Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
Condition: Charcot-Marie-Tooth Disease
MeSH terms: Tooth Diseases; Charcot-Marie-Tooth Disease; Nerve Compression Syndromes; Hereditary Sensory and Motor Neuropathy
Intervention: ACE-083; Placebo
Intervention description: Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution.; Recombinant fusion protein or buffer solution
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 63.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CMT1 / CMTX

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.
    

Eligibility 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 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.

          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