An Extension Study to Assess Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)

• ClinicalTrials.gov Identifier: NCT02760277
• Recruitment Status: Completed
• First Posted: May 3, 2016
• Results First Posted: July 23, 2019
• Last Update Posted: July 23, 2019
• Sponsor: ReveraGen BioPharma, Inc.
• Collaborators: University of Pittsburgh; National Institute of Neurological Disorders and Stroke (NINDS); Cooperative International Neuromuscular Research Group; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Information provided by (Responsible Party): ReveraGen BioPharma, Inc.

Tracking Information

• First Submitted Date: April 28, 2016
• First Posted Date: May 3, 2016
• Results First Submitted Date: February 25, 2019
• Results First Posted Date: July 23, 2019
• Last Update Posted Date: July 23, 2019
• Actual Study Start Date: July 28, 2016
• Actual Primary Completion Date: April 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 19, 2019)

• Number of Participants With Adverse Events as Assessed by CTCAE Version 4.03 [ Time Frame: 24 weeks ]
  Treatment-emergent adverse events (TEAEs) are defined as any adverse event or worsening of an existing conditions after initiation of the investigational product and through the subject's last study visit (study completion or early termination). Serious adverse events were recorded for up to 30 days after the final administration of study drug; To evaluate the long-term safety and tolerability of vamorolone, administered orally at daily doses up to 6.0 mg/kg/day over a 24- week Treatment Period, in boys ages 4-7 years with DMD.
• Total Number of Adverse Events as Assessed by CTCAE Version 4.03 [ Time Frame: 24 weeks ]
  Treatment-emergent adverse events (TEAEs) are defined as any adverse event or worsening of an existing conditions after initiation of the investigational product and through the subject's last study visit (study completion or early termination). Serious adverse events were recorded for up to 30 days after the final administration of study drug; To evaluate the long-term safety and tolerability of vamorolone, administered orally at daily doses up to 6.0 mg/kg/day over a 24- week Treatment Period, in boys ages 4-7 years with DMD.
• Muscle Function Measured by Time to Stand Test (TTSTAND)- Velocity [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 12, Week 24 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To compare the efficacy, as measured by the Time to Stand Test (TTSTAND), of vamorolone administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. untreated DMD historical controls in boys ages 4-7 years with DMD
• BMI Z-score [ Time Frame: 002 Baseline, 003 Week 12, Week 24 ]
  Summary of BMI Z-score of Safety Population. Please note 0 is the mean. A negative result indicates a response that is many standard deviations below the mean, and a positive result indicates a response that is many standard deviations above the mean. In this case, the closer the group mean BMI Z-score is to 0 is more favorable.

Original Primary Outcome Measures (submitted: April 30, 2016)

• Number of participants with treatment-related adverse events as assessed by CTCAE Version 4.03 [ Time Frame: 24 weeks ]
• Muscle function measured by Time to Stand Test (TTSTAND) [ Time Frame: 24 weeks ]
• Body size as measured by body mass index (BMI) z-score [ Time Frame: 24 weeks ]

Current Secondary Outcome Measures (submitted: July 19, 2019)

• Serum Pharmacodynamics Biomarkers Measured by Levels of HbA1c [ Time Frame: 002 Baseline, 003 Week 8, 003 Week 16, 003 Week 24, 003 Week 26-29 ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal axis suppression, and bone turnover). SomaScan aptamer panels testing 1,200 serum proteins were used to discover a candidate set of prednisone-responsive biomarkers, with a subset of these validating in a longitudinal sample set (individual DMD patients pre/post steroid treatment). These PD biomarkers were assigned to a safety panel or efficacy panel based on comparison to normal controls and information concerning the function of each protein.
• Serum Pharmacodynamics Biomarkers Measured by Levels of ACTH [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 8, 003 Week 16, 003 Week 24, 003 Week 26-29 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal axis suppression, and bone turnover). SomaScan aptamer panels testing 1,200 serum proteins were used to discover a candidate set of prednisone-responsive biomarkers, with a subset of these validating in a longitudinal sample set (individual DMD patients pre/post steroid treatment). These PD biomarkers were assigned to a safety panel or efficacy panel based on comparison to normal controls and information concerning the function of each protein.
• Serum Pharmacodynamics Biomarkers Measured by Levels of Fasting Glucose [ Time Frame: 002 Baseline, 003 Week 12, 003 Week 24 ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal axis suppression, and bone turnover). SomaScan aptamer panels testing 1,200 serum proteins were used to discover a candidate set of prednisone-responsive biomarkers, with a subset of these validating in a longitudinal sample set (individual DMD patients pre/post steroid treatment). These PD biomarkers were assigned to a safety panel or efficacy panel based on comparison to normal controls and information concerning the function of each protein.
• Serum Pharmacodynamics Biomarkers Measured by Levels of Fasting Insulin [ Time Frame: 002 Baseline, 003 Week 12, 003 Week 24 ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal axis suppression, and bone turnover). SomaScan aptamer panels testing 1,200 serum proteins were used to discover a candidate set of prednisone-responsive biomarkers, with a subset of these validating in a longitudinal sample set (individual DMD patients pre/post steroid treatment). These PD biomarkers were assigned to a safety panel or efficacy panel based on comparison to normal controls and information concerning the function of each protein.
• Serum Pharmacodynamics Biomarkers Measured by Levels of Osteocalcin [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 8, 003 Week 16, 003 Week 24, 003 Week 26-29 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal axis suppression, and bone turnover). SomaScan aptamer panels testing 1,200 serum proteins were used to discover a candidate set of prednisone-responsive biomarkers, with a subset of these validating in a longitudinal sample set (individual DMD patients pre/post steroid treatment). These PD biomarkers were assigned to a safety panel or efficacy panel based on comparison to normal controls and information concerning the function of each protein.
• Serum Pharmacodynamics Biomarkers Measured by Levels of P1NP [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 8, 003 Week 16, 003 Week 24, 003 Week 26-29 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal axis suppression, and bone turnover). SomaScan aptamer panels testing 1,200 serum proteins were used to discover a candidate set of prednisone-responsive biomarkers, with a subset of these validating in a longitudinal sample set (individual DMD patients pre/post steroid treatment). These PD biomarkers were assigned to a safety panel or efficacy panel based on comparison to normal controls and information concerning the function of each protein.
• Serum Pharmacodynamics Biomarkers Measured by Levels of CTX [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 8, 003 Week 16, Week 24, 003 Week 26-29 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal axis suppression, and bone turnover). SomaScan aptamer panels testing 1,200 serum proteins were used to discover a candidate set of prednisone-responsive biomarkers, with a subset of these validating in a longitudinal sample set (individual DMD patients pre/post steroid treatment). These PD biomarkers were assigned to a safety panel or efficacy panel based on comparison to normal controls and information concerning the function of each protein.
• Muscle Strength, Mobility, and Functional Exercise Capacity as Measured by Time to Climb Test (TTCLIMB)- Velocity [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 12, 003 Week 24 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period, on muscle strength, mobility and functional exercise capacity vs. historical controls as measured by Time to Climb Test (TTCLIMB) in boys ages 4-7 years with DMD.
• Muscle Strength, Mobility, and Functional Exercise Capacity as Measured by Time to Run/Walk 10 Meters Test (TTRW)- Velocity [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 12, 003 Week 24 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period, on muscle strength, mobility and functional exercise capacity vs. historical controls as measured by Time to Run/Walk Test (TTRW) in boys ages 4-7 years with DMD.
• Muscle Strength, Mobility, and Functional Exercise Capacity as Measured by North Star Ambulatory Assessment (NSAA) [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 12, 003 Week 24 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period, on muscle strength, mobility and functional exercise capacity vs. historical controls as measured by North Star Ambulatory Assessment (NSAA) in boys ages 4-7 years with DMD. ***Total NSAA score is being reported. The score can range from 0 to 32. Higher scores (approaching 32) indicate a better outcome assessing functional mobility.
• Muscle Strength, Mobility, and Functional Exercise Capacity vs. Historical Controls as Measured by 6-minute Walk Test (6MWT) Meters [ Time Frame: 002 Baseline, 003 Baseline, 003 Week 12, 003 Week 24 (Note: 002 Baseline is from VBP15-002 4 week study (NCT02760264), previous to VBP15-003) ]
  To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period, on muscle strength, mobility and functional exercise capacity vs. historical controls as measured by 6-minute Walk Test (6MWT) in boys ages 4-7 years with DMD.

Original Secondary Outcome Measures (submitted: April 30, 2016)

• Serum pharmacodynamics biomarkers measured by levels of cortisol, ACTH, PINP, osteocalcin, CTX, 17-hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, glucose and insulin [ Time Frame: 24 weeks ]
• Muscle strength measured by Quantitative Muscle Testing (QMT) [ Time Frame: 24 weeks ]
• Muscle function measured by Time to Climb Test (TTCLIMB) [ Time Frame: 24 weeks ]
• Muscle function measured by Time to Run/Walk 10 Meters Test (TTRW) [ Time Frame: 24 weeks ]
• Muscle function measured by North Star Ambulatory Assessment (NSAA) [ Time Frame: 24 weeks ]
• Muscle function measured by Six-minute Walk Test (6MWT) [ Time Frame: 24 weeks ]

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

Descriptive Information

• Brief Title: An Extension Study to Assess Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)
• Official Title: A Phase II Open-label, Multicenter Extension Study to Assess the Long-term Safety and Efficacy of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)
• Brief Summary: The main purposes of this study are to see if it is safe to use a new medication called vamorolone for more than two weeks in children with Duchenne muscular dystrophy (DMD), to see if vamorolone works for the treatment for DMD, and to see how any potential side effects compare to those seen in boys using steroids.
• Detailed Description: This study will evaluate if it is safe to use a new medication called vamorolone for more than two weeks in children with DMD, if boys with DMD who take the study medication have improved muscle function compared to boys with DMD in other studies who did not take any type of steroid, and to see if boys with DMD who take the study medication gain less weight compared to boys with DMD in a prior study who took another type of steroid called prednisone. Enrolled participants will take the study medication for 24 weeks.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Duchenne Muscular Dystrophy

Intervention

• Drug: Vamorolone 0.25 mg/day/day
  Oral administration of 0.25 mg/kg/day daily for 24 weeks.
  Other Name: VBP15
• Drug: Vamorolone 0.75 mg/day/day
  Oral administration of 0.75 mg/kg/day daily for 24 weeks.
  Other Name: VBP15
• Drug: Vamorolone 2.0 mg/day/day
  Oral administration of 2.0 mg/kg/day daily for 24 weeks.
  Other Name: VBP15
• Drug: Vamorolone 6.0 mg/day/day
  Oral administration of 6.0 mg/kg/day daily for 24 weeks.
  Other Name: VBP15

Study Arms

• Experimental: Dose Level Group 1
  Participants enrolled in Dose Level Group 1 will receive vamorolone 0.25 mg/kg/day.
  Intervention: Drug: Vamorolone 0.25 mg/day/day
• Experimental: Dose Level Group 2
  Participants enrolled in Dose Level Group 2 will receive vamorolone 0.75 mg/kg/day.
  Intervention: Drug: Vamorolone 0.75 mg/day/day
• Experimental: Dose Level Group 3
  Participants enrolled in Dose Level Group 3 will receive vamorolone 2.0 mg/kg/day.
  Intervention: Drug: Vamorolone 2.0 mg/day/day
• Experimental: Dose Level Group 4
  Participants enrolled in Dose Level Group 4 will receive vamorolone 6.0 mg/kg/day.
  Intervention: Drug: Vamorolone 6.0 mg/day/day

• Publications *: Smith EC, Conklin LS, Hoffman EP, Clemens PR, Mah JK, Finkel RS, Guglieri M, Tulinius M, Nevo Y, Ryan MM, Webster R, Castro D, Kuntz NL, Kerchner L, Morgenroth LP, Arrieta A, Shimony M, Jaros M, Shale P, Gordish-Dressman H, Hagerty L, Dang UJ, Damsker JM, Schwartz BD, Mengle-Gaw LJ, McDonald CM; CINRG VBP15 and DNHS Investigators. Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study. PLoS Med. 2020 Sep 21;17(9):e1003222. doi: 10.1371/journal.pmed.1003222. eCollection 2020 Sep.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 7, 2016): 48
• Original Estimated Enrollment (submitted: April 30, 2016): 30
• Actual Study Completion Date: April 26, 2018
• Actual Primary Completion Date: April 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Participant's parent or legal guardian has provided written informed consent/HIPAA authorization prior to any extension study-specific procedures;
2. Participant has previously completed study VBP15-002 up to and including the Week 4 Follow-up assessments within 8 weeks prior to enrollment; and
3. Participant and parent/guardian are willing and able to comply with scheduled visits, study drug administration plan, and study procedures.

Exclusion Criteria:

1. Participant had a serious or severe adverse event in study VBP15-002 that, in the opinion of the Investigator, was probably or definitely related to vamorolone use and precludes safe use of vamorolone for the subject in this study;
2. Participant has current or history of major renal or hepatic impairment, diabetes mellitus or immunosuppression;
3. Participant has current or history of chronic systemic fungal or viral infections;
4. Participant 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. Participant has evidence of symptomatic cardiomyopathy. [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary];
6. Participant 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 3 months 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. Inhaled and/or topical corticosteroids prescribed for an indication other than DMD are permitted but must be administered at stable dose for at least 3 months prior to study drug administration];
7. Subject has used idebenone within 4 weeks prior to the first dose of study medication;
8. Participant has an allergy or hypersensitivity to the study medication or to any of its constituents;
9. Participant has severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the Investigator;
10. Participant 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; or
11. Participant is currently taking any investigational drug, or has taken any investigational drug other than vamorolone within 3 months prior to the start of study treatment.

Note: Participants may be re-evaluated if ineligible due to a transient condition which would prevent the subject from participating

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 4 Years to 7 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Israel, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02760277
• Other Study ID Numbers: VBP15-003; 1R44NS095423-01 ( U.S. NIH Grant/Contract ); 1U34AR068616-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: ReveraGen BioPharma, Inc.
• Study Sponsor: ReveraGen BioPharma, Inc.

Collaborators

• University of Pittsburgh
• National Institute of Neurological Disorders and Stroke (NINDS)
• Cooperative International Neuromuscular Research Group
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Study Chair: Paula R Clemens, MD; University of Pittsburgh

• PRS Account: ReveraGen BioPharma, Inc.
• Verification Date: July 2019