A Natural History Study of Fibrodysplasia Ossificans Progressiva (FOP)

A Natural History, Non-Interventional, Two-Part Study in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) that result in abnormal bone formation in muscles, tendons, and ligaments. Flare-ups begin early in life and may occur spontaneously or after soft tissue trauma, vaccinations, or influenza infections. Recurrent flare-ups progressively restrict movement by locking joints leading to cumulative loss of function and disability. This 3-year, non-interventional, two-part, natural history study is designed to gain insight into total body HO, FOP disease progression, the impact of FOP on subjects' physical functioning, and clinical features and biomarkers that may be useful in the diagnosis and monitoring of disease progression. This natural history study will also provide important information to inform the design of subsequent interventional trials.

Study Overview

• Status: Completed
• Conditions: Fibrodysplasia Ossificans Progressiva

Detailed Description

This is a multi-center, natural history, non-interventional, longitudinal study in subjects with classic FOP. A thorough baseline examination will be performed to determine the current status of disease in each subject. In Part A, two imaging modalities assessed total body HO at baseline, and the optimal method (low-dose whole body CT scan [excluding head]) will be employed in Part B for the balance of the study. Progression will be assessed at annual in-clinic visits (ie, at Months 12, 24, and 36) at which time the procedures conducted at the baseline visit will be repeated. In addition, site personnel will telephone subjects midway between the annual visits (ie, at Months 6, 18, and 30).

During the 36-month follow-up period, at least one new flare-up (with a maximum of one per year) will be carefully studied. An in-clinic visit will be performed within 14 days following the subject's identification of his/her flare-up. Additional visits at Day 42 and Day 84 (after the initial flare-up clinic visit) will be performed. An additional future visit may be scheduled after Day 84 at the discretion of the Principal Investigator (PI) for prolonged flare-ups. However, subjects with an eligible flare-up may elect to participate in an ongoing Clementia interventional study rather than continue in this natural history study.

• Study Type: Observational
• Enrollment (Actual): 114

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Italiano de Buenos Aires, Department of Pediatrics
• Australia
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)
• France
  • Paris, France
    • Hôpital Necker-Enfants Malades, Department of Genetics
• Italy
  • Genoa, Italy
    • Gaslini Institute, Unit of Rare Diseases, Department of Pediatrics
• United Kingdom
  • Middlesex
    • Stanmore, Middlesex, United Kingdom, HA7 4LP
      • The Royal National Orthopaedic Hospital, Brockley Hill
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco, Division of Endocrinology and Metabolism
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Center for FOP & Related Bone Disorders

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Individuals with classic FOP (R206H mutation).

Description

Inclusion Criteria:

- Subjects clinically diagnosed with classical FOP with documented R206H mutation or believed to carry the R206H mutation

Exclusion Criteria:

- Participation in an interventional clinical research study within the 4 weeks prior to enrollment

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
All Subjects; All subjects enrolled in the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in the total body burden of heterotopic ossification as assessed by the optimal imaging modality (low-dose whole body CT [excluding head]).	Month 36

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in physical function as assessed by range of motion.	Month 12, Month 24, and Month 36
Change from baseline in patient-reported use of assistive devices and adaptations.	Month 6, Month 12, Month 18, Month 24, Month 30, and Month 36
Change from baseline in a disease-specific patient-reported outcome measure (FOP-Physical Function Questionnaire [FOP-PFQ]).	Month 6, Month 12, Month 18, Month 24, Month 30, and Month 36
Change from baseline in a patient-reported measure of physical and mental health (PROMIS Global Health Scale).	Month 6, Month 12, Month 18, Month 24, Month 30, and Month 36
Change from baseline in biomarkers.	Month 12, Month 24, and Month 36
Flare-up progression as assessed by the change from baseline in heterotopic ossification at the flare-up site.	Flare-up initiation, Flare-up Days 42 and 84
Flare-up progression as assessed by the change from baseline in pain and swelling at the flare-up site.	Flare-up initiation, Flare-up Days 42 and 84
Flare-up progression as assessed by the change from baseline biomarkers.	Flare-up initiation, Flare-up Days 42 and 84
Flare-up progression as assessed by the change from baseline in physical function as assessed by range of motion.	Flare-up initiation, Flare-up Days 42 and 84
Flare-up progression as assessed by the change from baseline in a disease-specific patient-reported outcome measure (FOP-Physical Function Questionnaire [FOP-PFQ]).	Flare-up initiation, Flare-up Days 42 and 84
Flare-up progression as assessed by the change from baseline in a patient-reported outcome measure of physical and mental health (PROMIS Global Health Scale).	Flare-up initiation, Flare-up Days 42 and 84

Collaborators and Investigators

• Sponsor: Clementia Pharmaceuticals Inc.

Publications and helpful links

General Publications

• Connor JM, Evans DA. Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Joint Surg Br. 1982;64(1):76-83. doi: 10.1302/0301-620X.64B1.7068725.
• Zhang W, Zhang K, Song L, Pang J, Ma H, Shore EM, Kaplan FS, Wang P. The phenotype and genotype of fibrodysplasia ossificans progressiva in China: a report of 72 cases. Bone. 2013 Dec;57(2):386-91. doi: 10.1016/j.bone.2013.09.002. Epub 2013 Sep 17.
• Cohen RB, Hahn GV, Tabas JA, Peeper J, Levitz CL, Sando A, Sando N, Zasloff M, Kaplan FS. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am. 1993 Feb;75(2):215-9. doi: 10.2106/00004623-199302000-00008.
• Warner SE, Kaplan FS, Pignolo RJ, Smith SE, Hsiao EC, De Cunto C, Di Rocco M, Harnett K, Grogan D, Genant HK. Whole-body Computed Tomography Versus Dual Energy X-ray Absorptiometry for Assessing Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva. Calcif Tissue Int. 2021 Dec;109(6):615-625. doi: 10.1007/s00223-021-00877-6. Epub 2021 Jul 31.
• Kou S, De Cunto C, Baujat G, Wentworth KL, Grogan DR, Brown MA, Di Rocco M, Keen R, Al Mukaddam M, le Quan Sang KH, Masharani U, Kaplan FS, Pignolo RJ, Hsiao EC. Patients with ACVR1R206H mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of Fibrodysplasia Ossificans Progressiva. Orphanet J Rare Dis. 2020 Jul 29;15(1):193. doi: 10.1186/s13023-020-01465-x.
• Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone. 2020 Jan;130:115116. doi: 10.1016/j.bone.2019.115116. Epub 2019 Oct 23.
• Pignolo RJ, Baujat G, Brown MA, De Cunto C, Di Rocco M, Hsiao EC, Keen R, Al Mukaddam M, Sang KLQ, Wilson A, White B, Grogan DR, Kaplan FS. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis. 2019 May 3;14(1):98. doi: 10.1186/s13023-019-1068-7. Erratum In: Orphanet J Rare Dis. 2019 May 23;14(1):113.

Helpful Links

• website for the International FOP Association
• Click here for more information about this study: A Natural History, Non-Intervention Study in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2014
• Primary Completion (Actual): April 9, 2020
• Study Completion (Actual): April 9, 2020

Study Registration Dates

• First Submitted: December 8, 2014
• First Submitted That Met QC Criteria: December 19, 2014
• First Posted (Estimate): December 23, 2014

Study Record Updates

• Last Update Posted (Actual): June 26, 2020
• Last Update Submitted That Met QC Criteria: June 25, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Observational Study; Natural History Study; Non-interventional Study; Heterotopic ossification; Fibrodysplasia Ossificans Progressiva; Palovarotene; Clementia; Munchmeyer's Disease; FOP; FOP disease progression; FOP flare-up progression; Myositosis Ossificans Progressiva
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Muscular Diseases; Myositis; Myositis Ossificans
• Other Study ID Numbers: PVO-1A-001