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

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ClinicalTrials.gov Identifier: NCT03124459
Recruitment Status : Active, not recruiting
First Posted : April 21, 2017
Last Update Posted : November 6, 2019
Sponsor:
Information provided by (Responsible Party):
Acceleron Pharma, Inc.

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 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.

Condition or disease Intervention/treatment Phase
Charcot-Marie-Tooth Disease Drug: ACE-083 Drug: Placebo Phase 2

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 63 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease Types 1 and X
Actual Study Start Date : July 31, 2017
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : July 2020


Arm Intervention/treatment
Experimental: Part 1 Cohort 1
ACE-083 150 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses.
Drug: ACE-083
Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution.

Experimental: Part 1 Cohort 2
ACE-083 200 mg IM, (tibialis anterior muscle), once every 3 weeks for up to 5 doses.
Drug: ACE-083
Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution.

Experimental: Part 1 Cohort 3
ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses.
Drug: ACE-083
Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution.

Experimental: Part 2 (double-blind placebo controlled)
ACE-083 up to 250 mg IM (tibialis anterior muscle) or placebo, once every 3 weeks for up to 9 doses
Drug: ACE-083
Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution.

Drug: Placebo
Recombinant fusion protein or buffer solution

Experimental: Part 2 (open label)
ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 8 doses
Drug: ACE-083
Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution.




Primary Outcome Measures :
  1. Part 1: Frequency of adverse events [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Number of subjects with adverse events related to treatment intervention

  2. Part 2: Change in muscle volume [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Percent change from baseline in volume of injected muscle, by MRI


Secondary Outcome Measures :
  1. Change in amount of intramuscular fat tissue [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Percent change from baseline in intramuscular fat fraction of the injected muscle, by MRI

  2. Change in muscle strength [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Percent change from baseline in strength of the injected muscle, by Quantitative Muscle Testing (QMT)

  3. Change in muscle function - walk/run time [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Percent change from baseline in functional assessments, as measured by 10-meter walk/run time

  4. Change in muscle function - walk distance [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Percent change from baseline in functional assessments, as measured by 6-minute walk distance

  5. Change in balance and fall risk [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Percent change from baseline in static and dynamic balance, as measured by the Berg Balance Scale, a 14-item scoring system to assess balance and fall risk in adults

  6. Change in clinical examination score [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Percent change from baseline in the CMT Examination Score (CMTES2), a composite scoring system to assess sensory and motor impairment in subjects with CMT

  7. Change in patient-reported quality of life [ Time Frame: From initiation of treatment (Study Day 1) to end of follow-up period (Study Day 141). ]
    Percent change from baseline in CMT-HI, a disease-specific, patient-reported health index score



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria

  1. Age ≥ 18 years
  2. Diagnosis of CMT1 or CMTX confirmed by:

    1. Clinical presentation and electrodiagnostics
    2. Genetically-confirmed CMT1 or CMTX for the patient or first-degree relative
  3. Part 1:

    1. Six-minute walk distance (6MWD) of at least 150 meters (without a brace or walker)
    2. Independent ambulation for at least 10 meters, without a brace
    3. Left and right ankle plantar flexion MRC grade 4+ to 5, inclusive

    Part 2:

    1. 6MWD ≥ 150 and ≤ 500 meters (without a brace or walker); a maximum of 20% of enrolled patients with 6MWD ≥ 450 meters will be included
    2. Left and right ankle plantar flexion MRC grade 4- to 5, inclusive
  4. Left and right ankle dorsiflexion Medical Research Council (MRC) manual muscle testing (MMT) grade 4- to 4+, inclusive
  5. 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.
  6. Ability to adhere to the study visit schedule/procedures, and to understand and comply with protocol requirements
  7. Signed written informed consent

Key Exclusion Criteria

  1. 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
  2. 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
  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; low dose aspirin [≤ 100 mg daily] is permitted)
  8. Severe deformity or ankle fixation that would sufficiently limit passive range of motion to affect assessment of dorsiflexion strength
  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
  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 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)
  14. Any previous or current exposure to ACE-083
  15. 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
  16. 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)
  17. Known active substance abuse, including alcohol
  18. History of sensitivity to protein pharmaceuticals
  19. Female that is lactating/breast-feeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03124459


Locations
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United States, California
University of California-Irvine
Orange, California, United States, 92868
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80045
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, Kansas
University of Kansas Medical Center - Neurology Department
Kansas City, Kansas, United States, 66160
United States, Minnesota
University of Minnesota, Neurology Department
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Columbia University
New York, New York, United States, 10032
University of Rochester Medical Center, Neurology
Rochester, New York, United States, 14642
United States, North Carolina
Carolinas Healthcare System Neurosciences Institute
Charlotte, North Carolina, United States, 28203
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112
United States, Vermont
University of Vermont
Burlington, Vermont, United States, 05401
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Acceleron Pharma, Inc.
Investigators
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Study Chair: Kenneth M. Attie, MD Acceleron Pharma, Inc.

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Responsible Party: Acceleron Pharma, Inc.
ClinicalTrials.gov Identifier: NCT03124459     History of Changes
Other Study ID Numbers: A083-03
ACE-083 ( Other Identifier: Acceleron Pharma Inc. )
First Posted: April 21, 2017    Key Record Dates
Last Update Posted: November 6, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Acceleron Pharma, Inc.:
CMT1 / CMTX
Additional relevant MeSH terms:
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Tooth Diseases
Charcot-Marie-Tooth Disease
Nerve Compression Syndromes
Hereditary Sensory and Motor Neuropathy
Stomatognathic Diseases
Nervous System Malformations
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Polyneuropathies
Peripheral Nervous System Diseases
Neuromuscular Diseases
Congenital Abnormalities
Genetic Diseases, Inborn