Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
a study on Charcot-Marie-Tooth Disease
This is a multicenter, phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with CMT1 and CMTX, to be conducted in two parts. Part 1 is non-randomized, open-label, dose-escalation and Part 2 is randomized, double-blind, and placebo-controlled.
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease Types 1 and X
Part 1 (non-randomized, open-label, dose-escalation)
Part 1 will consist of up to 3 cohorts of 6 patients each and will evaluate multiple ascending dose levels of ACE-083 administered bilaterally once every 3 weeks for up to 5 doses in the tibialis anterior (TA) muscle. Patients in each cohort will be enrolled in a 4-week screening period before beginning treatment.
Part 2 (randomized, double-blind, placebo-controlled) Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted by the SRT to determine the recommended dose level (maximum 250 mg/muscle). A total of up to 40 new patients may be enrolled and randomized (1:1 randomization) to receive either ACE 083 (n=20) or placebo (n=20) bilaterally by injection into both TA muscles once every 3 weeks for up to 17 doses.
Study duration for Parts 1 and 2 for each patient will be approximately 24 weeks, including a 4-week screening period, a 12-week treatment period, and an 8-week follow-up period after the last dose.
Study duration for Part 2 will be 15 months, including 4-week screening, 6 months double blind placebo-controlled , 6 months open-label and 8 week follow-up.
Charcot-Marie-Tooth DiseaseCMT1 / CMTXTooth DiseasesNerve Compression SyndromesHereditary Sensory and Motor NeuropathyACE-083
For people ages 18 years and up
Key Inclusion Criteria
- Age ≥ 18 years
- Diagnosis of CMT1 or CMTX confirmed by:
- Clinical presentation and electrodiagnostics
- Genetically-confirmed CMT1 or CMTX for the patient or first-degree relative
- Part 1:
- Six-minute walk distance (6MWD) of at least 150 meters (without a brace or walker)
- Independent ambulation for at least 10 meters, without a brace
- Left and right ankle plantar flexion MRC grade 4+ to 5, inclusive
- 6MWD ≥ 150 and ≤ 500 meters (without a brace or walker); a maximum of 20% of enrolled patients with 6MWD ≥ 450 meters will be included
- Left and right ankle plantar flexion MRC grade 4- to 5, inclusive
- Left and right ankle dorsiflexion Medical Research Council (MRC) manual muscle testing (MMT) grade 4- to 4+, inclusive
- Females of childbearing potential must have negative urine pregnancy test prior to enrollment and use highly effective birth control methods during study participation and for 8 weeks following the last dose of ACE-083. 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 he has undergone a successful vasectomy.
- Ability to adhere to the study visit schedule/procedures, and to understand and comply with protocol requirements
- Signed written informed consent
Key Exclusion Criteria
- History of active malignancy, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin
- Symptomatic cardiopulmonary disease, significant functional impairment, significant orthopedic or neuropathic pain, or other co morbidities that in the opinion of the investigator would limit a patient's ability to complete strength and/or functional assessments on study
- 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; low dose aspirin [≤ 100 mg daily] is permitted)
- Severe deformity or ankle fixation that would sufficiently limit passive range of motion to affect assessment of dorsiflexion strength
- 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
- . 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
- . 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)
- . Previous exposure to any investigational agent 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)
- . Any previous or current exposure to ACE-083
- . 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
- . Any condition that would prevent MRI scanning or compromise the ability to obtain a clear and interpretable scan of the lower leg, as applicable (e.g., knee/hip replacement metallic implants)
- . Known active substance abuse, including alcohol
- . History of sensitivity to protein pharmaceuticals
- . Female that is lactating/breast-feeding
- University of California-Irvineaccepting new patients
- University of Utahaccepting new patients
Salt Lake CityUtah84112United States
Lead Scientist at UC Irvine
- Tahseen Mozaffar
Authored (or co-authored) 89 research publications
- accepting new patients
- Start Date
- Completion Date
- Acceleron Pharma, Inc.
- Phase 2
- Study Type
- Last Updated
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