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    Summary
    EudraCT Number:2020-002858-24
    Sponsor's Protocol Code Number:D-CA-60130-452
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-07-27
    Trial 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 ConcernedSpain - AEMPS
    A.2EudraCT number2020-002858-24
    A.3Full title of the trial
    A Phase 2, two-part, placebo-controlled, parallel-group, double-blind study to assess the efficacy and safety of 2 dosage regimens of oral IPN60130 for the treatment of fibrodysplasia ossificans progressiva in male and female participants 5 years of age and older
    Estudio de fase II, de dos partes, con doble enmascaramiento y grupos paralelos, controlado con placebo, para evaluar la eficacia y la seguridad de 2 pautas posológicas de IPN60130 por vía oral para tratar la fibrodisplasia osificante progresiva en participantes de ambos sexos a partir de 5 años de edad.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study assessing the efficacy and safety of an investigational drug called IPN60130 for the treatment of fibrodysplasia ossificans progressiva in participants aged 5 years of age and older
    Un estudio que evalúa la eficacia y la seguridad de un fármaco en investigación llamado IPN60130 para el tratamiento de la fibrodisplasia osificante progresiva en participantes a partir de 5 años de edad
    A.4.1Sponsor's protocol code numberD-CA-60130-452
    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 SponsorClementia Pharmaceuticals Inc, an Ipsen Company
    B.1.3.4CountryCanada
    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 supportClementia Pharmaceuticals, an Ipsen Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClementia Pharmaceuticals Inc, an Ipsen Company
    B.5.2Functional name of contact pointEric SOLIMAN
    B.5.3 Address:
    B.5.3.1Street Address1000 de la Gauchetière West, Suite 1200
    B.5.3.2Town/ cityMontreal, Quebec
    B.5.3.3Post codeH3B 4W5
    B.5.3.4CountryCanada
    B.5.4Telephone number+1514940-3614
    B.5.6E-maileric.soliman@ipsen.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/3/20/2352
    D.3 Description of the IMP
    D.3.1Product nameIPN60130 10 mg capsules
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot yet available
    D.3.9.2Current sponsor codeIPN60130
    D.3.9.3Other descriptive name(R)-tetrahydrofuran-3-yl 4-(6-(5-(4-ethoxy-1-isopropylpiperidin-4- yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate sesquisuccinate
    D.3.9.4EV Substance CodeSUB206522
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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.IMP: 2
    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/3/20/2352
    D.3 Description of the IMP
    D.3.1Product nameIPN60130 50 mg capsules
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet available
    D.3.9.2Current sponsor codeIPN60130
    D.3.9.3Other descriptive name(R)-tetrahydrofuran-3-yl 4-(6-(5-(4-ethoxy-1-isopropylpiperidin-4- yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate sesquisuccinate
    D.3.9.4EV Substance CodeSUB206522
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral 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 osificante progresiva (FOP)
    E.1.1.1Medical condition in easily understood language
    fibrodysplasia ossificans progressiva
    fibrodisplasia osificante progresiva
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    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
    • Evaluate the efficacy of IPN60130 monotherapy compared with placebo recipients in inhibiting new heterotopic ossification (HO) volume in adult and paediatric participants with FOP as assessed by low-dose whole body computed tomography (WBCT) (excluding the head)
    • Evaluate the safety of IPN60130 in adult and paediatric participants with FOP
    • Evaluar la eficacia de la monoterapia con IPN60130, en comparación con los pacientes que reciben el placebo, a la hora de inhibir el volumen de OH nuevo en participantes adultos y pediátricos con FOP, medido con una WBCT de dosis baja (se excluye la cabeza)

    • Evaluar la seguridad de IPN60130 en los participantes adultos y pediátricos con FOP
    E.2.2Secondary objectives of the trial
    • Change in HO volume of new HO lesions over time by WBCT at M12.
    • Number of new HO lesions by WBCT at M12.
    • Rate and number of flare-up days at M12.
    • The number of body regions with new HO at M12.
    • To evaluate the effect of IPN60130 on pain intensity over time at M12.
    • Proportion of participants with new HO by WBCT
    • Change in HO volume over time as detected by WBCT.

    Pharmacokinetic
    • From the PK interim analysis, to evaluate the plasma pharmacokinetics
    of low and high doses of IPN60130.
    • From the overall study, to evaluate the plasma PK of low and high
    doses of IPN60130.

    Exposure-Response
    •To evaluate the exposure-response relationship, if feasible.
    •Cambios de volumen de OH en lesiones nuevas de OH a lo largo del tiempo, medidos por WBTC en el M12
    •Número de lesiones nuevas de OH determinadas por WBTC en el M12
    •Tasa y número de días con brotes hasta el M12
    •El número de zonas del cuerpo con OH nueva en el M12
    •Evaluar el efecto de IPN60130 en la intensidad del dolor a lo largo del tiempo en el M12
    •Proporción de participantes con OH nueva determinada por WBCT
    •Cambios en el volumen de OH a lo largo del tiempo, medidos por WBTC

    Farmacocinética
    •A partir del análisis intermedio de la FC, evaluar la farmacocinética plasmática de dosis altas y bajas de IPN60130
    •A partir del estudio global, evaluar la FC plasmática de dosis altas y bajas de IPN60130


    Exposición y respuesta
    •Evaluar la relación entre la exposición y la respuesta, si es posible
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Fluorine-18-labelled natrium fluoride ([18F]NaF) Positron Emission Tomography-Computed Tomography PET-CT Substudy:

    Objectives:
    • Change from baseline in HO lesion activity as detected by [18F]NaF PET-CT
    • Change from baseline in number of HO lesion by [18F]NaF PET-CT
    • Correlation of HO lesion activity by [18F]NaF PET-CT in new HO lesions by WBCT

    Inclusion criterion (Age):
    • Participants must be at least 15 years of age at the time of signing the informed participant/parent consent for the main study and, for participants who are minors, age-appropriate assent.
    Subestudio de tomografía computarizada-tomografía por emisión de positrones (TC-TEP) con fluoruro de sodio marcado con flúor-18 ([18F]NaF):
    Objetivos:
    • Cambio desde el inicio en la actividad de las lesiones OH según lo detectado mediante TC-TEP con [18F]NaF
    • Cambio desde el inicio en el número de lesiones OH según TC-TEP con [18F]NaF
    • Correlación de la actividad de las lesiones OH, según TC-TEP con [18F]NaF, en las nuevas lesiones OH según TC de cuerpo entero
    Criterio de inclusión (edad):
    • Los participantes deben tener al menos 15 años de edad en el momento de firmar el consentimiento informado del participante/progenitor para el estudio principal y, en aquellos participantes que son menores de edad, el asentimiento adecuado a la edad.
    E.3Principal inclusion criteria
    1. Participants must be at least 5 years of age, to be confirmed (entry for younger paediatric participants <15 years of age will only be once safety in adult and older paediatric participants ≥15 years of age has been established) at the time of signing the informed participant/parent consent and, for participants who are minors, age-appropriate assent.
    Age – [18F]NaF PET-CT Imaging Substudy
    2. Participants must be at least 15 years of age at the time of signing the informed participant/parent consent for the main study and, for participants who are minors, age-appropriate assent.
    3. Participants must be clinically diagnosed with FOP, with the R206H ACVR1 mutation or other FOP variants associated with progressive HO.
    4. Participants must have at least one flare-up in the preceding year of the screening visit.
    5. Participants who have participated in a prior clinical study using another investigational product for the treatment of FOP may be enrolled after a washout of at least 5 half-lives of the other investigational product. Participants with prior treatment such as, but not limited to, imatinib, isotretinoin, or palovarotene may be enrolled 30 days after discontinuation or after washout of at least 5 half-lives, whichever is longer.
    6. Participants must be able to perform pulmonary function tests adequately and reliably.
    7. Participants must be able to have an adequate echocardiography assessment at screening for evaluation of left ventricular structure and function as defined by the protocol.
    8. Participants must be accessible for treatment and follow-up and be able to undergo all study procedures. Participants living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all on-site follow-up visits. Participants must be able to undergo low-dose WBCT (excluding head) without sedation.
    9. Body weight ≥10 kg.
    10.Male and/or female participants:
    Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    a. Male participants:
    Male participants of child bearing potential must agree to remain abstinent from heterosexual sex during treatment and for 90 days after treatment or, if sexually active, to use two effective methods of birth control, one of which must be highly effective during and for 90 days after treatment. The agreement to remain abstinent or use two effective methods (one of which must be highly effective) of birth control will be clearly defined in the informed consent; the participant or legally authorized representatives (e.g. parents, caregivers, or legal guardians) must sign this specific section.
    b. Female participants:
    Females of childbearing potential (defined in Appendix 10.5.1) must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of study drug. FOCBP participants must agree to remain abstinent from heterosexual sex during treatment and for 1 month after treatment or, if sexually active, to use two effective methods of birth control, one of which must be highly effective during and for 1 month after treatment. Additionally, sexually active FOCBP participants in a heterosexual relationship must already be using two effective methods of birth control (one of which must be highly effective) 1 month before treatment is to start.
    Specific risks of study drug use during pregnancy as well as the agreement to remain abstinent or use two effective methods of birth control (one of which must be highly effective) will be clearly defined in the informed consent; the participant or legally authorized representatives (e.g. parents, caregivers, or legal guardians) must sign this specific section.
    11. Participants must be capable of giving written, signed, and dated informed participant/parent consent; and for participants who are minors, age-appropriate assent (performed according to local regulations).
    1. Los participantes deben tener al menos 5 años de edad, que se confirmará (únicamente se incluirá a los participantes <15 años de edad cuando se haya establecido la seguridad en los participantes adultos y jóvenes ≥15 años de edad) en el momento de firmar el consentimiento informado del participante/progenitor y, en aquellos participantes que son menores de edad, el asentimiento adecuado a la edad.
    Edad – subestudio de imágenes mediante TC-TEP con [18F]NaF
    2. Los participantes deben tener al menos 15 años de edad en el momento de firmar el consentimiento informado del participante/progenitor para el estudio principal y, en aquellos participantes que son menores de edad, el asentimiento adecuado a la edad.
    3. Los participantes deben haber recibido un diagnóstico clínico de FOP, con mutación R206H en ACVR1 u otras variantes de la FOP asociadas a OH progresiva.
    4. Los participantes deben haber padecido al menos un brote durante el año anterior a la visita de selección.
    5. Los participantes que hayan participado en un estudio clínico anterior con otro producto en investigación para el tratamiento de la FOP pueden incluirse en el estudio tras un periodo de reposo farmacológico de al menos 5 semividas del otro producto en investigación. Los participantes que hayan recibido un tratamiento anterior como, por ejemplo, imatinib, isotretinoína o palovaroteno, pueden incluirse 30 días después de la interrupción o tras un periodo de reposo farmacológico de al menos 5 semividas, lo que sea mayor.
    6. Los participantes deben ser capaces de realizar las pruebas funcionales pulmonares de forma adecuada y fiable.
    7. Los participantes deben ser capaces de someterse a una evaluación ecocardiográfica adecuada en la selección para evaluar la función y estructura ventricular izquierda, según lo definido en el protocolo.
    8. Los participantes deben encontrarse disponibles para recibir el tratamiento y realizar el seguimiento y ser capaces de someterse a todos los procedimientos del estudio. Los participantes que vivan en lugares distantes del centro de investigación deben ser capaces de desplazarse hasta el centro, y estar dispuestos a hacerlo, para realizar la visita inicial y todas las visitas de seguimiento que tengan lugar en el centro. Los participantes deben ser capaces de someterse a una TC de cuerpo entero (excluyendo la cabeza) con dosis bajas sin sedación.
    9. Peso corporal ≥10 kg.
    10. Participantes de ambos sexos: El uso de métodos anticonceptivos por parte de hombres y mujeres participantes debe estar en consonancia con las normativas locales relativas a los métodos anticonceptivos para los participantes en estudios clínicos.
    a. Hombres participantes: Los hombres participantes que puedan engendrar hijos deben acceder a abstenerse del sexo heterosexual durante el tratamiento y hasta 90 días después del tratamiento o, si son sexualmente activos, utilizar dos métodos anticonceptivos efectivos, uno de los cuales debe ser muy efectivo, durante el tratamiento y hasta 90 días después. La aceptación de mantener la abstinencia o utilizar dos métodos anticonceptivos efectivos (uno de los cuales debe ser muy efectivo) quedará claramente definida en el consentimiento informado; el participante o los representantes legales (p. ej., progenitores, cuidadores o tutores legales) deben firmar este apartado concreto.
    b. Mujeres participantes: Las mujeres que puedan quedarse embarazadas (según lo definido en el apéndice 10.5.1) deben obtener un resultado negativo en una prueba de embarazo en sangre o en orina (de una sensibilidad mínima de 50 mUI/ml) antes de la administración del fármaco del estudio. Las mujeres participantes que puedan quedarse embarazadas deben acceder a abstenerse del sexo heterosexual durante el tratamiento y hasta 1 mes después del tratamiento o, si son sexualmente activas, utilizar dos métodos anticonceptivos efectivos, uno de los cuales debe ser muy efectivo, durante el tratamiento y hasta 1 mes después. De forma adicional, las participantes que puedan quedarse embarazadas sexualmente activas en una relación heterosexual deben haber comenzado a utilizar dos métodos anticonceptivos efectivos (uno de los cuales debe ser muy efectivo) 1 mes antes de que empiece el tratamiento.
    Los riesgos específicos del uso del fármaco del estudio durante el embarazo, así como la aceptación de mantener la abstinencia o utilizar dos métodos anticonceptivos efectivos (uno de los cuales debe ser muy efectivo) quedarán claramente definidos en el consentimiento informado; la participante o los representantes legales (p. ej., progenitores, cuidadores o tutores legales) deben firmar este apartado concreto.
    11. Los participantes deben ser capaces de proporcionar el consentimiento informado del participante/progenitor por escrito, firmado y fechado y, en el caso de los participantes menores de edad, el asentimiento adecuado a la edad (llevado a cabo conforme a las normativas locales).
    E.4Principal exclusion criteria
    Participants are excluded from the study if any of the following criteria apply:

    Medical Conditions
    1. Participants with complete heart block and left bundle branch block on screening electrocardiogram.
    2. Participants with screening echocardiograph showing septal or left ventricular free wall thickness >12 mm for adult participants or a z-score >3 compared with population norms for children and adolescent participants or LVEF <50%.
    3. Participants with severe mitral or tricuspid regurgitation on echocardiograph at screening.
    4. Participants with significant underlying lung disease requiring supplementary oxygen or forced vital capacity <35% of predicted at screening.
    5. Participants with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease as judged by the investigator.
    6. Participants with severe hepatic impairment.

    Prior/Concomitant Therapy
    7. Concomitant medications that are strong inhibitors (including grapefruit juice) or inducers (including St John’s Wort) of cytochrome P450 (CYP) 3A4 activity and strong inhibitors or inducers of CYP2C19 activity; or kinase inhibitors such as imatinib.
    8. Prior use in the past year and concomitant use of bisphosphonates for participants in the PET-CT substudy.

    Prior/Concurrent Clinical Study Experience
    9. Concurrent participation in another interventional clinical study, or a noninterventional study with radiographic measures or invasive procedures (e.g. collection of blood or tissue samples).

    Other Exclusions
    1. Amylase or lipase >2× the upper limit of normal (ULN) or with a history of chronic pancreatitis.
    2. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5×ULN.
    3. Participants with hematologic abnormalities:
    • Hgb<10g/dL
    • Platelets<75,000/mm3
    • WBC<2000/mm3
    • Participants with coagulation test (prothrombin time [PT]/ international normalised ratio [INR], and activated partial thromboplastin time [aPTT]) measurements outside of the normal range at screening.
    4. Female participants who are breastfeeding.
    5. Any reason that, in the opinion of the investigator, would lead to the inability of the participant and/or family to comply with the protocol
    Individuals with disqualifying laboratory abnormalities may be rescreened once within the screening window. Rescreening may be repeated more than once if the results are atypical for the participant based on prior results from preceding year.
    Se excluirá del estudio a los participantes que cumplan cualquiera de los criterios siguientes:
    Afecciones médicas
    1. Participantes con bloqueo auriculoventricular completo y bloqueo de la rama izquierda del haz de His en el electrocardiograma de la selección.
    2. Participantes con un ecocardiograma en la selección que muestre un grosor >12 mm de la pared libre del ventrículo izquierdo o el tabique en participantes adultos, o una puntuación z >3 comparado con las normas poblaciones en los participantes niños y adolescentes o FEVI < 50%.
    3. Participantes con insuficiencia tricuspídea o mitral grave en el ecocardiograma de la selección.
    4. Participantes con una enfermedad pulmonar subyacente significativa que precise oxigenoterapia o una capacidad vital forzada <35 % de la prevista, en la selección.
    5. Participantes con una enfermedad no controlada cardiovascular, hepática, pulmonar, gastrointestinal, endocrina, metabólica, oftálmica, inmunitaria, psiquiátrica o de otro tipo que sea significativa a juicio del investigador.
    6. Participantes con insuficiencia hepática grave.
    Tratamientos previos y concomitantes
    7. Medicamentos concomitantes que sean potentes inhibidores (incluido el zumo de pomelo) o inductores (incluido el hipérico) de la actividad del citocromo P450 (CYP) 3A4, así como potentes inhibidores o inductores de la actividad de CYP2C19, o inhibidores de cinasas tales como imatinib.
    8. Uso previo, durante el último año, y uso concomitante de bifosfonatos para los participantes del subestudio de TC-TEP.
    Experiencia previa o simultánea en estudios clínicos
    9. Participación simultánea en otro estudio clínico intervencionista o en un estudio observacional con mediciones radiográficas o procedimientos invasivos (p. ej., extracción de muestras de sangre o de tejido).
    Otros criterios de exclusión
    1. Amilasa o lipasa >2 veces el límite superior de la normalidad (LSN) o con antecedentes de pancreatitis crónica.
    2. Niveles altos de aspartato-aminotransferasa (AST) o alanina-aminotransferasa (ALT) >2,5 veces el LSN.
    3. Participantes con alteraciones hemáticas:
    • Hb <10 g/dl
    • Plaquetas <75 000/mm3
    • Leucocitos <2000/mm3
    • Participantes con resultados en una prueba de coagulación (tiempo de protrombina [TP]/índice internacional normalizado [IIN] y tiempo de tromboplastina parcial activada [TTPa]) que se encuentren fuera del intervalo normal en la selección.
    4. Mujeres participantes que estén en periodo de lactancia.
    5. Cualquier razón que, a juicio del investigador, motivaría que el participante o su familia fueran incapaces de cumplir el protocolo
    A los pacientes con anomalías analíticas que les impidan cumplir los requisitos de inclusión se les puede volver a realizar la selección una vez más, dentro del intervalo de selección permitido. Esta nueva selección se puede volver a repetir más de una vez si los resultados son atípicos para el participante en comparación con los resultados obtenidos en el año anterior.
    E.5 End points
    E.5.1Primary end point(s)
    • The annualized change from baseline in HO volume as assessed by low-dose WBCT (excluding the head) in treated participants receiving IPN60130 through M12 compared with placebo
    • Adverse events / serious adverse events (AEs/SAE), cardiac outcomes (electrocardiogram (ECG), echocardiograms, cardiac biomarkers), vital signs, physical examinations, body weight and height, laboratory parameters, serum or urine pregnancy tests for females of childbearing potential (FOCBP), concomitant medications
    • Cambio anualizado desde el inicio hasta el mes 12 en el volumen de OH, según lo evaluado mediante TC de cuerpo entero (excluyendo la cabeza) con dosis bajas en participantes tratados que reciben IPN60130, en comparación con el placebo
    • Acontecimientos adversos/acontecimientos adversos graves (AA/AAG), resultados cardiacos (electrocardiograma [ECG], ecocardiogramas, biomarcadores cardiacos), constantes vitales, exploraciones físicas, estatura y peso corporal, parámetros analíticos, pruebas de embarazo en suero o en orina para las mujeres que pueden quedarse embarazadas, medicamentos concomitantes
    E.5.1.1Timepoint(s) of evaluation of this end point
    -WBCT: Pt A: D1, M6, M12; Pt B: M18, M24, ET
    -AEs/SAEs & Concomitant medications: Screening; at every participant
    contact
    -ECG & echocardiograms: Pt A: Screening, M1, M3, M6, M12; Pt B: M13,
    M15, M18, M24, ET
    -Cardiac biomarkers (inc. Troponin I (HS) & NT-proBNP): Pt A:
    Screening, D1, M1, M3, M6, M12; Pt B: M13, M15, M18, M24, ET
    -Vital Signs: Pt A: Screening, D1, M1, M3, M6, M12; Pt B: M13, M15,
    M18, M24, ET
    -Physical examination: Pt A: Screening, D1, M6, M12; Pt B: M18, M24,
    ET
    -Body weight & height: Pt A: Screening, D1, M1, M3, M6, M12; Pt B: M13,
    M15, M18, M24, ET
    -Laboratory parameters: Pt A: Screening, D1, M1, M3, M6, M12; Pt B:
    M13, M15, M18, M24, ET
    -Serum / urine pregnancy tests: every month

    Where
    Pt = Part
    D = Day
    M = Month
    ET = early termination
    • TC de cuerpo entero: pt.A: D1,M6,M12; pt. B: M18,M24,FA
    • AA/AAG y medicación concomitante: selección (Sel.); en cada contacto con el participante
    • ECG y ecocardiogramas: pt.A : Sel.,M1,M3,M6,M12; pt. B: M13,M15,M18,M24,FA
    • Biomarcadores cardiacos (inc. troponina I [ultrasensible] y NT-proBNP): pt.A: Sel., D1,M1,M3,M6,M12; pt. B: M13,M15,M18,M24,FA
    • Constantes vitales: pt.A: Sel., D1,M1,M3,M6,M12; pt. B: M13,M15,M18,M24, FA
    • Exploracion fisica; pt.A: Sel., D1, M6,M12; pt. B: ,M18,M24, FA
    • Estatura y peso corporal: pt.A: Sel., D1,M1,M3,M6, M12; pt. B: M13,M15,M18,M24,FA
    • Parámetros analíticos: pt.A: Sel., D1,M1,M3,M6,M12; pt. B: M13,M15,M18,M24, FA
    • Pruebas de embarazo en suero/orina: todos los meses
    Donde: pt=parte ; D=día ; M=mes; FA=finalización anticipada;
    E.5.2Secondary end point(s)
    • Change from baseline in HO volume of new HO lesions as detected by WBCT in participants receiving IPN60130 compared with placebo recipient at M12.
    • Change from baseline in number of HO lesions by WBCT in participants receiving IPN60130 compared with placebo recipients at M12.
    • Flare-up rate and number of flare-up days in participants receiving INP60130 compared with placebo at M12
    • The number of body regions with new HO in participants treated with IPN60130 compared with placebo recipients at M12
    • Change from baseline in pain intensity over time assessed using the NRS in participants ≥13 years of age and the Wong Baker FPS in participants <13 years of age for participants receiving IPN60130 compared with placebo recipients at M12
    • The proportion of participants with any new HO in participants receiving IPN60130 compared with placebo recipients through M24.
    • Change from baseline in HO volume as detected by WBCT in participants receiving IPN60130 compared with placebo recipients and with participants receiving the standard of care in the NHS through M24.

    Pharmacokinetic
    •Pharmacokinetic parameters by population PK modelling using all
    sparse samples collected through Month 1
    • Pharmacokinetic parameters by population PK modelling using all
    sparse samples collected during the study

    Exposure-Response
    • Exposure-response analysis by modelling using relevant efficacy and safety parameters
    • Cambio desde el inicio hasta el mes 12 en el volumen de OH de las lesiones OH nuevas, según se detecte en una TC de cuerpo entero, en los participantes que reciben IPN60130 comparado con los que reciben el placebo
    • Cambio desde el inicio hasta el mes 12 en el número de lesiones OH según una TC de cuerpo entero en los participantes que reciben IPN60130 comparado con los que reciben el placebo
    • Tasa de brotes y número de días con brotes en el mes 12 en los participantes que reciben INP60130 comparado con los que reciben el placebo
    • Número de regiones corporales con OH nueva en el mes 12 en los participantes tratados con IPN60130 comparado con los que reciben el placebo
    • Cambio desde el inicio hasta el mes 12 en la intensidad del dolor a lo largo del tiempo, evaluado con la NRS en los participantes ≥13 años de edad y con la FPS de Wong-Baker en los participantes <13 años de edad, en los participantes que reciben IPN60130 comparado con los que reciben el placebo
    • Proporción de participantes con alguna OH nueva hasta el mes 24 en los participantes que reciben IPN60130 comparado con los que reciben el placebo
    • Cambio desde el inicio hasta el mes 24 en el volumen de OH, según se detecte en una TC de cuerpo entero, en los participantes que reciben IPN60130 comparado con los que reciben el placebo y con los participantes que reciben el tratamiento de referencia en el Servicio Nacional de Salud.

    Farmacocinética
    •Parámetros farmacocinéticos mediante la elaboración de modelos FC de población utilizando todas las muestras dispersas obtenidas hasta el mes 1
    •Parámetros farmacocinéticos mediante la elaboración de modelos FC de población utilizando todas las muestras dispersas obtenidas durante el estudio

    Exposición-respuesta
    • Análisis de exposición-respuesta mediante modelos en los que se utilizan parámetros de eficacia y seguridad pertinentes
    E.5.2.1Timepoint(s) of evaluation of this end point
    As per E.5.1.1 and additionally;

    NRS and FPS: Pt A: D1, M1 - M12 ; Pt B: M13 - M24

    PK: Pt A: D1, M1, M3, M6, M12; Pt B: M18, M24
    Según E.5.1.1 y de forma adicional;
    NRS y FPS: pt. A: D1, M1-M12; pt. B: M13- M24
    FC: pt A: D1, M1, M3, M6, M12; pt B: M18, M24
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 No
    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 trial3
    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 EEA14
    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
    Argentina
    Australia
    Brazil
    Canada
    China
    Colombia
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Russian Federation
    Spain
    Sweden
    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
    LVLS
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days19
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 41
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 18
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 23
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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 35
    F.4.2.2In the whole clinical trial 90
    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)
    None
    Ninguno
    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 Decision2021-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-07
    P. End of Trial
    P.End of Trial StatusOngoing
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