Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes

Abstract

Background: Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP.

Methods: All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed.

Results: Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm3/year. There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52).

Conclusions: Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients.

Trial registration: This study ( NCT02322255 ) was first posted on 23 December, 2014.

Keywords: Clinical trial endpoints; Cross-sectional analysis; Disease progression; Fibrodysplasia Ossificans Progressiva; Heterotopic ossification; Natural history.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved initially by The Committee on Human Research at the University of California San Francisco (approval number: 14–13854) and subsequently approved by the ethics committees at the six other study site institutions (University of Pennsylvania Institutional Review Board; Comité de Protection des Personnes, Ile de France II; Comitado Etico Regionale San Martino; Hospital Italiano Comité de Ética de Protocolos de Investigacion; NHS Health Research Authority, London-Stanmore Research Ethics Committee; Metro South Human Research Ethics Committee). The study was registered at Consent for publication

Not applicable.

Competing interests

AW, BW, and DRG are Clementia employees. All other authors received funding from Clementia to implement and conduct the study. In addition, the authors’ travel expenses were paid to attend Investigator meetings at which study activities and results were discussed.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Correlation between Subject Age and Measures of Functional Disability. Correlation analysis of CAJIS Total Score and age (top) and FOP-PFQ Percent Total Score and age (bottom) in subjects with FOP. Correlation assessed using linear regression with baseline age as a covariate

Fig. 2

Correlation between Subject Age and HO Volume. Correlation analysis of total body volume of HO and age in subjects with FOP. Correlation assessed using linear regression with baseline age as a covariate

Fig. 3

Whole Body Computed Tomography Images from Representative Subjects

Fig. 4

Correlation between Total Body Volume of HO and Measures of Functional Disability. Correlation analysis of CAJIS Total Score and volume of total body HO (top) and FOP-PFQ Percent Total Score and volume of total body HO (bottom) in subjects with FOP. Correlation assessed using linear regression with baseline age as a covariate

Fig. 5

Correlation between CAJIS and FOP-PFQ. Correlation analysis of CAJIS Total Score and FOP-PFQ Percent Total Score in subjects with FOP. Correlation assessed using linear regression with baseline age as a covariate