A Phase 2, Open-Label Extension, Efficacy and Safety Study of a Retinoic Acid Receptor Gamma (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
- 58
- 试验地点
- 8
- 主要终点
- Parts B and C: Annualized Change in New HO Volume
研究概览
简要总结
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement.
In this study, the ability of different palovarotene dosing regimens to prevent the formation of new HO will be evaluated in adult and pediatric participants with FOP.
详细描述
The main objective of this Phase 2, multicenter, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in participants with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the formation of new heterotopic ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan, excluding head.
The study was divided into four parts: Part A (completed on July 2017), Part B (completed on October 2018), Part C (completed) and Part D (completed). Each part was associated with revised palovarotene treatment regimens.
In Part A, all pediatric and adult participants who successfully completed Study PVO-1A-201 were enrolled and followed for up to 36 months. Participants who had an eligible flare-up received 10 mg palovarotene daily for 14 days, followed by 5 mg palovarotene daily for 28 days (or weight-based equivalent).
In Part B, participants who successfully completed Study PVO-1A-201 (including any participant who participated in Part A of Study PVO-1A-202) as well as up to 20 new adult participants were followed for up to 24 months. The Adult Cohort included all participants with at least 90% skeletal maturity, regardless of age. The Pediatric Cohort included all participants with less than 90% skeletal maturity. Any Pediatric Cohort participant who achieved ≥90% skeletal maturity during Part B was considered for enrollment into the Adult Cohort at the discretion of the Investigator. Part B added a 5 mg palovarotene daily chronic treatment regimen administered between flare-ups for participants in the Adult Cohort for up to 24 months. Part B also increased the flare-up dosing to 20 mg palovarotene daily for 28 days, followed by 10 mg palovarotene daily for 56 days (or weight-adjusted equivalents in the Pediatric Cohort). Treatment could be extended if the flare-up was still ongoing.
In Part C, participants from Part B are being followed for up to an additional 48 months. There will be no new participants in Part C. All eligible participants, including skeletally immature participants, are receiving 5 mg palovarotene daily chronic treatment regimen (weight-adjusted doses for skeletally immature participants).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Completion of Study PVO-1A-202/Part B.
- •Written, signed, and dated informed consent and, for participants who are minors, age-appropriate participant assent (performed according to local regulations).
- •Accessible for treatment with palovarotene and follow-up (able and willing to travel to a site for the initial and all follow-up clinic visits).
- •Able to undergo low-dose, WBCT scan, excluding head.
- •Females of child-bearing potential must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene.
- •Male and FOCBP participants must agree to remain abstinent from heterosexual sex during treatment and for 1 month after treatment or, if sexually active, to use two effective methods of birth control during and for 1 month after treatment. Additionally, sexually active females of childbearing potential (FOCBP) participants must already be using two effective methods of birth control 1 month before treatment is to start. Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two effective methods of birth control will be clearly defined in the informed consent and the participant or legally authorized representatives.
排除标准
- •Any reason that, in the opinion of the Investigator, would lead to the inability of the participant and/or family to comply with the protocol.
- •Amylase or lipase >2x above the upper limit of normal or with a history of pancreatitis.
- •Elevated aspartate aminotransferase or alanine aminotransferase >2.5x the upper limit of normal.
- •Fasting triglycerides >400 mg/dL with or without therapy.
- •Currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.
- •Participants experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the Columbia Suicide Severity Rating Scale (C-SSRS).
研究组 & 干预措施
Palovarotene dose level 1 (completed)
Participants received 10 mg palovarotene for 14 days, followed by 5 mg palovarotene for 28 days (or weight-based equivalent) for eligible flare-ups (Part A).
干预措施: Palovarotene dose level 1 (Drug)
Palovarotene dose level 2
Participants with at least 90% skeletal maturity received 5 mg palovarotene for up to 24 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B).
干预措施: Palovarotene dose level 2 (Drug)
Palovarotene dose level 3
Participants with less than 90% skeletal maturity received weight-adjusted doses of 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B).
干预措施: Palovarotene dose level 3 (Drug)
Palovarotene dose level 4
All participants will receive 5 mg palovarotene for up to 48 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part C). Skeletally immature participants will receive weight-adjusted doses.
干预措施: Palovarotene dose level 4 (Drug)
结局指标
主要结局
Parts B and C: Annualized Change in New HO Volume
时间窗: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
The annualized change in new HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding head. Results are presented for overall intent to treat (ITT) period.
Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12
时间窗: Baseline and Week 12
A responder was defined as a participant with no or minimal new HO at original flare-up site compared with baseline (pre-dose data from PVO-1A-201 study). Minimal new HO was defined as new HO with an HO score \<=3 in both the anterior/posterior (AP) and lateral projections (or if 1 view is noninterpretable or non-evaluable, then remaining evaluable view was used). The HO score ranged 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. Highest HO score from 2 projections was used.
次要结局
- Parts A and B: Volume of New Heterotopic Bone Formed at Month 12(Month 12)
- Parts A and B: Percentage of Participants Across the 7 HO Scores at Month 12 of Part A; and Weeks 6 and 12 for Part B(Part A: Baseline (pre-dose data from Study PVO-1A-201 for follow-up component and flare-up screening/Day 1 for flare-up component) and Month 12; Part B: Baseline (flare-up screening/baseline) and Weeks 6 and 12)
- Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12(Part A and B: At Week 12)
- Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48(Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48)
- Parts A and B: Change From Baseline in Active Range of Motion (ROM) at Flare-up Site at Week 12(Baseline and Week 12)
- Part B: Change From Baseline in ROM at Week 12(Baseline and Week 12)
- Part B: Participant and Investigator Global Assessment of Movement at Week 12(Week 12)
- Part A: Change From Baseline in Numeric Rating Scale (NRS) Pain and Swelling or Faces Pain Scale-Revised (FPS-R) at Weeks 2, 4, 6, 9, and 12(Baseline and Weeks 2, 4, 6, 9, and 12)
- Parts A and B: Change From Baseline in Physical Function at Weeks 2, 4, 6, 9, and 12 of Part A; and Weeks 4, 8, and 12 of Part B(Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12)
- Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48(Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48)
- Parts A and B: Change From Baseline in Physical and Mental Health at Weeks 2, 4, 6, 9, and 12 of Part A; and Weeks 4, 8, and 12 of Part B(Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12)
- Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48(Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48)
- Parts A and B: Number of Any Assistive Devices and Adaptations by FOP Participants at Weeks 6 and 12 of Part A; and Week 12 of Part B(Part A: Weeks 6 and 12; and Part B: Week 12)
- Part A: Percentage of Responders at Week 12(Week 12)
- Parts A and B: Change From Baseline in Amount of Bone Formation Biomarker at Weeks 6 and 12 of Part A; and Week 12 of Part B(Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12)
- Parts A and B: Number of Flare-ups With Soft Tissue Swelling and/or Cartilage Formation at Weeks 6 and 12 of Part A; and Week 12 of Part B(Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12)
- Parts A and B: Duration of Active Symptomatic Flare-up(Part A: From Baseline up to 36 months; and Part B: From Baseline up to 24 months)
- Part B: Change From Baseline in Whole Body Burden of HO at Months 12 and 24(Baseline and Months 12 and 24)
- Part B: Mean Percentage of Flare-ups Per Participant-Month Overall(From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months)
- Part C: Mean Percentage of Flare-ups Per Participant-Month Overall(From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months)
- Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit)(Months 12, 24, 36, 60, and 72 (last visit))