Resumen

La fibrodisplasia osificante progresiva (FOP) es una enfermedad rara y gravemente discapacitante caracterizada por la formación de hueso en tejidos blandos donde normalmente no existe hueso, fenómeno conocido como osificación heterotópica (OH). Con frecuencia se asocia a episodios dolorosos y recurrentes de inflamación de tejidos blandos (brotes) que conducen a rigidez anormal e inmovilidad (anquilosis) de las articulaciones principales, con pérdida acumulativa e irreversible de la movilidad y discapacidad. Este estudio evaluará la eficacia de 2 regímenes de dosificación de IPN60130 en la inhibición del volumen de nueva OH en comparación con placebo (tratamiento simulado) en participantes adultos y pediátricos con FOP, mediante una exploración de tomografía computarizada de cuerpo entero de baja dosis (WBCT), excluyendo la cabeza. Los adultos y participantes de 5 años de edad o mayores también son elegibles para un subestudio destinado a evaluar las lesiones de OH mediante otro tipo de exploración: tomografía por emisión de positrones-tomografía computarizada con fluoruro de sodio marcado con flúor-18 ([18F]NaF PET-CT).

Descripción detallada

Nota sobre la fecha de finalización primaria y divulgación de resultados: La fecha de finalización primaria (DFP) refleja la fecha en que se completa la recopilación de datos para todos los desenlaces primarios, según lo definido en la norma final (42 CFR Parte 11). En este estudio, los desenlaces de seguridad se designan como primarios y se recopilan hasta el final del estudio. Por lo tanto, la DFP se ha actualizado para alinearse con esta definición. Los análisis intermedios procederán conforme al protocolo y al plan de análisis estadístico (SAP). Los resultados se divulgarán de acuerdo con los plazos reglamentarios aplicables.

Elegibilidad

Edad mínima: 5 YearsSexo: ALL

Criterios de inclusión

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.
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
Participants must be clinically diagnosed with FOP, with the R206H ACVR1 mutation or other FOP variants associated with progressive HO.
Participants must have disease progression in the preceding year of the screening visit.
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, garetosmab, or palovarotene may be enrolled 30 days after discontinuation or after washout of at least 5 half-lives, whichever is longer.
Washout period for palovarotene is 30 days
Washout period for garetosmab is 4 months
Participants must be able to perform pulmonary function tests adequately and reliably.
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.
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.
Body weight ≥10 kg.
Abstinent or using two highly effective forms of birth control. Females must also have a negative blood or urine pregnancy test prior to administration of study drug.
Participants must be capable of giving written, signed, and dated informed participant/parent consent; and for participants who are minors, age-appropriate assent and/or legal guardian consent (performed according to local regulations)

Criterios de exclusión

Participants with complete heart block and left bundle branch block on screening electrocardiogram.
Participants with screening echocardiography 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 left ventricular ejection fraction (LVEF) \<50%.
Participants with severe mitral or tricuspid regurgitation on echocardiography at screening.
Participants with significant underlying lung disease requiring supplementary oxygen or forced vital capacity \<35% of predicted at screening.
Participants with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or another significant disease as judged by the investigator.
Participants with severe hepatic impairment.
Concomitant medications that are strong inhibitors (including grapefruit juice) or inducers (including St John's Wort) of cytochrome P450 (CYP) 3A4 activity; or kinase inhibitors such as imatinib.
Prior use in the past year and concomitant use of bisphosphonates for participants in the PET-CT sub study.
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).
Amylase or lipase \>2× the upper limit of normal (ULN) or with a history of chronic pancreatitis.
Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>5×ULN.
Participants with hematologic abnormalities:
Hgb\<10g/dL
Platelets\<75,000/mm3
WBC\<2000/mm3

Estudio de fase 2 para evaluar la eficacia y seguridad de 2 regímenes de dosificación de fidrisertib oral (IPN60130) para el tratamiento de la fibrodisplasia osificante progresiva en participantes pediátricos y adultos, de sexo masculino y femenino.

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

IPN60130

IPN60130

Placebo

Ubicaciones

Hospital Italiano de Buenos Aires

Patrocinadores