This Phase II study is an open-label, multiple dose study to evaluate the safety, tolerability, PK, PD, clinical efficacy, behavior and neuropsychology, and physical functioning vamorolone over a treatment period of 12 weeks in steroid-naïve boys ages 2 to \<4 years, and glucocorticoid-treated and currently untreated boys ages 7 to \<18 years with DMD.
This Phase II study is an open-label, multiple dose study to evaluate the safety, tolerability, PK, PD, clinical efficacy, behavior and neuropsychology, and physical functioning of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg over a treatment period of 3 months in steroid-naïve boys ages 2 to \<4, and glucocorticoid-treated and currently untreated boys ages 7 to \<18 years with DMD. The study is comprised of a 5-week Pretreatment Screening Period; a 1-day Pretreatment Baseline Period; a 3-month open-label Treatment Period (Weeks 1-12); and a 4-8 week open-label Dose-tapering Period (starting from Weeks 13) for subjects who will not transition directly to further vamorolone or standard of care (SoC) glucocorticoid treatment at the end of the study. Subjects will be enrolled into the study at the Screening Visit, at the time written informed consent is obtained. Within the 2 to \<4 years age group, the initial 10 eligible subjects will be assigned to the 2.0 mg/kg/day treatment group at the Baseline Day -1 Visit. The subsequent 10 eligible subjects will be assigned to the 6.0 mg/kg/day treatment group at the Baseline Day -1 Visit. Within the 7 to \<18 years age group, both corticosteroid-treated and untreated, the initial 12 eligible subjects will be assigned to the 2.0 mg/kg/day treatment group at the Baseline Day -1 Visit. The subsequent 12 eligible subjects will be assigned to the 6.0 mg/kg/day treatment group at the Baseline Day -1 Visit. The first 6 subjects in each age group at 2 mg/kg will serve as the PK/safety run-in cohorts. PK assessments will be performed at week 2 and together with the safety assessment during the first 4 weeks of treatment this will be the basis to confirm whether 2 and 6 mg/kg/day will be used in the subsequent patients or if a dose adjustment is needed to avoid over or under-exposure in patients for any of the two age groups. Glucocorticoid-treated subjects in the 7 to \<18 years age group will take their final dose of SoC glucocorticoid therapy for DMD on Baseline Day -1, within 24 hours prior to administration of the first dose of vamorolone study medication. All subjects in both age groups will begin their assigned vamorolone treatment on Treatment Period Day 1, and will continue to receive their assigned vamorolone treatment throughout the duration of the 3 month Treatment Period (Weeks 1-12). At the end of the 3-month Treatment Period (Week 12), subjects will be given the option to receive vamorolone in an expanded access or compassionate use program, if possible, or to transition to SoC treatment for DMD (may include glucocorticoids). Subjects completing VBP15-006 and enrolling directly into the expanded access or compassionate use program or transitioning directly to SoC glucocorticoid treatment will not need to taper their vamorolone dose prior to participation in the expanded access or compassionate use program or initiation of SoC glucocorticoid treatment. All subjects who will not transition directly to further vamorolone or SoC glucocorticoid treatment will begin a 4 -8 week open label Dose tapering Period during which the dose of study medication will be progressively reduced and discontinued.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
54
Oral administration of vamorolone for 12 weeks.
Alberta's Children Hospital
Calgary, Alberta, Canada
British Columbia Children's Hospital
Vancouver, British Columbia, Canada
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada
The Hospital for Sick Children
Toronto, Ontario, Canada
Number of Participants With Any Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
An Adverse Event is any untoward medical occurrence in a subject and does not necessarily have to have a causal relationship with the intervention. Pre-existing conditions that worsen during the study are to be reported as AEs.
Time frame: From the date of the subject's written informed consent until the final Week 16 Visit or the subject's participation in the study was completed
Number of Participants With Drug Related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
Drug related Adverse Events are TEAEs whose Causality were labeled as 'DEFINITE', 'POSSIBLE' or 'PROBABLE
Time frame: From the date of the subject's written informed consent until the final Week 16 Visit or the subject's participation in the study was completed
Number of Participants With Severe Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
Severe or medically significant but not immediately life -threatening: hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; incapacitating with inability to work or perform normal daily activity.
Time frame: From the date of the subject's written informed consent until the final Week 16 Visit or the subject's participation in the study was completed
Number of Participants With Serious Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
A Serious Adverse Event (SAE) is defined as any AE regardless of causality that meets any of the following criteria: * Results in death * Is life-threatening * Requires inpatient hospitalization or prolongation of an existing hospitalization * Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions * Results in a congenital anomaly/birth defect * Is an important medical event that may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above
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Montreal Childrens Hospital
Montreal, Canada
Time frame: From the date of the subject's written informed consent until the final Week 16 Visit or the subject's participation in the study was completed (SAEs through 30 days after final dose of study drug)
Number of Participants With Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03) Leading to Study Treatment Discontinuation
Adverse Events leading to Study treatment discontinuation
Time frame: From the date of the subject's written informed consent until the final Week 16 Visit or the subject's participation in the study was completed
Change in Height (Absolute) From Baseline to Week 12
Standing height will be assessed for subjects ages 2-\<4 years; height calculated from ulnar length in subjects ages 7-\<18.
Time frame: Baseline, 12 weeks
Change in Height (Percentile) From Baseline to Week 12
Standing height will be assessed for subjects ages 2-\<4 years; height calculated from ulnar length in subjects ages 7-\<18.
Time frame: Baseline, 12 weeks
Change in Height (Z-score) From Baseline to Week 12
Standing height will be assessed for subjects ages 2-\<4 years; height calculated from ulnar length in subjects ages 7-\<18. The z-score (standard score) is the number of standard deviations by which the outcome measure is above or below the value in the general population. A Z-score of 0 represents the population mean. A measure above the normal value has a positive z-score (higher height).
Time frame: Baseline, 12 weeks
Change in Weight (Absolute) From Baseline to Week 12
Body weight will be assessed at each of the scheduled time points.
Time frame: Baseline, 12 weeks
Change in Weight (Percentile) From Baseline to Week 12
Body weight will be assessed at each of the scheduled time points.
Time frame: Baseline, 12 weeks
Change in Weight (Z-score) From Baseline to Week 12
Body weight will be assessed at each of the scheduled time points. The z-score (standard score) is the number of standard deviations by which the outcome measure is above or below the value in the general population. A Z-score of 0 represents the population mean. A measure above the normal value has a positive z-score (higher weight).
Time frame: Baseline, 12 weeks
Change in Body Mass Index (BMI) (Absolute) From Baseline to Week 12
Body Mass Index is a measure of weight adjusted for height.
Time frame: Baseline, Week 12
Change in Body Mass Index (BMI) (Percentile) From Baseline to Week 12
Body Mass Index is a measure of weight adjusted for height.
Time frame: Baseline, Week 12
Change in Body Mass Index (BMI) (Z-score) From Baseline to Week 12
Body Mass Index is a measure of weight adjusted for height. The z-score (standard score) is the number of standard deviations by which the outcome measure is above or below the value in the general population. A Z-score of 0 represents the population mean. A measure above the normal value has a positive z-score (higher BMI).
Time frame: Baseline, Week 12
Change in Diastolic Blood Pressure
Change from Baseline to Week 12 in diastolic sitting blood pressure.
Time frame: Day 1, Week 2, Week 6, Week 12, Week 16
Change in Systolic Blood Pressure
Change from Baseline to Week 12 in systolic sitting blood pressure.
Time frame: Day 1, Week 2, Week 6, Week 12, Week 16
Number of Participants With Treatment Emergent Cushingoid Features
Treatment emergent cushingoid features based on physical examination at all baseline, on-treatment and post-treatment assessments
Time frame: Baseline through Week 16
Number of Participants With Clinically Significant Treatment-emergent Abnormal Clinical Laboratory Test Result
Each subject had blood drawn and urine collected for the standard hematology, chemistry and lipids clinical laboratory tests. In addition, fasting glucose and insulin, morning cortisol, as well as, in the additional 12 to \<18 years age group, LH, FSH, TSH, FT4 were collected. HbA1c determination had also to be performed if urine glucose was positive and/or fasted glucose levels was above normal limits. Any treatment-emergent clinically significant abnormal laboratory test result was reporte
Time frame: Day 1, Week 6, Week 12, Week 16
Categorical Analysis of QTcF at Week 12
12-lead 1electrocardiogram (ECG) as recorded after subject has rested quietly in a supine position for at least 5 minutes. ECG components are QRS duration, PR \[PQ\] interval, RR interval, QT interval and QTc.
Time frame: Baseline, Week 12
Number of Eyes With Cataract
Cataract was diagnosed by the presence of partial or complete opacity of the crystalline lens at Baseline and Week 12.
Time frame: Baseline - Week 12
Number of Eyes With Glaucoma
Glaucoma was diagnosed by ocular pressure at Baseline and Week 12.
Time frame: Baseline - Week 12
Pre-dose and Post-dose Plasma Concentration Measurements of Vamorolone at Day 1 and Week 2
The plasma concentration of vamorolone was measured on Day 1 and Week 2 predose, and 1h, 2h and 6h postdose and also 4h and 8h post in the 7-18 year groups.
Time frame: Day 1, Week 2
Descriptive Statistics of PK Parameters - Tmax
Tmax is the time to reach the maximum observed concentration collected during a dosing interval
Time frame: Day 1, Week 2
Descriptive Statistics of PK Parameters - Cmax
Cmax is the maximum observed concentration
Time frame: Day 1, Week 2
Descriptive Statistics of PK Parameters in Subjects Aged 2 to 4 Years - AUC 0-6
AUC 0-6 is the area under the concentration-time curve during the first 6 hours after dosing
Time frame: Day 1, Week 2
Descriptive Statistics of PK Parameters in Subjects Aged 7 to 18 Years - AUC 0-inf
AUC 0-8 is the area under the concentration-time curve after dosing extrapolated to infinity
Time frame: Day 1, Week 2