Fibrodysplasia ossificans progressiva FOP Stone man syndrome
Conditions
Interventions
Patients will be randomized to receive either AZD0530 100mg once daily or
matched place-bo, taken orally for the first 6 months, immediately followed by
an open-label extension in which all patients
Sponsors
Vrije Universiteit Medisch Centrum
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
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-like FOP phenotype by the documentation of an ACVR1R206H/+ or variant 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.
Exclusion criteria
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 9%; 8. Significant viral illness or active infections at screening or randomisation; Subjects should not have subacute or acute fevers of >101*F 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 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Objectives: To assess the effectivity and safety of treatment with AZD0530 on HO formation. The primary endpoint of the study is: Incidence and severity of treatment-emergent adverse events The objective change between the two arms in number of new heterotopic bone lesions measured by [18F]NaF PET/low-dose whole body computer tomography (CT) over the initial 6 month RCT; | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Objectives: To assess the safety and tolerability of AZD0530 and to further assess effectivity by functional and other radiological/nuclear imaging endpoints. The secondary endpoints are, summarised: 1. The incidence and severity of adverse events (AE) 2. Change in new heterotopic bone lesions over six and/or twelve months treatment during open label expension of AZD 0530 as measured by [18F] NaF PET/CT compared to the previous placebo arm RCT and compared to historical data as of Clemetia 3. Change in [18F] NaF PET, an imaging biomarker, that will be performed in addition to the whole body low-dose CT between time of enrolment and after 6 and 12 months treatment to measure the clinical efficacy of the compound AZD0530 on magnitude and localization of the osteogenic activity; 4. Change in functional, clinical and patient-reported outcome measures including: a. the cumulative analogue joint involvement scale for FOP (CAJIS), b. the quantitative detailed multi-joint assessment, c. the 36-item Short Form Health Survey (SF-36) and d. FOP Independent Activity of Daily Living (FOP I-ADL) will provide the effect of the compound AZD0530 on general physical function, flare-ups (as measured by swelling, pain and other features as reported in the International Clinical Counsel (ICC) on FOP (https://www.ifopa.org/international_clinical_council_on_foparticle), 5. 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) and selected miRNA*s. A detailed description of the endpoints can be found in section 8 of the protocol. | — |
Countries
Netherlands
Outcome results
None listed