| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| fibrodysplasia ossificans progressiva (FOP) |
|
| E.1.1.1 | Medical condition in easily understood language |
| fibrodysplasia ossificans progressiva |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068715 |
| E.1.2 | Term | Fibrodysplasia ossificans progressiva |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main 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
|
|
| E.2.2 | Secondary 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 through M12.
• Proportion of participants with new HO by WBCT.
• Change in HO volume over time as detected by WBCT.
• To evaluate the effect of IPN60130 on ROM as evaluated by CAJIS over time.
• To evaluate the effect of IPN60130 on physical function as evaluated by FOP-PFQ over time.
Pharmacokinetic (PK)
• To characterize the PK profile of IPN60130 in FOP patients.
Exposure-Response
• To evaluate the exposure-response relationship, if feasible.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full 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. |
|
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age – Main Study
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.
Type of Participant and Disease Characteristics
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, imatinib, 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.
Weight
9. Body weight ≥10 kg.
Sex
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 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.
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.
Informed Consent
11. 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). |
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| E.4 | Principal 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
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
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. |
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| E.5 End points |
| E.5.1 | Primary 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, eye exams, laboratory parameters, serum or urine pregnancy tests for females of childbearing potential (FOCBP), concomitant medications
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Vital signs, physical exam, ECG, echocardiograms, cardiac biomarkers: Scr; PtA [D1 (vital signs, physical exam & biomarkers), M1, M3, M6, M12]; PtB [M13, M15, M18, M24]; ET
• WBCT: PtA [D1, M6, M12]; PtB [M18, M24]; ET
• AEs/SAEs: Scr; every participant contact; ET; EOS
• Triplicate ECG: PtA [D1, M1]
• Body weight, height, lab parameters: Scr; PtA [D1, M1, M3, M6, M12]; PtB [M13, M15, M18, M24]; ET (exc. linear height)
• Serum / urine pregnancy tests: monthly (urine test: ET; EOS)
• Eye exam: PtA [D1, M12]; PtB [M24]; ET
In Part C:
Safety monitoring: every 6 months (exc. linear height & eye exam - performed yearly)
Efficacy & patient reported outcomes: every 6 months
Scr = Screening, Pt = Part, ET = early termination, EOS = end of study |
|
| E.5.2 | Secondary 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.
• Rate of flare-up (as confirmed by Investigator evaluation) 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 through M12.
• The proportion of participants with any new HO in participants receiving IPN60130 compared with placebo recipients through M12.
• 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.
• 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.
• 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
Pharmacokinetic
• 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
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
As per E.5.1.1 and additionally;
NRS and FPS: PtA [D1, M1-M12]; PtB [M13 - M24]; ET
PK: PtA [D1, M1, M6, M12]; PtB [M18, M24]
Flare-up assessment: at every participant contact.
Patient Global Impressions (PGI-CS, PGI-FS): PtA: D1, M12; PtB: M24; PtC: M36, M48, M60.
Patient Global Impressions (PGI-CC, PGI-FC): PtA: M12; PtB: M24; PtC: M36, M48, M60.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If 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 |
| Japan |
| Korea, Republic of |
| Mexico |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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