Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD)

Study Overview
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Brief Summary
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Study A083-02 is a multi-center, Phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of locally-acting ACE-083 in patients with Facioscapulohumeral muscular dystrophy (FSHD) to be conducted in two parts. Part 1 is open-label, dose-escalation and Part 2 is randomized, double-blind, and placebo-controlled.

Detailed Description
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Part 1 (dose escalation, open-label) Part 1 will consist of up to 6 cohorts of patients and will evaluate multiple ascending dose levels of ACE-083 administered unilaterally or bilaterally to either the tibialis anterior (TA) or biceps brachii (BB) muscle(s). Patients in each cohort will be enrolled in a 4-week screening period before beginning treatment. A Safety Review Team (SRT) will meet to review data for each cohort when at least 4 patients within a cohort have completed their Day 43 visit prior to dose escalation of the next cohort. Study duration for Part 1 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. Part 2 (randomized, double-blind, placebo-controlled, with open-label extension) Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted to determine whether cohorts for one or both muscles will be pursued in Part 2, as well as the recommended dose level for each muscle. A total of up to 56 new patients (28 patients per muscle) may be enrolled and randomized (1:1) to receive either ACE-083 (n=14/muscle) or placebo (n=14/muscle) bilaterally to either the TA or BB muscles (but not both). Patients will receive blinded study drug once every three weeks for approximately 6 months (9 doses). Patients who complete the double-blind treatment period will immediately roll over to open-label treatment with ACE-083, receiving the same dose of active drug, bilaterally in either the TA or BB muscle, once every three weeks for approximately 6 months (8 doses). In Part 2, the SRT will periodically review blinded safety data for each muscle treated. Study duration for Part 2 for each patient will be approximately 15 months, including a 1-month screening period, a 12-month treatment period (6-month double-blind, placebo-controlled and a 6-month open-label extension), and a 2-month follow-up period after the last dose

Official Title
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A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy

Conditions
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Facioscapulohumeral Muscular Dystrophy

Intervention / Treatment
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* Drug: ACE-083
* Drug: ACE-083 or placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 years Genetically confirmed Facioscapulohumeral muscular dystrophy type 1 (FSHD1) or FSHD2 (or a first-degree relative with genetically confirmed FSHD1 or FSHD2) and clinical findings meeting FSHD criteria Part 1 TA cohorts: 6-minute walk distance (6MWD) ≥ 150 meters (without a brace) Mild to moderate weakness in left and/or right ankle dorsiflexion Part 1 BB cohorts: a. Mild to moderate weakness in left and/or right elbow flexion Part 2 TA cohorts: 6MWD ≥ 150 and ≤ 500 meters (without a brace) Mild to moderate weakness in left and right ankle dorsiflexion Part 2 BB cohorts: a. Mild to moderate weakness in left and/or right elbow flexion Females of childbearing potential must have negative urine pregnancy test prior to enrollment and use highly effective birth control methods during study participation. Hormonal birth control use must be stable for at least 14 days prior to Day 1. Males must agree to use a condom during any sexual contact with females of childbearing potential while participating in the study even if he has undergone a successful vasectomy. Key Exclusion Criteria: Current/ active malignancy (e.g., remission less than 5 years duration), with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin Symptomatic cardiopulmonary disease, significant functional impairment, 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 Renal impairment (serum creatinine ≥ 2 times the upper limit of normal,(ULN)) Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN Increased risk of bleeding (i.e., due to hemophilia, platelet disorders, or use of any anti-coagulation/platelet modifying therapies up to 2 weeks prior to Study Day 1; low dose aspirin [≤ 100 mg daily] is permitted) Major surgery within 4 weeks prior to Study Day 1 Chronic systemic corticosteroids (≥ 2 weeks) within 4 weeks before Study Day 1 and for duration of study; intra-articular/topical/inhaled therapeutic or physiologic doses of corticosteroids are permitted Androgens or growth hormone within 6 months before Study Day 1 and for duration of study; topical physiologic androgen replacement is permitted Any condition that would prevent MRI scanning or compromise the ability to obtain a clear and interpretable scan of the TA or BB muscles, as applicable (e.g., pacemaker, knee/hip replacement, or metallic implants)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150mg<br>ACE-083 150 mg TA unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083<br>* Recombinant fusion protein.<br>|
| Experimental: ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200mg<br>ACE-083 200 mg TA unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083<br>* Recombinant fusion protein.<br>|
| Experimental: ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200mg<br>ACE-083 200 mg TA bilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083<br>* Recombinant fusion protein.<br>|
| Experimental: ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg<br>ACE-083 150 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083<br>* Recombinant fusion protein.<br>|
| Experimental: ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg<br>ACE-083 200 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083<br>* Recombinant fusion protein.<br>|
| Experimental: ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg<br>ACE-083 240 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083<br>* Recombinant fusion protein.<br>|
| Placebo Comparator: Placebo (Part 2, DB-PC) Tibialis Anterior (TA)<br>Part 2, double-blind (DB) placebo-controlled (PC). Placebo TA bilaterally, once every 3 weeks for up to 9 doses. Drug: Placebo Normal saline Afterwards, participants were rolled over into the open-label portion and received ACE-083 240 mg TA bilaterally, once every 3 weeks for up to 8 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083 or placebo<br>* Recombinant fusion protein or normal saline.<br>|
| Experimental: ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg<br>Part 2, double-blind placebo-controlled. ACE-083 240 mg TA bilaterally, once every 3 weeks for up to 9 doses. Drug: ACE-083 Recombinant fusion protein Afterwards, participants were rolled over into the open-label portion and received ACE-083 240 mg TA bilaterally, once every 3 weeks for up to 8 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083<br>* Recombinant fusion protein.<br>|
| Placebo Comparator: Placebo (Part 2, DB-PC) Biceps Brachii (BB)<br>Part 2, double-blind placebo-controlled. Placebo BB bilaterally, once every 3 weeks for up to 9 doses. Drug: Placebo Normal saline Afterwards, participants were rolled over into the open-label portion and received ACE-083 240 mg Biceps Brachii (BB) bilaterally, once every 3 weeks for up to 8 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083 or placebo<br>* Recombinant fusion protein or normal saline.<br>|
| Experimental: ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg<br>Part 2, double-blind placebo-controlled. ACE-083 240 mg Biceps Brachii (BB) bilaterally, once every 3 weeks for up to 9 doses. Drug: ACE-083 Recombinant fusion protein Afterwards, participants were rolled over into the open-label portion and received ACE-083 240 mg Biceps Brachii (BB) bilaterally, once every 3 weeks for up to 8 doses. Drug: ACE-083 Recombinant fusion protein | Drug: ACE-083<br>* Recombinant fusion protein.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability (Incidence of Adverse Events) | The number of participants that had a least one Treatment Emergent Adverse Event for the duration of each of the respective study parts. | From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2 | 
| Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher). | The number of participants that had a least one Treatment Emergent Adverse Event with CTCAE Grade 3 or Higher for the duration of each of the respective study parts. | From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2 | 
| Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal) | The number of participants that had a least one Treatment Emergent Adverse Event that led to dose interruption, dose reduction and/or drug withdrawn. | From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2 | 
| Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion) | Total Muscle Volume (TMV)of the treated muscle in Patients with FSHD administered ACE-083 or placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Total Muscle volume was measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190. Baseline and Day 190 total muscle volume, means and standard deviations are reported. | Time Frame: From initiation of treatment to Study Visit Day 190 | 
| Percent Change of Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion) | Percent Change of Total Muscle Volume (TMV)of the treated muscle in Patients with FSHD administered ACE-083 or placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Total Muscle volume was measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190. Percent Change from Baseline to Day 190 total muscle volume, mean and standard deviation is reported. | Time Frame: From initiation of treatment to Study Visit Day 190 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Total Muscle Volume (TMV) in Muscle in Patients With FSHD Administered ACE-083 During Part 1 (Open-label, Dose-escalation Portion) | Percent Change in Total Muscle Volume (TMV) in muscle in patients with FSHD administered ACE-083 During 1 (open-label, dose-escalation portion) from Baseline to Day 106. Total Muscle volume was measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, and Day 106, change from Baseline and Day 106 reported. | Time Frame: From initiation of treatment to Study Visit Day 106 | 
| Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion) | Absolute change in Fat Fraction (FF) of the muscle in patients with FSHD administered ACE-083 or Placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Absolute change in intramuscular fat fraction in the tibialis anterior and biceps brachii were measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190, change from Baseline and Day 190 reported. | Time Frame: From initiation of treatment to Study Visit Day 190 | 
| Percent Change From Baseline in Function of Tibialis Anterior, Part 2 (Randomized, Controlled Portion) | Percent change from baseline in function of Tibialis Anterior during Part 2 assessed by: 6-minute walk test, 10 meter walk/run and 4-stair climb (ascend) | From initiation of treatment (Study Day 1) to Study Visit Day 190 | 
| Percent Change From Baseline in Strength of Biceps Brachii, Part 2, Randomized-controlled | Elbow flexion strength measured by hand-held dynamometry (quantitative muscle testing), maximum voluntary isometric contraction (MVIC). | From initiation of treatment (Study Day 1) to Study Visit Day 190 | 
| Percent Change From Baseline in Performance of the Upper Limb (PUL) Mid-Level Elbow Dimension, Part 2, Randomized-controlled | Percent Change from Baseline in Performance of the Upper Limb (PUL) Mid-Level Elbow Dimension, Part 2, Randomized-controlled, PUL from baseline to end of treatment (Day 190). The Performance of the Upper Limb is an assessment specifically designed for patients with Duchenne muscular dystrophy. The measures used in this study was a subset of the assessment. PUL was assessment by measures of high-level of movement (lifting weights of 50g, 200g, 500g and 1000g at shoulder height and above shoulder height) and mid-level movement by performing tasks with and without weights: hand to mouth with and without weights (50, 200g), hand to table, moving weights on table (100g, 200g, 500g and 1000g), lift light and heavy cans, stack light and heavy cans, remove lid from container, tearing paper). | From initiation of treatment (Study Day 1) to Study Visit Day 190 | 
| Change From Baseline in Facioscapulohumeral Muscular Dystrophy-health Index (FSHD-HI), Patient-reported Outcome (PRO) Measures Part 2 (Randomized, Controlled Portion)- Total Score | The facioscapulohumeral muscular dystrophy-health index (FSHD-HI) is a disease-specific patient-reported outcome (PRO) tool assessed by health-related quality of life and disease burden. The FSHD-HI questionnaire was designed to measure both overall FSHD health-related quality-of-life and 14 separate subdomains designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. The 116 questions are combined into a total score, the score is transformed onto a percentage scale; with a range of 0-100, with 100 representing maximal disability, and lower scores representing decreasing disability, 0 representing no disability. The mean and standard deviation for baseline and day 190 are reported as is the absolute change from baseline to Day 190 during the randomized controlled portion of Part 2. | Time Frame: From initiation of treatment (Study Day 1) to Study Visit Day 190 | 
| ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Tibialis Anterior (TA) Bilaterally) Day 2, 24-hours After Dose | Pharmacokinetic assessment included ACE-083 serum concentration collection and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. Timepoints that have data are reported; Day 2, 24-hours after dose is reported. | Day 2, 24-hours after dose | 
| ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Tibialis Anterior (TA) Bilaterally) Day 85, 6-hours After Dose | Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 86, 6-hours post-dose is reported. | Study Day 85 (6 hours post-dose) | 
| ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 1, 6-hours Post-dose | Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 1, 6-hours post-dose, is reported. | Study Day 1, 6-hours post-dose | 
| ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 85, 4-hours Post-dose | Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. | Study Day 85, 4-hours post-dose | 
| ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Tibialis Anterior (TA) Bilaterally) Day 2, 24- Hours Post-dose | Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 2, 24-hours post-dose is reported. | Day 2, 24-hours post-dose | 
| ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Tibialis Anterior (TA) Bilaterally) Day 86, 24- Hours Post-dose | Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 86, 24-hours post-dose is reported. | Day 86, 24-hours post-dose | 
| ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Biceps Brachii (BB) Bilaterally) Day 2, 24- Hours Post-dose | Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 2, 24-hours post-dose is reported. | Day 2, 24-hours post-dose | 
| ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Biceps Brachii (BB) Bilaterally) Day 86, 24 Hours Post-dose | Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 86, 24-hours post-dose is reported. | Day 86, 24- hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FSHD