E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fibrodyplasia 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 |
To assess the effectivity of treatment with AZD0530 on HO formation |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of AZD0530 and to further assess effectivity by functional and other radiological/nuclear imaging endpoints |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female aged 18-65 with a clinical diagnosis of FOP at screening, including congenital malformation of the great toes and a history of spontaneous or injury-induced heterotopic ossification (HO), and have a confirmed classic FOP phenotype by the documentation of an ACVR1R206H/+ genomic sequence. a. Female participants who are women of child-bearing potential will be required to use a highly effective method of contraception as defined in section 5.4, in combination with a condom or diaphragm or cervical/vault caps with spermicidal foam/gel/film/suppository), from the time of enrolment until 4 weeks after final dose of study drug, unless practicing true sexual abstinence as defined in section 5.4. b. Male participants will be required to avoid procreative sexual intercourse with women of child-bearing potential from time of enrollment until 4 weeks after final dose of study drug through use of highly effective contraceptive methods. Male participants with a pregnant female partner will be required to use a condom for the duration of the study and for 4 weeks final dose of study drug. Male study participants will not be permitted to donate sperm for from the time of enrolment and until 4 weeks after final dose of study drug.
2. Participants will have to be able to understand and complete study and willing to sign informed consent (IC). They have to be able to attend and comply with the study visits and related activities, adhere to all study-related restrictions, and able to undergo pro-cedures such as PET and CT imaging.
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study: 1. Not willing to strictly adhere to the reproductive restrictions as defined in section 5.4 2. Women who are pregnant or breast-feeding (from the time 3 months prior to 4 weeksafter completion of participation in the study) 3. The presence of significant concomitant illness or history of significant illness such as cardiac, respiratory, renal, rheumatologic, neurologic, psychiatric, endocrine, metabolic, lymphatic disease, or infectious disease, that might confound the results of the study or pose additional risk to the patient; 4. Evidence of active bleeding (including hematuria or hematochezia,) acute or chronic gastrointestinal illness, inflammatory bowel disease, or mucositis 5. Malignant disease / cancer requiring treatment in the past 3 years (except some primary non melanoma skin cancer); 6. Severely impaired renal function defined as estimated glomerular filtration rate <30 mL/min/1.73 m2 calculated by the Modification of Diet in Renal Disease equation; 7. Showing uncontrolled diabetes mellitus with an HbA1C > 9%; 8. Significant viral illness or active infections at screening or randomisation; Subjects should not have subacute or acute fevers of >101F at time of screening or randomisation 9. Evidence of prolonged QT interval at screening or randomization (defined as QTc of >450 ms) .or known congenital long-QT syndrome. 10. Neutropenia defined as an absolute neutrophil count of <1,500/µl, 11. Thrombocytopenia defined as platelet count <100 × 103/µl, 12. Current blood clotting or bleeding disorder, or significantly abnormal INR-prothrombin time or partial thromboplastin time at screening, or clinically significant abnormalities in other screening laboratories, including significant abnormalities in vitamin B12 or thyroid function tests would be cause for exclusion.- 13. Abnormal liver function test results defined as aspartate aminotransferase (AST) >2.0 x upper limit of normal (ULN); alanine aminotransferase (ALT) >2.0 x ULN; and / or total bilirubin >1.5 x ULN; 14. Known allergy or intolerance to AZD0530 or any excipients used in the investigational medicinal products. 15. Simultaneous participation in another interventional clinical study or a non-interventional study with imaging measures or invasive procedures (eg. collection of blood or tissue samples); Participation in the FOP Connection Registry (www.fopconnection.org) or other studies in which patients completed study questionnaires are possible. 16. Treatment with another investigational or drug that might interfere with HO formation and the interpretation of the study drug in the last 90 days 17. Current use or history of regular alcohol consumption exceeding 14 units/week (6 glasses of 13.0% wine (175ml), 6 pints of 4.0% lager or ale (568ml), 5 pints of 4.5% cider (568 ml) or 14 glasses of 10.0% spirits (25ml)) within 6 months of screening. 18. Currently active metabolic bone disease, other than FOP.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. the objective change between the two arms measured in heterotopic bone volume measured by low-dose whole body CT over the initial 6 month RCT. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
All evaluation will be done after the study has been finished (18 months) |
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E.5.2 | Secondary end point(s) |
- Safety and tolerability assessments are the incidence and severity of adverse events (AE) during the RCT at the end of week 28. It will be an assessment of the net adverse clinical events with regard to safety, efficacy and Qol, but only if the components are well balanced, which will be assessed by the Data Safety Monitoring Board (DSMB) and at the end of the study in collaboration with the STOPFOP.team
- The change in heterotopic bone volume measured by low-dose whole body CT over six-months treatment during open-label extension of AZD0530 compared to the pre-vious placebo arm of the RCT
- The change in heterotopic bone volume measured by low-dose whole body CT over twelve-months treatment during open-label extension of AZD0530 compared to the historical data of Clementia (NCT02322255)
- Change in the volume of individual HO lesions measured by low-dose whole body CT over the initial 6 month RCT and in addition the change over twelve-months ther-apy during open-label extension of AZD0530 compared to the historical data of Clementia and compared to the 6 months placebo-arm.
- Change in number of HO lesions measured by CT over the initial 6 month RCT and in addition the change over twelve-months during open-label extension of AZD0530 compared to the historical data of Clementia and compared to the 6 months placebo-arm.
- In patients with at least 1 active leasion at baseline: Change (and AUC analysis) of le-sion activity by 18F-NaF PET over the initial 6 month RCT and over months 6-12 compared to the 6 months RCT of the placebo arm, including change from baseline in 18F-NaF Standard Uptake Volume (SUVmean or peak) of individual active HO site - In patients with at least 1 active leasion at baseline:Change in number of active lesion on 18F-NaF PET from baseline to 6, and 12 and 18 months - In patients with at least 1 active leasion at baseline: Change in number of lesions that are only 18F-NaF PET detectable at baseline to CT detectable lesions at 1218 months - Change and percent change from baseline in biomarkers of bone formation levels in serum over time, including Total Procollagen Type 1 N-Terminal Propeptide (P1NP), Alkaline Phosphatase (AP) fasting cross-linked C-terminal telopeptide of type I colla-gen (βCTX). Selected genetic markers for FOP activity
- Joint function assessment by physician at baseline and week 3, month 3,6,9,12,and18 by the cumulative analog joint involvement scale (CAJIS) and the quantitative detailed multi-joint assessment at baseline and month 6, 12 and 18.
- Patient-reported global health status the 36-item Short Form Health Survey (SF-36) at baseline and week 3, month 3,6,9,12,and 18 - FOP disease activity assessed by movement disabilities and quality of life using FOP Independent Activity of Daily Living (FOP I-ADL)
- Number of reported flare-ups by the patient (diary by email Castor questionnaire)
- Pharmacokinetic measurements: blood for determination of plasma concentrations of AZD0530 (pre-dose)on the day of the study visits at 6, 12 and 18months |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All evaluation will be done after the study has been finished (18 months) |
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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 | No |
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 |
Double blind RCT followed by open-label extension phase |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 |