Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
- Registration Number
- NCT03124459
- Lead Sponsor
- Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
- 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.
- 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 Safety Review Team (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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 63
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 2 (double-blind placebo controlled) Placebo ACE-083 up to 250 mg IM (tibialis anterior muscle) or placebo, once every 3 weeks for up to 9 doses Part 2 (double-blind placebo controlled) ACE-083 ACE-083 up to 250 mg IM (tibialis anterior muscle) or placebo, once every 3 weeks for up to 9 doses Part 1 Cohort 1 ACE-083 ACE-083 150 mg intramuscular (IM) (tibialis anterior muscle), once every 3 weeks for up to 5 doses. Part 1 Cohort 2 ACE-083 ACE-083 200 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses. Part 1 Cohort 3 ACE-083 ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses. Part 2 (open label) ACE-083 ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 8 doses
- Primary Outcome Measures
Name Time Method Part 2: Percent Change in Muscle Volume 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). 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.
Part 1: Frequency of Adverse Events From initiation of treatment (Study Day 1) to end of follow-up period for Part 1 (Study Day 141). 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.
- Secondary Outcome Measures
Name Time Method Part 2: Percent Change in Balance and Fall Risk From Baseline 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). Percent change was calculated for the difference from baseline and Day 190 Assessment scores on the Berg Balance Scale. The Berg Balance Scale, is a 14-item scoring system to assess balance and fall risk in adults. The Berg balance scale is used to objectively determine a patient's ability (or inability) to safely balance during a series of predetermined tasks. It is a 14 item list with each item consisting of a five-point ordinal scale ranging from 0 to 4, with 0 indicating the lowest level of function and 4 the highest level of function. Total scores are used for reporting, with a range of 0-56, with higher scores mean a better demonstration of function. A score of 56 indicates functional balance. A score of \< 45 indicates individuals may be at greater risk of falling. The pre-specified timepoints for reporting are baseline Berg scale score and Day 190 score, therefore data for the open-label arm of the study is not reported.
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). 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. The Berg balance scale is used to objectively determine a patient's ability (or inability) to safely balance during a series of predetermined tasks. It is a 14 item list with each item consisting of a five-point ordinal scale ranging from 0 to 4, with 0 indicating the lowest level of function and 4 the highest level of function. Total scores are used for reporting, with a range of 0-56, with higher scores mean a better demonstration of function. A score of 56 indicates functional balance. A score of \< 45 indicates individuals may be at greater risk of falling. The pre-specified timepoints for reporting are baseline Berg scale score and Day 190 score, therefore data for the open-label arm of the study is not reported.
Part 2: Percent Change in Clinical Examination Score in Baseline to 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). Percent change was calculated for the difference in the Charcot-Marie-Tooth (CMT) Examination Score (CMTES2) from baseline and Day 190 Assessment scores. The pre-specified timepoints for reporting are baseline Berg scale score and Day 190 score, therefore data for the open-label arm of the study is not reported.
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). Percent change from baseline in strength of the injected muscle, by Quantitative Muscle Testing (QMT) compared to 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.
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). Percent change from baseline in functional assessments, as measured by 6-minute walk distance when compared to 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.
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). The absolute change from baseline in intramuscular fat fraction of the injected muscle, by MRI compared to 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.
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). The percent change from baseline in functional assessments, as measured by 10-meter walk/run time when compared to 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.
Part 2: Change in Clinical Examination Score From Baseline to 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). Change from baseline in the Charcot-Marie-Tooth (CMT) Examination Score, version 2 (CMTES2), a composite scoring system to assess sensory and motor impairment in subjects with CMT. The total score is a subset of the following items from the CMT neuropathy score instrument: Sensory symptoms, Motor symptoms (legs), Motor symptoms (arms), Pinprick Sensibility, Vibration, Strength (legs), and Strength (arms). Each individual item is assessed using a rating from 0 to 4 inclusive. The range of CMTES2 scores is from 0 to 28 inclusive. A higher score means a greater degree of symptom severity. The Baseline score and score on the Day 190 Assessment are reported. The pre-specified timepoints for reporting are baseline Berg scale score and Day 190 score, therefore data for the open-label arm of the study is not reported.
Part 2: Change in Patient-reported Quality of Life From Baseline 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). The absolute change from baseline in Charcot-Marie-Tooth Health Index (CMT-HI), a disease-specific, patient-reported health index score from baseline and Day 190 Assessment scores. The pre-specified timepoints for reporting are baseline Berg scale score and Day 190 score, therefore data for the open-label arm of the study is not reported.
Trial Locations
- Locations (16)
University of Vermont
🇺🇸Burlington, Vermont, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
University of California-Irvine
🇺🇸Orange, California, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Rochester Medical Center, Neurology
🇺🇸Rochester, New York, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Columbia University
🇺🇸New York, New York, United States
Carolinas Healthcare System Neurosciences Institute
🇺🇸Charlotte, North Carolina, United States
University of Minnesota, Neurology Department
🇺🇸Minneapolis, Minnesota, United States
University of Kansas Medical Center - Neurology Department
🇺🇸Kansas City, Kansas, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
University of Florida
🇺🇸Gainesville, Florida, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States