Efficacy and Safety Evaluation of Fidrisertib (IPN60130) in Fibrodysplasia Ossificans Progressiva: A Phase 2 Randomized Controlled Trial
- Trial ID
- 2024-511469-13-00
- Protocol
- D-CA-60130-452
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 study is to evaluate the **efficacy** of IPN60130 monotherapy compared with placebo in inhibiting new **heterotopic ossification** (HO) volume in adult and pediatric participants with **fibrodysplasia ossificans progressiva** (FOP), as assessed by low-dose whole body computed tomography (WBCT), excluding the head. This is clinically relevant as it aims to address the progression of HO, a debilitating condition in FOP patients, potentially improving their quality of life. Additionally, the study seeks to evaluate the safety of IPN60130 in this patient population.
Secondary objectives include: - Change in HO volume of new lesions over time by WBCT at 12 months (M12). - Number of new HO lesions by WBCT at M12. - Rate and number of flare-up days at M12. - Number of body regions with new HO at M12. - Evaluation of the effect of IPN60130 on pain intensity over time through M12. - Proportion of participants with new HO by WBCT. - Change in HO volume over time as detected by WBCT. - Evaluation of the effect of IPN60130 on range of motion (ROM) as evaluated by CAJIS over time. - Evaluation of the effect of IPN60130 on physical function as evaluated by FOP-PFQ over time. - Pharmacokinetic (PK) characterization of the IPN60130 profile in FOP patients. - Evaluation of the exposure-response relationship, if feasible.
Participants
The clinical trial involves a total of **67 participants** diagnosed with **Fibrodysplasia Ossificans Progressiva** (FOP), a rare genetic disorder characterized by progressive heterotopic ossification. The study population includes both male and female subjects, with an age range starting from 5 years old, encompassing both pediatric and adult participants. The selection criteria require participants to have a clinical diagnosis of FOP, with the R206H ACVR1 mutation or other variants associated with progressive heterotopic ossification. Participants must have demonstrated disease progression within the year preceding the screening visit. The trial includes individuals who have previously participated in other clinical studies for FOP treatment, provided they have completed a specified washout period. Participants are required to be capable of performing pulmonary function tests and undergoing echocardiography assessments. They must also be able to undergo low-dose whole-body computed tomography (excluding the head) without sedation. The trial population is selected based on their ability to provide informed consent and their accessibility for treatment and follow-up. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, as it involves minors and individuals with a rare and progressive condition.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of two dosage regimens of oral **fidrisertib** (IPN60130) in treating **fibrodysplasia ossificans progressiva** (FOP) in both pediatric and adult participants. This study is a Phase 2, randomized, double-blind, placebo-controlled trial. The trial is expected to run until August 31, 2029, with recruitment having commenced on December 1, 2021. Participants will be randomly assigned to receive either the investigational product or a placebo, with the primary objective being to assess the annualized change in heterotopic ossification (HO) volume using low-dose whole-body computed tomography (WBCT), excluding the head.
Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit, or screening, will confirm eligibility based on criteria such as age, clinical diagnosis of FOP, and disease progression. Participants must be at least 5 years old, with specific conditions for those under 15. Follow-up visits will occur at regular intervals to monitor safety and efficacy, including assessments of adverse events, cardiac outcomes, and other health parameters. The end-of-study visit will conclude the participant's involvement, summarizing the treatment's impact and any long-term effects.
Participant involvement is expected to last up to 60 months, with conditions for early termination including significant adverse events or non-compliance with study protocols. Participants must adhere to contraceptive guidelines and be capable of undergoing all study procedures, including pulmonary function tests and echocardiography. The trial aims to provide valuable insights into the treatment of FOP, with secondary endpoints exploring changes in HO lesions, flare-up rates, and pain intensity, among other factors.
Treatment
The clinical trial involves the administration of the experimental medication **IPN60130**, which is chemically identified as (R)-tetrahydrofuran-3-yl 4-(6-(5-(4-ethoxy-1-isopropylpiperidin-4-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate sesquisuccinate. This compound is provided in the form of a hard capsule and is intended for **oral use**. The trial includes two dosage regimens of IPN60130, with a maximum treatment period of 60 days. The specific dosage in milligrams is not detailed, as the maximum daily and total dose amounts are recorded as 0.00 mg, indicating that the precise dosing schedule will be determined based on the study protocol. The medication is developed by Clementia Pharmaceutical, Inc., and is designated as an orphan drug under the number EU/3/20/2352.
In addition to the experimental medication, the study employs a **placebo** control, which is also administered in the form of a capsule. The placebo capsule is designed to match the experimental medication in appearance but does not contain the active substance. The use of a placebo is critical for evaluating the efficacy and safety of IPN60130 by providing a baseline for comparison. The placebo is administered following the same oral route as the experimental drug, ensuring consistency in administration across study participants.
Participant compliance with the dosing regimen will be monitored throughout the trial to ensure adherence to the prescribed treatment schedule. This monitoring is essential for maintaining the integrity of the study data and for accurately assessing the outcomes related to the efficacy and safety of IPN60130 in treating fibrodysplasia ossificans progressiva. The trial aims to evaluate the ability of IPN60130 to inhibit new heterotopic ossification volume in both adult and pediatric participants, as assessed by low-dose whole-body computed tomography, excluding the head.
Efficacy
The efficacy of the investigational drug IPN60130 in the treatment of **fibrodysplasia ossificans progressiva** (FOP) will be assessed through a series of primary and secondary endpoints. The primary endpoint involves evaluating the annualized change from baseline in heterotopic ossification (HO) volume, as measured by low-dose whole body computed tomography (WBCT), excluding the head, in participants receiving IPN60130 compared to those receiving a placebo. This assessment will be conducted through month 12 (M12) of the trial.
Secondary endpoints include several measures: the change from baseline in the volume of new HO lesions detected by WBCT, the change in the number of HO lesions, and the rate and number of flare-up days, all compared between IPN60130 and placebo recipients at M12. Additionally, the number of body regions with new HO, changes in pain intensity assessed using the Numerical Rating Scale (NRS) for participants aged 13 and older, and the Wong Baker Faces Pain Scale (FPS) for those under 13, will be evaluated. The proportion of participants with any new HO and changes in the Cumulative Analogue Joint Involvement Scale (CAJIS) and the FOP-Physical Function Questionnaire (FOP-PFQ) will also be assessed. These efficacy parameters will be compared with placebo recipients and participants receiving the standard of care in the Natural History Study (NHS) across all available timepoints.
Pharmacokinetic parameters will be analyzed using population pharmacokinetic (PK) modeling with all sparse samples collected during the study. An exposure-response analysis will be conducted by modeling relevant efficacy and safety parameters. These assessments will provide comprehensive data on the efficacy of IPN60130 in inhibiting new HO formation and managing symptoms in FOP patients.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age – Main Study: 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: 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. by having at least one of the following: a. A self-reported flare-up with at least one major symptom of a flare-up, including swelling, pain (a new onset pain in a new site), decreased movement, stiffness, warmth, or redness b. A new palpable HO c. A new joint ankylosis d. An increase in Cumulative Analogue Joint Involvement Scale (CAJIS) score (if previous CAJIS assessment is available).
- 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 isotretinoin, garetosmab, or palovarotene may be enrolled 30 days after discontinuation or after washout of at least 5 half-lives, whichever is longer. a. Washout period for palovarotene is 30 days. b. Washout period for garetosmab is 4 months.
- Participants must be able to perform pulmonary function tests as defined in the protocol 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.
- 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.
- Male participants: Male participants of childbearing 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.
- 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.
- Informed Consent: 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).
Exclusion Criteria
- Participants with complete heart block and left bundle branch block on screening electrocardiogram.
- 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 left ventricular ejection fraction (LVEF)<50%.
- Participants with severe mitral or tricuspid regurgitation on echocardiograph 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 other significant disease as judged by the investigator.
- Participants with severe hepatic impairment.
- Concomitant medications that are strong inhibitors or inducers of cytochrome activity or kinase inhibitors.
- Prior use in the past year and concomitant use of bisphosphonates for participants in the PET-CT substudy.
- 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
- Female participants who are breastfeeding.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Dec 2021 | 3 |
 France | Not Recruiting | 01 Dec 2021 | 12 |
 Germany | Not Recruiting | 01 Dec 2021 | 1 |
 Italy | Not Recruiting | 01 Dec 2021 | 3 |
 The Netherlands | Not Recruiting | 01 Dec 2021 | — |
 Portugal | Not Recruiting | 01 Dec 2021 | 2 |
 Spain | Not Recruiting | 01 Dec 2021 | 7 |
 Sweden | Not Recruiting | 01 Dec 2021 | 2 |
| Netherlands | — | — | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo capsule | Placebo | N/A | — | — | — | N/A |