A Phase 2 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of a RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 4
- 主要终点
- Percentage of Responders at Week 6
研究概览
简要总结
Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) that result in abnormal bone formation in muscles, tendons, and ligaments. Flare-ups begin early in life and may occur spontaneously or after soft tissue trauma, vaccinations, or influenza infections. Recurrent flare-ups progressively restrict movement by locking joints leading to cumulative loss of function and disability. Mouse models of FOP have demonstrated the ability of retinoic acid receptor (RAR) gamma agonists to prevent heterotopic ossification (HO) following injury. The purpose of the study is to evaluate whether palovarotene, an RAR gamma agonist, will prevent HO during and following a flare-up in subjects with FOP.
详细描述
The primary objective is to evaluate the ability of different doses of palovarotene to prevent HO at the flare-up site in subjects with FOP as assessed by plain radiographs.
This is a Phase 2, multi-center, randomized, double-blind, sponsor-unblinded, placebo-controlled study. Two cohorts of subjects will be randomized into different dosing regimens of palovarotene for a 6-week (42 days) treatment period. The study will consist of three periods:
- A Screening period to occur within 7 days of a distinct flare-up. The first dose of study drug will be taken within 7 days of the flare-up initiation.
- A double-blind treatment period of 6 weeks (42 days) duration.
- A follow-up period of 6 weeks (42 days) duration.
An initial cohort (Cohort 1) of subjects will be randomly assigned 3:1 to either palovarotene or placebo daily for 42 days. Subjects randomized to palovarotene in Cohort 1 will receive an initial daily dose of 10 mg for 14 days followed by 5 mg daily for 28 days.
In Cohort 2, new FOP subjects meeting all inclusion/exclusion criteria will be randomly assigned 3:3:2 to two dose regimens of palovarotene (10 mg for 14 days and 5 mg for 28 days; 5 mg for 14 days and 2.5 mg for 28 days) or placebo daily for 42 days. Doses will be weight-adjusted and subjects randomized within three weight-range categories (20 to <40 kg, 40 to <60 kg, and ≥60 kg).
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written, signed, and dated informed subject/parent consent or age-appropriate assent.
- •Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva (FOP).
- •Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study drug) and defined by the presence of at least two of six of the following symptoms: pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth. Flare-up must be confirmed by the physician at the Screening visit.
- •Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days.
- •Abstinent or using two highly effective forms of birth control.
- •Subjects must be accessible for treatment and follow-up. Subjects living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all follow-up visits.
排除标准
- •Weight <20 kg.
- •Intercurrent non-healed fracture at any location.
- •Complete immobilization of joint at site of flare-up.
- •The inability of the subject to undergo imaging assessments using plain radiographs.
- •If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products for the duration of the study.
- •Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature of the informed consent).
- •Concurrent treatment with tetracycline due to the potential increased risk of pseudotumor cerebri.
- •History of allergy or hypersensitivity to retinoids or lactose.
- •Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity.
- •Amylase or lipase >1.5x above the upper limit of normal or with a history of chronic pancreatitis.
- •Elevated aspartate aminotransferase or alanine aminotransferase >2.5x the upper limit of normal.
- •Fasting triglycerides >400 mg/dL with or without therapy.
研究组 & 干预措施
Palovarotene dose level 1 (Cohort 1)
Doses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days.
干预措施: Palovarotene (Drug)
Palovarotene dose level 2 (Cohort 2)
Weight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days.
干预措施: Palovarotene (Drug)
Palovarotene dose level 3 (Cohort 2)
Weight-adjusted doses of palovarotene in dose level 3 are 5 mg palovarotene once daily, followed by 2.5 mg once daily for 28 days.
干预措施: Palovarotene (Drug)
Sugar pill
The placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2.
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage of Responders at Week 6
时间窗: Baseline (Day 1) and Week 6 (Day 42)
A responder was defined as a subject with no or minimal new heterotopic ossification (HO) at flare-up site versus baseline as assessed by plain radiographs at Week 6. Minimal new HO is defined as new HO with an HO score \<=3 in both anterior/posterior (AP) and lateral projections (or if one view is non-interpretable or non-evaluable, then remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension \>2 diameters of reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. Only subjects with interpretable outcomes were evaluated.
次要结局
- Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12(Baseline, Weeks 2, 4, 6 and 12)
- Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12(Baseline, Weeks 2, 4, 6 and 12)
- Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12(Baseline, Weeks 2, 4, 6 and 12)
- Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12(Baseline, Weeks 2, 4, 6 and 12)
- Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12(Baseline, Weeks 6 and 12)
- Percentage of Subjects With New HO at Weeks 6 and 12(Weeks 6 and 12 (Day 84))
- Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12(Weeks 6 and 12)
- Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12(Baseline, Weeks 6 and 12)
- Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12(Baseline, Weeks 2, 4, 6, 9 and 12)
- Percentage of Responders at Week 12(Baseline and Week 12)
- Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12(Baseline, Weeks 2, 4, 6 and 12)
- Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12(Baseline, Weeks 6 and 12)
- Subject and Investigator Global Assessment of Movement at Weeks 6 and 12(Weeks 6 and 12)
- Maximum Measured Plasma Concentration (Cmax) of Palovarotene(Pre-dose and 3, 6, 10, and 24 hours (hrs) post-dose at Week 2, and at Week 4 or 6)
- Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene(Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6)
- Apparent Clearance of Palovarotene (CL/F)(Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6)
- Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12(Baseline, Weeks 2, 4, 6, 9 and 12)
- Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12(Weeks 6 and 12)
- Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene(Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6)
- Duration of Active Symptomatic Flare-up(From Day 1 to Day 84)
- Minimum Measured Plasma Concentration (Cmin) of Palovarotene(Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6)
- Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12(Baseline, Weeks 2, 4, 6, 9 and 12)
- Apparent Terminal Elimination Half-life (t1/2) of Palovarotene(Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6)