Clinical trial NCT03188666: A Study to Examine the Safety, Tolerability and Effects on Abnormal Bone Formation of REGN2477 in Patients With Fibrodysplasia Ossificans Progressiva
Official title: A Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effects on Heterotopic Bone Formation of REGN2477 in Patients With Fibrodysplasia Ossificans Progressiva
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fibrodysplasia Ossificans Progressiva
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2017-06-15
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a three period study design consisting of a 6-month, randomized, double-blind placebo-controlled treatment (period 1) followed by a 6-month, open-label treatment (period 2) and a follow-up treatment period (period 3).

Primary safety objective of the study is to assess the safety and tolerability of REGN2477 in male and female patients with fibrodysplasia ossificans progressiva (FOP).

Primary efficacy objective of the study is to assess the effect of REGN2477 versus placebo on the change from baseline in heterotopic ossification (HO) in patients with FOP, as determined by 18-NaF uptake in HO lesions by positron emission tomography (PET) and in total volume of HO lesions by computed tomography (CT).

Key Secondary objectives are:

* To compare the effect of REGN2477 versus placebo on pain due to FOP, as measured by the area under the curve (AUC) for pain based on daily pain numeric rating scale (NRS) scores
* To assess the effect of REGN2477 versus placebo on the change from baseline in HO, as determined by the number of new HO lesions identified by 18F-NaF PET or by CT
* To assess the effect of REGN2477 versus placebo on the change from baseline in 18F-NaF standardized uptake value maximum (SUVmax) of individual active HO site(s) by PET
* To assess the effect of REGN2477, between week 28 and week 56, on the number, activity, and volume of HO lesions identified by 18F-NaF PET or by CT in patients who switch from placebo to REGN2477 at week 28 versus the same patients between baseline and week 28
* To assess the effect of REGN2477 versus placebo on the change from baseline in biochemical markers of bone formation
* To characterize the concentrations of total activin A at baseline and over time following the first dose of study drug
* To characterize the concentration-time profile (pharmacokinetics \[PK\]) of REGN2477 in patients with FOP
* To assess the immunogenicity of REGN2477


Eligibility criteria: Key Inclusion Criteria:

* Men and women 18 to 60 years of age at screening.
* Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, episodic soft tissue swelling, and/or progressive heterotopic ossification (HO)).
* Confirmation of FOP diagnosis with documentation of any ACVR1 mutation.
* FOP disease activity within 1 year of screening visit. FOP disease activity is defined as pain, swelling, stiffness, and other signs and symptoms associated with FOP flare-ups; or worsening of joint function, or radiographic progression of heterotopic ossifications (increase in site or number of HO lesions) with/without being associated with flare-up episodes.
* Willing and able to undergo PET and CT imaging procedures and other procedures as defined in this study.

Key Exclusion Criteria:

* Significant concomitant illness or history of significant illness such as, but not limited to cardiac, renal, rheumatologic, neurologic, psychiatric, endocrine, metabolic or lymphatic disease, that in the opinion of the study investigator might confound the results of the study or pose additional risk to the patient by their participation in the study.
* Previous history or diagnosis of cancer.
* Use of bisphosphonate within 1 year of screening.
* Concurrent participation in another interventional clinical study, or a non-interventional study with radiographic measures or invasive procedures (e.g. collection of blood or tissue samples). Participation in the FOP Connection Registry or other studies in which participants complete study questionnaires are allowed.
* Treatment with another investigational drug, denosumab, imatinib or isotretinoin in the last 30 days or within 5 half-lives of the investigational drug, whichever is longer.
* Pregnant or breastfeeding women.
* Male and women of childbearing potential participants who are unwilling to practice highly effective contraception.

Note: Other protocol defined Inclusion/Exclusion criteria apply

Primary outcomes:
measure: Period 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Up to Week 28
measure: Period 1: Number of Participants With TEAEs by Severity
timeFrame: Up to Week 28
measure: 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)
timeFrame: Baseline and Week 28
measure: Period 1: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by Computed Tomography (CT) at Week 28 (AHO)
timeFrame: Week 28
measure: Period 2: Number of New HO Lesions as Assessed by CT at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28
measure: Period 1: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by CT at Week 28 (AHOC)
timeFrame: Week 28
Secondary outcomes:
measure: 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)
timeFrame: Week 28
measure: 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)
timeFrame: Week 28
measure: 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)
timeFrame: Week 8
measure: 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)
timeFrame: Week 8
measure: Period 1: Change From Baseline in Number of HO Lesions as Assessed by 18^F-NaF PET at Week 28 (AHOC)
timeFrame: Week 28
measure: Period 1: Change From Baseline in Number of HO Lesions as Assessed by 18^F-NaF PET at Week 28 (AHO)
timeFrame: Week 28
measure: Period 1: Change From Baseline in Number of HO Lesions Detectable by CT at Week 28 (AHOC)
timeFrame: Week 28
measure: Period 1: Change From Baseline in Number of HO Lesions Detectable by CT at Week 28 (AHO)
timeFrame: Week 28
measure: 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)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28, Week 56
measure: Period 2: Number of New HO Lesions as Assessed by CT Only at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28, Week 56
measure: Period 2: Number of New HO Lesions as Assessed by CT at Week 56 Relative to Baseline (AHO COVID-19 mITT)
timeFrame: Baseline, Week 56
measure: Period 2: Number of New HO Lesions as Assessed by CT Only at Week 56 Relative to Baseline (AHO COVID-19 mITT)
timeFrame: Week 56
measure: Period 2: Percentage of Participants With New HO Lesions as Assessed by CT at Week 56 Relative to Baseline (AHO COVID-19 mITT)
timeFrame: Week 56
measure: Period 2: Number of New HO Lesions as Assessed by 18^F-NAF PET at Week 56 Relative to Baseline (AHO COVID-19 mITT)
timeFrame: Week 56
measure: 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)
timeFrame: Week 56
measure: Period 2: Total Volume of New HO Lesions as Assessed by CT at Week 56 Relative to Week 28 Scan (AHO COVID-19 mITT)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28, Week 56
measure: 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)
timeFrame: Week 28, Week 56
measure: Period 2: TLA in New HO Lesions as Assessed by 18^F-NaF PET at Week 56 Relative to Baseline (AHO COVID-19 mITT)
timeFrame: Week 56
measure: Period 2: Total Volume of New HO Lesions as Assessed by CT Only at Week 56 Relative to Baseline (AHO COVID-19 mITT)
timeFrame: Week 56
measure: Period 2: Percent Change From Baseline in TLA as Assessed by 18^F-NaF PET to Week 56 (AHO COVID-19 mITT)
timeFrame: Week 56
measure: Period 2: Percent Change From Baseline in the Total Volume of HO Lesions as Assessed by CT to Week 56 (AHO COVID-19 mITT)
timeFrame: Week 56
measure: Period 2: Percent Change From Week 28 in SUVmax as Assessed by 18^F-NaF to Week 56 (AHO COVID-19 mITT)
timeFrame: Week 28 to Week 56
measure: Period 2: Percent Change From Baseline in 18^F-NaF PET SUVmax to Week 56 (AHO COVID-19 mITT)
timeFrame: Baseline, Week 56
measure: Period 2: Daily Average Pain Due to FOP Measured Using the Daily NRS
timeFrame: Week 28 up to Week 56
measure: Period 2: Percentage of Participants With Flare-ups Assessed by Participant E-diary
timeFrame: Week 28 to Week 56
measure: Period 2: Percentage of Participants With Investigator-assessed Flare-ups
timeFrame: Week 28 to Week 56
measure: Periods 1, 2, and 3: Concentration of Total Activin A in Serum
timeFrame: Week 28, Week 56, Week 76
measure: Periods 1, 2, and 3: Concentrations of Functional REGN2477 in Serum
timeFrame: Week 28, Week 56, Week 76
measure: Periods 1, 2, and 3: Number of Participants With Clinical Impact of Treatment-Emergent Anti-drug Antibodies (ADA) to REGN2477
timeFrame: Up to Week 76
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hopital Lariboisiere,Hospitalier Universitaire Nord
city: Genova
country: Italy
facility: Giannina Gaslini Institute
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
state: North Holland
city: Rzeszow
country: Poland
facility: Szpital Wojewodzki Nr 2
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Stanmore
country: United Kingdom
facility: Royal National Orthopaedic Hospital, Brockley Hill
state: Middlesex
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References:
citation: Vanhoutte F, Liang S, Ruddy M, Zhao A, Drewery T, Wang Y, DelGizzi R, Forleo-Neto E, Rajadhyaksha M, Herman G, Davis JD. Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti-Activin A): Results From a First-in-Human Phase 1 Study. J Clin Pharmacol. 2020 Nov;60(11):1424-1431. doi: 10.1002/jcph.1638. Epub 2020 Jun 18.
citation: Aykul S, Corpina RA, Goebel EJ, Cunanan CJ, Dimitriou A, Kim HJ, Zhang Q, Rafique A, Leidich R, Wang X, McClain J, Jimenez J, Nannuru KC, Rothman NJ, Lees-Shepard JB, Martinez-Hackert E, Murphy AJ, Thompson TB, Economides AN, Idone V. Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop. Elife. 2020 Jun 9;9:e54582. doi: 10.7554/eLife.54582.