# Lessons Learned From Clinical Studies in Centronuclear Myopathies: The Patient Perspective-A Qualitative Study

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

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## To cite this version:

Lizan Stinissen, Johann Böhm, Sietse Bouma, Jeno van Tienen, Holger Fischer, et al.. Lessons Learned From Clinical Studies in Centronuclear Myopathies: The Patient Perspective-A Qualitative Study. Clinical Therapeutics, 2024, 46 (10), pp.742 - 751. 10.1016/j.clinthera.2024.03.008. hal-05027121

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Submitted on 9 Apr 2025

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Original Research

# Lessons Learned From Clinical Studies in Centronuclear Myopathies: The Patient Perspective—A Qualitative Study

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Lizan Stinissen, MSc<fnref n="1" />, Johann Böhm, PhD<fnref n="2" />, Sietse Bouma, MSc<fnref n="1" />, Jeno van Tienen<fnref n="3" />,
Holger Fischer, PhD<fnref n="3" />, Zak Hughes<fnref n="4" />, Anne Lennox, MBA<fnref n="4" />, Erin Ward, MEd<fnref n="5" />, Marie Wood, BSc<fnref n="5" />,
A. Reghan Foley, MD<fnref n="6" />, Wija Oortwijn, PhD<fnref n="7" />, Heinz Jungbluth, PhD<fnref n="8" />,<fnref n="1" />,<fnref n="9" />,
Nicol C. Voermans, MD, PhD<fnref n="1" />,*

ARTICLE INFO

Keywords:

Antisense oligonucleotide

Centronuclear myopathy

Gene therapy

X-linked myotubular myopathy

ABSTRACT

**Background:** Since 2014, several clinical studies focusing on centronuclear myopathies have been conducted, including a prospective natural history study, a gene transfer clinical trial and a clinical trial using an antisense oligonucleotide. Dedicated patient organizations have played an important role in this process. The experience of members of these organizations, either as a study participant, parent or as a patient organization member communicating with the sponsors are potentially very informative for future trial design.

**Methods:** We investigated the burden of and the lessons learned from the first natural history studies and clinical trials from a patient perspective using a qualitative approach. We arranged 4 focus groups with a total of 37 participants from 3 large international patient organizations: ZNM-ZusammenStark!, the Myotubular Trust, and the MTM-CNM Family Connection. 4 themes, based on a systematic literature search were discussed: Expectations and preparation, Clinical study participation, Communication and Recommendations for future clinical trials. The focus group recordings were transcribed, anonymized, and uploaded to Atlas-ti version 8.1 software. The data were analyzed using a thematic content analysis.

**Results:** Overall, participants were realistic in their expectations, hoping for small improvements of function and quality of life. The realization that trial participation does not equate to a treatment was challenging. Participating in a clinical study had a huge impact on many aspects of daily life, both for patients and their immediate families. First-hand insights into the burden of the design and its possible effect on performance were provided, resulting in numerous compelling recommendations for future clinical studies. Furthermore, participants stressed the importance of clear communication, which was considered to be especially vital in cases of severe adverse events. Finally, while patients were understanding of the importance of adhering to the regulations of good clinical practice, they indicated that they would strongly appreciate a greater understanding and/or acknowledgment of the patient perspective and a reflection of this perspective in future clinical trial design.

**Conclusion:** The acknowledgment and inclusion of patients' perspectives and efficient and effective communication is expected to improve patient recruitment and retention in future clinical studies, as well as more accurate assessment of the patient performance related to suitable planning of the study visits.

<footnote n="1">¹ Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands</footnote>

<footnote n="2">² Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France</footnote>

<footnote n="3">³ ZNM-ZusammenStark!, Stuttgart, Germany</footnote>

<footnote n="4">⁴ Myotubular Trust, London, United Kingdom</footnote>

<footnote n="5">⁵ MTM-CNM Family Connection, Methuen, Massachusetts, United States</footnote>

<footnote n="6">⁶ Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, Maryland, United States</footnote>

<footnote n="7">⁷ Department Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands</footnote>

<footnote n="8">⁸ Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom</footnote>

<footnote n="9">⁹ Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London, United Kingdom</footnote>

<footnote>* Address correspondence to: Nicol C. Voermans, MD, PhD, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
E-mail address: Nicol.Voermans@radboudumc.nl (N.C. Voermans).</footnote>
## Introduction

Congenital myopathies are a group of neuromuscular disorders defined by distinct morphological changes and characterized by severe clinical symptoms due to weakness of skeletal, bulbar and respiratory muscles.¹ Centronuclear myopathy (CNM) is one of these congenital myopathies. There are 3 genetic forms of CNM including an X-linked form (myotubular myopathy; XLMTM) an autosomal recessive (AR) and autosomal dominant (AD) forms.²,³ Over the past decade, great advances have been made in the development of genetic therapies for CNM. Novel technologies will further advance the scope and success of genetic approaches targeting these neuromuscular disorders.

Since 2014, a number of clinical studies in CNM have been conducted, including the clinical assessment natural history study in XLMTM (INCEPTUS), the gene transfer clinical study in XLMTM (ASPIRO), and the early-phase clinical trial to investigate dynamin-101 (DYN101, an antisense oligonucleotide (ASO)(Unite-CNM)) (Supplementary Data 1). The ASPIRO gene therapy trial has been put on hold, and the Unite-CNM trial was terminated in 2022, both due to severe adverse events and suspected unexpected serious adverse reactions (SUSARs).⁴,⁵

ZNM–ZusammenStark https://znm-zusammenstark.org (Germany, the Netherlands and Austria), the Myotubular Trust https://myotubulartrust.org (UK) and the MTM-CNM Family Connection http://www.mtm-cnm.org (USA) are patient organizations for XLMTM and CNM with an international remit. The common goal is to connect those affected and their families, for mutual support and sharing of information via yearly family conferences, webinars and dedicated closed Facebook support groups. These organizations also invest in research activities aimed at improving the daily lives of patients and their families, focusing on proof-of-principle or clinical research projects that would not otherwise be funded by public or private funding bodies. The patient organizations collaborate with medical professionals, researchers, industry sponsors, regulatory agencies, and all stakeholders, striving to ensure the patient and caregiver voice are a part clinical trial decision-making and design.⁶ Many members of the patient organizations have been involved in the recent clinical studies and trials for CNMs, either as a study participant, a parent or as a patient advocacy group member communicating with the study sponsors.

The results of the ASPIRO trial have recently been published. Both the effect and side effects were striking. Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function. Four children had fatal cholestatic liver failure following gene therapy.⁴ Several lessons could be learned from this study. To improve future study design it is important to openly communicate about this with all stakeholders, including the patients (organizations).⁵ The members of ZusammenStark, the Myotubular Trust, and the MTM-CNM Family Connection have learned important lessons from participation and involvement in these first natural history studies and trials, and feel obliged to share the experience of individual study participants, and of their organizations, with clinicians, researchers and sponsors involved in future clinical trial design. Gaining insights into the patient perspective can minimize barriers for trial participation and optimize the trial experience.⁵,⁶ We therefore assessed the burden of and the lessons learned from the first natural history studies and trials from a patient perspective using focus groups.

## Methods

### Literature Review and Focus Group Guide

We performed a scoping literature review focusing on the lessons learned by patients and patient advocacy groups.⁶ The results of this review were used to draft the focus group protocol, which was subsequently discussed with members of ZNM-ZusammenStark! and revised accordingly. The final protocol covered 4 main topics: Expectations and

preparation; Clinical study participation; Communication and interpretation; and Recommendations (Supplemental Data 2).

### Ethical Approval

The study protocol was approved by the Radboudumc Ethics Review Board (ERB number 2022-13739). This ensures that the study will be carried out in accordance with the applicable legislation (Medical Research involving Human Subjects Act and Medical Treatment Contracts Act).

### Focus Groups and Data Analysis

We organized 4 focus groups for discussion of 1.5 hours each: one German and one English focus group at the 2022 Family conference of ZNM-ZusammenStark! (Bad Nauheim, Germany, May 2022), and 2 focus groups in English with the Myotubular Trust and the MTM-CNM Family Connection (online via Teams, respectively in September 2022 and January 2023). Each group consisted of 6 to 11 members and was led by a professional moderator (M. Offenberg, Nowwork). This group size is standard for focus groups, and considered to be large enough to generate sufficient discussion among all participants.⁷ Other participants, not involved in the group discussions, were N. Voermans (principal investigator of Unite-CNM study, medical expert and member of the scientific advisory board of ZNM-ZusammenStark!), H. Jungbluth (medical expert), and L. Stinissen (biomedical researcher), who provided background information prior to the start of the discussions. The industry sponsors (Dynacure and Audentes/Astellas) were informed by email at onset.

Inclusion criteria for the focus groups were: (parents or other caretakers of) participants of one of the recent clinical studies (age ≥ 18 years); member of patient organization (board, working group) who were involved in the preparation for or communication concerning the clinical studies; or other active members of patient organization who are interested in (future) clinical study participation and have followed the updates concerning these studies.

Patients and parents were recruited by the patient organizations (announcements on website; mailings to their members; Supplemental Data 3). The participant information and consent form were also sent by the patient organizations. Reasons for non-participation were noted. Only patients or other members who agreed to participate were contacted by one of 2 researchers (NV and LS). We collected demographic data of all focus group participants, including age, sex, role in study ((parent of) study or trial participant, patient advocacy group representative), and which trial study.

Most participants had signed a non-disclosure-agreement with the sponsor and were therefore not allowed to share data about the protocol or (side-)effects. Focus group participants were therefore only encouraged to talk about their experience of being a clinical study participant: the burden of taking part in a study, barriers and facilitators to study participation in general, and suggestions for future studies.

### Data Analysis and Interpretation

Data analysis and interpretation is included in Supplemental Data 4. Additionally, a summarized overview can be seen in Figure 1, showing the steps of the data analysis from the recording of the focus groups until the discussion of the preliminary results.

## Results

### Participants

In total, 37 participants attended 4 focus groups encompassing 6 to 11 participants each. A concise summary of the demographic data
<table><caption>**Table 1A**

Characteristics of focus group participants (summarized table).</caption><thead><tr><th></th><th>ZNM (G)</th><th>ZNM (E)</th><th>MTT</th><th>MTM-CNM</th><th>Total</th></tr></thead><tbody><tr><td>Total participants</td><td>11</td><td>10</td><td>6</td><td>10</td><td>37</td></tr><tr><td>N</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age: median (range) (years)</td><td>42 (18–56)</td><td>40 (21–61)</td><td>48 (26–57)</td><td>40 (32–48)</td><td>42 (18–61)</td></tr><tr><td>Male</td><td>6 (55)</td><td>5 (50)</td><td>3 (50)</td><td>4 (40)</td><td>18 (49)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>5 (45)</td><td>5 (50)</td><td>3 (50)</td><td>6 (60)</td><td>19 (51)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Study or trial participants</td><td>3 (27)</td><td>1 (10)</td><td>1 (17)</td><td>-</td><td>5 (14)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Parents or other caretakers</td><td>-</td><td>4 (40)</td><td>2 (33)</td><td>3 (30)</td><td>9 (24)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Active members who were involved in preparation<br>or communication</td><td>-</td><td>-</td><td>2 (33)</td><td>1 (10)</td><td>3 (8)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Other active members</td><td>6 (55)</td><td>2 (20)</td><td>1 (17)</td><td>1 (10)</td><td>10 (27)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Participants with multiple roles in process</td><td>2 (18)</td><td>3 (30)</td><td>-</td><td>5 (50)</td><td>10 (27)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>American participants</td><td>-</td><td>-</td><td>-</td><td>10 (100)</td><td>10 (27)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Belgian participants</td><td>-</td><td>1 (10)</td><td>-</td><td>-</td><td>1 (3)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>British participants</td><td>-</td><td>-</td><td>4 (67)</td><td>-</td><td>4 (11)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Irish participants</td><td>-</td><td>-</td><td>2 (33)</td><td>-</td><td>2 (5)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Dutch participants</td><td>-</td><td>2 (20)</td><td>-</td><td>-</td><td>2 (5)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>German participants</td><td>11 (100)</td><td>7 (70)</td><td>-</td><td>-</td><td>18 (49)</td></tr><tr><td>N (%)</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

This table shows the demographics of the participants. ZNM (G) and ZNM (E): ZusammenStark! (German and English discussion); MTT: Myotubular Trust; MTM-CNM: MTM-CNM Family Connection.

<figure><img src="image_5.png" /><figcaption>**Figure 1.** Overview of data analysis and interpretation.</figcaption></figure>

can be found in Table 1A. The full demographic data can be found in Supplemental Data 5. Some participants had more than one role in the process, including 8 study or trial participants, 18 parents or other caretakers, 10 active members of the patient organizations who were involved in preparation for or communication about the trial; and 12 other active members of the patient organizations who were interested in (future) trial participation and were following the updates. The cohort included 10 American participants (including 1 Mexican/American), 1 Belgian, 4 British, 2 Irish, 2 Dutch and 18 German participants (including 1 German/Ecuadorean). Participants were involved in one of the 8 studies. The Myotubular Trust encountered many members that were reluctant to participate. Hence, the size of the Myotubular Trust group was smaller (n = 6) compared to the size of the group of ZusammenStark! and MTM-CNM Family Connection, which consisted of 10 to 11 participants. Reasons for not-participation are presented in Table 1B.

## Themes, Subthemes and Related Quotes Derived From the Focus Groups

A number of subthemes were extracted from the data, all related to the main themes identified in the scoping literature review and which were used to guide the focus group discussions: Expectations and preparation (Table 2), Clinical study participation (Table 3), Communication (Table 4), and Recommendations for future clinical trials (Table 5). An overview of the main themes and subthemes can be found in Figure 2. We defined 22 specific codes (Supplemental Data 6) which were categorized into key aspects which best reflected the content of the discussion. Selected quotes are presented per key aspect to illustrate the importance to participants. Tables 2 to 5 show a summarized version of the selected quotes, the full tables can be found in Supplemental Data 7.

The total number of quotes coded in Atlas.ti was 425 (Supplemental Data 6). There was an nearly equal contribution of quotes by the 4 different groups: 91 and 116 for the English and German groups of ZNM-
<table><caption>**Table 1B**
Reasons for non-participation.</caption><tr><td>Painful emotions</td><td>The topic of taking part in studies seems to be very painful, according to the patients who've responded informally to us - it's painful if you were never selected, and it's painful if you were selected and the trial stopped<br>People are wary of sharing negative views in public - this may be different in an in-person situation/conference because it is easier to read the room<br>English culture is very different in terms of speaking out - very reserved and not very direct</td></tr><tr><td>Logistic reasons</td><td>We have picked up over time that parents in particular are angry - maybe people are wary of sharing anger on a zoom call<br>The time of day may be difficult - those with younger children are still settling children for bed, older patients report that their voices are weaker as the day goes by and prefer day time meetings (Saturday morning webinars have worked for us in the past)</td></tr><tr><td>Virtual instead of live meeting</td><td>In general maybe these are all very complex emotions to convey, and probably ones that people have buried as much as they can. It is a different choice to make to walk into a room at a conference you've already chosen to be part of, versus signing up to a Teams call in isolation<br>We feel that people who know the researchers would naturally and instinctively trust would her - so at an in person conference in Germany being in a room with her be appealing even for those who might normally be reluctant to share<br>Taking part and sharing difficult memories and emotions, and knowing that once the call was over you would be "alone" with those issues, and at night, could be an influence</td></tr><tr><td>Responsibility towards future trial participants</td><td>Some patients have reported that they feel that sharing the downsides of taking part in a trial may stop others taking part in the future - it feels like a big responsibility<br>People who felt "left out" of the gene therapy trial - and there were many - may find it difficult to say that, because of "survivor guilt." It's a challenging message to get across that you fervently wanted your child to take part in a trial, but you now feel guiltily relieved because they might have died had they been dosed.</td></tr><tr><td>Trial situation specific in UK</td><td>The UK environment was different as the gene therapy trial never opened here - maybe there's a view that "trials were never about us" in the under 18 age group<br>The tamoxifen trial has just started recruiting - maybe some families would be hesitant to open up in public in case they compromised their child's chance of joining it. A guarantee of anonymity is possibly harder in an online situation</td></tr></table>

This table shows the reasons for not-participating of members of the Myotubular trust. This is a summary provided by the active members of the patient association (AL, ZH).

ZusammenStark!, and 100 and 118 quotes for the Myotubular Trust and MTM-CNM Family Connection groups. The themes Trial participation (n=131) and Communication (n = 140) were more extensively discussed compared to the themes Expectations (n = 77) and Recommendations (n = 77).

Differences in the discussion between the focus groups mainly reflected geographical and/or cultural differences in the countries where the patient organizations are based. For example, the experiences of trial participation in the USA included extensive travel to the study site, requiring family members to be absent from work, whereas in the UK, a participant reported challenges of transportation and accommodation in central London. Despite these differences, all groups provided broad insights into participation in clinical studies.

<figure><img src="image_6.png" /><figcaption>**Figure 2.** Overview of the main themes and subthemes.</figcaption></figure>

## Theme 1: Expectations and Preparation

The total number of quotes related to this main theme was 77 (15-23 per group). Most frequently identified subthemes were “General,” “Better quality of life,” and “Helping others.” In the analysis, the quotes were further categorized in 4 key aspects of importance to participants as reported below: “Treatment and improved quality of life”; “Helping others”; “Balance between therapy effects and expected risks”; and “Deciding for your child’s versus your own participation.” Illustrative quotes of these key aspects of importance to patients are presented in Table 2. Overall, participants were realistic in their expectations, although they reported that it was challenging for them to acknowledge that a trial is not a treatment.

## Treatment and Improved Quality of Life

Hope for a treatment was a major motivation for trial participation. Many participants understood that this should not be the main incentive; however, they were frank in admitting that this was a very important motivation. This implied hope for a cure, hope for mild improvement (with fewer barriers in daily life enabling more independency), or hope for remaining stable. Examples that were mentioned included general improvement in strength and energy and having less pain, but also the regaining of lost motor skills and more specific ways of improving daily life activities. Improving the quality of life was the second important reason for trial participation.

In all 4 groups, patients discussed their impression of the presentations by researchers and sponsors during the annual conferences of the patient organizations, and how they tried to manage their expectations. They were fully aware of the differences between preclinical studies and clinical trials, and that positive results obtained on mouse or other animal models may not be easily extrapolated to patients. Many patients and family members reported that it was challenging, but also important to keep this in mind.

## Helping Others

Helping future research and future patients was another important reason for trial participation. While many participants mentioned that they wanted to learn more about the disease, they expressed a strong
<table><caption>**Table 2**
Illustrative quotes on trial expectations and preparation.</caption><thead><tr><td>Key aspect</td><td>Quotes</td></tr></thead><tbody><tr><td>Treatment and improved quality of life</td><td>"He had, you know, expressed that his hope had been really to improve minimal strength so that he could better and more easily communicate with his friends. So I think similar to what has been said, like maybe not necessarily looking for big curative outcomes, but things that would impact quality of life." (active member patient organization, MTM-CNM)</td></tr><tr><td>Helping others</td><td>"We really did it with the hope that it would impact future generations, that it was going to be something that would help people in the future because we were not sure that it would help us" (parent of trial/study participant, MTM-CNM)</td></tr><tr><td>Balance between therapy effects and expected risks</td><td>"My task in the patient association was to try to tell others, look this clinical trial has not the objective to cure your kids, but to figure out whether it works or not. But it is very difficult to keep telling that to people that are in desperate hope to get cured or to get their kids to be cured." (active member patient organization, ZSM (E))</td></tr><tr><td>Deciding for your child's versus your own participation</td><td>"For me I found it a worry, because I took the decision after all, because the children were simply young, and if they really do die of it, then I would have the responsibility all on my own, and then I'm guilty" (parent of trial/study participant, ZSM (G))</td></tr></tbody></table>

motivation to contribute to the knowledge that will likely benefit future patients, both children and adults. The majority of participants showed a broad understanding that participating in the trial is not only about a chance of improving their own situation, but mainly about the long-term scientific and clinical trajectory towards a treatment for CNM and other myopathies in the future.

## A Trial Is Not a Treatment: Balance Between Therapy Effects and Expected Risks

As stated above, all focus groups discussed the fact that trial participation is not a treatment. If high expectations are presented during (virtual) meetings of patient organizations, the trial compound can incorrectly be considered an approved treatment. It was deemed very important that the distinction between a trial compound and an approved treatment is clear throughout the process, considering the understandable but potentially misplaced hope for a treatment for their child or themselves. In all groups, it was emphasized that the patient organizations can play an important role in communication of both potential effectiveness of the trial drug and potential risks before and during the trial.

## Deciding for Your Child's Versus Your Own Participation

The significant burden of responsibility for parents to decide about trial participation of their child was discussed, in particular where this seemed like a life-or-death decision. In line with this observation, parents of adolescents expressed relief that their child could make their own decisions (or take part in decision-making as part of a joint process).

## Theme 2: Clinical Study Participation

The total number of quotes related to this theme was 131 (20–44 per group). In the focus group of the Myotubular Trust (UK), this was the most extensively discussed theme (n = 44/100 quotes). The most frequently identified subthemes across the 4 focus groups were “Experience” (n = 68) and “Financial compensation” (n = 36). In the analysis, the quotes were further categorized into 3 key aspects of importance to patients which are reported below: “Daily life,” “Clinical study experience,” and “Financial Compensation” (Table 3). The results show that participating in a clinical study, especially a clinical trial, had a major impact on many aspects of daily life, both of the patients and their family members. Participants were able to provide a vivid insight into the burden experienced, and their concerns about the influence of the strenuous study design on their performance in the specific tests, resulting in many specific and helpful recommendations (Theme 4).

## Daily Life

Trial participation had a very strong impact on daily life, affecting school and work of participants and/or their family members. Many parents had to take time off from work, and adult participants were

dependent on colleagues willing to take over their tasks at work. The time to travel and the frequency of visits impacted on daily life. This was frustrating in the case of study visits that only consisted of simple examinations that could have been performed locally; some parents mentioned that they had not realized at the start how large this impact would be. The required financial expense seemed feasible at first but appeared different after 2 years. Furthermore, the coincidence of the trials with the COVID-19 pandemic posed an additional unrelated but confounding burden, resulting in almost complete self-isolation of the families and a sense that their lives were put on hold. Nevertheless, various parents stated that they never experienced fundamental doubts regarding their participation.

## Clinical Study Experience

Various participants underscored the positive effect of a dedicated Principal Investigator (PI) who was familiar to them and knew the condition in general and the specific health issues of the participant. Flexibility and accessibility of the PI were evaluated very positively. Several participants had study visits planned at affiliated centers, where they encountered health care providers who, in their experience, were not always fully informed and/or fully dedicated, resulting in an overall more negative experience.

Another major topic was the logistics of the study visits, including traveling, hotel stays, study visit programs, and reimbursement arrangements. According to participants, the study teams in various centers did not sufficiently consider how much needs to be organized before a patient with nocturnal (non-invasive) ventilation and wheelchair use can travel to the hospital. This caused stress for patients and families. Some patients expressed serious concerns about their perceived underperformance on functional tests; e.g. after having to skip breakfast or to hurry to get to the hospital. Many patients always plan many aspects of daily life in detail to function optimally, and trial participation did not offer sufficient flexibility to do this.

## Financial Compensation

2 aspects of financial compensation were discussed. First, the reimbursement of costs for hotel, travel and food was often delayed. Allowances were provided for this, however, some participants had to pay for this themselves and reimbursement took place afterwards. This was challenging for some families, bearing in mind the considerable costs involved (up to 2500 dollar per visit for North American participants). Some participants were concerned that this may create a barrier to participation for those in a less financially advantageous situation, resulting in a selection bias. In other centers, a credit card system was provided for costs for travelling, hotels and meals, which participants found generally more convenient.

The second aspect discussed in all groups was that of compensation of the time invested, something generally not allowed by ethical regulations, because a financial compensation should not be an incentive for patients to participate in a clinical study. However, most participants
<table><caption>**Table 3**
Illustrative quotes on clinical study participation.</caption><thead><tr><td>Key aspect</td><td>Quotes</td></tr></thead><tbody><tr><td>Daily life</td><td>“We would actually be taking more than one month off just to be there, on site to be able to give him the best care that he needs. Which also meant taking huge time off, getting all our vacations and taking it in.” (parent of trial/study participant, ZSM (E))</td></tr><tr><td>Clinical study experience</td><td>“When we came there we had an environment that was totally unaware of our special situation and inattentive. And just like to illustrate that, we went there for a whole day, and there were not even breaks planned to have something to eat.” (parent of trial/study participant, ZSM (E))</td></tr><tr><td>Financial compensation</td><td>“As a lot of those parents might be hesitant to participate because they’re worried about, OK, if I participate in this study and I lose funds, is that going to impact if I have other children, is that gonna impact the roof over my head? Is that gonna impact whether or not I can provide medical necessity, even for this child” (active member patient organization, MTM-CNM)</td></tr></tbody></table>

felt that it is unfair that healthy individuals in clinical studies generally receive a financial compensation, whereas patients cannot. Both patient and/or parents make significant indirect costs by delaying their school or college career and having to pay additional tuition, or they might have missed income due to absence from work. This seemed especially unfair since many families with a child with XLMTM often have a reduced income since one of the parents has given up their job to take care of the child. Finally, it was discussed that it is somewhat patronizing to think that patients would participate in the clinical study only for the financial compensation, considering that in the view of most participants indirect costs and the social and emotional investment is always exceeding any financial compensation, and that hence, patients will only participate if they or their parents are genuinely intrinsically motivated.

### Theme 3: Communication

The total number of quotes related to this theme was 140 (20–44 per group). It was most extensively discussed in the German Focus group of ZNM-ZusammenStark! (n = 44/116 quotes). The most frequently identified subtheme was communication with “Clinician (PI)” (n = 65). The quotes were further categorized into 5 key aspects: the different lines of communication in clinical trials; the communication in case SUSARs; and the importance of managing expectations regarding potential benefits of a study compound. We discuss this below; illustrative quotes are presented in Table 4.

In all focus groups, participants stressed the importance of clear communication, including the time points at which information is provided, the way communication takes place and the content of the messages. This aspect is important in all clinical studies, but it was deemed most vital in case of SUSARs in a clinical trial, and an aspect where standard operating procedures concerning communication could be substantially improved.

### Communication Between Study Team and Participants

In all groups, participants emphasized the importance of open communication with the PI and nurses of the study team. There was a strong preference for regular planned meetings, so the patients and their families knew when they would be contacted, even if no updates could be provided. This aspect was well organized in several study centers and much appreciated. Not knowing when a parent or patient would receive additional information about the study progress by the study team was difficult to deal with. However, some participants understood that the PIs could only inform them if they would be informed themselves by the sponsor.

A key aspect discussed in all focus groups was the transparency of communication, which was crucial for both patients and their family members. Some participants appreciated the communication with the study team as teamwork. Another feature of the study team considered to be crucial by participants was a personal and attentive approach; some participants were very positive about their experience in this regard, whereas others missed this.

One specific topic discussed in the ZNM-ZusammenStark! Group was how participants had prepared for the consent process. Many participants had read the informed consent form at home and discussed their

questions with the PI during the site visit, however, for many participants it was very challenging to fully understand the language used in the exhaustive documents. One participant had made an appointment with a notary to have the form read out and explained at his own costs.

### Communication Between Participants and Patient Organizations

In all groups, the fundamental role of the patient organizations was extensively discussed. This did not only concern the support given during the clinical studies, but the entire process of being diagnosed, acceptance of the diagnosis, mourning, adaptation to the diagnosis, and consideration of clinical study participation. Annual meetings of the patient organizations were considered very helpful, with longstanding friendships across different countries having developed over the years.

These strong connections between patients and their families made the instruction not to talk about experience in the trials challenging; patients generally understood the need for discretion, but also felt the need to share their experiences and feelings. Their fellow patients and families had been ideal partners for discussions about many disease-related issues but could not be approached to share more specific experiences and talk about expectations or fears. However, in general, all participants made substantial efforts to adhere to confidentiality requirements, with various families even refraining from visiting the annual patient organization meetings because of concerns that the effect of the study compound might be visible to others. Finally, instructions for keeping confidentiality were too general and participants would appreciate more precise guidelines. A final topic concerning the communication within the patient community was the feeling of “survivor’s guilt” by parents of children that had experienced positive effects of the study drug, in relation to others who had not received the study drug.

### Communication Between Sponsor and Patient Organizations

Clinical trials involving human subjects should be conducted according to national and international legislation and regulations. This includes that trial sponsors are not allowed to be in direct contact with trial participants. Sponsors therefore generally hire a contract research organization (CRO) to perform a trial, thus ensuring participant privacy. However, (pharmaceutical) companies often reach out to patient organizations in the time preceding and during a trial to learn the patient perspective and to provide general updates. This is an essential part of clinical research and generally much appreciated; however, these interactions need to be consistently conducted professionally throughout the whole process; participants commented on perceived changes in attitude and approaches of companies over time which they found difficult to process.

### Communication in Case of SUSARs

A common theme was the insufficient communication between sponsors and PIs during the ASPIRO trial, when a series of SUSARs occurred, resulting in the death of 4 participants. Some families read about these events on social media before they were personally informed by the PI of the study at their site, and this delay in communication to individual patients, families and the patient organizations was often experienced
<table><caption>**Table 4**
Illustrative quotes on communication.</caption><thead><tr><td>Key aspect</td><td>Quotes</td></tr></thead><tbody><tr><td>Communication between study team and participants</td><td>“We are only a number in a system, and a fuel of data, but not a person looking after that. We came to some doctors and we saw them behind the PC and asking, asking, asking and no look to the people sitting there and that’s the first problem.” (active member patient organization, ZSM (E))</td></tr><tr><td>Communication between participants and patient organizations</td><td>“This community has been so helpful to us and has been so welcoming and something that is not necessarily the way you want to meet people. It’s not on a positive note that we came into this, but it’s absolutely been a welcoming warm community.” (active member patient organization, MTM-CNM)</td></tr><tr><td>Communication between sponsor and patient organizations</td><td>“We’re not your friends, you’re not our friends. We work together because we have for a very far horizon the same objective, we want you to be successful because when you have success it is good for us.’ And that is what was very difficult with the US American company to make them aware.” (active member patient organization, ZSM (E))</td></tr><tr><td>Communication in case of SUSARs</td><td>“Yes I mean, there’s nothing worse, you open Facebook and read there that a child has died that was in exactly the same cohort as yours. That’s absolutely not OK. It was truly terrible.” (parent of trial/study participant, ZSM (E))</td></tr><tr><td>Management of expectations concerning trial drugs</td><td>“and I think overhyping from patient organizations is incredibly dangerous. So I think there’s a role for patient organizations, not just clinicians… because we can often be the first point of contact and the voice” (active member patient organization, MTT)</td></tr></tbody></table>

as devastating. Some patients even remarked that they thought that the lack of real-time communication between sites resulted in PIs and sites being unaware that patients at other sites had developed liver failure following systemic gene therapy delivery. This might have been a barrier to optimal treatment and was thus of great concern to the entire patient community. In general, the communication delay after the fatal events was experienced as particularly difficult for many families.

## Management of Expectations Concerning Trial Drugs

A topic extensively discussed in the focus group of the MTM-CNM Family Connection was the role of the patient organization in preventing exaggerating the potential benefits of the study compounds. The participants in this group experienced that the often disproportionate promotion of the expected success of gene therapy by some groups of patient representatives created unrealistic expectations among some families, which might have influenced their decision to participate in a trial. The patient organization felt a great responsibility to keep explaining that a trial is not a treatment, but a strictly regulated and supervised study to assess the safety and/or efficacy of a study drug. There seems to be an unmet need for PIs to explain this aspect more clearly.

## Theme 4: Recommendations for Future Clinical Studies

The total number of quotes related to this theme was 77 (16–24 per group). The most frequently identified subtheme was (recommendations for) “Clinicians” (n = 40). We only identified one quote related to recommendations for “Patient Organization.” In the analysis, the quotes were further categorized into 3 key aspects: “Recommendations for study team,” “Recommendations for sponsor,” and “Recommendations for patients.” The recommendations mainly target the issues identified in the discussions around trial participation and communication. Illustrative quotes are presented in Table 5. Overall, patients understood the importance of adhering to the regulations of good clinical practice, but they would appreciate if trials would be designed with a greater understanding and or acknowledgment of the patient perspective. In all focus groups, patients expressed their willingness to contribute to the design of future studies.

## Recommendations for Study Team

The main recommendations for the study team concerned the logistics of the study visits. This included planning of appointments that fit the patient’s care schedule as closely as possible, offering support in transportation (e.g. prearranged taxi transport), and providing the service of a study coordinator that is easily accessible in case of any questions. Another important factor was flexibility during the study visits, for example, allowing a patient to leave 10 minutes earlier in order to be able to catch a train. Furthermore, flexibility in the study design with local or home visits if only blood and urine samples have to be

collected would be much appreciated. Nevertheless, if it is necessary to travel to the study site to perform tests with the exact same equipment, participants are generally willing to do this.

Many recommendations for the study team concerned communication. Participants emphasized the importance of transparency, being fully informed and having a central point of contact. There was a strong preference for regular, fixed interaction, so the participants and their families knew when they would be contacted. Finally, focus on the patient as an individual rather than an anonymous trial participant was considered crucial, although the regulations for anonymization were acknowledged.

## Recommendations for Sponsor

Although pharmaceutical companies are not allowed to directly communicate with participants, there is indirect communication via the patient organizations. This is considered important, and participants asked for straightforward, open communication, as otherwise patients and families may develop a range of anxieties. This kind of communication is important before the start of the trial, when patients and families are considering participation, to manage potentially unrealistic communications and clearly explain the remit and limitations of the trial.

Open communication is even more important once SUSARs occur. It was discussed that sponsors should be aware that participants and families often know each other and might learn about developments very rapidly. For some participating families it was devastating to read about the fatal events in the ASPIRO gene therapy trial on social media before being informed by the PI. Companies should therefore develop a clear communication plan in case of SUSARs.

Another recommendation for the sponsors and study teams is to offer a service for emotional support during and after trials. It was discussed throughout different focus groups that the discontinuation of the 2 trials caused substantial disappointment for the participants, their families and the whole patient community. In addition, many other emotions were reported, including anxiety concerning side-effects, “survivor’s guilt,” and uncertainty about the disease course. Some participants sought psychological support on their own.

Finally, following the discussion on the reimbursement system, it was brought up that inclusivity is an important issue to consider. The reimbursement system directly influences who can and who cannot participate, and this needs to be considered when thinking about clinical trial participation.

## Recommendations for Patients

Patients that consider participating should be aware of the large impact of clinical study (clinical trial) participation, both logistically and emotionally. Participants mentioned that the decision whether to participate in a clinical trial is very personal. Patients and their caregivers should consider this carefully, balancing the possible costs and benefits.
<table><caption>**Table 5**
Illustrative quotes on recommendations for future clinical trials.</caption><thead><tr><td>Key aspect</td><td>Quotes</td></tr></thead><tbody><tr><td>Recommendations for study team</td><td>“The key thing is patient centricity. I think that’s key, right. We’re not just numbers as I think only said earlier we are people feeling like people, you know we are vulnerable. As it is taking the sting out of the process as much as possible, showing some empathy, showing people respect and some compassion, clear communication.” (parent of trial/study participant, MTT)</td></tr><tr><td>Recommendations for sponsors</td><td>“If you advertise your product into the high heavens, if you raise expectations that high and something goes wrong and then the communication cut comes, we will get angry...be consistent and be professional” (trial/study participant, ZSM (E))</td></tr><tr><td>Recommendations for patients</td><td>“But just as this disease has its own individual characteristics, it is also up to each individual to decide whether or not to take part in the study.” (trial/study participant, ZSM (G))</td></tr></tbody></table>

Availability of comprehensive information is essential to make a fully informed decision.

Discussion

In this qualitative study, we focused on the experiences of patients and parents, or others involved in clinical studies on CNM. The 4 focus groups comprised 37 participants with 6 to 11 participants per group. Clinical study participation and Communication were the most extensively discussed themes. We observed that participants were realistic in their expectations, hoping for small improvements of function and quality of life. However, they felt it was challenging to keep in mind that a trial is not a treatment. Participating in a clinical study, especially a clinical trial, had a significant impact on many aspects of daily life, both for patients and their family members. Participants emphasized the experienced burden and their concerns about the influence of the strenuous study design on their performance on functional tests. Furthermore, participants stressed the importance of structured communication. This is important in all clinical studies; however, it was deemed particularly vital in case of SUSARs.⁵ Finally, patients expressed a clear understanding of the importance of adhering to the regulations of good clinical practice but also expressed how they would strongly appreciate if clinical trials were designed with a greater understanding and acknowledgment of the patient perspective. Patients provided several recommendations for future trials, mainly concerning patients, sponsors and study teams. We discuss these main findings in more detail below.

Regarding expectations of clinical study participation, parents expressed being mostly motivated by improving the quality of their child's life. Some parents were influenced by expectations based on preclinical studies and preliminary results of clinical studies. The delicate balance between expected effects and risks contributed to the large burden of the decision-making process regarding clinical trial participation of their child. Patients and parents tried to maintain an awareness that there is never a guarantee of a treatment effect; however, most patients and parents hoped for at least mild functional improvements. These results are in line with previous literatures regarding the barriers and facilitators of trial participation in patients with neuromuscular disorders.⁸⁻¹² In these studies, the fear of side-effects was seen as the most important barrier, whereas the hope for a better future was the main facilitator. An additional facilitator in our and previous studies was the positive interaction with the study team. The limited availability of previous research on trial participation experiences for congenital myopathies emphasizes the relevance of the current study.

Our findings make it clear that the patient organizations play a crucial role in various aspects of clinical study participation. Many patients with CNM are diagnosed at birth, and they and their families have a long-term involvement with the patient organizations. The 3 CNM patient organizations who participated in this study unanimously expressed that they felt a strong need to prevent exaggeration of the potential benefits of a study drug as well as the importance to focus on the balance between expected effects and risks. The researchers, patient organizations, sponsors, CROs, study teams and physicians have a shared responsibility that the information on the study compound and study design is clear, consistent, and understandable. This is in line with the

recommendations from the studies by Peay et al⁹ and Peterson et al,¹² which emphasize the importance of providing sound information and building trusting relationships.

Furthermore, our study clearly demonstrates that patient organizations in different countries not only played a role before the start of a trial, but also during the entire disease course. They serve as a vital source for patients and families by providing educational support and a sense of community during the diagnostic process, counseling, symptomatic treatment, and even through providing pastoral support to families after a patient has passed away. This aspect was experienced as very important, since participants felt the need to talk about their considerations on participation and study experiences, while at the same time being aware of the limitations imposed by the necessary adherence to confidentiality.¹³

This divergence is a unique feature of the rare disease field, in which patients and families in different countries have met at family conferences and many having formed life-long friendships based on the shared experience of living with a severe rare condition. This strong sense of community has become further intensified through increased social media use and will have to be considered in future trial designs. It is increasingly acknowledged that online communities for patients with more common chronic conditions (e.g. thyroid disease) are becoming essential in managing the care of these conditions,¹⁴ and this aspect is likely even more pronounced in rare diseases. Patient organizations are increasingly at the forefront of policy design, research, and drug development for the disease concerned.¹⁵,¹⁶ Figure 3 illustrates the position of the patient organizations and social media in the rare disease landscape: the sponsor, PI, patient organization(s) and individual patients are not distinct parties but clearly interconnected.

This study was initiated with members of ZNM-ZusammenStark! In spring 2021. While discussing the design, the patient representatives proposed to extend the study to the UK and North American CNM patient organizations. The CNM patient organizations coordinated the recruitment of participants and participated in all key meetings. Hence, this study reflects a strong desire of the study group, to promote the involvement of patients and/or patient representatives as highly qualified partners in the design and execution of clinical studies. The importance of this partnership in the rare diseases clinical research field has been highlighted, for ensuring the feasibility and success of research protocols by assisting with study design and patient recruitment.¹⁵

This study has several strengths. First, the focus group protocol was based on a systematic literature review and discussed with patient representatives. The study team was broad, including PIs from Europe, the UK and USA, and patient (representatives). The inclusion criteria were wide, meaning that not only participants of both phase 1 and 2 trials were included, but also participants of other clinical studies. The participants of the focus groups were from 8 different nationalities. The German focus group transcript was translated into English by a professional translator for comparison reasons, and all focus groups were moderated by the same moderator. Finally, the Consolidated criteria for reporting qualitative research (COREQ) checklist was used to ensure that methods, results and discussion were reported in an appropriate manner (Supplemental Data 8). This study does also have several limitations. Two focus groups were held in person, and 2 focus groups were
<figure><img src="image_7.png" /><figcaption>**Figure 3.** The position of the patient organizations and social media in the ultra-rare disease landscape. The sponsor, PI, patient organizations and individual patients are not distinct parties but clearly interconnected, which calls for very clear and strict standard operating procedures concerning communication during clinical studies, so that, for example, SUSARs are not mentioned on social media before study participants and their families are informed by the PIs.</figcaption></figure>

organized as online meetings. This has induced a bias for at least the participants from the UK, as the reasons for not participating were partly related to a reluctance to talk online with strangers about very delicate, painful experiences (Table 1B). However, many participants had already become very familiar with online meetings on various topics, through webinars periodically organized by the patient organizations. Additionally, there could be potential presence of selection bias. There is an absence of information regarding the number of potential participants within the inclusion criteria that could have been approached. By recruiting through the patient organizations we have included only the active members. To ensure a comparative data analysis, both in-person and online focus groups were also recorded via MS Teams for transcription. Furthermore, qualitative research with use of focus group has some general limitations. For example, certain participants may have a dominant role in the discussion. However, our experienced moderator ensured a balanced contribution of all participants, reflecting their degree of experience with the studies. Furthermore, it is possible that participants may be inclined to give socially acceptable answers which may only partially reflect their opinion. Again, our moderator introduced the meeting with a statement that each contribution was valued. Next, the fact that we included not only study participants but also family members and other active members of the patient organization might be interpreted as a limitation. However, we have clearly shown that both observational clinical studies and trials have an impact on the patient and their family environment, which in our opinion makes this design a strength rather than a limitation. This study has a retrospective design; however, it is almost impossible to do a similar study prospectively with focus groups, especially as patients are not allowed to talk about their ongoing trial participation. One could consider performing a prospective questionnaire study on the patients’ perspective on participation in clinical studies, in particular clinical trials; however, it is widely accepted that focus groups will result in a deeper understanding of a topic compared to surveys.¹⁷

To conclude, this qualitative study was performed as co-creation of academic researchers and patient organization leaders in 2 continents. The study results provide important insights in recent clinical study experiences in CNMs, resulting in clear recommendations for future trial participation. Collaboration not only with academic researchers but also with patient organizations should be viewed as being of the utmost importance for the design of future trials, not only for CNM but also other (ultra)rare diseases. Such a partnership is expected to contribute to optimal patient recruitment and retention, efficient and effective communication, as well as more accurate assessment of the patient performance related to suitable planning of the study visits.⁶,¹⁵ Integration of the patient and caregiver voice, throughout the clinical trial process, including design and development, will ensure that patient priorities, preferences and perspectives on meaningful outcomes are prioritized.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

### Data availability statement

Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not publicly available. Request for collaborative research projects making use of the Focus Group Transcripts can be send to the corresponding author by email. She will discuss these with the involved patient organizations.

### Acknowledgments

The authors would like to thank all participants of this study for their time and openness on the discussed topic. We acknowledge the positive responses of Studentes / Astellas and Dynacure when we initiated this study. 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).

### Funding

The patient organizations covered the costs of the moderator. The authors received no funding.

### Author contributions

L. Stinissen: data collection, data analysis, data interpretation, writing of report. J. Böhm: study design, data interpretation, writing of report. S. Bouma: data collection, data interpretation, writing of report. J. van Tienen: study design, data collection, data interpretation, writing of report. H. Fischer: study design, data collection, writing of report. Z. Hughes: study design, data collection, data interpretation, writing of report. A. Lennox: study design, data collection, data interpretation, writing of report. E. Ward: study design, data collection, data interpretation, writing of report. M. Wood: study design, data collection, data interpretation, writing of report. R. Foley: study design, data interpretation, writing of report. W. Oortwijn: study design, data interpretation, writing of report. H. Jungbluth: study design, data interpretation, writing of report. N. Voermans: study design, data collection, data analysis, data interpretation, writing of report.

### Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.clinthera.2024.03.008.
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