Clinical trial NCT03943290: Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Facioscapulohumeral Muscular Dystrophy
Charcot-Marie-Tooth Disease
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2019-05-09
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Key Inclusion Criteria:

1. Completion of treatment with study drug per protocol and completion of the end of treatment (ET) visit in Study A083-02 or Study A083-03.
2. 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-083. Hormonal birth control use must be stable for at least 14 days prior to Day 1. 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.
3. Ability to adhere to the study visit schedule/procedures and to understand and comply with protocol requirements
4. Signed written informed consent

Key Exclusion Criteria:

1. 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
2. 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
3. Type 1 or type 2 diabetes mellitus
4. 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
5. Renal impairment (serum creatinine ≥ 2 times the upper limit of normal \[ULN\])
6. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN
7. 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)
8. Severe deformity or ankle fixation that would sufficiently limit passive range of motion to affect functional assessments (TA patients only)
9. Major surgery within 4 weeks prior to Study Day 1
10. 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
11. Androgens, growth hormone, insulin or oral hormone replacement therapy within 6 months before Study Day 1 and for duration of study; topical physiologic androgen replacement is permitted. Chronic insulin therapy is permitted for diabetic FSHD patients. Oral HRT is permitted if started at least 3 months prior to receiving study drug
12. Any change in medications potentially affecting muscle strength or function within 4 weeks of Study Day 1 and for duration of study (e.g., creatinine, CoQ10, systemic beta-adrenergic agonists)
13. Previous exposure to any other investigational agent (not including ACE-083) potentially affecting muscle volume, muscle strength, or muscle or nerve function within 5 half-lives of last dose plus an additional 8-week washout period (or 12 weeks prior to Study Day 1 if half-life is unknown)
14. Significant change in physical activity or exercise (e.g., significant increase or decrease in intensity or frequency) within 8 weeks before Study Day 1 or inability to maintain the baseline level of physical activity throughout the study
15. Any condition that would prevent MRI scanning or compromise the ability to obtain a clear and interpretable scan of the treated muscles (e.g., knee/hip replacement metallic implants)
16. Known active substance abuse, including alcohol
17. History of sensitivity to protein pharmaceuticals
18. Female that is pregnant or lactating/breast-feeding

Primary outcomes:
measure: Part 2- Frequency of Adverse Events - Presence and Nature of Adverse Events (AE) During Part 2
timeFrame: From baseline to end of participation of the Part 2 portion of the study
measure: Part 2: Frequency of Adverse Events - Presence and Nature of Grade 3 or Higher Adverse Events (AE) During the Part 2 of the Study.
timeFrame: From baseline to the end of the part 2 portion of the study
measure: 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
timeFrame: During the Part 2 portion of the study: Baseline to Day 113
Secondary outcomes:
measure: 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
timeFrame: Baseline and End of Treatment visit for Part 2 of the study
measure: 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
timeFrame: Baseline and End of Treatment visit for Part 2 of the study
measure: Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle: 6-minute Walk Test
timeFrame: Baseline and End of Treatment Visit during Part 2 of the study
measure: Part 2: Change in Muscle Function - Percent Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle in 6-minute Walk Test
timeFrame: Baseline and End of Treatment visit during Part 2 of the study
measure: 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)
timeFrame: Baseline, End of Treatment visit during Part 2
measure: 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)
timeFrame: Baseline, End of Treatment visit during Part 2
measure: 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)
timeFrame: Baseline, End of Treatment visit during Part 2
measure: 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)
timeFrame: Baseline, End of Treatment visit during Part 2
measure: Part 2: Change in Muscle Function. Absolute Change From Baseline in Functional Assessment for Tibialis Anterior (TA) Muscle: 100-meter Timed Test
timeFrame: Baseline, End of Treatment visit for Part 2 of the study
measure: Part 2: Change in Muscle Function - Percent Change From Baseline for Tibialis Anterior (TA) Muscle in 100-meter Timed Test
timeFrame: Baseline, End of Treatment visit, Part 2
measure: 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.
timeFrame: Baseline, End of Treatment visit during Part 2
measure: 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
timeFrame: Baseline, End of Treatment
measure: 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.
timeFrame: Baseline, End of Treatment visit during part 2 of the study
measure: 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.
timeFrame: Baseline, End of Treatment visit during Part 2
measure: 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)
timeFrame: Baseline, End of Treatment visit during part 2
measure: 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)
timeFrame: Baseline, Day 113 during Part 2
measure: Part 1: ACE-083 Serum Concentration Samples Part 1-Day1, 24-hour Post-dose
timeFrame: day 1, 24 -hours post-dose in Part 1
measure: Part1: ACE-083 Serum Concentration Samples Part 1-Day 85, 24-hour Post-dose
timeFrame: day 85, 24 -hours post-dose in Part 1
measure: Part1: Pharmacokinetics Parameter of Time to Maximum Serum Concentration Following Administration (Tmax)
timeFrame: From baseline to End of Treatment in Part 1
measure: Part1: Pharmacokinetics Parameter of Area Under the Plasma Concentration Versus Time Curve (AUC)
timeFrame: From baseline to End of Treatment in Part 1
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California-Irvine
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester School of Medicine
state: New York
city: Charlotte
country: United States
facility: Carolinas Healthcare System Neurosciences Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Montréal
country: Canada
facility: Montreal Neurological Institute & Hospital
state: Quebec
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
Study officials:
References: