Clinical trial NCT05039515: A Study to Assess the Effectiveness and Safety of 2 Dosage Regimens of Oral Fidrisertib (IPN60130) for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP).
Official title: A Phase 2 Study to Assess the Efficacy and Safety of 2 Dosage Regimens of Oral Fidrisertib (IPN60130) for the Treatment of Fibrodysplasia Ossificans Progressiva in Male and Female Paediatric and Adult Participants.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Fibrodysplasia Ossificans Progressiva
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
Collaborators: name: Ipsen
First posted: 2021-09-09
Enrollment: 113
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by the presence of bone in soft tissue where bone normally does not exist, known as Heterotopic Ossification (HO). It is often associated with painful, recurrent episodes of soft tissue swelling (flare-ups) that lead to abnormal stiffening and immobility (ankyloses) of major joints with cumulative and irreversible loss of movement and disability.

This study will evaluate the efficacy of 2 dosing regimens of IPN60130 in inhibiting new HO volume compared with placebo (a dummy treatment) in adult and paediatric participants with FOP. It will be assessed by a scan (provides internal images of the body) called low dose Whole Body Computed Tomography (WBCT), excluding head.

Adults and participants 5 years of age or older are also eligible for a sub study to evaluate HO lesions assessed by another type of scan, Fluorine-18-labelled natrium fluoride Positron Emission Tomography-Computed Tomography (\[18F\]NaF PET-CT ).


Eligibility criteria: Key Inclusion Criteria:

* 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.

  1. Washout period for palovarotene is 30 days
  2. 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)

Key Exclusion Criteria:

* 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

Primary outcomes:
measure: Annualized change in HO volume as assessed by low-dose WBCT (excluding the head) in treated participants receiving IPN60130 compared with placebo.
timeFrame: From baseline to 12 months
measure: Incidence of Adverse Events / Serious Adverse Events (AEs/SAE)
timeFrame: From baseline until the end of study (63 months)
measure: Change from baseline in clinically significant abnormal values in laboratory parameters (haematology, biochemistry, and urinalysis)
timeFrame: From baseline until the end of study (63 months)
measure: Change from baseline in physical examination findings
timeFrame: From baseline until the end of study (63 months)
measure: Change from baseline in clinically significant vital signs
timeFrame: From baseline until the end of study (63 months)
measure: Change from baseline in clinically significant Electrocardiogram (ECG) readings
timeFrame: From baseline until the end of study (63 months)
Secondary outcomes:
measure: Change in HO volume of new HO lesions as detected by WBCT in participants receiving IPN60130 compared with placebo recipients
timeFrame: From baseline up to 12 months
measure: Change in number of HO lesions by WBCT in participants receiving IPN60130 compared with placebo recipients
timeFrame: From baseline up to 12 months
measure: Flare-up rate and number of flare-up days in participants receiving IPN60130 compared with placebo recipients
timeFrame: From baseline up to 12 months
measure: The number of body regions with new HO in participants receiving IPN60130 compared with placebo recipients
timeFrame: From baseline up to 12 months
measure: Change in pain intensity
timeFrame: From baseline up to 12 months
measure: The proportion of participants with any new HO in participants receiving IPN60130 compared with placebo recipients
timeFrame: From baseline up to 12 months
measure: 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 Natural history study (NHS)
timeFrame: From baseline up to 60 months
measure: Change from baseline in Cumulative Analogue Joint Involvement Scale for FOP (CAJIS) by treatment arm compared with placebo recipients and participants receiving the standard of care in the NHS across all available timepoints
timeFrame: From baseline up to 60 months
measure: Change in the FOP Physical Function Questionnaire (FOP-PFQ) by treatment arm compared with placebo recipients and participants receiving the standard of care in the NHS from baseline across all available timepoints
timeFrame: From baseline up to 60 months
measure: Pharmacokinetic (PK) parameter: Cmax of IPN60130
timeFrame: From baseline up to Month 24
measure: PK parameter: AUC of IPN60130
timeFrame: Every 6 months up to Month 24
measure: PK parameter: Ctrough of IPN60130
timeFrame: Every 6 months up to Month 24
measure: PK parameter: Cmin of IPN60130
timeFrame: Every 6 months up to Month 24
measure: Assessment of the exposure-response relationship
timeFrame: From baseline up to 60 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco (UCSF)
state: California
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: The Perelman School of Medicine - The University of Pennsylvania
state: Pennsylvania
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Sidney
country: Australia
facility: Royal North Shore Hospital - New South Wales
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Edmonton
country: Canada
facility: University of Alberta, Alberta Health Services (AHS)
city: Toronto
country: Canada
facility: University Health Network (UHN), Toronto General Hospital (TGH)
city: Beijing
country: China
facility: Children's Hospital Capital Institute of Pediatrics (CIP)
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Shanghai
country: China
facility: Shangai Children Medical Center
city: Shanghai
country: China
facility: Tongi University - Tongi Hospital
city: Paris
country: France
facility: Groupe Hospitalier Necker Enfants Malades
city: Paris
country: France
facility: Hopital Lariboisiere
city: Genoa
country: Italy
facility: Irccs Gaslini Institute
city: Nagoya
country: Japan
facility: Nagoya University Hospital
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
city: Ōbu
country: Japan
facility: Aichi Children's Health and Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Ciudad de mexico
country: Mexico
facility: Instituto Nacional De Rehabilitacion
city: Lisboa
country: Portugal
facility: Hospital Center Lisbon North, E.P.E- Hospital Santa Maria
city: Pozuelo De Alarcón
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Valencia
country: Spain
facility: Hospital Universitario Y Politecnico La Femerge
city: Umeå
country: Sweden
facility: Norrlands Universitetssjukhus
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References: