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

Study Description

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Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Facioscapulohumeral Muscular Dystrophy	Drug: ACE-083; Drug: ACE-083 or placebo	Phase 2

Detailed Description:

Part 1 (dose escalation, open-label) Part 1 will consist of up to 6 cohorts (A to F) of patients and will evaluate multiple ascending dose levels of ACE-083 in either the tibialis anterior (TA) or biceps brachii (BB) muscle. 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.

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 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.

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

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	92 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy
Study Start Date :	November 2016
Estimated Primary Completion Date :	March 2020
Estimated Study Completion Date :	June 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: ACE-083 (Part 1, Cohort 1); ACE-083 150 mg IM, once every 3 weeks for up to 5 doses.	Drug: ACE-083; Recombinant fusion protein.
Experimental: ACE-083 (Part 1, Cohort 2); ACE-083 200 mg IM, once every 3 weeks for up to 5 doses.	Drug: ACE-083; Recombinant fusion protein.
Experimental: ACE-083 (Part 1, Cohort 3); ACE-083 up to 250 mg IM, once every 3 weeks for up to 5 doses.	Drug: ACE-083; Recombinant fusion protein.
Experimental: ACE-083 (Part 2, DB-PC, IM tibialis anterior muscle); 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.	Drug: ACE-083 or placebo; Recombinant fusion protein or normal saline.
Experimental: ACE-083 (Part 2, PL, IM tibialis anterior muscle); Open-Label ACE-083 up to 250 mg IM (tibialis anterior muscle) once every 3 weeks for up to 8 doses.	Drug: ACE-083; Recombinant fusion protein.
Experimental: ACE-083, (Part 2, DB-PC, IM biceps brachii muscle); Double-Blind, Placebo-Controlled ACE-083 up to 250 mg IM (biceps brachii muscle) or placebo, once every 3 weeks for up to 9 doses.	Drug: ACE-083 or placebo; Recombinant fusion protein or normal saline.
Experimental: ACE-083 (Part 2, OP, biceps brachii muscle); Open-Label ACE-083 up to 250 mg IM (biceps brachii muscle), once every 3 weeks for up to 8 doses.	Drug: ACE-083; Recombinant fusion protein.

Outcome Measures

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Primary Outcome Measures :

1. Safety and Tolerability (data collection on the incidence, nature and severity of adverse events). [ Time Frame: From initiation of treatment (Study Day 1) to end-of-study visit (Study Day 141). ]
   Adverse events will be recorded and coded in accordance with MedDRA v.20,0

Secondary Outcome Measures :

1. Estimation of systemic exposure to ACE-083 following local intramuscular administration. [ Time Frame: From initiation of treatment (Study Day 1) to end-of-study visit (Study Day 141). ]
   Bioanlaytical assay for the quantitative of ACE-083 in serum
2. Percent change from baseline in strength of injected muscle [ Time Frame: From initiation of treatment (Study Day 1) to end of treatment visit. ]
   Strength measurements by hand-held or fixed-system dynamometry (quantitative muscle testing).
3. Percent change from baseline in function of injected muscle [ Time Frame: From initiation of treatment (Study Day 1) to end-of-study visit (Study Day 141). ]
   Function assessed by a battery of motor function tests; 4-stair climb, 6-minute walk test, gait analysis and performance of the upper limb (PUL) test
4. Change from baseline in patient-reported outcome (PRO) measures [ Time Frame: From initiation of treatment (Study Day 1) to end-of-study visit (Study Day 141). ]
   PRO assessed by health-related quality of life and disease burden, as measured by the FSHD Health Index questionnaire (FSHD-HI).

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Key Inclusion Criteria:

1. Age ≥ 18 years
2. Genetically-confirmed FSHD1 or FSHD2 (or a first-degree relative with genetically confirmed FSHD1 or FSHD2) and clinical findings meeting FSHD criteria

3. Part 1 TA cohorts:

   1. 6-minute walk distance (6MWD) ≥ 150 meters (without a brace)
   2. 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:

   1. 6MWD ≥ 150 and ≤ 500 meters (without a brace)
   2. 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

4. 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:

1. 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
2. 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
3. Renal impairment (serum creatinine ≥ 2 times the upper limit of normal [ULN])
4. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN
5. 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; low dose aspirin [≤ 100 mg daily] is permitted)
6. Major surgery within 4 weeks prior to Study Day 1
7. 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
8. Androgens or growth hormone within 6 months before Study Day 1 and for duration of study; topical physiologic androgen replacement is permitted
9. 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)

Contacts and Locations

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Contacts

Contact: Clinical Trial Manager		clinicaltrials083@acceleronpharma.com

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Sponsors and Collaborators

Acceleron Pharma, Inc.

More Information

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Responsible Party:	Acceleron Pharma, Inc.
ClinicalTrials.gov Identifier:	NCT02927080 History of Changes
Other Study ID Numbers:	A083-02; ACE-083 ( Other Identifier: Acceleron Pharma Inc. )
First Posted:	October 6, 2016
Last Update Posted:	October 12, 2018
Last Verified:	October 2018

Keywords provided by Acceleron Pharma, Inc.:

FSHD

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Facioscapulohumeral; Muscular Disorders, Atrophic; Muscular Diseases	Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn