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Abstract
Background and Objectives The goal of this work was to determine whether locally acting ACE-083 is safe and well tolerated and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1.
Methods This phase 2 study enrolled adults with CMT1 or CMTX (N = 63). Part 1 was open label and evaluated the safety and tolerability of different dose levels of ACE-083 for use in part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally into the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-m walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests.
Results In part 1 (n = 18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious adverse events, TEAEs of grade 3 or greater, or death reported. In part 2 (n = 45 enrolled, n = 44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (least-squares mean difference 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate to mild injection-site reactions were the most common TEAEs.
Discussion Despite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo.
Trial Registration Information Clinical Trials Registration: NCT03124459.
Classification of Evidence This study provides Class II evidence that intramuscular ACE-083 is safe and well tolerated and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.
Glossary
- AE=
- adverse event;
- CMAP=
- compound muscle action potential;
- CMT=
- Charcot-Marie-Tooth disease;
- CMT-HI=
- CMT-Health Index;
- CMV=
- contractile muscle volume;
- FSHD=
- facioscapulohumeral muscular dystrophy;
- GDF=
- growth differentiation factor;
- ISR=
- injection-site reaction;
- LS=
- least-squares;
- MRC=
- Medical Research Council;
- MMT=
- manual muscle testing;
- QoL=
- quality of life;
- SAE=
- serious AE;
- 6MWT=
- 6-minute walk test;
- SRT=
- Safety Review Team;
- TA=
- tibialis anterior;
- TEAE=
- treatment-emergent AE;
- 10 mW/R=
- 10-m walk/run;
- TMV=
- total muscle volume
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editors were José Merino, MD, MPhil, FAAN, and Anthony Amato, MD, FAAN.
This Null Hypothesis article is published as part of a collaborative effort, between Neurology and CBMRT.
Null Hypothesis: NPub.org/Null
Class of Evidence: NPub.org/coe
- Received March 18, 2021.
- Accepted in final form February 17, 2022.
- © 2022 American Academy of Neurology
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