Clinical Trial Results:
A Phase 2, Open-Label, Efficacy and Safety Study of an RARγ-Specific Agonist (Palovarotene) to Prevent Heterotopic Ossification in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)
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Summary
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EudraCT number |
2016-002526-36 |
Trial protocol |
FR |
Global end of trial date |
28 Jun 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Jul 2023
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First version publication date |
08 Jul 2023
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Other versions |
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Summary report(s) |
Notice of Combined Results_2016-002526-36 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PVO-1A-204
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02979769 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Clementia Pharmaceuticals Inc.
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Sponsor organisation address |
1000 De La Gauchetière, Suite 1200, Montreal, Quebec, Canada, H3B 4W5
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Public contact |
Medical Director, Ipsen, clinical.trials@ipsen.com
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Scientific contact |
Medical Director, Ipsen, clinical.trials@ipsen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001662-PIP01-14 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Jun 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Jun 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the safety and efficacy of different palovarotene dosing regimens to prevent heterotopic ossification (HO) following a flare-up in participants with fibrodysplasia ossificans progressiva (FOP). Efficacy will be based on the ability of palovarotene to prevent HO as assessed by low-dose whole body computed tomography (WBCT) scan, excluding head.
99999 is "not applicable" value. As this study is a country-specific protocol (France) of PVO-1A-202 study, the safety and efficacy results were reported in PVO-1A-202 study (2014-002496-28).
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Protection of trial subjects |
The clinical study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, inclusive of any subsequent amendment(s), and that are consistent with the International Council for Harmonisation Good Clinical Practice (E6), European Union Directive 2001/20/EC, United States Food and Drug Administration Code of Federal Regulations, and other applicable local regulatory requirements, which ever affords the greater participant protection.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Nov 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
France: 99999
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Worldwide total number of subjects |
99999
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EEA total number of subjects |
99999
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
99999
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This Phase 2, open-label, France-specific study is equivalent to Parts B, C and D of PVO-1A-202 (2014-002496-28) study. A country-specific protocol was requested by French regulatory authorities. | ||||||
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Pre-assignment
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Screening details |
Participants who successfully completed Part A of PVO-1A-202 study were followed for up to 24 months. A total of 9 participants were enrolled in this France-specific study. | ||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Palovarotene | ||||||
Arm description |
All eligible participants from Part A of PVO-1A-202 study were enrolled in this study to receive palovarotene 5 milligram (mg) once daily for up to 24 months (weight-adjusted doses for skeletally immature participants). Participants with flare-ups received palovarotene 20 mg once daily for 4 weeks followed by 10 mg once daily for 8 weeks. All weight-based dosing was ceased when participants were skeletally mature, but radiographic assessment of the growth plate continued until these participants achieved 100% skeletal maturity at both knee and hand/wrist locations. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Palovarotene
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received palovarotene 20 mg daily for 4 weeks followed by 10 mg once daily for 8 weeks (or exposure-equivalent doses based on weight) during flare-ups, totaling 12 weeks of treatment. Palovarotene was to be taken orally with food at approximately the same time each day.
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Baseline characteristics reporting groups
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Reporting group title |
Palovarotene
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Reporting group description |
All eligible participants from Part A of PVO-1A-202 study were enrolled in this study to receive palovarotene 5 milligram (mg) once daily for up to 24 months (weight-adjusted doses for skeletally immature participants). Participants with flare-ups received palovarotene 20 mg once daily for 4 weeks followed by 10 mg once daily for 8 weeks. All weight-based dosing was ceased when participants were skeletally mature, but radiographic assessment of the growth plate continued until these participants achieved 100% skeletal maturity at both knee and hand/wrist locations. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Palovarotene
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Reporting group description |
All eligible participants from Part A of PVO-1A-202 study were enrolled in this study to receive palovarotene 5 milligram (mg) once daily for up to 24 months (weight-adjusted doses for skeletally immature participants). Participants with flare-ups received palovarotene 20 mg once daily for 4 weeks followed by 10 mg once daily for 8 weeks. All weight-based dosing was ceased when participants were skeletally mature, but radiographic assessment of the growth plate continued until these participants achieved 100% skeletal maturity at both knee and hand/wrist locations. | ||
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End point title |
Annualized Change in New HO Volume [1] | ||||||||
End point description |
The annualized change in new HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding head.
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End point type |
Primary
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End point timeframe |
Month 12
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Efficacy results were reported in PVO-1A-202 study (2014-002496-28). |
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| Notes [2] - Efficacy results were reported in PVO-1A-202 study (2014-002496-28). |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants With New HO | ||||||||
End point description |
New HO was defined as total WBCT new HO volume >0.
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End point type |
Secondary
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End point timeframe |
Months 12, 24, 36, 48, 60 and 72
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| Notes [3] - Efficacy results were reported in PVO-1A-202 study (2014-002496-28). |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Range of Motion (ROM) at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72 | ||||||||
End point description |
The ROM was assessed by the Investigator using Cumulative Analogue Joint Involvement Scale. It includes 12 joints (shoulder, elbow, wrist, hip, knee, and ankle on both the right and left sides), and 3 body regions (jaw, cervical spine [neck], and thoracic/lumbar spine). Each joint/region was assessed as: 0=uninvolved; 1=partially involved; and 2=completely ankylosed. The total score range is 0 (no involvement) to 30 (maximally involved). Higher scores indicates worst outcome.
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End point type |
Secondary
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End point timeframe |
Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72
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| Notes [4] - Efficacy results were reported in PVO-1A-202 study (2014-002496-28). |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72 | ||||||||
End point description |
The effect of palovarotene on physical function was determined using FOP-Physical Function Questionnaire. The questionnaire consisted of 28 items ranging from 1 (not able to do) to 5 (with no trouble; without help or assistive device). Lower scores denoted more difficulty, with items categorized into upper extremity and mobility sections.
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End point type |
Secondary
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End point timeframe |
Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72
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| Notes [5] - Efficacy results were reported in PVO-1A-202 study (2014-002496-28). |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Physical and Mental Function for Participants >=15 Years Old and Mental Function for Participants <15 Years Old at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72 | ||||||||
End point description |
The patient reported outcomes measurement information system (PROMIS) global health scale was administered to evaluate the effect of palovarotene on physical and mental health in participants >=15 years of age and mental health in participants <15 years of age, age-appropriate forms of the PROMIS global health scales were administered. A T-score of 50 is normal and increments of 10 are +/- standard deviation away from the norm. A T-score <50 indicates worse health, while a T-score >50 indicates better health. Higher values (positive changes) indicate better health.
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End point type |
Secondary
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End point timeframe |
Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72
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| Notes [6] - Efficacy results were reported in PVO-1A-202 study (2014-002496-28). |
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| No statistical analyses for this end point | |||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Information on adverse events were reported in PVO-1A-202 study (2014-002496-28).
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Adverse event reporting additional description |
As this study is a country-specific protocol (France) of PVO-1A-202 study, the safety results will be reported in PVO-1A-202 study (2014-002496-28).
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Assessment type |
Systematic | ||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||
Dictionary version |
999999
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Reporting groups
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Reporting group title |
Palovarotene
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Reporting group description |
All eligible participants from Part A of PVO-1A-202 study were enrolled in this study to receive palovarotene 5 mg once daily for up to 24 months (weight-adjusted doses for skeletally immature participants). Participants with flare-ups received palovarotene 20 mg once daily for 4 weeks followed by 10 mg once daily for 8 weeks. All weight-based dosing was ceased when participants were skeletally mature, but radiographic assessment of the growth plate continued until these participants achieved 100% skeletal maturity at both knee and hand/wrist locations. | ||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||
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| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: As this study is a country-specific protocol (France) of PVO-1A-202 study, the safety results will be reported in PVO-1A-202 study (2014-002496-28). |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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07 Sep 2016 |
Specified that Adult Cohort participants under the age of 18 years are to receive weight-adjusted doses of 20 mg palovarotene (for 28 days) and 10 mg palovarotene (for 56 days) during a flare-up. Added an electrocardiogram assessment on Flare-up Day 7 (Week 1). |
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22 Mar 2018 |
Blood sampling for pharmacokinetic analysis added during chronic dosing for all participants. Participants receiving weight-adjusted dosing for non-flare-up based treatment changed from “participants under the age of 18 years” to “skeletally immature participants.” The Investigator will be notified about any protocol-specified safety laboratory test that could not be obtained despite at least two attempts. Included a reference to and description of the PVO-1A-301 Bone Safety Management Plan and additional safety assessments to be followed in this study. Added that if the study is closed due to safety concerns, then all participants exposed to the investigational drug will be followed for safety with the length of follow-up determined based on the safety risk. |
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08 Mar 2019 |
Changed the timing of clinical laboratory assessments during non-flare-up based treatment from every 3 months to every 6 months. Blood volumes were adjusted to reflect the change. Changed the timing of clinical laboratory assessments, Columbia-Suicide Severity Rating Scale, vital signs, and body weight determination during a Flare-Up Cycle. Noted that flare-up based dosing should be initiated if the Investigator confirms the presence of a substantial, high-risk traumatic event likely to lead to a flare-up. |
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31 Oct 2019 |
Added radiographic assessments of the knee and hand/wrist to be performed every 3 months in those participants who (1) received the flare-up dosing regimen in the period of time since their last radiographic assessment; and (2) had not achieved 100% skeletal maturity on their last radiographic assessment. Added 6-month radiographic assessments of the knee and hand/wrist in skeletally immature participants. During flare-up dosing, safety assessments will recur every 12 weeks (instead of every 8 weeks) after Flare-up Cycle Safety Day 1 until treatment of the last flare-up or traumatic event in the cycle is completed. The 4-week safety assessment will no longer be performed. |
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18 Dec 2020 |
References to Parts B/C/D are to PVO-1A-202 Parts B/C/D which corresponds to PVO-1A-204, ongoing in France. Part D was added for skeletally immature participants who stopped taking study medication for any reason before completion of Part A/B/C. In Part C, participants may continue on the study for up to an additional 12 months. Added assessments for spinal health carried out on low dose WBCT scans collected in the study. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
