biomedical research protocol relating to a medicinal … · scientific justification due to its...

«Prospective multicenter randomized open trial assessing efficacy and

safety of dapsone as a second-line option in adult Immune

Thrombocytopenia (DAPS-ITP study)”

BIOMEDICAL RESEARCH PROTOCOL RELATING TO A MEDICINAL PRODUCT

Version N°3 du 19/10/2016

Code projet : P140925 / N° EUDRACT: 2015-001971-35

Coordinating Investigator: Prof Marc MICHEL M.D Department of Internal Medicine, national referral center for adults’ immune cytopenias. Filière de santé maladies rares MARIH

Hospital: Henri Mondor university hospital, Tel: 01 49 81 20 76 E-mail: [email protected]

Sponsor: Assistance Publique – Hôpitaux de Paris (AP-HP)

AP-HP- DRCD, Saint-Louis Hospital 1, avenue Claude Vellefaux – 75010 Paris Référent projet : M. Agnes Dorion Tél : 01 44 84 17 08 / Fax : 01 44 84 17 01 E-mail: [email protected]

Entity responsible for monitoring research :

Clinical Research Unit (Pr. S Bastuji-Garin) Henri-Mondor Hospital 51, Avenue du Maréchal de Lattre de Tassigny, 94000 Creteil Tel : 01 49 81 37 06 E-mail : [email protected]

Methodologist: Dr Florence CANOUI-POITRINE Recherche Clinique - Santé Publique Hôpital Henri-Mondor, LIC EA 4393 Université Paris Est Créteil, Créteil, France

Clinical Research and Development Department (DRCD)

Saint Louis Hospital 75010 PARIS

mailto:[email protected]:[email protected]:[email protected]

Page de SIGNATURE D'UN PROTOCOLE de recherche biomédicale

Code de la Recherche biomédicale : P140925 / N° EUDRACT: 2015-001971-35 Titre : Chirurgie précoce en cas de rétrécissement aortique sévère et asymptomatique

Titre de la recherche: “Prospective multicenter randomized open trial assessing efficacy

and safety of dapsone as a second-line option in adult Immune Thrombocytopenia (DAPS-

ITP study)”

Version N°3 du 19/10/2016

Version n° 1.0 du 21/04/2015

La recherche sera conduite conformément au protocole et aux dispositions législatives et

réglementaires en vigueur.

L’investigateur coordonnateur :

Prof Marc MICHEL M.D Département de Médecine Interne. Filière de

santé maladies rares MARIH Hôpital Henri

Mondor

51, avenue du maréchal de Lattre de Tassigny

94000 Créteil

Date : ……………/………/………..

Signature :

Le représentant du promoteur:

Florence Favrel Feuillade,

Directrice du DRCD

Assistance publique – hôpitaux de Paris

Département de la Recherche Clinique et du

Développement

Hôpital Saint Louis 75010 PARIS

Date : ……………/………/………..

Signature :

Cette version du protocole a reçu a reçu un avis favorable du CPP IDF III en date du 30/10/2015

Protocole DAPS-ITP, version 3 du 19/10/2016 3/69

CONTENTS

1 SUMMARY…………………………………………………………………………………………..6

2. SCIENTIFIC JUSTIFICATION FOR THE RESEARCH………………………………………..9

2.1 Background…………………………………………………………………………….....9

2.2 Hypothesis for the research…………………………………………………………..10

2.3 Summary of relevant pre-clinical experiments and clinical trial………………… .10

2.4 Description of the population to be studied and justification for the choice of

participants……………………………………………………………………………….11

2.5 Identification and description of the experimental medications……………………12

2.6 Description and justification of the dosage, administration method, administration

design and treatment period…………………………………………………………..12

2.7 Summary of the known and foreeeable benefits and trisks for the research

participants……………………………………………………………………………….12

3. OBJECTIVES……………………………………………………………………………………..13

3.1 Primary objective………………………………………………………………………..13

3.2 Secondary objectives…………………………………………………………………..13

3.3 Objectives of future ancillary research……………………………………………….14

4. PLAN FOR THE RESEARCH…………………………………………………………………..15

4.1 Description of the primary and secondary assessment criteria……………………15

4.2 Description of research methodology………………………………………………...16

5. PROCEDURE FOR THE RESEARCH…………………………………………………………18

5.1 Inclusion visit…………………………………………………………………………….19

5.2 Follow-up visits…………………...……………………………………………………..19

5.3 End of the research visit……………………………………………………………….20

5.4 Expected length of participation and description of the chronology and duration of

the research……………………………………………………………………………...20

5.5 Table summarising the chronology of the research…………………………………20

5.6 Distinction between care and research………………………………………………21

5.7 Biological collection…………………………………………………………………….21

5.8 Termination rules……………………………………………………………………….22

6 ELIGIBILITY CRITERIA………………………………………………………………………….24


6.1 Inclusion criteria…………………………………………………………………………24

6.2 Non-inclusion criteria…………………………………………………………………...25

6.3 Recruitment methods…………………………………………………………………..25

7. TREATMENT ADMINISTERED TO RESEARCH PARTICIPANTS………………………..26

7.1 Description of the experimental medications………………………………………..26

7.2 Description of the non-investigational treatment (medication required for carrying

out the research) ……………………………… ………………………………..27

7.3 Supply of treatments……………………………………………………………………28

7.4 Description of the traceability elements that accompany the experimental

medications……………………………………………………………………………..28

7.5 Authorised and prohibited treatments including rescue medications……………..28

7.6 Methods for monitoring compliance with the treatment…………………………….29

8. SPECIFIC RESEARCH COMMITTEES………………………………………………………..29

8.1 Steering committee……………………………………………………………………..29

8.2 Endpoint adjucation committee………………………………………………………..29

9 SAFETY ASSESSMENT-RISKS AND RESTRICTIONS ADDED BY THE

RESEARCH ……………………………………………………………………………………30

9.1 Procedures in place for recording and reporting adverse events…………………. 30

9.1.1 Definition for assessing safety …………………………………………………… 30

9.1.2 Investigator’s role…………………………………………………………………… 31

9.1.3 Specific features of the protocol …………………………………………………..32

9.1.4 Procedures and deadline for notifying the sponsor………………………….…...35

9.1.5 Period for notifying the sponsor ……………………………………………………36

9.1.6 The sponsor’s roles………………………………………………………………….36

10 STATISTICAL ASPECTS……………………………………………………………………...38

10.1 Description of statistical methods………………………………………………………. 38

10.2 Calculation hypotheses for the number of subject required and the result………….40

10.3 Anticipated level of statistical significance……………………………………………...40

10.4 Method for taking into account missing, unused of invalid data……………………...40

10.5 Management of modifications made to the analysis plan for the initial strategy……41

10.6 Selection of populations……………………………………………………....................41


11. RIGHT OF ACCESS TO DATA AND SOURCE DOCUMENTS………………………......41

12. QUALITY CONTROL………………………………………………………………………......41

12.1 Monitoring procedure………………………………………………………………41

12.2 Data transcription in electronic Case Report Form (e-CRF)………………......42

13. ETHICAL AND REGULATORY ASPECTS………………………………………………… 43

13.1 Ethical consideration……………………………………………………………… 43

13.2 Submission to Ethical committee (CPP)………………………………………... 43

13.3 Substantial changes to the protocol………………………………………………44

13.4 CNIL authorization………………………………………………………………….44

13.5 Patient protection…………………………………………………………………...44

14. DATA PROCESSING AND DATA CONSERVATION……………………………………...46

15. INSURANCE AND SCIENTIFIC undertaking………………………………………………46

15.1 Insurance………………………………………………………………………………46

15.2 Scientific undertaking………………………………………………………………...47

16. PUBLICATION RULES………………………………………………………………………...47

17. BIBLIOGRAPHY………………………………………………………………………………..48

18. LIST OF ADDENDA…………………………………………………………………………..50

18.1 List of investigators…………………………………………………………………...50

18.2 Bleeding scale………………………………………………………………………...51

18.3 SmPC for the Disulone specificity ………………………………………………….52

18.4 SmPC for the Cortancyl ………………………………………………………..….. .57

18.5 Special form for reporting SAE ……………………………………………………...65

18.6 Form for monitoring a pregnancy that developed during a biomedical

research ………………………….…………………………………………………... 67


1 SUMMARY

Full title Prospective multicenter randomized open-label controlled trial assessing efficacy and safety of DAPSone as a second-line option in adult Immune Thrombocytopenia

Acronym DAPS-ITP

Coordinating Investigator Prof Marc MICHEL M.D Department of Internal Medicine, national referral center for adult’ immune cytopenias, Filière de Santé Maladies Rares MARIH (Maladies Rares en Immuno-Hématologie). Henri Mondor university hospital, Phone number: +33 (0) 1 49 81 20 76 Email: [email protected]

Sponsor Assistance Publique – Hôpitaux de Paris

Scientific justification Due to its expected efficacy based on the retrospective data available in ITP, its relatively good safety profile and its very low cost (~ 3 € per month), dapsone could be a good steroid-sparing second-line option for adults with ITP.

Primary objective and assessment criterion

To demonstrate the efficacy of dapsone based on the overall response rate (including response and complete response) as a second-line treatment for adults with newly-diagnosed, persistent or chronic ITP not achieving a durable response with corticosteroids. The primary endpoint will be the overall response-rate (response or complete response according to standard definitions in both arms at week 52 (1 year).

Secondary objectives and assessment criteria

- To assess the safety of dapsone over the study period and especially the incidence of cutaneous reactions. - To analyze the overall response rate (platelet count > 30 x 109/L with at least a doubling of the pre-treatment count in the absence of any other ITP treatment) in both treatment arms at week 24. - To compare the rate of complete response and failure in both arms at 24 and 52 weeks. - To compare time to treatment failure (TTF) in both arms - To investigate the mechanisms of action of dapsone in ITP in a subgroup of patients (ancillary study)

Experimental design Phase III prospective multicenter randomized open trial comparing two treatment strategies: - Arm A (experimental arm): prednisone at 1 mg/kg for 3 weeks + dapsone at 100 mg per day up to week 52 if an initial response is achieved. - Arm B (control arm): prednisone alone at 1 mg/kg for 3 weeks followed by monitoring and “standard of care”

Population involved Adult patients with newly-diagnosed or persistent ITP


Inclusion criteria - Age ≥ 18 years - Diagnosis of primary ITP according to the standard definition and international guidelines. - Previous transient response to corticosteroids ± intravenous immunoglobulin defined by an increase of the platelet count above 30 x 109/L with at least a twofold increase of the pre-treatment count. - At least one platelet count ≤ 30 x 109/L within the 2 weeks before inclusion with a platelet count at time of inclusion below 50 x 109/L, or < 50 x 109/L at any time point in patients requiring treatment (i.e., patients with bleeding symptoms, elderly patients with comorbidities and/or patients on aspirin for example) - Normal marrow aspirate for patients aged of 60 and above. - Negative pregnancy test and effective method of contraception for women of childbearing age over the study period. - Informed consent. - Patient affiliated to the French National Social Security System

Non-inclusion criteria -Secondary ITP. Patients with positive antinuclear antibodies and/or positive antiphospholipid antibodies not fulfilling the classification criteria for systemic lupus erythematosus and/or antiphosholipid antibody syndrome will not be excluded. - Platelet count ≥ 50 x 109/L or between 30 and 50 x 109/L and no bleeding symptoms and no need for treatment - Severe bleeding manifestations defined a bleeding score ≥ 8 (Khellaf et al. 2005, see appendix). - No previous transient response to corticosteroids ± intravenous immunoglobulin. - Previous ITP treatment other than corticosteroids and intravenous immunoglobulin (including rituximab and splenectomy). - Active severe infection or history of severe infection within 4 weeks before inclusion. - History of allergy to sulfonamides. - G6PD deficiency. - History of methemoglobinemia - Hemoglobin level < 11g/dL and/or neutrophil count <

1,500/L. - History of autoimmune (Evans’ syndrome) or hereditary haemolytic anemia. - Liver or kidney function impairment (creatinine clearance < 30 ml/min, ALT, AST >2 times upper normal limit). - HCV Ab, HIV Ab, HBsAg, b seropositive status. - Concomitant medical condition requiring anticoagulation therapy. - Pregnancy or lactation.

Treatment being tested Dapsone: Disulone® given orally at 100 mg per day


Benchmark treatment Prednisone (Cortancyl®) alone at 1 mg/kg for 3 weeks followed by monitoring and “standard of care” (control arm)

Risks added by the research Level C. The safety profile and the side-effects (haemolytic anemia, skin rashs) of dapsone are well known and there is no evidence from the literature suggesting that the risk of toxicity could be different in the setting of ITP. However, since dapsone is not licensed for ITP the risk level will therefore be C.

Number of subjects chosen Based on previous findings obtained in a randomized controlled study reported by our group for corticosteroids long-term efficacy (Godeau et al. Lancet 2002) basically corresponding to the population of our control group and on retrospective data for dapsone, we postulated an absolute increase of 20% of primary endpoint (overall response at 12 months, 50% in the group dapsone (conservative hypothesis) + prednisone versus 30% in the control group). Based on a two-sided alpha risk of 5%, a power of 80%, 103 patients are needed per group. With a 5% of lost of follow up or primary endpoint not available, 108 patients will be included per group, 216 in total.

Number of centres N = 33(France)

Research period

Duration of inclusions: 30 months Duration of follow-up: 12 months Total duration of the study: 42 months.

Number of inclusions expected per centre and per month

1 to 2 patients per trimester

Statistical analysis To limit the risk of classification bias, we choose an objective endpoint (response) adjudicated by a blinded independent committee Analysis will be conducted according a pre-specified analysis plan. All tests will be two tailed and P-values lower than 0.05 will be considered statistically significant. All patients will be analyzed in their group of randomization, according to the intention-to-treat principle (ITT). The descriptive analysis will compare the two randomized groups in terms of general baseline characteristics of patients (demographics, history, baseline clinical, and biological status) to assess the quality of randomization process. A Kaplan-Meier curve will be build for each randomized group to present the incidence of failure within the 12 months of follow-up and the two curves will be compared using log-rank test. The effect size will be expressed by the absolute difference rate and hazard ratio between the experimental and control groups and their 95% confidence interval.

Funding source PHRC National


Data Safety Monitoring Board anticipated

No

2. SCIENTIFIC JUSTIFICATION for the research

2.1 Background

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disease characterized

by increased platelet destruction and impaired platelet production. ITP affects both children

and adults with an overall female to male ratio of 2:1. The age-adjusted prevalence of ITP is

estimated to be 9.5 per 100 000 persons in the USA while its annual incidence is estimated

to be 2.68 per 100 000 in Northern Europe and increases with age (1). ITP is classified as

”primary” or as ”secondary” when associated to an underlying disorder, and the different

phases of the disease are defined as followed (2): The “newly-diagnosed” ITP phase

corresponds to the initial phase of the disease, within the first 3 months after ITP onset; it is

followed by the “persistent” (from 3 to 12 months) and “chronic” phases (> 12 months). ITP in

adults is generally chronic, the onset is often insidious and spontaneous recovery is

uncommon. The goal of treatment is to raise the platelet count to a hemostatically safe level.

Persistent platelet counts of < 30 x 109/l are associated with an increased incidence of

bruising, mucosal bleeding and seldom intracranial hemorrhage. For patients with a newly-

diagnosed immune thrombocytopenia (ITP), treatment is generally indicated in patients with

a platelet count below 30 x 109/L or 50 x 109/L in cases of bleeding manifestations and/or

associated risks of bleeding (2,3,4). Corticosteroids alone or in combination with intravenous

immunoglobulin (IVIg) are the mainstay of initial therapy (3,4). While 70 to 80% of patients

achieve an initial response, most of them relapse within few days or weeks after

corticosteroids tapering or withdrawal and, on average, only a third of adult patients may

achieve a lasting remission after a single course of corticosteroids (4, 5). Beyond first-line,

there is no consensus regarding the best second-line option in adults with steroid-dependent

ITP and none of the treatments commonly used as a second-line (such as rituximab) have

been licensed in ITP (3,6). Splenectomy is not recommended at this stage and should be

considered only in case of chronic (defined by a disease duration > 12 months) and severe

ITP (3, 6). The two available thrombopoietin receptor (Tpo-R) agonists romiplostim and

eltrombopag, represent a highly effective but coastly alternative and, in Europe, there have

been approved only for adults with chronic ITP who have previously failed splenectomy or in

whom splenectomy is contra-indicated (3).


2.2 Hypothesis for the research

To date, there is no consensus regarding the best second-line treatment for adult ITP (3,4,6).

Dapsone is commonly used off-label for ITP in many countries (France, Italy, India) and has

been mentioned as a one possible second-line option in some recent guidelines (3).

However, evidence-based data are lacking and the efficacy and safety of dapsone have not

been yet demonstrated in a randomized prospective randomized trial. Based on the data

from the literature on both corticosteroids and dapsone (7-13), we postulate that dapsone

could be an effective second-line treatment for adult ITP with an expected 50% rate of overall

response at 1 year.

2.3 Summary of relevant pre-clinical experiments and clinical trials

Dapsone is an old antibacterial sulfonamide with antimicrobial properties against

leprosy, pneumocystic Jiroveci pneumonia in AIDS, toxoplamosis, and malaria (14,15). Since

1950s, dapsone was also recognized to have activity in a number of non-infectious

inflammatory diseases of the skin such as dermatitis herpetiformis (16). The anti-

inflammatory effect of dapsone is not fully understood, but it appears at least targeted

against neutrophils, with interference of myeloperoxidase, inhibition of lysosomal enzymes,

chemotaxis, and integrin-mediated adherence function (17). Since the early 1990s, the

efficacy of dapsone in ITP has been reported in several uncontrolled retrospective studies

including some reported by our group (7-13), with a 40 to 60% response rate (see table 1

here below). Dapsone is therefore used off-label for ITP in many countries (including France,

Italy and India) and has been mentioned as a one possible second-line option in a recent

international consensus report as well as in the French guidelines on ITP (2,18). The

hydroxylamine metabolites of dapsone are potent oxidants and could be responsible for well-

known haematological adverse effects, including methemoglobinemia and hemolytic anemia

that usually do not lead to treatment withdrawal. For this reason, dapsone is contraindicated

in patients with G6PD deficiency. Severe skin hypersensitivity reaction may rarely occur (19)

but in our experience, especially if corticosteroids are initially combined with dapsone, the

risk of severe hypersensitivity reaction seems to be low in ITP (6,20). The aim of this study is

to assess prospectively the efficacy and safety of dapsone as a second-line option in adults

with a newly-diagnosed of persistent ITP who have transiently responded to corticosteroids

and then relapsed.


Table 1: Dapsone use for the treatment of ITP: summary of the data from the literature

Item / study first author (year)

Hernandez et al. (1995)

Godeau et al.(1997)

Radaelli et al. (1999)

Damodar et

al (2005)

Vancine-Califani et al.(2008)

Zaja et al.

(2012)

Number of patients

15

62

8

55

52

20

Median age (years)

58 46 63 29 38 51

Duration of ITP at time of dapsone initiation (months)

41 52 147 27 5 46

Previous splenectomy

4/15 10/62 6/8 7/55 0 5/20

Baseline median platelet count (x109/L)

16 23 17 13 20 19

Overall response rate

40% 50% 62% 62% 44% 55%

Complete response

27% 21% 12% 49% NA 20%

Relapse-rate on dapsone

NA 5% 0 NA NA 0%

Dapsone withdrawal because of side-effect

2/15 7/62 2/8 3/55 2/52 0/20

2.4 Description of the population to be studied and justification for the choice

of participants

The target population is based on adults with a definite diagnosis of primary ITP according to

the standard definition (2) regardless the duration of the disease. In ITP patients requiring

treatment (i.e., with a platelet count < 30 x 109/L) who achieve an initial response after a first-

line therapy with prednisone ± intravenous immunoglobulin and then relapse, there is no

consensus for second-line treatment (2,3,5). Giving a second course of corticosteroids

(prednisone or dexamethasone) is an option, but then patients who have a corticosteroid-

dependent persistent ITP may be exposed to the many side-effects induced repeated

courses or continuous use of corticosteroids. Avoiding the use of corticosteroids is therefore

one important aim in ITP (2, 5) and testing alternative strategies for maintaining a durable

response and postponing the time or avoiding the need of splenectomy is necessary.


2.5 Identification and description of the experimental medications

The experimental drug is Disulone ® (Sanofi-Aventis France), a tablet containing 100 mg of

dapsone (4-4' diaminodiphnylsulfone) and 200 mg or iron oxalate. It is given orally once a

day. The intestinal absorption of the drug is very good, the peak concentration is reached

within 1 to 3 hours after intake and the average half-life is 28 hours (extreme values: 10 and

50 hours). Disulone® has a good bio-availability and cross the placenta. Dapsone is

acetylated and in the liver and then undergoes an entero-hepatic cycle. The clearance of the

drug, both on its native form or its metabolites, is mostly renal (70-80%). Patients from both

arms will also received during the first 3 weeks prednisone (Cortancyl ® 20 mg tablets), a

synthetic corticosteroid drug with minimal mineralocorticoid activity and with a good plasma

availability. Prednisone is a dehydrogenated analogue of cortisol thas has no substantial

biological effects until converted via hepatic metabolism to prednisolone. It is administered

orally as tablets, once daily before breakfast. It will be used at the initial daily dose of 1 mg

per kg (20 mg tablets) for 2 consecutive weeks and then tapered every 48 hours and stopped

on day 21.

2.6 Description and justification of the dosage, administration method,

administration design and treatment period.

For dapsone, 100 mg per day is the “standard” dose used for adults in ITP (7-13)

According the French guidelines on ITP management, prednisone is recommended at the

initial daily dose of 1 mg/kg for at least 2 weeks, followed by rapid tapering over 1 week for a

total of 3 weeks (Protocole National de Diagnostic et de Soins HAS, 19)

2.7 Summary of the known and foreseeable benefits and risks for the research

participants

To date, there is no consensus regarding the best treatment to be used as a second-line in

adults with persistent or chronic ITP requiring treatment. The long-term use of corticosteroids

does not modify the natural history of the disease and may lead to a number of limiting and

well known adverse events. The major expected individual benefit is that dapsone could be

an useful second-line treatment for avoiding or at least postponing splenectomy, a surgical

procedure which is now indicated mostly for chronic severe ITP (5). The potential risks of

dapsone are hematological and dermatological. The occurrence of a mild haemolytic anemia

with methemoglobinemia is relatively frequent, but it is usually not a limiting factor (8). The

risk of neutropenia is lower and cases of agranulocytosis have been only exceptionally

reported (21). A skin rash may occur in patients treated with dapsone and dapsone-induced

hypersensitivity syndrome (DHS) develops in about 0.5 to 3.6% of persons treated with the

http://en.wikipedia.org/wiki/Corticosteroidhttp://en.wikipedia.org/wiki/Prednisolone


drug (19). DHS was originally described in leprosy and combines a generalized skin rash

with one or more of the following symptoms: 1) fever, 2) lymphadenopathy or 3) hepatitis.

DHS occurs within 2 months (and mostly in the first 3 to 6 weeks) after treatment initiation

and, based on a retrospective study from our center, the outcome of DHS in the setting of

ITP was good, with no life-threatening complications (20). This observation could be due to

the concomitant initial short course of corticosteroids (


2) To compare the overall response rate in both treatment arms at week 24.

3) To compare the rate of complete response and failure in both arms at 24 and 52

weeks.

4) To compare time to failure (TTF) in both arms.

5) To identify some biological parameters potentially associated with a better response

to dapsone in the experimental arm and to investigate the biological pathways

involved into the mechanisms of action of the experimental drug (ancillary study)

3.3 Objective of ancillary research

The objective of the ancillary research is to identify whether there are some biological

pathways associated with a better response to dapsone in ITP the experimental arm.

To study the mechanisms of action of dapsone in ITP in a subset of patients an ancillary

reseach study will be performed in a subset of patients (n ≥30) exposed to the study drug

who will give their consent. We have recently observed, in an in vitro model, that ITP

platelets were phagocyted by peripheral CD14+ cells but also by neutrophils (unpublished

work, IMRB, Inserm U955, Team 2). Using this system, we first aim to investigate whether

dapsone may influence or not the degree of phagocytosis of autologous platelets and red

blood cells (RBCs). Blood samples will be drawn in at least 30 patients (presumably half

of them will respond to dapsone) from the experimental arm prior to and after (at 3

months) exposure to dapsone or between week 6 and week 12 and before starting a new

treatment in non-responders. Monocytes and neutrophils phenotype and activation profile

will be assessed by flow cytometry. Morevover, to determine if dapsone can modulates

the cytokines profile expression (including IL-8), a 40-plex analysis will be performed on

patients’ sera before and after treatment. Lastly, a gene expression analysis

(transcriptome) will be performed later with devoted funding at the Necker Imagine

Institute. Recent, gene expression analysis of whole blood has revealed in children, a

distinct oxidative stress-related pathways signature (23). We plan to collect RNA samples

from the same ITP patients at inclusion (off treatment) and on dapsone (at 3 months) and

to compare the whole blood gene expression signature between responders and non-

responders. This is an exploratory research with no hypothesis regarding the expected

difference between responders and non responders regarding the cytokines and /or gene

expression profiles. Therefore no sample size calculation was made. The sample size was

based on feasibility criteria and on the expected rate of response in the experimental arm.

4. Plan for the research


4.1 Concise description of the primary and secondary assessment criteria

Primary assessment criterion

The primary endpoint will be the overall response-rate (response + complete response) in

both arms at 52 weeks. According to international definition criteria (2), the criteria of

response will be defined as followed:

- Response (R) will be defined as sustained platelet count >30x109/L with at least

doubling of the platelet count from baseline and in the absence of bleeding or use of

any other ITP directed therapies between week 6 and week 52.

- Complete response (CR) by a platelet count > 100 x 109/L, in the absence use of any

other ITP directed therapies between week 6 and week 52.

- Patients will be considered as being non-responders (NR) if:

1) Their platelet count at the end of the study is < 30 x 109/L but also, in the setting

of this study if:

2) They need a rescue therapy (a new course of corticosteroids and/or intravenous

immunoglobulin) more than 6 weeks after inclusion except for a transient

corticosteroids use in preparation for a planned surgery or invasive procedure (for

patients who with a response who require a higher platelet count).

or

3) They receive any other treatment for ITP than dapsone or prednisone (including

rituximab, splenectomy and Tpo-R agonists) over the study period

Secondary assessment criteria

1) Serious adverse events and especially the incidence of skin rash in both arms over the

study period. For every suspected cutaneous reaction potentially induced by dapsone,

the patient will be seen by the referral dermatologist at each participating center and a

skin biopsy will be performed. All toxicity (except platelet count) will be graded according

to CTCAE v 4.0 guidelines.

2) The overall response rate (R + CR) at 24 weeks in both arms.

4) The rate of CR at 24 and 52 weeks in both arms

5) The rate of primary failure (i.e., the proportion of non-responders) at 24 and 52 weeks

in both arms.

6) The time to treatment failure over the study period (52 weeks) among patients

achieving an initial response (primary responders) and the time elapsed with a platelet

count ≥ 30 x 109/L without any other intervention.


4.2 Description of research methodology

Experimental plan

A phase III prospective multicenter randomized open label controlled trial in two parallel arms

with blinded adjudication of main endpoint to assess the efficacy and safety of dapsone as a

second-line treatment for newly-diagnosed or persistent ITP in adults.

We choose an open-label design because the experimental treatment (i.e., Disulone® which

is the only manufactured form of dapsone available in France) contains 200 mg of iron

oxalate per tablet and usually leads to a dark coloration of the stools. Moreover, dapsone

may lead to some degree of haemolysis also precluding the feasibility and relevance of a

double-blind placebo-controlled design. To limit the risk of classification bias, we choose an

objective endpoint (overall response) that will be adjudicated by a blinded and independent

expert, to test the superiority of dapsone and prednisone over prednisone alone for overall

response rate at 52 weeks in adults with newly-diagnosed or persistent ITP

Eligible patients will be randomized in one of the 2 treatment arms (Arm A: dapsone +

prednisone versus prednisone alone in arm B) in 1/1 ratio comparing 2 therapeutical

strategies. Eligible patients randomized in the experimental group (arm A) will receive

dapsone at a fixed dose of 100 mg per day in combination with prednisone at a daily dose of

1 mg per kg for 2 weeks and then tapered and stopped over a week for a total of 3

consecutive weeks. After prednisone withdrawal, patients from this arm will pursue dapsone

at the same dose for a total of 12 months unless they fail to respond to the treatment.

Patients randomized in the control arm (arm B) will be treated only prednisone at a daily

dose of 1 mg per kg for 2 weeks and then tapered and stopped over a week for a total of 3

consecutive weeks. After this 3 weeks period, patients from arm B will be left without

treatment and monitored.


Number of centres participating

A total of 33 centers from public and mainly university hospitals in France, including the

coordinating center, will participate (see appendix 1). They all belong to the national network

on adult’ immune cytopenias set up by the national referral center coordinating the study.

Inclusion and random allocation:

After obtaining their written consent, eligible patients will be individually included online

(secured internet protocol) using the Cleanweb software as part of public contract between

APHP and TELEMEDICINE TECHNOLOGIES S.A notified on November 17th 2003 and

referenced under number 033845. Inclusion/Randomization data will be centralized on a

server hosted at the APHP Department des Services Operational (DSO), 67 boulevard

Bessières, 75017 PARIS.

The patient inclusion number allocated by Cleanweb will be as follow:

000-0000-XX

(centre number / number of inclusion / first initial of the name and first name)

Random allocation list will be drawn up by the clinical research unit statistician (URC-CHU

Henri Mondor), Dr Florence Canouï-Poitrine, before the beginning of the study.


Randomization will be centralized, individual, stratified according to center (n=33) by blocks

of variable size.

To ensure concealment of randomization to the investigators, randomization will be

performed online using the cleanweb software. Depending on the random result, the patient

will be assigned either to the dapsone + prednisone arm (=experimental arm) or

prednisone alone arm (control arm).

5. PROCEDURE FOR THE RESEARCH

A written consent should be obtained from each patient in accordance with the

recommendation of the revised Declaration of Helsinki.

Written informed consent will be obtained from the patient before any study specific

procedure is undertaken.

Patients will be informed about the study, both verbally and by reviewing the patient

information sheet and consent form. The patient must be given the opportunity to ask

questions and given time to consider his or her participation.

The investigator and the patient will both sign and personally date the consent form as

confirmation of consent.

5.1 Inclusion visit

The criteria of eligibility will be checked before during this visit and the following workup will

be needed prior to randomization:

1) Clinical examination: vital signs, weight, bleeding score assessment.

2) Biological workup:

a. Complete blood count.

b. Blood smear.

c. Bone marrow aspiration in patients aged of 60 or more if not already

performed at time of ITP onset.

d. Renal and liver function tests.

e. Markers of hemolysis: Lactate dehydrogenase (LDH), indirect bilirubin and

serum haptoglobin levels

f. Serologic tests for hepatitis B (HBsAg), hepatitis C (anti-HCV) and HIV unless

previously performed and negative (less than 6 months prior to inclusion).

g. Direct Antiglobulin Test (DAT).


h. G6PD activity

i. Anti Nuclear Antibodies (ANA), lupus anticoagulant and anti-cardiolipin

antibodies (if not already available).

j. Pregnancy test in women of child-bearing age

All laboratory tests will be performed in local laboratories in every participating center.

Subjects whose consent is sought

Who informs the subject and

collects their consent

When is the subject informed

When is the subject's consent

collected

The patient

The investigator

At inclusion

At inclusion

5.2 Follow-up Visits

After inclusion, the patient will be randomized in one of the 2 treatment arms and will receive

the study treatment.

The blood level of methemoglobinemia will be checked one a week during the first month for

patient randomized in the experimental group (Arm A).

Renal and liver functions will be also checked after 1 month of treatment and then every 3

months until the end of the study in the experimental group. For liver functions, alkaline

phosphatase (ALP), gamma glutamyl transferase (GGT), alanine transaminase (ALT) and

bilirubin levels were recorded. For renal function, blood urea, serum creatinine and estimate

glomerular filtration rate were analysed.

Eight follow-up visits are planned during the study period at the following time-points: at

weeks 3, 6 and 12, at week 20 and then every 8 weeks at weeks 28, 36, 44 and 52 (see

table here below at paragraph 5.5). At each visit, the patient will be seen by the investigator

and a clinical exam will be performed including the assessment of the bleeding score. At

each visit, the status of the patient in term of response to treatment (R, CR or NR) will be

assessed and every adverse event will be registered. The complete blood cell count

including the platelet count will be monitored weekly until week 6 and then every 4 weeks

until the end of the study at week 52.


5.3 End of research visit

The end of research visit will take place on week 52 (± 4 days). During this visit, the

investigator will conclude about the primary endpoint and the final response pattern (see

paragraph 4.1.1) based on the last platelet count and also on the use of concomittant ITP

medications that the patient may have received during the follow-up period. Patients

randomized in the experimental arm (arm A) responding to daspone could be either left on

the same treatment, or be switched if necessary to another ITP medication or yet left with no

treatement in case of stable complete response (decision left at the investigator discretion).

The platelet count often fluctuates over time from one blood count to another. As an

example, the pIt ct could be


5.5 Table summarising the chronology of the research

Inclusion End of the

Study

Study visits 1 2 3 4 5 6 7 8

Week 2 days 0 1 2 3 4 5 6 10 12 16 20 24 28 32 36 40 44 48 52

Criteria of Eligibil ityX

Informed Consent X

Clinical exam* X X X X X X X X X

Bleeding score** X X X X X X X X X

CBC + retic. X X X X X X X X X X X X X X X X X X X

Inclusion blood

work-up#X

MethemoglobinemiaX X X X

Renal and liver

functionsX X X X

Blood specimens for

ancillary study## X X

Study drug

administrationX X X X X*** X*** X*** X*** X*** X*** X*** X*** X*** X*** X*** X*** X*** X***

Concomitant ITP

medicationsX X X X X X X X

AE/ SAE X X X X X X X X

Follow-up visits

Notes:

* vital signs, general exam (skin and mucosa). ** Khellaf M et al. Haematologica 2005 (see appendix 2) *** dapsone 100 mg/day only in patients from arm A achieving an initial response ∞ only for patients on dapsone (arm A) # See 5.1

# # only in a subgroup of patients (n 30) who will give their specific consent for participating in this ancillary sub-study. CBC = complete blood count; retic. = reticulocytes count; AE = adverse events; SAE = serious adverse events; ITP = immune thrombocytopenia. During the first 6 weeks of follow-up the timing of the visits are in weeks ± 2 days and beyond week 6 up to week 52, the timing is in weeks± 4 days.

5.6 Distinction between care and research

TABLE: Distinction between procedures associated with "care" and procedures added because of the "research"

Procedures and treatments carried out as part of the research

Procedures and treatments associated with care

Procedures and treatments added because of the research

Treatments Prednisone for 3 weeks in relapsing ITP

Dapsone 100 mg per day

Consultations Visits at weeks 3 and 12, and then every 8 weeks from week 12 to week 52

Visit at week 6

Blood samples CBC weekly the first month And than monthly from week 6 to week

52

G6PD activity and markers of hemolysis at inclusion (10 ml)

Methemoglobinemia level weekly until week 4 (7 ml)


Blood samples for renal and liver functions (10 ml)

Blood samples for exploring biomarkers (ancillary study) in a subgroup of patients from the

experimental arm (n≥30) at inclusion and at week 12

(35ml x 2)

5.7 Biological Collection

Some blood samples (serum, PBMC and RNA total = 40 ml) will be collected in at least 30

patients (at inclusion and at week 12) to explore the mechanisms of action of dapsone in ITP

as part of the research and will be included in a dedicated biological collection. To avoid any

extra-expenses, only patients randomized in arm A recruited in one of the 6 participating

centres from the Assistance Publique Hôpitaux de Paris will be included if they provide a

specific informed consent. The ancillary research will be proposed to each new patient

randomized in the dapsone arm to reach at least 30 patients.

The collection will be stored and frozen at the laboratory of the Etablissement Français du

Sang (EFS) at Henri Mondor Créteil U955, Equipe 2 (head Prof. F Noizat-Pirenne) under the

supervision of Dr Matthieu MAHEVAS (MD, PhD) for a 3 years duration. Dr Mahevas will be

in charge of the cytokines panel testing and functional tests (phagocytosis). The gene

expression analysis (transcriptome) will be performed later at Unité INSERM U955 Equipe 2

(Pr F. Noizat-Pirenne), Institut Mondor de Recherche Biomédicale (Plateforme IMRB).

The collection will be declared to the ANSM in the context of biomedical research.

At the end of the research and 3 years of storage, the samples will be destroyed

Type of sample

Quantity Storage location

Collection supervisor Purpose of the collection

Storage period

Outcome

Serum

5 ml

EFS

U955, Equipe 2

Dr Mahevas

Ancillary research

exploratory study

3 years

Destruction of residual samples

PBMC 30 ml EFS Dr Mahévas Exploratory study on the

mechanisms of action of dapsone,

Transcriptome analysis

3 years

Same outcome


5.8 Termination rules

Criteria and methods for prematurely terminating the research treatment

5.8.1 Different situations

For the patients included and randomized in arm A (dapsone arm):

- The blood level of methemoglobinemia will be systematically checked one a week

during the first month. In case of a methemoglobinemia level above 10% with clinical

related symptoms (cyanosis, shortness of breath), the treatment will be stopped. In

case of hemolytic anemia, if the hemoglobin level decreases below 10 g/dl with at

least a 2 g decrease from baseline in the absence of any concomitant cause of

anemia the treatment will be stopped. A re-introduction of dapsone could be

considered only for patients with a platelet response if the hemoglobin level goes up

to at least 10g/dL without the need of any transfusion.

- The treatment will also be definitely stopped if the neutrophils count decreased below

1,000 per cubic mm in the absence of any other cause.

- Some cutaneous reactions may occur on dapsone. They usually occur within the first

2 months of therapy. The patient will be seen by the referral dermatologist from

his/her participating center who will fill a specific study form set up for cutaneous

reactions and will decide whether or not to stop dapsone. Every skin rash will be

reported (brief clinical description with pictures of the rash and/or skin biopsy when

available) to a committee of 3 certified dermatologists from the primary investigator

site (Prof. O Chosidow, Dr S Oro and Dr Tu-Anh DUONG at Henri Mondor University

Hospital) who will conclude about the severity of the rash and the relationship with the

study drug (i.e., dapsone) and the need to stop the medication. In case of a definite

dapsone-induced hypersensitivity syndrome, the treatment will be systematically

stopped.

- Temporary termination of treatment, the investigator must document the reason for

stopping and restarting the treatment in the subject's source file and the case report form

(CRF)

- Premature termination of treatment, but the subject is still included in the research, until

the end of the subject's participation, the investigator must document the reason

- Premature termination of treatment and end of participation in the research.

The investigator must:

o Document the reason(s)


o Collect the assessment criteria when participation in the research ends, if the

subject agrees

5.8.2 Criteria and methods for the premature termination of the research - Any subject can withdraw from participating in the research at any time and for any

reason.

- The investigator can temporarily or permanently end a subject's participation in the

research for any reason that affects the subject's safety or which would be in the subject's

best interests.

- If a patient is lost of follow-up, the investigator must make everything possible to contact

the patient and to get some updated information about the outcome

If a subject leaves the research prematurely, data relating to the subject can be used unless

an objection was recorded when the subject signed the consent form.

If consent is withdrawn, no data about the subject may be used unless the subject states in

writing that he/she does not object. In practice, the subject is excluded from the research.

The case report form must list the various reasons for ending participation in the research:

Ineffective

Adverse reaction

Other medical problem

Subject's personal reasons

Explicit withdrawal of consent

Follow-up of the subjects after the premature termination of treatment

Ending a subject's participation does not affect the normal management of the subject's

illness in any way.

If there are serious adverse events, the investigator must notify the sponsor and monitor the

subject for 1 month following the premature termination of treatment. If treatment is stopped

prematurely due to a serious adverse event, a serious adverse event notification form will be

sent by fax (01 44 84 17 99) to the sponsor. The serious adverse event will be monitored

until it is resolved.

Terminating part or all of the research


AP-HP as sponsor or the Competent Authority (ANSM) can prematurely terminate all or part

of the research, temporarily or permanently in the following situations:

- First of all, if suspected unexpected serious adverse reactions (SUSARs) are seen in an

arm being treated or if there is a discrepancy in the serious adverse reactions between the

2 arms being treated, and which require a reassessment of the benefit-risk ratio for the

research.

- Likewise, unexpected facts, new information about the product, in light of which the

objectives of the research or of the clinical programme are unlikely to be achieved, can

lead AP-HP as sponsor or the Competent Authority (ANSM) to prematurely halt the

research.

- AP-HP as sponsor reserves the right to permanently suspend inclusions at any time if it

appears that the inclusion objectives are not met.

If the research is terminated prematurely, the decision and justification will be given by the

sponsor, AP-HP, to the Competent Authority (ANSM) and to the CPP within 15 days.

6. ELIGIBILITY CRITERIA

6.1 Inclusion criteria

1. Age ≥ 18 years

2. Diagnosis of primary ITP according to the standard definition (2).

3. Previous transient response to corticosteroids ± intravenous immunoglobulin defined

by an increase of the platelet count above 30,000 with at least a twofold increase of the

pre-treatment count.

4

5. At least platelet count ≤ 30 x 109/L within the 2 weeks before inclusion with a platelet

count at time of inclusion below 50 x 109/L, or platelet count < 50 x 109/L at any time

point in patients requiring treatment (i.e., patients with bleeding symptoms, elderly

patients with comorbidities and/or patients on aspirin for example, or other reason at the

investigator discretion)

6. Normal marrow aspirate for patients aged of 60 and above.

7. Negative pregnancy test and effective method of contraception for women of

childbearing age over the study period.

8. Informed consent.

9. Patient affiliated to the French National Social Security System


6.2 Non-inclusion criteria

1. Secondary ITP. Patients with positive antinuclear antibodies and/or positive

antiphospholipid antibodies not fulfilling the classification criteria for systemic lupus

erythematosus and/or antiphosholipid antibody syndrome will not be excluded.

2. 3. Platelet count ≥ 50 x 109/L or between 30 and 50 x 109/L and no bleeding symptoms

and no need for treatment

4. Severe bleeding manifestations defined a bleeding score ≥ 8 (Khellaf et al. 2005, see

appendix 2).

5. No previous response to corticosteroids ± intravenous immunoglobulin

6. Previous ITP treatment other than corticosteroids and intravenous immunoglobulin

(including rituximab and splenectomy).

7. Active severe infection of history of severe infection within 4 weeks before inclusion.

8. History of allergy to sulfonamides.

9. G6PD deficiency.

10. Hemoglobin level < 11g/dL and/or neutrophil count < 1,500/L.

11. History of autoimmune (Evans’ syndrome) or hereditary haemolytic anemia.

12. History of methemoglobinemia

13. Liver or kidney function impairment (creatinine clearance < 30 ml/min, ALT, AST >2

times upper normal limit).

14. HCV Ab, HIV Ab, HBsAg, seropositive status.

15. Concomitant medical condition requiring anticoagulation therapy.

16. Pregnancy or lactation.

17. Patients currently involved in another clinical trial with evaluation of drug treatment.

18. Unwillingness to participate.

6.3 Recruitment methods

In total 216 will be enrolled in the study (108 in each treatment arm) over a 30 months period.

Inpatients or outpatients fulfilling the criteria of eligibility who will give their informed consent

will be included consecutively in 33 participating centres. Adults patients diagnosed with ITP

are almost exclusively seen and followed in public hospitals in France. Most of the

investigators, who belong to the network of the national referral center for adult’ immune

cytopenias, have already successfully participated in the past to some clinical trials and

prospective surveys (see references 4, 24 and 25) and every participating center has a great

potential of inclusion as a regional referral center. All parts of France (metropolitan territory)

will be represented.


Number

Total number of subjects chosen 216

Number of centres 33

Inclusion period (months) 30

Number of subjects/centre 6-7

Number of subjects/centre/month 1 every 3 months

7. TREATMENT ADMINISTERED TO RESEARCH PARTICIPANTS

7.1 Description of the investigational medication

The experimental medication will be provided by the sponsor. Labelling will be made by the

Clinical Trial Department of AGEPS AP-HP.

- Dapsone (Disulone® 100 mg): commercial boxes of 100 tablets labelled for clinical trial, Sanofi Company. Storage conditions: The dapsone boxes will be stored at a temperature below 25 °C.

- Dapsone (Disulone®): tablets are yellow and contain 100 mg of dapsone and 200 mg of iron

oxalate. The tablets contain the following inactive ingredients: magnesium stearate and

wheat starch.

-The dosing of dapsone is 100 mg per day. Dapsone tablet is to be administered orally once

daily (in the morning) with or without food intake for a total of 52 weeks in the experimental

arm unless the patient fails to respond to the treatment or a serious adverse event occurs.

No dose-reduction will be possible.

In case of a missed tablet of dapsone, patients should be instructed to take the missed dose

as soon as possible on the same day. Patients should be warned that doubling the next dose

with a missed dose of the study drug under is not allowed whatever the circumstances.

A dispensation will be provided for 3 months. Each patient of arm A will have 4

dispensations: at J0, M3, M5 and M9.

Specific safety issues with the use of dapsone:


The enzymatic activity of the Glucose-6-phosphate dehydrogenase (G6PD) will be

systematically tested in every patient before inclusion and in case of decreased activity; the

patient will not be included. For the patients included and randomized in arm A (dapsone

arm), the blood level of methemoglobinemia will be systematically checked one a week

during the first month of treatment. Renal and liver function will be also checked in the

experimental group (arm A) after the first month of treatment and every 3 month until the end

of the study.

Some cutaneous reactions may occur on dapsone. They usually occur within the first 2

months of therapy. Every patient from arm A will be informed of such a risk and will be seen

by a certified dermatologist at each participating center in case of a skin rash. Every patient

randomized in the dapsone arm will be given a personal protocol card with the name and the

contact information of the referent dermatologist to call in case of a skin rash.

7.2 Description of the non-investigational treatment (medication required for

carrying out the research)

- Prednisone (Cortancyl®) 20 mg, scored tablets and white. The tablets contain the following

inactive ingredients: lactose, corn starch, talc and magnesium stearate.

- Prednisone will be given at 1 mg per kg for 2 weeks and then tapered every 48 hours and

stopped over a week for a total of 3 consecutive weeks. The dose will be rounded to the

tenth of milligram Prednisone tablets are to be taken orally once daily in the morning with

breakfast. The exact schedule for the tapering of prednisone during the 3rd week will be

clearly specified on a written prescription for each patient.

For missed dose, patients should be instructed to take the missed dose as soon as possible

on the same day. Patients should be warned to never double the next dose with a missed

dose of study drug under any circumstances.

- For prednisone, the packaging approved for marketing is used (manufacturer Sanofi-

Aventis) with 100 tablets per packaging. Prednisone will be prescribed on a classic written

prescription for the three weeks of treatment for a delivery in a community pharmacy.

Prednisone will be prescribed in accordance with the summary of product characteristic

(SmPC) provides in appendix 4.


7.3 Supply of study medication

An initial stock of 4 boxes of dapsone (for the treatment of 4 patients for 3 months) will be

sent to each participating centre once the opening visit will be performed.

Resupply will be made according to inclusions (after 2 inclusions) on the hospital

pharmacist’s demand.

7.4 Description of the traceability elements that accompany the experimental

medication or medications

The pharmacist is responsible for ensuring adequate storage and management of all used

and unused investigational medication. This includes acknowledgement of receipt of each

shipment of experimental medication (quantity and conditions).

Dapsone accountability records will be provided to each study site in order to:

- Record the date of receipt, quantity, batch numbers, and expiry date of experimental

medication

- Record the date, subject number, subject initials, quantity, batch numbers and expiry date

of dispensed investigational drug.

- Record the date, quantity of used and unused medication.

For prednisone, the non-experimental treatment, no accountability and traceability will be made.

7.5 Authorised and prohibited treatments (medicinal, non medicinal, surgical),

including rescue medications

The concomitant use of oral potassium in combination with prednisone during the first 3

weeks of treatment will be allowed as well as the use of folic acid (5 mg per day given orally)

in patients treated with dapsone (experimental arm) in case of mild haemolytic anemia. If

required by the patient’s condition or platelet count, prednisone could be started at 1 mg/kg

per day before randomization during the time needed to check the eligibility criteria

(especially the G6PD activity) but the duration of treatment with prednisone could not exceed

7 days before randomization.

The use of the following medications will be prohibited: didanosine and zidovudine.

The following medications could be used with caution: prilocaïne, vitamin K antagonists

For the purpose of the study, if any other treatment known to be active in ITP including

rescue medication is used (except for corticosteroids and/or intravenous immunoglobulin in

the first 6 weeks or a transient use of corticosteroids or IVIg in preparation for a scheduled


surgery or an invasive procedure after week 6), the patient will be then considered as a non-

responder in intention to treat. The recommendations for using a rescue medication will be

based on usual guidelines (3, 4, 18) and left at the investigator discretion.

7.6 Methods for monitoring compliance with the treatment

Each patient will receive at J0 a compliance booklet.

- Patients of arm A will bring back this first compliance booklet at each visit (S3, S6 and

M3). They will track all administrations of dapsone and prednisone for 3 weeks, and

omissions of dapsone for the following 11 weeks (until month 3).

- Patients of arm B will receive a compliance booklet of the 3 weeks of prednisone

treatment.

Patient of arm A will receive a new compliance bimonthly booklet at M3, M5, M7, M9, and

M11.

Experimental medications will be counted by the pharmacist from the participating center at

M3, M9 and M12 in order to monitor the subject’s adherence with the study drug regimen.

During the monitoring visit, the research assistant will check the accountability of

experimental medication and the compliance of treatment and then he will authorize the

destruction on site.

8. SPECIFIC RESEARCH COMMITTEES

8.1 Steering committee

It will be formed by the principal investigator coordinating the study (MM), the biostatistician

in charge of the project (FCP), representatives of the URC from Henri Mondor university

hospital (SB). The committee will define the general organization, timing and the progress of

the research and will coordinate all the information. Members of the committee will determine

the whole methodology and will be responsible for the course of the research. They will

monitor by regular meetings the progress of the research and the rate of inclusions and the

safety issues and the unwanted events.

8.2 Endpoint Adjudication Committee:

The Endpoint Adjudication “Committee” will be made up by a certified hematologist (Dr

Jehan DUPUIS M.D from the department of Clinical Hematology at Henri Mondor university

Hospital, Créteil) and a certified internist (Dr Antoine FROISSART M.D, department of


Internal Medicine, Centre Hospitalier intercommunal de Créteil), both familiar with the

management of adut’s ITP, independent from the trial and unaware of the arm allocated.

They will blindly assess the pattern of response (i.e, response or complete response) to each

patient at week 52. A meeting will be scheduled after a group of 50 patients have reached 52

weeks of follow-up.

9. SAFETY ASSESMENT-RISKS AND RESTRICTIONS ADDED BY THE RESEARCH

According to Article R1123-39 of the French Public Health Code and the guideline on good

pharmacovigilance practices (EMA, 2012):

9.1 Procedures in place for recording and reporting adverse events

9.1.1 Definitions for assessing safety

• Adverse Event (AE)1

Any untoward medical occurrence in a patient or clinical trial subject administered a

medicinal product and which does not necessarily have a causal relationship with this

treatment.

• Adverse Drug Reaction (ADR)1

Any reaction to a medical product which is noxious and unintended.

• Serious Adverse Event (SAE)2

Any untoward medical occurrence that at any dose results in death, is life-threatening,

requires inpatient hospitalisation or prolongs an ongoing hospitalisation, results in persistent

or significant disability/incapacity, or is a congenital anomaly/birth defect.

• Unexpected Adverse Reaction1

An adverse reaction, which by nature, severity or outcome is not consistent with the

applicable product information: the summary of product characteristics (SmPC) for an

authorised product or the investigator's brochure for an unauthorised investigational product.

According to the notice to sponsors of clinical trials for medications (ANSM):

1 Guideline on good pharmacovigilance practices (GVP), Annex I, 2012, EMA 2 Communication from the Commission — Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’), 2011


Any new information regarding safety:

- that could significantly alter the assessment of the benefit-risk ratio for the experimental

medication, or for the trial

- or which could lead to the possibility of altering the administration of the experimental

medication or altering the conduct of the trial

Examples:

a) any clinically significant increase in the frequency of an expected serious adverse reaction

occurring

b) suspected unexpected serious adverse reactions (SUSAR) occurring in patients who have

finished the trial and about whom the sponsor is notified by the investigator, who also

provides any follow-up reports

c) any new fact relating to the conduct of the clinical trial or the development of the

experimental medication, if the new fact is likely to affect participant safety

Examples:

- a serious adverse event likely to be related to the investigations and to the trial's

diagnostic procedures and which could modify the conduct of this trial

- a significant risk for the trial participants such as ineffectiveness of the experimental

medication used in the trial in treating a life-threatening illness

- significant safety results from a recently completed research carried out on animals

(such as a carcinogenicity research)

- the premature termination, or temporary interruption, of a trial conducted with the

same experimental medication in another country, for safety reasons

- an unexpected serious adverse reaction associated with a non-experimental

medication required for carrying out the trial, (e.g., challenge agents, rescue

treatment)

d) recommendations from the data safety monitoring board (DSMB), if applicable, if they are

relevant to the safety of the participants

e) any unexpected serious adverse reaction reported to the sponsor by another sponsor of a

trial carried out in a different country but relating to the same medication

9.1.2 The investigator’s roles

9.1.2.1 Regulatory obligations of the investigator (Art R1123-54 of the French Public Health

Code)

The investigator must notify the sponsor, immediately on the day when the investigator

becomes aware, of all the serious adverse events, except those that are listed in the


protocol (see. section 9.1.3.1) or in the investigator's brochure as not requiring immediate

notification.

These serious adverse events are recorded in the "adverse event" section of the case report

form and the investigator must immediately notify the sponsor's Vigilance division (see

10.3.4).

9.1.2.2 The investigator’s other roles

The investigator must document the serious adverse event as thoroughly as possible and

provide the medical diagnosis, if possible.

For serious adverse events related to the procedure of the research and which are expected

(non experimental treatment required for carrying out the research), only related SAEs of

grade 3 or 4 according to Common Terminology Criteria for Adverse Events (CTCAE),

version 4, will need to be notified to the sponsor

The investigator assesses the severity of the adverse events by using more general terms:

- Mild: tolerated by the patient, does not interfere with daily activities

- Moderate: sufficiently uncomfortable to affect daily activities

- Serious: preventing daily activities

The investigator assesses the causal relationship between the serious adverse events and

the experimental medication(s).

9.1.3 Specific features of the protocol

All serious and non-serious adverse events must be reported in the CRF.

9.1.3.1 Serious adverse events that do not require the investigator to immediately notify

the sponsor

These serious adverse events are only recorded in the "adverse event" section of the case

report form.

• Hospitalizations for normal and natural evolution of the pathology:

In the absence of treatment efficacy, a marked thrombocytopenia may occur as a marker of

disease activity as well as some related bleeding manifestations such as: petechiae, bruises,

gum bleeding, nose bleeding, oral bullae, menhorragia in women of childbearing age, gross

hematuria, gastro-intestinal tract hemorrhage or intracranial hemorrhage. In case of marked


bleeding manifestations, every patient will be given an appropriate rescue medication (high

dose of corticosteroids ± IVIg) at each investigator discretion. In case of overt bleeding (GI

tract, urinary tract or vaginal bleeding), an acute anemia with or without features of iron

deficiency may also occur in the setting of ITP.

Regardless the haemoglobin level, an unusual fatigue can also be observed in some ITP

patients who have low platelet counts

If a non-life threatening profound bleeding (i.e., platetelet count below 15 x 109/L and

symptomatic thrombocytopenia) occurs during the study period requiring a rescue therapy

(IVIg for example) in hospital, this will not require an immediate report by the investigator

being part of the management of the disease (standard of care) and not a SAE. Moreover, if

a splenectomy is considered to treat ITP for a patient included into the study by one

investigator, this procedure will not be considered as a SAE and will not need to be

immediately reported to the promoter of the study.

• Adverse events likely to be associated with the non-experimental treatment

(i.e., prednisone)

- Hypertension

- Corticosteroid-induced diabetes

- Hypokaliemia

- Mood changes, mania, irritability, anxiety, depression

Other common side-effects specific of corticosteroids such as osteoporosis, Cushing

syndrome, glaucoma or cataract are not supposed to occur here since prednisone will be

only used on a short-term (3 weeks).

• Adverse events likely to be associated with the treatments prescribed as part of

the patient's care during the monitoring of the research

9.1.3.2 Serious adverse events that require the investigator to immediately notify

the sponsor

The investigator must report all adverse events that meet one of the seriousness criteria

below, except for events listed in section 9.1.3.1 as not requiring notification:

1- Death

2- Life threatening situation

3- Requiring hospitalisation or prolonging hospitalisation

4- Persistent or significant disability or incapacity


5- Congenital abnormality or birth defect

6- Or any other adverse event considered "medically significant"

For serious adverse events related to the experimental medication and which are

expected:

- the -SmPC for the Disulone® (Dapsone) should be consulted (appendix 3).

For serious adverse events related to the procedure of the research and which are

expected (non experimental treatment required for carrying out the research):

- the SmPC of Cortancyl® (prednisone) should be consulted (appendix 4).

9.1.3.3 Other events that require the investigator to immediately notify the sponsor

• Adverse events that are "not serious" but which are significant for the safety of

participants

For patients randomized in group A, the following adverse events will be notified immediately

to the sponsor as an SAE:

- Mild hemolytic anemia defined by a hemoglobin (Hb) decrease of at least 1.5 g/dL

from baseline but a Hb level > 10g/dL

- Any skin rash occurring on dapsone will be notified as an adverse event.

- Mild and asymptomatic methemoglobinemia ( 8% < blood level < 15%) detected

during the first month of treatment (checked every week)

The investigator must notify the sponsor about these "non serious" adverse events, in

accordance with the same procedures and deadlines as serious adverse events (see section

9.1.4). These events can be considered "medically significant".

• In utero exposure

The sponsor must be notified immediately about any pregnancy during which the foetus

(from the pre-embryonic stage up to birth) could have been exposed at a given time to an

experimental medication, even if the pregnancy is not associated with an adverse event.

• Exposure while breastfeeding


Exposure while breastfeeding occurs if an infant or child could have been exposed to a

medication via the breast milk of a mother being treated with an experimental medication.

Even if such exposure is not associated with an adverse event, the investigator must always

notify the sponsor about exposure while breastfeeding as soon as the investigator becomes

aware.

9.1.4 Procedures and deadlines for notifying the sponsor

Notification of an SAE must initially be provided in a written report using the special form for

reporting SAE (see Appendix 6). The report must be signed by the investigator.

Each item in the form must be completed by the investigator so that the sponsor can carry

out the appropriate analysis.

This initial notification must be followed by one or more detailed follow-up report(s), in writing

and signed, within a maximum of 8 days in the case of a fatal or life-threatening event and

within 15 days for all other cases.

Whenever possible, the investigator will provide the sponsor with any documents that may be

useful (medical reports, laboratory test results, results of additional exams, etc.). These

documents must be made anonymous. In addition, the documents must include the

following: research acronym, number and initials of the subject, nature and date of the

serious adverse event.

Any adverse event will be monitored until fully resolved (stabilisation at a level considered

acceptable by the investigator, or return to the previous state) even if the subject has left the

trial.

The initial notification, the SAE follow-up reports and all other documents must be sent to the

sponsor via fax only to the Vigilance Division of the DRCD, fax No. 01 44 84 17 99.

For studies using e-CRF:

- the investigator completes the SAE notification form in the e-CRF, validates, prints and

signs the form before sending it via fax.

- if it is not possible to connect to the e-CRF, the investigator will complete, sign and send the

SAE notification form found in Appendix. As soon as the connection is restored, the SAE

notification form in the e-CRF must be duly completed.


The investigator must comply with all requests from the sponsor for additional information.

For all questions relating to the notification of an adverse event, the Vigilance Division of the

DRCD can be contacted via email: [email protected]

In utero exposure

The investigator completes the "form for monitoring a pregnancy that developed during a

biomedical research", found in Appendix 6 and sends it by fax to the Vigilance Division at 01

44 84 17 99.

The investigator must monitor the pregnant woman throughout her pregnancy or until the

pregnancy is terminated, and must notify the sponsor of the outcome of the pregnancy, using

this form.

If the outcome of the pregnancy falls within the definition of a serious adverse event

(miscarriage, pregnancy termination, foetal death, congenital abnormality, etc.), the

investigator must follow the procedure for reporting SAE.

If the exposure involves the father, the investigator must obtain the mother's permission

before collecting information about the pregnancy.

The initial pregnancy notification, the SAE follow-up reports and all other documents must be

sent to the sponsor via fax only to the Vigilance Division - of the DRCD, fax No. 01 44 84 17

99.

9.1.5 Period for notifying the sponsor

The investigator must report all SAE that occur in research subjects:

- since the date on which the 1st treatment dose was administered

- throughout the period during which the participant is monitored, as determined by the

research

- for up to 1 week after the participant stops treatment using the treatment (dapsone or

prednisone)

- with no time limit, if the SAE is likely to be due to the experimental medication (dapsone)

9.1.6 The sponsor's roles

The sponsor, represented by its Vigilance Division, continuously assesses the safety of each

experimental medication throughout the research.

mailto:[email protected]


9.1.6.1 Analysis and declaration of serious adverse events

The sponsor assesses:

- the seriousness of all adverse events reported

- the causal relationship of these events with each experimental medication and/or

specific medical procedures/exams added by the research and with other possible

treatments

- the expected or unexpected nature of these adverse reactions

All serious adverse events which the investigator and/or the sponsor believe could

reasonably have a causal relationship with the experimental medication are considered as

suspected adverse reactions.

All suspected unexpected serious adverse reactions (SUSAR) are declared by the sponsor,

within the legal time frame, to the Agence Française de Sécurité Sanitaire des Produits de

Santé (ANSM, French Health Products Safety Agency) and to the relevant Comité de

Protection des Personnes (CPP, ethical committee).

• The initial declaration must be made no later than 7 calendar days after the date on

which the serious adverse event occurs in the case of death or of a life-threatening

diagnosis.

• The initial declaration must be made no later than 15 calendar days after the date on

which the serious adverse event occurs in the case of other serious situations.

• The follow-up declaration must be made no later than 8 days after the 7- or 15-day

deadline (depending on the seriousness).

Any suspected unexpected serious adverse reaction must also be declared electronically in

the Eudravigilance European database for adverse events due to medications, established

by the European Medicines Agency (EMA).

The sponsor must notify all relevant investigators about any data that could adversely affect

the safety of the research subjects.

9.1. 6.2 Analysis and declaration of other safety data


This relates to any safety data or new fact that could significantly alter the assessment of the

benefit-risk ratio for the experimental medication, or for the research, or which could lead to

the possibility of altering the administration of the experimental medication or altering the

conduct of the research.

New facts must be declared to the competent authorities within 15 calendar days of the

sponsor becoming aware. Additional relevant information must be sent within an additional 8

days after the 15 day deadline.

9.1.6.3 Annual safety report

Once a year for the duration of the clinical trial, the sponsor must draw up an annual safety

report (Development Safety Update Report - DSUR) which includes, in particular:

- an analysis of the safety of the research subjects

- a description of the patients included in the trial (demographic characteristics, etc.)

- a line listing of suspected serious adverse reactions that occurred during the period

covered by the report

- a cumulative summary tabulation of serious adverse events that have occurred since the

start of the research

The report must be delivered no later than 60 days after the anniversary of the date on which

the ANSM authorised the trial.

10. STATISTICAL ASPECTS

10.1 Description of statistical methods:

Analysis will be conducted according a pre-specified analysis plan. All tests will be two tailed

and P-values lower than 0.05 will be considered statistically significant. All patients will be

analyzed in their group of randomization, according to the intention-to-treat principle (ITT).

No interim analysis will be performed. A statistical report will be written with all paramaters of

the CONS0RT statement (http://www.consort-statement.org/). A detailed flow-chart will be

realized. Analyses will be performed with STATA version 12.0 under the responsibility of Dr

Florence Canouï-Poitrine (URC-Mondor/Santé Publique).

http://www.consort-statement.org/


The descriptive analysis will compare the two randomized groups in terms of general

baseline characteristics of patients (demographics, history, baseline clinical, and biological

status) to assess the quality of randomization process. Categorical variables will be

described as numbers and percentages and continuous variables as means (standard

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