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    The EU Clinical Trials Register currently displays   43839   clinical trials with a EudraCT protocol, of which   7280   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2016-005035-33
    Sponsor's Protocol Code Number:R2477-FOP-1623
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-03-08
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    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
    Studio randomizzato, controllato con placebo per valutare sicurezza, tollerabilità, farmacocinetica e effetti sulla formazione di osso eterotopico di REGN2477 in pazienti con fibrodisplasia ossificante 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
    Studio per esaminare la sicurezza, la tollerabilità e gli effetti sulla formazione ossea anormale
    di REGN2477 in pazienti affetti da Fibrodisplasia ossificante progressiva
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberR2477-FOP-1623
    A.5.4Other Identifiers
    Name:130595Number:NUMERO IND
    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.1.3.4CountryUnited 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.5.4Telephone number0000000000
    B.5.5Fax number0000000000
    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 Powder for 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.3.9.2Current 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 number50
    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. cell therapy medicinal product Information not present in EudraCT
    D. therapy medical product Information not present in EudraCT
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboPowder for solution 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)
    Fibrodisplasia ossificante 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.
    ondizione genetica che provoca la formazione anormale di osso in posizioni inusuali
    come nei muscoli, nei tendini e nei legamenti.
    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).
    L'obiettivo primario di sicurezza dello studio è di valutare la sicurezza e
    la tollerabilità di REGN2477 in pazienti di sesso maschile e femminile affetti da fibrodisplasia
    ossificante progressiva (FOP).
    L’obiettivo primario di efficacia dello studio è di valutare l'effetto di
    REGN2477 rispetto al placebo sulla variazione dal basale nell’ossificazione eterotopica
    (‘heterotopic ossification’, HO) in pazienti affetti da FOP, determinata dall’assorbimento di 18-NaF nelle lesioni HO mediante tomografia ad emissione di positroni (PET) e nel volume totale
    di lesioni HO mediante tomografia computerizzata (TC).
    E.2.2Secondary objectives of the trial
    - 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 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
    numeric rating scale (NRS) scores
    - 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
    - Valutare l'effetto di REGN2477 rispetto al placebo sulla variazione dal basale nell’HO, determinato dal numero di nuove lesioni HO identificate mediante PET di 18F-NaF o mediante TC
    - Valutare l'effetto di REGN2477 rispetto al placebo sulla variazione dal basale nell’assorbimento standardizzato di 18F-NaF il valore massimo standardizzato di assorbimento (‘standardized uptake value maximum’, SUVmax) del sito/dei siti
    HO individuale/i attivo/i mediante PET
    - Confrontare l'effetto di REGN2477 rispetto al placebo sul dolore dovuto a FOP, misurato mediante l'area sottostante la curva (‘area under the curve’. AUC) per dolore basato su punteggi giornalieri della Scala di valutazione numerica (‘numeric rating scale’, NRS)
    - Valutare l'effetto di REGN2477 rispetto al placebo sulla variazione dal basale nei marcatori biochimici di formazione ossea
    - Caratterizzare le concentrazioni di Attivina A totale al basale e nel corso del tempo a seguito della prima dose di farmaco in studio.
    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 classic FOP diagnosis with documentation of the ACVR1[R206H] 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.
    1. Uomini e donne, dai 18 ai 60 anni di età allo screening.
    2. Diagnosi clinica di FOP (in base a riscontri di malformazione congenita dell’alluce, rigonfiamento episodico del tessuto morbido e/o ossificazione eterotopica progressiva).
    3. Conferma di diagnosi classica di FOP con documentazione della
    mutazione ACVR1[R206H].
    4. Attività da malattia FOP entro 1 anno della visita di screening. L’attività da malattia FOP
    viene definita come dolore, gonfiore, rigidità e altri segni e sintomi associati a recrudescenza di FOP; o peggioramento della funzione articolare, o progressione radiografica o ossificazioni eterotopiche (aumento dei siti o del numero di lesioni HO) con/senza essere associate ad
    episodi di recrudescenza.
    5. Disposto/a e in grado di sottoporsi a procedure PET e TC e altre procedure definite in questo studio.
    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 (eg 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.
    1. Significativa malattia concomitante o anamnesi di malattia significativa come, ma non limitatamente, malattia cardiaca, renale, reumatologica, neurologica, psichiatrica,
    endocrina, metabolica o linfatica, che a parere dello sperimentatore dello studio potrebbe confondere i risultati dello studio o porre ulteriori rischi per il/la paziente in caso di partecipazione allo studio.
    2. Uso di bisfosfonati entro 1 anno dallo screening.
    3. Simultanea partecipazione ad altro studio clinico interventistico, o ad uno studio
    non-interventistico con misurazioni radiografiche o procedure invasive (per es. raccolta di sangue o di campioni tissutali). È ammessa la partecipazione al Registro “FOP Connection Registry” o ad altri studi in cui i pazienti completano questionari relativi allo studio.
    4. Donne in stato di gravidanza o allattamento.
    5. Pazienti di sesso maschile e femminile potenzialmente fertili che non sono disposti
    ad utilizzare metodi contraccettivi altamente efficaci.
    E.5 End points
    E.5.1Primary end point(s)
    Primary safety end point:
    Incidence and severity of treatment-emergent adverse events (TEAEs) through the end of the Treatment Period 1 at week 28 Co-primary efficacy endpoints:
    - Time-weighted average (standardized area under the curve [AUC]) percent change from baseline in total lesion activity by 18F-NaF PET over 28 weeks
    - Percent change from baseline in the total volume of HO lesions as assessed by CT at week 28
    Endpoint di sicurezza primario:
    Incidenza e gravità di eventi avversi emergenti dal trattamento (‘treatment-emergent adverse events’, TEAE) fino alla fine del Periodo di Trattamento 1 alla settimana 28
    Endpoint di efficacia co-primari:
    - Percentuale di variazione della media ponderata dal tempo (area standardizzata sottostante la curva [AUC]) dal basale nell’attività totale delle lesioni mediante PET 18F-NaF nel corso di 28 settimane
    - Percentuale di variazione dal basale nel volume totale di lesioni HO valutato mediante TC alla settimana 28
    E.5.1.1Timepoint(s) of evaluation of this end point
    Treatment Period 1 at week 28
    Periodo di trattamento 1 a 28 settimane
    E.5.2Secondary end point(s)
    The key efficacy secondary endpoints:
    - Percent change from baseline in 18F-NaF SUV max of individual active HO site(s) by PET at week 8
    - Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28
    - Change from baseline in number of HO lesions detectable by CT at 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
    Other secondary endpoints are:
    - Change from baseline in the volume of individual HO lesions as assessed by CT at week 28
    - Incidence and severity of TEAEs through the end of study
    - Time weighted average (standardized AUC) percent change from baseline in biomarkers of bone formation levels in serum over time, 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
    - 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
    Principali endpoint secondari di efficacia:
    - Percentuale di variazione dal basale nell’SUVmax di 18F-NaF del sito/dei siti HO individuale/i attivo/i mediante PET alla settimana 8
    - Variazione dal basale nel numero di lesioni HO valutata mediante PET 18F-NaF alla settimana 28
    - Variazione dal basale nel numero di lesioni HO rilevabile mediante TC alla settimana 28
    - Media ponderata dal tempo (AUC standardizzato) della variazione dal basale nel dolore quotidiano dovuto a FOP, misurato utilizzando l’NRS quotidiano nel corso di 28 settimane
    Altri endpoint secondari sono i seguenti:
    - Variazione dal basale nel volume di lesioni individuali HO valutata mediante TC alla settimana 28
    - Incidenza e gravità di TEAE fino alla fine dello studio
    - Percentuale di variazione della media ponderata dal tempo (AUC standardizzato) dal
    basale nei biomarcatori dei livelli di formazione ossea nel siero nel corso del tempo, compreso propeptide N-terminale del collagene di tipo 1 (P1NP), fosfatasi alcalina osso-specifica (BSAP), e fosfatasi alcalina totale (tAP)
    - Concentrazione di attivina A totale nel siero nel corso del tempo
    - Profilo PK di REGN2477, valutata come concentrazioni di REGN2477 nel siero nel corso del tempo
    - Immunogenicità di REGN2477, determinata dall'incidenza, titolo ed impatto clinico di ADA emergenti dal trattamento per REGN2477 nel corso tempo
    E.5.2.1Timepoint(s) of evaluation of this end point
    Through study (week 8, 28 and 56) and end of study, week 76.
    Nel corso dello studio (settimana 8, 28 e 56) e fine dello studio, settimana 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
    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. 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. trial design description
    2 periodi di trattamento: 1 periodo randomizzato in doppio cieco + 1 periodo con REGN2477 in aperto
    2 treatment periods: 1 period randomized to double blind + 1 open period with REGN2477
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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.
    La fine di questo studio è definita come l'utlima visita dell'ultimo paziente
    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.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state4
    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
    trattamento standard
    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 Decision2017-12-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-27
    P. End of Trial
    P.End of Trial StatusCompleted
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