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
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. The scheduled Week 12 and Week 24 assessments may be performed over a 2-day period, if necessary, to facilitate scheduling. Subjects who complete the VBP15-BMD-001 study assessments through the Week 24 Visit may be given the opportunity to continue to receive vamorolone as part of an expanded access or compassionate use program. Subjects who complete the VBP15-BMD-001 study and will enroll directly into an expanded access or compassionate use program to continue vamorolone treatment will be discharged from the VBP15-BMD-001 study following completion of all Week 24 assessments. Subjects who will not continue vamorolone treatment in the expanded access or compassionate use program will have their study medication dose tapered during a 4-week Dose-tapering Period to taper study medication prior to discharge from the study. For these subjects, site study staff will contact the subject or parent(s)/guardian(s) by telephone at Week 26 to ensure that the dose tapering is proceeding according to protocol, to assess potential signs or symptoms of adrenal suppression, and to address any questions the subject or parent(s)/guardian(s) may have. In the event that any clinical or laboratory parameters remain abnormal at the time of discharge from the study, the subject will be followed medically, as clinically indicated. Any subject who discontinues the study prior to the Week 24 Visit should return to the study unit for scheduled Week 24 assessments at the time of early withdrawal and a Week 28 Visit following the taper, whenever possible, assuming the subject has not withdrawn consent. Any subject who withdraws early from the study after study medication dosing has begun should undergo dose-tapering following early completion of the Week 24 assessments and a Week 28 Visit following the taper.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
46
Vamorolone 4.0% wt/wt oral suspension will be administered for the duration of the study.
Placebo to Vamorolone 4.0% wt/wt oral suspension will be administered for the duration of the study.
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
Azienda Ospedale Universita Padova
Padua, Italy
Safety as measured by Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) by system organ class (SOC and PT)
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
Time frame: 24 weeks
Safety as measured by Sitting Blood Pressure
Change in Sitting Blood Pressure from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Time frame: Day 1, Week 4, Week 12, Week 24, Week 28
Safety as measured by Heart Rate
Change in Heart Rate from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Time frame: Day 1, Week 4, Week 12, Week 24, Week 28
Safety as measured by Respiratory Rate
Change in Respiratory Rate from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Time frame: Day 1, Week 4, Week 12, Week 24, Week 28
Safety as measured by Body Temperature
Change in Body Temperature from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Time frame: Day 1, Week 4, Week 12, Week 24, Week 28
Safety as measured by Body Weight
Change in Body Weight from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
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Time frame: Week 12, Week 24, Week 28
Safety as measured by Height
Change in Height from screening to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group.
Time frame: Week 12, Week 24, Week 28
Safety: concentration of blood laboratory biomarkers as assessed by standardized clinical laboratory reference ranges
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.
Time frame: Week 4, Week 12, Week 24
Safety: concentration of urine laboratory biomarkers as measured by dipstick and microscopic analysis
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.
Time frame: Week 4, Week 12, Week 24
Safety as measured by 12-lead ECG
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.
Time frame: Week 12, Week 24
Tolerability as measured by incidence of Premature Discontinuation
Premature Discontinuation of study treatment due to adverse event.
Time frame: 24 weeks
Pharmacokinetics as measured by AUCinf
Blood will be collected from all subjects at the Day 1 Visit, at 1, 2 and 3 hours post-dose, for vamorolone PK analysis
Time frame: Day 1
Safety as measured by serum concentration of osteocalcin
Change from baseline to Week 24 will be assessed for each treatment group.
Time frame: Week 24
Safety as measured by serum concentration of hemoglobin A1c (HbA1c)
Change from baseline to Week 24 will be assessed for each treatment group.
Time frame: Week 24
Safety as measured by fasting serum concentration of glucose
Change from baseline to each of the scheduled study assessment time points for each treatment group.
Time frame: Week 12, Week 24
Safety as measured by fasting serum concentration of insulin
Change from baseline to each of the scheduled study assessment time points for each treatment group.
Time frame: Week 12, Week 24
Efficacy as measured by concentration of serum pharmacodynamic biomarkers
CD23 (also known as Fc epsilon RII) and Macrophage Derived Chemokine (MDC) and concentration from baseline to Week 24.
Time frame: Week 12, Week 24
Safety as measured by concentration of Salivary Cortisol
First-in-morning salivary cortisol levels will be measured. Cortisol measures falling below 3.6 µg/dL (or 100 nM) will be considered to be indicative of the development of adrenal suppression. Cortisol will be assessed for each treatment group.
Time frame: Day 1, Week 12, Week 24