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

Duchenne Muscular Dystrophy Clinical Trial

Official title:

A Phase IIb Randomized, Double-blind, Parallel Group, Placebo- and Active-controlled Study With Double-Blind Extension to Assess the Efficacy and Safety of Vamorolone in Ambulant Boys With Duchenne Muscular Dystrophy (DMD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03439670
• Other study ID #: VBP15-004
• Status: Completed
• Phase: Phase 2
• Start date: June 29, 2018
• Est. completion date: August 19, 2021

Study information

• Verified date: March 2023
• Source: ReveraGen BioPharma, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Brief Summary: 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 121
• Est. completion date: August 19, 2021
• Est. primary completion date: February 23, 2021
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 4 Years to 7 Years

Eligibility

Inclusion Criteria:

1. 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

2. 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;

3. Subject is = 4 years and <7 years of age at time of enrollment in the study;

4. Subject weighs >13.0 kg and = 39.9 kg at the Screening Visit;

5. Subject is able to walk independently without assistive devices;

6. Subject is able to complete the Time to Stand Test (TTSTAND) without assistance in <10 seconds, as assessed at the Screening Visit;

7. 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. [Notes: Serum gamma glutamyl transferase (GGT), creatinine, and total bilirubin all must be = upper limit of the normal range at the Screening Visit. An abnormal vitamin D level that is considered clinically significant will not exclude a subject from randomization];

8. 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.

9. Subject is able to swallow tablets, as confirmed by successful test swallowing of placebo tablets during the Screening Period; and

10. Subject and parent(s)/guardian(s) are willing and able to comply with scheduled visits, study drug administration plan, and study procedures.

Exclusion Criteria:

1. Subject has current or history of major renal or hepatic impairment, diabetes mellitus or immunosuppression;

2. Subject has current or history of chronic systemic fungal or viral infections;

3. Subject has had an acute illness within 4 weeks prior to the first dose of study medication;

4. 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;

5. Subject has a history of primary hyperaldosteronism;

6. Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary];

7. 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];

8. Subject has an allergy or hypersensitivity to the study medication or to any of its constituents;

9. Subject has used idebenone within 4 weeks prior to the first dose of study medication;

10. Subject has severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the Investigator;

11. 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;

12. 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);

13. 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;

14. Subject has been administered a live attenuated vaccine within 14 days prior to the first dose of study medication;

15. 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;

16. 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

17. 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.

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Vamorolone
Oral administration of 2.0 mg/kg/day for the duration of the study.
• Prednisone
Oral administration of 0.75 mg/kg/day for 24 weeks.

Other:
• Placebo
Oral administration of placebo daily for 24 weeks.

Drug:
• Vamorolone
Oral administration of 6.0 mg/kg/day for the duration of the study.
• Prednisone
Oral administration of 0.75 mg/kg/day for 24 weeks.

Other:
• Placebo
Oral administration of placebo daily for 24 weeks.

Drug:
• Vamorolone
Oral administration of 2.0 mg/kg/day for 20 weeks.
• Vamorolone
Oral administration of 6.0 mg/kg/day for 20 weeks.

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Melbourne
Australia	Sydney Children's Hospital	Westmead
Belgium	Ghent University Hospital	Ghent
Belgium	University Hospitals Leuven	Leuven
Canada	Alberta's Children Hospital	Calgary	Alberta
Canada	Montreal Children's Hospital	Montréal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Czechia	University Hospital Brno	Brno
Czechia	Charles University	Prague
Greece	Agia Sofia Children's Hospital	Athens
Israel	Schneider Children's Medical Center	Petah Tikvah
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Radboud University	Nijmegen
Spain	Sant Joan de Deu Hospital - Barcelona, Spain	Barcelona
Spain	Hospital Universitario y Politécnico La Fe	Valencia
Sweden	Queen Silvia Children's Hospital	Gothenburg
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	Royal Hospital for Children	Glasgow
United Kingdom	Leeds Teaching Hospital Trust	Leeds
United Kingdom	Alder Hey Children's NHS Foundation Trust	Liverpool
United Kingdom	Great Ormond Street Hospital	London
United Kingdom	Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Ann & Robert H. Lurie Children's Hospital	Chicago	Illinois
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of California Davis	Davis	California
United States	Duke Children's Hospital	Durham	North Carolina
United States	University of California Los Angeles	Los Angeles	California
United States	Nemours Children's Hospital	Orlando	Florida
United States	Children's Hospital of Virginia of Virginia Commonwealth University	Richmond	Virginia
United States	Gillette Children's Speciality Health Care	Saint Paul	Minnesota
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (5)

Lead Sponsor	Collaborator
ReveraGen BioPharma, Inc.	Cooperative International Neuromuscular Research Group, European Union, Newcastle University, University of Pittsburgh

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  Greece,  Israel,  Netherlands,  Spain,  Sweden,  United Kingdom, 

References & Publications (43)

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* Note: There are 43 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy Measured by Time to Stand Test (TTSTAND) Velocity in Rises/Second Change From Baseline	Vamorolone at 6.0mg/kg/day vs. placebo group in change from baseline to the Week 24 assessment	24 weeks