Exostoses, Multiple Hereditary
Conditions
Keywords
Multiple osteochondromas, Osteochondroma, Palovarotene, Hereditary multiple exostoses, HME, MO, Retinoic acid receptor gamma agonist, Retinoic acid receptor agonist
Brief summary
This is a randomized, double-blind, placebo-controlled study comparing the safety and efficacy of 2 dosage regimens of palovarotene versus placebo in preventing disease progression in pediatric subjects with multiple osteochondromas (MO).
Detailed description
Multiple osteochondromas is a rare condition where children develop multiple benign cartilage-capped bony tumors called osteochondromas on bones throughout the body, resulting in pain, deformity, limb length discrepancy, disability, and eventually arthritis and possible malignancy. The primary objective is to compare the efficacy of two dosage regimens of palovarotene with placebo to prevent the formation of new osteochondromas in pediatric MO subjects with exostosin 1 or exostosin 2 gene mutations. Osteochondroma formation was assessed by whole body magnetic resonance imaging (MRI). Secondary efficacy objectives were to compare the effects of palovarotene with placebo on the volume of osteochondromas as assessed by MRI; the proportion of subjects with no new osteochondromas as assessed by whole-body MRI; the annualized rate of new or worsening deformities; the annualized rate of MO-related surgeries; and palatability. The overall safety and pharmacokinetics of palovarotene and the effects of palovarotene on linear growth, bone growth plates, bone mineral density, quality of life, and pain due to osteochondromas was also studied.
Interventions
DRUGPalovarotene 2.5 mg
Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months.
DRUGPalovarotene 5.0 mg
Subjects received a weight-adjusted dose equivalent of 5.0 mg palovarotene, once daily, for up to 24 months.
OTHERPlacebo
Subjects received placebo, once daily, for up to 24 months.
Sponsors
Clementia Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Multicenter, randomized, double-blind, placebo-controlled
Eligibility
Sex/Gender
ALL
Age
2 Years to 14 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Written, signed, and dated informed subject/parent consent and age-appropriate assent (performed according to local regulations). * A clinical diagnosis of MO with disease-causing exostosin 1 or 2 gene mutations. * Male or female from 2 to 14 years of age. * Female subjects must be premenarchal at screening. * A bone age at screening of 14 years or less. * Symptomatic MO, defined as five or more clinically evident osteochondromas and a new or enlarged osteochondroma that occurred in the preceding 12 months, five or more clinically evident osteochondromas and the presence of a painful osteochondroma, a skeletal deformity, a joint limitation, or prior surgery for a MO-related complication. * The ability to undergo whole body MRI with or without sedation/general anesthesia. * Use of two effective methods of birth control during treatment, and for 1 month after treatment discontinuation, unless committed to true abstinence from heterosexual sex. Sexually active females of child-bearing potential must also agree to start effective methods of birth control at screening. Key
Exclusion criteria
* Weight under 10 kg. * Other syndromic conditions such as Langer-Giedion or Potocki-Shaffer. * Any subject with neurologic signs suggestive of spinal cord impingement. * Concomitant medications that are strong inhibitors or inducers of cytochrome P450 3A4 activity. * Amylase or lipase \>2 times the above the upper limit of normal (\>2×ULN) or with a history of chronic pancreatitis. * Elevated aspartate aminotransferase or alanine aminotransferase above 2.5×ULN. * Any surgical implant that is contraindicated for MRI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of New Osteochondromas (OCs) | Month 12 | The annualized rate of new OCs was assessed by whole-body magnetic resonance imaging (MRI) (that is, the total number of new OCs divided by the time in years between the baseline and latest post-baseline MRI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With No New OCs | Month 12 | The percentage of participants with no new OCs as assessed by whole-body MRI. Participants with new OCs not identified by MRI due to surgical resection during the treatment period were categorized as having new OCs for this analysis. |
| Annualized Rate of New or Worsening Deformities | Month 12 | The annualized rate of new or worsening deformities as assessed by radiographic imaging of both upper and lower limbs. |
| Annualized Rate of MO-Related Surgeries | Month 12 | The MO-related surgeries included any procedure indicated for the treatment of MO, such as an excision of a symptomatic OC or correction of a limb deformity. |
| Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene | Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose | The Cmax,ss of palovarotene was evaluated. The pharmacokinetic (PK) sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit. |
| Mean Change From Baseline in the Total Volume of New OCs at Month 12 | Baseline (Day 1) and Month 12 | The change from baseline in the total volume of OCs was assessed by whole-body MRI. Baseline was defined as the last available value prior to first administration of study drug. |
| Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene | Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose | The Tmax,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit. |
| Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene | Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose | The AUC0-24,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit. |
| Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 and Month 1 | Palatability of palovarotene and placebo when sprinkled on specific foods as assessed with a 5-point hedonic face scale at the first dose (Day 1) and at Month 1 in all participants (including \<4 years old) who sprinkled the palovarotene or placebo onto a spoonful of specific foods. The hedonic face scale ranges from 1 to 5 where, 1= dislike very much, 2= dislike slightly, 3= neither like nor dislike, 4= like slightly, 5= like very much. Higher scores indicate positive outcome. |
| Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene | Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose | The Cmin,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit. |
Countries
Australia, Belgium, Canada, France, Italy, Japan, Netherlands, Portugal, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This Phase 2 placebo-controlled study was conducted in pediatric participants with multiple osteochondromas (MO) at 29 study sites in 11 countries between 22 March 2018 and 30 October 2020. For sites in the European Union, participants from 7 to \<15 years of age were enrolled first and participants from 2 to \<7 years of age were enrolled after the 6-month bone safety data from at least 20 skeletally immature participants.
Pre-assignment details
Study consisted of a screening period (up to 35 days), followed by a double-blind treatment period (24 months) and safety follow-up period (6 months). Participants were randomized in a 1:1:1 ratio to palovarotene 2.5 milligram (mg) or 5.0 mg or placebo. A total of 193 participants received at least 1 dose of study drug and were included in the study analysis.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were to receive placebo matching with palovarotene capsules orally once daily, for up to 24 months. | 62 |
| Palovarotene 2.5 mg Participants were to receive weight-adjusted dose equivalent of palovarotene 2.5 mg capsules orally once daily, for up to 24 months. | 66 |
| Palovarotene 5.0 mg Participants were to receive weight-adjusted dose equivalent of palovarotene 5.0 mg capsules orally once daily, for up to 24 months. | 65 |
| Total | 193 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 5 | 2 | 7 |
| Overall Study | Sponsor Request | 55 | 60 | 54 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 4 |
Baseline characteristics
| Characteristic | Placebo | Palovarotene 2.5 mg | Palovarotene 5.0 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 7.9 years STANDARD_DEVIATION 2.5 | 7.8 years STANDARD_DEVIATION 3.1 | 7.4 years STANDARD_DEVIATION 3.1 | 7.7 years STANDARD_DEVIATION 2.9 |
| Age, Customized 11 to 14 years | 11 Participants | 16 Participants | 11 Participants | 38 Participants |
| Age, Customized 2 to 5 years | 13 Participants | 17 Participants | 19 Participants | 49 Participants |
| Age, Customized 6 to 10 years | 38 Participants | 33 Participants | 35 Participants | 106 Participants |
| Race/Ethnicity, Customized American Indian Or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 3 Participants | 3 Participants | 11 Participants |
| Race/Ethnicity, Customized Black Or African American | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 6 Participants | 7 Participants | 7 Participants | 20 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 1 Participants | 1 Participants | 8 Participants |
| Race/Ethnicity, Customized Multiple | 6 Participants | 7 Participants | 5 Participants | 18 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 56 Participants | 58 Participants | 57 Participants | 171 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 48 Participants | 50 Participants | 52 Participants | 150 Participants |
| Sex: Female, Male Female | 23 Participants | 26 Participants | 27 Participants | 76 Participants |
| Sex: Female, Male Male | 39 Participants | 40 Participants | 38 Participants | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 66 | 0 / 65 |
| other Total, other adverse events | 41 / 62 | 56 / 66 | 56 / 65 |
| serious Total, serious adverse events | 0 / 62 | 2 / 66 | 2 / 65 |
Outcome results
Primary
Annualized Rate of New Osteochondromas (OCs)
The annualized rate of new OCs was assessed by whole-body magnetic resonance imaging (MRI) (that is, the total number of new OCs divided by the time in years between the baseline and latest post-baseline MRI).
Time frame: Month 12
Population: The Full Analysis Set (FAS) included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Annualized Rate of New Osteochondromas (OCs) | 0.119 number of new OCs per year |
| Palovarotene 2.5 mg | Annualized Rate of New Osteochondromas (OCs) | 0.363 number of new OCs per year |
| Palovarotene 5.0 mg | Annualized Rate of New Osteochondromas (OCs) | 0.172 number of new OCs per year |
Comparison: Palovarotene 2.5 mg versus (vs) Palovarotene 5.0 mg: The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.255695% CI: [0.583, 7.638]Negative binomial regression model
Comparison: Palovarotene 2.5 mg vs Placebo: The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.178895% CI: [0.601, 15.373]Negative binomial regression model
Comparison: Palovarotene 5.0 mg vs Placebo: The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.65795% CI: [0.287, 7.234]Negative binomial regression model
Secondary
Annualized Rate of MO-Related Surgeries
The MO-related surgeries included any procedure indicated for the treatment of MO, such as an excision of a symptomatic OC or correction of a limb deformity.
Time frame: Month 12
Population: The FAS included randomized participants who received at least 1 dose of study drug. Participants with planned surgeries within 6 months of enrollment to remove symptomatic OCs or to correct deformities present at baseline, and/or had surgical procedures that were a continuation of a previous procedure were excluded in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Annualized Rate of MO-Related Surgeries | 2.087 number of MO-related surgeries per year |
| Palovarotene 2.5 mg | Annualized Rate of MO-Related Surgeries | 3.454 number of MO-related surgeries per year |
| Palovarotene 5.0 mg | Annualized Rate of MO-Related Surgeries | 2.231 number of MO-related surgeries per year |
Comparison: Palovarotene 2.5 mg vs Palovarotene 5.0 mg: The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.218695% CI: [0.772, 3.108]Poisson regression model
Comparison: Palovarotene 2.5 mg vs Placebo: The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.2795% CI: [0.676, 4.052]Poisson regression model
Comparison: Palovarotene 5.0 mg vs Placebo: The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.854695% CI: [0.524, 2.178]Poisson regression model
Secondary
Annualized Rate of New or Worsening Deformities
The annualized rate of new or worsening deformities as assessed by radiographic imaging of both upper and lower limbs.
Time frame: Month 12
Population: The FAS included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Annualized Rate of New or Worsening Deformities | 1.797 number of deformities per year |
| Palovarotene 2.5 mg | Annualized Rate of New or Worsening Deformities | 1.802 number of deformities per year |
| Palovarotene 5.0 mg | Annualized Rate of New or Worsening Deformities | 1.895 number of deformities per year |
Comparison: Palovarotene 2.5 mg vs Palovarotene 5.0 mg: The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.815595% CI: [0.623, 1.451]Negative binomial regression model
Comparison: Palovarotene 2.5 mg vs Placebo: The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.991895% CI: [0.592, 1.699]Negative binomial regression model
Comparison: Palovarotene 5.0 mg vs Placebo: The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.p-value: 0.799795% CI: [0.7, 1.589]Negative binomial regression model
Secondary
Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene
The AUC0-24,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit.
Time frame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Population: The PKS included participants receiving treatment with palovarotene and with evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene | 112 hour*ng/mL | Geometric Coefficient of Variation 29.1 |
| Palovarotene 2.5 mg | Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene | 241 hour*ng/mL | Geometric Coefficient of Variation 42.7 |
Secondary
Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene
The Cmax,ss of palovarotene was evaluated. The pharmacokinetic (PK) sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit.
Time frame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Population: The Pharmacokinetic Set (PKS) included participants receiving treatment with palovarotene and with evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene | 18.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 50.2 |
| Palovarotene 2.5 mg | Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene | 34.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 63.3 |
Secondary
Mean Change From Baseline in the Total Volume of New OCs at Month 12
The change from baseline in the total volume of OCs was assessed by whole-body MRI. Baseline was defined as the last available value prior to first administration of study drug.
Time frame: Baseline (Day 1) and Month 12
Population: The FAS included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in the Total Volume of New OCs at Month 12 | 10476.7 cubic millimeter | Standard Deviation 23294.9 |
| Palovarotene 2.5 mg | Mean Change From Baseline in the Total Volume of New OCs at Month 12 | 5250.5 cubic millimeter | Standard Deviation 11754.7 |
| Palovarotene 5.0 mg | Mean Change From Baseline in the Total Volume of New OCs at Month 12 | 10911.0 cubic millimeter | Standard Deviation 35869.6 |
Comparison: Palovarotene 2.5 mg vs Palovarotene 5.0 mg: The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.p-value: 0.425295% CI: [-15257.3, 6432.1]Unadjusted estimation equation model
Comparison: Palovarotene 2.5 mg vs Placebo: The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.p-value: 0.405395% CI: [-15570.8, 6289]Unadjusted estimation equation model
Comparison: Palovarotene 5.0 mg vs Placebo: The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.p-value: 0.967795% CI: [-11265, 10808.4]Unadjusted estimation equation model
Secondary
Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene
The Cmin,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit.
Time frame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Population: The PKS included participants receiving treatment with palovarotene and with evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene | 0.314 ng/mL | Geometric Coefficient of Variation 86.1 |
| Palovarotene 2.5 mg | Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene | 0.674 ng/mL | Geometric Coefficient of Variation 83.3 |
Secondary
Number of Participants With Palatability of Sprinkled Palovarotene and Placebo
Palatability of palovarotene and placebo when sprinkled on specific foods as assessed with a 5-point hedonic face scale at the first dose (Day 1) and at Month 1 in all participants (including \<4 years old) who sprinkled the palovarotene or placebo onto a spoonful of specific foods. The hedonic face scale ranges from 1 to 5 where, 1= dislike very much, 2= dislike slightly, 3= neither like nor dislike, 4= like slightly, 5= like very much. Higher scores indicate positive outcome.
Time frame: Day 1 and Month 1
Population: The Safety set included randomized participants who received at least 1 dose of study drug. Only data from the participants analyzed at Day 1 and Month 1 were included in the analysis.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Dislike very much | 0 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Dislike a little | 1 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Not sure | 6 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Like a little | 3 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Dislike very much | 1 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Dislike a little | 1 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Not sure | 5 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Like very much | 6 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Like very much | 11 Participants |
| Placebo | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Like a little | 8 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Like very much | 5 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Like a little | 5 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Dislike very much | 0 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Dislike a little | 1 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Not sure | 1 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Like very much | 8 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Dislike very much | 1 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Dislike a little | 1 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Like a little | 5 Participants |
| Palovarotene 2.5 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Not sure | 3 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Dislike a little | 0 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Like very much | 5 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Not sure | 3 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Dislike very much | 0 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Dislike very much | 0 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Like very much | 6 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Dislike a little | 1 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Day 1 | Like a little | 3 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Like a little | 1 Participants |
| Palovarotene 5.0 mg | Number of Participants With Palatability of Sprinkled Palovarotene and Placebo | Month 1 | Not sure | 3 Participants |
Secondary
Percentage of Participants With No New OCs
The percentage of participants with no new OCs as assessed by whole-body MRI. Participants with new OCs not identified by MRI due to surgical resection during the treatment period were categorized as having new OCs for this analysis.
Time frame: Month 12
Population: The FAS included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With No New OCs | 62.5 percentage of participants |
| Palovarotene 2.5 mg | Percentage of Participants With No New OCs | 47.1 percentage of participants |
| Palovarotene 5.0 mg | Percentage of Participants With No New OCs | 56.5 percentage of participants |
p-value: 0.502595% CI: [0.177, 2.335]Regression, Logistic
p-value: 0.376395% CI: [0.128, 2.175]Regression, Logistic
p-value: 0.771495% CI: [0.215, 3.123]Regression, Logistic
Secondary
Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene
The Tmax,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit.
Time frame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Population: The PKS included participants receiving treatment with palovarotene and with evaluable PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene | 3.00 hour |
| Palovarotene 2.5 mg | Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene | 3.01 hour |