A Study of Tadalafil for Duchenne Muscular Dystrophy

• ClinicalTrials.gov Identifier: NCT01865084
• Recruitment Status: Terminated
• First Posted: May 30, 2013
• Results First Posted: March 1, 2017
• Last Update Posted: October 9, 2019
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: May 24, 2013
• First Posted Date: May 30, 2013
• Results First Submitted Date: September 30, 2016
• Results First Posted Date: March 1, 2017
• Last Update Posted Date: October 9, 2019
• Study Start Date: September 2013
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 10, 2017)

Change From Baseline in Six Minute Walk Distance (6MWD) in Meters [ Time Frame: Baseline, Week 48 ]

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.

• Original Primary Outcome Measures (submitted: May 24, 2013): Change from Baseline in Six Minute Walk Distance (6MWD) in Meters [ Time Frame: Baseline, Week 48 ]

Current Secondary Outcome Measures (submitted: January 10, 2017)

• Change From Baseline in the North Star Ambulatory Assessment (NSAA) Global Score [ Time Frame: Baseline, Week 48 ]
  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.
• Change From Baseline in Timed Function Tests in Seconds [ Time Frame: Baseline, Week 48 ]
  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.
• Time to Persistent 10% Worsening in 6MWD [ Time Frame: Baseline through Week 48 ]
  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.
• Time to Persistent 10% Worsening in Timed Function Tests (TFT) [ Time Frame: Baseline through Week 48 ]
  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.
• Change From Baseline in Pediatric Outcomes Data Collection Instrument (PODCI) Scores [ Time Frame: Baseline, Week 48 ]
  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.
• Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil [ Time Frame: Weeks 4, 12, 24 and 36: -1 Hour up to 24 Hours Postdose ]
  The data reported are population estimate and inter-patient variability.

Original Secondary Outcome Measures (submitted: May 24, 2013)

• Change from Baseline in the North Star Ambulatory Assessment (NSAA) Global Score [ Time Frame: Baseline, Week 48 ]
• Change from Baseline in Timed Function Tests in Seconds [ Time Frame: Baseline, Week 48 ]
• Time to Persistent 10% Worsening in 6MWD [ Time Frame: Baseline through Week 48 ]
• Time to Persistent 10% Worsening in Timed Function Tests [ Time Frame: Baseline through Week 48 ]
• Change from Baseline in Pediatric Outcomes Data Collection Instrument (PODCI) Scores [ Time Frame: Baseline, Week 48 ]
• Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil [ Time Frame: 1 Hour up to 24 Hours Postdose; Weeks 4, 12, 24 and 36 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Tadalafil for Duchenne Muscular Dystrophy
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Tadalafil for Duchenne Muscular Dystrophy
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Muscular Dystrophy, Duchenne

Intervention

• Drug: Tadalafil
  Administered orally
  Other Names:

  • LY450190
  • Cialis
• Drug: Placebo
  Other Name: Administered orally

Study Arms

• Experimental: Placebo
  Placebo taken orally once daily.
  Intervention: Drug: Placebo
• Experimental: 0.3 mg/kg Tadalafil
  0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily.
  Intervention: Drug: Tadalafil
• Experimental: 0.6 mg/kg Tadalafil
  0.6 mg/kg tadalafil taken orally once daily.
  Intervention: Drug: Tadalafil

Publications *

• McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Elfring GL, Atkinson L, Reha A, Hirawat S, Miller LL. The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve. 2010 Apr;41(4):500-10. doi: 10.1002/mus.21544.
• Victor RG, Sweeney HL, Finkel R, McDonald CM, Byrne B, Eagle M, Goemans N, Vandenborne K, Dubrovsky AL, Topaloglu H, Miceli MC, Furlong P, Landry J, Elashoff R, Cox D; Tadalafil DMD Study Group. A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy. Neurology. 2017 Oct 24;89(17):1811-1820. doi: 10.1212/WNL.0000000000004570. Epub 2017 Sep 29.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 10, 2017): 331
• Original Estimated Enrollment (submitted: May 24, 2013): 306
• Actual Study Completion Date: March 2016
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 7 Years to 14 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Belgium, Canada, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Puerto Rico, Russian Federation, Spain, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT01865084
• Other Study ID Numbers: 15122; H6D-MC-LVJJ ( Other Identifier: Eli Lilly and Company )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: September 2019