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A Study of Tadalafil for Duchenne Muscular Dystrophy

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Terminated
CT.gov ID
NCT01865084
Collaborator
(none)
331
Enrollment
62
Locations
3
Arms
30
Duration (Months)
5.3
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
331 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Tadalafil for Duchenne Muscular Dystrophy
Study Start Date :
Sep 1, 2013
Actual Primary Completion Date :
Dec 1, 2015
Actual Study Completion Date :
Mar 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Placebo

Placebo taken orally once daily.

Drug: Placebo
Other Names:
  • Administered orally

    		•
    Experimental: 0.3 mg/kg Tadalafil

    0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily.

    Drug: Tadalafil
    Administered orally
    Other Names:
  • LY450190
  • Cialis

    		•
    Experimental: 0.6 mg/kg Tadalafil

    0.6 mg/kg tadalafil taken orally once daily.

    Drug: Tadalafil
    Administered orally
    Other Names:
  • LY450190
  • Cialis

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Six Minute Walk Distance (6MWD) in Meters [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.

    Secondary Outcome Measures

    1. Change From Baseline in the North Star Ambulatory Assessment (NSAA) Global Score [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.

    2. Change From Baseline in Timed Function Tests in Seconds [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.

    3. Time to Persistent 10% Worsening in 6MWD [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.

    4. Time to Persistent 10% Worsening in Timed Function Tests (TFT) [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.

    5. Change From Baseline in Pediatric Outcomes Data Collection Instrument (PODCI) Scores [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.

    6. Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil [Weeks 4, 12, 24 and 36: -1 Hour up to 24 Hours Postdose]

      The data reported are population estimate and inter-patient variability.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    7 Years to 14 Years
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Cedars Sinai Medical Center Los Angeles California United States 90048
    2 University of California, Davis - Health Systems Sacramento California United States 95817
    3 Children's Hospital Aurora Colorado United States 80045
    4 University of Florida Health Science Center Gainesville Florida United States 32610
    5 NW Florida Clinical Research Group Gulf Breeze Florida United States 32561
    6 Nemours Children's Hospital Orlando Florida United States 32827
    7 Ann and Robert Lurie Children's Hospital of Chicago Chicago Illinois United States 60611
    8 University of Iowa Iowa City Iowa United States 52242
    9 University of Kansas Medical Center Kansas City Kansas United States 66160
    10 Washington University Medical Center Saint Louis Missouri United States 63110
    11 Carolinas Healthcare System Charlotte North Carolina United States 28203
    12 Duke University Medical Center Durham North Carolina United States 27705
    13 Childrens Hospital Medical Center Cincinnati Ohio United States 45229
    14 Oregon Health and Science University Portland Oregon United States 97239
    15 Pennsylvania State University College of Medicine Hershey Pennsylvania United States 17033
    16 Childrens Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    17 Childrens Hospital of Pittsburgh Pittsburgh Pennsylvania United States 15224
    18 Vanderbilt University Medical Center Nashville Tennessee United States 37232
    19 Children's Medical Center Dallas Dallas Texas United States 75207
    20 Univ of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    21 University of Utah School of Medicine Salt Lake City Utah United States 84132
    22 Children of the King's Daughters Norfolk Virginia United States 23510
    23 Seattle Children's Hospital Research Foundation Seattle Washington United States 98105
    24 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Caba Argentina C1204AAD
    25 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Gent Belgium 9000
    26 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Leuven Belgium 3000
    27 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Liège Belgium 4000
    28 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Calgary Alberta Canada T3B 6A8
    29 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Vancouver British Columbia Canada V6H 3V4
    30 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Winnipeg Manitoba Canada R3A 1R9
    31 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Halifax Nova Scotia Canada B3K 6R8
    32 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. London Ontario Canada N6C 2V5
    33 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Ottawa Ontario Canada K1H 8L1
    34 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Angers France 49933
    35 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nantes France 44093
    36 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Dresden Germany 01307
    37 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Essen Germany 45122
    38 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Freiburg Germany 79106
    39 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Göttingen Germany 37075
    40 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Munich Germany 80337
    41 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Genova Italy 16147
    42 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Milano Italy 20122
    43 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Padova Italy 35128
    44 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Rome Italy 00165
    45 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Aichi Japan 467-8602
    46 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nagano Japan 390-8621
    47 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Saitama Japan 349-0196
    48 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tokyo Japan 187-8551
    49 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Seoul Korea, Republic of 110-744
    50 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Leiden Netherlands 2300 RC
    51 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nijmegen Netherlands 6500 HB
    52 University of Puerto Rico, Medical Sciences Campus San Juan Puerto Rico 000935
    53 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Moscow Russian Federation 125412
    54 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Barcelona Spain 08025
    55 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Madrid Spain 28046
    56 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. San Sebastian Spain 20014
    57 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Valencia Spain 46026
    58 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kaohsiung Taiwan 807
    59 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Taipei Taiwan 100
    60 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Adana Turkey 01330
    61 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Ankara Turkey 06100
    62 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Oxford Oxfordshire United Kingdom OX3 9DU

    Sponsors and Collaborators

    • Eli Lilly and Company

    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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT01865084
    Other Study ID Numbers:
    • 15122
    • H6D-MC-LVJJ
    First Posted:
    May 30, 2013
    Last Update Posted:
    Oct 9, 2019
    Last Verified:
    Sep 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Muscular Dystrophies
    Muscular Dystrophy, Duchenne
    Tadalafil

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Arm/Group Description Placebo taken orally once daily. 0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.
    Period Title: Double Blind Period (DB)
    STARTED 116 102 113
    Received at Least One Dose of Study Drug 116 102 112
    COMPLETED 111 98 107
    NOT COMPLETED 5 4 6
    Period Title: Double Blind Period (DB)
    STARTED 0 150 165
    COMPLETED 0 139 158
    NOT COMPLETED 0 11 7

    Baseline Characteristics

    Arm/Group Title Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil Total
    Arm/Group Description Placebo taken orally once daily. 0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily. Total of all reporting groups
    Overall Participants 116 102 113 331
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    9.4
    (1.76)
    9.9
    (2.26)
    9.5
    (1.71)
    9.6
    (1.92)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Male
    116
    100%
    102
    100%
    113
    100%
    331
    100%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    2
    1.8%
    2
    0.6%
    Asian
    15
    12.9%
    16
    15.7%
    20
    17.7%
    51
    15.4%
    Native Hawaiian or Other Pacific Islander
    3
    2.6%
    1
    1%
    3
    2.7%
    7
    2.1%
    Black or African American
    0
    0%
    0
    0%
    1
    0.9%
    1
    0.3%
    White
    96
    82.8%
    82
    80.4%
    84
    74.3%
    262
    79.2%
    More than one race
    2
    1.7%
    3
    2.9%
    2
    1.8%
    7
    2.1%
    Unknown or Not Reported
    0
    0%
    0
    0%
    1
    0.9%
    1
    0.3%
    Region of Enrollment (Count of Participants)
    Argentina
    7
    6%
    4
    3.9%
    6
    5.3%
    17
    5.1%
    Russian Federation
    4
    3.4%
    4
    3.9%
    4
    3.5%
    12
    3.6%
    United States
    39
    33.6%
    34
    33.3%
    34
    30.1%
    107
    32.3%
    Japan
    6
    5.2%
    5
    4.9%
    6
    5.3%
    17
    5.1%
    Spain
    9
    7.8%
    7
    6.9%
    12
    10.6%
    28
    8.5%
    Canada
    8
    6.9%
    7
    6.9%
    8
    7.1%
    23
    6.9%
    Netherlands
    2
    1.7%
    1
    1%
    3
    2.7%
    6
    1.8%
    Turkey
    5
    4.3%
    7
    6.9%
    8
    7.1%
    20
    6%
    Belgium
    8
    6.9%
    5
    4.9%
    4
    3.5%
    17
    5.1%
    Taiwan
    6
    5.2%
    4
    3.9%
    8
    7.1%
    18
    5.4%
    Korea, Republic of
    3
    2.6%
    4
    3.9%
    5
    4.4%
    12
    3.6%
    Italy
    8
    6.9%
    8
    7.8%
    8
    7.1%
    24
    7.3%
    France
    3
    2.6%
    2
    2%
    2
    1.8%
    7
    2.1%
    Germany
    8
    6.9%
    10
    9.8%
    5
    4.4%
    23
    6.9%

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Six Minute Walk Distance (6MWD) in Meters
    Description 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.
    Time Frame Baseline, Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug who had a baseline and at least one post-baseline measurement.
    Arm/Group Title Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Arm/Group Description Placebo taken orally once daily. 0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg taken tadalafil orally once daily.
    Measure Participants 113 101 111
    Least Squares Mean (Standard Error) [Meters]
    -50.99
    (9.316)
    -64.71
    (9.809)
    -59.08
    (9.397)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 0.3 mg/kg Tadalafil
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.307
    Comments The p-value is based on the treatment difference LS Mean changes from baseline between tadalafil and placebo.
    Method Mixed Models Analysis
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, 0.6 mg/kg Tadalafil
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.538
    Comments The p-value is based on the treatment difference LS Mean changes from baseline between tadalafil and placebo.
    Method Mixed Models Analysis
    Comments
    2. Secondary Outcome
    Title Change From Baseline in the North Star Ambulatory Assessment (NSAA) Global Score
    Description 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.
    Time Frame Baseline, Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug who had a baseline and at least one post-baseline measurement.
    Arm/Group Title Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Arm/Group Description Placebo taken orally once daily. 0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.
    Measure Participants 116 102 112
    Least Squares Mean (Standard Error) [Units on a scale]
    -8.80
    (1.104)
    -9.31
    (1.181)
    -8.96
    (1.115)
    3. Secondary Outcome
    Title Change From Baseline in Timed Function Tests in Seconds
    Description 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 Frame Baseline, Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug who had a baseline and at least one post-baseline measurement.
    Arm/Group Title Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Arm/Group Description Placebo taken orally once daily. 0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.
    Measure Participants 116 96 110
    Rise from the Floor(n=92,75,89)
    4.16
    (1.120)
    3.60
    (1.223)
    4.81
    (1.156)
    10 Meter Walk/Run(n=105,90,100)
    1.11
    (0.204)
    0.95
    (0.226)
    1.12
    (0.217)
    Stair Climb (n=116,96,110)
    3.96
    (1.041)
    4.10
    (1.154)
    5.82
    (1.072)
    Stair Descend(n=115,95,110)
    3.19
    (0.827)
    2.07
    (0.915)
    3.27
    (0.853)
    4. Secondary Outcome
    Title Time to Persistent 10% Worsening in 6MWD
    Description 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 Frame Baseline through Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug who had complete evaluable data. Complete evaluable data was defined as having baseline measurement, complete dates at evaluable visits and a post-baseline measurement at each evaluable visit. Censored participants: placebo=71, 0.3 mg/kg=63, 0.6 mg/kg=61.
    Arm/Group Title Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Arm/Group Description Placebo taken orally once daily. 0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.
    Measure Participants 115 101 111
    Median (95% Confidence Interval) [Days]
    NA
    NA
    NA
    5. Secondary Outcome
    Title Time to Persistent 10% Worsening in Timed Function Tests (TFT)
    Description 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.
    Time Frame Baseline through Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study drug who had complete evaluable data.Censored participants:Rise from Floor;placebo(pl)=40,0.3 mg/kg=39,0.6 mg/kg=43;Stair Climb;pl=55,0.3 mg/kg=45,0.6 mg/kg=52;10 Meter Walk/Run pl=61,0.3 mg/kg=65,0.6 mg/kg=58,Stair Descend;pl=63,0.3 mg/kg=60,0.6 mg/kg=59.
    Arm/Group Title Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Arm/Group Description Placebo taken orally once daily. 0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.
    Measure Participants 116 102 113
    Rise from the Floor (n=81,67,77)
    253.0
    NA
    NA
    Stair Climb (n=112,91,107)
    255.0
    259.0
    253.0
    10 Meter Walk/Run (n=98,83,91)
    NA
    NA
    NA
    Stair Descend (n=110,91,108)
    NA
    NA
    NA
    6. Secondary Outcome
    Title Change From Baseline in Pediatric Outcomes Data Collection Instrument (PODCI) Scores
    Description 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.
    Time Frame Baseline, Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug who had a baseline and at least one post-baseline measurement. The reason the number of participants analyzed is significantly less than the total number of randomized participants is because PODCI was administered only in English.
    Arm/Group Title Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Arm/Group Description Placebo taken orally once daily. 0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.
    Measure Participants 41 35 34
    Global Functioning Scale (n=41,34,34)
    -8.81
    (1.770)
    -7.36
    (1.929)
    -7.34
    (1.888)
    Upper Extremity & Physical Function
    -5.47
    (1.901)
    -3.73
    (2.060)
    -2.47
    (2.042)
    Transfer/Basic Mobility Core Scale
    -14.26
    (3.037)
    -12.50
    (3.260)
    -12.78
    (3.279)
    Sports/Physical Functioning Core Scale
    -12.47
    (2.362)
    -11.98
    (2.552)
    -7.88
    (2.537)
    7. Secondary Outcome
    Title Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil
    Description The data reported are population estimate and inter-patient variability.
    Time Frame Weeks 4, 12, 24 and 36: -1 Hour up to 24 Hours Postdose

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and had evaluable PK data.
    Arm/Group Title 0.3 mg/kg Tadalafil and 0.6 mg/kg Tadalafil
    Arm/Group Description 0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.
    Measure Participants 210
    Geometric Mean (Geometric Coefficient of Variation) [Liter per hour (L/hr)]
    1.79
    (29.6)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description All randomized participants who received at least one dose of study drug for Placebo - DB, 0.3 mg/kg Tadalafil -DB and 0.6 mg/kg Tadalafil - DB arms during the DB period. All randomized participants who received at least one dose of study drug for 0.3 mg/kg Tadalafil - OLE and 0.6 mg/kg Tadalafil - OLE arms during the OLE period.
    Arm/Group Title Placebo - DB 0.3 mg/kg Tadalafil -DB 0.6 mg/kg Tadalafil - DB 0.3 mg/kg Tadalafil - OLE 0.6 mg/kg Tadalafil - OLE
    Arm/Group Description Placebo taken orally once daily. 0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily. 0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.
    All Cause Mortality
    Placebo - DB 0.3 mg/kg Tadalafil -DB 0.6 mg/kg Tadalafil - DB 0.3 mg/kg Tadalafil - OLE 0.6 mg/kg Tadalafil - OLE
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Placebo - DB 0.3 mg/kg Tadalafil -DB 0.6 mg/kg Tadalafil - DB 0.3 mg/kg Tadalafil - OLE 0.6 mg/kg Tadalafil - OLE
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/116 (4.3%) 4/102 (3.9%) 6/112 (5.4%) 6/150 (4%) 9/165 (5.5%)
    Cardiac disorders
    Myocarditis 0/116 (0%) 0 1/102 (1%) 1 0/112 (0%) 0 0/150 (0%) 0 0/165 (0%) 0
    Gastrointestinal disorders
    Vomiting 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    General disorders
    Abasia 1/116 (0.9%) 1 0/102 (0%) 0 0/112 (0%) 0 1/150 (0.7%) 1 0/165 (0%) 0
    Infections and infestations
    Appendicitis 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Bronchitis 1/116 (0.9%) 1 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 0/165 (0%) 0
    Gastroenteritis 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Gastroenteritis viral 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Gastrointestinal infection 0/116 (0%) 0 1/102 (1%) 1 0/112 (0%) 0 0/150 (0%) 0 0/165 (0%) 0
    Influenza 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Pharyngotonsillitis 0/116 (0%) 0 0/102 (0%) 0 1/112 (0.9%) 1 0/150 (0%) 0 0/165 (0%) 0
    Pneumonia 0/116 (0%) 0 1/102 (1%) 1 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Pneumonia adenoviral 0/116 (0%) 0 0/102 (0%) 0 1/112 (0.9%) 1 0/150 (0%) 0 0/165 (0%) 0
    Varicella 0/116 (0%) 0 0/102 (0%) 0 1/112 (0.9%) 1 0/150 (0%) 0 0/165 (0%) 0
    Injury, poisoning and procedural complications
    Ankle fracture 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 1/150 (0.7%) 1 0/165 (0%) 0
    Fall 1/116 (0.9%) 1 0/102 (0%) 0 2/112 (1.8%) 2 1/150 (0.7%) 1 1/165 (0.6%) 1
    Femoral neck fracture 1/116 (0.9%) 1 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 0/165 (0%) 0
    Femur fracture 0/116 (0%) 0 0/102 (0%) 0 2/112 (1.8%) 2 1/150 (0.7%) 1 1/165 (0.6%) 1
    Lower limb fracture 1/116 (0.9%) 1 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 0/165 (0%) 0
    Spinal fracture 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Metabolism and nutrition disorders
    Decreased appetite 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 1/150 (0.7%) 1 0/165 (0%) 0
    Musculoskeletal and connective tissue disorders
    Muscle contracture 0/116 (0%) 0 1/102 (1%) 1 0/112 (0%) 0 0/150 (0%) 0 0/165 (0%) 0
    Tendinous contracture 1/116 (0.9%) 1 0/102 (0%) 0 1/112 (0.9%) 1 1/150 (0.7%) 1 0/165 (0%) 0
    Tendon disorder 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Nervous system disorders
    Extrapyramidal disorder 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 1/150 (0.7%) 1 0/165 (0%) 0
    Psychiatric disorders
    Self injurious behaviour 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Suicidal ideation 0/116 (0%) 0 0/102 (0%) 0 0/112 (0%) 0 0/150 (0%) 0 1/165 (0.6%) 1
    Other (Not Including Serious) Adverse Events
    Placebo - DB 0.3 mg/kg Tadalafil -DB 0.6 mg/kg Tadalafil - DB 0.3 mg/kg Tadalafil - OLE 0.6 mg/kg Tadalafil - OLE
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 83/116 (71.6%) 82/102 (80.4%) 92/112 (82.1%) 68/150 (45.3%) 84/165 (50.9%)
    Gastrointestinal disorders
    Abdominal pain 6/116 (5.2%) 7 4/102 (3.9%) 4 9/112 (8%) 9 2/150 (1.3%) 2 3/165 (1.8%) 3
    Abdominal pain upper 7/116 (6%) 7 5/102 (4.9%) 6 8/112 (7.1%) 8 4/150 (2.7%) 5 2/165 (1.2%) 2
    Diarrhoea 10/116 (8.6%) 10 6/102 (5.9%) 9 10/112 (8.9%) 19 9/150 (6%) 13 7/165 (4.2%) 7
    Nausea 2/116 (1.7%) 2 7/102 (6.9%) 8 3/112 (2.7%) 3 1/150 (0.7%) 1 1/165 (0.6%) 1
    Vomiting 14/116 (12.1%) 20 6/102 (5.9%) 6 17/112 (15.2%) 25 9/150 (6%) 12 10/165 (6.1%) 11
    General disorders
    Abasia 6/116 (5.2%) 6 14/102 (13.7%) 14 9/112 (8%) 9 12/150 (8%) 12 16/165 (9.7%) 16
    Pyrexia 4/116 (3.4%) 4 11/102 (10.8%) 11 9/112 (8%) 10 7/150 (4.7%) 8 6/165 (3.6%) 6
    Infections and infestations
    Gastroenteritis 6/116 (5.2%) 6 4/102 (3.9%) 4 3/112 (2.7%) 3 3/150 (2%) 3 2/165 (1.2%) 2
    Influenza 9/116 (7.8%) 9 8/102 (7.8%) 9 5/112 (4.5%) 5 3/150 (2%) 3 2/165 (1.2%) 2
    Nasopharyngitis 16/116 (13.8%) 26 8/102 (7.8%) 10 18/112 (16.1%) 24 8/150 (5.3%) 10 12/165 (7.3%) 12
    Sinusitis 6/116 (5.2%) 11 4/102 (3.9%) 5 3/112 (2.7%) 3 1/150 (0.7%) 1 0/165 (0%) 0
    Upper respiratory tract infection 10/116 (8.6%) 18 10/102 (9.8%) 21 12/112 (10.7%) 16 6/150 (4%) 15 8/165 (4.8%) 10
    Injury, poisoning and procedural complications
    Fall 24/116 (20.7%) 41 18/102 (17.6%) 30 22/112 (19.6%) 41 16/150 (10.7%) 22 15/165 (9.1%) 18
    Musculoskeletal and connective tissue disorders
    Back pain 9/116 (7.8%) 15 11/102 (10.8%) 12 7/112 (6.3%) 7 7/150 (4.7%) 7 9/165 (5.5%) 9
    Muscle spasms 7/116 (6%) 9 3/102 (2.9%) 3 3/112 (2.7%) 4 0/150 (0%) 0 2/165 (1.2%) 2
    Pain in extremity 8/116 (6.9%) 14 6/102 (5.9%) 6 10/112 (8.9%) 11 2/150 (1.3%) 2 4/165 (2.4%) 4
    Nervous system disorders
    Headache 36/116 (31%) 92 40/102 (39.2%) 57 43/112 (38.4%) 68 8/150 (5.3%) 12 14/165 (8.5%) 19
    Reproductive system and breast disorders
    Erection increased 3/116 (2.6%) 3 10/102 (9.8%) 11 17/112 (15.2%) 18 2/150 (1.3%) 2 4/165 (2.4%) 4
    Spontaneous penile erection 4/116 (3.4%) 6 13/102 (12.7%) 13 13/112 (11.6%) 14 3/150 (2%) 3 4/165 (2.4%) 4
    Respiratory, thoracic and mediastinal disorders
    Cough 10/116 (8.6%) 11 4/102 (3.9%) 4 5/112 (4.5%) 5 4/150 (2.7%) 5 5/165 (3%) 5
    Epistaxis 5/116 (4.3%) 11 10/102 (9.8%) 15 6/112 (5.4%) 8 4/150 (2.7%) 6 3/165 (1.8%) 5
    Skin and subcutaneous tissue disorders
    Rash 7/116 (6%) 7 3/102 (2.9%) 3 5/112 (4.5%) 5 3/150 (2%) 3 1/165 (0.6%) 1
    Vascular disorders
    Flushing 3/116 (2.6%) 3 8/102 (7.8%) 8 8/112 (7.1%) 9 2/150 (1.3%) 2 2/165 (1.2%) 2

    Limitations/Caveats

    The Sponsor concluded that the efficacy results do not provide sufficient justification for continuance of the open-label extension (OLE) period of the study, where all participants were receiving daily treatment with tadalafil.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-545-5979
    Email
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT01865084
    Other Study ID Numbers:
    • 15122
    • H6D-MC-LVJJ
    First Posted:
    May 30, 2013
    Last Update Posted:
    Oct 9, 2019
    Last Verified:
    Sep 1, 2019