# The experience of clinical study and trial participation in rare diseases: A scoping review of centronuclear myopathy and other neuromuscular disorders

Lizan Stinissen, Sietse Bouma, Johann Böhm, Jeno van Tienen, Holger Fischer, Zak Hughes, Anne Lennox, Erin Ward, Marie Wood, A Reghan Foley, et al.

► To cite this version:

Lizan Stinissen, Sietse Bouma, Johann Böhm, Jeno van Tienen, Holger Fischer, et al.. The experience of clinical study and trial participation in rare diseases: A scoping review of centronuclear myopathy and other neuromuscular disorders. Neuromuscular Disorders, 2024, 38, pp.1-7. 10.1016/j.nmd.2023.12.014. hal-05043223

HAL Id: hal-05043223

https://hal.science/hal-05043223v1

Submitted on 23 Apr 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Review

# The experience of clinical study and trial participation in rare diseases: A scoping review of centronuclear myopathy and other neuromuscular disorders

<figure><img src="image_2.png" /></figure>

Lizan Stinissen<sup>a</sup>, Sietse Bouma<sup>a</sup>, Johann Böhm<sup>b</sup>, Jeno van Tienen<sup>c</sup>, Holger Fischer<sup>c</sup>, Zak Hughes<sup>d</sup>, Anne Lennox<sup>d</sup>, Erin Ward<sup>e</sup>, Marie Wood<sup>e</sup>, A. Reghan Foley<sup>f</sup>, Wija Oortwijn<sup>g</sup>, Heinz Jungbluth<sup>h,i</sup>, Nicol C. Voermans<sup>a,∗</sup>

ARTICLE INFO

Article history:
Received 24 May 2023
Revised 9 November 2023
Accepted 22 December 2023

Keywords:
Participants' experience
Trial participation
Congenital myopathies
Neuromuscular disorders

A B S T R A C T

The design of a clinical trial for a rare disease can be challenging. An optimal study design is required to effectively study the clinical outcomes for possible therapies for these types of disorders. Understanding the study participants' experiences as well as barriers and facilitators of participation are important to optimize future research and to inform clinical trial management. Centronuclear myopathies (CNMs) including X-linked myotubular myopathy (XLMTM) are a group of rare congenital myopathies for which there is no cure currently. Since 2014, a number of natural history studies and clinical trials have been conducted in CNMs. Two trials have been prematurely terminated because of severe adverse events. Since no research has been conducted regarding trial experience in CNM, we performed a scoping literature research on clinical trial experience of patients with neuromuscular disorders in general. The most common barriers to trial participation of patients comprise concerns about potential harmful effects, opportunity loss and the expected burden on daily life. The most common facilitators were an expected benefit on the disease course, altruism and collateral benefit. While several results are in line with trial experiences of other types of patients, for example oncological patients, distinctions can be made for patients with CNM and other neuromuscular disorders. However, the limited availability of relevant literature suggests that future (qualitative) research should focus on trial experiences in CNM patients.

© 2024 The Authors. Published by Elsevier B.V.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

1. Introduction

Rare diseases collectively affect 300 million people worldwide. More than 6000 distinct disorders are described, mostly genetic, pediatric in onset and severely disabling or even life-threatening

[1]. Commercial interest in drugs for rare disease has flourished with scientific advances and the orphan drug status legislation. This has rapidly expanded the field of orphan drug development.

However, studying rare diseases is challenging. Participant populations are small, and inclusion is restricted by rigid inclusion and exclusion criteria. There is often incomplete understanding of genotype-phenotype correlation and natural history data are scarce. Finally, sensitive, non-invasive biomarkers, clinical outcome measures and patient-reported outcome measures to monitor

Article history:
Received 24 May 2023
Revised 9 November 2023
Accepted 22 December 2023

Keywords:
Participants' experience
Trial participation
Congenital myopathies
Neuromuscular disorders

<footnote><sup>a</sup> Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands</footnote>

<footnote><sup>b</sup> Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U 1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France</footnote>

<footnote><sup>c</sup> ZNM ZusammenStark!, Germany</footnote>

<footnote><sup>d</sup> Myotubular Trust, United Kingdom</footnote>

<footnote><sup>e</sup> MTM-CNM Family Connection, USA</footnote>

<footnote><sup>f</sup> Neuromuscular & Neurogenetic Diseases of Childhood, Neurogenetics Branch (NGB), NIH, USA</footnote>

<footnote><sup>g</sup> Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands</footnote>

<footnote><sup>h</sup> Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom</footnote>

<footnote><sup>i</sup> Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College, London, United Kingdom</footnote>

<footnote>* Corresponding author.
E-mail address: Nicol.Voermans@radboudumc.nl (N.C. Voermans).</footnote>
treatment responses are limited for many diseases. Hence, designing a clinical trial for rare diseases is often extremely difficult. Optimal study design and partnerships between academia and industry are required for the successful development, delivery, and clinical approval of effective therapies in this group of disorders [2]. Centronuclear myopathies (CNMs) are a group of rare inherited neuromuscular disorders for which preclinical research has led to two international clinical trials in the past decade. Until then no cure was available for CNM, and its management had been symptomatic and supportive [3,4]. The ASPIRO trial was conducted at seven centres in Canada, France, Germany, and the USA. 24 boys (aged <5 years) with X-linked myotubular myopathy who were on mechanical ventilatory support were enrolled (NCT03199469). In parallel, the unite-CNM trial included 18 patients (aged >16 years) with X-linked myotubular myopathy or autosomal dominant DNMT2-related CNM (NCT04033159). The trials were both stopped prematurely because of severe liver side effects, ranging from reversible liver failure abnormalities to fatal liver failure.

These developments have led to a range of preclinical and clinical studies on the liver involvement in these diseases and on the pathophysiology in liver tissue. In parallel, important lessons can be learnt from the experiences of the participants in these and in previous trials, and of the patient organisations that have often played important roles in the long way towards clinical trials, during the trials, and afterwards.

Research on experience of clinical trial participation in rare neuromuscular disorders is limited, and has not been performed in CNM or other congenital myopathies. The goal of this scoping review was therefore to review the literature on the clinical study or trial participation experience of patients with neuromuscular disorders in general. The ultimate aim was to learn from participant experience for future trials. This has led to the following research questions: (1) What is the experience of patients with neuromuscular disorders participating in natural history studies and trials? and (2) What are potential barriers and facilitators of participation, and how could those probably be mitigated and trial experiences improved?

## 2. Methods

This scoping review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-Scr) guidelines, which follows a systematic approach to map evidence on a topic with emerging, heterogeneous evidence and to identify main concepts, theories, sources, and knowledge gaps [5]. This approach allowed us to structurally synthesize evidence and assess the scope of literature on experiences of clinical study and trial participation in neuromuscular disorders.

**Information sources and search strategy.** The literature search was performed in PubMed with the assistance of an information specialist at the library of the Medical Sciences at the Radboud University in Nijmegen, the Netherlands. Due to the limited availability of articles specifically about trial participation in CNM patients, the search was subsequently extended to neuromuscular disorders in general. The search strategy combined two search items; neuromuscular disorders and trial participation. This has led to the following search strategy that was used to identify relevant and suitable articles: ((("Muscular Diseases"[Mesh] OR centronuclear myopath*[tiab] OR CNM[tiab] OR congenital myopath*[tiab] OR muscle atroph*[tiab] OR Muscle disease*[tiab] OR Muscle disorder*[tiab] OR muscular atroph*[tiab] OR Muscular disease*[tiab] OR Muscular disorder*[tiab] OR Myopath*[tiab])) AND ((("Epidemiologic Study Characteristics"[Mesh] AND ("Patient Participation"[Mesh] OR "Patient Dropouts"[Mesh])) OR Trial participation[tiab]))). Trial participants were defined as including

patients, parents and/or caregivers included in the study. There was no restriction on publication year. No additional filters were used, but only articles in English were selected with a publication range from 1990 until December 22nd 2022. Only articles in English were selected. Subsequently, the included articles in this review were analysed in Web of Science to possibly identify any additional literature that cited these articles.

**Inclusion strategy.** Any case report, case series, clinical study or conference abstract with information on the experience of clinical study and trial participation in neuromuscular disorders was included. Literature reviews were used to identify new case studies through backward and forward screening but were not themselves included in our analysis in order to prevent double inclusion of studies. All identified studies were collected in EndNote 20 and duplicates were removed. Each article was independently screened for eligibility by two authors (LS and NV) based on title and abstract by using Rayyan Systems Inc (http://rayyan.qcrl.org). Full texts of all potentially relevant studies were subsequently retrieved and further examined for eligibility. Inconsistencies were discussed until consensus was reached. The PRISMA flow diagram provides more detailed information regarding the selection process of studies (See Fig. 1).

**Data extraction.** The data-charting process was jointly developed by three researchers (LS, WO and NV). They determined which variables to extract following the research questions. Data was systematically extracted by two independent researchers (LS and NV) using the predesigned extraction sheet, including neuromuscular diagnosis, number of participants, study design of which experiences were assessed, and most important motivator(s) or facilitator(s) and burden(s). They subsequently discussed the results and updated the data-charting form in an iterative process. Most important motivator(s) or facilitator(s) and burden(s) were defined as factors which makes trial participation either more easy or difficult for the trial participants.

## 3. Results

Seventy-nine article titles and abstracts were scanned for relevance. Sixty-nine were excluded since they did not fulfil the inclusion criteria. This was mainly because the study was not about experiences of clinical study and trial participation or because the study population did not consist of patients with neuromuscular disorders. The remaining 10 articles had a full-text assessment, after which five were excluded based on the content (Fig. 1). This was mainly due to the wrong outcomes or the unavailability of the full text. The additional search in Web of Science did not yield any additional results. Hence, 5 articles were used for this review.

Table 1 shows an overview of the five included studies, which mainly involved patients with DMD, BMD and SMA. The main results of these studies are summarized in Fig. 2. The study of Zolkipli-Cunningham et al. in primary mitochondrial myopathies reported that muscle weakness, chronic fatigue, and exercise intolerance were the lead symptoms encouraging trial participation. The main reasons for patients to participate in a trial included expectation of a potential cure, improvement of disease symptoms, prevention of progression and potentially helping other patients. The realization of not having any existing or affordable alternative treatment option also prompted patients to participate in the trial. Motivating factors in the study trial design included not having to travel, or local travelling. The communication between the patient and the physician was described as a key factor in trial participation. Barriers in the design included needing an overnight stay, international travel, the need for additional expenses, and concerns about potential major side effects, including worsening of the disease [6].
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Flowchart illustrating the methodology of the systematic literature search. *n* = number of articles.</figcaption></figure>

The study of Peay et al. focused on the trial experience of patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and spinal muscular atrophy (SMA) [7]. In this group, the parental interest in clinical trials was high, and barriers consisted of concerns about the possibility of receiving a placebo and not being randomized into the study arm; the latter concerns lead to some parents specifically searching for clinical trials that did not have a placebo arm. Additionally, another barrier reported was receiving insufficient information about potential risks and benefits. The main facilitators consisted of an expectation to enhance disease knowledge and recommendation of the trial by the child's physician. Parents found it important that their perceptions and expectations matched their clinician's, and they valued transparency in communication between participants and their physician. However, provider communication

could also adversely affect potential participant interest since knowledge of the actual trial burden could become more apparent.

Naarding et al. reviewed the reasons why patients or caregivers declined participation and compared characteristics of participants and non-participants to assess possible selection bias in four observational studies, three on DMD and one on BMD [8]. They reported the following potential barriers for trial participation: travel time to the study site, burden of the protocol in general (related to the time that had to be invested, and missed days at school or work), and having to undergo an MRI. This part of the studies was considered to be difficult, unpleasant, long, or frightening. Children often preferred study visits during holidays and/or on weekends, while others preferred working days. Additional perceived burdens included the potential psychological

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Overview of barriers and facilitators in trial participation of patients with muscle disorders.</figcaption></figure>
<table><caption>**Table 1**
Overview of studies regarding trial participation in patients with muscular diseases.</caption><thead><tr><th>Study</th><th>NMD</th><th>Participants</th><th>Study design</th><th>Most important motivator(s) or facilitator(s)</th><th>Most important burden(s)</th></tr></thead><tbody><tr><td>Zolkipli-Cunningham et al. (2018)[8]</td><td>Primary mitochondrial disease (PMD)</td><td>Adults (n = 15)<br>Children (n = 15)</td><td>Online electronic survey: Demographics, Symptom checklist of 35 options, Drug therapy, Study Design, and Additional Study Design Factors</td><td>Potential treatment effect Helping others Communication between patient and clinician</td><td>Travel time<br>Overnight stay<br>Concerns about side effects</td></tr><tr><td>Peay et al. (2018)[7]</td><td>Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and spinal muscular atrophy</td><td>Parents of children with disease (n = 203)</td><td>Online electronic survey: Sociodemographic and Disease Characteristics, Unmet Psychosocial Needs, Respite Care Needs, Caregiving Facilitators, Open-item need and self-care items</td><td>Expectation to enhance disease knowledge Expectation to receive recommendation of the clinician</td><td>Concerns about placebo Insufficient information about potential risks and benefits</td></tr><tr><td>Moultrie et al. (2018) [9]</td><td>Duchenne/Becker muscular dystrophy (DBMD), Spinal muscular atrophy (SMA).</td><td>Parents of children with DBMD (n = 86)<br>Parents of children with SMA (n = 53)</td><td>Evidenced-based clinical trial deliberation tool derived from exploratory survey data and previous qualitative studies</td><td>Helping others Potential treatment effect Psychological benefit Enhancing disease knowledge N.A.</td><td>Harm to child<br>Opportunity loss<br>Lack of information<br>Travel and costs burden<br>Burden of protocol</td></tr><tr><td>Naarding et al. (2020) [8]</td><td>Duchenne muscular dystrophy (DMD), and Becker muscular dystrophy (BMD)</td><td>3 pediatric DMD studies (n = 35, n = 12, n = 22) 1 adult BMD study (n = 36)</td><td>Four observational studies regarding decision-making for participation focusing on DMD and BMD using the Dutch Dystrophinopathy Database (DDD) for recruitment</td><td></td><td>Travel time Having to undergo an MRI</td></tr><tr><td>Peterson et al. (2022) [10]</td><td>Spinal muscular atrophy (SMA)</td><td>Patients or parents of patients with SMA (n = 70)</td><td>Literature screening complemented by discussions with parents and caregivers of SMA trial participants. Online electronic survey: experiences with recruitment and enrollment, research visits, and study teams.</td><td>Positive interaction with study team Potential treatment effect Access to study drug Helping others Receiving information and timely updates</td><td>Travel time Conflicts with work and school</td></tr></tbody></table>

n = number of participants, N.A. = not applicable.

impact, pre-existing behavioural difficulties of patients, and the effort and stress involved. These barriers were similar in both DMD and BMD patients.

The study of Moultrie et al. in DMD, BMD and SMA patients used exploratory survey data and previous qualitative research to describe different domains regarding potentially harmful impacts of trial participation [9]. The first domain included harm to child, which could, for example, be caused by side-effects or not gaining any benefit from the trial. The second domain included opportunity loss, which meant missing out on participating in another trial or receiving a placebo. The third domain was about burden, which included travel time, strain on family, costs and schooldays that were missed. The final domain was lack of information, which included not being kept up-to-date during the trial or after the trial has ended. Additionally, Moultrie et al. also formulated four domains regarding the benefits of trial participation. The first domain included altruism, which meant the benefit for future participants, or the knowledge that scientists could gain from the results of the trial. The second domain included child benefit. Child benefit meant that the trial could potentially result in the development of a successful drug, improving or extending the life span of the child. The third domain included psychological benefits, in particular giving parents a sense that were doing everything to help their child and making them feel more optimistic about the future of their child. The last domain included collateral benefits, which meant allowing parents to better understand the illness of their child and connecting them to similar families.

Finally, Peterson et al. reported the overall perspectives, concerns and stressors in patients with SMA, and their parents or caregivers [10]. The respondents reported an overall positive experience regarding trial management. This included the communication with the study team, receiving sufficient information about the trial and the trial logistics in general. The main motivators for trial participation included the expectation of a clinical benefit and improving the quality of life of the patient. Other motivators, which were less significant but were still mentioned, included the interaction with the study team, the contribution to science, the hope for a better future and helping other patients with SMA. The most important concerns regarding trial participation included the uncertainty about the safety, benefits and potential adverse effects, and the fear of physical and mental pain. Moreover, the long-term commitment to the trial, travel time, time in general and its influence on a patient's daily life were concerns as well. Overall, the motivators weighted more heavily than the concerns that the participants experienced.

## 4. Discussion

The rationale of this scoping review was the premature stop of two recent phase1-2 trials in CNMs. We aimed to explore the trial participation experience of patients with neuromuscular disorders in general, since we anticipated that this had not yet been investigated in CNM or other congenital myopathies. We planned to describe the barriers, facilitators and lessons learnt. We will discuss the main findings below.
The five studies in various neuromuscular disorders pointed to several common themes. First, gaining a better understanding about the disease was a prominent motivation for participation in four studies [7–10]. This aspect is clearly influenced by the communication between the patient and the clinicians, the contract research organization and/or the patient organization. Improving the communication is likely to improve the understanding of the disease, the possible benefits and harms, and the trial in general, ultimately taking away some of the uncertainty regarding trial participation. Parents found it also important that their perceptions and expectations corresponded with those of their clinician. Another common reason for participation was the hope for a better future by finding a treatment and extending a patient's life span.

The main barrier for trial participation in all studies consisted of fear of parents concerning the possible harm to the child, for example caused by side-effects and/or possible worsening of the disease. Additionally, the possibility of being randomized into the placebo arm instead of the study arm was a main reason for patients not to participate in a trial, considering the potentially associated opportunity loss stated in the study of Peay et al. and Moultrie et al. [7,9]. Other barriers included the anticipated impact on normal life, for example related to the travel time necessary to get to the hospital or research facility and/or having to take off days from school or work.

The findings of these five studies present important recommendations for future trials in rare neuromuscular disorders and possibly also for other rare diseases. Reducing the travel time and costs for the participants is likely to facilitate trial participation. In particular, having to travel during rush hour increased the travel time, a consideration that should be taken into account when planning visits to the clinical trial facility. According to the study of Naarding et al., optimization of the MRI protocol was also an important factor: the duration of the MRI should be re-evaluated and adjustments concerning patient comfort should be made in particular when the participant is a child. This can for example be done through the use of distracting videos or the presence of a parent in the MRI room [8]. Finally, providing information and building trusting a relationship with the healthcare/study provider were found to be critical factors as well, especially in the study of Peay et al. and Peterson et al. [7,10]. The patient organizations, sponsors, study sites and physicians can all play a role in this by ensuring that information and communication is clear and consistent. The preferences in trial logistics, like accommodational logistics, visit schedules and site selection should all be discussed among these different stakeholders. Zolkipli-Cunningham et al. mentioned the need to provide patient-centric solutions to reduce travel time, costs and the amount of study visits, since these were considered to be common barriers in trial participation [6]. Naarding et al. elaborated on this topic as well, by stating travel time with private wheelchair transportation as an important barrier [8].

Travelling with a wheelchair is likely to take considerably more time and patients might require additional respiratory equipment or other medical devices as well. Time off from school or work was also considered as an important burden. Even though patients might not mention financial implications, out-of-pocket expenses have shown to be major deterrents. Patients might already face economic challenges regarding cost of care and medical equipment that is not covered by their health insurance, so absence from work can have an enormous impact on these patients or the parents of patients. After we had completed our review, an interesting study on the experience of trial participation in DMD patients and their parents was published. Boys with DMD experienced a better overall quality of life when they participated in a clinical trial compared to boys with DMD that did not participate. This might

be related to the frequent study visits. Furthermore, participating in a trial might provide hope, leading to a better emotional quality of life. Mothers and fathers are likely to be impacted differently by the trial participation of their child. Finally, the researchers recommended psychosocial support for decision making in trial participation and for patients that are screened but not found eligible to participate [11].

The outcomes of this scoping review have an overlap with results of research on trial experiences in oncology patients [12,13]. These include various burdens reported at different trial stages. During the informed consent process, patients reported a fear of not being treated, for example by receiving a placebo. Other demotivating factors were being anxious to participate while waiting for inclusion; the fear of being a 'guinea pig'; and not understanding or being confused by the trial information and terminologies at inclusion and during follow-up. Other themes were negatively conceptualizing placebos, which is in line with some of the results of the patients with muscle disorders; and the economic and physical impacts (e.g. missed income, travel expenses) [12]. Understanding the effectiveness of the treatment and possible risks was also considered to be an important factor in oncology trial participation [13]. It was suggested that oncology nurses can address patient enrolment barriers by providing targeted education and participating in the informed consent process. This is in line with a different study regarding patient's experiences in a Phase I clinical trial among oncological patients that states the position of nurses to offer information to their patients regarding trial participation. Mainly the hope for a therapeutic benefit and the trust in their physician were facilitators in participation [14]. Other motivators for trial participation we encountered are in line with those observed in a qualitative study in genomics research. These motivators included personal benefit and benefit for others, specifically family members. Subsequently, altruism was considered an important motivator as well. A trusting clinical relationship with the study provider or healthcare provider was also deemed as an motivating factor [15]. Finally, the study of Meyer-Macauley et al. elaborates on parent and family led resources regarding decision-making around tracheostomy placement in children, which can be relatable for children with muscular disorders [16]. The uncertainty, but also hope that caregivers have for their child is being mentioned. The lack of normalcy is also stated; parents are being careful when going out and explain how it can be isolating and difficult to relate to other people. This emotional impact could be relatable for many patients with NMDs. Additionally, financial concerns were experienced by the caregivers in this study. The acceptance of the condition and the importance of the quality of life were mentioned as well. Caregivers shared advice and talked about moral support, all these factors can be equally important for patients or caregivers of patients with NMDs [16]. Even though these results are to some extent similar, differences in disease course could influence someone's trial experience. Oncological patients are generally diagnosed suddenly and unexpectedly, whereas patients with CNM and other neuromuscular disorders often have a congenital onset and receive their diagnosis in the first years of life. Consequently, the role of patient organizations differs significantly. In contrast to oncological patients, patients with CNM have often been involved in a patient organization within the rare disease community for many years, being informed about developments in preclinical research which has provided hope. Patient organizations could play an important role in reducing the possible barriers and enhancing facilitators in various ways. They could review the patient information forms before review by the ethical board to check whether the text is understandable. Furthermore, they may provide informative resources, such as instruction videos and webinars, whose distribution among advocates, parents, and clinicians, may
<figure><img src="image_5.png" /><figcaption>**Fig. 3.** Specific features of the process of clinical trials in (ultra) disorders. There are approximately 10 international patient organizations and support groups. They have been contributing to preclinical and clinical research by co-funding specific research projects and keeping patients and family members updated about the progress of the research they fund. The patient organizations are also collaborating with industry partners, researchers, and all stakeholders involved to ensure the priorities of the patient community. Moreover, information about meaningful outcomes from the patient perspective they provide is an important part of clinical trial decision-making and design. Furthermore, patient organization and support groups facilitate dedicated peer support to many patients and have played an important role in informing their members about clinical studies. This has a significant impact on the practice of conducting trials.</figcaption></figure>

assist decision-making processes around rare disease clinical trials and treatments [17]. Furthermore, many patients with a rare disease such as CNM know each other and regularly meet at family conferences, and the sponsor may be in direct contact with the board and other members of the patient organizations (Fig. 3).

This scoping review has several limitations. First of all, none of the articles discussed the experience of CNM patients, emphasizing the importance of future research. Other limitations included the social desirability bias that some participants may have had, for example that parents may have felt obliged to find altruism more important than their individual benefits. Since these were all retrospective studies, in which the participants received surveys, there could also be recall bias. Recently, the importance of improving diversity in clinical trials has been underscored. This is essential in order to produce generalizable results. A study focusing on trial participation in Lupus patients concluded how several demographic factors, for example ethnicity, and medical factors, for example disease severity, contributed to this [18]. Community engagement is an integral part of recruitment and retention of underrepresented groups [19]. The diversity in trials in neuromuscular disorders is also challenging [20]. This most likely caused a selection bias for participation in the studies this scoping review has selected. Finally, the number of selected studies was limited to five.

The lack of studies on trial experiences in neuromuscular disorders call for future research. This should preferably be done prospectively as part of the study protocol of trials. Both trial expectations and experiences can be assessed quantitatively by online surveys for participants. This is expected to also offer a check on the preparedness of patients and the execution of the trial. In addition, qualitative studies via interviews or focus groups are expected to provide deeper insights into this topic. We have recently performed a qualitative study on the patient perspective and lessons learnt in trials in centronuclear myopathies [21]. The rationale for this study was to make the experiences within the patient organizations available in the medical literature. Exploring grey literature (including reports of the pharmaceutical company patient advisory boards, information on websites of patient organizations, and/or content on online platforms for specific rare diseases) would be a valuable addition for future research. Efforts to understand the trial experience of CNM patients and caregivers to date would provide valuable information to better inform future trial design from a patient-centred perspective; mitigate barriers to future participation, and ultimately optimize the patient experience in future trials.

Declaration of competing interest

None.

Acknowledgment

Several authors of this publication are members of the Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for rare neuromuscular diseases (EURO-NMD). We are grateful to the patient organizations supporting all CNM patients participating in natural history studies and clinical trials: ZNM Zusammen Stark!, Myotubular Trust (United Kingdom), MTM-CNM Family Connection (USA), Guerreros Miotubulares Organisation (Argentina), Heroes MTM (Brazil), Fundacion Weychafe (Chile), Fimm Italia Organisation (Italy), Oswoic Miopatie Organisation (Poland), Petits Superherois (Spain), Where There's A Will There's A Cure (USA), Joshua Frase Foundation (USA) and MTM1_Fighter_Redkie_Deti (Russia).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.nmd.2023.12.014.

References

[1] Nguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020;28:165-73.

[2] Pizzamiglio C, Vernon HJ, Hanna MG, Pitceathly RDS. Designing clinical trials for rare diseases: unique challenges and opportunities. Nat Rev Methods Prim 2022;2.

[3] Wang CH, Dowling JJ, North K, Schroth MK, Sejersen T, Shapiro F, et al. Consensus statement on standard of care for congenital myopathies. J Child Neurol 2012;27:363-82.

[4] Lawlor MW, Dowling JJ. X-linked myotubular myopathy. Neuromuscul Disord 2021;31:1004-12.

[5] Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med 2018;169:467-73.

[6] Zolkipli-Cunningham Z, Xiao R, Stoddart A, McCormick EM, Holberts A, Burrill N, et al. Mitochondrial disease patient motivations and barriers to participate in clinical trials. PLoS ONE 2018;13:e0197513.

[7] Peay HL, Biesecker BB, Wilfond BS, Jarecki J, Umstead KL, Escolar DM, et al. Barriers and facilitators to clinical trial participation among parents of children with pediatric neuromuscular disorders. Clin Trials 2018;15:139-48.

[8] Naarding KJ, Doorenweerd N, Koeks Z, Hendriksen RGF, Chotkan KA, Krom YD, et al. Decision-making and selection bias in four observational studies on duchenne and becker muscular dystrophy. J Neuromuscul Dis 2020;7:433-42.
[9] Moultrie RR, Lewis MA, Paquin RS, Lucas A, Jarecki J, Peay HL. An evidence-based, community-engaged approach to develop an interactive deliberation tool for pediatric neuromuscular trials. J Genet Couns 2018;27:416–25.

[10] Peterson IS, Mazzella AJ, Belter LT, Curry MA, Cruz RE, Jarecki J. The Cure SMA clinical trial experience survey: a study of trial participant perspectives on clinical trial management and patient-centric management practices. Neurol Ther 2022;11:1167–81.

[11] Geuens S, Willen J, Antonis C, Stegen G, Gielis E, Cuveele E, et al. The impact of clinical trial participation on quality of life and psychosocial well-being in children with Duchenne muscular dystrophy and their parents. Neuromuscul Disord 2023;33:877–81.

[12] Naidoo N, Nguyen VT, Ravaud P, Young B, Amiel P, Schante D, et al. The research burden of randomized controlled trial participation: a systematic thematic synthesis of qualitative evidence. BMC Med 2020;18:6.

[13] McKinney M, Bell R, Samborski C, Attwood K, Dean G, Eakle K, et al. Clinical trial participation: a pilot study of patient-identified barriers. Clin J Oncol Nurs 2021;25:647–54.

[14] Schutta KM, Burnett CB. Factors that influence a patient's decision to participate in a phase I cancer clinical trial. Oncol Nurs Forum 2000;27:1435–8.

[15] Berrios C, James CA, Raraigh K, Bollinger J, Murray B, Tichnell C, et al. Enrolling genomics research participants through a clinical setting: the impact

of existing clinical relationships on informed consent and expectations for return of research results. J Genet Couns 2018;27:263–73.

[16] Meyer-Macaulay CB, Graham RJ, Williams D, Dorste A, Teele SA. New trach mom here...": a qualitative study of internet-based resources by caregivers of children with tracheostomy. Pediatr Pulmonol 2021;56:2274–83.

[17] Nguyen CQ, Alba-Concepcion K, Palmer EE, Scully JL, Millis N, Farrar MA. The involvement of rare disease patient organisations in therapeutic innovation across rare paediatric neurological conditions: a narrative review. Orphanet J Rare Dis 2022;17:167.

[18] Harry O, Langefeld CD, Crosby LE, Modi AC. Factors associated with participation in clinical trials among patients with lupus. J Clin Rheumatol 2022;28:132–6.

[19] Kelsey MD, Patrick-Lake B, Abdulai R, Broedl UC, Brown A, Cohn E, et al. Inclusion and diversity in clinical trials: actionable steps to drive lasting change. Contemp Clin Trials 2022;116:106740.

[20] Ramdharry G. INV05: engaging patients from diverse backgrounds in NMD research. UCL Queen Square, Institute of Neurology, National Hospital for Neurology and Neurosurgery, UCLH NHS Trust; 2023.

[21] Stinissen L, Bohm J, Bouma S, van Tienen J, Lennox A, Fischer H, et al. Poster 409: lessons learnt from trials in centronuclear myopathies: a qualitative study from the patient perspective. Radboud University Medical Center; 2023.