An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) Previously Enrolled in Study A083-02 and in Patients With Charcot-Marie Tooth (CMT) Disease Types 1 and X Previously Enrolled in Study A083-03
Overview
- Phase
- Phase 2
- Intervention
- ACE-083
- Conditions
- Facioscapulohumeral Muscular Dystrophy
- Sponsor
- Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
- Enrollment
- 62
- Locations
- 24
- Primary Endpoint
- Part 2- Frequency of Adverse Events - Presence and Nature of Adverse Events (AE) During Part 2
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
This is an open-label, multicenter, phase 2 extension study to evaluate the safety, tolerability, PK, PD, and efficacy of ACE-083 in subjects with FSHD previously enrolled in Study A083-02 and subjects with CMT1 and CMTX previously enrolled in Study A083-03. This study will be conducted in two Parts: Part 1, which is a loading phase of 6 months' duration, and Part 2, the maintenance phase, which will last up to 24 months.
Detailed Description
Part 1 (6-month, non-randomized, open-label, loading phase for subjects from A083-02 Part 1 and A083-03 Part 1) Part 1 will consist of 3 cohorts of up to 18 subjects each. Subjects enrolled in Cohorts 1a and 1b will have completed Part 1 of Study A083-02; subjects enrolled in Cohort 1c will have completed Part 1 of Study A083-03. In this loading phase, 240 mg/muscle ACE-083 will be administered bilaterally every 4 weeks (q4w) for 6 doses (6 months) into either the tibialis anterior (TA) muscle or the biceps brachii (BB) muscle, depending on the muscle injected in the previous study; subjects may not switch muscle cohort upon enrollment in this study. Subjects will participate in a screening period of up to 4 weeks before receiving the first dose of ACE-083. Part 2 (24-month, randomized, open-label rollover maintenance phase for subjects from A083-02 Part 2, A083-03 Part 2, and A083-04 Part 1) Subjects who complete Part 1 of this study (the loading phase), Part 2 of A083-02, or Part 2 of A083-03 will enroll directly into the Part 2 open-label maintenance phase of treatment with ACE-083 and will consist of 6 cohorts of up to 23 FSHD or 29 CMT subjects each. These subjects will be randomized (1:1) to receive ACE-083, 240 mg/muscle bilaterally, either q4w or q8w. Thus, subjects enrolled in Cohorts 2a, 2b, and 2c will be FSHD TA, FSHD BB, and CMT TA treated q4w, and subjects enrolled in Cohorts 3a, 3b, and 3c will be FSHD TA, FSHD BB, and CMT TA treated q8w. Study duration for a subject initially enrolled in Part 1 and then extended to Part 2 will be approximately 33 months, including a 1-month screening period, 6-month Part 1 loading phase, 24-month Part 2 maintenance phase, and 2-month follow-up period. For subjects who enrolled directly into Part 2 of this study from Part 2 of Studies A083-02 and A083-03, the duration of the study will be approximately 26 months, including a 24-month maintenance phase and a 2-month follow-up period.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Completion of treatment with study drug per protocol and completion of the end of treatment (ET) visit in Study A083-02 or Study A083-
- •Females of childbearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine pregnancy test prior to enrollment and use highly effective birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 8 weeks following the last dose of ACE-
- •Hormonal birth control use must be stable for at least 14 days prior to Day
- •Males must agree to use a condom during any sexual contact with females of childbearing potential while participating in the study and for 8 weeks following the last dose of ACE-083, even if they have undergone a vasectomy. Subjects must be counseled about contraception prior to the first dose of ACE-083 and every three months thereafter during the study.
- •Ability to adhere to the study visit schedule/procedures and to understand and comply with protocol requirements
- •Signed written informed consent
Exclusion Criteria
- •Current/active malignancy (e.g., remission less than 5 years' duration), with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin
- •Co-morbidities, including symptomatic cardiopulmonary disease, significant orthopedic or neuropathic pain, or other conditions that, in the opinion of the investigator, would limit a subject's ability to complete strength and/or functional assessments
- •Type 1 or type 2 diabetes mellitus
- •Thyroid disorder unless condition is stable with no change in treatment for at least 4 weeks before the first dose and no expected change for duration of study
- •Renal impairment (serum creatinine ≥ 2 times the upper limit of normal \[ULN\])
- •Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN
- •Increased risk of bleeding (i.e., due to hemophilia, platelet disorders, or use of any anticoagulation/platelet modifying therapies up to 2 weeks prior to Study Day 1 and for duration of study; single agent low dose aspirin \[≤ 100 mg daily\] is permitted)
- •Severe deformity or ankle fixation that would sufficiently limit passive range of motion to affect functional assessments (TA patients only)
- •Major surgery within 4 weeks prior to Study Day 1
- •Chronic pharmacologic doses of systemic corticosteroids (≥ 2 weeks) within 4 weeks before Study Day 1 and for duration of study; intra-articular/topical/inhaled/intranasal physiologic doses of systemic corticosteroids are permitted
Arms & Interventions
Part 1 Cohort 1a
ACE-083 240 mg/muscle administered bilaterally by injection into the TA muscle every 4 weeks for up to 6 doses for FSHD patients
Intervention: ACE-083
Part 1 Cohort 1b
ACE-083 240 mg/muscle administered bilaterally by injection into the BB muscle every 4 weeks for up to 6 doses for FSHD patients
Intervention: ACE-083
Part 1 Cohort 1c
ACE-083 240 mg/muscle administered bilaterally by injection into the TA muscle every 4 weeks for up to 6 doses for CMT patients
Intervention: ACE-083
Part 2 Cohort 2a
ACE-083 Administered into the TA muscle q4w for up to 24 months (24 doses) for FSHD patients
Intervention: ACE-083
Part 2 Cohort 2b
ACE-083 Administered into the BB muscle q4w for up to 24 months (24 doses) for FSHD patients
Intervention: ACE-083
Part 2 Cohort 2c
ACE-083 Administered into the TA muscle q4w for up to 24 months (24 doses) for CMT patients
Intervention: ACE-083
Part 2 Cohort 3a
ACE-083 Administered into the TA muscle q8w for up to 24 months (12 doses) for FSHD patients
Intervention: ACE-083
Part 2 Cohort 3b
ACE-083 Administered into the BB muscle q8w for up to 24 months (12 doses) for FSHD patients
Intervention: ACE-083
Part 2 Cohort 3c
ACE-083 Administered into the TA muscle q8w for up to 24 months (12 doses) for CMT patients
Intervention: ACE-083
Outcomes
Primary Outcomes
Part 2- Frequency of Adverse Events - Presence and Nature of Adverse Events (AE) During Part 2
Time Frame: From baseline to end of participation of the Part 2 portion of the study
The number of participants that had a least one Treatment Emergent Adverse Event during the Part 2 of the study. The pre-specified analysis for this outcome measure was for those participants in the part 2 cohorts of this study therefore, only data of part 2 portion of the study are reported.
Part 2: Frequency of Adverse Events - Presence and Nature of Grade 3 or Higher Adverse Events (AE) During the Part 2 of the Study.
Time Frame: From baseline to the end of the part 2 portion of the study
The number of participants that had a least one grade 3 or higher Treatment Emergent Adverse Event during Part 2 of the study. The pre-specified analysis for this outcome measure was for those participants in the double-blind, placebo-controlled Part 2 of the study therefore, only data from the part 2 portion of the study are reported.
Part 2: Change in Total Muscle Volume - Percent Change From Baseline to Day 113 in Total Muscle Volume of Injected Muscle by Magnetic Resonance Imaging (MRI) During the Part 2 Portion
Time Frame: During the Part 2 portion of the study: Baseline to Day 113
The primary pharmacodynamic variable was the difference in mean percent change in total muscle volume (average of left and right side) at the first 6 months of the maintenance phase (Day 169; q4w or q8w) from the total muscle volume (average of left and right sides) at the start of the maintenance phase (or equivalently the end of the loading phase). Due to the early termination of this trial, percent change is only able to be reported as percent change from baseline to Day 113. The pre-specified analysis for this outcome measure was for those participants in the part 2 portion in cohorts with data to Day 113. Therefore, only data from these part 2 arms- 2b, 2c, 3b and 3c of the study are reported.
Secondary Outcomes
- Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle:10-meter Walk/Run During Part 2 of the Study(Baseline and End of Treatment visit for Part 2 of the study)
- Part 2: Change in Muscle Function. Percent Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle: 4-stair Climb Down (in Patients With FSHD Only)(Baseline, End of Treatment visit during Part 2)
- Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle: 4-stair Climb Down (in Participants With FSHD Only)(Baseline, End of Treatment visit during Part 2)
- Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Biceps Brachii (BB) Muscle: Mid-level Performance of the Upper Limb (PUL) Test.(Baseline, End of Treatment visit during Part 2)
- Part1: ACE-083 Serum Concentration Samples Part 1-Day 85, 24-hour Post-dose(day 85, 24 -hours post-dose in Part 1)
- Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle: 6-minute Walk Test(Baseline and End of Treatment Visit during Part 2 of the study)
- Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle: 4-stair Climb Up (in Participants With FSHD Only)(Baseline, End of Treatment visit during Part 2)
- Part 2: Change in Muscle Function - Percent Change From Baseline for Tibialis Anterior (TA) Muscle in 100-meter Timed Test(Baseline, End of Treatment visit, Part 2)
- Part 2: Change in Patient-reported Quality of Life. Absolute Change From Baseline in FSHD-health Index Total Score (FSHD-HI, in Patients With FSHD Only)(Baseline, End of Treatment visit during part 2)
- Part2: Change in Patient-reported Quality of Life. Absolute Change From Baseline in CMT Health Index Total Score (CMT-HI, in Patients With CMT Only)(Baseline, Day 113 during Part 2)
- Part 2: Change in Muscle Function. Percent Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle:10-meter Walk/Run During Part 2 of the Study(Baseline and End of Treatment visit for Part 2 of the study)
- Part 2: Change in Muscle Function - Percent Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle in 6-minute Walk Test(Baseline and End of Treatment visit during Part 2 of the study)
- Part 2: Change in Muscle Function - Percent Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle in 4-stair Climb Up (in Participants With FSHD Only)(Baseline, End of Treatment visit during Part 2)
- Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle: 100-meter Timed Test(Baseline, End of Treatment visit for Part 2 of the study)
- Part 2: Change in Muscle Function - Percent Change From Baseline for Biceps Brachii (BB) Muscle in Mid-level Performance of the Upper Limb (PUL) Test(Baseline, End of Treatment)
- Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Biceps Brachii (BB) Muscle: Upper Level Performance of the Upper Limb (PUL) Test.(Baseline, End of Treatment visit during part 2 of the study)
- Part 1: ACE-083 Serum Concentration Samples Part 1-Day1, 24-hour Post-dose(day 1, 24 -hours post-dose in Part 1)
- Part1: Pharmacokinetics Parameter of Time to Maximum Serum Concentration Following Administration (Tmax)(From baseline to End of Treatment in Part 1)
- Part 2: Change in Muscle Function. Percent Change From Baseline in Functional Assessment for Biceps Brachii (BB) Muscle: Upper Level Performance of the Upper Limb (PUL) Test.(Baseline, End of Treatment visit during Part 2)
- Part1: Pharmacokinetics Parameter of Area Under the Plasma Concentration Versus Time Curve (AUC)(From baseline to End of Treatment in Part 1)