Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease

NCT03124459 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: A083-03ACE-083
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 16

Brief Summary

This is a multicenter, phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with Charcot-Marie-Tooth Disease Type 1 and Type X (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.

Conditions

Charcot-Marie-Tooth Disease

Keywords

CMT1 / CMTX

Outcome Measures

Primary Outcomes (2)

• Part 1: Frequency of Adverse Events

  Number of subjects with at least one adverse event related to treatment intervention from Part 1 of this study. Since this outcome measure was only pre-specified for Part 1, only data from the Part 1 participants is reported.

  From initiation of treatment (Study Day 1) to end of follow-up period for Part 1 (Study Day 141).

• Part 2: Percent Change in Muscle Volume to the End of the Double-blind Placebo-controlled Portion of the Study.

  The percent change from baseline in volume of injected muscle, by MRI compared to the Day 190 Assessment is reported. The pre-specified timepoint for this outcome was only for data collected from participants to the end of the double-blind placebo controlled portion of the study, therefore data for the open-label arm of the study is not reported.

  From initiation of treatment (Study Day 1) to end of follow-up period of the double-blind placebo-controlled portion of the study (Study Day 190).

Secondary Outcomes (9)

• Part 2: Absolute Change in Amount of Intramuscular Fat Tissue to the End of the Double-blind Placebo-controlled Portion of the Study

  From initiation of treatment (Study Day 1) to end of follow-up period of the double-blind placebo-controlled portion of the study (Study Day 190).

• Part 2: Percent Change in Muscle Strength to the End of the Double-blind Placebo-controlled Portion of the Study

  From initiation of treatment (Study Day 1) to end of follow-up period of the double-blind placebo-controlled portion of the study (Study Day 190).

• Part 2: Percent Change in Muscle Function - Walk/Run Time to the End of the Double-blind Placebo-controlled Portion of the Study

  From initiation of treatment (Study Day 1) to end of follow-up period of the double-blind placebo-controlled portion of the study (Study Day 190).

• Part 2: Percent Change in Muscle Function - Walk Distance Assessed at the End of the Double-blind Placebo-controlled Portion of the Study

  From initiation of treatment (Study Day 1) to end of follow-up period for the double-blind placebo-controlled portion of the study (Study Day 190).

• Part 2: Change in Balance and Fall Risk at the End of the Double-blind Placebo-controlled Portion of the Study.

  From initiation of treatment (Study Day 1) to end of follow-up period of the double-blind placebo-controlled portion of the study (Study Day 190).

Study Arms (5)

Part 1 Cohort 1

EXPERIMENTAL

ACE-083 150 mg intramuscular (IM) (tibialis anterior muscle), once every 3 weeks for up to 5 doses.

Drug: ACE-083

Part 1 Cohort 2

EXPERIMENTAL

ACE-083 200 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses.

Drug: ACE-083

Part 1 Cohort 3

EXPERIMENTAL

ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses.

Drug: ACE-083

Part 2 (double-blind placebo controlled)

EXPERIMENTAL

ACE-083 up to 250 mg IM (tibialis anterior muscle) or placebo, once every 3 weeks for up to 9 doses

Drug: ACE-083; Drug: Placebo

Part 2 (open label)

EXPERIMENTAL

ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 8 doses

Drug: ACE-083

Interventions

ACE-083 DRUG

Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution.

Part 1 Cohort 1; Part 1 Cohort 2; Part 1 Cohort 3; Part 2 (double-blind placebo controlled); Part 2 (open label)

Placebo DRUG

Recombinant fusion protein or buffer solution

Part 2 (double-blind placebo controlled)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Part 2:
• MWD ≥ 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 3 to 4+ inclusive. No more than 12 of the 40 subjects may have a grade of 3 or 3+ on one or both sides.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA: lead

Study Sites (16)

University of California-Irvine

Orange, California, 92868, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

University of Kansas Medical Center - Neurology Department

Kansas City, Kansas, 66160, United States

Location

University of Minnesota, Neurology Department

Minneapolis, Minnesota, 55455, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Columbia University

New York, New York, 10032, United States

Location

University of Rochester Medical Center, Neurology

Rochester, New York, 14642, United States

Location

Carolinas Healthcare System Neurosciences Institute

Charlotte, North Carolina, 28203, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

University of Vermont

Burlington, Vermont, 05401, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

Related Publications (1)

• Thomas FP, Brannagan TH 3rd, Butterfield RJ, Desai U, Habib AA, Herrmann DN, Eichinger KJ, Johnson NE, Karam C, Pestronk A, Quinn C, Shy ME, Statland JM, Subramony SH, Walk D, Stevens-Favorite K, Miller B, Leneus A, Fowler M, van de Rijn M, Attie KM. Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease. Neurology. 2022 Jun 6;98(23):e2356-e2367. doi: 10.1212/WNL.0000000000200325.

  PMID: 35545446 DERIVED

MeSH Terms

Conditions

Charcot-Marie-Tooth Disease; Charcot-Marie-Tooth disease, X-linked, 1

Condition Hierarchy (Ancestors)

Hereditary Sensory and Motor Neuropathy; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Limitations and Caveats

The study was terminated because the statistically significant increase in total muscle volume (TMV) failed to translate to statistically significant improvements in functional or disease-related quality of life secondary endpoints in the study.

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Jay Backstrom, MD

  Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2017
• First Posted: April 21, 2017
• Study Start: July 31, 2017
• Primary Completion: March 11, 2020
• Study Completion: March 11, 2020
• Last Updated: September 26, 2022
• Results First Posted: July 28, 2021

Record last verified: 2022-09

Locations

US (16)