalt

Signatures ...................................................................................................................... 2

Responsibility ................................................................................................................. 5

Study-Synopsis .............................................................................................................. 6

Summary ..................................................................................................................... 10

1. Introduction and aims ............................................................................................... 11

1.1 Background, initial situation and medical problem ................................................................. 11

1.2 Rationale for the EARLY study .................................................................................................. 12

2. Objectives ................................................................................................................ 13

3. Study design ............................................................................................................ 14

4. Study endpoints ....................................................................................................... 15

4.1 Primary endpoint ......................................................................................................................... 15

4.2 Secondary endpoints .................................................................................................................. 16

5. Study population ...................................................................................................... 18

5.1 Inclusion criteria .......................................................................................................................... 18

5.2 Exclusion criteria ......................................................................................................................... 20

5.3 Sample size calculation .............................................................................................................. 20

6. Treatment of subjects .............................................................................................. 22

6.1 Investigational products ............................................................................................................. 22

6.2 Titration schemes ........................................................................................................................ 22

6.3 Use of concomitant medication ................................................................................................. 26

6.4 Treatment after the end of the double-blind treatment phase ................................................ 27

7. Investigational product ............................................................................................. 28

7.1 Contraindications ........................................................................................................................ 28

7.2 Interactions .................................................................................................................................. 29

7.3 Manufacturing of Trial Medication ............................................................................................ 31

7.4 Storage, Formulation, packaging and labelling ....................................................................... 31

7.5 Emergency unblinding ................................................................................................................ 32

8. Methods ................................................................................................................... 33

8.1 Randomisation ............................................................................................................................. 33

8.2 Description of study visits.......................................................................................................... 33

8.3 Special safety aspects during the intervention period ............................................................ 36

8.4 Naturalistic extension study....................................................................................................... 37

8.5 Description of rating scales and assessments ........................................................................ 37

8.6 Discontinuation of the study ...................................................................................................... 41

8.7 Study flow chart ........................................................................................................................... 43

9. Statistical Analysis ................................................................................................... 45


11. Feasibility of patient recruitment ............................................................................ 49

12. Safety reporting ..................................................................................................... 50

12.1 AE, SAE and Susar definitions and reporting procedures ................................................... 50

12.2 Follow-up of adverse events .................................................................................................... 53

12.3 Unblinding .................................................................................................................................. 55

12.4 Pregnancy .................................................................................................................................. 55

12.5 Overdose .................................................................................................................................... 56

12.6 Annual safety report (Safety Update Report (DSUR)) ............................................................ 56

12.7 Safety Monitoring Board (SMB) ............................................................................................... 56

13. Ethical and regulatory aspects ............................................................................... 57

13.1 Sponsor‘s and investigator’s responsibilities........................................................................ 57

13.2 Ethics committees and health authorities .............................................................................. 57

13.3 Ethical performance of the study ............................................................................................ 57

13.4 Informed consent of the study participants ........................................................................... 57

14. Study administration .............................................................................................. 59

14.1 Documentation and Data collection ........................................................................................ 59

14.2 Database management ............................................................................................................. 59

14.3 Audits and inspections ............................................................................................................. 59

14.4 Monitoring .................................................................................................................................. 60

14.5 Archiving .................................................................................................................................... 60

14.6 Reporting .................................................................................................................................... 60

14.7 Insurance for subjects participating in clinical studies ........................................................ 61

14.8 Data Privacy Protection and Confidentiality protection ........................................................ 62

14.9 Protocol amendments or changes in trial conduct ............................................................... 62

15. Abbreviation ........................................................................................................... 64

16. Annex ..................................................................................................................... 65

16.1 Declaration of Helsinki .............................................................................................................. 65

16. Reference List ........................................................................................................ 66


Responsibility

S

po

nso

r

Sponsor

Bezirkskliniken Schwaben


Tel.: (0821) 4803 - 2727

Fax.: (0821) 4803 - 2702

E-Mail: [email protected]

Pro

toco

l C

om

mit

tee

Sponsor Delegated Person

Project Leader

Prof. Dr. med. Alkomiet Hasan

Director

Department of Psychiatry, Psychotherapy and

Psychosomatics, Medical Faculty, University of

Augsburg, BKH Augsburg

Bezirkskliniken Schwaben Dr.-Mack-Straße 1 - D – 86156 Augsburg Tel.: (0821) 4803-1001 Fax: (0821) 4803-1002 E-Mail: [email protected]

Co-Project Leader

Prof. Dr. med. Stefan Leucht

Deputy Director

Department of Psychiatry and Psychotherapy,

TU Munich,

Ismaningerstr. 22, 81675 München,

Tel.: +49-89/4140-4249


Clinical Project Management

Dr. med. Wolfgang Strube

Department of Psychiatry, Psychotherapy and

Psychosomatics, Medical Faculty, University of

Augsburg, BKH Augsburg

Bezirkskliniken Schwaben Dr.-Mack-Straße 1 - D – 86156 Augsburg Tel.: (0821) 4803-3225 Fax: (0821) 4803-1002 E-Mail: [email protected]

IME

DIS

Statistican

PD Dr. rer. nat. Alexander Hapfelmeier

Institute of Medical Informatics, Statistics and

Epidemiology

Technische Universität München

Ismaningerstr. 22, 81675 München

Tel.: +49-89/4140-4340

Fax.: +49-89/4140-4350


MS

Z

Project Management

Monitoring

Data Management

Safety Management


School of Medicine

Münchner Studienzentrum

Ismaninger Straße 22; 81675 München


Tel.+49-89/4140-6321

Fax:+49-89/4140-6322

mailto:[email protected]





Study-Synopsis

Synopsis

Study Title Effects of early clozapine treatment on remission rates in acute

schizophrenia (EARLY)

Indication / Population Schizophrenia

Phase

Design

Phase III Study

Multicenter, randomized, double-blind, parallel-group, controlled design

Medication / Dosing Clozapine (75 to 600 mg/d), Olanzapine (2.5 to 20 mg/d)

Number of Patients 220

Study Objectives

The primary objective is to investigate the symptomatic remission rates in

non-treatment-refractory patients with schizophrenia randomized to either

early clozapine or olanzapine over an 8-week period.

Secondary objectives include differences in side effects, symptom

severity, safety measures and cognitive functions as detailed below.

Efficacy and Safety

Primary Endpoint:

Relative frequency of patients in the clozapine group in remission

(Remission in Schizophrenia Working Group [RSWG] consensus criteria) at

week eight compared to the olanzapine group.

Secondary endpoints and other assessments:

The following measures will be compared between study arms: early

response and remission rates (Positive and Negative Symptom Scale,

PANSS); Other assessments: Thought and Language Disorder (TALD)

scale, cognition (Trail-Making Test, TMT); Clinical Global Impression (CGI);

functioning (Global Assessment of Functioning, GAF); depression (Calgary

Depression Scale for Schizophrenia, CDSS);, abbreviated quality of life

enjoyment and satisfaction questionnaire (Q-LES-Q-18); health situation

(SF-12); adverse events: Glasgow Antipsychotic Side-effects Scale for

Clozapine, GASS for Clozapine); Drug Attitude Inventory (DAI); views of

patients and relatives on treatment (Subjective Wellbeing under

Neuroleptics, SWN); Change in Personal and Social Performance Scale

(PSP); Attitude towards participation in clinical research; InterSePT scale for

suicidal thinking (ISST);

Assessment of Safety:

Electrocardiography (ECG) and blood investigations (every week: white and

complete blood count, WBC, CBC; creatinine kinase, CK, Troponine),

general side effects, adverse events (AEs) and serious adverse events

(SAEs) according to ICH-GCP; in addition other assessments such as vital

signs, electroencephalography (EEG), metabolic parameters (weight gain,

BMI); treatment-associated constipation according to Cleveland Clinic

constipation score (CCCS); St. Hans Rating Scale (SHRS); Barnes akathisia

rating scale (BARS)

Inclusion criteria 1. Age 18 to 65 years


2. Signed informed consent

3. DSM-V diagnosis of schizophrenia confirmed by the Mini international

Neuropsychiatric Interview

4. At least one documented prior hospitalization due to the illness in the

medical history (the current hospitalization can be considered as

“prior” hospitalization if its ≥ 4 weeks) at screening

5. For treatment-naïve patients (defined as no previous antipsychotic treatment or a maximum of 30 days of treatment), an antipsychotic treatment attempt of at least 30 days with an antipsychotic in a therapeutic dose according to local guidelines other than clozapine and olanzapine before the screening phase is needed. For non-treatment-naïve patients (defined as having been treated for more than 30 days with an antipsychotic), a discontinuation of a foregoing antipsychotic treatment prior to the screening phase within a maximum of six months (=180 days) is possible (corresponding to the estimated average time for an antipsychotic washout phase and the expected time to develop a relapse of the disease). For patients being treated with a long-acting antipsychotic (other than PP3M), an inclusion is possible if inclusion date corresponds to the planned date of the next injection plus five to seven days. For patients being treated with oral olanzapine, an inclusion is possible if this treatment has lasted for no longer than 2 weeks prior to inclusion and if exclusion criteria 8 is not fulfilled.

6. Clinical need for a medication switch because of clinical inefficacy or side-effects or clinical need for a reintroduction of an antipsychotic treatment after treatment discontinuation prior to the screening phase (see 5.)

7. Moderate symptomatology on the PANSS, defined as a score ≥ 4 for

two or more symptoms from P1-P7 or a score of ≥ 6 for one symptom

from P1-P7 (minimum threshold definition) at screening

8. Male participants and female participants who are not capable of

bearing children or who use a method of contraception that is

medically approved by the health authority of the respective country

at screening

This includes:

A woman who is not capable of bearing a child is defined as follows:

post-menopausal (12 months natural (spontaneous) amenorrhea or

6 months spontaneous amenorrhea with serum-FSH-values (follicle-

stimulating hormone) of >40 mIU/mL); 6 weeks after a bilateral

ovariectomy with or without hysterectomy or sterilization by means of

tubal ligation

A woman capable of bearing child is defined as follows: a woman who

is physiologically capable of becoming pregnant, including women

whose occupation, lifestyle or sexual orientation exclude sexual

intercourse with a male partner and women whose partners have

been sterilized by vasectomy or other measures.

Medically-approved methods of contraception can include the

following: hormonal contraceptives, intrauterine device and double

barrier method. Acceptable preventive measures can include total

abstinence at the discretion of the investigator, in cases where

compliance is ensured because of the study participant’s age,

occupation, lifestyle or sexual orientation. Periodical abstinence (e.g.

calendar, ovulation, symptothermal methods or abstinence until the

4th day after the ovulation) as well as coitus interruptus are not

acceptable methods of contraception.

A reliable method of contraception (CTFG guideline) must be used

for the entire duration of the study.


Exclusion criteria

1. Patients who are not suitable for the study in the opinion of the

investigator

2. Patients who are unable to give informed consent

3. Coercive treatment at the time of study inclusion

4. White blood cell count (WBC) at inclusion not meeting the

requirements for clozapine use in Germany. Patients must have

normal leukocyte findings (white blood cell count ≥ 3500/mm3 (≥

3.5x109/l), and Absolute Neutrophil Count (ANC) ≥ 2000/mm3 (≥

2.0x109/l) at the screening visit

5. The presence of one or more of the contraindications against any of the study drugs as mentioned in the SmPC

6. Treatment-naïve or treatment-resistant schizophrenia. Treatment-

naïve will be defined as no previous antipsychotic treatment or a

maximum of 30 days of treatment. Treatment resistance is defined as

2 antipsychotic trials (with antipsychotics from two different chemical

classes) for a period of ≥ 6 weeks with CPZ equivalent doses ≥ 600

mg/day, both of which took place immediately before the screening

phase

7. Diagnosis of primary substance dependency other than nicotine

8. Documented previous non-response to an 8-week drug trial with

olanzapine or any documented previous treatment with clozapine

9. Intolerance to one of the study drugs

10. Pregnancy (incl. positive blood pregnancy test) / lactation (female

patients)

Study Procedures

Experimental intervention/index test: Application of double-blind, early

clozapine in acute schizophrenia patients not meeting the criteria for

treatment resistance

Control intervention/reference test: Application of double-blind olanzapine

in acute schizophrenia patients not meeting the criteria for treatment

resistance

Schedule / Follow up

Inclusion of the first patient (FPFV): approx. quarter II 2019

Inclusion of the last patient (LPFV): approx. quarter I 2022

End of the study (LPLV): approx. quarter IV 2022

End of naturalistic follow-up: approx. quarter IV 2024

Integrated final report of primary outcome: approx. quarter IV 2023

Statistics Sample size

To be assessed for eligibility (n = 880)

To be allocated to trial (n = 220)

To be analysed (n = 220)

Statistics

Efficacy/test accuracy: Relative frequency of patients in remission at week

eight in both study groups

Description of the primary efficacy/test accuracy analysis and population:

The primary efficacy endpoint will be compared between groups with a

Mantel-Haenszel test with centres as strata on a two-sided 5% significance

level. This analysis will be performed in the intention-to-treat (ITT)

population.

Safety: Absolute and relative frequencies of categorical safety outcomes will

be assessed along the course of the trial. Differences between groups will

also be tested for statistical significance by Fisher’s exact test. Continuous


safety outcomes will be presented by descriptive statistics and compared

with t-tests or Mann-Whitney U tests.

Secondary endpoints: Depending on the data distribution, continuous and

categorical secondary endpoints will be compared between groups by linear

or binary logistic regression analysis including a factor variable for centres.

Baseline values will be included as another covariate if existing. In case of

non-normally distributed residuals in the linear model, a van Elteren test with

centres as strata will be applied in an additional analysis. Corresponding

descriptive statistics and confidence intervals will also be given. All tests will

be computed for the ITT and per protocol (PP) populations in an explorative

manner at a two-sided 5% significance level.

Rationale

Achieving symptomatic remission quickly after the onset of psychotic

symptoms is the critical objective in schizophrenia treatment and determines

the subsequent disease course. In this context, only every second patient

with acute schizophrenia achieves symptomatic remission within three

months of initiating antipsychotic treatment, meaning that half of patients do

not achieve this key objective. Increasing the likelihood to achieve

symptomatic remission in acute schizophrenia will improve the overall

outcome, reduce disease-associated burden and potentially prevent mid-

and long-term disease chronicity. With this randomized, double-blind,

parallel-group multicentre trial we aim to provide evidence for the superior

efficacy of the ‘last resort’ antipsychotic clozapine compared to one of the

most effective second-generation antipsychotics (SGAs), olanzapine, in

acute schizophrenia patients who do not meet the criteria for treatment-naive

or treatment-resistant schizophrenia. Our target population represents the

largest group of schizophrenia patients; these patients are frequently

hospitalized and receive ~20% of all psychiatric inpatient treatments in

Germany. A total of 220 patients from several departments of psychiatry with

acute schizophrenia will be randomized to a double-blind, eight-week

treatment with either clozapine or olanzapine. The primary endpoint is the

number of patients in symptomatic remission at the end of week eight

according to the international consensus criteria (‘Andreasen criteria’).

Secondary endpoints and other assessments include e.g. symptom severity,

disease severity, global functioning, cognition, side-effect dimensions and

patients’ and relatives’ view on treatment.


Summary

Achieving symptomatic remission quickly after the onset of psychotic symptoms is the critical

objective in schizophrenia treatment and determines the subsequent disease course. In this context,

only every second patient with acute schizophrenia achieves symptomatic remission within three

months of initiating antipsychotic treatment, meaning that half of patients do not achieve this key

objective. Increasing the likelihood to achieve symptomatic remission in acute schizophrenia will

improve the overall outcome, reduce disease-associated burden and potentially prevent mid- and

long-term disease chronicity. With this randomized, double-blind, parallel-group multicentre trial we

aim to provide evidence for the superior efficacy of the ‘last resort’ antipsychotic clozapine compared

to one of the most effective second-generation antipsychotics (SGAs), olanzapine, in acute

schizophrenia patients who do not meet the criteria for treatment-naive or treatment-resistant

schizophrenia. Our target population represents the largest group of schizophrenia patients; these

patients are frequently hospitalized and receive ~20% of all psychiatric inpatient treatments in

Germany. A total of 220 patients from several departments of psychiatry and psychotherapy with

acute schizophrenia will be randomized to a double-blind, eight-week treatment with either clozapine

or olanzapine. The primary endpoint is the number of patients in symptomatic remission at the end

of week eight according to the international consensus criteria (‘RSWG criteria’, ‘Andreasen criteria’).

Secondary endpoints and other assessments include e.g. symptom severity, disease severity, global

functioning, cognition, side-effect dimensions and patients’ and relatives’ view on treatment.


1. Introduction and aims

1.1 Background, initial situation and medical problem

Despite the significant social and healthcare burden caused by the difficult therapy of schizophrenia,

no novel antipsychotic concepts have been established in psychiatric care since the mid-1990s.

Even worse, the industry is increasingly withdrawing from the field of schizophrenia research (Insel

and Sahakian 2012). Therefore, urgently needed new antipsychotics with the capacity to improve

outcomes and remission rates in schizophrenia are unlikely to be introduced in the coming years.

Remission rates in schizophrenia trials have been reported to be in the range of ~30% to 50%

(Leucht, Beitinger et al. 2007, Boter, Peuskens et al. 2009, Lambert, Karow et al. 2010, AlAqeel and

Margolese 2012) and one in two patients is discussed to be at risk of a chronic disease course (An

der Heiden and Hafner 2010). One recently published meta-analysis investigated 167 double-blind

randomized-controlled trials comparing antipsychotics to placebo with 28102 schizophrenia patients

and was able to show a minimal response in 51% of the patients treated with antipsychotics (30%

with placebo) and a good response, which is principally related to remission, in only 23% of all

patients (14% with placebo) (Leucht, Leucht et al. 2017). However, the most effective antipsychotic

clozapine was excluded from this meta-analysis. A related meta-analysis investigated the response

rates in first-episode schizophrenia patients and showed a minimal response in 81.3% and a good

response in 51.9% of all patients (Zhu, Li et al. 2017). These sources of evidence show that

schizophrenia patients have a high likelihood of response during their first-episode, but that response

rates drop after the first relapse. As many patients do not remit after the first relapse and as remission

is related to good functional outcome and improved quality of life (Lambert, Karow et al. 2010), new

evidence-based strategies are urgently needed to increase remission rates. An increase in remission

will not only improve the aforementioned outcome domains, but is likely to reduce the risks for

hospitalization and treatment discontinuation.

In this context, the early application of clozapine, the most effective antipsychotic, has been

discussed now for years as one possibility to improve outcome in relapsing schizophrenia

(Remington, Agid et al. 2013). This issue of a potential indication extension of clozapine from being

the ‘last-resort antipsychotic’ to being applied at an earlier stage is supported by several lines of

evidence (Remington, Agid et al. 2013), but respective clinical trials to test these hypotheses are

lacking. This application of clozapine as a second-line treatment (Remington, Agid et al. 2013) is

discussed on the basis of the observations that (1) contrary to treatment with the first antipsychotic,

the response rates for consecutive treatments with non-clozapine antipsychotics are low, (2)

clozapine is the most effective antipsychotic for treatment-resistant cases and (3) clozapine

treatment is associated with earlier and longer remission intervals.

As indicated above, sufficiently powered clinical trials investigating the proposed superior efficacy of

early clozapine application compared to standard treatment are lacking. A recently published

retrospective cohort study confirmed the hypothesized superior effectiveness of clozapine compared

to standard antipsychotics with regard to time to hospitalization and risk for treatment discontinuation

(Stroup, Gerhard et al. 2015), and clozapine is still the gold standard in treatment-refractory cases

(DGPPN 2006, Buchanan, Kreyenbuhl et al. 2010, Hasan, Falkai et al. 2012). Moreover, one

nationwide cohort-study investigated the real-world effectiveness of 29823 patients with

schizophrenia and showed that clozapine treatment was associated with the lowest rates of

treatment failure compared to all other oral antipsychotics (Tiihonen, Mittendorfer-Rutz et al. 2017).

In contrast to guideline recommendations (DGPPN 2006, Buchanan, Kreyenbuhl et al. 2010, Hasan,

Falkai et al. 2012), in clinical practice clozapine use is delayed by many years, making clear that

more convincing evidence is needed to overcome this discrepancy (Howes, Vergunst et al. 2012).


The EARLY trial will

(1) allow for novel evidence-based recommendations,

(2) foster the future risk-benefit evaluation of clozapine use in acute schizophrenia and

(3) help to decrease the time lag before clozapine is introduced.

(4) will test whether low-dosages of clozapine are effective in achieving symptomatic

remission

(5) will provide a comprehensive risk-benefit-assessment of the early application of

clozapine

We hypothesize that the early introduction of clozapine in patients with acute schizophrenia will result

in higher remission frequencies and thus reduce the risk to develop unfavourable disease outcomes.

In summary, there is broad evidence that clozapine is an effective antipsychotic that can be safely

used in non-treatment-refractory patients and that has superior effectiveness in real-world settings.

However, high-quality clinical trials investigating the role of clozapine in acute relapsing

schizophrenia are lacking (second-line treatment). Such an approach also has to specifically address

the potentially high levels of side effects and AEs to allow for a comprehensive risk-benefit

evaluation.

1.2 Rationale for the EARLY study

There is a pressing need for new treatments that increase remission rates in patients with relapsing

schizophrenia. Symptomatic remission is associated with better social functioning, a better quality of

life, a more stable disease course and better cognitive functioning (Lambert, Karow et al. 2010). The

possible earlier and broader application of clozapine to reach this objective is extensively discussed

in the field (Remington, Agid et al. 2013, Schooler, Marder et al. 2016), but as detailed in the

paragraph above until now adequately powered and designed trials with a comprehensive

assessment of outcome and burden are lacking. All foregoing trials in non-refractory patients need

to be considered as proof-of-concept trials with no clear rationale to investigate whether clozapine

should be introduced before treatment resistance and no extensive assessment of side effects and

risks. Therefore, our trial is needed to answer the clinically meaningful question whether clozapine

really is superior to other SGAs in non-treatment-refractory schizophrenia patients. Because we will

compare clozapine with olanzapine, one of the most effective SGAs, superiority of clozapine would

impact guideline recommendations and clinical practice. The individual patient and the patient

population will have several benefits from our trial:

(1) in case of superior remission rates in the clozapine arm, a novel treatment option will emerge

that will significantly change guideline recommendations (earlier clozapine application),

(2) increased remission rates will reduce the disease-associated burden of patients and families

and

(3) the broad assessment of side effects and treatment-associated burden will allow an improved

risk-benefit assessment of clozapine.

An increase in the likelihood of remission has the potential to prevent treatment resistance and long-

standing disability in schizophrenia patients with a relapsing disease course and thus to reduce the

overall socioeconomic burden.

Poor remission rates and frequent relapses in schizophrenia lead to the highest direct costs of all

brain disorders in Europe, totaling 29 billion Euros per year (Gustavsson, Svensson et al. 2011).


Furthermore, early disease chronicity entails physical and mental comorbidity, enduring social and

vocational exclusion and excess mortality, which alone in Europe amount to annual indirect costs of

65 billion Euros (Gustavsson, Svensson et al. 2011). An estimation of the societal benefit of

increased remission rates highlights the importance of our approach. First, Zeidler et al. (Zeidler,

Slawik et al. 2012) investigated the direct costs generated by patients with unstable (U; N=1449) or

stable (S; N=8497, U/S ratio=15%) courses of schizophrenia and found that direct costs amounted

to €24,377,976 and €34,234,413, respectively. In this context, a 10% reduction of unstable disease

courses would hypothetically translate into a €1,906,455 reduction of direct treatment costs. Second,

clozapine treatment has been linked to faster remission rates (Lieberman, Phillips et al. 2003) and

less treatment discontinuation and hospitalization (Stroup, Gerhard et al. 2015, Schooler, Marder et

al. 2016), making clear that a clozapine-related increase in remission rates will have a direct

socioeconomic benefit. In accordance with the DFG guidelines, we will involve a patient-relatives

organisation (German Federal Association of the Relatives of Mentally-ill Patients (BApK) in our

project. The organization participated in the application process and will assist in investigating the

patients’ view on treatment and also serve as peer-to-peer consultants for study patients. The aspect

of the patients’ view on treatment is especially important, because some studies have found that

psychiatrists and patients have different valuations of clozapine side effects (Hodge and Jespersen

2008), and one Cochrane review states that former trials have neglected patients’ attitude towards

clozapine (Essali, Al-Haj Haasan et al. 2009). Our trial offers the unique possibility for an in-depth

investigation of this important treatment moderator and will help to increase the acceptance of

clozapine by patients, relatives and professionals. Because neither study drug is under patent

protection, no commercial interest for any pharmaceutical company exists. Therefore, this trial has

the potential to change guideline recommendation in an area where no new development from the

perspective of the pharmaceutical industry can be expected.

Moreover, this trial will also allow investigating whether low-dosages of those highly effective

antipsychotics are sufficient to reach symptomatic remission following the discussions of minimal

effective dose treatment for an optimal risk-benefit evaluation. The latter will be possible, because

the EARLY trial includes the so far most extensive side-effect evaluation of clozapine and olanzapine

in a controlled design going far beyond the safety assessment in clinical practice.

In medication-naïve and first-episode patients (first line treatment), an outstanding superiority of

clozapine could not be established (Remington, Agid et al. 2013) and thus the application is restricted

following the risk/benefit evaluation. In treatment-resistant schizophrenia patients (Kane, Honigfeld

et al. 1988) (third line treatment), clozapine is more effective than other antipsychotics, but due to

the progressed stage of the illness, remission rates are not satisfying. Thus, an early clozapine

application as proposed in the EARLY trial in disease stages after the first episode and before

treatment resistance (second line treatment) has the potential to increase remission rates and to

prevent poor disease outcomes and chronicity.

2. Objectives

With this randomized, double-blind, parallel-group, controlled multicentre trial we aim to provide

evidence for the superior efficacy of the ‘last resort’ antipsychotic clozapine compared to one of the

most effective second-generation antipsychotics (SGAs), olanzapine, in acute schizophrenia

patients who do not meet the criteria for treatment-naive or treatment-resistant schizophrenia. The

primary endpoint (see paragraph 4.1) is the number of patients in symptomatic remission at the end

of week eight according to the international consensus criteria (‘RSWG-criteria’). Secondary

endpoints and other assessments (see paragraph 4.2) include e.g. symptom severity, disease

severity, global functioning, cognition, side-effect dimensions and patients’ and relatives’ view on

treatment. Moreover, we will provide a comprehensive safety assessment and we will provide


measures to disentangle the relationship between early clozapine response and biological factors

(e.g. brain morphology)

3. Study design

The Effects of Early Clozapine Treatment on Remission Rates in Acute Schizophrenia (EARLY) trial

is a double-blind, randomized, controlled parallel group multicentre trial investigating the

symptomatic remission rates in non-treatment-refractory patients with schizophrenia randomized to

either early clozapine or olanzapine over an 8-week period.

Number of patients:

N = 880 schizophrenia patients will be assessed for eligibility

N = 220 schizophrenia patients will be allocated to trial

N = 220 will be analysed (N = 110 in each study group)

Timelines:

Inclusion of the first patient (FPFV): approx. quarter II 2019

Inclusion of the last patient (LPFV): approx. quarter I 2022

End of the study (LPLV): approx. quarter IV 2022

End of naturalistic follow-up: approx. quarter IV 2024

Integrated final report of primary outcome: approx. quarter IV 2023

Operating requirements for the site:

The following requirements must be available:

Enough place for medication and study records

Access to an emergency room/or and emergency unit

Possibility to refer patients to a department of internal medicine

Condition precedent is an adequate number of patients and sufficient infrastructure for treatment at the study site

EARLY is a randomized, double-blind controlled parallel-group multicenter trial to compare the

relative frequency of patients in the clozapine group in remission (Remission in Schizophrenia

Working Group (RSWG) consensus criteria,) (Andreasen, Carpenter et al. 2005) at week eight

compared to the olanzapine group. 220 acute schizophrenia patients not meeting the criteria for

treatment-naïve or treatment-resistant schizophrenia will be recruited from inpatient and outpatients

units of the participating centers. After providing informed consent, patients will be screened for

eligibility to the study. Potential contraindications concerning the use of any of the study drugs will to

be ruled out before starting treatment in the study. Diagnosis and psychiatric comorbidities will be

investigated with the MINI interview. Physical health will be checked in a physical examination.

Several demographic and clinical variables will be assessed, including year of birth, sex, educational

level, previous psychiatric disorders and duration of untreated psychosis. Thus, this phase will serve

the dual purpose of conducting or completing such examinations and, if necessary, gradually

reducing medication. The screening phase will be completed before the baseline visit and will

preferably not be longer than two weeks. At baseline, the standard rating scales will be used

including PANSS, CGI, CDSS and other scales as displayed in the study visit flow-chart.


Figure 1: Schematic Study Flow-Chart. Please see paragraph 8.7 and the Study Flow-Chart there for a detailed visit

plan and paragraph 8.2 for the detailed visit descriptions. Legend: BL= baseline.

4. Study endpoints

For all aims of the study (described in paragraph 1), the primary and secondary endpoints are defined below. The assessment of primary and secondary endpoints will be documented in the eCRF as detailed below.

4.1 Primary endpoint

The primary endpoint is the relative frequency of patients in remission after eight weeks according

to the RSWG criteria (Andreasen, Carpenter et al. 2005), without the time criterion (Gorwood,

Peuskens et al. 2012, Leucht 2014). The RSWG criteria (Andreasen, Carpenter et al. 2005) link

DSM-IV symptoms of schizophrenia with items of the Positive and Negative Syndrome Scale

(PANSS) (Kay, Fiszbein et al. 1987). As detailed elsewhere (Andreasen, Carpenter et al. 2005,

Leucht, Beitinger et al. 2007, Beitinger, Lin et al. 2008), three symptom clusters need to be

considered: (1) psychoticism/reality distortion (PANSS items: delusions, unusual thought content

and hallucinatory behaviour), (2) disorganisation (PANSS items: conceptual disorganisation and

mannerisms/posturing), and (3) negative symptoms (PANSS items: blunted affect, social

withdrawal, lack of spontaneity). According to the RSWG criteria, the symptomatic criterion states

that to achieve symptomatic remission all items (see table 1) must be rated as absent or present

only to a mild degree (PANSS value ≤ 3). All eight items of the primary endpoint will be recorded in

the eCRF (scores).


Dimension of psychopathology

PANSS Item number Criterion Score for remission

Psychoticism (reality distortion)

Delusions P1 ≤ 3

Unusual thought content G9 ≤ 3

Hallucinatory behaviour P3 ≤ 3

Disorganization Conceptual disorganisation P2 ≤ 3

Mannerisms/posturing G5 ≤ 3

Negative symptoms Blunted affect N1 ≤ 3

Social withdrawal N4 ≤ 3

Lack of spontaneity N6 ≤ 3

Table 1: RSWG criteria for remission (primary endpoint) (Andreasen, Carpenter et al. 2005)

4.2 Secondary endpoints

4.2.1 Secondary Endpoints:

1. Relative frequency of patients in remission after four weeks (V5) according to the RSWG

criteria (Andreasen, Carpenter et al. 2005).

2. Change in Positive and Negative Syndrome Scale (PANSS) (Kay, Fiszbein et al. 1987) total

and in the three PANSS subscales (positive, negative, general) from baseline (V1) to week

four (V5) and week eight (V9).

3. Frequency of patients in remission according to the RSWG criteria without the negative

symptom Items (N1, N4 and N6) after four (V5), six (V7) and eight weeks (V9)

4. Frequency of patients with a clinical response according to PANSS (≥ 20% change from

baseline, corrected PANSS formula) (Leucht 2014) after four (V5) and eight weeks (V9).

Secondary Endpoints: Side-effects and safety

1. Change in white/complete blood count (WBC/CBC), creatinine kinase (CK) blood levels from

screening (V0) to every visit during the study period (V13) (see Study Laboratory under

8.5.4).

2. Relative change in Troponine, frequency of 2-fold elevated Troponine, and absolute change

in C-reactive protein (CRP) (values) from screening to every visit during the first four weeks

of the intervention period (V1-V5) and at week 6 (V7) and week eight (V9).

3. Changes in standard parameters of Electrocardiography (ECG) (QT interval-value, heart

rate value from screening/baseline (V1) to week 2 (V3), week 4 (V5), week 6 (V7) and week

eight (V9).

Other clinical assessments:

1. Relationship between drug blood levels/concentration (central laboratory KUM) and

clinical and side-effect endpoints

Change in physical examinations from baseline (V1) to every visit until during the

intervention period (V9)

2. Change in Thought and Language Disorder (Kircher, Krug et al. 2014) (TALD, total scores

of 30 items, each item ranging from 0-4 points) (Kircher, Krug et al. 2014) from baseline

(V1) to week eight (V9).


3. Change in Clinical Global Impression scale (CGI) (Endicott, Spitzer et al. 1976) score

(scores from 1-7) from baseline (V1) to week four (V5) and week eight (V9) and to the

follow-up visits.

4. Change in Personal and Social Performance scale (PSP) (total score from 1-100)

(Nasrallah, Morosini et al. 2008) from baseline (V1) to week eight (V9) and to the follow-

up visits.

5. Change in Global Assessment of Functioning scale (GAF) scores (total score from 0-100)

from baseline (V1) to week four (V5) and week eight (V9).

6. Change in Calgary Depression Scale for Schizophrenia (CDSS) (Addington, Addington

et al. 1993) total score (total score from 0-27) from baseline (V1) to week four (V5) and

week eight (V9).

7. Trail-Making Test A and B (total scores for speed and errors). Change in total TMT scores

from baseline (V1) to week eight (V9).

8. Change in suicidal ideations based on the InterSePT scale (ISST) (total score)

(Lindenmayer, Czobor et al. 2003) from baseline (V1) to week eight (V9).

9. Change in quality of life measures according to the abbreviated quality of life enjoyment

and satisfaction questionnaire (Q-LES-Q-18) (total score) (Ritsner, Kurs et al. 2005) from

baseline (V1) to week eight (V9) and to the follow-up visits.

10. Change in SF-12 score items (12 separate items) (Ware, Kosinski et al. 1996) from

baseline (V1) to week eight (V9).

11. Change in Drug Attitude Inventory (DAI10) (total score) (Stjernsward, Persson et al. 2013)

scores from baseline (V1) to week eight (V9).

12. Change in Subjective Wellbeing under Neuroleptics short form (SWN-K) (Naber 1995)

(Naber 1995) total score (from baseline (V1) to week eight (V9)

13. Attitude of patients towards participation in clinical research and towards the treatment

with olanzapine and clozapine at baseline (self-developed questionnaire) in collaboration

with BApK (a relatives-driven pan-organisation that represents the interests of relatives

and persons affected by mental illness) at screening. Here, a likert-scale will be used to

present descriptive statistics.

Other assessments- Side effects and Safety:

1. Changes in blood pressure and heart rate (values) from baseline (V1) to every visit during

the intervention period (V9).

2. Changes in Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS for Clozapine)

(Hynes, Keating et al. 2015) scores from baseline (V1) to week 2 (V3), week 4 (V5) and

week eight (V9).

3. Changes in the St Hans Rating Scale (SHRS) (Gerlach, Korsgaard et al. 1993) (Gerlach,

Korsgaard et al. 1993) scores from baseline (V1) to week eight (V9).

4. Week eight Changes in Cleveland Clinic Constipation Score (CCCS) (Agachan, Chen et

al. 1996) scores from baseline (V1) to week 2 (V3), week 4 (V5) and week eight (V9).

5. Changes in the Barnes Akathisia Rating Scale (BARS) (Barnes 1989) scores from

baseline (V1) and week eight (V9)

6. Change in fasting glucose, cholesterol, HDL (values) from baseline (V1) to week 4 (V5)

and week eight (V9).

7. Change in weight and BMI from baseline (V1) to week four (V5) and week eight (V9)

8. Change in number of cigarettes from baseline (V1) to week two (V3), week four (V5),

week five (V6) and week eight (V9).


9. Changes in standard parameters of Electroencephalography (EEG) (e.g. frequency

bands) from baseline (V1) to week eight (V9).

Optional activities

Additional facultative assessments: (these data are not part of the study database, see optional activities 8.5.6)

Changes in parameters of transthoracic echocardiography (TTE) from baseline (V1) to week

eight (V9) (optional) (such as, e.g. change in left ventricular ejection fraction (LVEF) in %,

inter-ventricular septum and posterior wall thickness in mm, chamber dimensions

(sizes/diameters of left ventricle, left atrium, right ventricle in cm), RV function (tricuspid

annular plane systolic excursion: TAPSE)

Changes in 30 min ECG parameters from baseline (V1) to week eight (V9) (optional) (change

in 30min-heart rate variability scores)

MRI/rsMRI (facultative)

Changes in brain morphology and functions (MRI, rs-fMRI) from baseline (V1) to week eight

(V9) (optional). Longitudinal MRI/rs-fMRI analyses will be performed using the most recent

version of SPM to detect volumetric (Redlich, Opel et al. 2016, Hasan, Wobrock et al. 2017)

and functional network changes (Hahn, Kircher et al. 2015) over time. Moreover, baseline

MRI/fMRI will be used to develop single-subject predictors based on MVPA approaches

(Hahn, Kircher et al. 2015, Koutsouleris, Wobrock et al. 2017, Redlich, Burger et al. 2017).

For MRI/rsMRI, TTE and 30 min ECG monitor, we will document in the eCRF whether these

measures have been performed or not. All optional activities can be performed with a range of –max.

7 days before baseline, as long as informed consent was given a priori.

Missing data of variables defined as other assessments and optional activities will not result in a

protocol violation.

Investigators will be encouraged to keep patients in the trial for the full of 8 weeks study period and

to perform V9 regardless of them deciding to stay on the study medication or to discontinue the

study. Patients do not automatically drop out from the study if they discontinue medication, they will

be invited for the same visits as patients who did not discontinue medication (with the exclusion of

patients who have withdrawn consent).

5. Study population

5.1 Inclusion criteria

1. Age 18 to 65 years

2. Signed informed consent

3. DSM-V diagnosis of schizophrenia confirmed by the Mini International Neuropsychiatric

Interview


4. At least one documented prior hospitalization due to the illness in the medical history (the

current hospitalization can be considered as ’prior’ hospitalization if its ≥ 4 weeks) at

screening

5. For treatment-naïve patients (defined as no previous antipsychotic treatment or a maximum

of 30 days of treatment), an antipsychotic treatment attempt of at least 30 days with an

antipsychotic in a therapeutic dose according to local guidelines other than clozapine and

olanzapine before the screening phase is needed. For non-treatment-naïve patients (defined

as having been treated for more than 30 days with an antipsychotic), a discontinuation of a

foregoing antipsychotic treatment prior to the screening phase within a maximum of six

months (=180 days) is possible (corresponding to the estimated average time for an

antipsychotic washout phase and the expected time to develop a relapse of the disease). For

patients being treated with a long-acting antipsychotic (other than PP3M), an inclusion is

possible if inclusion date corresponds to the planned date of the next injection plus five to

seven days. For patients being treated with oral olanzapine, an inclusion is possible if this

treatment has lasted for no longer than 2 weeks prior to inclusion and if exclusion criteria 8

is not fulfilled.

6. Clinical need for a medication switch because of clinical inefficacy or side-effects or clinical

need for a reintroduction of an antipsychotic treatment after treatment discontinuation prior

to the screening phase (see 5.)

7. Moderate symptomatology on the PANSS, defined as a score ≥ 4 for two or more symptoms

from P1-P7 or a score of ≥ 6 for one symptom from P1-P7 (minimum threshold definition) at

screening

8. Male participants and female participants who are not capable of bearing children or who use

a method of contraception that is medically approved by the health authority of the respective

country at screening

This includes:

a. A woman who is not capable of bearing a child is defined as follows: post-menopausal

(12 months natural (spontaneous) amenorrhea or 6 months spontaneous

amenorrhea with serum-FSH-values (follicle-stimulating hormone) of >40 mIU/mL); 6

weeks after a bilateral ovariectomy with or without hysterectomy or sterilization by

means of tubal ligation

b. A woman capable of bearing child is defined as follows: a woman who is

physiologically capable of becoming pregnant, including women whose occupation,

lifestyle or sexual orientation exclude sexual intercourse with a male partner and

women whose partners have been sterilized by vasectomy or other measures

c. Medically-approved methods of contraception can include the following: hormonal

contraceptives, intrauterine device and double barrier method. Acceptable preventive

measures can include total abstinence at the discretion of the investigator, in cases

where compliance is ensured because of the study participant’s age, occupation,

lifestyle or sexual orientation. Periodical abstinence (e.g. calendar, ovulation,

symptothermal methods or abstinence until the 4th day after the ovulation) as well as

coitus interruptus are not acceptable methods of contraception

d. A reliable method of contraception (CTFG guideline) must be used for the entire

duration of the study


5.2 Exclusion criteria

1. Patients who are not suitable for the study in the opinion of the investigator (including acutely

suicidal patients)

2. Patients who are unable to give informed consent

3. Coercive treatment at the time of study inclusion

4. White blood cell count (WBC) at inclusion not meeting the requirements for clozapine use in

Germany according to the SmPC. Patients must have normal leukocyte findings (white blood

cell count ≥ 3500/mm3 (≥ 3.5x109/l), and Absolute Neutrophil Count (ANC) ≥ 2000/mm3 (≥

2.0x109/l) at the screening visit

5. The presence of one or more of the contraindications against any of the study drugs as

mentioned in the SmPC

6. Treatment-naïve or treatment-resistant schizophrenia. Treatment-naïve will be defined as no

previous antipsychotic treatment or a maximum of 30 days of treatment. Treatment

resistance is defined as two antipsychotic trials (with antipsychotics from two different

chemical classes) for a period of ≥ 6 weeks with CPZ equivalent doses ≥ 600 mg/day (Howes,

McCutcheon et al. 2017), both of which took place immediately before the screening phase

7. Diagnosis of primary substance dependency other than nicotine: exclusion alcohol

dependency via AUDIT-screening (Bohn, Babor et al. 1995, Babor 2001) and DSM V criteria

(MINI-interview); exclusion of other drug dependencies other than alcohol and nicotine: drug

screening of urine and DSM V criteria (MINI-interview: patient fulfilling early (> 3 months) or

sustained (>12 months) remission criteria and/or with low severity of substance use disorder

according to MINI (DSM-V) are eligible for the study)

8. Documented previous non-response to an 8-week drug trial with olanzapine or any

documented previous treatment with clozapine

9. Documented intolerance to one of the study drugs

10. Pregnancy (incl. positive blood pregnancy test) / lactation (female patients)

Existing legal representatives for health care issues have to be informed and will also sign the IC or

will give their agreement via speaking to the responsive study doctor. An agreement (signed IC) from

the respective legal representative for health care issues can also obtained via fax or as a scan via

e-mail. This contact will be documented as a “Note to file”.

5.3 Sample size calculation

The sample size calculation was performed on the basis of previous studies, meta-analyses and

systematic reviews (Leucht, Beitinger et al. 2007, Galderisi, Davidson et al. 2009, Lambert, Karow

et al. 2010, AlAqeel and Margolese 2012), which indicate remission rates of approximately 30% after

four weeks (Gorwood, Peuskens et al. 2012) for antipsychotics in acute schizophrenia and mean

remission rates of ~ 50% after 8 to 12 weeks. Because olanzapine is one of the most effective SGAs

and its efficacy is similar to or even higher than that of amisulpride (Lieberman, Stroup et al. 2005,

Kahn, Fleischhacker et al. 2008, Leucht, Cipriani et al. 2013), we assume a remission rate of 55%

in the non-clozapine group after eight weeks.

Assuming that 55% (= p2) of acute schizophrenia patients will remit after treatment with olanzapine

and assuming a superiority of clozapine in the range of 10% to 30% in achieving remission (Kane,


Honigfeld et al. 1988) in severely affected patients, we expect that clozapine will be associated with

a ≥20% (= p1 – p2) increased likelihood of achieving remission compared to non-clozapine

treatment. A two-group Chi² test (α = 0.05, two-sided, power [1-β]: 80%) will detect a difference

between groups after adjusting p1 (clozapine) to 0.74 and p2 (olanzapine) to 0.56 (odds ratio of

2.236) when the sample size in each group is 110 (computed by nQuery Advisor 7.0). Thus, the total

required sample size is 220. The adjustment of relative frequencies is due to the conservative

assessment of the primary outcome (as described in the next paragraph) assuming less than 2%

losses to follow-up with no primary outcome data. As we are aiming at evaluating the primary

outcome in every participant, irrespective whether he or she discontinues treatment or not, the

estimated rate of 2% losses to follow-up/drop-outs is realistic. As in other double-blind schizophrenia

trials with an intervention period of 8 weeks, we expect that 20% to 40% patients discontinue

treatment due to any reasons.

The analysis will be performed in the ITT population, which will include all patients as randomized.

To ensure a conservative assessment of the primary outcome, losses to follow-up in the

experimental group will be rated as failures, while those in the control group will be rated as

successes. This approach is designed to avoid a beneficial bias for the experimental group which

might be induced by non-compliance and losses to follow-up. As a consequence, there is no need

to include further participants or increase sample size. Study participants will be allowed to

discontinue the study at any time and without any reason, in accordance with national and

international guidelines for the handling of missing data (EMA 2010, BfArM 2011). We will assess

the primary outcome criterion for study participants that did not drop out but discontinued study

treatment as long as the visit corresponding to V9 (with an obligatory assessment of the RSWG

criteria) is performed as defined in paragraph 8.2. In our clozapine sample we considered the

probability of potential life-threatening events, i.e. agranulocytosis and myocarditis. Agranulocytosis

has an estimated event rate in the literature of 1% (0.01) and myocarditis of 0.1% (0.001) (De Fazio,

Gaetano et al. 2015). Consequently, the probability to not observe any of these events in our sample

of 110 patients is 0.99110 = 33% for agranulocytosis and 0.999110 = 90% for myocarditis. We used

the sample size of the clozapine group (n=110) as the exponent and the literature-based likelihood

for the complement of the incidence as basis for this calculation.


6. Treatment of subjects

6.1 Investigational products

Subjects participating in the current study will be randomized to one of two arms:

- Clozapine or

- Olanzapine

Treatment following randomization is double-blind to reduce the risk for expectation effects and to

main the highest quality of head-to-head studies. Study medication will be provided centrally by the

pharmacy of the University of Heidelberg. The dose ranges of the study medication in acutely ill

patients with schizophrenia are well documented. The dose range of clozapine will be 75 – 600

mg/day and for olanzapine the dose range will be 2.5 – 20 mg/day. The distribution of the doses

over the day will be at the discretion of the investigators, but it is recommended to give study

medication at least twice a day according to the description below.

Olanzapine as comparator

As the objective of the EARLY trial is to compare early clozapine-treatment to non-clozapine

treatment in a clinically relevant setting, we will use one highly effective SGA with a comparable side-

effect profile to maintain the blind. Clozapine and olanzapine are very comparable in terms of weight-

gain/appetite increase, motor-side effects, sedation and obstipation – these side-effects may allow

unblinding and by comparing those drugs, this risk is reduced. In the population of acute and chronic

schizophrenia, olanzapine can be considered as one of the most effective antipsychotic agents. In

the CATIE-trial, olanzapine had compared to three other SGAs and one FGA the longest time to

treatment discontinuation (Lieberman, Stroup et al. 2005, Swartz, Stroup et al. 2008). In the largest

available network meta-analysis, olanzapine received a top ranking in terms of overall efficacy and

all-cause treatment discontinuation (Leucht, Cipriani et al. 2013). Evidence-based treatment

guidelines also confirm the high efficacy of olanzapine in acute schizophrenia (DGPPN 2006,

Buchanan, Kreyenbuhl et al. 2010, Hasan, Falkai et al. 2012). As detailed below, clozapine and

olanzapine have a comparable side-effect profile and one previous trial using both agents showed

that a double-blind procedure for this head-to-head comparison is feasible (Meltzer, Bobo et al.

2008).

6.2 Titration schemes

The titration phase starts at day 1 (V1) and may last until day 14 (V3). During this phase, prestudy

antipsychotics have to be tapered down and study medication will be started at day 1. It is

recommended to be at least at stage 2 at the end of the titration phase (exceptions are described in

the text below). Dosages higher than stage 8 are not allowed. Please see Table 2, Table 3 and Table

4 for the schedule of capsules. According to the 2018 published (Konsultationsfassung) national

schizophrenia guideline (DGPPN 2018), a cross-taper strategy with reduction of the foregoing

antipsychotic medication is recommended. According to the guideline, this is particular important for

the start and slow up-titration of clozapine. This guideline-based procedure is recommended to

reduce the risk of antipsychotic-withdrawal-symptoms or a worsening of psychosis. Moreover, it

allows a slow up-titration of the new antipsychotics, which is from particular importance for clozapine.

Furthermore, Galling et al. (Galling, Roldan et al. 2017) analyzed data of 20 clinical trials that

investigated clozapine combination strategies with a first- or second-generation antipsychotic. In

these trials, clozapine was combined with a second antipsychotic. As a consequence, parallel


antipsychotic medication alongside clozapine has been extensively investigated in international

clinical trials. In EARLY, no combination of two antipsychotics is allowed beyond V3 – From V1 to

V3 the combination is needed for the guideline-recommended cross-taper strategy. The add-on

treatment with haloperidol in the first two weeks of the study (see 6.3) as rescue medication is

established in clinical practice and was used in previous clinical trials using clozapine (Meltzer, Bobo

et al. 2008).

Clozapine will be started with 12.5 mg/day and dosages should be increased a maximum of 1

capsule per day of the titration blister (25 mg/capsule) from the day after start of titration during the

first week. The dose has to be increased by using capsules of the titration blister until stage 1 (75

mg/day) has been reached, which should be preferably 3 to 7 days after day 1. Next, dosage should

be up-titrated until stage 2 (150 mg/day) has been reached. Stage 2 is the minimal target dosage in

this trial and dosage below stage 2 (namely stage 1) is only permitted due to tolerability reasons and

this down titration must be documented. Stage 2 should be reached 3 to 7 days after stage 1. From

stage 2, a dose increase to the next stage is possible by using titration capsules (up to 2/day) and

increasing the dosage by maximal 1 capsule/day). Between each stage a minimum of 3 days and a

maximum of 7 days for up-titration should be fulfilled. It is not allowed to use the capsules of the next

stages without the aforementioned up-titration steps. The hierarchy of the following rules is:

1. From stage 2 onwards, the use of at least two capsules per day is obligatory.

2. In general, the lowest possible amount of capsules should be used if tolerated

3. The titration capsules are not meant for maintenance treatment and should only be used

for up-titration

4. Titration can be slowed or stopped below the target dose if subjects cannot tolerate the

standard titration schedule because of adverse effects

5. If a dose reduction is needed, a dose reduction to the stage below is recommended

without down-titration.

A daily dosage of < 75mg (stage 1) for > 7 consecutive days constitutes a protocol violation. A

protocol deviation must be recorded. The visit corresponding to V9 must be scheduled for week eight

where RSWG criteria must be assessed. There is no overall target dose, but as indicated above

stage 2 (150 mg/day) should be the minimal dose and it is not allowed to give a dosage above stage

8 (600 mg/day). In our study, a daily dosage over 600mg/d for > 3 consecutive days constitutes a

protocol violation. A protocol deviation must be recorded. The visit corresponding to V9 must be

scheduled for week eight where RSWG criteria must be assessed. 600 mg/day is below that of trials

conducted in treatment-refractory patients, which allowed up to 900 mg/day. However, the mean

dose actually reached in the double-blind treatment-refractory patients trials were e.g. 400 mg

(Meltzer, Bobo et al. 2008), 304 mg (Tollefson, Birkett et al. 2001) or 291 mg (Bondolfi, Dufour et al.

1998) and one recent meta-analysis analyzed trials of treatment-resistant schizophrenia patients

and showed that the mean clozapine dose was only 392 mg/d (Samara, Dold et al. 2016).

Furthermore, the patients in our study are not treatment resistant, so we do not expect them to

require such high doses as the treatment-resistant patients in the earlier studies.

Dosage can be adjusted to higher or lower dosages if a patient fails to improve or if patients develop

relevant side-effects.

Olanzapine will be started with 0 mg/day (placebo) to maintain the blind between both treatment

arms. Dosages should be increased a maximum of 1 capsule/day of the titration blister from the day

after start of titration during the first week. The dose has to be increased by using capsules of the

titration blister (0mg/capsule, placebo) until stage 1 (2.5 mg/day) has been reached, which should

be preferably 3 to 7 days after day 1. Next, dosage should be up-titrated until stage 2 (5 mg/day)

has been reached. Stage 2 is the minimal target dosage in this trial and dosage below stage 2


(namely stage 1) is only permitted due to tolerability reasons and this down titration must be

documented. Stage 2 should be reached 3 to 7 days after stage 1. From stage 2, a dose increase

to the next stage is possible by using titration capsules (up to 2/day) and increasing the dosage by

maximal 1 capsule/day). Between each stage a minimum of 3 days and a maximum of 7 days for

up-titration should be fulfilled. It is not allowed to use the capsules of the next stages without the

aforementioned up-titration steps. There is no overall target dose, but as indicated above stage 2 (5

mg/day) should be the minimal dose and it is not allowed to give a dosage above stage 8 (20

mg/day). Dosage can be adjusted to higher or lower dosages if a patient fails to improve or if patients

develop relevant side-effects. Titration can be slowed or stopped below the target dose if subjects

cannot tolerate the standard titration schedule because of adverse effects. For uptitrating the

capsules of the titration blister have to be used according to the described procedures, but there is

no need for down-titrating. If a dose reduction is needed, the capsules of the lower stage can be

used instead of those of the current stage. A daily dosage of <2.5mg (stage 1) for > 7 consecutive

days constitutes a protocol violation. A protocol deviation must be recorded. The visit corresponding

to V9 must be scheduled for week eight where RSWG criteria must be assessed. A daily dosage

over 20 mg/d for > 3 consecutive days constitutes a protocol violation. A protocol deviation must be

recorded. The visit corresponding to V9 must be scheduled for week eight where RSWG criteria

must be assessed.

The hierarchy of the following rules is:

1. From stage 2 onwards, the use of at least two capsules per day is obligatory

2. In general, the lowest possible amount of capsules should be used if tolerated

3. The titration capsules are not meant for maintenance treatment and should only be used

for up-titration

4. Titration can be slowed or stopped below the target dose if subjects cannot tolerate the

standard titration schedule because of adverse effects

5. If a dose reduction is needed, a dose reduction to the stage below is recommended

without down-titration.

Thus, the titrations schemes of both drugs are the same to maintain the blind. Blisters will be color-

coded to improve the usability. The recommended dose range in this trial is stage 4 (300 mg

clozapine or 10 mg olanzapine). Patient-specific used and unused blisters should be collected at

V9/Early Termination Visit. For this reason, it is recommended that the study staff collects remaining

(both used and unused) blisters.

Table 2: Stages and dose ranges of the trial. The rules for using the lowest dosages (clozapine 75 mg/ olanzapine 2.5

mg) in cases of lacking tolerability are indicated in the text above.

Stage 1 75 mg Clozapine or 2.5 mg Olanzapine, earliest timepoint: day 4

Stage 2 150 mg Clozapine or 5 mg Olanzapine, earliest timepoint: day 7





Stage 7 525 mg Clozapine or 17,5 mg Olanzapine, earliest timepoint: day 22



Table 3: Minimal and maximal dose ranges for the study visits. The rules for using the lowest dosages (clozapine 75 mg/ olanzapine 2.5 mg) in cases of lacking tolerability are indicated in the text above. Maximal doses can be higher than the given dose ranges (but must be always according to defined study medication titration scheme), if visits are performed within the range of max. + 2 working days.

V1 (day 0-1) 12,5 mg Clozapine or 0 mg Olanzapine

V2 (day 7) 75-150 mg Clozapine or 2.5-5 mg Olanzapine

V3 (day 14) 150-325 mg Clozapine or 5-10 mg Olanzapine







Table 4: Description of capsule and blisters

Blister Contains To be used for

Starting blister Red-Label

12.5 mg clozapine or placebo

First day of the treatment phase (first day with study medication only!)

Titration blister Blue-Label

25 mg clozapine or placebo

Titration at the start of the study and uptitration between stages

Maintenance blister I Yellow-Label

75 mg clozapine or 2.5 olanzapine

Stage 1, Stage 2, Stage 3, Stage 5 and Stage 7

Maintenance blister II White-Label

150 mg clozapine or 5 mg olanzapine

Stage 3, Stage 4, Stage 5, Stage 6, Stage 7, Stage 8

The blood level of clozapine (and desmethylclozapine) and olanzapine (desmethylolanzapine) will

be measured 2 and 4 weeks after randomization at visits V3 and V5 at the central laboratory of the

Klinikum der Universität München. If the assessment of the blood levels is not possible at these

visits, the respective blood draw for blood level analyses should be performed at the next planned

visit. The reason for the delayed blood draw must be documented in the eCRF. All sites will send

blood to this central laboratory via the Department of Psychiatry and Psychotherapy at the Klinikum

der Universität München. If the reference ranges of the trial drugs have not been reached and

patients have not obtained remission criteria (assessed at visit V5 and visit V7), the dose should be

increased in order to reach blood levels within the recommended range. To avoid unblinding

investigators, patients and raters will only receive blinded qualitative information about the drug

levels. Thus, the rater will be informed if the patient’s blood level is within the therapeutic range or

not and the actual blood level of the investigational drug will be graded according to the following

ranges:


1) below (<) recommended therapeutic range

2) lower third within recommended therapeutic range

3) middle third within recommended therapeutic range

4) upper third within recommended therapeutic range

5) above (>) recommended therapeutic range, but below warning threshold

6) warning threshold)

The quantitative information of the drug levels will be stored blinded at the laboratory and included

post hoc in the study data-base after the end of the study for further statistical analyses. In the eCRF

we will document whether blood has been taken for this procedures and the qualitative rating as

indicated above. Investigators will only receive the descriptive information detailed above.

6.3 Use of concomitant medication

Non-permissible medication: The use of any antipsychotic in addition to the study medication is not

permitted from one day after V3 until V9. During the two-week titration phase, the on-demand use of

haloperidol (max. 10 mg/day) is permitted as rescue medication in accordance with previous trials

(Meltzer, Bobo et al. 2008). Pre-study antipsychotics will be tapered down during the titration phase

and from day 15 onwards only study antipsychotics are permitted. The use of haloperidol as a rescue

medication has to be considered as standard care in Germany (especially during clozapine titration

to avoid high doses of benzodiazepines) and the permitted use during the titration phase will reduce

the disease-associated stress and increase the willingness of patients with acute schizophrenia to

participate.

Concomitant medication: Benzodiazepines are allowed (in accordance with the German

recommendation for their use in combination with clozapine (Benkert and Hippius 2013), The

following concomitant medication is allowed:

Lorazepam of max. 4 mg/d, diazepam of max 40 mg/d and oxazepam of max 80 mg/d are

permitted; Lorazepam expidet is not permitted due to possible clozapine interactions.

Biperiden and pirenzepine: The permitted maximum daily dose of biperiden is 4mg/day and

of pirenzepine is 50 mg/day to reduce the risk of anticholinergic side-effects.

Zopiclone up to 7.5 mg/d and zolpidem up to 10mg/d and doxepine (or trimipramine) up to

50 mg/d or mirtazapine (up to 15 mg/day) for sleep disturbances. Investigators should be

aware of a possible increase in anticholinergic side-effects when using doxepine /

trimipramine and of a possible increase in weight gain when using mirtazapine.

An antidepressant treatment is only permitted in cases of clinically relevant depression

(CDSS > 6, depressive symptoms for a minimum of 2 weeks) and only if antidepressants are

used that do not have relevant interactions with any of the study drugs.

The introduction of mood-stabilizers during the trial is not permitted. Pretrial mood-stabilizers

can be continued if the used substances do not have relevant interactions with any of the

study drugs.

All drugs to treat somatic conditions (e.g. weight gain, high blood pressure, tachycardia,

constipation) are permitted if the used substances do not have relevant interactions with any

of the study drugs.


Prior to the introduction of concomitant medication, the possibility of clinically relevant drug-

interactions with the medicinal products has to be checked. Other drugs that have relevant

interactions with the study drugs are not permitted. Daily doses of concomitant medication including

start and stop dates need to be documented throughout the study.

6.4 Treatment after the end of the double-blind treatment phase

Unblinding patients at the end of the double-blind treatment phase (until V9) is sensitive, as it is not

acceptable that the advantages of a double blind study are diminished by the possibility to change

previously collected data after the treatment is unblinded. Therefore, a SOP will be implemented

how to continue treatment after the end of the double-blind treatment phase. After visit 9 (day 56),

the physicians being responsible for the further treatment have the possibility to receive an envelope

with the information in which arm the patient has been allocated (unblinding according to protocol).

People involved in the trial will not receive this information. For patients who drop out prior to visit 9,

unblinding according to protocol will also only be possible following the aforementioned principles.

For patients who meet the remission criteria at week eight, it is recommended to stay on the same

drug. For patients who do not meet remission criteria at week eight and being treated with clozapine,

it is recommended to carry on treatment and perhaps increase the dose as clinical knowledge is

available that the effect of clozapine may occur with a delay. For patients being treated with

olanzapine not meeting remission criteria, it is recommended to increase the dose and if not

successful, to switch to clozapine.

However, the decision of any further treatment after visit 9 will be made between the treating

physicians and the patients following national guideline recommendations. The study team will not

be involved in this decision. Clozapine should not be stopped abruptly but tapered down according

to clinical standard procedures. Therefore, our SOP is written to assure that patients at the end of

the double-blind treatment phase will have enough study medication until the next meeting with their

treating physician. However, we are aiming at coordinating the meeting with the treating physician

at the same day of V9. This means that all centers have to have study doctors and must either have

treating physicians or be in contact with those persons.


7. Investigational product

Name of the investigational products:

Clozapine

Olanzapine

Placebo (Mannitol/Siliciumdioxid 99.8/0.2 %)

Clozapine general information

Clozapine is an antipsychotic that is used for the treatment and maintenance treatment of acute and

chronic schizophrenia, but usually the use is restricted treatment-resistant schizophrenia and

psychosis during the course of Parkinson’s disease. Please see the SmPC for further information.

Olanzapine general information

Olanzapine is an antipsychotic that is used for the treatment of acute and chronic schizophrenia, for

the treatment of mania and for maintenance treatment of schizophrenia and mania. Please see the

SmPC for further information.

Placebo

Placebo are capsules containing lactose-monohydrate, magnesium stearate and cellulose powder.

Placebo is considered to be without a direct clinical relevant physiological mechanism except the

“placebo effect”.

7.1 Contraindications

Clozapine: According to the SmPC, the following contraindications need to be considered:

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the SmPC

Patients unable to undergo regular blood tests.

History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).

History of Clozapine-induced agranulocytosis.

Impaired bone marrow function.

Uncontrolled epilepsy

Alcoholic and other toxic psychoses, drug intoxication, comatose conditions

Severe renal or cardiac disorders (e.g. myocarditis).

Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure

Paralytic ileus

Treatment with clozapine must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged.


Olanzapine: According to the SmPC, the following contraindications need to be considered:

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. of the SmPC

Patients with known risk for narrow-angle glaucoma.

Placebo: Contraindications may be known allergic reactions or intolerance of ingredients (mostly cellulose and/or magnesium stearat and/or lactulose).

7.2 Interactions

Please see SmPC’ s for a full description of possible drug interactions.

For clozapine the SmPC describes the following interactions with other medicinal products and

other forms of interactions:

Substances known to have a substantial potential to depress bone marrow function must not

be used concurrently with clozapine

Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used

concurrently with clozapine because these cannot be rapidly removed from the body in

situations where this may be required

Alcohol should not be used concomitantly with Clozapine due to possible potentiation of

sedation.

Clozapine may enhance the central effects of CNS depressants such as narcotics,

antihistamines and benzodiazepines. Particular caution is advised when clozapine therapy

is initiated in patients who are receiving a benzodiazepine or any other psychotropic agent.

These patients may have an increased risk of circulatory collapse, which, on rare occasions,

can be profound and may lead to cardiac and/or respiratory arrest. It is not clear whether

cardiac or respiratory collapse can be prevented by dose adjustment.

Because of the possibility of additive effects, caution is essential in the concomitant

administration of substances possessing anticholinergic, hypotensive, or respiratory

depressant effects.

Owing to its anti-alpha-adrenergic properties, clozapine may reduce the blood-pressure-

increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and

reverse the pressor effect of epinephrine.

Concomitant administration of substances known to inhibit the activity of some cytochrome

P450 isozymes may increase the levels of clozapine, and the dose of clozapine may need to

be reduced to prevent undesirable effects. This is more important for CYP 1A2 inhibitors such

as caffeine (see below), perazine and the selective serotonin reuptake inhibitor fluvoxamine.

Some of the other serotonin reuptake inhibitors such as fluoxetine, paroxetine, and, to a

lesser degree, sertraline, are CYP 2D6 inhibitors and, as a consequence, major

pharmacokinetic interactions with clozapine are less likely. Similarly, pharmacokinetic

interactions with CYP 3A4 inhibitors such as azole antimycotics, cimetidine, erythromycin

and protease inhibitors are unlikely, although some have been reported. Hormonal

contraceptives (including combinations of estrogen and progesterone or progesterone only)

are CYP 1A2, CYP 3A4 and CYP 2C19 inhibitors. Therefore, initiation or discontinuation of

hormonal contraceptives, may require dose adjustment of clozapine according to the


individual medical need. Because the plasma concentration of clozapine is increased by

caffeine intake and decreased by nearly 50% following a 5-day caffeine-free period, dosage

changes of clozapine may be necessary when there is a change in caffeine-drinking habit.

In cases of sudden cessation of smoking, the plasma clozapine concentration may be

increased, thus leading to an increase in adverse effects.

Cases have been reported of an interaction between citalopram and clozapine, which may

increase the risk of adverse events associated with clozapine. The nature of this interaction

has not been fully elucidated.

Concomitant administration of substances known to induce cytochrome P450 enzymes may

decrease the plasma levels of clozapine, leading to reduced efficacy. Substances known to

induce the activity of cytochrome P450 enzymes and with reported interactions with clozapine

include, for instance, carbamazepine (not to be used concomitantly with clozapine, due to its

myelosuppressive potential), phenytoin and rifampicin. Known inducers of CYP1A2, such as

omeprazole, may lead to decreased clozapine levels. The potential for reduced efficacy of

clozapine should be considered when it is used in combination with these substances

Concomitant use of lithium or other CNS-active agents may increase the risk of development

of neuroleptic malignant syndrome (NMS).

Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and

isolated cases of delirium where clozapine was co-administered with valproic acid have been

reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism

of which has not been determined.

Caution is called for in patients receiving concomitant treatment with other substances which

are either inhibitors or inducers of the cytochrome P450 isozymes. With tricyclic

antidepressants, phenothiazines and type 1C anti-arrhythmics, which are known to bind to

cytochrome P450 2D6, no clinically relevant interactions have been observed thus far.

As with other antipsychotics, caution should be exercised when clozapine is prescribed with

medicines known to increase QTc interval, or causing electrolyte imbalance.

For olanzapine the SmPC describes the following interactions with other medicinal products and

other forms of interactions:

Caution should be exercised in patients who consume alcohol or receive medicinal products

that can induce hypotension, bradycardia, respiratory or central nervous system depression

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or

inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

o Induction of CYP1A2: The metabolism of olanzapine may be induced by smoking and

carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to

moderate increase in olanzapine clearance has been observed. The clinical

consequences are likely to be limited, but medical monitoring is recommended and

an increase of olanzapine dose may be considered if necessary

o Inhibition of CYP1A2: Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to

significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine

Cmax following fluvoxamine was 54 % in female nonsmokers and 77% in male

smokers. The mean increase in olanzapine AUC was 52 % and 108% respectively.

A lower starting dose of olanzapine should be considered in patients who are using

fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the


dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is

initiated.

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60 % and should

be taken at least 2 hours before or after olanzapine. Fluoxetine (a CYP2D6 inhibitor), single

doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly

affect the pharmacokinetics of olanzapine.

Olanzapine may antagonise the effects of direct and indirect dopamine agonists

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19,

3A4). Thus no particular interaction is expected as verified through in vivo studies where no

inhibition of metabolism of the following active substances was found: tricyclic antidepressant

(representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or

diazepam (CYP3A4 and 2C19).

Olanzapine showed no interaction when co-administered with lithium or biperiden.

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage

adjustment is required after the introduction of concomitant olanzapine.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with

Parkinson’s disease and dementia is not recommended

Placebo

Side effects are expected to be limited to allergic reactions on ingredients of the applied placebos.

7.3 Manufacturing of Trial Medication

For the production of the verum capsules, the approved medicinal product Clozapine or Olanzapine

tablets will be modified by encapsulation and packing in blister packaging. The tablets used remain

undamaged in this process, apart from the manufacturing of the 12.5 mg Clozapine starting dose

(here clozapine 25 mg tablets will be bisected); the quality of the tablets is not altered by the

encapsulation. The manufacturing process is described in the sIMPDs.

7.4 Storage, Formulation, packaging and labelling

Clozapine and Olanzapine hard capsules as well as placebo hard capsules are preserved when

stored in well-closed, light-resistant containers in a cool place at room temperature not more than

30°.

Study medication will be provided by the central pharmacy (University of Heidelberg).

Labeling of Study Medication

According to GCP-V § 5 (see trial application documents).

Shipping Department

The pharmacist of the study medication is:

Apotheke Universitätsklinikum Heidelberg / Pharmacy University

Hospital Heidelberg Im Neuenheimer Feld 670

69120 Heidelberg


Germany

Tel: +49-(0)6221- 56-32819

Fax: +49-(0)6221- 56-5413

Handling Placebo

The placebo capsules will contain mannitol / silica 99.8 / 0.2% (equivalent to the capsule filler

according to DAC / NRF). This will also be included in the Verum capsules in addition to the tablets

for refilling.

7.5 Emergency unblinding

Unblinding of study medication before database hardlock may only occur on an individual basis if

the information can help treat an (S)AE and for safety reasons. The decision to unblinding is at the

discretion of the investigator. For this purpose, investigators will have sealed envelopes comprising

the information on the type of medication stored used for a given randomization number. All sites

will have one sealed envelope for each randomization number. In the case of a medical emergency

as described below, the envelope must be opened and the treatment assignment of a patient will be

unblinded.

Emergency unblinding should be only performed in the following situations:

In case of an emergency treatment of the subject at the investigators discretion

In cases where unblinding is required by local laws or regulations (in case of SUSAR)

In cases where the Safety Monitoring Board decides that unblinding is necessary

When a study site is closed all closed emergency envelopes will be collected and returned to the

sponsor. Opened emergency envelopes will be kept in the Investigator Site File at the site.


8. Methods

Patients with a schizophrenia diagnoses will be prescreened for possible participation in this trials.

No study related procedures will take place prior to the informed consent process. Please see below

for a description of all scales and investigations and the Study Flow-chart for the detailed visit plan.

8.1 Randomisation

The study will be performed in a controlled, randomized, double-blind design. Patients will be

randomized at the end of the screening visit to one of the two treatment arms (clozapine or

olanzapine). The randomization lists will be created by MSZ using RANCODE 2015 professional

2015. Randomization will be performed block wise and for each centre. The randomization list will

then be forwarded to the pharmacy for distributing and labelling of concealed medication.

8.2 Description of study visits

Screening (Day -14 to 0): After providing informed consent, patients will be screened for eligibility

to the study. Potential contraindications concerning the use of any of the study drugs (clozapine,

olanzapine, placebo) will be ruled out before starting study treatment. Diagnosis and psychiatric

comorbidities will be investigated with the MINI interview. Physical health will be checked in a

physical examination. An AUDIT interview will be performed. Psychotic symptoms will be rated with

PANSS assessments (PANNS, PANSS RSWG items). Study laboratory will be taken for the first

time to check for contraindication in terms of the use of clozapine and olanzapine. Pre-study

medication will be assessed and stopped before visit 3 (V3). An ECG will be performed. Several

demographic and clinical variables will be assessed, including year of birth, sex, educational level,

marital status, occupation, living circumstances, previous psychiatric disorders and admissions,

duration of untreated psychosis and other variables, (medical history, cardiovascular risk factors). A

pregnancy test will be performed among female patients. Furthermore, a drug screening will be

performed. The screening phase will be completed before the baseline visit and should preferably

not be longer than one week. Randomization will be performed during screening and baseline visit

(V1). Screening visit and baseline visit (V1) can be performed together on the same day. If screening

visit and baseline visit are performed together within a maximum of 7 days, only one ECG is sufficient

instead of two. From baseline visit onwards, a study discontinuation check will be performed to raise

the safety standard of the clinical trial.

Baseline visit (Visit 1- Day 0-1): At baseline, the standard rating scales will be used for the first

time, including CGI, GAF, TALD, PSP, CDSS and other scales as displayed in the Study Flow-Chart,

EEG and ECG will be performed and cognitive functioning assessed. EEG can be performed with a

range of +/-5 working days around day 1. Fagerström-test will be performed (smokers). Number of

cigarettes will be assessed. A physical examination will be performed. Concomitant medication will

be assessed. An interaction check (e.g. via textbooks, tables or commercial software) of current

medication with our study medication will be performed (documented as performed: yes/no in the

eCRF). Optional investigations (MRI, echocardiography, 30 min ECG) will be performed (see the

Study Flow-Chart). Study medication will be dispensed for the first time at day 1. One study

laboratory at Screening is sufficient if the number of days between Screening visit and Baseline visit

is ≤ 3 days.

Visit 2 (Day 7): This visit has the main aim of assessing several safety parameters 1 week after start

of medication (especially WBC). Blood pressure and heart rate will be assessed. A physical


examination will be performed. Concomitant medication will be assessed. Enough study medication

will be (re-)dispensed until next visit.

Visit 3 (Day 14): This visit has the main aim of assessing several safety parameters 2 weeks after

start of medication (especially WBC). GASS and CCCS are performed. Moreover, an ECG is

performed within a possible range of +/-2 working days. in the same week of the visit. Number of

cigarettes will be assessed. Moreover, additional blood is taken for blinded drug-level analyses.

Blood pressure and heart rate will be assessed. A physical examination will be performed.

Remaining pre-study medication will be stopped. Concomitant medication will be assessed. Enough

study medication will be (re-)dispensed until next visit.

Visit 4 (Day 21): This visit has the main aim of assessing several safety parameters 3 weeks after

start of medication (especially WBC). Blood pressure and heart rate will be assessed. A physical



Visit 5 (Day 28): This visit is the first outcome parameter visit and many scales/questionnaires

(CCCS, GASS, CDSS, GAF, CGI, PANSS, PANSS RSWG items) have to be used to determine the

outcome four weeks after the start of the study medication. Moreover, safety parameters are

assessed including WBC, ECG and other parameters. ECG can be performed within a possible

range of +/-2 working days. Moreover, additional blood is taken for blinded drug-level analyses.

Number of cigarettes, weight and BMI, blood pressure and heart rate will be assessed. A physical



Visit 6 (V6 - Day 35): This visit has the main aim of assessing several safety parameters 5 weeks

after start of medication (especially WBC). Number of cigarettes will be assessed. Blood pressure

and heart rate will be assessed. A physical examination will be performed. Concomitant medication

will be assessed. Enough study medication will be (re-)dispensed until next visit.


after start of medication (especially WBC). Moreover, an ECG is performed within a possible range

of +/-2 working days. PANSS RSWG items will be assessed. Blood pressure and heart rate will be

assessed. A physical examination will be performed. Concomitant medication will be assessed.

Enough study medication will be (re-)dispensed until next visit.


after start of medication (especially WBC). Blood pressure and heart rate will be assessed. A

physical examination will be performed. Concomitant medication will be assessed. Enough study

medication will be (re-)dispensed until next visit.

Visit 9 (V9 - Day 56): This is the primary endpoint visit and this visit marks the end of the double-

blind treatment phase. The standard rating scales will be used, including PANSS, CGI, TALD, CDSS,

St. Hans Rating Scale (SHRS) and other scales as displayed in the Study Flow-Chart. EEG and

ECG will be performed and cognitive functioning assessed. EEG can be performed with a range of

+/-5 working days around Visit 9. Number of cigarettes, blood pressure and heart rate will be

assessed. A physical examination will be performed. Concomitant medication will be assessed.

Optional investigations (MRI, echocardiography, 30 min ECG) will be performed (see Study Flow-

Chart). Participants and responsible study doctors will be asked to estimate whether the given

participant was in the clozapine or olanzapine treatment arm. Unused and used patient-specific study

medication will be returned.

Safety follow-up I (V10 - Day 63): This visit has the main aim of safety parameters for all patients,

because even when clozapine has been stopped at Visit 9 (which should not be done, see above),

WBC has to be assessed for four 4 weeks after drug withdrawal on a weekly basis. At this visit, only


blood is taken. An objective value of WBC will be assessed The concomitant medication is only

documented at a new laboratory-related AE after V9/Early Termination or any SAE.

Safety follow-up II (V11 - Day 70): This visit has the main aim of safety parameters for all patients, because even when clozapine has been stopped at Visit 9 (which should not be done, see above), WBC has to be assessed for four 4 weeks after drug withdrawal on a weekly basis.

At this visit, only blood is taken. An objective value of WBC will be assessed The concomitant medication is only documented at a new laboratory-related AE after V9/Early Termination or any SAE.

Safety follow-up III (V12 - Day 77): This visit has the main aim of safety parameters for all patients, because even when clozapine has been stopped at Visit 9 (which should not be done, see above), WBC has to be assessed for four 4 weeks after drug withdrawal on a weekly basis. At this visit, only blood is taken. An objective value of WBC will be assessed. The concomitant medication is only documented at a new laboratory-related AE after V9/Early Termination or any SAE.

Safety follow-up IV (V13 - EOS - Day 84): This visit has the main aim of assessing safety parameters for all patients, because even when clozapine has been stopped at Visit 9 (which should not be done, see above), WBC has to be assessed weekly for 4 continuous weeks after drug withdrawal. At this visit, only blood is taken. An objective value of WBC will be assessed.

The concomitant medication is only documented at a new laboratory-related AE after V9/ Early Termination or any SAE.

The double-blind study phase ends with Visit 9 and patients will receive regular clinical treatment.

There is some flexibility in the visit window intervals and visits can be performed with a range of +/-

2 working days as long as it is ensured that WBC is controlled on a weekly basis (once a week),

dose ranges of study medication are not violated (see Table 2) and enough study medication is

available. If one of the questionnaires or interviews that are not required for inclusion/exclusion

criteria or the primary endpoint are not performed, this does not constitute a protocol violation. If a

patient has to discontinue the study for any reason, the primary outcome visit (V9) should be

scheduled for week eight (+/- 1 week) corresponding to V9. In case the patient has relevant side-

effects (e.g. agranulozytosis) or decides to leave the study earlier, a protocol deviation must be

recorded. (). The visit corresponding to V9 can be shortened if necessary, but the primary outcome

(8 PANSS items for calculating remission score) should be assessed and recorded in the eCRF. If

the patient has no recorded V9 visit (No RSWG criteria at V9), the patient is declared as a drop-out.

All patients leaving the trial prior to V9, but accepting the assessment of RSWG criteria at the

timepoint of V9 (+ 1 week), are no drop-outs. For patients who receive study medication below or

above the defined dose ranges for a certain time period (see paragraph 6.2), a protocol deviation

must be recorded. If patients cannot be discharged from inpatient treatment at week eight for medical

reasons, it must be assured that the treating physician is not the responsible study doctor. Patient

who have a valid V9 visit, are invited to participate in the naturalistic follow-up.

Please note exception for SAE:

A SAE will not be reported if patients are re-hospitalized for psychiatric reasons between V9 and

V13

Please note exceptions for safety FU V10-V13:

We strongly recommend that the safety FU-visits including laboratory tests (V10-V13) take place,

within the given timeframe (+/- 2 working days). V10 to V13 can be performed via telephone interview

as long as the necessary laboratory results are available for the investigators. It is allowed that

patients bring their own laboratory measures (e.g. from the attending physician or from an outpatient

unit) for V10 to V13. A serious protocol violation has to be documented if the WBC test of visits 10

to 13 is missing (exception: if patients do not appear to the scheduled visits or are not available for

a telephone visit, this will be documented as minor protocol violation)


8.3 Special safety aspects during the intervention period

Blood count / agranulocytosis

Patients will be informed at the screening visit that they must contact the study doctors or any other

physician immediately if any kind of infection begins to develop. According to the SmPC of clozapine,

particular attention must be paid to flu-like complaints such as fever or sore throat and to other

evidence of infection, which may be indicative of neutropenia. The SmPC further states that patients

and their caregivers (if patients agree) must be informed that, in the event of any of these symptoms,

they must have a blood cell count performed immediately. Due the double-blind nature of the study,

all patients and will receive an emergency card with the study information and the potential risks

associated with clozapine treatment.

Study medication has to be immediately discontinued if either the WBC count is less than 3000/mm3

(3.0x109/l) or the ANC is less than 1500/mm3 (1.5x109/l). In these cases, the clinical work-up

according to the SmPC of clozapine has be performed and the study ends.

In the event of eosinophilia (eosinophil count ≥ 3000/mm³ (3.0 x 109/l) or thrombocytopenia (platelet

count ≤ 5000/mm³ (5 x 109/l) study medication has to be discontinued. In these cases, the clinical

work-up according to the SmPC of clozapine has be performed and the study ends

If WBC drops by 3000/mm³ (3.0x109/l) between two visits or within three weeks or if the WBC is

between 3000/mm3 to 3500 mm³ (3.0 to 3.5 x109/l), WBC and ANC have to be controlled twice a

week.

In case of relevant changes in white blood count or relevant thrombocytopenia or eosinophilia

leading to fulfilment of discontinuation criteria (please see paragraph 8.6 for details), study

medication will be discontinued and the patient will be excluded from the study. According to the

SmPC of Clozapine, weekly blood tests will be performed for at least for four continuous weeks and

until normalization of the respective blood parameters after the treatment was discontinued (see

Safety Follow-up visits).

Myocarditis

According to the clozapine SmPC, myocarditis or cardiomyopathy should be suspected in patients

who experience persistent tachycardia at rest, especially in the first 2 months of treatment, and/or

palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained

fatigue, dyspnoea, tachypnoea) or symptoms that mimic myocardial infarction. At screening, CRP,

troponine T in the study laboratory, a physical examination and an ECG will be assessed and

performed in order to exclude a myocarditis and/or a cardiomyopathy. In the case that a myocarditis

and/or cardiomyopathy is assumed by these diagnostic procedures, the patient should be referred

to a cardiologist in order to perform echocardiography diagnostics. During the double-blind study

phase CRP and troponine T are assessed on a weekly basis during the first four weeks, and on a

two-weekly basis until the end of the double-blind treatment phase. If troponine T increases > 2 fold

of the reference level or CRP increases > 100 mg/l (>10 mg/dl), study medication should be

discontinued and patients should be referred to a cardiologist. If the heart-frequency is > 120/min or

has increased by >30/min between visits or CRP is between 50 to 100 mg/l (5 to 10 mg/dl) or

troponine T has been increased, but is ≤2-fold of the reference level, study medication should not

be elevated until normalisation. Also in these cases, the patient will be referred to a cardiologist. This

is in accordance with national and international myocarditis screening and monitoring

recommendations for clozapine (Benkert and Hippius 2013) (Ronaldson, Fitzgerald et al. 2011). If

myocarditis or cardiomyopathy are clinically suspected already by a study doctor, treatment will be

promptly discontinued and the patient immediately referred to a cardiologist. If troponine T is not

available as parameter at the specific study center, troponine I can be assessed. The same

thresholds as mentioned above for troponine T are applicable.


Other side-effects

Both study drugs can be associated with relevant side-effects as indicated in the SmPC. This trial

has a comprehensive assessment of all relevant side-effects that goes far beyond the surveillance

procedures of the clinical routine. Please see below (paragraph 8.6) regarding criteria for withdrawal

of individuals due to side-effects.

8.4 Naturalistic extension study

Visits of the naturalistic extension study are scheduled after the double-blind pharmacotherapy

phase is completed as defined above (valid V9 visit, see paragraph 8.2), to assess the current status

of the patient after the double-blind part of the study. The following visits (N1 to N3) are not part of

the primary study and will not be monitored as they are part of a naturalistic extension study. Patients

have to sign an additional consent form at the screening visit for this naturalistic extension study.

Naturalistic visit 1 (N1): This is the first naturalistic visit and will be performed 26 weeks (1/2 year)

after the primary outcome assessment. This visit can only be performed if the patients have already

been monitored and the data will be entered to an additional CRF. During this visit year of birth, sex,

living circumstances, working status, the PANSS, the PANSS-RSWG items and a limited amount of

clinical scales will be used (PANSS, PANSS RSWG items, CGI, GAF, PSP, Q-LES-Q-18, SF12).

Dates of hospitalizations and discharges from V13 until N1 will be recorded. Data of what psychiatric

medications patients were taking from V13 until N1 will be recorded. Loss of follow-up in the

naturalistic extension study and causes will be documented.

Naturalistic visit 2 (N2): This is the second naturalistic visit and will be performed 52 weeks (1 year)

after the primary outcome assessment and the data will be entered to an additional CRF. During this

visit living circumstances, working status, the PANSS, the PANSS-RSWG items and a limited

amount of clinical scales will be used (PANSS, PANSS RSWG items, CGI, GAF, PSP, Q-LES-Q-18,

SF12). Dates of hospitalizations and discharges from N1 until N2 will be recorded. Data of what

psychiatric medications patients were taking from N1 until N2 will be recorded. Loss of follow-up in

the naturalistic extension study and causes will be documented.

Naturalistic visit 3 (N3): This is the third naturalistic visit and will be performed 104 weeks (2 years)

after the primary outcome assessment and the data will be entered to an additional CRF. During this

visit living circumstances, working status, the PANSS, the PANSS-RSWG items and a limited

amount of clinical scales will be used (PANSS, PANSS RSWG items, CGI, GAF, PSP, Q-LES-Q-18,

SF12). Dates of hospitalizations and discharges from N2 until N3 will be recorded. Data of what

psychiatric medications patients were taking from N2 until N3 will be recorded. Loss of follow-up in

the naturalistic extension study and causes will be documented.

There is some flexibility in the visit window intervals of the naturalistic extension study and visits can

be performed with a range of +/- 1 month.

8.5 Description of rating scales and assessments

8.5.1 Clinical rating scales

Alcohol Use Disorders Screening Test (AUDIT) (Babor 2001): 10-item core questionnaire for

screening of alcohol use disorders. The range is from 0-40 points.

Fagerström Test for cigarette dependence (Fagerstrom and Schneider 1989): 6-item questionnaire

for screening of nicotine dependence. The range is from 0-10 points.


Mini International Neuropsychiatric Interview (MINI) for DSM-V is a structured interview for

classification of axis-I disorders according to DSM-V and ICD-10.

Positive and Negative Syndrome Scale (PANSS) (Kay, Fiszbein et al. 1987): PANSS is a 30-item

rating scale that has been developed to investigate the severity of psychopathology in schizophrenia

patients (total score). The scale is composed of three subscales (positive, negative, general), but

from a principle point of view five symptom components, positive, negative, depression, agitation-

excitement, and disorganisation, can be investigated.

PANSS RSWG items: According to the RSWG criteria, the symptomatic criterion states that to

achieve symptomatic remission all eight PANSS items (P1, P2, P3, N1, N4, N6, G5, G9) must be

must be rated as absent or present only to a mild degree (PANSS value ≤ 3, see table 1).

Thought and Language Disorder Scale (TALD) (Kircher, Krug et al. 2014): TALD is a 30-item rating

scale for formal thought disorders representing a core syndrome of schizophrenia. Principally, each

of the items can be investigated separately, total minimum score is 0 and total maximum score is

120 points.

Clinical global impression scale (CGI) (Guy W 1976): CGI is a scale to rate disease severity on two

7 point scales (ranging from 0-7). There is one for the present state (severity scale: CGI-S) and one

for the change in severity (improvement scale: CGI-I), both ranging from 0-7 respectively. Both

scales are used in this trial.

Global assessment of functioning (GAF) (Jones, Thornicroft et al. 1995): GAF is numeric scale with

a range from 1 (severe impairments) to 100 (high functioning, no symptoms). It is used to globally

rate social, occupational, and psychological functioning of adults with mental disorders.

Personal and Social Performance scale (PSP) (Nasrallah, Morosini et al. 2008): PSP is a clinician-

reported measure of severity of personal and social dysfunction being composed of a numeric scale

with a range from 1 to 100.

Calgary Depression Scale for Schizophrenia (CDSS) (Addington, Addington et al. 1993): This 9-item

scale (0-3 points for each item) is designed to assess depression in patients with schizophrenia

without overlap with negative symptoms and extrapyramidal symptoms. The range of CDSS is from

0 to 27.

The InterSePT scale for suicidal thinking (ISST) (Lindenmayer, Czobor et al. 2003) is a 12-item rating

scale (0-2 points for each item) that has been specifically developed to measure suicidal ideations

in patients with schizophrenia or schizoaffective disorder. The range of ISST is from 0-24 points.

Quality of life enjoyment and satisfaction questionnaire (Q-LES-Q-18) (Ritsner, Kurs et al. 2005): Q-

LES-Q-18 is an 18-item short-form self-rating scale to assess quality of life in persons with severe

mental illness. The domains are physical health (items 1-4), subjective feelings (items 5-9), leisure

time activity (items 10-12), social relationships (items 13-17), satisfaction with medication (item 18).

Scoring is from 1 to 5. Principally, each domain can be analyzed separately, but total score is

primarily investigated.

SF-12 Questionnaire (SF-12) (Ware, Kosinski et al. 1996): SF-12 is a 12-item short-form health

survey: each item can be ranked from 1-2, 1-3, 1-5 or 1-6. Each item is analyzed separately.

8.5.2 Side-effect and treatment-related rating scales

Drug Attitude Inventory (DAI) (Hogan, Awad et al. 1983, Stjernsward, Persson et al. 2013): The DAI

is self-rating questionnaire that has been originally developed based on 30 questions, but now being

used as a short version with 10 questions (+ I agree/- I disagree) that have been validated. The scale

is used to measured adherence (ranging from -10 to +10).


Subjective Wellbeing under Neuroleptics short form (SWN-K) (Naber 1995): The SWN-K is a self-

rating scale developed to measure mentally ill patients’ well-being under the antipsychotic drug

treatment. The SWN-K is compromised of 20 questions, each of which is rated using a 6-point scale

ranging from 1 to 6. Possible scores range from 20 to 120, with higher scores implying higher

subjective well-being.

Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS) (Hynes, Keating et al. 2015): The

GASS is a 16-item self-rating scale that has been developed to captures specifically clozapine-

related side-effects. Each item is rated using a 4-point scale ranging from 0-3 points (thus total scores

are ranging from 0-48 points). Higher scores indicate higher clozapine side-effects.. Moreover, the

frequency of severe or distressing side effects will be documented.

St. Hans Rating Scale (SHRS) (Gerlach, Korsgaard et al. 1993) The SHRS is a multidimensional

rating scale. The SHRS consists of 4 main components (neuroleptic-induced hyperkinesia,

parkinsonism, akathisia and dystonia). The hyperkinesia subscale consists of 8 items, the

parkinsonian subscale also consists of 8 items. Dystonia is only represented by a global score. The

akathisia component consists of a global score for psychic and motor akathisia. Each item is rated

from 0 (not present) to 6 (present to an extreme degree). This gives a total score from 0 to 48 for

hyperkinesia and for parkinsonism.

Barnes Akathisia Rating Scale (BARS) (Barnes 1989): BARS is scored as follows: objective

akathisia, subjective awareness of restlessness and subjective distress related to restlessness are

rated on a 4-point scale from 0-3 and are summed yielding a total score ranging from 0 to 9. The

Global Clinical Assessment of Akathisia uses a 5-point scale from 0-4.

Cleveland Clinic Constipation (Agachan, Chen et al. 1996) (CCCS) CCCS is a 8-item self-report

questionnaire. Items are rated on a 1-item Likert scale from 0-2 (symptom absent) to 4 (very

severe).Total score ranges from 0-30 points (item 6 of the CCCS questionnaire with a Likert-scale

from 0-2)-

8.5.3 Cognition

Trail-Making Test A and B (Tombaugh 2004) is a cognitive test to investigate complex visual

scanning, motor speed, and the ability to shift strategies. The time needed to draw lines to

connect either consecutively numbered circles (TMT-A) or to connect consecutively

alternating numbered and letters circles (TMT-B) in seconds, as well as the amount of errors

while doing this, are the outcome parameters.

8.5.4 Study laboratory

Regular study laboratory:

White blood count (WBC) including neutrophils, lymphocytes, monocytes, eosinophils and

basophils, absolute and relative neutrophile counts, red blood cell count (RBC), platelet count

(at all visits from Screening to V13)

Electrolytes (sodium, potassium), Creatinine, Creatinkinase (CK total), ASAT and ALAT (at

all visits from Screening to V10)

C-reactive protein (CRP) (at Screening, V1, V2, V3, V4, V5, V7 and V9)

Troponine T (at Screening, V1, V2, V3, V4, V5, V7 and V9). Only if local laboratories are not

able to measure troponine T, troponine I can be assessed.


Drug screening (urine) at Screening

Beta-HCG (serum) for female patients at Screening

Additional study laboratory (other assessment) (fasting blood collection at Screening, V1, V5, V9,

V13) includes:

Glucose, Triglycerides, LDL, HDL, cholesterol (only at Screening, V1, V5, V9 and V13)

8.5.5 Therapeutic drug monitoring

Blinded blood levels of clozapine or olanzapine and of their metabolites will be performed at week

two and week four (V3 and V5).

8.5.6 Additional assessments

Assessment of weight gain and BMI. The weight and the BMI are documented in the eCRF.

Participants and responsible study doctors will be asked to estimate whether the given participant

was in the clozapine or olanzapine treatment arm to allow for a post-hoc testing of blinding integrity

and this assessment will be documented in the eCRF.

Electrocardiography (ECG): Convention 12-channel ECG to evaluate rate and rhythm, axis,

amplitudes and intervals. The QTc time and whether the ECG is abnormal or not will be documented.

Electroencephalography (EEG): Convention, preferentially 64-channel, EEG to evaluate activity,

rhythms and bands (wave patterns). We will document whether the EEG was normal or not as well

as the information about activity, rhythms and wave patterns.

30 min ECG (optional): 30 minute-ECG to evaluate rate, rhythm and heart rate variability. We

document in the eCRF whether the 30 min ECG assessment was performed or not (these data is

not part of the study database)

Transthoracic echocardiography (TTE) to evaluate e.g. change in left ventricular ejection fraction

(LVEF) in %, inter-ventricular septum and posterior wall thickness in mm, chamber dimensions

(sizes/diameters of left ventricle, left atrium, right ventricle in cm), RV function (tricuspid annular

plane systolic excursion: TAPSE). We document in the eCRF whether the TTE monitor assessment

was performed or not (these data is not part of the study database)

8.5.7 Magnetic resonance imaging (MRI/ Optional)

Structural (sMRI) and resting-state (rsMRI) will consist of T1-weighted, T2-weighted and EPI1

sequences. MRI will only be offered to patients at sites with an access to an MRI scanner, preferably,

but not necessarily 3T. 1.5T scanners may also be used. Parameters will be certified in a MRI-

scanning protocol. Data will be analyzed with regard to volumetric changes over time, to the

predictive accuracy of baseline images and to the neurofunctional changes over time. It is planned

to perform a calibration study based on the PRONIA calibration protocol (https://www.pronia.eu/) or

other established protocols. We will document in the eCRF whether the MRI has been performed or

not (these data is not part of the study database)

https://www.pronia.eu/


8.6 Discontinuation of the study

The patient has the right to withdraw the informed consent at any time with no reason given, without

risk of being penalized and is declared a drop-out. The investigator, on the other hand, has the right

to exclude a patient from the study in the event of concomitant disease, adverse events, therapy

failure or any other reason or condition that warrants withdrawal in the interest of the patient. Such

patients are not primarily defined as drop-outs. If the patient has no recorded V9 visit (No RSWG

criteria at V9), the patient is declared as a drop-out (see also paragraph 8.2): If a patient has to

discontinue the study for any reason (relevant AEs/SAEs, intolerance to study drug, non-response,

incompliance regarding study drug intake or violation of study drug dose ranges as described in

paragraph 6.2, relevant concomitant disease), the primary outcome visit (V9) should be scheduled

for week eight (+/- 1 week) corresponding to V9. A protocol deviation must be recorded. The visit

corresponding to V9 can be shortened if necessary, but the primary outcome (8 PANSS items for

calculating remission score) should be assessed and recorded in the eCRF. All patients leaving the

trial prior to V9, but accepting the assessment of RSWG criteria at the timepoint of V9 (+ 1 week),

are no drop-outs.

Patient who have a valid V9 visit are invited to participate in the naturalistic follow-up.

We strongly recommend after discontinuation:

When for any reason study treatment is discontinued before Visit 9 or patients leave the study before visit 13, patients will be informed again about the necessity to have WBC controls for further four weeks. This clarifying consultation will be documented as being performed in the source data. Patients will have the possibility to receive WBC testing in the outpatient units of the participating study sites, but are free to consult other doctors such as their general practitioner or their psychiatrist. If a patient becomes a lost to FU after V9, the same procedure is used as described above.Every case of premature study drug treatment termination must be evaluated by the investigator and reasons for the termination assessed. The entire documentation must be as complete as possible. The final safety assessments should follow the protocol specifications. Any cases of premature termination must be documented in the eCRF, additional information is to be added, if applicable.

The patient’s study drug treatment will be terminated when

The patient withdraws her/his consent

The patient can no longer give informed consent according to the assessment of the study

doctor or due to any SAE

Intolerance to the study drug or non-tolerable side-effects

The nature of the patients treatment is changed to coercive treatment (based on judicial

ruling)

In particular, treatment needs to be discontinued due to changes in WBC/ANC (WBC count

less than 3000/mm3 or 3.0 x 109/l or the ANC is less than 1500/mm3 (1.5 x 109/l) see

paragraph 8.3 for details) or when a myocarditis and/or cardiomyopathy is assumed

according to protocol

Furthermore, treatment needs to be discontinued in case of eosinophilia (eosinophil count ≥

3000/mm³ (3.0 x 109/l) and should be restarted only after the eosinophil count has fallen

below 1000/mm³ (1.0 x 109/l)

Treatment needs to discontinued in case of thrombocytopenia (platelet count ≤ 5000/mm³

(5 x 109/l))

Treatment needs to be discontinued in case of paralytic ileus

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Treatment needs to be discontinued in case of epileptic seizure(s)

“Treatment needs to be discontinued if the patient suffers from relevant QT prolongation

(QTcF > 500msec and/or QTcF prolongation > 60msec compared to QTcF at baseline

Treatment needs to be discontinued in cases where hepatitis (including hepatocellular,

cholestatic or mixed liver injury) has been diagnosed

Treatment needs to be discontinued if a patient develops signs and symptoms indicative of

Neuroleptic Malignant Syndrome (NMS), or presents with unexplained high fever without

additional clinical manifestations of NMS

Patient becomes pregnant or initiates lactation

The investigator considers a patient’s continued participation in the study to be unjustifiable

on medical grounds (i.e., because of side-effects or unusual risks)

If an individual patient is discontinued due to one of the above mentioned reasons, this

patient will be treated as usual in normal clinical practice.

The sponsor has the right to terminate this study at any time. Reasons for terminating the study

may include but are not limited to the following:

The incidence or severity of AEs in this or other studies indicates a potential health hazard

to patients;

Unsatisfactory patient enrollment;

The continuation of study is unethical or it has been proven that the therapy has a clearly

negative influence;

Unforeseen complications arise that no longer justify a continuation of the study.

The sponsor will notify the investigator of a decision to discontinue the study. The sponsor has the

right to close a site at any time.

Reasons for closing a site may include, but are not limited to, the following:

Excessively slow recruitment (<5 inclusions/year)

Poor protocol adherence;

Inaccurate or incomplete data recording;

Non-compliance with the ICH-GCP guideline;

No study activity (i.e. all patients have completed and all obligations have been fulfilled);

If a study site discontinues the study on behalf of one of the above mentioned reasons, the patients

that have already been included will be followed up, but no new inclusions will be made.

The investigator can discontinue the clinical study at his site at any time if he no longer considers

the continuation of the study, for example if there are ethical and/or medical concerns.


8.7 Study flow chart

Study Visit Screening Baseline 1

2

3

4

5

6

7

8

9

10

11

12

13

Day -14 to 0 0-1 7 14 21 28 35 42 49 56

Endpoints* 63 70 77 84 (EOS)

Intervention of medication Administration from day 1 to day 56

Informed Consent X ****

Inclusion/exclusion criteria X

Drug Screening X

AUDIT interview and MINI X

Fagerström Test (Smoker) X Demographic data/ Medical / Psychiatric History X

Pre-study medication X X X X

Physical examination X X X X X X X X X X

Study laboratory X X X X X X X X X X X X X X

Pregnancy Test X

Number of cigarettes X X X X X

Interaction check****** X X X X X X X X X

PANSS *** X X X X

PANSS RSWG items X X X X X

CGI and GAF X X X

PSP, ISST, Trail-Making-Test (TMT) X X

CDSS X X X

Q-LES-Q-18, SF-12, DAI10, SWN-K, TALD X X

Attitude towards clinical trials X

BARS X X

GASS X X X X

St. Hans Rating Scale (SHRS) X X

CCCS X X X X

Assessment blood pressure and heart rate X X X X X X X X X

Assessment of weight and BMI X X X

EEG X X

ECG X X X X X X

Study medication (re-)dispensing X X X X X X X X *

Study medication return X

Blood draw Drug levels ** X X

Assessment of blinding integrity X

Discontinuation check X X X X X X X X

SAE/AE X X*****

Concomitant medication X X*****

* one additional blister of study medication can be distributed to the patient if the patient is discharged from inpatient treatment (lasting for around 4 days) **documentation of amount and type of capsules related to the timepoint of blood draw for drug level assessment; If a blood draw is not possible on the planned visits, the assessment of drug levels can be performed at the next planned visit. ***if psychopathological worsening is suspected, additional PANSS ratings should be performed in those visits where PANSS rating is not planned. **** also in case of relevant psychopathological worsening (increase in PANSS total score of at least 20%) or an emerging SAE.


***** Concomitant medication will be reported in case of a new laboratory-related AE after V9/Early Termination or any SAE between Visit 10-13, After completed V9, only laboratory-related AEs

and SAEs will be documented.

******Interaction check at baseline can be performed with textbooks, tables or commercial software. Interaction checks from V2-V9 have not to be performed with a specific instrument.

Study flow chart Optional activities

Study Visit

Screening Baseline,

1 2 3 4 5 6 7 8 9 10 11 12 13

Day -14 to 0 0-1 7 14 21 28 35 42 49 56

Endpoints 63 70 77 84 (EOS)

Optional activities*

Echocardiography (TTE) X X

30 minute ECG X X

MRI X X

* All optional activities can be performed with a range of –max. 7 days before baseline visit (=day 1), as long as informed consent was given a priori. At the endpoint, all

optional activities can be performed within a range of plus/minus 7 days around Visit 9.

Study flow chart Naturalistic follow-up

Study Visit

N1 N2 N3

Day +26 weeks (D 238 +/- 4 weeks) after

V9 +52 weeks (D 420 +/- 4 weeks)

after V9 +104 weeks (D 784 +/- 4

weeks) after V9

Naturalistic follow-up

Medical and psychiatric history X X X

Year of birth, Sex X

Living circumstance, working status X X X

Actual treatment X X X

PANSS X X X

PANSS RSWG items X X X

CGI X X X

GAF X X X

PSP X X X

Q-LES- Q-18 X X X

SF12 X X X


9. Statistical Analysis

The statistical analyses will be performed after data-base hardlock (end of study), but before the

end of the naturalistic follow-up. The latter is a secondary analysis that will be performed at the

end of the naturalistic follow-up period.

General statistical considerations

Descriptive statistics will be provided for all data broken down by treatment group, by visit and

by country. Mean, median, standard deviation, range, interquartile range and number of

observations will describe continuous variables. Absolute and relative frequencies will describe

categorical variables. All statistical tests will be carried out two-tailed; the alpha (level of

significance) is 5%. -

Baseline comparisons

The randomization procedure will be evaluated by a comparison of the two treatment groups for

all relevant variables recorded at baseline.

Primary analyses

The primary efficacy endpoint in the ITT population will be compared between groups by a

Mantel-Haenszel test, with centres as strata on a confirmatory two-sided significance level of

5%.

An additional subgroup analysis will be performed by logistic regression using the primary

efficacy endpoint as outcome and the factor variables group, centre and the categorized number

of previous lifetime treatments (cNLT categories: 0, 1, >1) as covariates. An interaction effect

between group and the cNLT subgroups will be included in the model. Parameter estimates of

the model will be used to obtain point and interval estimates (95% confidence intervals) of the

treatment effect, represented by Odds Ratios, within cNLT subgroups. The hypothesis test on

the model’s interaction effect equals the test for differences of the treatment effects between

subgroups. This subgroup analysis is exploratory and none of the hypothesis tests of effects

within and between subgroups is powered by the study’s sample size calculation. The major

objective is effect estimation instead.

Secondary analyses

Depending on the data distribution, group comparisons of continuous and categorical secondary

endpoints will be performed by linear or binary logistic regression analysis that includes a factor

variable for centres. Baseline values will be included as another covariate if existing. In case of

non-normally distributed residuals of the linear model, a van Elteren test (= stratified Wilcoxon

test) with centres as strata will be applied in an additional analysis. Corresponding descriptive

statistics and confidence intervals will also be given. Absolute and relative frequencies of

categorical safety outcomes will be assessed along the course of the trial (safety population).

Differences between groups will also be tested for statistical significance with Fisher’s exact test.

Likewise, continuously distributed safety outcomes (safety population) will be presented by

descriptive statistics and compared with t-tests or Mann-Whitney U tests, as appropriate. All

tests of secondary endpoints will be computed in the ITT and per protocol (PP) populations in

an explorative manner on a two-sided significance level of 5%.

Other assessments

Exploratory analyses will be performed as appropriate for other assessments.


Study populations

The intention-to-treat (ITT) population includes all patients as randomized. The per protocol (PP)

population will include all participants without major protocol violations. The safety population

will include all participants who received at least one study drug and will be analysed as treated.

The allocation of patients to the study populations will finally be determined in a blinded data

review meeting (BDRM). All analyses will be performed in full accordance with the ICH

Guidelines E9.


10. Analysis of risks and benefits

Participation in the EARLY trial implies that subjects contribute to the development of medical

knowledge of which they and other patients could benefit. An advantage of participation could

be that subjects will be more thoroughly followed and examined, and that therefore effects and

side effects are better measured. Moreover, patients may have an increased likelihood for

remission that will reduce the symptom burden. Patients will be treated with antipsychotics that

are used in clinical practice at this stage (especially olanzapine) with a far more sophisticated

side-effect evaluation increasing the individual safety. Clozapine is usually introduced at the

stage of treatment-resistance (Hasan, Falkai et al. 2012), but as indicated above in most cases

far too late. The participation in the EARLY trial increases the likelihood for an introduction of

clozapine before treatment resistance to reduce the risk of clozapine non-response.

As the inclusion criteria include a moderate symptomatology on the PANSS, defined as a score

≥ 4 for two or more symptoms from P1-P7 or a score of ≥ 6 for one symptom from P1-P7, it must

be concluded that these patients need antipsychotic treatment and both study drugs are

amongst the most effective antipsychotics (Leucht, Cipriani et al. 2013).

Use clozapine or olanzapine, the study drugs, will imply that there is a risk of drug-specific side

effects. From a principle point of view, the use of antipsychotics in this population is indicated

anyway in the treatment of subjects who are eligible for this study. However, clozapine is usually

applied a bit later in the disease stage so that the clozapine-associated risks of using clozapine

have to be considered as increased risk for 50% of the study participants. The potential benefits

are the expected higher likelihood for short-term and long-term response, the reduced risks of

motor-side effects and the reduced risk of a potential re-hospitalization. Moreover, the strict

safety protocol addressed all clozapine-associated risks and goes far beyond the recommended

safety procedures described in the SmPC increasing the patient safety. Another limitation all

subjects face within this study is that they cannot choose a side effect profile associated with an

individual antipsychotic, as they are randomized. In addition, participation of this trial will take

more of the subject’s time than regular treatment.

Clozapine is safe in both early-episode and chronically ill patients if the necessary monitoring

(especially complete and white blood cell count) is applied (Agid, Arenovich et al. 2011, Meltzer

2012, Remington, Agid et al. 2013, Sanz-Fuentenebro, Taboada et al. 2013). Thus, application

as second-line treatment can be warranted, especially in schizophrenia patients who experience

a relapse or who have not responded to an antipsychotic trial. Such patients are at high risk for

an unfavorable disease outcome and the experimental intervention with early clozapine is likely

to improve remission rates in these patients. By excluding first-episode patients who have a very

high likelihood to response to any kind of antipsychotic treatment (Zhu, Krause et al. 2017, Zhu,

Li et al. 2017), we reduce the risk of treating patients with drugs that are highly effective on the

one hand, but where the side-effects do not warrant the use in first-episode patients.

All available antipsychotics carry the risk of specific side effects, which need to be weighed

against the benefits. Clozapine is associated with a small risk of agranulocytosis and

myocarditis. On the basis of the literature, in our study we may have ~1 case of agranulocytosis

and ~0.1 case of myocarditis. However, as recently outlined in a literature review the absolute

risk for both complications is low and can be mitigated by regular monitoring and timely

interventions (Citrome, McEvoy et al. 2016). In addition to the regular monitoring of blood counts

and CK levels as well of troponine T, we will implement several levels of safety measures and

surveillance that go far beyond the usual assessments in other schizophrenia trials or clinical

practice. Moreover, we will perform 5 ECGs during the intervention phase and we will perform


two EEGs to monitor for potential epileptic activity and thus reduce the risk for clozapine-

associated seizures.

According to German guidelines, treatment will be discontinued immediately if leucocytes are

<3000/µl or neutrophil granulocytes are <1500/µl or both. Before study medication is dispensed,

a WBC must confirm leucocyte levels >3500/µl. If leucocytes drop to levels between 3000/µl and

3500/µl, the WBC will be controlled twice a week, in accordance with German guidelines. Study

medication can only be increased if WBC > 3500/µl and neutrophil granulocytes are > 1500/µl.

If a patient reports clinical signs of myocarditis (e.g. chest pain, palpitations, dyspnoea, and

discomfort) or shows a relevant CK elevation (assessed on a weekly basis) or respective ECG

abnormalities or changes in troponine T (Müller and Benkert 2017), treatment will be

discontinued and cardiac echography will be performed by a cardiologist. Please see paragraphs

8.3 (Special safety aspects during the intervention period) and 8.5 (Description of rating scales

and assessments) for a complete description of our safety procedures that will be implemented

in addition to those procedures necessary for every trial (see paragraph 12, Safety reporting).


11. Feasibility of patient recruitment

Although there are no pilot studies for the current trial, the study design resembles that of

previous randomised studies in the field of schizophrenia research (Lieberman, Phillips et al.

2003, Lieberman, Stroup et al. 2005, Meltzer, Bobo et al. 2008). In addition, the registration trials

for the antipsychotics in the current design (especially olanzapine) have recruited large patient

samples. Given that these studies have already been successfully completed, it seems

reasonable to assume that with respect to sample size, the chosen statistical methods, and the

estimated number of patients who will drop out, the present study can be realised. The present

study will not use any medication which is yet to be approved and does not ask many extra

activities of the patients, making recruitment all the easier.

Because participant compliance is the most critical point for study success, when designing

the study, we made great efforts to provide a setting for good compliance and took into account

our study we made great efforts to provide a setting for good compliance and took into account

our experience with previous large-scale multicentre trials in schizophrenia patients. We aim to

conduct the trial for eight weeks and focus on the main research question whether clozapine is

superior to olanzapine in achieving remission. This short trial period will have much higher

compliance rates than 26- or 52-week trials. The following design aspects will improve the

compliance rate:

Minimal exclusion and broad inclusion criteria

Different dose steps rather than a fixed-dose strategy, minimal number of needed

capsules

Possibility to add haloperidol as rescue medication during the titration phase

Possibility to add a broad array of rescue medication during the complete study phase

(e.g. lorazepam, zopiclone)

Slow titration of study drugs to reduce risk for side effects

No placebo control – two active comparators

No use of non-approved drugs and use of two highly effective SGAs

The expected loss to follow-up is low because patients who drop out of the study will still be

treated at the study centres. We will follow a strict intention-to-treat principle and still evaluate

patients at the primary outcome visit (unless they withdraw consent), even if patients are put on

another medication during the trial. Therefore, the primary outcome will be assessed at standard

routine visits during daily clinical work. We believe that we will have less than 1% total missing

values for the primary endpoint. To protect against missing values that might still occur we will

perform statistical analyses conservatively and include all randomized patients. The drop-out

rates of short-term clinical trials comparing two antipsychotics have been reported in the range

of 5% to 50%. Waiving a placebo arm and using SGAs are the main factors to decrease drop-

out rates (Kemmler, Hummer et al. 2005, Martin, Perez et al. 2006) and we addressed both

factors in our trial design. We are aware that drop-outs cannot be completely avoided. As

outlined above we will assess the primary outcome in nearly all patients, irrespective of whether

they are a completer or drop-out. Therefore, drop-outs are not lost patients. However, clinical

trial experience has shown us that despite all efforts we might lose some patients, and we have

therefore addressed this issue by adjusting our power analysis regarding the expected rates of

total missing values.


12. Safety reporting

12.1 AE, SAE and Susar definitions and reporting procedures

Adverse Event

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a

pre-existing medical condition in a patient or clinical investigation subject administered an

investigational (medicinal) product and that does not necessarily have a causal relationship with

this treatment. An AE can therefore be any unfavourable and unintended sign (including an

abnormal laboratory finding, for example), symptom, or disease temporally associated with the

use of investigational product, whether or not considered related to the investigational product.

Adverse events can be spontaneously reported or elicited during open-ended questioning,

examination, or evaluation of a subject (In order to prevent reporting bias, subjects should not

be questioned regarding the specific occurrence of one or more adverse events). Adverse

events will be recorded in the eCRF in relation to stage of the study drug. Furthermore, it will be

assessed if the patient was in a titration phase or not when the adverse event occurred.

Serious Adverse Event

A Serious Adverse Event (SAE) is any untoward medical occurrence at any dose that:

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE*: below for exceptions)

results in persistent or significant disability/incapacity is a congenital anomaly/birth defect

is an important medical event, defined as a medical event that may not be immediately life-threatening or result in death or hospitalization but, based on appropriate medical and scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed above. Examples of such events include but are not limited to intensive treatment in an emergency department or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.

Suspected transmission of an infectious agent (e.g., pathogenic or non-pathogenic) via the study drug is an SAE.

Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these events must be handled as SAEs.

The following hospitalizations are not considered SAEs:

Pre-planned hospitalizations, i.e. before enrolment into the study and which are not related to the underlying condition.

Hospitalization due to social reasons (e.g. homelessness) in absence of an AE


A planned hospitalization for a pre-existing condition, or a procedure required by the Clinical Protocol, without a serious deterioration in health.

Surgery or procedure planned before entry into the study.

re-hospitalized patient between V9 and V13 for psychiatric reasons.

Serious Adverse Reaction

Serious Adverse Reaction (SAR) is defined as an adverse drug reaction that is serious and at

least possibly related to the investigational medicinal product. In case of a SAR the investigator

has to provide a case narrative.

Suspected Unexpected Serious Adverse Reaction (SUSAR)

SUSARs are defined as Suspected Unexpected Serious Adverse Reactions, i.e. all suspected

adverse reactions related to the tested investigational medicinal product that is both: unexpected

and serious. SUSARs require expedited reporting

An event qualifies as a SUSAR when:

the criteria for an SAE are met and

it is plausible that the event is caused by the study medication and

the event is unexpected, meaning that the nature, or severity, is not consistent with the

applicable product information (i.e. Summary of Product Characteristics).

Second Assessment of Serious Adverse Events

All SAE will be subject to a second assessment by a medical expert, who will be independent

from the reporting investigator and the coordinating investigator.

The second assessor will monitor each SAE following the conditions below:

I. known SAR with unexpected outcome

II. assessment of relationship between SAE and IMP

III. assessment of expectedness of SAE (derived from IB)

IV. statement if the benefit/ risk assessment for the trial did change as a result of SAE (or

of an unexpected outcome of an expected SAR).

V. Statement, if there are any safety issues, which are sufficient to consider changes in

the conduct of the trial.

An “unexpected” adverse event is one the nature or severity of which is not consistent with the

applicable product information, e.g. Investigator Brochure (IB), device manual or scientific

literature.


Assessment of Adverse Events

Assessment of intensity

The intensity of adverse events will be graded using the CTCAE, Version 4.0 of the US NCI

(e.g. Website:https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-

14_QuickReference_5x7.pdf). For events not reported in the CTCAE Version 4.0, the

investigator will use the Grade or adjectives:

Grade I Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.

Grade II Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL)

Grade III Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL

Grade IV Life-threatening consequences; urgent intervention indicated

Grade V Death related to the adverse event

Table 5; Grading of adverse events

Note the distinction between the gravity and the intensity of an adverse event. Severe is a

measure of intensity. Thus, a severe reaction is not necessarily a serious reaction. For example,

a headache may be severe in intensity but would not be classified as serious unless it meets

one of the criteria for serious events listed above.

Assessment of causality

The investigator must make a causality assessment for all AEs. The relationship of an adverse

event to the study treatment regimen and the device has to be recorded on the eCRF and defined

as not related, unlikely, possible related, probable related or highly probable/definite:

Relatedness Description

Highly

probable/definite

An event that follows an established temporal sequence from the

study treatment regimen, the re-challenge is positive, or there is a

reoccurring pattern of characteristics during onset and cessation of

event.

Probably related An event that follows a reasonable temporal sequence from the

study treatment regimen and that is not easily explained by

another cause such as known characteristics of the subject´s

clinical state or the treatment

Possibly related An event that follows a reasonable temporal sequence from the

study treatment regimen but that may be due to another cause

Unlikely An event that follows such a temporal sequence from the study

treatment regimen that a relationship is not likely, and is likely to


be due to cause such as the subject`s clinical state or other

treatment

Not related The event is definitely not associated with the study treatment

regimen in the study but is judged clearly and incontrovertibly due

to causes other than the study treatment

The categories “Highly probable/definite”, “Probably related” and “Possibly related” will be

assumed as related, the categories “Unlikely” and “Not related” are assumed as not related.

12.2 Follow-up of adverse events

Period of Adverse Event reporting

All Adverse Events must be collected that occur during visit 1 (start of study treatment) and within

30 days of discontinuing dosing or until all drug-related toxicities are resolved, whichever is later,

or until the investigators assess AEs as “chronic” or “stable”. Open AE's and SAE's are only

observed until end of study (EOS). The investigator should report any Adverse Event occurring

after these time periods that is believed to be related to study drug or protocol-specified

procedure.

If the investigator believes that an SAE is not related to study drug, but is potentially related to

the conditions of the study (such as withdrawal of previous therapy, or a complication of a study

procedure), the relationship should be specified in the narrative section of the SAE Report Form.

SAEs, whether related or unrelated to the study drug, and pregnancies must be reported to the

MSZ immediately (latest within 24hours). SAEs must be recorded on the SAE Report Form;

Pregnancies on a Pregnancy Report Forms.

Münchner Studienzentrum (MSZ)

Klinikum rechts der Isar


Ismaningerstr. 22

81675 München

MSZ E-Mail: [email protected]

MSZ Fax Number: +49/89/4140-6480

If only limited information is initially available, follow-up reports are required.

If an ongoing SAE changes in its intensity or relationship to study drug or device or if new

information becomes available, a follow-up SAE report should be sent immediately (latest within

24 hours) to the MSZ using the same procedure used for transmitting the initial SAE report. All

SAEs should be followed to resolution or stabilization.

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Reporting requirement

Each adverse event is to be classified by the investigator as SERIOUS or NON-SERIOUS. This

classification of the gravity of the event determines the reporting procedures to be followed. If a

serious adverse event occurs, reporting will follow local and international regulations, as

appropriate. If a serious adverse event occurs, the Sponsor’s Drug Safety Officer are to be

notified, using the designated SAE Report form, immediately (latest within 24 hours of

awareness of the event) by the investigator. The respective Fax-number and E-Mail address will

be provided to the investigator as part of the ISF.

The initial report is to be followed by submission of a more detailed adverse event information

(only if new case information is available) as soon as possible. Reporting requirements for

adverse events are summarized in the following table.

Gravity Reporting time Type of Report

Serious Immediately (latest

within 24 hours)

Initial/Follow up report on

designated serious adverse event

form

Non-Serious Per case report form

submission procedure Appropriate case report forms

Table 6: Reporting of adverse events

Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in addition to being recorded on the AE page of the eCRF. AEs and SAEs will be recorded after first drug intake onwards and will be followed-up until end of study (EOS). After completed V9, only laboratory-related AEs and SAEs will be documented.

It should be noted that the form for collection of serious adverse event information is not the

same as the adverse event case report form. Where the same data are collected, the forms must

be completed in a consistent manner. For example, the same adverse event term should be

used on both forms.

In the rare case that the investigator does not immediately become aware of the occurrence of

a serious adverse event, the investigator must report the event immediately (latest within 24

hours after having been informed about it) and document his/her first awareness of that adverse

event.

Non-Serious-Adverse-Events are to be reported on the adverse event case report forms (eCRF)

which are to be submitted as specified in the adverse event report submission procedure for this

protocol.

The investigator will be requested to supply as much detailed information as possible regarding

the event that is available at the time of the initial contact. The investigator is also required to

complete missing or requested information and to submit follow-up reports to the person

mentioned above until the SAE or SUSAR has resolved or, in the case of permanent impairment,

until the SAE has stabilized.

The response time for queries to SAE reports is expected to be no more than five (5) business

days. Urgent queries (e.g. missing causality assessment) may be handled by phone.


MSZ as representative of the sponsor will ensure the reporting of all SUSARs and other safety

issues which require expedited reporting to the responsible authorities according to the legal

requirements. MSZ will report all SUSARs to the competent authority and Ethics Committee (EC)

within 15 calendar days after the Drug Safety Officer was first aware of the minimum criteria for

expedited reporting.

MSZ will report all fatal or life-threatening SUSARs to the competent authority and EC within 7

calendar days after the Drug Safety Officer has first knowledge of the minimum criteria for

expedited reporting.

In addition to reporting to competent authority and EC the MSZ will inform all investigators

concerned on findings that could adversely affect the safety of study patients.

Responsibilities of the investigator

A SAE-report form (initial report) must be sent immediately (latest within 24 hours of onset or

acknowledgement of the SAE) to the Sponsor’s Safety Officer.

Follow-up reports must be sent when further information becomes available using the route of

transmission described above.

Other documents must be submitted upon request (e.g., histology findings, case report forms).

All documents must be blinded with respect to the patient’s name. The confidentiality of patient

information is ensured by revealing only a patient number. All these documents will be forwarded

by fax as described above.

Although such information is not routinely sought or collected by the sponsor, SAE that occurred

after the patient had completed the clinical trial (including any protocol-required post-treatment

follow-up) will possibly be reported by an investigator to the sponsor. Such cases will be

regarded for expedited reporting purposes as though they were study reports. Therefore a

causality assessment and determination of expectedness will be obtained for a decision on

whether or not expedited reporting is required.

12.3 Unblinding

Unblinding of a patient in the case of emergency or in case of SUSAR reporting is ensured by a

set of special emergency envelopes which are available on site. For the blinded data review

meeting specific SOPs will be implemented for these cases.

12.4 Pregnancy

If, following initiation of the investigational product, it is subsequently discovered that a study

subject is pregnant or may have been pregnant at the time of investigational product exposure,

including during at least 5 half-lives after product administration, the investigational product will

be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for

subject safety).

The investigator must immediately notify MSZ of this event via the ”Report on the drug exposure

during pregnancy” immediately (latest within 24 hours) and in accordance with SAE reporting

procedures.


Follow-up information regarding the course of the pregnancy, including perinatal and neonatal

outcome and, where applicable, offspring information must be reported on a “Report on the

pregnancy outcome during drug exposure”.

Any pregnancy occurring in a female partner of a male study participant the investigator

becomes aware of should be reported to the MSZ. Information on this pregnancy may also be

collected on the pregnancy reporting forms.

12.5 Overdose

An overdose is defined as the accidental or intentional administration of any dose of a product

that is considered both excessive and medically important. All occurrences of overdose must be

reported as SAEs

12.6 Annual safety report (Safety Update Report (DSUR))

In addition to the expedited reporting, sponsors shall submit, once a year throughout the clinical

study or on request a safety report to the competent authority and the EC of the concerned

Member States, taking into account all new available safety information received during the

reporting period. The aim of the safety report is to concisely describe all new safety information

relevant for one or several clinical study(s) and to assess the safety conditions of subjects

included in the concerned study. The annual safety report should be the same for the competent

authorities concerned and the EC concerned.

12.7 Safety Monitoring Board (SMB)

The safety of the study will be judged by an independent committee of experts on regular basis,

at a frequency of at least once a year via personal meeting or telephone conference. The

members of this board will have access to the unblinded data, to all SAEs and SUSARs and to

the inclusion and drop-out rates. This Safety Monitoring Board (SMB) will suggest changes to

the protocol or provide an altered judgement of feasibility if information from the annual safety

report or new information about the applied study medication has become available


13. Ethical and regulatory aspects

13.1 Sponsor‘s and investigator’s responsibilities This study is conducted in compliance with all applicable laws and regulations and also the

Declaration of Helsinki. The sponsor has the overall responsibility for the ethical and scientific

conduct of the study. All participating investigators agree to adhere to the instructions and

procedures described in the study protocol and thereby to adhere to the principles of GCP that

it conforms too.

The ethics committee and BfArM will review the final study documents. The ethics committee's

and BfArM’s decision concerning the conduct of the study will be communicated in written form

to the sponsor. The sponsor will assure submission of required progress reports, annual safety

reports and substantial amendments for approval to the ethics committee and BfArM. Before

initiating the study, the sponsor must submit any required amendments to BfArM for review and

acceptance to begin the trial according to § 42 AMG. Furthermore, the sponsor has to inform the

ethics committee and BfArM within 90 days about completion of the trial and provide a brief

report of its outcome 1 year after completion of the trial.

13.2 Ethics committees and health authorities

Prior to the start of this study, the protocol and other required documents have to be reviewed

and approved by the ethics committee and BfArM before study initiation. Any amendments to

the protocol, other than administrative ones (of which the ethics committee and BfArM will merely

be informed), must be reviewed and approved by both.

Before inclusion of the first patient the federal state authorities (zuständige Regierungsbehörden

der Länder) will be informed about the study. A copy of this report needs to be forwarded to

BfArM and needs to be filed in the ISF and TMF.

13.3 Ethical performance of the study

The study is conducted according to the ethical principles as defined in the Declaration of

Helsinki. The present clinical study is conducted in accordance with principles published in the

Good Clinical Practice Guideline (ICH-GCP) and the applicable legal regulations (AMG, GCP-

V). These principles concern ethics committee procedures, patient information and informed

consent procedures, adherence to the protocol, administrative documents, documentation of the

study medication, data collection, patient records (source documents), recording and reporting

of AEs/SAEs, preparation of inspections and audits as well as storage and safekeeping of the

documents. All the investigators and personnel involved in the study have been informed that

the competent authorities and the sponsor are authorised to review the study documents and

patient files.

13.4 Informed consent of the study participants

A patient can only be included in the study, if he provides written consent after being informed

by a GCP-trained investigator (orally and in writing) about the nature, significance and scope of

the clinical study in an appropriate and understandable way. Additionally, a doctor that is not

associated to the study (board certified psychiatrist/Facharzt für Psychiatrie und Psychotherapie)


has to confirm and sign in the document that the patient can give informed consent in the

informed consent document. The assessment of the clinician (board certified

psychiatrist/Facharzt für Psychiatrie und Psychotherapie) is considered to be the gold standard

in the checking the capability of consent among schizophrenia patients (Cordes, Wölwer et al.

2013). The investigator must fully explain the purpose of the study to the patient or his/her

guardian prior to entering the patient into the study. The investigator is responsible for obtaining

written informed consent from each patient. The person signing the consent form will receive an

original of the signed form. By providing such consent the patient is declaring that he

understands and accepts the recording of data that is part of the study and its verification by

authorised monitors or federal authorities. The patient will be educated about the potential

benefits and complications of the IMP used in the study. It must be clear to him/her that he/she

can withdraw his/her consent at any point of time without any disadvantages to his/her further

treatment. One original of the written ICF will be kept in the study folder (ISF) of the study site.

Another original of the written patient information and ICF will be given to the patient.

Additionally, copies of both documents will be filed in the patient’s medical file. The patient

information and ICF will be submitted to the responsible ethics committee for assessment before

the study will be initiated.

During the study visits of the double-blind treatment phase, potential psychopathological

worsening of the patient is documented. Psychopathological worsening is defined as an increase

of at least 20 % in the PANSS total score. If psychopathological worsening is suspected, an

additional PANSS rating should be performed. The 20% threshold was derived from the

response criteria published by Leucht 2014. In the case of a psychopathological worsening or in

case of any SAE, a clinician that is not associated to the study (board certified

psychiatrist/Facharzt für Psychiatrie und Psychotherapie) has to reconfirm and document that

the patient continues to be capable to consent. If not, the patient has to be excluded from the

study.


14. Study administration

14.1 Documentation and Data collection

The documentation of the study data in adherence to the GCP-guidelines and the clinical trial

protocol is the responsibility of the investigator. Original data (source documents) remain in

hospital medical record and information on the eCRF must be traceable and consistent with the

original data. Source documents are e.g. laboratory results. Original written informed consent

signed by the patient is kept by the investigator and a signed copy will be given to the patient.

No information in source documents about the identity of the patients will be disclosed. All data

collected in this study must be entered in an eCRF which has to be completed by the investigator

or authorized trial personnel and signed by the investigator. This also applies for those patients

who do not complete the study. If a patient withdraws from the study, the reason must be

recorded on the eCRF. The investigator is responsible for ensuring the accuracy, completeness,

and timeliness of all data reported to the sponsor in the eCRFs and in all required reports.

After database lock, the principal investigator will receive data of the investigational site for

archiving in the Investigator Site File (ISF).

14.2 Database management

Data are administered and processed by data management of the MSZ with the support of a

study database (eCRF) according to the SOPs of the MSZ. Data of the optional assessments

will not be added to the eCRF – we will only document whether these procedures were

performed or not.

A description of the study specific processes is given in the Data Management Plan that details

the key planning and control elements for the data management component of the study.

The evaluation of the data takes place by programmed validity- and consistency checks. In

addition a manual/visual evaluation of plausibility is performed in accordance to the requirements

of GCP. Queries may occur, which will be visualized on the study database. The investigator

has to resolve all data discrepancies in the study database.

After entry of all collected data and clarification of all queries, the database will be closed at the

completion of the study. The database closure has to be documented.

Data and results electronically recorded will be archived according to legal guidelines. Separate

databases for the main study (V1-V13) and for the naturalistic follow-up study will be created.

All pseudonymized data can be shared between the main study and the naturalistic follow-up

study via a secure procedure fulfilling all necessities of data protection.

14.3 Audits and inspections

As part of quality assurance according to GCP, the sponsor and the competent health authorities

have the right to audit/inspect the study sites and any other institutions involved in the trial. The

aim of an audit/inspection is to verify the validity, accuracy and completeness of data, to establish

the credibility of the clinical trial, and to check whether the trial subject’s rights and trial subject

safety are being maintained. The sponsor may assign these activities to persons otherwise not

involved in the trial (auditors). These persons as well as inspectors are allowed to access all trial


documentation (especially the trial protocol, eCRFs, trial subjects’ medical records, drug

accountability documentation, and trial-related correspondence).

The sponsor and all investigators of the participating study sites undertake all efforts to support

auditors and inspections by the competent authorities at all times and to allow the persons

charged with these duties access to the necessary original documentation.

All persons conducting audits undertake to keep all trial subject data and other trial data

confidential.

After each external audit the investigator receives an audit confirmation from the responsible

auditor. This confirmation has to be stored in the ISF in order to provide access to it in case of

an inspection by the competent authorities. The audit report is provided to the sponsor for

control. At the end of the study an audit certificate is added to the final report. A respective

inspection report is provided to the trial centers for notification.

14.4 Monitoring

Monitoring activities are performed to ensure that the trial is conducted in accordance with the

trial protocol, the principles of GCP and local legislation. A monitoring plan describing the scope

of the monitoring activities in detail will be prepared.

The responsible monitor will contact the investigator and will be allowed, on request, to inspect

the various records of the trial (eCRF and other pertinent data) provided that patient

confidentiality is maintained in accord with local requirements. The monitor should have access

to patient records, any information needed to verify the entries in the eCRF and all necessary

information and essential study documents. The investigator agrees to cooperate with the

monitor to ensure that any problems detected in the course of these monitoring visits are

resolved. A monitoring visit report is prepared for each visit describing the progress of the clinical

trial and all identified problems. Monitoring will take place exclusively for the main study (until

V13).

14.5 Archiving

At the end of the clinical study all study-relevant data must be archived as required by law and

when indicated in addition according to the Clinical Trial Agreement. All documentation forms,

ICFs and other essential study documents must be retained as required by law. Patient ID lists

and patient files are retained in the respective study sites separately. The ICFs are kept in with

the study documents.

14.6 Reporting

Final report

Within one year of the completion of the trial, BfArM and the ethics committee will be supplied

with a summary of the final report on the clinical trial containing the principle results. The sponsor

delegated person is responsible for the generation of the final report.


Publications

The trial protocol will be published after initiation of the first study center in a peer-reviewed

scientific journal following the CONSORT guideline (www.consort-statement.org)..

We will build up a trial website with a section in layman’s language for patients and relatives,

involving national patient and relative societies from the beginning, and actively maintain social

media accounts (e.g. science-to-public [Facebook], science-to-science [LinkedIn,

ResearchGate], and science-to-press [Twitter]). During the trial, we will continuously inform

professionals and the public about the current progress via our website and social media

accounts.

Upon availability of the final results, we will publish all findings, positive or negative, in

international peer-reviewed journals and thereby use open-access options if possible to the

largest possible extent (e.g. according to the CONSORT statement). No secondary endpoint

result will be published prior to the publication of the primary endpoint.

Financing of the study

The study is funded by the Deutsche Forschungsgemeinschaft (DFG), grant number: HA

6091/4-1, project number: 316096538 (http://gepris.dfg.de/gepris/projekt/316096538).

Public Register

Before the study begins, the clinical study will be filed at an international public register (e.g.

clinicaltrials.gov or WHO clinical trials).

Data Sharing

Is not planned.

14.7 Insurance for subjects participating in clinical studies

In the clinical study of a drug all the participants are insured in accordance with the German

Medicines Act. The scope of the insurance coverage is derived from the insurance documents

that are included in the investigator’s folder. Before inclusion, the insurance conditions shall be

submitted to the patient for review without request to do so.

The insurance conditions should be furnished to the patient to take with him before being

included in the study on request and after inclusion in any case.

Insurance cover age is being provided by the following insurance provider:

HDI Global SE

Niederlassung Düsseldorf

Am Schönenkamp 45 – D-40599 Düsseldorf

Tel.: 0211/7482-199


Insurance Number: 76294201 03011

represented by

ECCLESIA Versicherungsdienst GmbH

Ecclesiastraße 1-4 - 32758 Detmold

Tel.: 05231/603-307

http://www.consort-statement.org/

http://gepris.dfg.de/gepris/projekt/316096538



Fax: 05231/603-60307

www.em-hospital.de

If an insured event is suspected to have occurred, the principal investigator of the clinical study

is to be notified of such event immediately. He shall notify the insurance provider about the

damages immediately.

The patient receives a copy of the notification to the insurance provider.

The patient may also inform the insurance provider by bypassing the personnel involved in the

study and reporting any claims. He must be told about both options. Furthermore, he should also

be informed that he shall inform the principal investigator of the clinical study in the event of any

notification sent by him on his own.

Moreover, a home-to-clinic accident insurance has been concluded:

SV SparkassenVersicherung AG

Bahnhofstr. 69, D-65021 Wiesbaden

Tel.: 0611/178-100

Fax: 0611/178-109

Insurance Number: 50074652021

Client Number: 0 049 107 784-4

represented by

ECCLESIA Versicherungsdienst GmbH

Ecclesiastraße 1-4 – D-32758 Detmold

Tel.: 05231/603-307

Fax: 05231/603-60307

www.em-hospital.de

14.8 Data Privacy Protection and Confidentiality protection

The applicable local regulations of data privacy protection will be followed. The patients will be

informed that any patient-related data and materials will be appropriately made pseudonymous

(pursuant to § 12 and § 13 of the GCP Regulations) and that these data may be used for analysis

and publication purposes. Furthermore, the patients will be informed that their data may be

inspected by representatives of BfArM or of the sponsor for the purpose of validation of a proper

study conduct. Patients who do not provide consent for transmission of their data, according to

the data protection agreement included in the ICF, will not be included in the clinical study.

14.9 Protocol amendments or changes in trial conduct

In order to insure comparable conditions in all study sites and in the interest of standardized

evaluations of the trial, changes in this protocol are not foreseen. However, changes in trial

conduct are possible. Any change (besides administrative changes) of this protocol requires a

written protocol amendment that must be reviewed by the sponsor before implementation.

Furthermore, consent needs to be obtained by the investigator of each participating site.

Amendments that significantly affect the safety of subjects, the scope of the investigation or the

scientific quality of the study, additionally require approval of the ethics committee and the

investigator at each study site. Examples of amendments requiring such approval are:

http://www.em-hospital.de/


Significant changes in the study design;

Increases in the number of invasive procedures.

However, these requirements for approval should in no way prevent the investigator or sponsor

to take any immediate action in the interests of preserving patient safety. If the investigator feels

an immediate change to the protocol is necessary and is implemented for safety reasons, the

sponsor, ethics committee and BfArM must be informed immediately. Amendments affecting

only administrative aspects of the study do not require formal protocol amendments or ethics

committee and BfArM approval. However, the ethics committee and BfArM must still be notified

about the changes.


15. Abbreviation

AE Adverse Event

BfArM Bundesinstitut für Arzneimittel und Medizinprodukte

BW Body Weight

CRF Case Report Form

eCRF electronic Case Report Form

FPFV First Patient First Visit

GCP Good Clinical Practice

ITT Intention to Treat

kg Kilogramm

LPFV Last Patient First Visit

LPLV Fast Patient Last Visit

MSZ Münchner Studienzentrum

PP Per Protocol

PLC Placebo

SAE Serious Adverse Event


16. Annex

16.1 Declaration of Helsinki

The declaration of Helsinki it its recent version is attached to the protocol.


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