E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fibrodysplasia Ossificans Progressiva (FOP) |
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E.1.1.1 | Medical condition in easily understood language |
Genetic condition which causes abnormal formation of bone at abnormal locations such as in the muscles, tendons and ligaments. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
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 |
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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 |
The primary safety objective of the study is to assess the safety and tolerability of REGN2477 in male and female patients with fibrodysplasia ossificans progressiva (FOP). The primary efficacy objective of the study is to assess the effect of REGN2477 versus placebo on the change from baseline in heterotopic ossification (HO) in patients with FOP, as determined by 18-NaF uptake in HO lesions by positron emission tomography (PET) and in total volume of HO lesions by computed tomography (CT). |
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E.2.2 | Secondary objectives of the trial |
- To compare the effect of REGN2477 versus placebo on pain due to FOP, as measured by the area under the curve for pain based on daily numeric rating scale scores - To assess the effect of REGN2477 versus placebo on the change from baseline in: - HO, as determined by the number of new HO lesions identified by 18F-NaF PET or by CT - 18F-NaF standardized uptake value maximum of individual active HO site(s) by PET - biochemical markers of bone formation - To assess the effect of REGN2477 between wk28 and wk56, on the number, activity, and volume of HO lesions identified by 18F-NaF PET or by CT in patients who switch from placebo to REGN2477 at wk 28 versus the same patients between baseline and wk28 - To characterize the concentrations of total activin A at baseline and over time following the first dose of study drug - To characterize the concentration-time profile (pharmacokinetics) of REGN2477 in patients with FOP - To assess the immunogenicity of REGN2477 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men and women 18 to 60 years of age at screening. 2. Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, episodic soft tissue swelling, and/or progressive heterotopic ossification). 3. Confirmation of FOP diagnosis with documentation of any ACVR1 mutation. 4. FOP disease activity within 1 year of screening visit. FOP disease activity is defined as pain, swelling, stiffness, and other signs and symptoms associated with FOP flare-ups; or worsening of joint function, or radiographic progression of heterotopic ossifications (increase in site or number of HO lesions) with/without being associated with flare-up episodes. 5. Willing and able to undergo PET and CT imaging procedures and other procedures as defined in this study. |
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E.4 | Principal exclusion criteria |
1. Significant concomitant illness or history of significant illness such as, but not limited to cardiac, renal, rheumatologic, neurologic, psychiatric, endocrine, metabolic or lymphatic disease, that in the opinion of the study investigator might confound the results of the study or pose additional risk to the patient by their participation in the study. 2. Use of bisphosphonate within 1 year of screening. 3. Concurrent participation in another interventional clinical study, or a non-interventional study with radiographic measures or invasive procedures (e.g. collection of blood or tissue samples). Participation in the FOP Connection Registry or other studies in which patients complete study questionnaires are allowed. 4. Pregnant or breastfeeding women. 5. Male and women of childbearing potential patients who are unwilling to practice highly effective contraception. 6. Previous history or diagnosis of cancer. 7. Patients who are on concomitant antiplatelet therapy (e.g., clopidogrel), anti-coagulants (e.g., warfarin, heparin, factor Xa inhibitor, or thrombin inhibitors) in the last 30 days or within 5 half-lives of the therapy, whichever is longer. Low dose (≤100 mg/day) acetylsalicylic acid (aspirin) is acceptable. 8. Patients with a history of severe, non-traumatic bleeding requiring transfusion or hospitalization for hemodynamic compromise 9. Patients with a known pre-existing medical history of a bleeding diathesis (e.g., hemophilia A, von Willebrand’s Factor deficiency, platelet count ≤20x10^9/L).
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary safety end point: (Period 1 [week 28]): Incidence and severity of TEAEs through the end of the Period 1 at week 28
Primary efficacy endpoints: (Period 1 [week 28]): - Time-weighted average (standardized AUC) of the percent change from baseline in total lesion activity by 18F-NaF PET over 28 weeks (AHO - Baseline active HO analysis set) - Percent change from baseline in the total volume of HO lesions as assessed by CT at week 28 (AHO) - Time-weighted average (standardized area under the curve [AUC]) of the percent change from baseline in total lesion activity by 18F-NaF PETover 28 weeks (AHOC - Baseline active HO classic ACVR1[R206H] mutation analysis set) - Percent change from baseline in the total volume of HO lesions as assessed by CT at week 28 (AHOC)
Primary Efficacy Endpoint (Period 2 [Week 56]) The primary efficacy endpoint in Period 2 is: - Number of new HO lesions as assessed by CT at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Period 1 Baseline and end of Period 1 at week 28
Period 2 At week 56 |
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E.5.2 | Secondary end point(s) |
The key efficacy secondary endpoints (Period 1 [week28]):
- Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily NRS over 28 weeks (AHO) - Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily NRS over 28 weeks (AHOC)
Other secondary endpoints are (Period 1 week 28]): - Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by PET at week 8 (AHOC) - Percent change from baseline in 18F-NaF SUVmax of individual active HO site(s) by PET at week 8 (AHO) - Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 (AHOC) - Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 (AHO) - Change from baseline in number of HO lesions as assessed by 18F-NaF PET at week 28 (FAS - Full Analysis Set) - Change from baseline in number of HO lesions detectable by CT at week 28 (AHOC) - Change from baseline in number of HO lesions detectable by CT at week 28 (AHO) - Change from baseline in number of HO lesions detectable by CT at week 28 (FAS) - Time-weighted average (standardized AUC) of the change from baseline in daily pain due to FOP, as measured using the daily NRS over 28 weeks (FAS) - Time weighted average (standardized AUC) of the percent change from baseline in biomarkers of bone formation levels in serum over 28 weeks, including Total Procollagen Type 1 N-Terminal Propeptide (P1NP), bone specific alkaline phosphatase (BSAP), and total alkaline phosphatase (tAP) (FAS) -Incidence and severity of TEAEs
Other Secondary Endpoints Related to Clinical Pharmacology (Period 1, Period 2, Period 3) These secondary endpoints will be analyzed for all 3 study periods: Period 1 (week 28), Period 2 (week 56) and Period 3 (week 76). - Concentration of total activin A in serum over time - PK profile of REGN2477, assessed as concentrations of REGN2477 in serum over time - Immunogenicity of REGN2477, as determined by the incidence, titer, and clinical impact of treatment-emergent ADA to REGN2477 over time
Key Secondary Efficacy Endpoints (Period 2 [Week 56]) The key secondary efficacy endpoints for Period 2 analyses (in AHO) are: - Total volume of new HO lesions as assessed by CT at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO) - Number of new HO lesions as assessed by 18F-NaF PET at week 56 relative to week 28 (in patients switching from placebo to REGN2477 after the double-blind period) (AHO) - Total lesion activity by 18F-NaF PET in new HO lesions at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after double-blind period) (AHO) - Percent of patients with new HO lesions as assessed by CT at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO) - Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO)
Other Secondary Efficacy Endpoints (Period 2 [Week 56]) The other secondary efficacy variables for Period 2 analyses (all in AHO) are: - Number of new HO lesions as assessed by CT only at week 56 relative to week 28 scan (in patients switching from placebo to REGN2477 after the double-blind period) (AHO) - Percent of patients with investigator-assessed flare-ups in Period 2 (in patients switching from placebo to REGN2477 after the double-blind period) (AHO) - Percent of patients with flare-ups assessed by patient e-diary in Period 2 (in patients switching from placebo to REGN2477 after the double- blind period) (AHO) - Number of new HO lesions as assessed by CT at week 56 relative to baseline scan (in patients who continue REGN2477 after the double- blind period) (AHO) - Total volume in new HO lesions as assessed by CT at week 56 relative to baseline scan (in patients who continue REGN2477 after the double- blind period) (AHO) - Percent of patients with new HO lesions as assessed by CT at week 56 relative to baseline scan (in patients who continue REGN2477 after the double-blind period) (AHO) - Number of new HO lesions as assessed by 18F-NaF PET at week 56 relative to baseline scan (in patients who continue REGN2477 after the double-blind period) (AHO) - Total lesion activity in new HO lesions as assessed by 18F-NaF PET at week 56 relative to baseline scan (in patients who continue REGN2477 after the double-blind period) (AHO) - Percent of patients with new HO lesions as assessed by 18F-NaF PET at week 56 relative to baseline scan (in patients who continue REGN2477 after the double-blind period) (AHO)
A full list of the endpoints can be found in section 4.3.3 of the protocol
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Through study (week 8, 28 and 56) and end of study, week 76. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Canada |
Colombia |
France |
Italy |
Mexico |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
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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
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The end of study for this study is defined as the last visit of the last patient. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |