A Study to Examine the Safety, Tolerability and Effects on Abnormal Bone Formation of REGN2477 in Patients With Fibrodysplasia Ossificans Progressiva (LUMINA-1)

• ClinicalTrials.gov Identifier: NCT03188666
• Recruitment Status: Active, not recruiting
• First Posted: June 15, 2017
• Last Update Posted: April 15, 2019
• Sponsor: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Tracking Information

• First Submitted Date: June 13, 2017
• First Posted Date: June 15, 2017
• Last Update Posted Date: April 15, 2019
• Actual Study Start Date: February 26, 2018
• Estimated Primary Completion Date: September 16, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 11, 2019)

• Incidence and severity of treatment-emergent adverse events (TEAEs) through the end of the Period 1 [ Time Frame: Baseline to week 28 ]
• Time-weighted average (standardized area under the curve [AUC]) of the percent change from baseline in total lesion activity by 18F-NaF positron emission tomography (PET) using Baseline-Active HO Classic Mutation (AHOC) [ Time Frame: Baseline to week 28 ]
  AHOC includes all randomized patients with a classic mutation and who had active heterotopic ossification (HO) lesion at baseline
• Percent change from baseline in the total volume of HO lesions as assessed by computed tomography (CT) using AHOC [ Time Frame: Baseline to week 28 ]
• Time-weighted average (standardized AUC) of the percent change from baseline in total lesion activity by18F-NaF PET using Baseline-Active HO (AHO) [ Time Frame: Baseline to week 28 ]
  AHO includes all randomized patients who had active HO lesion
• Percent change from baseline in the total volume of HO lesions as assessed by CT using AHO [ Time Frame: Baseline to week 28 ]

Original Primary Outcome Measures (submitted: June 13, 2017)

• Incidence and severity of treatment-emergent adverse events (TEAEs) through the end of the Treatment Period 1 at week 28 [ Time Frame: Baseline to week 28 ]
• Time-weighted average (standardized area under the curve [AUC]) percent change from baseline in total lesion activity by 18F-NaF PET over 28 weeks [ Time Frame: Baseline to week 28 ]
• Percent change from baseline in the total volume of HO lesions as assessed by CT at week 28 [ Time Frame: Baseline to week 28 ]

• Change History: Complete list of historical versions of study NCT03188666 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: April 11, 2019)

• Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily numeric rating scale (NRS) using AHOC [ Time Frame: Baseline to week 28 ]
• Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily NRS using AHO [ Time Frame: Baseline to week 28 ]
• Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by PET using AHOC [ Time Frame: Baseline to week 8 ]
• Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by PET using AHO [ Time Frame: Baseline to week 8 ]
• Change from baseline in number of HO lesions as assessed by 18F-NaF PET using AHOC [ Time Frame: Baseline to week 28 ]
• Change from baseline in number of HO lesions as assessed by 18F-NaF PET using AHO [ Time Frame: Baseline to week 28 ]
• Change from baseline in number of HO lesions as assessed by 18F-NaF PET using Full Analysis Set (FAS) [ Time Frame: Baseline to week 28 ]
  FAS includes all randomized patients; it is based on the treatment allocated (as randomized)
• Change from baseline in number of HO lesions detectable by CT using AHOC [ Time Frame: Baseline to week 28 ]
• Change from baseline in number of HO lesions detectable by CT using AHO [ Time Frame: Baseline to week 28 ]
• Change from baseline in number of HO lesions detectable by CT using FAS [ Time Frame: Baseline to week 28 ]
• Percent change in total lesion activity by 18F-NaF PET versus the same patients between baseline and week 28 using AHOC [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Percent change in total lesion activity by 18F-NaF PET versus the same patients between baseline and week 28 using AHO [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Percent change in the total volume of HO lesions as assessed by CT versus the same patients between baseline and week 28 using AHOC [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Percent change in the total volume of HO lesions as assessed by CT versus the same patients between baseline and week 28 using AHO [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Change in the total volume of HO lesions as assessed by CT versus the same patients between baseline and week 28 using FAS [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Change in number of HO lesions by 18F-NaF PET versus the same patients between baseline and week 28 using AHOC [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Change in number of HO lesions by 18F-NaF PET versus the same patients between baseline and week 28 using AHO [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Change in number of HO lesions by CT versus the same patients between baseline and week 28 using AHOC [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Change in number of HO lesions by CT versus the same patients between baseline and week 28 using AHO [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Change in number of HO lesions by CT versus the same patients between baseline and week 28 using FAS [ Time Frame: Week 28 to week 56 ]
  In patients switching from placebo in double-blind period and who have active HO lesions at week 28
• Percent change from baseline in total lesion activity by 18F-NaF PET using AHOC [ Time Frame: Baseline to week 56 ]
• Percent change from baseline in total lesion activity by 18F-NaF PET using AHO [ Time Frame: Baseline to week 56 ]
• Percent change from baseline in the total volume of HO lesions as assessed by CT using AHOC [ Time Frame: Baseline to week 56 ]
• Percent change from baseline in the total volume of HO lesions as assessed by CT using AHO [ Time Frame: Baseline to week 56 ]
• Change from baseline in the total volume of HO lesions as assessed by CT using FAS [ Time Frame: Baseline to week 56 ]
• Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily NRS using FAS [ Time Frame: Baseline to week 28 ]
• Incidence and severity of TEAEs [ Time Frame: Baseline to week 80 ]
• Time weighted average (standardized AUC) of the percent change from baseline in biomarkers of bone formation levels in serum over 28 weeks using full analysis set (FAS) [ Time Frame: Up to week 28 ]
  Including Total Procollagen Type 1 N-Terminal Propeptide (P1NP), bone specific alkaline phosphatase (BSAP), and total alkaline phosphatase (tAP)
• Concentration of total activin A in serum over time [ Time Frame: Baseline to week 80 ]
• PK profile of REGN2477, assessed as concentrations of REGN2477 in serum over time [ Time Frame: Baseline to week 80 ]
• Immunogenicity of REGN2477, as determined by the incidence, titer, and clinical impact of treatment-emergent ADA to REGN2477 over time [ Time Frame: Baseline to week 80 ]

Original Secondary Outcome Measures (submitted: June 13, 2017)

• Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by PET at week 8 [ Time Frame: Baseline to week 8 ]
• Change from baseline in number of HO lesions detectable by CT at week 28 [ Time Frame: Baseline to week 28 ]
• Time-weighted average (standardized AUC) change from baseline in daily pain due to FOP, as measured using the daily NRS over 28 weeks [ Time Frame: Baseline to week 28 ]
• Change from baseline in the volume of individual HO lesions as assessed by CT at week 28 [ Time Frame: Baseline to week 28 ]
• Incidence and severity of TEAEs through the end of study [ Time Frame: Baseline to week 76 (end of study) ]
• Time weighted average (standardized AUC) percent change from baseline in biomarkers of bone formation levels in serum over time [ Time Frame: Baseline to week 76 ]
• Concentration of total activin A in serum over time [ Time Frame: Baseline to week 76 ]
• PK profile of REGN2477, assessed as concentrations of REGN2477 in serum over time [ Time Frame: Baseline to week 76 ]
• Immunogenicity of REGN2477 [ Time Frame: Baseline to week 76 ]
  As determined by the incidence, titer, and clinical impact of treatment-emergent ADA to REGN2477 over time

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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).

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

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Fibrodysplasia Ossificans Progressiva

Intervention

• Drug: REGN2477
  Pharmaceutical form: Powder for solution for injection/infusion; Route of administration: Intravenous (IV); Administered during treatment periods 1 and 2.
• Drug: Matching placebo
  Pharmaceutical form: Powder for solution for injection/infusion; Route of administration: Intravenous (IV); Administered during treatment period 1 only.

Study Arms

• Experimental: REGN2477
  Intervention: Drug: REGN2477
• Experimental: Placebo
  Intervention: Drug: Matching placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 11, 2019): 44
• Original Estimated Enrollment (submitted: June 13, 2017): 40
• Estimated Study Completion Date: August 17, 2020
• Estimated Primary Completion Date: September 16, 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Colombia, Italy, Netherlands, United Kingdom, United States

Administrative Information

• NCT Number: NCT03188666
• Other Study ID Numbers: R2477-FOP-1623; 2016-005035-33 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Regeneron Pharmaceuticals
• Study Sponsor: Regeneron Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

• PRS Account: Regeneron Pharmaceuticals
• Verification Date: April 2019