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A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)

key information

study id #: NCT03439670

condition: Duchenne Muscular Dystrophy

status: recruiting

purpose:

This Phase IIb study is a randomized, double-blind, parallel group, placebo and active-controlled study to evaluate the efficacy, safety, PD, and population PK of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 24 weeks, and to evaluate persistence of effect over a Treatment Period of 48 weeks in ambulant boys ages 4 to <7 years with DMD.

intervention: Vamorolone, Prednisone, Placebo

mechanism of action: Glucocorticoids to delay decline in muscle strength

results: https://clinicaltrials.gov/ct2/show/results/NCT03439670

last updated: August 14, 2019

study details

start date: June 19, 2018

estimated completion: May 1, 2020

phase of development: Phase 2

size / enrollment: 120

study description:
This Phase IIb study is a randomized, double-blind, parallel group, placebo and active-controlled study to evaluate the efficacy, safety, PD, and population PK of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 24 weeks, and to evaluate persistence of effect over a Treatment Period of 48 weeks in ambulant boys ages 4 to <7 years with DMD.
The study is comprised of a 5-week Pretreatment Screening Period, a 1-day Pretreatment Baseline Period, a 24-week Treatment Period #1 (Weeks 1-24), a 4-week Transition Period (Weeks 25-28), a 20-week Treatment Period #2 (Weeks 28 + 1 day to 48), and a 4-week Dose-tapering Period (Weeks 49-52).
Subjects will be randomized to one of six treatment groups in a 2:2:1:1:1:1 ratio, where the two prednisone groups in Treatment Period #1 (Groups 3 and 4) will be combined and the two placebo groups in Treatment Period #1 (Groups 5 and 6) will be combined, effectively resulting in a 1:1:1:1 randomization (vamorolone 2.0 mg/kg/day : vamorolone 6.0 mg/kg/day : prednisone 0.75 mg/kg/day : placebo) for Treatment Period #1.
Subjects will be stratified based on age at study entry (<6 vs. ≥ 6 years). During the 4-week Transition Period between Treatment Period #1 and Treatment Period #2, all subjects will continue on the same oral suspension (vamorolone 2.0 mg/kg or 6.0 mg/kg, or matching placebo) they received during Treatment Period #1 and all subjects will have their tablet dose tapered to zero. Thus, subjects randomized to receive vamorolone during Treatment Period #1 (Groups 1 and 2) will continue to receive vamorolone at the same dose, while subjects randomized to receive prednisone will have their dose tapered to zero, and subjects randomized to placebo will continue to receive placebo.
The prednisone group will be used as an active control comparison for safety and efficacy endpoints as requested by the European Medicines Agency (EMA). The placebo group will be used as comparator for efficacy endpoints (superiority model) as requested by the EMA and Food and Drug Administration (FDA) protocol advisory board. Although glucocorticoids are part of the care recommendations for DMD, their adverse effect profile has limited their use. The age at which glucocorticoids should be started in DMD boys is uncertain, ranging from 4 to 7 years, based on a balance between benefits and side effects. In view of the age inclusion criteria and duration of the placebo-controlled study period (6 months), the use of a placebo group has been considered acceptable as in clinical practice it will not cause a real delay in prescription of an accepted treatment for this condition. Any exposure of placebo longer than 6 months was considered unethical.
At the end of the Treatment Period #2, subjects may be given access to vamorolone through an additional study or general access program, or given the option to transition to standard of care treatment for DMD (may include glucocorticoids). Subjects completing VBP15-004 and enrolling directly into an additional vamorolone study or general access program to receive vamorolone will not need to taper their vamorolone dose prior to enrollment. All other subjects will begin a 4-week double-blind Dose-tapering Period during which the dose of study medication will be progressively reduced and discontinued.

primary outcomes:

  • Muscle function measured by Time to Stand Test (TTSTAND) [ Time Frame: 24 weeks ]
    (vamorolone at 2.0mg/kg/day and 6.0mg/kg/day vs. placebo)
  • Body Size as measured by body mass index (BMI) z-score [ Time Frame: 24 weeks ]
    (vamorolone at 2.0mg/kg/day and 6.0mg/kg/day vs. prednisone at 0.75 mg/kg/day)

secondary outcomes:

  • Safety measure by Treatment emergent adverse events (TRAEs) and serious adverse events (SAEs) by organ system class (SOC). [ Time Frame: 48 weeks ]
    Overall by treatment, by treatment and relationship, and by treatment and intensity.
  • Safety measure assessed by sitting blood pressure. [ Time Frame: Day 1, Week 2, Week 6, Week 12,Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Safety measure assessed by heart rate. [ Time Frame: Day 1, Week 2, Week 6, Week 12,Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Safety measured assessed by respiratory rate. [ Time Frame: Day 1, Week 2, Week 6, Week 12,Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Safety measure assesed by body temperature. [ Time Frame: Day 1, Week 2, Week 6, Week 12,Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Safety measure assessed by body weight. [ Time Frame: Week 2, Week 6, Week 12, Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Safety measure assessed by height [ Time Frame: Week 12, Week 24, Week 34, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Cushingoid features measured by the presence of buffalo hump obesity, striations, adiposity, hypertension, diabetes, or osteoporosis [ Time Frame: Week 6, Week 12, Week 18, Week 24, Week 28, Week 34, Week 40, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Safety measure assessed by blood laboratory measures. [ Time Frame: Day 1, Week 2, Week 6, Week 12, Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Safety measure assessed by urine laboratory measures. [ Time Frame: Day 1, Week 2, Week 6, Week 12, Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48 ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Cardiac function measured by 12 lead electrocardiogram (ECG) [ Time Frame: Week 12, Week 24, Week 40, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Cardiac function measured by 2-D echocardiogram. [ Time Frame: Week 24, Week 48. ]
    Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
  • Safety measure based on dual-energy x-ray absorptiometry (DXA) scan. [ Time Frame: Week 24, Week 48. ]
    Change from baseline to Week 24 and Week 48 in BMD Z-score.
  • Spine Fracture measured by spine X-ray [ Time Frame: 24 weeks ]
    Change from baseline to Week 24 assessment.
  • Cataracts measured by the presence of partial or complete opacity of the crystalline lens of one or both eyes. [ Time Frame: Week 24, Week 48 ]
    Week 24 and Week 48 assessments compared to baseline
  • Glaucoma measured by measured by ocular pressure. [ Time Frame: Week 24, Week 48 ]
    Week 24 and Week 48 assessments compared to baseline
  • Safety measured assessed by Synacthen (ACTH) test [ Time Frame: 24, 48 weeks ]
  • Efficacy measured by Time to Stand Test (TTSTAND) [ Time Frame: 48 weeks ]
    (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
  • Efficacy measured by Time to Climb (TTCLIMB). [ Time Frame: 24, 48 weeks ]
    (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
  • Efficacy as measured by Time to Run/Walk Test (TTRW). [ Time Frame: 24, 48 weeks ]
    (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
  • Efficacy as measured by total distance traveled in meters, in completing the Six-minute Walk Test (6MWT) [ Time Frame: 24, 48 weeks ]
    (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
  • Efficacy as measured by the North Star Ambulatory Assessment (NSAA) [ Time Frame: 24, 48 weeks ]
    (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
  • Efficacy as measured by hand-held myometry (elbow flexors and knee extensors) [ Time Frame: 24, 48 weeks ]
    (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
  • Efficacy as measured by range of motion in the ankles (ROM) [ Time Frame: 24, 48 weeks ]
    (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
  • Safety as measured by serum pharmacodynamic biomarkers by morning cortisol. [ Time Frame: 48 weeks ]
  • Safety as measured by serum pharmacodynamic biomarkers by levels of fasting glucose. [ Time Frame: 48 weeks ]
  • Safety as measured by serum pharmacodynamic biomarkers by levels of fasting insulin. [ Time Frame: 48 weeks ]
  • Safety as measured by serum pharmacodynamic biomarkers by levels of osteocalcin. [ Time Frame: 48 weeks ]
  • Safety as measured by serum pharmacodynamic biomarkers by levels of CTX1. [ Time Frame: 48 weeks ]
  • Safety as measured by serum pharmacodynamic biomarkers by levels of P1NP. [ Time Frame: 48 weeks ]
  • Safety as measured by serum pharmacodynamic biomarkers by levels of differential lymphocyte percentage. [ Time Frame: 48 weeks ]
  • Extremity Fracture Questionnaire [ Time Frame: 24, 48 weeks ]
  • Physical examination findings at each of the pretreatment, on treatment, and post treatment assessment time points determined by change from baseline in physical examination findings, with assessment of clinical significance [ Time Frame: 48 weeks ]

inclusion criteria:
• Subject's parent(s) or legal guardian(s) has (have) provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization, where applicable, prior to any study-related procedures; participants will be asked to give written or verbal assent according to local requirements
• Subject has a centrally confirmed (by TRiNDS central genetic counselor[s]) diagnosis of DMD as defined as:
-Dystrophin immunofluorescence and/or immunoblot showing complete dystrophin deficiency, and clinical picture consistent with typical DMD, OR
-Identifiable mutation within the DMD gene (deletion/duplication of one or more exons), where reading frame can be predicted as 'out-of-frame,' and clinical picture consistent with typical DMD, OR
-Complete dystrophin gene sequencing showing an alteration (point mutation, duplication, other) that is expected to preclude production of the dystrophin protein (i.e., nonsense mutation, deletion/duplication leading to a downstream stop codon), with a clinical picture consistent with typical DMD;
• Subject is >= 4 years and <7 years of age at time of enrollment in the study;
• Subject weighs >13.0 kg and =< 39.9 kg at the Screening Visit;
• Subject is able to walk independently without assistive devices;
• Subject is able to complete the Time to Stand Test (TTSTAND) without assistance in <10 seconds, as assessed at the Screening Visit;
• Clinical laboratory test results are within the normal range at the Screening Visit, or if abnormal, are not clinically significant, in the opinion of the Investigator. [Note: Serum gamma glutamyl transferase (GGT), creatinine, and total bilirubin all must be <= upper limit of the normal range at the Screening Visit];
• Subject has evidence of chicken pox immunity as determined by:
- Presence of IgG antibodies to varicella, as documented by a positive test result from the local laboratory from blood collected during the Screening Period, OR
- Documentation, provided at the Screening Visit, that the subject has had 2 doses of varicella vaccine, with or without serologic evidence of immunity; the second of the 2 immunizations must have been given at least 14 days prior to randomization.
• Subject is able to swallow tablets, as confirmed by successful test swallowing of placebo tablets during the Screening Period; and
• Subject and parent(s)/guardian(s) are willing and able to comply with scheduled visits, study drug administration plan, and study procedures.

exclusion criteria:
• Subject has current or history of major renal or hepatic impairment, diabetes mellitus or immunosuppression;
• Subject has current or history of chronic systemic fungal or viral infections;
• Subject has had an acute illness within 4 weeks prior to the first dose of study medication;
• Subject has used mineralocorticoid receptor agents, such as spironolactone, eplerenone, canrenone (canrenoate potassium), prorenone (prorenoate potassium), mexrenone (mexrenoate potassium) within 4 weeks prior to the first dose of study medication;
• Subject has a history of primary hyperaldosteronism;
• Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary];
• Subject is currently being treated or has received previous treatment with oral glucocorticoids or other immunosuppressive agents [Notes: Past transient use of oral glucocorticoids or other oral immunosuppressive agents for no longer than 1 month cumulative, with last use at least 3 months prior to first dose of study medication, will be considered for eligibility on a case-by-case basis, unless discontinued for intolerance. Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to first dose of study medication or if administered at stable dose beginning at least 4 weeks prior to first dose of study medication and anticipated to be used at the stable dose regimen for the duration of the study];
• Subject has an allergy or hypersensitivity to the study medication or to any of its constituents;
• Subject has used idebenone within 4 weeks prior to the first dose of study medication;
• Subject has severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the Investigator;
• Subject has previous or ongoing medical condition, medical history, physical findings or laboratory abnormalities that could affect safety, make it unlikely that treatment and follow-up will be correctly completed or impair the assessment of study results, in the opinion of the Investigator;
• Subject is taking (or has taken within 4 weeks prior to the first dose of study medication) herbal remedies and supplements which can impact muscle strength and function (e.g., Co-enzyme Q10, creatine, etc);
• Subject is taking (or has taken within 3 months prior to the first dose of study medication) any medication indicated for DMD, including Exondys51 and Translarna;
• Subject has been administered a live attenuated vaccine within 14 days prior to the first dose of study medication;
• Subject is currently taking any other investigational drug or has taken any other investigational drug within 3 months prior to the first dose of study medication;
• Subject has a sibling who is currently enrolled in any vamorolone study or Expanded Access Program, or who intends to enroll in any vamorolone study or Expanded Access Program during the subject's participation in the VBP15-004 study; or
• Subject has previously been enrolled in the study. Note: Any parameter/test may be repeated at the Investigator's discretion during Screening to determine reproducibility. In addition, subjects may be rescreened if ineligible due to a transient condition which would prevent the subject from participating, such as an upper respiratory tract infection or injury, or if ineligible due to negative anti-varicella IgG antibody test result.

study contacts

sponsor: ReveraGen BioPharma, Inc.

contacts:
Andrea Smith, +1 (412) 436-9139, asmith@trinds.com;
Eric P Hoffman (PhD), eric.hoffman@reveragen.com

investigators: Michela Guglieri, MD; Paula Clemens, MD

locations: United States, Australia, Canada, Israel, Netherlands, Sweden, United Kingdom

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