A Phase II Pilot Trial of Vamorolone vs. Placebo for the Treatment of Becker Muscular Dystrophy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 4
- 主要终点
- Safety as measured by Body Temperature
研究概览
简要总结
This Phase II pilot study is a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, PD, and exploratory clinical efficacy of vamorolone 500mg (250mg for body weight <50 kg) daily administered orally compared to placebo over a treatment period of 24 weeks in males with BMD.
Funding Source - FDA OOPD
详细描述
This Phase II pilot study is a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, PD, and exploratory clinical efficacy of vamorolone 500mg (250mg for body weight <50 kg) daily administered orally compared to placebo over a treatment period of 24 weeks in males with BMD.
The study is comprised of a Pretreatment Screening Period of up to 5 weeks duration (unless extended to accommodate varicella vaccination), a 1-day Pretreatment Baseline Period, a 24-week Treatment Period, and a 4-week Dose-tapering Period (for subjects not continuing directly with further vamorolone treatment). Subjects will be enrolled into this study at the time written informed consent is given, and administered study medication only after completion of all Pretreatment Screening assessments to confirm eligibility.
Subjects will be assessed for safety, tolerability, PK, PD, and effect on physical functioning at scheduled visits throughout the study. Screening assessments will be performed prior to baseline assessments on Day -1 and first administration of study medication on Day 1.
After completion of Screening and Baseline assessments, subjects will return to the study clinic on Day 1 for safety, PK and PD assessments prior to administration of the first dose of study medication. Additional on-site study visits will occur at Week 4, Week 12, and Week 24. Adverse events, including serious adverse events (SAEs), and concomitant medications will be recorded throughout the study. A Data and Safety Monitoring Board (DSMB) will review SAEs and other pertinent safety data at regular intervals during the study, and make recommendations to the Sponsor and Study Team regarding study conduct.
Subject diaries will be dispensed at the Day 1, Week 12, and Week 24 (for subjects participating in the Dose-tapering Period) Visits to record AEs, changes to concomitant medications taken during the study, and any missed or incomplete doses of study medication.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 64 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Subject or 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;
- •Subject is a male and has a confirmed diagnosis of Becker dystrophy as defined as:
- •Identifiable mutation within the DMD gene (deletion/duplication of one or more exons), where reading frame can be predicted as 'in-frame', and clinical picture consistent with Becker dystrophy, OR
- •Complete dystrophin gene sequencing showing an alteration (small mutation, duplication, other) that is expected to allow production of an internally deleted dystrophin protein, with a typical clinical picture of Becker dystrophy;
- •Subject is ≥ 18 years of age and <65 years of age at time of informed consent;
- •Subject is able to perform the timed run/walk 10 meters assessment (TTRW) in ≤ 30 sec at screening; assistive devices, cane or walker, are allowed.
- •Subject has an NSAA score ≤ 32 at screening.
- •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). While AST and ALT can be elevated due to disease of muscle or liver, the study PI will review any increases of AST or ALT. If above upper limit of normal (ULN), then study PI will assess whether the increases are likely of muscle origin to determine inclusion.
- •Subject has not received oral glucocorticoids or other oral immunosuppressive agents for at least 3 months prior to first administration of study medication. [Note: Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to first administration of study medication or if administered at stable dose beginning at least 4 weeks prior to first administration of study medication and anticipated to be used at the stable dose regimen for the duration of the study];
- •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 received 2 doses of varicella vaccine, with or without serologic evidence of immunity, with the second of the 2 immunizations given at least 14 days prior to first administration of study medication;
- •Subject is willing and able to comply with scheduled visits, study medication administration plan, and study procedures.
- •Subject agrees to use barrier contraception methods during his participation in this study and for 30 days after the tapering dose is completed.
排除标准
- •Subject has current or history of major renal or hepatic impairment, uncontrolled diabetes mellitus (defined as a diagnosis of diabetes with random glucose more than 1.5x ULN at screening and the patient has symptoms of polyuria or polydipsia) 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), or mexrenone (mexrenoate potassium) within 4 weeks prior to administration of study medication;
- •Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary unless cardiac ejection fraction is less than 40%];
- •Subject has an allergy or hypersensitivity to the study medication or to any of its constituents;
- •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 first dose of study medication) herbal remedies and supplements which can impact muscle strength and function (e.g., Co-enzyme Q10, creatine, etc);
- •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 first dose of study medication; or
- •Subject has previously been enrolled in the VBP15-BMD-001 study or any other vamorolone study.
研究组 & 干预措施
Placebo
Subjects will be randomized to one of two treatment groups in a 1:2 ratio (placebo:vamorolone).
干预措施: Placebo (Drug)
Vamorolone 500mg/day [250mg if <50kg body weight]
Subjects will be randomized to one of two treatment groups in a 1:2 ratio (placebo:vamorolone).
干预措施: Vamorolone (Drug)
结局指标
主要结局
Safety as measured by Body Temperature
时间窗: Day 1, Week 4, Week 12, Week 24, Week 28
Change in Body Temperature from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Safety as measured by Height
时间窗: Week 12, Week 24, Week 28
Change in Height from screening to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Safety as measured by Sitting Blood Pressure
时间窗: Day 1, Week 4, Week 12, Week 24, Week 28
Change in Sitting Blood Pressure from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Safety as measured by Heart Rate
时间窗: Day 1, Week 4, Week 12, Week 24, Week 28
Change in Heart Rate from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Safety: concentration of blood laboratory biomarkers as assessed by standardized clinical laboratory reference ranges
时间窗: Week 4, Week 12, Week 24
Blood biomarkers are White Blood cells (WBCs), Red Blood Cells, (RBCs), hemoglobin, Platelets, Sodium, Potassium, Chloride, Calcium, Blood Urea Nitrogen (BUN), Creatinine, Total Protein, Albumin, Total Bilirubin, Glucose, Alkaline Phosphatase (ALP), Gamma Glutamyl Transferase (GGT), Glutamate Dehydrogenase (GLDH), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Creatine kinase (CK), Bicarbonate, Triglycerides, Total cholesterol, Low Density Lipoprotein (LDL) and High density Lipoprotein (HDL). Change from baseline to each of the scheduled on treatment and post-treatment time points will be assessed.
Safety as measured by Respiratory Rate
时间窗: Day 1, Week 4, Week 12, Week 24, Week 28
Change in Respiratory Rate from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Safety: concentration of urine laboratory biomarkers as measured by dipstick and microscopic analysis
时间窗: Week 4, Week 12, Week 24
Urine biomarkers are protein, glucose, ketones, leukocyte esterase, White Blood Cells (WBCs), Red Blood Cells, (RBCs) and bacteria. Change from baseline to each of the scheduled on treatment and post-treatment time points will be assessed.
Tolerability as measured by incidence of Premature Discontinuation
时间窗: 24 weeks
Premature Discontinuation of study treatment due to adverse event.
Safety as measured by Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) by system organ class (SOC and PT)
时间窗: 24 weeks
Clinical AEs and clinical laboratory AEs will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, dated June 14, 2010. Dose-limiting toxicities will be defined as follows: 1. The presence of a CTCAE Grade ≥ 3 AE, considered to be probably or definitely related to study drug 2. The presence of a CTCAE Grade ≥ 3 clinical laboratory AE considered to be probably or definitely related to study drug 3. Deterioration of the muscle condition, unexpected for the natural course of BMD and without other clear cause
Safety as measured by Body Weight
时间窗: Week 12, Week 24, Week 28
Change in Body Weight from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Safety as measured by 12-lead ECG
时间窗: Week 12, Week 24
12-lead ECG as recorded after subject has rested quietly in a supine position for at least 5 minutes. ECG components are QRS duration, PR interval, QT interval and QTc interval. Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE Version 5.0
时间窗: 24 weeks
Clinical AEs and clinical laboratory AEs will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 Dose-limiting toxicities will be defined as follows: 1. The presence of a CTCAE Grade ≥ 3 AE, considered to be probably or definitely related to study drug 2. The presence of a CTCAE Grade ≥ 3 clinical laboratory AE considered to be probably or definitely related to study drug 3. Deterioration of the muscle condition, unexpected for the natural course of BMD and without other clear cause
Total Number of Adverse Events as Assessed by CTCAE Version 5.0
时间窗: 24 weeks
Clinical AEs and clinical laboratory AEs will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 Dose-limiting toxicities will be defined as follows: 1. The presence of a CTCAE Grade ≥ 3 AE, considered to be probably or definitely related to study drug 2. The presence of a CTCAE Grade ≥ 3 clinical laboratory AE considered to be probably or definitely related to study drug 3. Deterioration of the muscle condition, unexpected for the natural course of BMD and without other clear cause
次要结局
- Pharmacokinetics as measured by AUCinf(Day 1)
- Safety as measured by fasting serum concentration of glucose(Week 12, Week 24)
- Safety as measured by concentration of Salivary Cortisol(Day 1, Week 12, Week 24)
- Safety as measured by serum concentration of osteocalcin(Week 24)
- Safety as measured by serum concentration of hemoglobin A1c (HbA1c)(Week 24)
- Safety as measured by fasting serum concentration of insulin(Week 12, Week 24)
- Efficacy as measured by concentration of serum pharmacodynamic biomarkers(Week 12, Week 24)
- Pharmacokinetics as Measured by Cmax(Day 1)
- Pharmacokinetics as Measured by Tmax(Day 1)
- Pharmacokinetics as Measured by Dose-normalized Cmax(Day 1)
- Safety as Measured by Serum Concentration of Osteocalcin(Week 24)
- Safety as Measured by Serum Concentration of Hemoglobin A1c (HbA1c)(Week 24)
- Safety as Measured by Fasting Serum Concentration of Glucose(Week 24)
- Safety as Measured by Fasting Serum Concentration of Insulin(Week 24)
- Safety as Measured by Concentration of Salivary Cortisol(Week 24)
- Efficacy as Measured by Concentration of Serum Pharmacodynamic Biomarkers (CD23)(Week 24)
- Efficacy as Measured by Concentration of Serum Pharmacodynamic Biomarkers (MDC)(Week 24)
- Efficacy as Measured by Time to Run/Walk Velocity (TTRWV)(Week 24)
- Efficacy as Measured by North Star Ambulatory Assessment (NSAA) Score(Week 24)