Fibrodysplasia Ossificans Progressiva
Conditions
Keywords
Interventional study, Clinical trial phase 3, Efficacy and safety, Heterotopic ossification, Flare-up, Palovarotene, Retinoic acid receptor agonist, Retinoic acid receptor gamma agonist, Clementia, Myositis Ossificans Progressiva, Munchmeyer's Disease, FOP, FOP variants
Brief summary
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO) often associated with painful, recurrent episodes of soft tissue swelling (flare-ups) that lead to ankyloses of major joints with cumulative and irreversible loss of movement and disability.
Detailed description
One of the primary objectives was to evaluate the efficacy of palovarotene in decreasing new HO in participants with FOP as assessed by low-dose, whole body computed tomography (WBCT), excluding head, compared to untreated participants from Clementia's FOP natural history study (Study PVO-1A-001, NHS). The other primary objective was to evaluate the safety of palovarotene in participants with FOP. This study was conducted in three parts. Part A was the main part of the study, Part B, the 2-year (24-month) extension and Part C was an up-to-2-year post last dose of study treatment follow-up for skeletally immature participants. Participants in Part A and B received a chronic/flare-up dosing regimen of palovarotene for up to 4 years (48 months) as follows: * Chronic treatment: orally administered 5 mg palovarotene once daily. * Flare-up treatment: orally administered 20 mg palovarotene once daily for 4 weeks (28 days) followed by orally administered 10 mg palovarotene once daily for 8 weeks (56 days). Flare-up treatment may be extended until the Investigator determines that the flare-up has resolved. Note that all dosing was weight-adjusted in skeletally immature participants (those under the age of 18 years with less than 90% skeletal maturity on hand/wrist x-rays performed at Screening). In part C, participants who were enrolled in Parts A or B who discontinued the study and were skeletally immature were invited back to participate in the off-treatment safety follow-up. No new participants were enrolled into Part C.
Interventions
DRUGPalovarotene
Palovarotene was taken orally once daily at approximately the same time each day following a meal.
Sponsors
Clementia Pharmaceuticals Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A multicenter, open-label study. NHS data (study PVO-1A-001) will be used as an external control in the analysis.
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Written, signed, and dated informed subject/parent consent; and for subjects who are minors, age-appropriate assent (performed according to local regulations). * Males or females at least 4 years of age. * No flare-up symptoms within the past 4 weeks, including at the time of enrollment. * Abstinent or using two highly effective forms of birth control. * Accessible for treatment and follow-up; able to undergo all study procedures including low-dose WBCT (excluding head) without sedation. Key
Exclusion criteria
* Weight \<10 kg. * Concomitant medications that are strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity; or kinase inhibitors such as imatinib. * Amylase or lipase \>2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis. * Elevated aspartate aminotransferase or alanine aminotransferase \>2.5x ULN. * Fasting triglycerides \>400 mg/dL with or without therapy. * Female subjects who are breastfeeding. * Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease. * Simultaneous participation in another clinical research study (other than palovarotene studies) within 4 weeks prior to Screening; or within five half-lives of the investigational agent, whichever is longer. * Any reason that, in the opinion of the Investigator, would lead to the inability of the subject and/or family to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized New Heterotopic Ossification (HO) | Baseline (within one month of screening/Day 1) and up to 24 months | The annualized new HO was assessed by low-dose, whole body computed tomography (WBCT), excluding head. The weighted linear mixed effect method without square-root transformation and negatives included was used for annualized new HO analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Any New HO | From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) | The new HO was assessed by WBCT scan. The percentage of participants with any new HO (volume \> 0 mm\^3) were analyzed using the Bayesian distribution. Results are presented for overall ITT period. |
| Number of Body Regions With New HO | From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) | All participants were analyzed for number of body regions with any new HO (new HO \> 0 mm\^3). The presence of HO across various body regions was analyzed using WBCT scan. Results are presented for overall ITT period |
| Percentage of Participants With Flare-Ups | Month 12 | Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary. |
| Ratio of Flare-Up Per Participant-Month of Exposure | From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) | Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary. The flare-up rate per participant-month exposure was analyzed using a negative binomial regression. Results are presented for overall ITT period. |
Countries
Argentina, Australia, Brazil, Canada, France, Italy, Japan, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This Phase 3, open-label study conducted in adult and pediatric participants with fibrodysplasia ossificans progressiva (FOP) at 16 centers in 11 countries (Argentina, Australia, Brazil, Canada, France, Italy, Japan, Spain, Sweden, the United Kingdom, and the US) between 30 November 2017 and 07 September 2022.
Pre-assignment details
This study included 3 parts: Part A, the main part of the study, Part B, the 24-month extension and Part C, up to 2 year post last dose of study treatment follow-up. A total of 107 participants were enrolled and treated in this study. Data from participants in PVO-1A-001 were used as an external control for only primary endpoint of this study. Hence, data for participants in PVO-1A-001 are reported in participant flow, baseline characteristics and adverse events section only.
Participants by arm
| Arm | Count |
|---|---|
| Palovarotene Participants were administered 5 mg palovarotene orally once daily up to 48 months. Participants with flare-up symptoms or traumatic events received palovarotene 20 mg once daily for 4 weeks after the flare-up confirmation by the Investigator. Followed by palovarotene 10 mg once daily for 8 weeks. | 99 |
| Untreated (PVO-1A-001) Participants from study PVO-1A-001 (NCT02322255) were included with FOP caused by the R206H mutation and with baseline data. Participants were not administered palovarotene in this study and only compared as external control. | 114 |
| Total | 213 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Enrolled in an interventional study | 0 | 52 |
| Overall Study | Enrolled in an interventional study at time of a flare-up | 0 | 9 |
| Overall Study | Enrolled into non-interventional study | 0 | 5 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance | 0 | 2 |
| Overall Study | Other | 13 | 0 |
| Overall Study | Participant did not want to travel | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Sponsor request | 2 | 0 |
| Overall Study | Withdrawal by Subject | 31 | 9 |
| Overall Study | Worsening clinical condition | 0 | 1 |
Baseline characteristics
| Characteristic | Palovarotene | Total | Untreated (PVO-1A-001) |
|---|---|---|---|
| Age, Categorical <=18 years | 75 Participants | 145 Participants | 70 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 68 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 42 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants | 142 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 29 Participants | 18 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants | 17 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Multiple | 6 Participants | 8 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown | 11 Participants | 26 Participants | 15 Participants |
| Race/Ethnicity, Customized White | 70 Participants | 154 Participants | 84 Participants |
| Sex: Female, Male Female | 46 Participants | 98 Participants | 52 Participants |
| Sex: Female, Male Male | 53 Participants | 115 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 107 | 0 / 81 | 1 / 114 |
| other Total, other adverse events | 105 / 107 | 77 / 81 | 0 / 114 |
| serious Total, serious adverse events | 34 / 107 | 19 / 81 | 0 / 114 |
Outcome results
Primary
Annualized New Heterotopic Ossification (HO)
The annualized new HO was assessed by low-dose, whole body computed tomography (WBCT), excluding head. The weighted linear mixed effect method without square-root transformation and negatives included was used for annualized new HO analysis.
Time frame: Baseline (within one month of screening/Day 1) and up to 24 months
Population: The Principal FAS includes all enrolled participants in the Principal EP who had a baseline HO volume measurement and at least 1 post-baseline HO volume measurement in study PVO-1A-301. For study PVO-1A-001, the Principal FAS included participants enrolled in study PVO-1A-001 with available baseline and at least 1 post-baseline HO volume measurement. Study PVO-1A-001 was used as an external control.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palovarotene | Annualized New Heterotopic Ossification (HO) | 9427.1 cubic millimeters (mm^3) | Standard Error 3084 |
| Untreated (PVO-1A-001) | Annualized New Heterotopic Ossification (HO) | 23720.2 cubic millimeters (mm^3) | Standard Error 4850 |
Secondary
Number of Body Regions With New HO
All participants were analyzed for number of body regions with any new HO (new HO \> 0 mm\^3). The presence of HO across various body regions was analyzed using WBCT scan. Results are presented for overall ITT period
Time frame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
Population: The Principal FAS included all enrolled participants in the Principal EP who had a baseline HO volume measurement and at least 1 post-baseline HO volume measurement in the study PVO-1A-301. Only data from the participants analyzed were reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palovarotene | Number of Body Regions With New HO | 3.0 body regions | Standard Deviation 1.68 |
Secondary
Percentage of Participants With Any New HO
The new HO was assessed by WBCT scan. The percentage of participants with any new HO (volume \> 0 mm\^3) were analyzed using the Bayesian distribution. Results are presented for overall ITT period.
Time frame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
Population: The Principal FAS included all enrolled participants in the Principal EP who had a baseline HO volume measurement and at least 1 post-baseline HO volume measurement in study PVO-1A-301.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palovarotene | Percentage of Participants With Any New HO | 83.5 percentage of participants |
Secondary
Percentage of Participants With Flare-Ups
Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary.
Time frame: Month 12
Population: The Principal SS included all enrolled participants in the Principal EP set (ie, participants with the R206H ACVR1 mutation) receiving at least 1 dose of palovarotene in study PVO-1A-301. Only data from the participants analyzed at Month 12 reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palovarotene | Percentage of Participants With Flare-Ups | 64.6 percentage of participants |
Secondary
Ratio of Flare-Up Per Participant-Month of Exposure
Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary. The flare-up rate per participant-month exposure was analyzed using a negative binomial regression. Results are presented for overall ITT period.
Time frame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
Population: The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in study PVO-1A-301.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palovarotene | Ratio of Flare-Up Per Participant-Month of Exposure | 0.2 ratio of flare-up | Standard Deviation 0.4 |