trial synopsis 205.446 dr - boehringer ingelheim€¦ · (sd 11.101%). at study baseline (visit2),...

abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis ‐ which is part of the clinical study report ‐ had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non‐approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.

Name of company:

Boehringer IngelheimTabulated

Trial Report ABCD

Synopsis No.:

Name of finished product:

Spiriva® Respimat®

EudraCT No.:

2011-001777-43

Name of active ingredient:

Tiotropium bromide

Page:

2 of 11

Module: Volume:

Report date:

29 SEP 2015Trial No. / U No.:

205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable

Proprietary confidential information 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.

This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

entered: 401

Tiotropium 2.5 µg (Tio R2.5):entered: 137 treated: 136 analysed (for primary endpoint): 136

Tiotropium 5 µg (Tio R5):entered: 130 treated: 130 analysed (for primary endpoint): 130

Placebo:entered: 134 treated: 134 analysed (for primary endpoint): 134

Diagnosis and maincriteria for inclusion:

Outpatients of either sex; aged 6 to 11 years; documented history (at least6 months) of asthma and a current diagnosis of severe persistent asthma (according to GINA [Global Initiative for Asthma] guidelines 2010); confirmed diagnosis of asthma at Visit 1 (bronchodilator reversibility: increase in FEV1 of ≥12% within 15 to 30 minutes after 200 µg salbutamol [albuterol]); on maintenance treatment with an inhaled corticosteroid (ICS) either at a stable high dose in combination with another controller medication or at stable medium dose in combination with 2 other controller medications for at least 4 weeks prior to Visit 1; symptomatic (partly controlled) as defined by Interviewer Administered Asthma Control Questionnaire (ACQ-IA) mean score ≥1.5 at Visit 1 and Visit 2; pre-bronchodilator FEV1 ≥60% and ≤90% predicted at Visit 1; variation of absolute FEV1 values of Visit 1 compared to Visit 2 within ±30%.

No significant disease other than asthma or any other condition where anticholinergic treatment was contraindicated; no acute asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1 and/or in the 4 weeks prior to Visit 2.

Test product: Tiotropium solution for inhalation

dose: 2.5 µg (2 actuations of 1.25 µg) once daily in the evening

5 µg (2 actuations of 2.5 µg) once daily in the evening

mode of admin.: Oral inhalation via the Respimat® Inhaler

batch no.: 2.5 µg per actuation: B302712, B201347, B002966

1.25 µg per actuation: B302743, B201346, B002895

Boehringer Ingelheim BI Trial No.:

Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Page 2 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

3 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable



Reference therapy: Placebo solution for inhalation

dose: Not applicable

mode of admin.: Oral inhalation via the Respimat® Inhaler

batch no.: B301088, B201120, B003854

Duration of treatment: 12 weeks followed by 3-week follow-up after study drug termination

Criteria for evaluation:

Efficacy: Primary endpoint:

The primary endpoint was forced expiratory volume in 1 second within 3 hours (h) post dosing (FEV1 peak0-3h response [change from baseline]) after 12 weeks of treatment.

Key secondary endpoint:

The key secondary endpoint was trough FEV1 response (change from baseline) after 12 weeks of treatment.

Secondary endpoints:

All secondary endpoints were analysed as response (change from baseline) after 12 weeks of treatment, unless specified otherwise. Secondary endpoints were

- Peak forced vital capacity (FVC) within 3 h post dosing (FVC peak0-3h)

- Trough FVC

- FEV1 area under the curve (AUC) from 0 to 3 h post dosing FEV1 (AUC0-3h)

- FVC (AUC0-3h)

- Weekly mean use of as required rescue medication (used during daytime, nighttime, per day)

- Weekly mean morning and evening peak expiratory flow response (PEFam/PEFpm)



Page 3 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

4 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable



Efficacy(continued):

- Weekly mean PEF variability

- Weekly mean FEV1 am / FEV1 pm response

- Weekly mean asthma symptom free days

- Asthma control as assessed by Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score (absolute value) and number of responders

The remaining secondary endpoints are described in the clinical trial report body.

Safety: Incidence and intensity of adverse events (AEs), clinical laboratory tests, changes in vital signs (seated blood pressure and pulse rate), 12-lead electrocardiogram (ECG), and physical examination. A Data Safety Monitoring Board (DSMB) was established to monitor safety.

Statistical methods: The primary analysis was a restricted maximum likelihood (REML)-based mixed effect model with repeated measures (MMRM). The analyses included the fixed, categorical effects of treatment, country, visit and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. Patient was included as random effect. First-order autoregressive (AR1) for equally spaced visits was used to model the within-patient errors. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. To control the probability of type I error, a hierarchical testing procedure was used for the analysis of the primary and key secondary endpoints: 1) compare tiotropium 5 µg vs. placebo for the primary endpoint; 2) compare tiotropium 2.5 µg vs. placebo for the primary endpoint; 3) compare tiotropium 5 µg vs. placebo for the key secondary endpoint; 4) compare tiotropium 2.5 µg vs. placebo for the key secondary endpoint. Each step was only considered confirmatory providing all the previous steps were successful. The primary comparison was the contrast between each tiotropium dose and placebo after 12 weeks of treatment. Adjusted mean values as well as treatment contrasts were calculated, together with 95% confidence intervals (CIs) and p-values. Analyses of the secondary endpoints and safety were descriptive in nature.

No interim analysis was performed.



Page 4 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

5 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable



SUMMARY – CONCLUSIONS:

Efficacy results: Disposition and exposure

In total, 401 patients were randomised and 400 patients received at least 1 dose of study medication (Tio R5: 130; Tio R2.5: 136; placebo: 134); 8 patients (2%) prematurely discontinued study medication (Tio R5: 4; Tio R2.5: 0; placebo: 4). The reasons for premature discontinuation included withdrawal due to AEs (Tio R5: 2 patients; placebo: 2 patients), consent withdrawn not due to AE (Tio R5: 1 patient; placebo: 1 patient), and ‘other’ reasons (Tio R5: 1 patient; placebo: 1 patient). The median treatment duration was 85 days (12 weeks) in all 3 treatment groups.

Demographics, baseline characteristics, and compliance

Demographic and baseline disease characteristics were balanced across treatment groups. About two thirds of patients were male (69.8%) and most patients were White (89.5%) and non-Hispanic/Latino (82.0%). The mean age was 9.0 years (standard deviation [SD] 1.6 years). Few patients were exposed to second-hand smoke (7.8%) and 21.8% of patients were exposed to household pets. Patients had a mean duration of asthma of 4.93 years (SD 2.48 years) and 75.5% had asthma for ≥3 years.

At Visit 1, mean pre-bronchodilator (i.e. pre-salbutamol [albuterol]) FEV1 was 1.474 L (SD 0.308 L) or 76.537 % predicted normal (SD 7.918%); mean post-bronchodilator FEV1 was 1.871 L (SD 0.398 L) or 97.143% predicted normal (SD 11.101%). At study baseline (Visit 2), FEV1 values had improved compared with the pre-bronchodilator FEV1 values measured at Visit 1. Mean pre-dose FEV1 was 1.572 L (SD 0.346 L) or 81.641% predicted normal (SD 11.450%).

Treatment compliance was comparable across treatment groups; median compliance was 88.96% based on eDiary entries. The majority of patients (70.8%) had compliance between 80% and 100%.



Page 5 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

6 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable



Efficacy results(continued):

Primary endpoint

Both doses of tiotropium showed numerically better adjusted mean FEV1 peak0-3h responses than placebo after 12 weeks of treatment (Tio R5: 0.391 L; Tio R2.5: 0.287 L; placebo: 0.252 L). The adjusted mean difference between Tio R5 and placebo was 0.139 L and was statistically significant (95% CI 0.075, 0.203; p<0.0001); the adjusted mean difference between Tio R2.5 and placebo was 0.035 L and was not statistically significant (95% CI -0.028, 0.099; p = 0.2724). As the second step of the hierarchical testing (superiority of Tio R2.5 over placebo) was not statistically significant, the analyses of the key secondary endpoint were considered descriptive. All sensitivity analyses performed for the primary endpoint were consistent with the results of the primary analyses.

Secondary endpoints

Details for all secondary endpoints are provided in Table 1.

Pulmonary function tests

The key secondary endpoint trough FEV1 and the secondary endpoint FEV1 AUC0-3h were in line with the results of the primary endpoint. For both endpoints, Tio R5 and Tio R2.5 showed better responses than placebo; the difference to placebo in the adjusted means were statistically significant for Tio R5 but not for Tio R2.5.

For FVC peak0-3h, trough FVC, and FVC AUC0-3h, the adjusted mean responses after 12 weeks of treatment were numerically larger for patients treated with Tio R5 but the treatment differences to placebo in the adjusted means were not statistically significant; patients treated with Tio R2.5 showed lower adjusted mean responses than placebo.

Peak flow meter and eDiary (AM3®)

The use of rescue medication (per day, during the daytime, during the nighttime) decreased in all 3 treatment groups with no statistically significant difference between either of the tiotropium doses and placebo. For both morning and evening weekly mean PEF as well as for weekly mean PEF variability, theanalyses showed no statistically significant difference to placebo for either



Page 6 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

7 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable




tiotropium dose after 12 weeks of treatment. The adjusted mean response for both weekly mean FEV1 am and FEV1 pm after 12 weeks of treatment was numerically lower in both tiotropium groups compared with the placebo group. The weekly mean number of asthma symptom free days was similar in all treatment groups after 12 weeks of treatment.

Interviewer-Administered Asthma Control Questionnaire (ACQ-IA)

The adjusted mean ACQ-IA total score improved from baseline in all 3 treatment groups after 12 weeks of treatment, with no statistically significant difference to placebo for either tiotropium dose. The percentage of responders (based on the ACQ-IA total score) increased over time in all treatment groups; after the 12-week treatment period, 80.8% (Tio R5), 79.4% (Tio R2.5), and 76.9% (placebo) of patients were responders.



Page 7 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

8 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable




Table 1 Efficacy results for secondary endpoints after 12 weeks of treatment – FAS

Endpoint Treatment

N Adjusted mean (SE)1 Adjusted mean difference (SE)1

95% CI p-value for superiority2

Trough FEV1 [L] (key secondary endpoint)Placebo 130 0.136 (0.027)Tio R2.5 135 0.154 (0.026) 0.018 (0.034) (-0.048, 0.085) 0.5898Tio R5 128 0.223 (0.027) 0.087 (0.034) (0.019, 0.154) 0.0117

FEV1 AUC0-3h [L] Placebo 130 0.175 (0.023)Tio R2.5 135 0.206 (0.022) 0.031 (0.029) (-0.026, 0.088) 0.2907Tio R5 128 0.301 (0.023) 0.126 (0.030) (0.068, 0.184) <0.0001

FVC peak0-3h [L] Placebo 130 0.244 (0.028)Tio R2.5 135 0.201 (0.027) -0.043 (0.036) (-0.113, 0.027) 0.2277Tio R5 128 0.275 (0.028) 0.030 (0.036) (-0.040, 0.101) 0.3998

Trough FVC [L] Placebo 130 0.141 (0.029)Tio R2.5 135 0.094 (0.029) -0.048 (0.037) (-0.121, 0.026) 0.2030Tio R5 128 0.150 (0.030) 0.009 (0.038) (-0.066, 0.083) 0.8194

FVC AUC0-3h [L] Placebo 130 0.145 (0.025)Tio R2.5 135 0.105 (0.024) -0.041 (0.032) (-0.103, 0.022) 0.2008Tio R5 128 0.182 (0.025) 0.037 (0.032) (-0.026, 0.100) 0.2545

Use of rescue medication (as needed); weekly mean24 h [puffs]

Placebo 128 -0.570 (0.096)Tio R2.5 136 -0.553 (0.094) 0.017 (0.124) (-0.227, 0.261) 0.8916Tio R5 127 -0.660 (0.097) -0.089 (0.126) (-0.336, 0.158) 0.4789

Daytime [puffs]Placebo 127 -0.279 (0.057)TioR2.5 136 -0.294 (0.055) -0.015 (0.074) (-0.160, 0.129) 0.8361TioR5 126 -0.365 (0.057) -0.087 (0.075) (-0.233, 0.060) 0.2461

Nighttime [puffs]Placebo 128 -0.285 (0.051)TioR2.5 136 -0.250 (0.050) 0.035 (0.067) (-0.096, 0.165) 0.6029TioR5 126 -0.310 (0.052) -0.026 (0.067) (-0.158, 0.107) 0.7034



Page 8 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

9 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable




Table 1 Efficacy results for secondary endpoints after 12 weeks of treatment – FAS(continued)

Endpoint Treatment

N Adjusted mean (SE)1 Adjusted mean difference (SE)1

95% CI p-value for superiority2

PEFam [L/min]; weekly meanPlacebo 128 8.343 (3.613)Tio R2.5 136 13.119 (3.500) 4.776 (4.686) (-4.419, 13.970) 0.3083Tio R5 126 13.086 (3.630) 4.743 (4.747) (-4.571, 14.057) 0.3179

PEFpm [L/min]; weekly meanPlacebo 127 7.892 (3.717)Tio R2.5 136 8.459 (3.599) 0.567 (4.807) (-8.866, 10.001) 0.9061Tio R5 126 3.785 (3.731) -4.107 (4.867) (-13.658, 5.444) 0.3990

PEF variability [%]; weekly meanPlacebo 127 0.150 (0.777)Tio R2.5 136 -0.800 (0.749) -0.950 (1.025) (-2.959, 1.060) 0.3542Tio R5 125 -0.352 (0.780) -0.502 (1.042) (-2.545, 1.541) 0.6298

FEV1 am [L]; weekly meanPlacebo 128 0.174 (0.030)Tio R2.5 136 0.142 (0.029) -0.032 (0.038) (-0.107, 0.043) 0.4066Tio R5 126 0.125 (0.030) -0.049 (0.039) (-0.125, 0.027) 0.2032

FEV1 pm [L]; weekly meanPlacebo 127 0.155 (0.031)Tio R2.5 136 0.104 (0.030) -0.051 (0.041) (-0.131, 0.028) 0.2064Tio R5 126 0.094 (0.032) -0.061 (0.041) (-0.142, 0.020) 0.1410

Asthma symptom-free days; weekly meanPlacebo 128 0.147 (0.031)Tio R2.5 136 0.130 (0.030) -0.017 (0.041) (-0.097, 0.063) 0.6748Tio R5 127 0.172 (0.031) 0.025 (0.041) (-0.056, 0.105) 0.5497

ACQ-IA total score Placebo 130 1.026 (0.060)Tio R2.5 136 1.046 (0.059) 0.020 (0.078) (-0.133, 0.173) 0.7980Tio R5 126 0.948 (0.061) -0.079 (0.079) (-0.233, 0.076) 0.3166

Note: All endpoints listed in the table were analysed as response (change from baseline) after 12 weeks of treatment, except for ACQ-IA total score (analysed based on absolute values).1

Adjusted for treatment, country, visit, study baseline, treatment*visit and study baseline*visit2 2-sided p-value for superiority (descriptive)

Safety results: Adverse events

During the treatment period, AEs were reported in total for 181 of 400 treated patients (45.3%). The percentage of patients reporting any AEs was lower in the2 active treatment groups Tio R5 and Tio R2.5 than in the placebo group(Tio R5: 43.1%; Tio R2.5: 43.4%; placebo: 49.3%). In all 3 treatment groups,



Page 9 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

10 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable



Safety results(continued):

patients were most frequently reported with AEs in the system organ classes (SOCs) infections and infestations (Tio R5: 19.2%; Tio R2.5: 22.1%; placebo: 26.1%) and respiratory, thoracic, and mediastinal disorders (Tio R5: 21.5%;Tio R2.5: 17.6%; placebo: 25.4%).

Table 2 provides the most frequently reported AEs on preferred term(PT) level for the treated set (TS).

Table 2: Most frequently reported AEs on PT level – TS

System organ class (SOC) Placebo Tio R2.5 Tio R5Preferred term (PT) N (%) N (%) N (%)

Number of patients 134 (100.0) 136 (100.0) 130 (100.0)Patients with any adverse event (AE) 66 (49.3) 59 (43.4) 56 (43.1)Infections and infestations 35 (26.1) 30 (22.1) 25 (19.2)

Nasopharyngitis 11 (8.2) 6 (4.4) 6 (4.6)

Respiratory, thoracic, and mediastinal disorders

34 (25.4) 24 (17.6) 28 (21.5)

Asthma1 30 (22.4) 20 (14.7) 24 (18.5)

Investigations 20 (14.9) 15 (11.0) 15 (11.5)

Peak expiratory flow rate decreased 20 (14.9) 15 (11.0) 15 (11.5)1 Please note that the PT ‘asthma’ summarises several lowest level terms; in this study, for almost all patients ‘exacerbation of asthma’was reported, 1 patient was reported with ‘asthma aggravated’.

Most AEs were of mild or moderate intensity; AEs of severe intensity were reported for 8 patients overall, with similar frequencies across treatment groups: 3 patients in the Tio R5 group (2.3%), 2 patients in the Tio R2.5 group (1.5%), and 3 patients in the placebo group (2.2%). AEs leading to discontinuation were reported for 4 patients (1.0%) in total: 2 patients in the Tio R5 group (1.5%) and 2 patients in the placebo group (1.5%); all of these AEs were also reported as ‘other significant’ AEs (according to ICH E3).

Adverse events considered to be drug-related by the investigator were reported for 3 patients overall, 1 patient in the Tio R5 group (0.8%) and 2 patients in the placebo group (1.5%). In the Tio R5 group, 1 patient was reported with dizziness; in the placebo group, 1 patient was reported with cough and 1 patient was reported with cough, asthma, decreased appetite, fatigue, and metabolic cardiomyopathy.

There were no deaths during the course of this trial. Serious AEs (SAEs) were reported for 4 patients in the Tio R5 group (3.1%), 2 patients in the Tio R2.5



Page 10 of 11205.446 c03243044-01

Synopsis

Name of company:


Trial Report ABCD

Synopsis No.:



EudraCT No.:

2011-001777-43


Tiotropium bromide

Page:

11 of 11

Module: Volume:

Report date:


205.446 / c03243044-01

Dates of trial:

24 JUL 2012 – 18 MAY 2015

Date of revision:

Not applicable



Safety results(continued):

group (1.5%), and 2 patients in the placebo group (1.5%). Seven of these patients had SAEs that required hospitalisation. None of the SAEs were assessed to be drug-related by the investigator or resulted in premature discontinuation of study medication.

No AEs associated with laboratory parameters were reported.

Vital signs

Mean systolic blood pressure values, mean diastolic blood pressure values, and mean pulse rate were similar across the treatment groups at trial baseline and over the 3 h post-dose time period at each clinic visit. No noteworthy changes were observed in the mean values for any parameter during the treatment period.

Conclusions: Tiotropium solution for inhalation via the Respimat® inhaler was effective as an add-on therapy to a stable dose of the patient’s usual maintenance treatment in a population of children (6 to 11 years old) with persistent asthma. Compared to placebo, Tio R5 once daily statistically significantly improved adjusted mean FEV1 peak0-3h response after 12 weeks of treatment. Tio R2.5 numerically improved adjusted mean FEV1 peak0-3h response compared to placebo after 12 weeks of treatment. The primary analysis of the primary endpoint was supported by all sensitivity analyses and by analyses of (key) secondary and further endpoints based on FEV1 (trough FEV1, FEV1 AUC0-3h, and FEV1 overtime). The safety profile of tiotropium as add-on therapy to ICS and other controller medication was comparable to that of placebo. Both tiotropium doses were well tolerated over 12 weeks of treatment.



Page 11 of 11205.446 c03243044-01

Synopsis

trial synopsis 205.446 dr - boehringer ingelheim€¦ · (sd 11.101%). at study baseline (visit2),...

Documents