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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Clementia Pharmaceuticals Inc. An Ipsen Company

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

19 Oct 2021 → 27 Mar 2026

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ipsen Bioscience Inc.

External identifiers

EU CT number

2024-511469-13-00

EudraCT number

2020-002858-24

ClinicalTrials.gov

NCT05039515

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Dose response, Efficacy, Pharmacokinetic

1. 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).
2. Evaluate the safety of IPN60130 in adult and paediatric participants with FOP.

Secondary objectives 11

1. Change in HO volume of new HO lesions over time by WBCT at M12.
2. Number of new HO lesions by WBCT at M12.
3. Rate and number of flare-up days at M12.
4. The number of body regions with new HO at M12.
5. To evaluate the effect of IPN60130 on pain intensity over time through M12.
6. Proportion of participants with new HO by WBCT.
7. Change in HO volume over time as detected by WBCT.
8. To evaluate the effect of IPN60130 on ROM as evaluated by CAJIS over time.
9. To evaluate the effect of IPN60130 on physical function as evaluated by FOP-PFQ over time
10. Pharmacokinetic (PK): To characterize the PK profile of IPN60130 in FOP patients.
11. Exposure-Response: To evaluate the exposure-response relationship, if feasible.

Conditions and MedDRA coding

Fibrodysplasia Ossificans Progressiva

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003133-PIP01-21

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants. Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board. Supporting Information Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later. Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available at https://vivli.org/members/ourmembers/.”

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 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.
2. 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.
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 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).
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 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.
6. Participants must be able to perform pulmonary function tests as defined in the protocol 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.
11. 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.
12. 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.
13. 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 14

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 left ventricular ejection fraction (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.
7. Concomitant medications that are strong inhibitors or inducers of cytochrome activity or kinase inhibitors.
8. Prior use in the past year and concomitant use of bisphosphonates for participants in the PET-CT substudy.
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).
10. Amylase or lipase >2× the upper limit of normal (ULN) or with a history of chronic pancreatitis.
11. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5×ULN.
12. Participants with hematologic abnormalities: • Hgb<10g/dL • Platelets<75,000/mm3 • WBC<2000/mm3
13. Female participants who are breastfeeding.
14. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.
2. Adverse events / serious adverse events (AEs/SAE), outcomes, vital signs, physical examinations, body weight and height, laboratory parameters, serum or urine pregnancy tests for females of childbearing potential (FOCBP), concomitant medications.

Secondary endpoints 11

1. Change from baseline in HO volume of new HO lesions as detected by WBCT in participants receiving IPN60130 compared with placebo recipient at M12.
2. Change from baseline in number of HO lesions by WBCT in participants receiving IPN60130 compared with placebo recipients at M12
3. Rate of flare-up (as confirmed by Investigator evaluation) and number of flare-up days in participants receiving INP60130 compared with placebo at M12.
4. The number of body regions with new HO in participants treated with IPN60130 compared with placebo recipients at M12.
5. 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 through M12.
6. The proportion of participants with any new HO in participants receiving IPN60130 compared with placebo recipients through M12.
7. 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) in all available timepoints
8. Change from baseline in CAJIS by treatment arm compared with placebo recipients and participants receiving the standard of care in the NHS across all available timepoints.
9. Change from baseline in the FOP-PFQ by treatment arm compared with placebo recipients and participants receiving the standard of care in the NHS across all available timepoints.
10. Pharmacokinetic: Pharmacokinetic parameters by population PK modelling using all sparse samples collected during the study.
11. Exposure-Response: Exposure-response analysis by modelling using relevant efficacy and safety parameters

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Clementia Pharmaceuticals Inc. An Ipsen Company

Sponsor organisation

Clementia Pharmaceuticals Inc. An Ipsen Company

Address

1155 Metcalfe Street Suite 1500

City

Montreal

Postcode

H3B 2V6

Country

Canada

Scientific contact point

Organisation

Clementia Pharmaceuticals Inc. An Ipsen Company

Contact name

Ipsen Clinical Study Enquiries

Public contact point

Organisation

Clementia Pharmaceuticals Inc. An Ipsen Company

Contact name

Ipsen Clinical Study Enquiries

Third parties 8

Locations

8 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 113 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications