Trial Outcomes & Findings for A Study to Examine the Safety, Tolerability and Effects on Abnormal Bone Formation of REGN2477 in Patients With Fibrodysplasia Ossificans Progressiva (NCT NCT03188666)

Last Updated: 2022-12-02

Results Overview

Treatment-emergent adverse events (TEAEs) are adverse events not present at baseline or represent the exacerbation of a pre-existing condition during the on-treatment period. A serious TEAE was defined as any untoward medical occurrence that resulted in any of following outcomes not present at baseline or represent the exacerbation of a pre-existing condition during the on-treatment period: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. Number of participants with TEAEs and Serious TEAEs are reported.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

44 participants

Primary outcome timeframe

Up to Week 28

Results posted on

2022-12-02

Participant Flow

A total of 48 participants were screened, out of which, 44 participants were randomized and treated.

This was a three period study design which consisted of a 6-month (28 weeks), randomized, double-blind placebo-controlled treatment period (Period 1) followed by a 6-month (28 weeks), open-label treatment period (Period 2) and a 20 week follow-up treatment period (Period 3). Participants could continue receiving REGN2477 every 4 weeks beyond week 76 provided that no safety signals were identified.

Participant milestones

Participant milestones
Measure	Placebo Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	Placebo/REGN2477 10 mg/kg Q4W Participants who were in the placebo group in Period 1 crossed over to receive a single dose of REGN2477 IV infusion Q4W for 28 weeks during Period 2 followed by 20 weeks during Period 3.	REGN2477/REGN2477 10 mg/kg Q4W Participants who were in the REGN2477 group in Period 1 continued treatment with a single dose of REGN2477 IV infusion Q4W for additional 28 weeks during Period 2 followed by 20 weeks during Period 3.
Period 1 (28 Weeks Double-blind) STARTED	24	20	0	0
Period 1 (28 Weeks Double-blind) COMPLETED	24	19	0	0
Period 1 (28 Weeks Double-blind) NOT COMPLETED	0	1	0	0
Period 2 (28 Weeks Open-label) STARTED	0	0	24	19
Period 2 (28 Weeks Open-label) COMPLETED	0	0	24	18
Period 2 (28 Weeks Open-label) NOT COMPLETED	0	0	0	1
Period 3 (20 Weeks Follow-up) STARTED	0	0	24	18
Period 3 (20 Weeks Follow-up) COMPLETED	0	0	21	16
Period 3 (20 Weeks Follow-up) NOT COMPLETED	0	0	3	2

Reasons for withdrawal

Reasons for withdrawal
Measure	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	Placebo/REGN2477 10 mg/kg Q4W Participants who were in the placebo group in Period 1 crossed over to receive a single dose of REGN2477 IV infusion Q4W for 28 weeks during Period 2 followed by 20 weeks during Period 3.	REGN2477/REGN2477 10 mg/kg Q4W Participants who were in the REGN2477 group in Period 1 continued treatment with a single dose of REGN2477 IV infusion Q4W for additional 28 weeks during Period 2 followed by 20 weeks during Period 3.
Period 1 (28 Weeks Double-blind) Adverse Event	1	0	0
Period 2 (28 Weeks Open-label) Death	0	0	1
Period 3 (20 Weeks Follow-up) Withdrawal by Subject	0	2	0
Period 3 (20 Weeks Follow-up) Death	0	1	2

Baseline Characteristics

The baseline-active HO analysis set (AHO) includes all randomized patients who had at least one active HO lesion at baseline; it is based on the treatment allocated (as randomized).

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	Total n=44 Participants Total of all reporting groups
Age, Continuous	27.8 Years STANDARD_DEVIATION 8.54 • n=24 Participants	27.3 Years STANDARD_DEVIATION 8.67 • n=20 Participants	27.6 Years STANDARD_DEVIATION 8.50 • n=44 Participants
Sex: Female, Male Female	14 Participants n=24 Participants	11 Participants n=20 Participants	25 Participants n=44 Participants
Sex: Female, Male Male	10 Participants n=24 Participants	9 Participants n=20 Participants	19 Participants n=44 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=24 Participants	0 Participants n=20 Participants	0 Participants n=44 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	24 Participants n=24 Participants	20 Participants n=20 Participants	44 Participants n=44 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=24 Participants	0 Participants n=20 Participants	0 Participants n=44 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=24 Participants	0 Participants n=20 Participants	0 Participants n=44 Participants
Race (NIH/OMB) Asian	1 Participants n=24 Participants	2 Participants n=20 Participants	3 Participants n=44 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=24 Participants	0 Participants n=20 Participants	0 Participants n=44 Participants
Race (NIH/OMB) Black or African American	1 Participants n=24 Participants	0 Participants n=20 Participants	1 Participants n=44 Participants
Race (NIH/OMB) White	22 Participants n=24 Participants	17 Participants n=20 Participants	39 Participants n=44 Participants
Race (NIH/OMB) More than one race	0 Participants n=24 Participants	0 Participants n=20 Participants	0 Participants n=44 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=24 Participants	1 Participants n=20 Participants	1 Participants n=44 Participants
Total Lesion Activity by fluorine-18 sodium fluoride (18 F-NaF) PET (AHO Analysis Set)	473.40 gram (g) STANDARD_DEVIATION 348.373 • n=24 Participants • The baseline-active HO analysis set (AHO) includes all randomized patients who had at least one active HO lesion at baseline; it is based on the treatment allocated (as randomized).	418.18 gram (g) STANDARD_DEVIATION 372.801 • n=20 Participants • The baseline-active HO analysis set (AHO) includes all randomized patients who had at least one active HO lesion at baseline; it is based on the treatment allocated (as randomized).	448.30 gram (g) STANDARD_DEVIATION 356.510 • n=44 Participants • The baseline-active HO analysis set (AHO) includes all randomized patients who had at least one active HO lesion at baseline; it is based on the treatment allocated (as randomized).
Total Volume of HO Lesions as Assessed by Computed Tomography (CT) (AHO Analysis Set)	235.78 cubic centimeter (cm^3) STANDARD_DEVIATION 253.329 • n=24 Participants	251.43 cubic centimeter (cm^3) STANDARD_DEVIATION 327.881 • n=20 Participants	242.89 cubic centimeter (cm^3) STANDARD_DEVIATION 286.167 • n=44 Participants
Total Lesion Activity by 18F-NaF PET (AHOC Analysis Set)	464.27 gram (g) STANDARD_DEVIATION 350.479 • n=22 Participants • The baseline-active HO classic ACVR1 \[R206H\] mutation analysis set (AHOC) includes all randomized patients with the classic ACVR1 \[R206H\] mutation and who had at least one active HO lesion(s) at baseline, as defined by 18F-NaF PET positivity; it is based on the treatment allocated (as randomized)	418.18 gram (g) STANDARD_DEVIATION 372.801 • n=20 Participants • The baseline-active HO classic ACVR1 \[R206H\] mutation analysis set (AHOC) includes all randomized patients with the classic ACVR1 \[R206H\] mutation and who had at least one active HO lesion(s) at baseline, as defined by 18F-NaF PET positivity; it is based on the treatment allocated (as randomized)	442.32 gram (g) STANDARD_DEVIATION 357.581 • n=42 Participants • The baseline-active HO classic ACVR1 \[R206H\] mutation analysis set (AHOC) includes all randomized patients with the classic ACVR1 \[R206H\] mutation and who had at least one active HO lesion(s) at baseline, as defined by 18F-NaF PET positivity; it is based on the treatment allocated (as randomized)
Total Volume of HO Lesions as Assessed by CT (AHOC Analysis Set)	239.72 cubic centimeter (cm^3) STANDARD_DEVIATION 263.813 • n=22 Participants • The baseline-active HO classic ACVR1 \[R206H\] mutation analysis set (AHOC) includes all randomized patients with the classic ACVR1 \[R206H\] mutation and who had at least one active HO lesion(s) at baseline, as defined by 18F-NaF PET positivity; it is based on the treatment allocated (as randomized)	251.43 cubic centimeter (cm^3) STANDARD_DEVIATION 327.881 • n=20 Participants • The baseline-active HO classic ACVR1 \[R206H\] mutation analysis set (AHOC) includes all randomized patients with the classic ACVR1 \[R206H\] mutation and who had at least one active HO lesion(s) at baseline, as defined by 18F-NaF PET positivity; it is based on the treatment allocated (as randomized)	245.29 cubic centimeter (cm^3) STANDARD_DEVIATION 292.408 • n=42 Participants • The baseline-active HO classic ACVR1 \[R206H\] mutation analysis set (AHOC) includes all randomized patients with the classic ACVR1 \[R206H\] mutation and who had at least one active HO lesion(s) at baseline, as defined by 18F-NaF PET positivity; it is based on the treatment allocated (as randomized)
Fibrodysplasia Ossificans Progressiva (FOP) Genetic Mutation Active HO classic ACVR1 (R206H)	22 Participants n=24 Participants	20 Participants n=20 Participants	42 Participants n=44 Participants
Fibrodysplasia Ossificans Progressiva (FOP) Genetic Mutation Other	2 Participants n=24 Participants	0 Participants n=20 Participants	2 Participants n=44 Participants

PRIMARY outcome

Timeframe: Up to Week 28

Population: The safety analysis set included all randomized participants who received any study drug and was analyzed as treated.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs Participants with at least one TEAE	24 Participants	20 Participants
Period 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs Participants with at least one serious TEAE	2 Participants	4 Participants

PRIMARY outcome

Timeframe: Up to Week 28

Population: The safety analysis set included all randomized participants who received any study drug and was analyzed as treated.

Severity of TEAEs were graded as follows: Mild: Does not interfere in a significant manner with the participant's normal functioning level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms but may be given because of personality of the participants. Moderate: Produces some impairment of functioning but is not hazardous to health. It was uncomfortable or an embarrassment. Treatment for symptom may be needed. Severe: Produces significant impairment of functioning or incapacitation and was a definite hazard to the participant's health. Treatment for symptom may be given and/or participants hospitalized. Number of participants with TEAEs by severity is reported.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Number of Participants With TEAEs by Severity Participants with at least one Moderate TEAE	12 Participants	10 Participants
Period 1: Number of Participants With TEAEs by Severity Participants with at least one Severe TEAE	3 Participants	3 Participants
Period 1: Number of Participants With TEAEs by Severity Participants with at least one Mild TEAE	9 Participants	7 Participants

PRIMARY outcome

Timeframe: Baseline and Week 28

Population: Baseline-active heterotopic ossification analysis set (AHO) included all randomized participants who had at least one active HO lesion at baseline; and was based on the treatment allocated (as randomized).

18\^F-NaF PET is used to assess lesion and disease activity. Time-weighted average (standardized area under the curve \[AUC\]) of the percent change from baseline in total lesion activity by 18\^F-NaF PET up to Week 28 in AHO analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Time-Weighted Average (Standardized Area Under the Curve [AUC]) of the Percent Change From Baseline in Total Lesion Activity by Fluorine-18-labeled Sodium Fluoride (18^F-NaF) Positron Emission Tomography (PET) at Week 28 (AHO)	16.6 Percent Change Standard Error 9.11	-8.1 Percent Change Standard Error 9.93

PRIMARY outcome

Timeframe: Week 28

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline was based on the treatment allocated (as randomized).

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Percent change from baseline in the total volume of HO lesions as assessed by CT during Period 1 at Week 28 is reported.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by Computed Tomography (CT) at Week 28 (AHO)	32.0 Percent Change Standard Error 18.66	7.1 Percent Change Standard Error 20.43

PRIMARY outcome

Timeframe: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. HO detectable by CT that developed after baseline are referred to as "new HO lesions." Number of new HO lesions as assessed by CT at Week 56 relative to Week 28 scan is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Number of New HO Lesions as Assessed by CT at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)	0 New HO Lesions	—

PRIMARY outcome

Timeframe: Week 28

Population: AHOC analysis set included all randomized participants with the classic ACVR1 \[R206H\] mutation and who had at least one AHO at baseline, as defined by 18\^F-NaF PET positivity; and was based on the treatment allocated (as randomized). "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure.

18\^F-NaF PET is used to assess lesion and disease activity. Time-weighted average (Standardized AUC) of the percent change from baseline in total lesion activity as assessed by 18\^F-NaF PET in Active HO Classic ACVR1 Mutation (AHOC) analysis set up to Week 28 is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Time-weighted Average (Standardized AUC) of the Percent Change From Baseline in Total Lesion Activity Assessed by 18^F-NaF PET at Week 28 (AHOC)	17.6 Percent Change Standard Error 9.73	-8.0 Percent Change Standard Error 10.14

PRIMARY outcome

Timeframe: Week 28

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Percent change from baseline in the total volume of HO lesions was assessed by CT at Week 28 in AHOC analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by CT at Week 28 (AHOC)	34.9 Percent Change Standard Error 19.90	7.0 Percent Change Standard Error 20.87

SECONDARY outcome

Timeframe: Week 28

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline; based on the treatment allocated (as randomized). "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure.

The pain NRS is a patient reported outcome (PRO) used by participants to rate their pain associated with FOP. Participants were asked to rate their pain on a scale that ranges from "0" (no pain) to "10" (worst possible pain), where the highest score indicated worst outcome. Time-weighted average (Standardized AUC) of the change from baseline in daily pain due to FOP assessed by daily NRS at Week 28 in AHO analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=23 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=18 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Time-weighted Average (Standardized AUC) of the Change From Baseline in Daily Pain Due to Fibrodysplasia Ossificans Progressiva (FOP) Assessed by Daily Numeric Rating Scale (NRS) at Week 28 (AHO)	-0.17 Score on a Scale Standard Error 0.205	-0.51 Score on a Scale Standard Error 0.231

SECONDARY outcome

Timeframe: Week 28

The pain NRS is a PRO used by participants to rate their pain associated with FOP. Participants were asked to rate their pain on a scale that ranges from "0" (no pain) to "10" (worst possible pain), where the highest score indicated worst outcome. Time-Weighted average (standardized AUC) of the change from baseline in daily pain due to FOP assessed by daily NRS at Week 28 in AHOC analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=18 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Time-weighted Average (Standardized AUC) of the Change From Baseline in Daily Pain Due to FOP, Assessed by Daily NRS at Week 28 (AHOC)	-0.12 Score on a Scale Standard Deviation 0.221	-0.48 Score on a Scale Standard Deviation 0.237

SECONDARY outcome

Timeframe: Week 8

Standardized uptake value max (SUVmax) was a measurement of the maximum radiopharmaceutical uptake within the volume of interest. Relative accuracy of a particular radiotracer in a particular tissue is determined by expressing the absolute accuracy (obtained in the primary outcome measure) in terms of percent difference between SUVmax values obtained from PET/CT. Percent Change in 18\^F-NaF SUVmax of Individual Active HO Site(s) assessed by 18\^F-NaF PET in AHOC analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Percent Change From Baseline in 18^F-NaF SUVmax of Individual Active HO Site(s) Assessed by 18^F-NaF PET at Week 8 (AHOC)	-6.7 Percent Change Standard Deviation 28.79	-21.6 Percent Change Standard Deviation 30.25

SECONDARY outcome

Timeframe: Week 8

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline; based on the treatment allocated (as randomized).

Percent change in 18\^F-NaF SUVmax of individual active HO site(s) as assessed by 18\^F-NaF PET at Week 8 in AHO analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Percent Change From Baseline in 18^F-NaF SUVmax of Individual Active HO Site(s) as Assessed by 18^F-NaFPET at Week 8 (AHO)	-7.9 Percent Change Standard Deviation 28.80	-21.6 Percent Change Standard Deviation 30.25

SECONDARY outcome

Timeframe: Week 28

Change from baseline in number of HO lesions was assessed by 18\^F-NaF PET at Week 28 in AHOC analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Change From Baseline in Number of HO Lesions as Assessed by 18^F-NaF PET at Week 28 (AHOC)	-1.0 HO Lesions Standard Deviation 2.66	-2.3 HO Lesions Standard Deviation 2.24

SECONDARY outcome

Timeframe: Week 28

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline; based on the treatment allocated (as randomized).

Change from baseline in number of HO lesions was assessed by 18\^F-NaF PET in AHO analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Change From Baseline in Number of HO Lesions as Assessed by 18^F-NaF PET at Week 28 (AHO)	-1.0 HO Lesions Standard Deviation 2.59	-2.3 HO Lesions Standard Deviation 2.24

SECONDARY outcome

Timeframe: Week 28

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Change from baseline in number of HO lesions was detectable by CT using AHOC analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Change From Baseline in Number of HO Lesions Detectable by CT at Week 28 (AHOC)	1.2 HO Lesions Standard Deviation 2.00	-0.3 HO Lesions Standard Deviation 1.34

SECONDARY outcome

Timeframe: Week 28

Population: AHO analysis set included all randomized participants who had at least one active HO lesion at baseline; based on the treatment allocated (as randomized).

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Change from baseline in number of HO lesions detectable by CT at Week 28 in AHO analysis set is reported.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 1: Change From Baseline in Number of HO Lesions Detectable by CT at Week 28 (AHO)	1.2 HO Lesions Standard Deviation 1.93	-0.3 HO Lesions Standard Deviation 1.34

SECONDARY outcome

Timeframe: Week 28, Week 56

Number of new HO lesions as assessed by 18\^F-NaF PET at Week 56 Relative to Week 28 Scan is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Number of New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)	1 New HO lesions	—

SECONDARY outcome

Timeframe: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to baseline for participants on treatment during both periods (REGN2477/REGN2477) as planned.

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Percentage of participants with new HO lesions as assessed by CT at week 56 relative to week 28 scan is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percentage of Participants With New HO Lesions as Assessed by CT at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)	0.0 Percentage of Participants	—

SECONDARY outcome

Timeframe: Week 28, Week 56

18\^F-NaF PET is used to assess lesion and disease activity. Percentage of participants with new HO lesions as assessed by 18\^F-NaF PET at week 56 relative to week 28 scan is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percentage of Participants With New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)	4.5 Percentage of Participants	—

SECONDARY outcome

Timeframe: Week 28, Week 56

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT Only: Computed Tomography (CT) assessment without reference to positron-emission tomography (PET). Number of new HO lesions as assessed by CT only at week 56 relative to week 28 scan is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Number of New HO Lesions as Assessed by CT Only at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)	3 New HO lesions	—

SECONDARY outcome

Timeframe: Week 28, Week 56

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT Only: Computed Tomography (CT) assessment without reference to Positron-Emission Tomography (PET). Percentage of participants with new HO lesions as assessed by CT only at week 56 relative to week 28 scan is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percentage of Participants With New HO Lesions as Assessed by CT Only at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)	9.1 Percentage of Participants	—

SECONDARY outcome

Timeframe: Week 28, Week 56

18\^F-NaF PET is used to assess lesion and disease activity. Difference of Change from Week 28 to Week 56 as assessed by 18\^F-NaF PET versus from Baseline to Week 28

Outcome measures

Outcome measures
Measure	Placebo n=19 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=17 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2 vs. Period 1: Change From Week 28 in Number of Active HO Lesions as Assessed by 18^F-NaF PET to Week 56 (Period 2) Versus the Same Participants Between Baseline and Week 28 (Period 1) (AHO COVID-19 mITT)	-1.2 Active lesions Standard Deviation 4.31	1.3 Active lesions Standard Deviation 3.26

SECONDARY outcome

Timeframe: Week 28, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan is collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure.

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Difference of Change from Week 28 to Week 56 as assessed by CT Scan versus from Baseline to Week 28 is reported

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=18 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2 vs. Period 1: Change From Week 28 in Number of Active HO Lesions as Assessed by CT Scan at Week 56 (Period 2) Versus the Same Participants Between Baseline and Week 28 (Period 1) (AHO COVID-19 mITT)	-1.3 Active lesions Standard Deviation 2.40	0.3 Active lesions Standard Deviation 1.24

SECONDARY outcome

Timeframe: Baseline, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 only (Placebo/REGN2477) as planned.

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Number of new HO lesions as assessed by CT at week 56 relative to baseline.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Number of New HO Lesions as Assessed by CT at Week 56 Relative to Baseline (AHO COVID-19 mITT)	2 New HO Lesions	—

SECONDARY outcome

Timeframe: Week 56

Population: COVID-19 mITT: All AHO participants who receive a treatment in Period 2 for whom at least 1 post-Week 28 scan is collected and the period between any consecutive doses is less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT Only: Computed Tomography (CT) assessment without reference to Positron-Emission Tomography (PET); Number of new HO lesions as assessed by CT only at week 56 relative baseline is reported.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Number of New HO Lesions as Assessed by CT Only at Week 56 Relative to Baseline (AHO COVID-19 mITT)	1 New HO Lesions	—

SECONDARY outcome

Timeframe: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Percentage of participants with new HO lesions as assessed by CT at week 56 relative to baseline were reported.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percentage of Participants With New HO Lesions as Assessed by CT at Week 56 Relative to Baseline (AHO COVID-19 mITT)	11.1 Percentage of Participants	—

SECONDARY outcome

Timeframe: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

18\^F-NaF PET is used to assess lesion and disease activity. Number of new HO lesions as assessed by 18\^F-NAF PET at week 56 relative to baseline is reported.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Number of New HO Lesions as Assessed by 18^F-NAF PET at Week 56 Relative to Baseline (AHO COVID-19 mITT)	1 New HO Lesions	—

SECONDARY outcome

Timeframe: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

18\^F-NaF PET is used to assess lesion and disease activity. Percentage of participants with new HO lesions as assessed by 18\^F-NaF PET at week 56 relative to baseline.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percentage of Participants With New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Baseline (AHO COVID-19 mITT)	5.6 Percentage of Participants	—

SECONDARY outcome

Timeframe: Week 28, Week 56

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Total volume of new HO lesions as assessed by CT at Week 56 relative to Week 28 scan.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Total Volume of New HO Lesions as Assessed by CT at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)	0.0 cubic centimeter (cm^3) Standard Deviation 0.21	—

SECONDARY outcome

Timeframe: Week 28, Week 56

TLA is a measure of participant-level cumulative burden of metabolically active HO. Activity of individual HO lesions was calculated as the product of mean standard uptake value (SUVmean) and the PET volume of the active HO lesion. TLA was derived for each participant at each time point as the sum of HO lesion activity of individual target and new active HO lesions.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Total Lesion Activity (TLA) Assessed by 18^F-NaF PET in New HO Lesions at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)	13.2 gram (g) Standard Deviation 61.89	—

SECONDARY outcome

Timeframe: Week 28, Week 56

Difference of Percent Change from Week 28 to Week 56 versus from Baseline to Week 28 is reported

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=17 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2 vs. Period 1: Percent Change From Week 28 in TLA as Assessed by 18^F-NaF PET to Week 56 (Period 2) Versus the Same Participants Between Baseline and Week 28 (Period 1) (AHO COVID-19 mITT)	-66.9 Percent Change Standard Deviation 181.06	14.0 Percent Change Standard Deviation 41.17

SECONDARY outcome

Timeframe: Week 28, Week 56

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT scan acquired contemporaneously to the PET scan. Difference of Percent Change from Week 28 to Week 56 versus from Baseline to Week 28 is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=18 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2 vs. Period 1: Percent Change From Week 28 in the Total Volume of HO Lesions as Assessed by CT to Week 56 (Period 2) Versus the Same Participants Between Baseline and Week 28 (Period 1) (AHO COVID-19 mITT)	-31.8 Percent Change Standard Deviation 132.47	-11.1 Percent Change Standard Deviation 24.07

SECONDARY outcome

Timeframe: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

Total Lesion Activity (TLA) is a measure of participant-level cumulative burden of metabolically active HO. TLA in New (Relative to Baseline) Lesions at Week 56 is reported.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: TLA in New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Baseline (AHO COVID-19 mITT)	0.7 gram (g) Standard Deviation 2.13	—

SECONDARY outcome

Timeframe: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

CT is a diagnostic imaging test used to create detailed images of internal organs, bones, soft tissue, and blood vessels. CT Only: Computed Tomography (CT) assessment without reference to Positron-Emission Tomography (PET); Total volume of new HO lesions as assessed by CT only at week 56 relative to baseline is reported.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Total Volume of New HO Lesions as Assessed by CT Only at Week 56 Relative to Baseline (AHO COVID-19 mITT)	0.0 cubic centimeter (cm^3) Standard Deviation 0.02	—

SECONDARY outcome

Timeframe: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

Percent change from baseline in TLA as assessed by 18\^F-NaF PET to week 56 were reported.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percent Change From Baseline in TLA as Assessed by 18^F-NaF PET to Week 56 (AHO COVID-19 mITT)	-16.4 Percent Change Standard Deviation 53.10	—

SECONDARY outcome

Timeframe: Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by CT to Week 56 (AHO COVID-19 mITT)	2.6 Percent Change Standard Deviation 10.18	—

SECONDARY outcome

Timeframe: Week 28 to Week 56

Percent Change from Week 28 to Week 56 is reported.

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percent Change From Week 28 in SUVmax as Assessed by 18^F-NaF to Week 56 (AHO COVID-19 mITT)	-30.3 Percent Change Standard Deviation 15.03	—

SECONDARY outcome

Timeframe: Baseline, Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Separate analyses were conducted from week 56 relative to week 28 for participants on treatment during period 2 (Placebo/REGN2477) as planned.

Percent change from baseline in 18\^F-NaF PET SUVmax to week 56

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percent Change From Baseline in 18^F-NaF PET SUVmax to Week 56 (AHO COVID-19 mITT)	-41.9 Percent Change Standard Deviation 29.16	—

SECONDARY outcome

Timeframe: Week 28 up to Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure. Data were planned to be collected and analyzed only for participants switching to REGN2477 in period 2 for this outcome measure.

The pain NRS is a patient reported outcome used by participants to rate their pain associated with FOP. Participants were asked to rate their pain on a scale that ranges from "0" (no pain) to "10" (worst possible pain), where the highest score indicated worst outcome.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Daily Average Pain Due to FOP Measured Using the Daily NRS	1.60 Score on a Scale Standard Deviation 1.969	—

SECONDARY outcome

Timeframe: Week 28 to Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Data were planned to be collected and analyzed only for participants switching to REGN2477 in period 2 for this outcome measure.

Percentage of participants with flare-ups starting between week 28 and week 56 as assessed by participant E-diary is reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percentage of Participants With Flare-ups Assessed by Participant E-diary	13.6 Percentage of Participants	—

SECONDARY outcome

Timeframe: Week 28 to Week 56

Population: COVID-19 mITT: All AHO participants who received a treatment in Period 2 for whom at least 1 post-Week 28 scan was collected and the period between any consecutive doses was less than 9 weeks (63 days) before the 1st post-week 28 scan. Data were planned to be collected and analyzed only for participants switching to REGN2477 in period 2 for this outcome measure.

Percentage of participants with investigator-assessed flare-ups were reported.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Period 2: Percentage of Participants With Investigator-assessed Flare-ups	13.6 Percentage of Participants	—

SECONDARY outcome

Timeframe: Week 28, Week 56, Week 76

Population: The PK analysis set included all treated participants who received any study drug and who had at least 1 non-missing drug concentration following the first dose of study drug. ("Number Analyzed" equals number of participants evaluable at that time point)

Concentration of total activin A in serum over time is reported.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Periods 1, 2, and 3: Concentration of Total Activin A in Serum Week 28	0.0000813 milligram per Liter (mg/L) Standard Deviation 0.000164	0.0537 milligram per Liter (mg/L) Standard Deviation 0.0116
Periods 1, 2, and 3: Concentration of Total Activin A in Serum Week 56	0.0563 milligram per Liter (mg/L) Standard Deviation 0.0172	0.0503 milligram per Liter (mg/L) Standard Deviation 0.0113
Periods 1, 2, and 3: Concentration of Total Activin A in Serum Week 76	0.0487 milligram per Liter (mg/L) Standard Deviation 0.0192	0.0497 milligram per Liter (mg/L) Standard Deviation 0.0176

SECONDARY outcome

Timeframe: Week 28, Week 56, Week 76

Concentrations of REGN2477 capable of target binding were measured (functional drug).

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Periods 1, 2, and 3: Concentrations of Functional REGN2477 in Serum Week 56	100 mg/L Standard Deviation 27.3	122 mg/L Standard Deviation 54.8
Periods 1, 2, and 3: Concentrations of Functional REGN2477 in Serum Week 76	113 mg/L Standard Deviation 27.0	113 mg/L Standard Deviation 23.0
Periods 1, 2, and 3: Concentrations of Functional REGN2477 in Serum Week 28	0 mg/L Standard Deviation 0	130 mg/L Standard Deviation 46.6

SECONDARY outcome

Timeframe: Up to Week 76

Population: The Anti-Drug Antibody (ADA) analysis set included all participants who received study drug and had at least 1 non-missing ADA result following the first study dose. "Overall number of participants analyzed" are the participants who were evaluable for this outcome measure.

Immunogenicity was characterized by ADA responses \& titers. Responses categories: Negative - ADA negative response at all time points, regardless of missing samples; Pre-existing immunoreactivity - ADA positive response at baseline with all post first dose negative results or positive response at baseline with all post first dose ADA responses \< 9-fold over baseline titer levels; Treatment-boosted response - positive response in the assay post first dose, \>= 9-fold over baseline titer levels, when baseline results are positive; Treatment-emergent response - ADA positive response in the REGN2477 ADA assay post first dose when baseline results = negative or missing.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=19 Participants Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.
Periods 1, 2, and 3: Number of Participants With Clinical Impact of Treatment-Emergent Anti-drug Antibodies (ADA) to REGN2477 Negative	24 Participants	18 Participants
Periods 1, 2, and 3: Number of Participants With Clinical Impact of Treatment-Emergent Anti-drug Antibodies (ADA) to REGN2477 Pre-existing Immunoreactivity	0 Participants	0 Participants
Periods 1, 2, and 3: Number of Participants With Clinical Impact of Treatment-Emergent Anti-drug Antibodies (ADA) to REGN2477 Treatment-Boosted Response	0 Participants	0 Participants
Periods 1, 2, and 3: Number of Participants With Clinical Impact of Treatment-Emergent Anti-drug Antibodies (ADA) to REGN2477 Treatment-Emergent Response	0 Participants	1 Participants

Adverse Events

Placebo

Serious events: 2 serious events

Other events: 24 other events

Deaths: 0 deaths

REGN2477 10 mg/kg Q4W

Serious events: 4 serious events

Other events: 20 other events

Deaths: 0 deaths

Placebo/REGN2477 10 mg/kg Q4W

Serious events: 6 serious events

Other events: 24 other events

Deaths: 2 deaths

REGN2477/REGN2477 10 mg/kg Q4W

Serious events: 7 serious events

Other events: 18 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trials Administrator

Regeneron Pharmaceuticals, Inc

Phone: 844-734-6643

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator has the right to independently publish study results from the investigator's site after a multi-center publication, or a defined period after the completion of the study by all sites. The investigator must provide the sponsor a copy of any such publication derived from the study for review and comment in advance of any submission, and delay publication, if requested, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=24 participants at risk Participants received a single dose of placebo matched to REGN2477 intravenous (IV) infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	REGN2477 10 mg/kg Q4W n=20 participants at risk Participants received a single dose of REGN2477 10 milligrams per kilogram (mg/kg) IV infusion every 4 weeks (Q4W) for up to 28 weeks during Period 1.	Placebo/REGN2477 10 mg/kg Q4W n=24 participants at risk Participants who were in the placebo group in Period 1 crossed over to receive a single dose of REGN2477 IV infusion Q4W for 28 weeks during Period 2 followed by 20 weeks during Period 3.	REGN2477/REGN2477 10 mg/kg Q4W n=19 participants at risk Participants who were in the REGN2477 group in Period 1 continued treatment with a single dose of REGN2477 IV infusion Q4W for additional 28 weeks during Period 2 followed by 20 weeks during Period 3. Participants could continue receiving REGN2477 every 4 weeks beyond week 76 provided that no safety signals were identified.
Infections and infestations Gastroenteritis	0.00% 0/24 • From first dose of study drug to end of study	5.0% 1/20 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Infections and infestations Pneumonia	0.00% 0/24 • From first dose of study drug to end of study	5.0% 1/20 • Number of events 2 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Infections and infestations Sepsis	0.00% 0/24 • From first dose of study drug to end of study	5.0% 1/20 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Infections and infestations Urinary tract infection	0.00% 0/24 • From first dose of study drug to end of study	5.0% 1/20 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Infections and infestations Abscess	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Infections and infestations Abscess limb	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	4.2% 1/24 • Number of events 2 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Infections and infestations Gastroenteritis viral	4.2% 1/24 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Infections and infestations Perineal abscess	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	4.2% 1/24 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Infections and infestations Perirectal abscess	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Infections and infestations Respiratory tract infection viral	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Infections and infestations Subcutaneous abscess	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Gastrointestinal disorders Intestinal obstruction	0.00% 0/24 • From first dose of study drug to end of study	5.0% 1/20 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Gastrointestinal disorders Crohn's disease	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	4.2% 1/24 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/24 • From first dose of study drug to end of study	5.0% 1/20 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	4.2% 1/24 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
General disorders Pyrexia	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	4.2% 1/24 • Number of events 2 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Injury, poisoning and procedural complications Head injury	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Injury, poisoning and procedural complications Skull fracture	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	4.2% 1/24 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Injury, poisoning and procedural complications Splenic rupture	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	4.2% 1/24 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Musculoskeletal and connective tissue disorders Joint swelling	4.2% 1/24 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study
Nervous system disorders Cerebrovascular accident	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	0.00% 0/24 • From first dose of study drug to end of study	5.3% 1/19 • Number of events 1 • From first dose of study drug to end of study
Renal and urinary disorders Renal colic	0.00% 0/24 • From first dose of study drug to end of study	0.00% 0/20 • From first dose of study drug to end of study	4.2% 1/24 • Number of events 1 • From first dose of study drug to end of study	0.00% 0/19 • From first dose of study drug to end of study