A Phase II Open-Label, Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of Vamorolone in Boys Ages 2 to <4 Years and 7 to <18 Years With Duchenne Muscular Dystrophy (DMD)
Overview
- Phase
- Phase 2
- Intervention
- Vamorolone
- Conditions
- Duchenne Muscular Dystrophy
- Sponsor
- Santhera Pharmaceuticals
- Enrollment
- 54
- Locations
- 5
- Primary Endpoint
- Number of Participants With Any Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
- Status
- Completed
- Last Updated
- 6 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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;
- •Subject has a centrally confirmed (by TRiNDS central genetic counselor\[s\]) diagnosis of DMD, 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;
- •Subject is male, 2 to \<4 years or 7 to \<18 years of age at time of enrollment in the study;
- •If 7 to \<18 years of age and currently taking standard of care glucocorticoids for treatment of DMD, subject has been taking standard of care glucocorticoids at stable dose for at least 3 months prior to enrollment in the study, and will continue the same stable dose regimen through the date of the Baseline Day -1 Visit. \[Note: Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to enrollment or if administered at stable dose beginning at least 4 weeks prior to enrollment and anticipated to be used at the stable dose regimen for the duration of the study\];
- •If 7 to \<18 years of age, and not currently glucocorticoid-treated, subject has not received oral glucocorticoids or other oral immunosuppressive agents for at least 3 months prior to enrollment. \[Note: Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to enrollment or if administered at stable dose beginning at least 4 weeks prior to enrollment and anticipated to be used at the stable dose regimen for the duration of the study\];
- •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. \[Notes: Serum gamma glutamyl transferase (GGT), creatinine, and total bilirubin all must be ≤ upper limit of the normal range at the Screening Visit. An abnormal vitamin D level that is considered clinically significant will not exclude a subject from participating\];
- •Subject has evidence of chicken pox immunity as determined by:
Exclusion Criteria
- •Subject has current or history of major renal or hepatic impairment, diabetes mellitus or immunosuppression;
- •Subject has current or history of chronic systemic fungal or viral infections;
- •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 enrollment;
- •Subject has a history of primary hyperaldosteronism;
- •Subject has evidence of symptomatic cardiomyopathy \[Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary\];
- •If 2 to \<4 years of age, subject is currently being treated or has received previous treatment with oral glucocorticoids or other immunosuppressive agents \[Notes: Past transient use of oral glucocorticoids or other oral immunosuppressive agents for no longer than 1 month cumulative, with last use at least 3 months prior to enrollment, will be considered for eligibility on a case-by-case basis, unless discontinued for intolerance. Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to enrollment or if administered at stable dose beginning at least 4 weeks prior to enrollment and anticipated to be used at the stable dose regimen for the duration of the study\];
- •Subject has an allergy or hypersensitivity to the study medication or to any of its constituents;
- •Subject has used idebenone within 4 weeks prior to enrollment;
- •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;
Arms & Interventions
Treatment Group 1
Patients in Treatment Group 1 must be ages 2-\<4 years and will receive Vamorolone at 2.0 mg/kg/day for the duration of the study. Treatment Group 1 will be enrolled prior to Treatment Group 2.
Intervention: Vamorolone
Treatment Group 2
Patients in Treatment Group 2 must be ages 2-\<4 years and will receive Vamorolone at 6.0 mg/kg/day for the duration of the study. Treatment Group 2 will be enrolled after Treatment Group 1.
Intervention: Vamorolone
Treatment Group 3
Patients in Treatment Group 3 must be ages 7-\<18 years and must be steroid untreated at entry. Treatment Group 3 will receive Vamorolone at 2.0 mg/kg/day for the duration of the study.
Intervention: Vamorolone
Treatment Group 4
Patients in Treatment Group 4 must be ages 7-\<18 years and must be steroid untreated at entry. Treatment Group 4 will receive Vamorolone at 6.0 mg/kg/day for the duration of the study.
Intervention: Vamorolone
Treatment Group 5
Patients in Treatment Group 5 must be ages 7-\<18 years and must be on a stable dose of steroid for 3 months prior to entry. Treatment Group 5 will receive Vamorolone at 2.0 mg/kg/day for the duration of the study.
Intervention: Vamorolone
Treatment Group 6
Patients in Treatment Group 6 must be ages 7-\<18 years and must be on a stable dose of steroid for 3 months prior to entry. Treatment Group 6 will receive Vamorolone at 6.0 mg/kg/day for the duration of the study.
Intervention: Vamorolone
Treatment Sub-Group 7
Patients in Treatment Sub-Group 7 must be ages 12-\<18 years and must be on a stable dose of steroid for 3 months prior to entry. Treatment Group 7 will receive Vamorolone at 6.0 mg/kg/day for the duration of the study.
Intervention: Vamorolone
Outcomes
Primary Outcomes
Number of Participants With Any Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
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
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.
Number of Participants With Drug Related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
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
Drug related Adverse Events are TEAEs whose Causality were labeled as 'DEFINITE', 'POSSIBLE' or 'PROBABLE
Number of Participants With Severe Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
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
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.
Number of Participants With Serious Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03)
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)
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
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
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
Adverse Events leading to Study treatment discontinuation
Change in Height (Absolute) From Baseline to Week 12
Time Frame: Baseline, 12 weeks
Standing height will be assessed for subjects ages 2-\<4 years; height calculated from ulnar length in subjects ages 7-\<18.
Change in Height (Z-score) From Baseline to Week 12
Time Frame: Baseline, 12 weeks
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).
Change in Weight (Absolute) From Baseline to Week 12
Time Frame: Baseline, 12 weeks
Body weight will be assessed at each of the scheduled time points.
Change in Weight (Percentile) From Baseline to Week 12
Time Frame: Baseline, 12 weeks
Body weight will be assessed at each of the scheduled time points.
Change in Height (Percentile) From Baseline to Week 12
Time Frame: Baseline, 12 weeks
Standing height will be assessed for subjects ages 2-\<4 years; height calculated from ulnar length in subjects ages 7-\<18.
Change in Weight (Z-score) From Baseline to Week 12
Time Frame: Baseline, 12 weeks
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).
Change in Body Mass Index (BMI) (Absolute) From Baseline to Week 12
Time Frame: Baseline, Week 12
Body Mass Index is a measure of weight adjusted for height.
Change in Body Mass Index (BMI) (Percentile) From Baseline to Week 12
Time Frame: Baseline, Week 12
Body Mass Index is a measure of weight adjusted for height.
Change in Body Mass Index (BMI) (Z-score) From Baseline to Week 12
Time Frame: Baseline, 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).
Change in Diastolic Blood Pressure
Time Frame: Day 1, Week 2, Week 6, Week 12, Week 16
Change from Baseline to Week 12 in diastolic sitting blood pressure.
Change in Systolic Blood Pressure
Time Frame: Day 1, Week 2, Week 6, Week 12, Week 16
Change from Baseline to Week 12 in systolic sitting blood pressure.
Number of Participants With Treatment Emergent Cushingoid Features
Time Frame: Baseline through Week 16
Treatment emergent cushingoid features based on physical examination at all baseline, on-treatment and post-treatment assessments
Number of Participants With Clinically Significant Treatment-emergent Abnormal Clinical Laboratory Test Result
Time Frame: Day 1, Week 6, Week 12, Week 16
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
Categorical Analysis of QTcF at Week 12
Time Frame: Baseline, 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.
Number of Eyes With Cataract
Time Frame: Baseline - Week 12
Cataract was diagnosed by the presence of partial or complete opacity of the crystalline lens at Baseline and Week 12.
Number of Eyes With Glaucoma
Time Frame: Baseline - Week 12
Glaucoma was diagnosed by ocular pressure at Baseline and Week 12.
Secondary Outcomes
- Pre-dose and Post-dose Plasma Concentration Measurements of Vamorolone at Day 1 and Week 2(Day 1, Week 2)
- Descriptive Statistics of PK Parameters - Tmax(Day 1, Week 2)
- Descriptive Statistics of PK Parameters - Cmax(Day 1, Week 2)
- Descriptive Statistics of PK Parameters in Subjects Aged 2 to 4 Years - AUC 0-6(Day 1, Week 2)
- Descriptive Statistics of PK Parameters in Subjects Aged 7 to 18 Years - AUC 0-inf(Day 1, Week 2)