Muscle strengthening intervention for boys with haemophilia: Developing and evaluating a best‐practice exercise programme with boys, families and health‐care professionals

Abstract Background Muscle strengthening exercises have the potential to improve outcomes for boys with haemophilia, but it is unclear what types of exercise might be of benefit. We elicited the views of health‐care professionals, boys and their families to create and assess a home‐based muscle strengthening programme. Objective To design and develop a muscle strengthening programme with health‐care professionals aimed at improving musculoskeletal health, and refine the intervention by engaging boys with haemophilia and their families (Study 1). Following delivery, qualitatively evaluate the feasibility and acceptability of the exercise programme with the boys and the study's physiotherapists (Study 2). Design A person‐based approach was used for planning and designing the exercise programme, and evaluating it post‐delivery. The following methods were utilized: modified nominal group technique (NGT) with health‐care professionals; focus group with families; exit interviews with boys; and interviews with the study's physiotherapists. Results Themes identified to design and develop the intervention included exercises to lower limb and foot, dosage, age accommodating, location, supervision and monitoring and incentivization. Programme refinements were carried out following engagement with the boys and families who commented on: dosage, location, supervision and incentivization. Following delivery, the boys and physiotherapists commented on progression and adaptation, physiotherapist contact, goal‐setting, creating routines and identifying suitable timeframes, and a repeated theme of incentivization. Conclusions An exercise intervention was designed and refined through engagement with boys and their families. Boys and physiotherapists involved in the intervention's delivery were consulted who found the exercises to be generally acceptable with some minor refinements necessary.


| INTRODUC TI ON
Haemophilia is a bleeding disorder associated with bleeding into the muscles and joints. 1 It is a rare inherited disorder affecting 1:10 000 people where the blood does not clot normally. Over a period of time, repeated joint bleeding leads to chronic synovitis (inflammation of the joint) and arthropathy, which is associated with chronic joint deformity, pain, muscle atrophy and functional impairment. The recommended treatment for people with severe haemophilia is administration of prophylaxis (infusion of the clotting factor concentrate) to prevent bleeding and minimize long-term arthropathy. 2,3 Often exercise is used as an aid to recovery after episodes of musculoskeletal bleeding and can help to improve joint function. 4 Exercise interventions produce improvements in outcome measures including pain, range of motion, strength and walking tolerance. 1 There is evidence to suggest that exercise for adult males with haemophilia can help with increasing the range of motion and muscle strength enabling rapid mobilization and recovery of function. 1,3 Yet, there is a lack of robust evidence to determine whether muscle strengthening exercise can improve or negatively affect outcomes for young boys with haemophilia and it is unclear what types of exercises might be of benefit. 1 Due to the small-sized patient population and limited validated outcome measures, large randomized controlled trials (RCT) to establish whether an intervention is effective in rare diseases like haemophilia are often difficult to conduct without establishing whether a study is feasible. 5,6 In addition, resource use may not be optimally rationalized when a treatment or intervention is found to be ineffective or unsafe, or conversely, a treatment or intervention is not provided if it turns out to be effective. 57 Involving patients, carers and health-care providers at the early stages of intervention development and evaluation is widely recognized as good practice to elicit users' and practitioners' views in order to create a credible and motivating programme. 8 Inductive qualitative methods can contribute to intervention development gaining an indepth appreciation of how users may relate to a resulting intervention content and format, and allowing for modifications to take place as necessary. [8][9][10] McDermott et al 11 summarize how integral users' and practitioners' views are in the development of an intervention, which can help to clarify the mechanisms through which the intervention works, identify potential barriers to change, provide information on individual needs to users and explore relevant issues which can be used to further develop and refine the intervention model. 11 Q ualitatively exploring the acceptability and feasibility of an intervention following delivery is critical to tailor advice and techniques and modify the intervention to make it more usable, relevant, persuasive, accessible and engaging. 9,12-14 Using iterative qualitative approaches can help research teams make modifications to the intervention, as users report parts of the intervention they find hard to perform or indicate problems in reporting their physical activity levels correctly. 13 The current findings discussed in this paper report upon a recently completed feasibility study funded by the UK's National Institute for Health Research (NIHR) known as the 'DOLPHIN' study or Development Of a haemophiLia Physiotherapy INtervention for optimum musculoskeletal health (PB-PG-0215-36091). 15 This paper describes how a muscle strengthening intervention was designed, developed and refined for boys with haemophilia. It involved gaining an in-depth understanding of the users' needs and goals making the intervention more relevant, accessible and engaging. A person-based approach was used in both stages of the study: during the early stages of designing, developing and refining the intervention (Study 1), and then utilized to evaluate the acceptability and feasibility of the intervention (Study 2). 13,16

| OBJEC TIVE S
The study was carried out in two phases.
The aims of Study 1 were to engage boys with haemophilia, their families and health-care professionals to design, develop and refine a best-practice muscle strengthening exercise intervention aimed at improving musculoskeletal health by: • Exploring the perspectives of clinicians experienced in paediatric haemophilia care • Exploring the perspectives of boys with haemophilia and their families The objective of Study 2 was to qualitatively evaluate the acceptability and feasibility of the exercise programme and re-visit the intervention to amend any parts before progressing to a final trial by: • Discussing and capturing feedback with the participants (boys and parents) and the study's physiotherapists to identify any aspects requiring attention to help deliver the intervention for the larger study.

| Study design
We used the principles of a 'person-based' approach for intervention development (Study 1) and evaluation (Study 2). The person-based approach enables intervention developers to understand how different people in different situations may view and engage with the those of NIHR or the Department of Health and Social Care. We would like to thank the NIHR's RfPB programme for funding the study. delivery were consulted who found the exercises to be generally acceptable with some minor refinements necessary.

K E Y W O R D S
Boys, Exercise, Haemophilia, Life-experience, Muscle strength, Patient adherence, Physiotherapy intervention, and identify which elements may be relevant or may be rejected, thus helping to understand how the intervention could be more attractive, persuasive and feasible to implement in a larger study. According to Yardley et al, 13 the core elements of a personbased approach involve (a) intervention planning, (b) intervention design and (c) intervention evaluation of acceptability and feasibility. Due to time constraints, we combined elements (a) and (b) into Study 1 and undertook the evaluation of feasibility and acceptability in Study 2.
In Study 1, the intervention developers (academic physiotherapists, paediatric musculoskeletal physiotherapists, specialist haemophilia physiotherapists and members of the research team) designed the programme using their experiences and knowledge of the user group, as well as key messages presented from a literature review. Following development, the exercise programme was demonstrated to the boys and their families and then refined taking into account their views and actions. 16 In Study 2, following the delivery of the intervention, an evaluation was carried out to check whether the changes and refinements were successful in making the exercise programme acceptable and interesting and would enable the users to adhere to the intervention in the larger trial.
Qualitative data were collected by an experienced researcher with over 10 years' experience of data collection with children.

| Data collection
Study 1-Designing, developing and refining the best-practice muscle strengthening intervention.
Perspectives of health-care professionals: Qualitative data were collected from health-care professionals (n = 11) in January 2017 at the UK Haemophilia Society in London during one modified nominal group technique (NGT) discussion meeting (Table 1). Key findings from a literature review (unpublished) of interventional studies undertaken by DS, WD and MB from January to December 2016 were presented to health-care professionals in order to stimulate ideas for a prioritization exercise to identify key characteristics for designing and developing an exercise programme through peer discussion and consultation. The messages from the literature review used to design and develop the intervention included: (a) strong muscles are important because they help protect your joints from bleeds; (b) regular exercise can actually help prevent bleeds and joint damage; and (c) exercise can strengthen muscles to support joints. 1,[17][18][19] The group designed a draft intervention with regard to specific exercises (including frequency, intensity and timing), setting, and length of intervention and training needs.
A modified NGT was utilized to facilitate the discussion which was conducted by FH, and involved five stages: introduction and explanation, silent (independent) generation of ideas, sharing of ideas, group discussion, and ranking and voting. After sharing of ideas and discussion, participants were asked to anonymously rate key statements about the exercise intervention on a 4-point Likert scale (strongly disagree; disagree; agree; and strongly agree). [20][21][22] This was followed by a focus group discussion. 23 The modified NGT and focus group discussion were 175 minutes in length (with a short break in the middle). The focus group was audio-recorded, transcribed and anonymized, which, together with the NGT ratings, informed the design of the draft exercise intervention. Qualitative data Semi-structured discussion collected via one-to-one interview scale (strongly disagree; disagree; agree; and strongly agree). This was followed by a focus group discussion. The focus group discussion was 75 minutes in length (with a short break in the middle). The focus group was audio-recorded, transcribed and anonymized and together with the Likert scale ratings further informed the design of the exercise intervention.
A description of the final exercise intervention is provided in Figure 1.
Study 2-Evaluating the best-practice muscle strengthening intervention for the larger trial.

Perspectives of health-care professionals and boys plus parents:
Qualitative data were collected between October 2018 and April 2019 from boys plus parents and physiotherapists. Two data sources were generated: (a) one-to-one interview data with boys and parents

| Participant recruitment
For Study 1, health-care professionals were recruited through UK haemophilia and physiotherapy networks by the study's principal investigator (DS), who used snowballing techniques to invite interested individuals to take part, which included academic physiotherapists (n = 2), paediatric musculoskeletal physiotherapists (n = 2) and specialist haemophilia physiotherapists (n = 7). Boys and their parents were informed of the study by the UK Haemophilia Society who responded to a recruitment advertisement circulated via a newsletter. Boys were screened for eligibility (inclusion criteria: aged 6-11 years, severe or moderate haemophilia A or B, with or without inhibitors for prophylactic treatment with coagulation factor, boys with or without symptoms of joint damage). In total, there were five children and five parents. There were four dyads/triads (n = 4): two mothers with a single male child each; one mother with two male children; and a father and mother with a single male child. As with the health-care professionals, the boys and parents contacted DS directly who obtained informed consent from all participants by way of sending out a participant information sheet and attaining written consent from each participant on each of the data collection days in London.
For Study 2, once boys were screened for eligibility (inclusion criteria: as described above; exclusion criteria: von Willebrand disease, history of fracture or trauma to lower limb, orthopaedic surgery, acquired brain injury or other disturbance of the central nervous system, joint or muscle bleed in lower limb in the past 6 weeks, presence of lower limb pain or unable to fully comply with verbal instructions), the boys and parents were invited to take part in the exercise programme and provided informed consent, which was undertaken as part of the overall feasibility study. In the exercise group, the boys' ages ranged from 6 to 11 (M = 9.55, SD = 2.79) (n = 5), and in the usual care group, the ages ranged from 8 to 11 (M = 10.00, SD = 1.46) (n = 4). Regarding recruitment of the study's two physiotherapists, they were invited to take part by DS who were sent a participant information sheet with written consent being obtained in advance of the one-to-one interviews.

| Data analysis
Analysis of the modified NGT data and focus group discussion (Study 1) from the health-care professionals was twofold. The NGT rating data were entered into an excel spreadsheet, and the number of participants who strongly disagree, disagree, agree and strongly agree with each statement was reported as frequencies and percentages.
Analysis of all focus group data in Study 1, one-to-one interview data with the boys and parents and the study's two physiotherapists in Study 2, were supported by the use of a qualitative software analysis programme (NVIVO 12 Pro). A thematic approach was used for data analysis. 25 It was also suggested that inspiration for exercises should be sought from gymnastics, yoga and dance training as these activities have a focus on control through range, as well as an emphasis on motor patterns (ie everyday activities).

Theme 2: Dosage
The health-care professionals suggested that the dosage for the exercise intervention would practically and clinically be at around It was recommended from the focus group discussion that the age of the participants was limited to a younger age group from age six to 11.

Theme 5: Supervision and monitoring
The parents noted that the boys would need to be guided with help for learning the exercises especially at the beginning: Parent: Also I think, I know because with the angle it's a bit strange so they need guidance for the beginning.
(Parent-focus group) In addition, the health-care professionals discussed that the parents' input to facilitate the exercises to be carried out would need to be moderated. In order to reduce the influence of parental bias and ensure the exercises were completed correctly, the health-care professionals recommended supervision by a physiotherapist: …but I also think that also they [parents] will need more

| Study 2-Revising the best-practice muscle strengthening intervention for the larger trial
Physiotherapists, parents and boys reported that the majority of exercises were appropriate, indicating that the way they were structured, including a combination of stretching and body resistance, was suitable. They felt that the exercises were achievable. It was suggested that parents could be supported and trained to help with the intervention by using an online learning or video resource of the exercises. Exercises 'linked to everyday activities undertaken in the F I G U R E 2 Consensus on key considerations for exercise intervention playground such as football proved to be popular and held their interest'. Parents reported that the boys were less compliant with the three stretching exercises at the beginning of each session, which they described as 'continual and repetitive'. This father also commented about how important it was to incorporate the exercises into regular time points in the day:

| Perspectives of boys, parents and physiotherapists following intervention
Father: Once we got into the routine it was easy wasn't it. When we got into a routine of having dinner, you going up stairs to play for half an hour or something and then coming back downstairs it was all right wasn't it?
(Parent and child-Study Site 2) One parent and child pair indicated that starting the intervention at the end of the summer in September when temperatures had decreased, meant that the exercises were achievable given the climate, plus the child has the time to undertake the exercises: Child: Like in the summer I would go out and play football but like as it's winter I don't really go out that much so I had plenty of time to do that Child: [It was in] September…So it wasn't that hot so I could just…I had plenty of time

Theme 3: Incentivization
It is interesting to note that the health-care professionals and par- Although the parents felt that having a voucher did not primarily act as an incentive to ensure adherence, one of the physiotherapists noted in fact the parents retained control and accumulated the incentives for the younger boys. Yet for the older boys, they assumed control of expenditures for the voucher and had already planned how to spend it (Physiotherapist-Study Site 1).

Theme 4: Identifying training needs of physiotherapists and parents
The physiotherapists commented on the potential training requirements for a future larger RCT.

| D ISCUSS I ON
Where physiotherapy management and exercise are being trialled in rare conditions such as haemophilia, it is important to design, develop and refine the components of an intervention using a targeted approach focusing upon the experiences of the users in order to optimize acceptability and feasibility. 27, 28 We have (a)  preterm infants, they found that parents were generally positive in using websites for information and support; yet, finding relevant evidence-based information was challenging. Therefore, it is important to understand the information and support needs of parents to be able to obtain high-quality, evidence-based resources online which are easily accessible, easy-to-understand, trustworthy and parent-centred. 38

| Study Limitations
The findings from this study relate to a patient group with a specific rare disease, and it is acknowledged that their experiences may not be comparable to other conditions or disease groups. The literature review was undertaken to present the gaps in evidence to the healthcare professionals involved in the modified NGT activity (Study 1), rather than as a full systematic literature review, and it is therefore acknowledged that this has methodological limitations as only titles and abstracts were reviewed, rather than a full review of papers being conducted. As the participants in Study 1 were recruited via the UK Haemophilia Society, this may have created a bias around the boys and parents (almost all mothers) who may have positive views around exercise and physical activity. The eventual numbers included in the study may seem small, which is largely explained by the rare occurrence of haemophilia; however, it is expected that by progressing to a larger trial, recruitment across 11 to 12 study sites will increase recruitment pools.

| CON CLUS ION
The DOLPHIN study drew upon the person-based approach to involve boys, families and health-care professionals to design, develop and refine a muscle strengthening exercise programme for boys with haemophilia. A new intervention was designed, which was then demonstrated and refined through engagement with the boys and their families. The boys, families and the study's physiotherapists were consulted following its delivery to evaluate any elements of the programme that did not work. The intervention was generally acceptable to the patients with some refinements necessary prior to progressing to a future RCT. In addition, it has been shown how involving users can potentially help researchers to simply and effectively address any challenges posed when working with children with rare diseases.

ACK N OWLED G EM ENTS
We would like to thank all of the children, parents and health-care professionals who took part in the data collection, and in particular the UK Haemophilia Society who have provided their on-going support with the DOLPHIN project.

CO N FLI C T O F I NTE R E S T
The authors declare no conflicts of interest.

AUTH O R CO NTR I B UTI O N
FH involved in the study design, conduct and analysis of the qualitative data. FH, DS, WD, MB and TPH conceived the original study.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets generated and analysed during the current study are not publicly available due to privacy and ethical reasons but are available from the corresponding author on reasonable request.