A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 95
- 试验地点
- 24
- 主要终点
- Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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)
研究组 & 干预措施
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150mg
ACE-083 150 mg TA unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein
干预措施: ACE-083 (Drug)
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200mg
ACE-083 200 mg TA unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein
干预措施: ACE-083 (Drug)
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200mg
ACE-083 200 mg TA bilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein
干预措施: ACE-083 (Drug)
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg
ACE-083 150 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein
干预措施: ACE-083 (Drug)
ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg
ACE-083 200 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein
干预措施: ACE-083 (Drug)
ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg
ACE-083 240 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein
干预措施: ACE-083 (Drug)
Placebo (Part 2, DB-PC) Tibialis Anterior (TA)
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
干预措施: ACE-083 or placebo (Drug)
ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg
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
干预措施: ACE-083 (Drug)
Placebo (Part 2, DB-PC) Biceps Brachii (BB)
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
干预措施: ACE-083 or placebo (Drug)
ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg
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
干预措施: ACE-083 (Drug)
结局指标
主要结局
Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).
时间窗: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2
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.
Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)
时间窗: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2
The number of participants that had a least one Treatment Emergent Adverse Event that led to dose interruption, dose reduction and/or drug withdrawn.
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)
时间窗: 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) 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.
Safety and Tolerability (Incidence of Adverse Events)
时间窗: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2
The number of participants that had a least one Treatment Emergent Adverse Event for the duration of each of the respective study parts.
Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)
时间窗: Time Frame: From initiation of treatment to Study Visit Day 190
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.
次要结局
- Percent Change From Baseline in Function of Tibialis Anterior, Part 2 (Randomized, Controlled Portion)(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(Day 2, 24-hours after dose)
- ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 1, 6-hours Post-dose(Study Day 1, 6-hours post-dose)
- Percent Change From Baseline in Strength of Biceps Brachii, Part 2, Randomized-controlled(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(From initiation of treatment (Study Day 1) to Study Visit Day 190)
- ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Tibialis Anterior (TA) Bilaterally) Day 2, 24- Hours Post-dose(Day 2, 24-hours post-dose)
- ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Biceps Brachii (BB) Bilaterally) Day 2, 24- Hours Post-dose(Day 2, 24-hours post-dose)
- Percent Change in Total Muscle Volume (TMV) in Muscle in Patients With FSHD Administered ACE-083 During Part 1 (Open-label, Dose-escalation Portion)(Time Frame: From initiation of treatment to Study Visit Day 106)
- Change From Baseline in Facioscapulohumeral Muscular Dystrophy-health Index (FSHD-HI), Patient-reported Outcome (PRO) Measures Part 2 (Randomized, Controlled Portion)- Total Score(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 85, 6-hours After Dose(Study Day 85 (6 hours post-dose))
- ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 85, 4-hours Post-dose(Study Day 85, 4-hours post-dose)
- ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Tibialis Anterior (TA) Bilaterally) Day 86, 24- Hours Post-dose(Day 86, 24-hours post-dose)
- Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)(Time Frame: From initiation of treatment to Study Visit Day 190)
- ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Biceps Brachii (BB) Bilaterally) Day 86, 24 Hours Post-dose(Day 86, 24- hours post-dose)