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    Summary
    EudraCT Number:2016-005035-33
    Sponsor's Protocol Code Number:R2477-FOP-1623
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-05-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-005035-33
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to examine the safety, tolerability and effects on abnormal bone formation of REGN2477 in patients with Fibrodysplasia Ossificans Progressiva
    A.3.2Name or abbreviated title of the trial where available
    LUMINA-1
    A.4.1Sponsor's protocol code numberR2477-FOP-1623
    A.5.4Other Identifiers
    Name:IND NumberNumber:130595
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRegeneron Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRegeneron Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRegeneron Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address777 Old Saw Mill River Road
    B.5.3.2Town/ cityTarrytown, NY
    B.5.3.3Post code10591
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials@regeneron.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1779
    D.3 Description of the IMP
    D.3.1Product nameREGN2477
    D.3.2Product code REGN2477
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeREGN2477
    D.3.9.3Other descriptive nameREGN2477
    D.3.9.4EV Substance CodeSUB182187
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Fibrodysplasia Ossificans Progressiva (FOP)
    E.1.1.1Medical condition in easily understood language
    Genetic condition which causes abnormal formation of bone at abnormal locations such as in the muscles, tendons and ligaments.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10068715
    E.1.2Term Fibrodysplasia ossificans progressiva
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The 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).
    The 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).
    E.2.2Secondary objectives of the trial
    - To compare the effect of REGN2477 versus placebo on pain due to FOP, as measured by the area under the curve for pain based on daily numeric rating scale 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
    - 18F-NaF standardized uptake value maximum of individual active HO site(s) by PET
    - biochemical markers of bone formation
    - To assess the effect of REGN2477 between wk28 and wk56, 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 wk 28 versus the same patients between baseline and wk28
    - 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) of REGN2477 in patients with FOP
    - To assess the immunogenicity of REGN2477
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women 18 to 60 years of age at screening.
    2. Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, episodic soft tissue swelling, and/or progressive heterotopic ossification).
    3. Confirmation of FOP diagnosis with documentation of any ACVR1 mutation.
    4. 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.
    5. Willing and able to undergo PET and CT imaging procedures and other procedures as defined in this study.
    E.4Principal exclusion criteria
    1. 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.
    2. Use of bisphosphonate within 1 year of screening.
    3. 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 patients complete study questionnaires are allowed.
    4. Pregnant or breastfeeding women.
    5. Male and women of childbearing potential patients who are unwilling to practice highly effective contraception.
    6. Previous history or diagnosis of cancer.
    7. Patients who are on concomitant antiplatelet therapy (e.g., clopidogrel), anti-coagulants (e.g., warfarin, heparin, factor Xa inhibitor, or thrombin inhibitors) in the last 30 days or within 5 half-lives of the therapy, whichever is longer. Low dose (≤100 mg/day) acetylsalicylic acid (aspirin) is acceptable.
    8. Patients with a history of severe, non-traumatic bleeding requiring transfusion or hospitalization for hemodynamic compromise
    9. Patients with a known pre-existing medical history of a bleeding diathesis (e.g., hemophilia A, von Willebrand’s Factor deficiency, platelet count ≤20x10^9/L).
    E.5 End points
    E.5.1Primary end point(s)
    Primary safety end point: (Period 1 [week 28]):
    Incidence and severity of TEAEs through the end of the Period 1 at week 28

    Primary efficacy endpoints: (Period 1 [week 28]):
    - Time-weighted average (standardized AUC) of the percent change from baseline in total lesion activity by 18F-NaF PET over 28 weeks (AHO - Baseline active HO analysis set)
    - Percent change from baseline in the total volume of HO lesions as assessed by CT at week 28 (AHO)
    - Time-weighted average (standardized area under the curve [AUC]) of the percent change from baseline in total lesion activity by 18F-NaF PETover 28 weeks (AHOC - Baseline active HO classic ACVR1[R206H] mutation analysis set)
    - Percent change from baseline in the total volume of HO lesions as assessed by CT at week 28 (AHOC)

    Primary Efficacy Endpoint (Period 2 [Week 56]) The primary efficacy endpoint in Period 2 is:
    - Number of new HO lesions as assessed by CT at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Period 1
    Baseline and end of Period 1 at week 28

    Period 2
    At week 56
    E.5.2Secondary end point(s)
    The key efficacy secondary endpoints (Period 1 [week28]):

    - Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily NRS over 28 weeks (AHO)
    - Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily NRS over 28 weeks (AHOC)

    Other secondary endpoints are (Period 1 week 28]):
    - Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by PET at week 8 (AHOC)
    - Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by PET at week 8 (AHO)
    - Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 (AHOC)
    - Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 (AHO)
    - Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 (FAS - Full Analysis Set)
    - Change from baseline in number of HO lesions detectable by CT at week 28 (AHOC)
    - Change from baseline in number of HO lesions detectable by CT at week 28 (AHO)
    - Change from baseline in number of HO lesions detectable by CT at week 28 (FAS)
    - Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily NRS over 28 weeks (FAS)
    - Time weighted average (standardized AUC) of the percent change from baseline in biomarkers of bone formation levels in serum over 28 weeks, including Total Procollagen Type 1 N-Terminal Propeptide (P1NP), bone specific alkaline phosphatase (BSAP), and total alkaline phosphatase (tAP) (FAS)
    -Incidence and severity of TEAEs

    Other Secondary Endpoints Related to Clinical Pharmacology (Period 1, Period 2, Period 3)
    These secondary endpoints will be analyzed for all 3 study periods: Period 1 (week 28), Period 2 (week 56) and Period 3 (week 76).
    - Concentration of total activin A in serum over time
    - PK profile of REGN2477, assessed as concentrations of REGN2477 in serum over time
    - Immunogenicity of REGN2477, as determined by the incidence, titer, and clinical impact of treatment-emergent ADA to REGN2477 over time

    Key Secondary Efficacy Endpoints (Period 2 [Week 56])
    The key secondary efficacy endpoints for Period 2 analyses (in AHO) are:
    - Total volume of new HO lesions as assessed by CT at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)
    - Number of new HO lesions as assessed by 18F-NaF PET at week 56 relative to week 28 (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)
    - Total lesion activity by 18F-NaF PET in new HO lesions at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after double-blind period) (AHO)
    - Percent of patients with new HO lesions as assessed by CT at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)
    - Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)

    Other Secondary Efficacy Endpoints (Period 2 [Week 56])
    The other secondary efficacy variables for Period 2 analyses (all in AHO)
    are:
    - Number of new HO lesions as assessed by CT only at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)
    - Percent of patients with investigator-assessed flare-ups in Period 2 (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)
    - Percent of patients with flare-ups assessed by patient e-diary in Period
    2 (in patients switching from placebo to REGN2477 after the double- blind period) (AHO)
    - Number of new HO lesions as assessed by CT at week 56 relative to baseline scan (in patients who continue REGN2477 after the double- blind period) (AHO)
    - Total volume in new HO lesions as assessed by CT at week 56 relative to baseline scan (in patients who continue REGN2477 after the double- blind period) (AHO)
    - Percent of patients with new HO lesions as assessed by CT at week 56 relative to baseline scan (in patients who continue REGN2477 after the double-blind period) (AHO)
    - Number of new HO lesions as assessed by 18F-NaF PET at week 56 relative to baseline scan (in patients who continue REGN2477 after the double-blind period) (AHO)
    - Total lesion activity in new HO lesions as assessed by 18F-NaF PET at week 56 relative to baseline scan (in patients who continue REGN2477 after the double-blind period) (AHO)
    - Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 56 relative to baseline scan (in patients who continue REGN2477 after the double-blind period) (AHO)

    A full list of the endpoints can be found in section 4.3.3 of the protocol
    E.5.2.1Timepoint(s) of evaluation of this end point
    Through study (week 8, 28 and 56) and end of study, week 76.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    3-period study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Colombia
    France
    Italy
    Mexico
    Netherlands
    Poland
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study for this study is defined as the last visit of the last patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard treatment
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-08-15
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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