A Study of Tadalafil for Duchenne Muscular Dystrophy

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to determine if tadalafil can slow the decline in walking ability of boys who have Duchenne muscular dystrophy (DMD). The study will also assess the safety of tadalafil and any side effects that might be associated with it in boys who have DMD. Participants will receive study treatment (tadalafil or placebo) for the first 48 weeks of the study, and can then continue into an open label extension (OLE) that consists of two periods during which all participants will receive tadalafil. In OLE period 1, all participants will receive tadalafil for 48 weeks. Participants completing OLE period 1 will continue into OLE period 2 and will receive tadalafil for at least another 48 weeks.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Tadalafil for Duchenne Muscular Dystrophy

Conditions
-----------------
Muscular Dystrophy, Duchenne

Intervention / Treatment
-----------------
* Drug: Tadalafil
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ambulant males with Duchenne muscular dystrophy (DMD) confirmed by typical clinical presentation (onset of clinical signs or symptoms before 6 years of age supported by an elevated serum creatinine kinase level, and ongoing difficulty with walking) together with either a record of a genetic confirmation of the DMD diagnosis, or a record of muscle biopsy showing near-complete dystrophin deficiency (excluding revertant fibers) Receiving systemic corticosteroids for a minimum of 6 months immediately prior to screening, with no significant change in total daily dosage or dosing regimen (except those adjusting for weight changes) for a minimum of 3 months immediately prior to screening and a reasonable expectation that total daily dosage and dosing regimen will not change significantly (except for adjustments for weight) for the duration of the study Able to complete the six minute walk distance (6MWD) test with results within 20% of each other at a minimum of 2 pre-randomization assessments Left ventricular ejection fraction (LVEF) ≥50% as determined by echocardiogram Written informed consent from parents/legal guardian will be obtained prior to any study procedure being performed. In addition, the child may be required to give documented assent, if capable. Exclusion Criteria: Symptomatic cardiomyopathy or heart failure Change in prophylactic treatment for heart failure within 3 months prior to start of study treatment Cardiac rhythm disorder History of participation in gene or cell-based therapy , or antisense oligonucleotide or stop codon read-through therapy Unable to take orally administered tablets Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle strength within 3 months prior to the start of study treatment (for example, growth hormone, anabolic steroids including testosterone) New or changed treatment with herbal or dietary supplements being taken with an expectation of an effect on muscle strength or function during 1 month prior to first dose of study drug Surgery that might have an effect on muscle strength or function within 3 months before study entry or planned surgery at any time during the study Evidence of a lower limb injury that may affect performance on the 6MWD Severe behavioral problems, including severe autism or attention deficit disorders, that may interfere with completion of the 6MWD Any contraindication to tadalafil (use of any form of organic nitrate, either regularly and/or intermittently, or known serious hypersensitivity to tadalafil) History of significant renal insufficiency or clinical evidence of cirrhosis Have known allergy to any of the excipients in tadalafil tablets, notably lactose Current Phosphodiesterase Type 5 (PDE5) inhibitor therapy or treatment within the past 6 months

Ages Eligible for Study
-----------------
Minimum Age: 7 Years
Maximum Age: 14 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br>Placebo taken orally once daily. | Drug: Placebo<br> <br> * Other names: Administered orally;|
| Experimental: 0.3 mg/kg Tadalafil<br>0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily. | Drug: Tadalafil<br>* Administered orally<br>* Other names: Cialis;|
| Experimental: 0.6 mg/kg Tadalafil<br>0.6 mg/kg tadalafil taken orally once daily. | Drug: Tadalafil<br>* Administered orally<br>* Other names: Cialis;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Six Minute Walk Distance (6MWD) in Meters | 6MWD measured the distance in meters a participant was able to walk in 6 minutes. The study used 6MWD procedure modified specifically for use in boys with Duchenne muscular dystrophy (DMD), including standardized verbal encouragement at specific intervals to maintain attention to the test, and use of a safety chaser to walk behind the participant during testing (McDonald et al., 2010a). The LS mean (LSM) change from baseline, standard error was derived using mixed model repeated measures (MMRM) methodology with factors for pooled country, treatment, visit, treatment-by-visit interaction and baseline 6MWD as a covariate. | Baseline, Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the North Star Ambulatory Assessment (NSAA) Global Score | The NSAA is a functional scale specifically designed for ambulant boys with DMD that can provide additional information on motor functions important in maintaining normal ambulation and other activities important to everyday life. The NSAA is a 17-item evaluation of standing, ability to transition from lying to sitting, sitting to standing, and other mobility assessments. Each of the 17 items is evaluated on an ordinal scale of 0, 1, or 2, with higher scores reflecting better performance on the assessment, for a total maximum score of 34. This score was transformed to a 0 to 100 scale for the key analysis (referred to as linearized), with higher transformed scores reflecting better performance.The LS mean (LSM) change from baseline standard error was derived using mixed model repeated measures methodology (MMRM) with factors for pooled country, treatment, visit, treatment-by-visit interaction and Day 1 value as baseline covariate. | Baseline, Week 48 | 
| Change From Baseline in Timed Function Tests in Seconds | Timed function tests included time it took to rise from floor, walk 10 meters, ascend 4 stairs, and descend 4 stairs.The lower the time in seconds taken, the better the performance. The LS mean change from baseline, standard error, was derived using mixed model repeated measures methodology (MMRM) with factors for pooled country, treatment, visit, treatment-by-visit interaction and Day 1 value as baseline covariate. | Baseline, Week 48 | 
| Time to Persistent 10% Worsening in 6MWD | Time on study until the 6MWD becomes 10% less than the baseline 6MWD and continues at that level or lower until the end of study. | Baseline through Week 48 | 
| Time to Persistent 10% Worsening in Timed Function Tests (TFT) | Time on study until the TFT becomes 10% worse than the baseline TFT and continues at that level or lower until the end of study. The time to persistent 10% worsening is the observed time after baseline until the first observed timepoint where their time used for the TFTs is >110% of the baseline time and all the time values observed afterward are also >110% of baseline. If the participant discontinues prior to experiencing persistent worsening, this outcome for the participant is censored at the date of discontinuation of the double-blind period. Only participants with complete evaluable data were analyzed. Complete evaluable data was defined as having baseline measurement, complete dates at evaluable visits and a post-baseline measurement at each evaluable visit. | Baseline through Week 48 | 
| Change From Baseline in Pediatric Outcomes Data Collection Instrument (PODCI) Scores | PODCI includes a Global Functioning Scale and 5 core scales:Upper Extremity and Physical Function,Transfer/Basic Mobility, Sports/Physical Functioning, Pain/Comfort,and Happiness.The Global Functioning Scale is the mean of the mean scores from 4 of the 5 core scales (all except the happiness core scale).The following PODCI scores were prespecified in the protocol for analysis: Global Functioning, Upper Extremity and Physical Function,Transfer/Basic Mobility, and Sports/Physical Functioning. The Global Functioning Scale and each of the core scales were standardized so that a score of 0 represents a poor outcome/worse health, while 100 is the best possible outcome/best health (i.e., complete range of each score is 0 to 100, with higher scores representing better functioning). The LS mean (LSM) change from baseline,standard error was derived using MMRM with factors for pooled country, treatment, visit, treatment-by-visit interaction and baseline PODC scale as covariate. | Baseline, Week 48 | 
| Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil | The data reported are population estimate and inter-patient variability. | Weeks 4, 12, 24 and 36: -1 Hour up to 24 Hours Postdose |