Trial synopsis 527.66 GR D Denovo DS DR - Boehringer Ingelheim · best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may

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.

Boehringer Ingelheim BI Trial No.: 527.66–Group D Denovo Report

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1. - 15. CTR Main Part

Name of Company: Boehringer Ingelheim

Tabulated Trial Report ABCD

Synopsis No.:

Name of finished product: Eudra CT No.:

2006-004423-11

Name of active ingredient:

tamsulosin hydrochloride

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Disclosure Synopsis Date: 16 JUL 2015

Trial No. / U No.: 527.66/U09-3250-01

Dates of trial: 09 May 2006 – 27 Nov 2008

Date of revision (if applicable):Not applicable

Proprietary confidential information © 2009 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.

Title of trial: An uncontrolled, open-label, titration, long-term safety (up to 12 months) and efficacy study of tamsulosin hydrochloride in children with neuropathic bladder, with a randomized pharmacokinetic sub-study investigating low, medium and high dose ranges

Coordinating Investigator:

Trial sites: Multi-center study, at 29 sites, in 13 countries

Publication (reference): Data from this study have not been published.

Clinical phase: II

Objectives: To characterise the pharmacokinetic (PK) / pharmacodynamic (PD) profile and evaluate the safety and efficacy of tamsulosin hydrochloride in children with elevated detrusor leak point pressure associated with a known neurological disorder (e.g., spina bifida) for up to 12 months of treatment.

The PK/PD results have been previously summarized and are provided in a separate report

Methodology: This report for Study 527.66 covers the Group D Denovo patient population. It is an open-label, uncontrolled, multi-center, safety study with a PK subset of patients randomized to three dose levels (low, medium and high) of tamsulosin hydrochloride. Once the PK section was completed the patients continued in the study on their individual efficacious dose level, while non-PK patients were titrated to their individual efficacious dose level at the start of the study. There were 3 separate patient population groups within the 527.66 study, with 3 different study reports. The 3 groups were the PK/PD group, the Group D-Denovo and the Group D-527.51 Rollover. Group D – Denovo included PK patients and additional patients who did not receive any previous treatment via the PK / PD portion of the trial. Group D – 527.51 Rollover included patients who successfully completed tamsulosin HCl Study 527.51.

No. of subjects:

planned: Planned Enrolled 120; Planned Entered 100 (includes patients from PK Phase)

actual: Actual Enrolled 130; Actual Entered 88

This document is considered to be a full reporting of the 88 patients who were entered into the 527.66 study (Group D-Denovo). Patients from the 527.51 study are continuing in this study as part of an open-label rollover phase. These data will be analyzed in a separate Final Report.

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Weight (kg)

Low Dose level (0.001 – 0 002

mg/kg)

Medium Dose level (0.002 – 0.004 mg/kg)

High Dose level (0.004 – 0.008 mg/kg)

9.0 – 12.0 - 0.025 mg 0.05 mg

12.1 – 25.0 0.025 mg 0.05 mg 0.1 mg

25.1 – 50.0 0.05 mg 0.1 mg 0.2 mg

50.1 – 100.0 0.1 mg 0.2mg 0.4 mg



Synopsis No.:

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Diagnosis and main Children between two and 16 years-of-age with elevated detrusor leak point criteria for inclusion: pressure associated with a known neurological disorder (e.g., spina bifida)

Test product: tamsulosin hydrochloride

dose: 0.025 mg, 0.05 mg, 0.1 mg, 0.2 mg and 0.4 mg Active treatment groups:

mode of admin.: Per os. The drug was administered, 30 minutes after breakfast, by sprinkling the contents of the capsule(s) over a spoonful of apple sauce or yogurt, followed by a spoonful of water. batch no.: US Supplies: 0.025 – PD-2774; 0.1 – PD-2798; 0.2 – PD-2799

EU Supplies: 0.025 – B061002152; 0.1 – B061002154; 0.2 – B061002156

Re-Supply: US Supplies: 0.025 – B073000286; 0.1 – B073000264; 0.2 – B073000265 EU Supplies: 0.025 – B073000266; 0.1 – B073000268; 0.2 – B073000270

Reference therapy: N/A

dose: N/A

mode of admin.: N/A

batch no.: N/A

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Duration of treatment: Up to 12 months

Criteria for evaluation:

Efficacy / clinical Efficacy parameters: pharmacology:

Primary: response defined as patients who achieved a decrease in their detrusor leak point pressure (LPP) to less than 40 cm H2O based upon two confirmatory measurements at the end of treatment.

Secondary:

1) Early responders who maintain their detrusor leak point pressure (LPP) below 40 cm H2O during the study.

2) Improvement or stabilization of hydronephrosis and/or hydroureter based upon ultrasound grading at the end of treatment compared to baseline.

Pharmacokinetics parameters:

The PK/PD results are provided in a separate report.

Safety: Physical examination, vital signs measurements (blood pressure, pulse rate, respiration rate), orthostatic testing, electrocardiogram (ECG), standard laboratory measures, urinalysis, vision, cognitive testing and adverse events. Dipstick pregnancy tests were to be performed on all female patients who had the potential to become pregnant, in the investigator’s opinion (e.g., post-menarchal patients).

Statistical methods: Descriptive statistics were used to summarize the efficacy and safety. The primary analysis of LPP responders included the Full Analysis Set of patients with evaluable LPP measurements (FAS-LPP) who completed treatment to Week 52 (On Treatment [OT]). Additional LPP analyses included evaluable LPPmeasurements for treated patients who completed or discontinued (Non-completers considered failures [NCF]).

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SUMMARY – CONCLUSIONS:

Efficacy / clinical LPP Response (OT): Of the 70 evaluable patients (FAS-LPP) who completed pharmacology results the study, 32 (45.7%) patients met the definition of an LPP responder (LPP

<40 cm H2O) at Week 52 (OT; primary analysis).

Number (%) of Responders at Week 52, FAS-LPP (OT)

Tamsulosin Dose Group Response Group Low Medium High Total Number of patients 26 14 30 70

Responders, N (%) 19 (73.1) 5 (35.7) 8 (26.7) 32 (45.7)

Non-responders, N (%) 7 (26.9) 9 (64.3) 22 (73.3) 38 (54.3) Note: patients are classified according to the treatment they were receiving at Week 52.

LPP Response (NCF): Based on the NCF analysis, which includes discontinued patients, 32 (38.6%) patients met the definition of LPP responders at Week 52. Maintenance of LPP Response: Of the 58 patients who were LPP responders atany time during the study, 25 of these patients responded during the course the trial and maintained the LPP response through Week 52. Median change from baseline in LPP: A median change from baseline in LPP of -16.0 cm was observed at Week 52 which represents a 29.2% decline from baseline in LPP. A median change from baseline in LPP of -10.0 cm H2O was observed within the first week of tamsulosin HCl treatment, which represents a 15.7% decline from baseline in LPP.

Hydroureter and Hydronephrosis: Most patients showed either improvement or stabilization of hydroureter at Week 52 (88.5% right kidney; 85.9% left kidney). Most patients showed either improvement or stabilization of hydronephrosis at Week 52 when compared to baseline (88.5% right kidney; 82.1% left kidney).

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Safety results: Status / Demographics: Of the 87 treated patients, 73 (83.9%) completed 12 months of treatment. A total of 51.7% of the patients were male, mean age was 7.4 years, 44.8% of patients were white and 32.2% were American Indian. A total of 81.6% of patients had a primary neural tube defect of myelomeningocele.

Exposure: Mean duration of tamsulosin HCl therapy was 327.4 days (46.7 weeks). The majority of patients (85.1%) received ≥271 days of therapy. Atotal of 77 patients completed at least 6 months and 73 patients completed 12 months of tamsulosin HCl therapy.

Adverse Events: A total of 79 (90.8%) patients experienced adverse events while receiving tamsulosin HCl. Based on dose at end of treatment, 100%, 90.5%, and 83.8% of patients on the low, medium, and high dose, respectively, had adverse events during the study. Based on dose at onset, 62.2%, 42.6%, and 80.5% of patients had adverse events at the low, medium, and high doses, respectively. The most frequently occurring adverse events were urinary tract infection (41.4% of patients), pyrexia (23.0%), vomiting (17.2%), pharyngitis (16.1%), headache (12.6%), and cough (12.6%).

A total of 9.2% of patients experienced adverse events that were considered related to study medication; these included dizziness (3.4%), orthostatic hypotension (3.4%), headache (1.1%), hypotension (1.1%), diarrhea (1.1%), nausea (1.1%), photophobia (1.1%) and urinary incontinence (1.1%). A total of 11.5% of patients experienced severe adverse events; all but one of these events (hypotension) were considered unrelated to study medication.

Nine patients had serious adverse events while on treatment (2 low, 3 medium, and 4 high dose). All serious events were a result of a hospitalization, most of which were a result of the condition under study; none were considered related to study therapy. No deaths occurred during the study. Six patients discontinued treatment as a result of an adverse event(s), which included orthostatic hypotension (4 patients), hypotension (1), and headache (1).

Clinical Laboratory Measures: There were no clinically meaningful trends in laboratory values during the study. The majority of the abnormal laboratory values were not clinically relevant.

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Safety results: Orthostatic Testing: Five patients had drops in systolic blood pressure of ≥20 mm Hg drop during orthostatic testing. All reported cases of orthostatic hypotension were considered to be asymptomatic by the investigator.

Conclusions: Tamsulosin HCl was well tolerated in children with elevated LPP associated

with a known neurological disorder (e.g., spina bifida) during 12 months of treatment. There were few adverse events considered related to treatment, no related serious adverse events, and no clinically meaningful changes in clinical laboratory measures. Reductions in detrusor LPP were observed during the trial. However, a placebo-controlled trial would be required to determine the extent to which the declines in LPP were attributable to tamsulosin HCl treatment.

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Boehringer Ingelheim BI trial number 527.66 -Group D Denovo Report Trial Synopsis - Appendix

Trial Synopsis - Appendix

The appended tables on the following pages supplement the trial results presented in the Trial

Group D Denovo Synopsis. They complement patient disposition results, results for

secondary endpoints, and adverse events results for the trial.

Results for presented in

Patient disposition Table 15.1.1: 3

Maintenance of LPP Response through Week 52 Table 15.2.1.5: 3 Hydroureter Response defined as stabilization or improvement, measured by renal ultrasound at Week 52 compared to baseline Hydronephrosis Response defined as stabilization or improvement, measured by renal ultrasound at Week 52 compared to baseline

Table 15.2.3.1: 1

Adverse events Table 15.3.2.1: 2

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Table 15.1.1: 3 Disposition of patients by treatment group +

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−

Tams−low Tams−medium Tams−high Total−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−

Enrolled 130

Not entered/randomised 42

Entered/randomised 88

Not treated 1

Treated [N (%)] 29 (100.0) 21 (100.0) 37 (100.0) 87 (100.0)

Did not prematurely discont. trial med. [N (%)] 27 ( 93.1) 16 ( 76.2) 30 ( 81.1) 73 ( 83.9)

Prematurely discontinued from trial med. [N (%)] N 2 ( 6.9) 5 ( 23.8) 7 ( 18.9) 14 ( 16.1) AE (unexpected worsening of disease under study) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) AE (unexpected worsening of pre−existing disease) 0 ( 0.0) 1 ( 4.8) 0 ( 0.0) 1 ( 1.1) AE other 2 ( 6.9) 3 ( 14.3) 0 ( 0.0) 5 ( 5.7) Non compl. protocol 0 ( 0.0) 0 ( 0.0) 1 ( 2.7) 1 ( 1.1) Lost to follow−up 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Consent withdrawn, not due to AE 0 ( 0.0) 1 ( 4.8) 3 ( 8.1) 4 ( 4.6) Other 0 ( 0.0) 0 ( 0.0) 3 ( 8.1) 3 ( 3.4)

Completed planned observation time [N (%)] 27 ( 93.1) 16 ( 76.2) 30 ( 81.1) 73 ( 83.9)

Prematurely discontinued from trial [N (%)] N 2 ( 6.9) 5 ( 23.8) 7 ( 18.9) 14 ( 16.1) AE (unexpected worsening of disease under study) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) AE (unexpected worsening of pre−existing disease) 0 ( 0.0) 1 ( 4.8) 0 ( 0.0) 1 ( 1.1) AE other 2 ( 6.9) 3 ( 14.3) 0 ( 0.0) 5 ( 5.7) Non compl. protocol 0 ( 0.0) 0 ( 0.0) 1 ( 2.7) 1 ( 1.1) Lost to follow−up 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Consent withdrawn, not due to AE 0 ( 0.0) 1 ( 4.8) 4 ( 10.8) 5 ( 5.7) Other 0 ( 0.0) 0 ( 0.0) 2 ( 5.4) 2 ( 2.3)

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−

+ Patients are classified according to the treatment they were taking at week 52 or end of treatmentOne patient was randomized but never took drug

Source data: Appendix 16.2, Listing 1.2 xtdisp.sas 08APR2009

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Table 15.2.1.5: 3 Time to response for patients who maintained # a detrusor leak point pressure of < 40 cm H2O by treatment group + − full analysis set (on−treatment)

__________________________________________________________________________________________________ Tams−low Tams−medium Tams−high Total

Total number of responders* 26 16 16 58

Number of patients 17 ( 65.4) 5 ( 31.3) 3 ( 18.8) 25 ( 43.1) who maintained a response N(%)

Time(days) Mean 10.24 12.20 36.00 13.72 Median 8.00 15.00 22.00 8.00 Q25 8.00 8.00 22.00 8.00 Q75 9.00 15.00 64.00 15.00

_______________________________________________________________________________________________

Responder is defined as having 2 LPP values < 40 cm H2O+ Patients are classified according to the treatment they were taking at Week 52 or end of treatment.* Responders = LPP responders over the course of the trial (Weeks 1 − 52).# Patient who responded at any visit prior to week 52 and maintained a response.

Source data: Appendix 16.2, Listing 6.1 efficacy\eff1a1ma.sas 10APR2009

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Table 15.2.3.1: 1 Stabilization or improvement of hydroureter / hydronephrosis measured by renal ultrasound by treatment group + at week 52 − full analysis set (on−treatment)

__________________________________________________________________________________ Tams−low Tams−medium Tams−high Total N (%) N (%) N (%) N (%)

Number of patients 27 17 34 78

Hydroureter # Right Kidney 26 ( 96.3) 15 ( 88.2) 28 ( 82.4) 69 ( 88.5) Left Kidney 24 ( 88.9) 14 ( 82.4) 29 ( 85.3) 67 ( 85.9)

Hydronephrosis @ Right Kidney 26 ( 96.3) 15 ( 88.2) 28 ( 82.4) 69 ( 88.5) Left Kidney 24 ( 88.9) 14 ( 82.4) 26 ( 76.5) 64 ( 82.1) _________________________________________________________________________________

+ Patients are classified according to the treatment they were taking at Week 52 or end of treatment.# Hydroureter response is defined as improvement or stabilization based upon the presence or absence of hydroureter at end of treatment compared to baseline.@ Hydronephrois response is defined as an improvement or stabilization based upon ultrasound grading at the end of the study. The lower or same grade at end of treatment compared to baseline is considered an improvementor or stabilization.Source data: Appendix 16.2, Listing 6.4 efficacy\effh1.sas 10APR2009

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Table 15.3.2.1: 2 Adverse event overall summary − treated set

Treatment analysis: Treatment at end of trial

______________________________________________________ ____________ ______________ _______________ ________ Tams−low Tams−medium Tams−high Total N (%) N (%) N (%) N (%)___________________________________________________________________________________________________________

Number of patients 29 (100.0) 21 (100.0) 37 (100.0) 87 (100.0)

Patients with any AE 29 (100.0) 19 ( 90.5) 31 ( 83.8) 79 ( 90.8)

Patients with severe AEs 4 ( 13.8) 4 ( 19.0) 2 ( 5.4) 10 ( 11.5)

Patients with investigator defined drug−related 4 ( 13.8) 4 ( 19.0) 0 ( 0.0) 8 ( 9.2)AEs

Patients with other significant AEs (according to 2 ( 6.9) 4 ( 19.0) 0 ( 0.0) 6 ( 6.9)ICH E3)

Patients with AEs leading to discontinuation of 2 ( 6.9) 4 ( 19.0) 0 ( 0.0) 6 ( 6.9)trial drug

Patients with significant AEs (pre−specified 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)events)

Patients with serious AEs 2 ( 6.9) 3 ( 14.3) 4 ( 10.8) 9 ( 10.3) Fatal 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Imm life−threatening 1 ( 3.4) 0 ( 0.0) 0 ( 0.0) 1 ( 1.1) Disability/incap. 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Req.hospitalisation 2 ( 6.9) 3 ( 14.3) 4 ( 10.8) 9 ( 10.3) Prol.hospitalisation 1 ( 3.4) 0 ( 0.0) 0 ( 0.0) 1 ( 1.1) Congenital anomaly 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Other 1 ( 3.4) 0 ( 0.0) 0 ( 0.0) 1 ( 1.1)___________________________________________________________________________________________________________

A patient may be counted in more than one seriousness criterion.Percentages are calculated using total number of patients per treatment as the denominator.MedDRA version used for reporting: 11.1Other Significant Adverse event: All adverse events that are marked haematological and other laboratoryabnormalities (other than those meeting the definition of serious) and any events that led to a intervention.

Source data: Appendix 16.2, Listing 7.5 safety\xaetables.sas 25MAR2009

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Trial synopsis 527.66 GR D Denovo DS DR - Boehringer Ingelheim · best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may