Abstract
Introduction
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, autosomal dominant disorder characterized by episodic yet cumulative heterotopic ossification (HO) of connective tissues. Flare-ups, i.e., sites of local soft tissue inflammation, are associated with swelling, joint stiffness, and pain are commonly associated with FOP. This study aimed to investigate the content validity of the Flares Diary by gaining an in-depth understanding of the experience of FOP flare-ups in people with FOP and by debriefing the Flares Diary to assess the relevance, comprehensiveness, and understandability of the instrument.
Methods
Adults with FOP who participated in the Phase 2 LUMINA-1 trial (NCT03188666) of garetosmab, or who were recruited by email via the International Fibrodysplasia Ossificans Progressiva Association, were enrolled in this study. Trained qualitative researchers conducted in-depth semi-structured interviews with all participants comprising concept elicitation and cognitive debriefing of the Flares Diary, with participants encouraged to describe flare-up symptoms and impacts in their own words. All interviews were conducted between March 3, 2022, and March 7, 2023. A conceptual model was developed based on participant-reported symptoms and impacts of flare-ups.
Results
Thematically analyzed interview transcripts from 20 adults with FOP identified concepts of localized and systemic symptoms, as well as impacts on participants’ daily lives associated with flare-ups. Minimal issues were reported with understanding the Flares Diary, and participants found that the items were comprehensive and matched their own experience of flare-ups.
Conclusion
The results confirm the adequacy of the Flares Diary and that the symptoms assessed are important to people with FOP.
Graphical abstract available for this article.
Trial Registration
ClinicalTrials.gov identifier, NCT03188666.
Graphical Abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s12325-026-03506-6.
Keywords: Fibrodysplasia ossificans progressiva, Flares diary, LUMINA-1 clinical trial, PRO, Flare-up events
Key Summary Points
| Why carry out this study? |
| Participants in the LUMINA-1 trial confirmed the importance of symptoms measured by the Flares Diary (pain, swelling, redness, warmth, stiffness, decreased movement, and heterotopic ossification because of a flare-up) and found the items relevant to their personal experience with flare-ups. |
| This study aimed to investigate the content validity of the Flares Diary by gaining an in-depth understanding of the experience of FOP flare-ups in people with FOP and by debriefing the Flares Diary to assess the relevance, comprehensiveness, and understandability of the instrument. |
| What was learned from the study? |
| Participants were able to understand the Flares Diary and found the items all-encompassing. |
| This study (1) provides important insights into the burden of FOP symptoms and their impacts on daily living and (2) supports the use of the Flares Diary as an instrument for capturing symptoms and treatment effects experienced by people with FOP. |
Digital Features
This article is published with digital features, including a graphical abstract to facilitate understanding of the article. To view digital features for this article, go to 10.6084/m9.figshare.31099099.”
Introduction
Fibrodysplasia ossificans progressiva (FOP; OMIM#135100) is an ultra-rare, autosomal-dominant disorder with an estimated prevalence of approximately 0.28–1.46 per million individuals [1–4]. FOP is characterized by episodic and cumulative heterotopic ossification (HO) of connective tissues, including skeletal muscles, tendons, ligaments, fascia, and aponeuroses [5–8]. HO in FOP begins in the early years of life with a median onset at 5 years of age [9]. While FOP onset is typically localized to the neck and back, over time, more body regions become affected, and the accumulation of HO lesions leads to progressive disability and joint immobility, with most individuals with FOP requiring the use of a wheelchair by their 3rd decade of life [5, 7, 10, 11].
People with FOP may also experience local inflammatory symptoms referred to as Flare-ups [5, 11, 12]. While the exact nature of flare-ups is unknown, they can occur spontaneously or following injury. Symptoms experienced by people with FOP during a flare-up can last several weeks and include soft tissue swelling, pain, decreased range of movement, stiffness, and warmth [11]. In addition to experiencing high levels of pain and physical debilitation, many people with FOP report increased anxiety, irritability, and depression during flare-ups [13, 14].
FOP is caused by heterozygous missense mutations in ACVR1, the gene encoding activin A receptor type 1, a bone morphogenetic protein type I receptor [15]. FOP-causing variants of ACVR1 recognize activin A as an agonist, whereas wild-type ACVR1 does not [8, 16–18]. Garetosmab, an investigational human monoclonal antibody generated using VelocImmune™ technology [19, 20], binds activin A and blocks its ability to activate FOP-mutant ACVR1. In a genetically humanized murine FOP model, garetosmab blocked the emergence of new HO lesions and either stopped growth or induced regression of pre-existing lesions [8, 16]. LUMINA-1 (NCT03188666) was a Phase 2, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects of intravenous garetosmab 10 mg/kg every 4 weeks on HO [21]. In 44 adults with FOP and active HO at baseline (i.e., lesions with active mineralization), garetosmab treatment demonstrated substantial and durable reduction in new HO formation and soft tissue inflammatory flare-ups [21]. During the 28-week placebo-controlled period, serious adverse events (SAEs) occurred in four (20.0%) garetosmab-treated participants and two (8.3%) placebo-treated participants. Some participants experienced multiple SAEs. SAEs reported in the garetosmab group included three (15.0%) participants with infections and infestations, one (5.0%) participant with epistaxis, and one (5.0%) participant with intestinal obstruction.
To gain insights into the experience of flare-ups of people with FOP during treatment with garetosmab, patient-reported outcome (PRO) data were collected from participants in the LUMINA-1 trial using a set of draft questionnaires pertaining to flare-ups, which were collectively referred to as the Flares Diary. PRO data are commonly collected in clinical studies as they provide unique insights into individuals’ experiences of disease without interpretation of their responses by a clinician or anyone else. This is particularly important for a rare disease such as FOP, since it is associated with multiple, heterogeneous symptoms despite the small population [11, 22, 23]. To gauge the appropriateness of the Flares Diary as an outcome measure for use in future clinical trials to assess FOP flare-up events, it is first crucial to assess instrument content validity, i.e., the extent to which the instrument measures the concept of interest for the specific population being studied [23, 24]. The primary objective of this study was to investigate the content validity of the Flares Diary by gaining an in-depth understanding of the experience of FOP flare-ups from the perspective of people with FOP and by debriefing the Flares Diary to assess the relevance, comprehensiveness, and understandability of the instrument for this population.
Methods
Study Design
This qualitative, non-interventional, descriptive, cross-sectional study comprised interviews with adults with FOP. Initially, only participants who were enrolled in the LUMINA-1 trial were targeted for recruitment into this study. However, it became clear that meeting recruitment targets from this sample was not feasible. Therefore, to provide a larger sample for concept saturation, and to increase the robustness of the results, the study population was extended to also include non-trial adults diagnosed with FOP in the US or the UK who were recruited via the International Fibrodysplasia Ossificans Progressiva Association (IFOPA; North Kansas City, MO), a patient advocacy group. The additional recruitment via the IFOPA was limited to the US and the UK because of the cost of transcribing interview guides into different languages and the anticipated delays in obtaining approvals from additional countries.
Ethical approval for this study was provided by the Western Institutional Review Board-Copernicus Group (WCG® IRB) for research in the US and Canada. For LUMINA-1 trial participants at trial sites in the European Union, regulatory oversight was provided under the aegis of the clinical trial. In the UK, institutional review board oversight was not required, as confirmed by the Health Research Authority decision tool for ethics review requirements; https://www.hra-decisiontools.org.uk/ethics/. All participants provided written informed consent to be included in the study and for the results of the study to be published.
Study Population
Purposive sampling was used to select participants with specific characteristics relevant to the research question, ensuring rich, detailed data collection. Participants referred from the LUMINA-1 trial comprised adults aged 18–60 years with a clinical diagnosis of FOP (confirmed by documentation of an FOP-causing ACVR1 variant) and a history of disease activity within 1 year of screening [21]. FOP disease activity was defined as pain, swelling, stiffness, other signs and symptoms associated with FOP flare-ups, worsening joint mobility, or radiographic progression of HO (increase in size or number of HO lesions), with or without associated flare-up episodes. Participants were excluded from the study if they were active participants in a clinical trial other than LUMINA-1. Participants from LUMINA-1 who had approved the sharing of their contact information with the qualitative study research team were asked to provide additional consent to participate in the interview. Non-trial participants were recruited via an institutional review board-approved recruitment email sent by IFOPA staff. The non-trial participants recruited by the IFOPA were included if they were aged ≥ 18 years, had experienced a flare-up in the past year, were US or UK residents, and could describe flare-up–related symptoms and impacts. Non-trial participants were excluded if they had previously participated in an interview about their experience with FOP. Both the LUMINA-1 participants and the non-trial participants were only included if they were willing and able to participate in a 60–90-min interview in English, Polish, Spanish, French, Dutch, or Italian over the phone or online and if they had access to a computer, smartphone, or tablet during the interview.
Semi-Structured Interviews
All participants completed a single 60–90-min semi-structured interview at a location of their choosing in their native language (Dutch, English, French, Italian, Polish, or Spanish) via Microsoft Teams. Semi-structured interviews were conducted by JB (BS) and DEA (MSc), who were female qualitative researchers employed by Modus Outcomes and had received specific training on the interview objectives. JB and DEA have 3 and > 15 years of experience, respectively, in qualitative research. The interviewer and participant met for the first time on the day of the interview. No prior relationship between the interviewer and participant existed, and no characteristics or personal information of the interviewer were shared with the participant. Objectives of the research were shared with the participant in the informed consent form as well as before the interview commenced. Interview transcripts were not returned to the participants for comments/corrections. All interview and analysis staff completed adverse event (AE) reporting training to ensure that any AEs discussed during interviews were appropriately reported. All interviews were conducted between March 3, 2022, and March 7, 2023, and were audio-recorded and transcribed.
Concept Elicitation of the Experience of FOP
The interviews began with concept elicitation to gain an in-depth understanding of individuals’ experiences with FOP. Participants were asked open-ended questions to encourage them to describe flare-up symptoms and impacts in their own words. Targeted probes were only used to obtain specific information on concepts of interest (pain, swelling, redness, warmth, joint stiffness, and decreased movement) after the participant had been given the opportunity to respond spontaneously to the open-ended questions.
Cognitive Debriefing of the Flares Diary
The second part of the interview involved cognitive debriefing of the Flares Diary used in the study. The intent of cognitive debriefing was to ascertain the relevance, comprehensiveness, and understandability of the diary, including how well items captured flare-up symptoms. For participants who were not part of the LUMINA-1 trial, interviews included the same set of concept elicitation and cognitive debriefing questions as those asked of trial participants. The Flares Diary comprised three sections: (1) a historic flare-up questionnaire (used at baseline only); (2) a flare-up management questionnaire; (3) a new flare-up questionnaire. The historic flare-up questionnaire asked participants to report flare-up events over the last 12 months, while the flare-up management and new flare-up questionnaires were completed daily during the relevant clinical trial and study period to focus on ongoing and new symptoms and experiences associated with FOP flare-ups. In this study, participants completed the Flares Diary questionnaire through a “think-aloud” process, in which they verbalized the content and their thoughts as they answered the questions. If participants were not experiencing a flare-up at the time of the interview, they were asked to reflect on a prior experience to respond to items on the flare-up management and new flare-up questionnaires. The topics pertaining to the Flares Diary assessed as part of the cognitive debriefing are presented in Supplementary Table 1.
Qualitative Analysis
Audio-recordings of interviews were transcribed verbatim and anonymized. Non-English-language interviews were conducted by Global Perspectives in the chosen language. All non-English interviews were translated into English by TransPerfect.
Transcripts were analyzed thematically [25] using detailed, line-by-line open and inductive coding [26, 27] using ATLAS.ti software (ATLAS.ti Scientific Software Development GmbH, Berlin, Germany). To guide coding, an initial codebook was developed, which was based on the interview and only included high-level topics. The codebook was developed iteratively and inductively during the coding process. After two coders had independently coded the first transcript, they met to identify coding discrepancies, reach consensus on code application, and revise the codebook as needed. Subsequently, all transcripts were coded independently, and weekly coding meetings were held to further revise the codebook and coding approach as required until coding agreement was achieved. Codes were organized and inductively categorized into higher-order overarching categories using an iterative process of cross-referencing and comparison.
In qualitative research, unlike clinical research, predetermined sample sizes are not required. Rather, research (in this case participant interviews) is continued until enough data have been collected to draw conclusions, and any further data collection would not provide further valuable insights, i.e., data saturation. Conceptual saturation is described as the point at which no new concepts are likely to emerge from conducting additional individual interviews [28]. Saturation was assessed by dividing the total number of transcripts into five groups based on the chronological order of participant interviews. Concepts emerging in each group were compared with the previous group(s), and saturation was considered met when no new relevant concepts were introduced in the subsequent group of transcripts.
Standard analytical techniques of conceptual model development [25, 27] were used to inductively categorize codes and quotations into higher-order analytical categories referred to as concepts, sub-domains, and domains reflecting their conceptual content underpinning. From this, a conceptual model of related symptoms and impacts of FOP flare-ups reported by participants during interviews was developed. Participants did not provide feedback on the qualitative analysis findings.
Results
Participant Demographics and Baseline Characteristics
Overall, 20 adult participants with FOP were invited to enroll in this study. No participants declined to participate or discontinued participation. Seven participants were recruited from the LUMINA-1 trial, and 13 were recruited via the IFOPA. One participant had difficulty seeing so was assisted by a caregiver during the interview. This caregiver assisted the individual daily and could observe signs and symptoms that the participant could not see. In this instance, the caregiver’s data were included to supplement the participant's reported data. Participant demographics and baseline characteristics are detailed in Table 1. Seven participants with a mean (range) age of 32.8 (21–52) years had previously participated in the LUMINA-1 trial; 13 participants with a mean (range) age of 37.6 (19–65) years were recruited via the IFOPA. The two groups were generally well matched regarding baseline demographics and disease characteristics (Table 1). In the overall sample, most participants were White (80%), female (60%), had received their FOP diagnosis > 10 years prior to screening (95%), and had experienced symptoms for ≤ 5 years prior to their FOP diagnosis (80%). The treatments most often used to manage FOP symptoms were glucocorticoids and non-steroidal anti-inflammatory drugs (each n = 12). Chronic conditions or diseases experienced by participants included hair loss (n = 11), hearing loss (n = 9), anxiety (n = 8), depression (n = 6), and breathing issues (n = 6).
Table 1.
Baseline demographics and disease characteristics
| Study participants recruited from the LUMINA-1 trial (n = 7) | Study participants recruited by the IFOPA (n = 13) | Total study participants (N = 20) | |
|---|---|---|---|
| Age, years, mean (range) | 32.9 (21–52) | 37.6 (19–65) | |
| Race, n (%) | |||
| White | 5 (71.4) | 11 (84.6) | 16 (80.0) |
| White/native | 0 | 1 (7.7) | 1 (5.0) |
| Not available | 2 (28.5) | 1 (7.7) | 3 (15.0) |
| Sex, n (%) | |||
| Female | 4 (57.1) | 8 (61.5) | 12 (60.0) |
| Male | 3 (42.8) | 5 (38.5) | 8 (40.0) |
| Education, n (%) | |||
| High school graduate | 1 (14.2) | 3 (23.1) | 4 (20.0) |
| Bachelor’s degree or higher | 4 (57.1) | 9 (69.2) | 13 (65.0) |
| Employment, n (%) | |||
| Full time | 2 (28.5) | 2 (15.3) | 4 (20.0) |
| Retired | 2 (28.5) | 0 | 2 (10.0) |
| Time since FOP diagnosis, years, n (%) | |||
| ≤ 5 | 0 | 0 | 0 |
| 6–10 | 1 (14.2) | 0 | 1 (5.0) |
| > 10 | 6 (85.7) | 13 (100.0) | 19 (95.0) |
| Time symptoms were experienced before diagnosis, years, n (%) | |||
| 0–5 | 5 (71.4) | 11 (84.6) | 16 (80.0) |
| ≥ 6 | 2 (28.5) | 1 (7.7) | 3 (15.0) |
| Not reported | 0 | 1 (7.7) | 1 (5.0) |
| Symptom medications, n (%) | |||
| Glucocorticoids | 5 (71.4) | 7 (53.8) | 12 (60.0) |
| Nonsteroidal anti-inflammatories | 4 (57.1) | 8 (61.5) | 12 (60.0) |
| Cannabinoids | 3 (42.8) | 3 (23.1) | 6 (30.0) |
| Conditions/comorbidities, n (%) | |||
| Anxiety | 3 (42.8) | 5 (38.5) | 8 (40.0) |
| Dental issues | 2 (28.5) | 3 (23.1) | 5 (25.0) |
| Depression | 1 (14.2) | 5 (38.5) | 6 (30.0) |
| Hair loss | 4 (57.1) | 7 (53.8) | 11 (55.0) |
| Hearing loss | 3 (42.8) | 6 (46.2) | 9 (45.0) |
| Breathing issues | 1 (14.2) | 5 (38.5) | 6 (30.0) |
IFOPA International Fibrodysplasia Ossificans Progressiva Association, FOP fibrodysplasia ossificans progressiva, N/A not applicable
Conceptual Model of Flare-Up–Related Symptoms and Impacts
A total of 50 unique concepts related to the symptoms and impacts of FOP flare-ups were extracted from the 20 interviews conducted (Table 2). All concepts had emerged by the fourth group of interviews, with no new concepts emerging in the final set; therefore, conceptual saturation was achieved, and no further interviews were necessary. Almost all concepts (n = 49) were elicited spontaneously from at least one participant. Joint stiffness was the only concept that was not mentioned spontaneously.
Table 2.
Analysis of conceptual saturation
| Group 1 (n = 4 transcripts) 15 new concepts |
Group 2 (n = 4 transcripts) 18 new concepts |
Group 3 (n = 4 transcripts) 15 new concepts |
Group 4 (n = 4 transcripts) 2 new concepts |
Group 5 (n = 4 transcripts) 0 new concepts |
|---|---|---|---|---|
| Bathing | Difficulty using the bathroom | Bearing weight | Squirting saliva | |
| Bone growth | Change in appetite | Bending | Standing | |
| Decreased movement | Closed throat | Brushing hair | ||
| Dressing | Dizziness | Body locked in position | ||
| Unable to get out of bed | Eating | Depression | ||
| Headache | Feeling cold/hot | Fear that a new flare-up could come at any time | ||
| Inflammation | Itching | Fear of not knowing the severity of new flare-up symptoms | ||
| Loss of joint mobility | Loss of independence | Fever | ||
| Nerve pain | Low self-esteem | Frustration with not being able to do usual things | ||
| Pain | Rashes due to itching | Picking things up off the floor | ||
| Pressure/tightness | Sadness over loss of independence | Reaching | ||
| Redness | Slurred speech | Sitting | ||
| Sleep interference due to pain | Joint stiffness: probed | Typing | ||
| Swelling | Speaking | Unable to leave home | ||
| Warmth | Stress | Work/school | ||
| Swallowing | ||||
| Veins visible | ||||
| Walking |
A two-domain conceptual model was developed based on participant-reported flare-up–related symptoms and impacts. The flare-up symptoms domain of the conceptual model included traditional localized symptoms such as bone growth, swelling (tightness/pressure), warmth, redness, joint stiffness, pain (headache and nerve pain), itching (rashes from itching), visible veins, and jaw-related symptoms. However, some participants also described systemic symptoms such as whole body feeling hot/cold, dizziness, fever, and change in appetite (Fig. 1). The impacts domain of the conceptual model included activities of daily living, mobility, instrumental daily activities, emotions, and sleep interference (Supplementary Fig. 1).
Fig. 1.
Conceptual model: flare-up symptoms. Subdomains and concepts in italics were reported by only one participant. aSome participants also used the word inflammation to refer the tightness or pressure they associate with swelling; swelling is also associated with joint stiffness, which contributes to the loss of function even in the absence of a flare-up leading to new heterotopic ossification. bPins and needles, tingling, tenderness, and numbness were used by some participants as additional descriptors for mild pain and mild nerve pain
Participant-Reported Symptoms and Impacts of Flare-Ups
The most common localized symptoms were bone growth (n = 18) and swelling (n = 16), followed by pain, joint stiffness, and decreased movement (each n = 14), as well as warmth and redness (both n = 9). Four systemic symptoms of a flare-up were reported: whole body feeling hot and cold, dizziness, fever, and change in appetite (each n = 1). The most frequently reported first symptoms that participants experienced with a flare-up were pain (n = 9), swelling (n = 8), loss of movement (n = 4), and warmth (n = 4). Less frequently experienced first symptoms of a flare-up included stiffness, itchiness, and inflammation (all n = 1).
When asked about experiencing pain with a flare-up versus any pain outside of a flare-up, most participants reported that they experienced flare-up–related pain (n = 14) as well as general pain outside of a flare-up related to FOP (n = 13).
Participants were also asked to report the most bothersome and least bothersome symptoms and impacts associated with a flare-up. The most bothersome symptoms were pain (n = 4), swelling (n = 1), and bone growth (n = 1); the most bothersome impacts were loss of mobility because of a flare-up (n = 6), the unpredictable nature of the flare/fear of the unknown (n = 4), and the need to change/adapt (n = 2). Many participants did not comment about the least bothersome aspect of flare-ups as they felt all symptoms and impacts were bothersome and life-impacting. Of those who did answer, getting more sleep (n = 1), restriction (n = 1), and pain (n = 1) were reported as the least bothersome.
Quotations from participants describing flare-up symptoms and the impacts of flare-ups on daily life are summarized in Table 3 and Supplementary Table 2, respectively.
Table 3.
Selected participant quotations pertaining to the symptoms of flare-ups
| Symptom | Representative participant quotations |
|---|---|
| Swelling | “But it does seem to be more internal swelling, though. It’s hard to see a lot of swelling on the outside. Like my hip is swollen right now. It doesn’t really look swollen, but I can feel it on the inside.” (Female, aged 30–39 years) |
| Warmth | “You know when you touch your forehead on a fever? That’s kind of how it feels like. But the warmness is not constant. Like now, it’s just the same temperature as the skin around it. But some days, it’s just really warm.” (Male, aged 20–29 years) |
| Redness | “I do notice that the warmth and the redness seem to correlate. So the kind of surface flare-ups tend to be red and warm and very painful to someone prodding them. The ones that aren’t red don’t tend to be as warm.” (Female, aged 40–49 years) |
| Pain | “It’s a fairly new flare-up right now, and I can’t tell if a new bone is going to form. Because this pain in my ankle’s been going on for – I would say for a couple months now, but I don’t think it was a flare-up the whole time. Like I said, sometimes if it’s an area that I use a lot, sometimes it’s a flare-up, and other times, it’s just normal pain, which is also something I’m used to dealing with, because pain tends to come with FOP, flare-up or not. Usually everyone with FOP is dealing with some kind of pain, whether it’s back pain or whatever.” (Male, aged 20–29 years) |
| Headaches | “They’re up in my neck right now, and there isn’t much space for them, so it can give some headaches and stiffness and touch some nerves. So, it’s quite painful. But when the swelling is gone, it’s OK again.” (Female, aged 30–39 years) |
| Nerve pain | “I have a lot of them [flare-ups] in my neck and upper spine. And when they start, I just start feeling numb, and it hurts and feels stiff, and sometimes nerve pain can start, too.” (Female, aged 30–39 years) |
| Joint stiffness; decreased movement | “The decrease in movement is longer. It’s overall long period of time. The joint stiffness goes away after a couple of days.” (Male, aged 20–29 years) |
| Bone growth | “… there could be like a bone the size of a drop of glue that’s preventing me from being able to bend my elbow. It could be something as small as that. Or it could be a larger one. But in most cases, it could just be the smallest little piece that’s preventing you from being able to move a joint.” (Female, aged 40–49 years) |
| Itching | “It’s inside. Instinctively, I want to scratch, but it doesn’t work. In my case, it itches more and more at the beginning of the flare-up.” (Male, aged 30–39 years) |
| Visible veins | “You used to see actual veins start being—it was like something was alive in there, and veins were forming. It was moving.” (Male, aged 20–29 years) |
| Whole body feeling hot/cold | “I think the body itself also gets hot and cold a lot of the time, too.” (Male, aged 20–29 years) |
| Dizziness | “Just felt a little dizzy when I get up to do my little walks to exercise. It’ll be for like a day or so. So, it’s very weird. I don’t know what causes it. I just assumed it was the flare because I never really had it before.” (Male, aged 20–29 years) |
| Fever | “Sometimes, it’ll cause a fever, but not all the time.” (Female, aged 18–19 years) |
| Change in appetite | “You get more hungrier. I guess the body’s using more resources. But then you might just eat less, too.” (Male, aged 20–29 years) |
FOP fibrodysplasia ossificans progressiva
Frequency and Duration of Flare-Ups
Participants were also asked to describe the frequency and duration of their flare-ups. The frequency and duration varied between and within individuals, with events reported as random and occurring at any time. One participant described experiencing multiple flare-ups within a short time, but none for months thereafter.
Sometimes, I will go like 6 months without having one, and then there’s other times where I’ll get them left and right, and they’re called clusters. Sometimes, I’ll just get one right after another. If I get one, let’s say, in my ankle, more often than not, it moves upwards, so it’ll go from my ankle up to my upper part of my leg, and then usually it’ll stop after it moves from a certain area (Male, aged 20–29 years).
Other participants reported that flare-ups occurred more frequently during childhood or adolescence compared with adulthood. Participants also reported that, although it was challenging to determine with any precision when flare-ups started and ended, flare-up duration could range from weeks to years. Some participants thought flare-up duration could be associated with the body region where the flare-up occurred; a similar association was observed for flare-up severity. One participant identified the hips as a location where they had experienced long and severe flare-ups. Participants defined a severe flare-up as one where mobility was lost/reduced.
Cognitive Debriefing of the Flares Diary
Historic Flare-Up Section
In the historic flare-up questionnaire section of the Flares Diary, participants were asked to reflect on whether the following definition resonated with their experiences of a flare-up: "In this study, a flare-up is when you have two or more of the problems below: pain; swelling; joint stiffness; and decreased movement.” Participants strongly endorsed pain, swelling, joint stiffness, and decreased movement as part of their flare-up experience. Notably, 8 participants flagged that decreased movement and joint stiffness were conceptually similar, while 12 participants reported them as different concepts. Nine participants recommended adding other symptoms to the definition of a flare-up (e.g., inflammation, redness, warmth, dense joint, tingling, muscle tension, pressure, hardness, and numbness). However, some of these suggestions were considered different ways of describing similar symptoms, e.g., one participant noted they think of swelling and redness as part of inflammation.
When participants were asked, “In the past 12 months, how many flare-ups have you had?” minimal issues were reported with interpretation, recall period, or relevance. Some participants (n = 5) reported difficulty choosing a response, as it was difficult for them to distinguish between the start of a new flare-up and the end of a previous one (n = 2), or they were unable to tell whether a flare-up had ended without having imaging completed (n = 3).
When participants were asked, “In the past 12 months, how many flare-ups have resolved?” six participants had difficulty with this question as they interpreted “resolved” to mean the absence of HO or lasting effects from the flare-up. One participant described that the issue with using the word “resolved” is that there is no resolution with FOP.
No issues were reported with interpretation, recall period, or relevance when participants were asked to report how many flare-ups ended with HO. However, three participants reported they would need a diagnostic scan to know whether new HO had occurred and therefore could not select a response.
When participants had to select the part of the body where they had an ongoing flare-up (by selecting the closest dot on a picture of the body shown on the screen during the interview), four participants reported flare-ups in locations where there were no dots (e.g., hamstring or calf) and did not know which dot to choose. Six participants noted there should be more specific locations (e.g., index fingers), and one participant noted that symptoms can radiate (e.g., pain from their hip to their knee) and it can be difficult to tell where the flare-up is located.
Participants were also asked to report when their flare-up started and could select “less than a week ago,” “1 week to a month ago,” or “more than a month ago.” Generally, this item was well understood and interpreted as intended. However, four participants suggested adding a response option to measure a longer duration (e.g., 3–6 months or > 1 year).
Participants were asked to select any symptom(s) they were currently experiencing with an ongoing flare-up. The symptoms they could select were all deemed highly relevant and included pain, swelling, redness, warmth, stiffness, and decreased movement. However, four participants suggested adding other symptoms such as pressure, hardness, numbness, and muscle tension. As with the definition of the flare-up, eight participants reported decreased movement and stiffness as conceptually similar.
Finally, participants were asked to rate the severity of symptoms they were currently experiencing with an ongoing flare-up. Most participants reported no difficulty using the rating scale, which offered options of “mild,” “moderate,” or “severe.” One participant thought “mild” and “moderate” were too similar as response options. Two participants suggested different rating scales (e.g., 1–10).
Flare-Up Management Section
Participants were asked to select the symptoms they were currently experiencing with their flare-up. Symptoms included pain, swelling, redness, warmth, stiffness, and decreasd movement; eight participants reported decreased movement and stiffness as conceptually similar. No issues were reported with the interpretation, recall period, or relevance of this item. As with the historic flare-up section, some participants suggested adding additional symptoms, including pressure, hardness, numbness, and muscle tension.
Participants were asked to report whether they had had a new HO within the past 24 h and selected either a “yes,” “no,” or “not sure” response option. Overall, this item was well understood and interpreted as intended, and most participants had no difficulty with this item. Some participants stated they appreciated the “not sure” response option, as it can be difficult to know whether bone had formed.
New Flare-Up Section
When participants were asked to report whether they had experienced a new flare-up in the past 24 h and could select “yes” or “no,” most participants easily understood and interpreted the item as intended. Two participants flagged that it can be difficult to identify when a flare-up starts, and one participant suggested adding an “unsure” response option to this item.
Discussion
FOP is a severely debilitating disorder that negatively impacts quality of life secondary to progressive deterioration in physical abilities [7]; however, qualitative data in this setting are lacking. Therefore, this qualitative study was conducted to (1) establish the content validity of the Flares Diary used in both the LUMINA-1 trial and an ongoing Phase 3 trial of garetosmab in adult participants with FOP (OPTIMA; NCT05394116) and (2) a to gain an in-depth understanding of the flare-up experience within an adult FOP population.
Through interviews with 20 adult participants with FOP and a qualitative thematic analysis, we developed a conceptual model based on participants' reported flare-up–related symptoms and impacts. This study provides supportive evidence for the content validity of the Flares Diary used in the LUMINA-1 trial. As noted, LUMINA-1 trial participants were recruited first, followed by non-trial participants. Previous participation in an interview about their FOP was added to the exclusion criteria to ensure we did not recruit people who had already participated in our study. Participants strongly endorsed the symptoms measured in the diary (pain, swelling, redness, warmth, stiffness, decreased movement, and HO because of a flare-up) and found the items relevant to their personal experience with flare-ups. Although some participants recommended additional symptoms (dense joints, tingling, muscle tension, pressure, hardness, and numbness) to measure or describe a flare-up, these were either other descriptors of pain, swelling, redness, warmth, stiffness, decreased movement, and bone growth or were not commonly reported by participants. Systemic symptoms (whole body feeling hot and cold, dizziness, fever, and changes in appetite) were idiosyncratic and were reported by only one participant.
Symptoms such as bone growth, pain, swelling, redness, warmth, joint stiffness, and decreased movement were commonly experienced and highly endorsed by participants as important symptoms associated with flare-ups. Flare-up impacts by sub domain included activities of daily living, mobility, instrumental activities of daily living, emotions, and sleep interference.
Regarding response options, some items in the Flares Diary were difficult for participants to respond to. For instance, some participants reported difficulty distinguishing between a flare-up and normal everyday symptoms. Accordingly, these participants had difficulty reporting when a flare-up had started or stopped. Furthermore, some participants reported it could be difficult for them to determine whether the flare-up they were experiencing was new or recurring. Some participants found that using dots on the body map to accurately reflect flare-up locations was challenging because the dots were not specific enough or the symptoms tended to radiate.
Limitations of this study included participants’ ability to recall their last flare-up or distinguish between the impact of a flare-up and that of ongoing disease, as well as the timing of the Flares Diary administration. For this reason, we added the ability to describe symptoms and impacts associated with a flare-up as inclusion criteria for non-trial participants to ensure we could capture patient experience data and mitigate recall bias. During screening, recruiters asked participants whether they could describe the symptoms and impacts of their last flare-up. Although the addition of these criteria may add a potential bias between groups, no subgroup analyses were conducted, thus eliminating biases in the data presented. Some participants were not experiencing flare-ups at the time of the interviews. Although participants were asked to recall prior experience when answering items on the flare-up management and new flare-ups questionnaires, it is possible that recall bias could have been introduced; however, as flare-ups are intense, specific, and highly memorable events, this limitation was perhaps mitigated by excellent recall among participants who had not had a recent flare-up. Of note, some participants reported difficulty interpreting the word “resolved” as it was intended, when asked whether flare-ups had resolved. Participants interpreted “resolve” as either having no bone formation or lasting effects from the flare-up. In this sense, one participant reported that their flare-ups never resolve, as there are always lasting effects. Another participant described the issue with using the word resolve, stating that there is no resolution for FOP. Some participants also highlighted that it can be difficult to know whether new bone growth has occurred following a flare-up. In addition, the cognitive debriefing of the Flares Diary was not designed to systematically question participants’ disease history, including flare-ups or their location. Therefore, information regarding flare location and whether this was influenced by the age of the participant (given the age-related progression of HO flares from axial to appendicular locations [29]) was not captured.
Conclusions
The findings of this study confirm that the symptoms assessed in the Flares Diary are appropriate for the measurement of clinical benefit among participants with FOP in future clinical trials.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors would like to thank the participants, their families, and all investigators involved in this study, as well as Patrick Marquis and Sara Strozk from Modus for their intellectual contributions.
Medical Writing/Editorial Assistance
Medical writing support under the direction of the authors was provided by Samantha Cockburn, MSc, of Prime Group of Companies (Knutsford, UK), funded by Regeneron Pharmaceuticals, Inc., according to Good Publication Practice guidelines (10.7326/M22-1460). The sponsor was involved in the conceptualization of the study design and interpretation of data, as well as data checking of information provided in the manuscript.
Author Contribution
Jessica Baldasaro and Danielle E. Altman contributed to the data curation and formal analysis of the manuscript. Robert J. Sanchez and Christopher Hartford contributed to the conceptualization and writing of the original draft. Kathryn M. Dahir, Richard Keen, and Michelle Davis contributed to data curation. Thomas Funck-Brentano contributed to data curation and investigation. Robert J. Pignolo contributed to the investigation. All authors contributed to the writing, reviewing, and editing of this manuscript and have read and approved the final version.
Funding
This study was funded by Regeneron Pharmaceuticals, Inc. The journal’s Rapid Service and Open Access fees were funded by Regeneron Pharmaceuticals, Inc.
Data Availability
Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan) that support the methods and findings reported in this manuscript. Individual anonymized participant data will be considered for sharing 1) once the product and indication has been approved by major health authorities (e.g., FDA, EMA, PMDA, etc) or development of the product has been discontinued globally for all indications on or after April 2020 and there are no plans for future development 2) if there is legal authority to share the data and 3) there is not a reasonable likelihood of participant re-identification. Submit requests to https://vivli.org/.
Declarations
Conflict of Interest
Jessica Baldasaro and Danielle E. Altman are employees of Modus Outcomes. Robert J. Sanchez and Christopher Hartford are employees of and stockholders in Regeneron Pharmaceuticals, Inc. Kathryn M. Dahir is a principal investigator on the Regeneron Pharmaceuticals, Inc. LUMINA-1 trial. The project described was supported by CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors/sponsor and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Richard Keen is a principal investigator of clinical trials sponsored by Clementia/Ipsen and Regeneron Pharmaceuticals, Inc; and a non-paid member of the International Clinical Council on FOP and the IFOPA FOP registry medical advisory board. Thomas Funck-Brentano is a principal investigator for trials sponsored by Regeneron Pharmaceuticals, Inc., Ipsen, and Incyte. Robert J. Pignolo is a principal investigator of the Regeneron Pharmaceuticals, Inc. LUMINA-1 and Clementia/Ipsen MOVE trials; and a founding member and past president of the International Clinical Council (ICC) on FOP. At the time of the study, Michelle Davis was a non-paid member of the Rare Bone Disease Alliance Steering Committee.
Ethical Approval
Ethical approval for this study was provided by the Western Institutional Review Board-Copernicus Group (WCG® IRB) for research in the United States and Canada. For LUMINA-1 trial participants who participated at trial sites in the European Union, regulatory oversight was granted under the aegis of the clinical trial. In the UK, institutional review board oversight was not required as confirmed by the Health Research Authority decision tool for ethics review requirements; https://www.hra-decisiontools.org.uk/ethics/. All participants provided written informed consent to be included in the study and for the results of the study to be published.
Footnotes
Prior Presentation: Data in this manuscript have previously been presented at the 2024 Annual Meeting of the American Society for Bone and Mineral Research, September 27–30, 2024, Toronto, Canada (10.1093/jbmr/zjae183), and at the International FOP Association’s 6th Drug Development Forum, June 26–28, 2024, Stockholm, Sweden.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan) that support the methods and findings reported in this manuscript. Individual anonymized participant data will be considered for sharing 1) once the product and indication has been approved by major health authorities (e.g., FDA, EMA, PMDA, etc) or development of the product has been discontinued globally for all indications on or after April 2020 and there are no plans for future development 2) if there is legal authority to share the data and 3) there is not a reasonable likelihood of participant re-identification. Submit requests to https://vivli.org/.