Table 1.

The suitability of endpoints included in PVO-1A-001, PVO-1A-201, and PVO-1A-202

PVO-1A-001 (NHS)
Key endpoints	Secondary endpoints (12-week flare-up progression)	Secondary endpoints (disease progression)	Suitability of endpoints
Flare-up outcomes: Incidence and volume of new HO at Week 12 as assessed by flare-up body region CT scan Disease progression: Change from Baseline in the total body burden of HO as assessed annually by low-dose WBCT (excluding the head) over 36 months	• Pain and swelling at the flare-up body region using numeric rating scale for each symptom • Biomarkersa • Physical function as assessed by ROM (goniometer) • Disease-specific patient-reported outcome measure (FOP-PFQ) • Patient-reported outcome measure of physical and mental health (PROMIS Global Health Scale)	• ROM as assessed by CAJIS for FOP • Patient-reported use of aids, assistive devices, and adaptations • Disease-specific patient-reported outcome measure (FOP-PFQ) • Patient-reported measure of physical and mental health (PROMIS Global Health Scale) • Biomarkers	• Comparison of DXA and low-dose WBCT (excluding the head) determined that low-dose WBCT was the preferred imaging modality for measuring HO [31]. When measured by low-dose WBCT, total HO volume increased substantially over the course of the study, suggesting the usefulness of this approach as a meaningful endpoint to measure disease progression [24] • Use of aids, assistive devices, and adaptations also increased substantially across the study, suggesting that this endpoint may provide a valuable real-world indicator of decreased mobility [24] • Functional and patient-reported outcome assessments, such as CAJIS and FOP-PFQ, showed limited changes during the course of the study. A longer study duration would be required to detect substantial changes in these endpoints [24]
PVO-1A-201 (Phase II RCT)
Key endpoints	Secondary endpoints (12-week flare-up progression)	Secondary endpoints (disease progression)	Suitability of endpoints
Flare-up outcomes: Incidence and volume of new HO at Week 12, assessed by flare-up body region CT scan Disease progression: None	• Presence of soft tissue edema and/or cartilage as assessed by MRI (or soft tissue edema by ultrasound in participants unable to undergo MRI) • Active ROM measured by goniometer at flare-up body region • Patient and Investigator global assessment of movement • Pain and swelling at the flare-up body region using a numeric rating scale for each symptom • Use of aids, assistive devices, and adaptations for daily living • Disease-specific patient-reported outcome measure (FOP-PFQ) • Biomarkersa • Steady-state pharmacokinetics • Safety evaluation, including: adverse events, clinical safety laboratory parameters, vital signs, concomitant medications, assessment of suicide ideation/behavior using the C-SSRS, and assessment of physeal growth plate and linear growth in participants under the age of 18 years	• None	• Plain radiographs were insufficiently sensitive in identifying or quantifying new HO. Therefore, CT scans were considered the preferred imaging modality [26]; however, plain radiographs remained the most useful imaging approach for growth plate assessments • The 12-week period over which the trial was conducted may have been too short for new HO to be fully observed [26] • More than half of all patient-reported flare-ups did not result in new HO at the associated body region. This suggests that there may have been abortive flare-ups, or that symptoms were related to other disease processes [26]
PVO-1A-202 (Phase II OLE)
Key endpoints	Secondary endpoints (12-week flare-up progression)	Secondary endpoints (disease progression)	Suitability of endpoints
Flare-up outcomes: Incidence and volume of new HO at Week 12 as assessed by flare-up body region CT scan Disease progression: Change from Baseline in the total body burden of HO as assessed by low-dose WBCT (excluding the head) up to Month 72	• Presence of soft tissue edema and/or cartilage as assessed by MRI (or soft tissue edema by ultrasound in participants unable to undergo MRI) • Active ROM measured by goniometer at flare-up body region • Patient and Investigator global assessment of movement • Pain and swelling at the flare-up body region using a numeric rating scale for each symptom • Use of aids, assistive devices, and adaptations for daily living • Disease-specific patient-reported outcome measure (FOP-PFQ) • Biomarkersa • Steady-state pharmacokinetics • Safety evaluation, including: adverse events, clinical safety laboratory parameters, vital signs, concomitant medications, assessment of suicide ideation/behavior using the C-SSRS, and assessment of physeal growth plate and linear growth in participants under the age of 18 years	• The proportion of participants with any new HO • ROM as assessed by CAJIS for FOP • Disease-specific patient-reported outcome measure (FOP-PFQ) • Patient-reported measure of physical and mental health (PROMIS Global Health Scale)	• Not applicable as trial results are not yet publicly available in a peer-reviewed publication

^aOsteocalcin, bone-specific alkaline phosphatase, P1CP-C-terminal propeptide of type 1 procollagen, P1NP-N-terminal propeptide of type 1 procollagen, cartilage-derived retinoic acid-sensitive protein, C-terminal telopeptide, urinary basic fibroblast growth factor, erythrocyte sedimentation rate, C-reactive protein, interleukin-6, interleukin-1 beta, tumor necrosis factor-alpha, creatine phosphokinase, and lactate dehydrogenase.

CAJIS: Cumulative Analogue Joint Involvement Scale; C-SSRS: Columbia-Suicide Severity Rating Scale; CT: computed tomography; DXA: dual-energy X-ray absorptiometry; FOP: fibrodysplasia ossificans progressiva; FOP-PFQ: FOP physical function questionnaire; HO: heterotopic ossification; MRI: magnetic resonance imaging; NHS: natural history study; OLE: open-label extension; PROMIS: Patient-Reported Outcomes Measurement Information System; RCT: randomized controlled trial; ROM: range of motion; WBCT: whole-body CT.