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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 : Recruiting
First Posted : April 21, 2017
Last Update Posted : January 15, 2019
Sponsor:
Information provided by (Responsible Party):
Acceleron Pharma, Inc.

Tracking Information
First Submitted Date  ICMJE April 12, 2017
First Posted Date  ICMJE April 21, 2017
Last Update Posted Date January 15, 2019
Actual Study Start Date  ICMJE July 31, 2017
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 20, 2017)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03124459 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 14, 2018)
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: April 20, 2017)
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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 acoring system to assess sensory and motor impairment in subjects with CMT
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
Official Title  ICMJE A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease Types 1 and X
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Charcot-Marie-Tooth Disease
Intervention  ICMJE
  • Drug: ACE-083
    Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution.
  • Drug: Placebo
    Recombinant fusion protein or buffer solution
Study Arms  ICMJE
  • Experimental: Part 1 Cohort 1
    ACE-083 150 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses.
    Intervention: Drug: ACE-083
  • Experimental: Part 1 Cohort 2
    ACE-083 200 mg IM, (tibialis anterior muscle), once every 3 weeks for up to 5 doses.
    Intervention: Drug: ACE-083
  • Experimental: Part 1 Cohort 3
    ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses.
    Intervention: Drug: ACE-083
  • 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
    Interventions:
    • Drug: ACE-083
    • Drug: Placebo
  • Experimental: Part 2 (open label)
    ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 8 doses
    Intervention: Drug: ACE-083
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 20, 2017)
42
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2020
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Clinical Trial Manager 617-649-9200 clinicaltrials08303@acceleronpharma.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03124459
Other Study ID Numbers  ICMJE A083-03
ACE-083 ( Other Identifier: Acceleron Pharma Inc. )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Acceleron Pharma, Inc.
Study Sponsor  ICMJE Acceleron Pharma, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Kenneth M. Attie, MD Acceleron Pharma, Inc.
PRS Account Acceleron Pharma, Inc.
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP