Clinical trial NCT02927080: Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD)
Official title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Facioscapulohumeral Muscular Dystrophy
Keywords: FSHD
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2016-10-06
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: Key Inclusion Criteria:

1. Age ≥ 18 years
2. 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
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 anti-coagulation/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)

Primary outcomes:
measure: Safety and Tolerability (Incidence of Adverse Events)
timeFrame: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2
measure: Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).
timeFrame: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2
measure: Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)
timeFrame: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2
measure: Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)
timeFrame: Time Frame: From initiation of treatment to Study Visit Day 190
measure: 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)
timeFrame: Time Frame: From initiation of treatment to Study Visit Day 190
Secondary outcomes:
measure: Percent Change in Total Muscle Volume (TMV) in Muscle in Patients With FSHD Administered ACE-083 During Part 1 (Open-label, Dose-escalation Portion)
timeFrame: Time Frame: From initiation of treatment to Study Visit Day 106
measure: Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)
timeFrame: Time Frame: From initiation of treatment to Study Visit Day 190
measure: Percent Change From Baseline in Function of Tibialis Anterior, Part 2 (Randomized, Controlled Portion)
timeFrame: From initiation of treatment (Study Day 1) to Study Visit Day 190
measure: Percent Change From Baseline in Strength of Biceps Brachii, Part 2, Randomized-controlled
timeFrame: From initiation of treatment (Study Day 1) to Study Visit Day 190
measure: Percent Change From Baseline in Performance of the Upper Limb (PUL) Mid-Level Elbow Dimension, Part 2, Randomized-controlled
timeFrame: From initiation of treatment (Study Day 1) to Study Visit Day 190
measure: Change From Baseline in Facioscapulohumeral Muscular Dystrophy-health Index (FSHD-HI), Patient-reported Outcome (PRO) Measures Part 2 (Randomized, Controlled Portion)- Total Score
timeFrame: Time Frame: From initiation of treatment (Study Day 1) to Study Visit Day 190
measure: ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Tibialis Anterior (TA) Bilaterally) Day 2, 24-hours After Dose
timeFrame: Day 2, 24-hours after dose
measure: ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Tibialis Anterior (TA) Bilaterally) Day 85, 6-hours After Dose
timeFrame: Study Day 85 (6 hours post-dose)
measure: ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 1, 6-hours Post-dose
timeFrame: Study Day 1, 6-hours post-dose
measure: ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 85, 4-hours Post-dose
timeFrame: Study Day 85, 4-hours post-dose
measure: ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Tibialis Anterior (TA) Bilaterally) Day 2, 24- Hours Post-dose
timeFrame: Day 2, 24-hours post-dose
measure: ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Tibialis Anterior (TA) Bilaterally) Day 86, 24- Hours Post-dose
timeFrame: Day 86, 24-hours post-dose
measure: ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Biceps Brachii (BB) Bilaterally) Day 2, 24- Hours Post-dose
timeFrame: Day 2, 24-hours post-dose
measure: ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Biceps Brachii (BB) Bilaterally) Day 86, 24 Hours Post-dose
timeFrame: Day 86, 24- hours post-dose
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins Hugo W. Moser Research Inst. at Kennedy Krieger Inc.
state: Maryland
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Rochester
country: United States
facility: University of Rochester School of Medicine
state: New York
city: Charlotte
country: United States
facility: Carolinas Healthcare System Neurosciences Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Montréal
country: Canada
facility: Montreal Neurological Institute & Hospital
state: Quebec
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
Study officials:
References: