In total, there were 342 respondents to the survey (demographic details supplied in Table 1) of whom 204 reported a diagnosis of FRDA, 55 inherited CA and 70 idiopathic CA (Fig. 1). Respondents were predominantly (77.2%) patients, with parents (15.8%), carers (5%) and partners (2%) also completing the survey on the patients’ behalves. The majority (87.7%) of FRDA respondents were from the USA, with the UK providing the majority of inherited CA (98.1%) and idiopathic CA (91.4%) cases.
Symptoms to be targeted in future trials
Respondents were asked to identify the top three symptoms (of 16 options) that they would most like to see addressed by a clinical trial (Additional file 1: Appendix 1). The top five most frequently selected by the FRDA cohort were problems with walking (51.3%), balance problems/unsteadiness (47.3%), fatigue (34%), slurred speech (31.3%) and dexterity (29.3%). Analysis by ambulatory status subgroup demonstrated that patients who were wheelchair dependent selected slurred speech (41.5%) as the symptom they would most like addressed by a trial, while both subgroups of ambulatory patients selected balance problems (walking independently, 75% and walking with aids, 67.5%). The top five most frequently selected by inherited CA and idiopathic CA respondents had similar priorities with balance problems/unsteadiness (83.3% and 82.5% respectively), walking (47.2% and 35%), slurred speech (38.9% and 30%), fatigue (22% and 32.5%), and dexterity (13.9% and 15%) (Additional file 2: Table S1).
Motivations and barriers to trial participation
Respondents were asked what were their top six motivating factors for, and barriers to, joining a clinical trial (Additional files 3 and 4: Tables S2 and S3) from a list provided in the survey (Additional file 1: Appendix 1). Key motivating factors for the FRDA cohort were potential benefit to self (92%), potential benefit to others (80.2%), financial reimbursement of expenses i.e. covering costs of travel and accommodation if applicable (63%), recommendation of trial by physician (51.2%) and availability of a physician should there be any issues (49.4%). For inherited CA, the top factors were potential benefit to self (88.1%), potential benefit to others (85.7%), availability of a physician should there be any issues (57.1%), recommendation of the trial by a physician and a feeling of increased care/obtaining extra health check-ups (both 35.7%). Major deterrents for FRDA patients were costs associated with travel (67.9%), burden of travel (58%), fear of side effects (50.6%), stopping current regular medication (43.2%) and having to miss work/school (38.9%). For inherited CA the top five deterrents were fear of side effects (65.9%), costs associated with travel (48.8%), burden of travel (46.3%), worry that trial medication is not effective (31.7%) and stopping current regular medication (22%). For idiopathic CA, the main deterrents were fear of side effects (65.3%), burden of travel (61.2%), costs associated with travel (42.9%), not being able to take future medication due to potential interactions with study drug (28.6%) and stopping current regular medication (26.5%).
Interest in future trial participation
Across the cohort, FRDA respondents were most interested in participating in future trials (73.9%), ahead of those with inherited ataxia (65.2%) and idiopathic ataxia (59.2%). We explored factors influencing interest in trial participation, hypothesising that people who had previously taken part in a trial would be more likely to participate in a future one. Survey responses (n = 255) were dichotomised into very and extremely interested in joining a future trial (n = 207) and all other responses (n = 91) and a binary logistic regression model fitted. The only covariate that proved statistically significant was having previously taken part in more than one trial (OR = 2.761, 95% CI 1.208, 6.311, p = 0.016), thus confirming our hypothesis (Additional file 3: Table S2 and Additional file 4: Table S3).
Trial design factors influencing trial participation
The most popular phase of trial to participate in for FRDA and idiopathic CA respondents was phase 2 (89.5% and 85.7% respectively), and phase 3 for inherited CA respondents (78%) (see Additional file 1: Appendix 1 for phase definitions). Of FRDA respondents, 57.4% would take part in a phase 1 study, compared to 68.3% of inherited CA respondents and 65.3% of idiopathic CA respondents (Fig. 2, Table 2). Use of placebo proved to be a disincentive for participants; the percentage of respondents who would be very or extremely likely to participate in a clinical trial if it was placebo controlled was 59.5% for FRDA, compared to 73.9% to who would be very or extremely interested in participating in a future trial in general. Similar trends were seen in inherited CA, 48.9% versus 65.2% and for idiopathic CA, 20.8% versus 59.2%. We then looked to see if the aversion to placebo was mitigated by the option of an open label extension phase. Here, 68.9% of FRDA respondents stated they would be very or extremely more willing to participate, compared with 47.8% of inherited CA and 37.7% of idiopathic CA respondents (Table 2).
Level of evidence required before participating in a clinical trial
We first asked respondents what the lowest acceptable level of evidence would lead to their trial participation. Across all cohorts, 44.6% of respondents wanted the drug to ‘have shown potential benefits in people with my condition’ with 16.5% wanting it to have shown benefit in an animal model of ataxia, 13.7% in a cell model of ataxia and 14% in people not affected by ataxia, with 11.6% of respondents content with only theoretical benefit (Fig. 3, Additional file 5: Table S4). We compared those who would accept a lower level of evidence (theoretical/cell model/animal model) to those who required a more rigorous level of evidence using a binary logistic regression model (see methods for variables used). Men were significantly more likely to accept a lower level of evidence (OR = 1.966, 95% CI 1.114, 3.470, p = 0.02) as were respondents who used walking aids (OR = 2.904, 95% CI 1.380, 6.114, p = 0.005) and respondents who had been in multiple trials (OR = 2.183, 95% CI 1.021, 4.667, p = 0.044).
We asked respondents how likely they would be to enroll in a clinical trial if the medication had been proven safe for another unrelated condition. Of FRDA respondents, 75.2% would be ‘very’ or ‘extremely’ likely to enroll compared to 53.1% of inherited CA patients and 50.9% of idiopathic CA patients (Table 2).
Intrathecal drug administration
To explore the acceptability of the intrathecal (IT) route of administration, we asked how often respondents would be prepared to have a lumbar puncture (LP) as a method of drug administration. Overall, 30.3% would never be prepared to accept this, 15.2% would be willing to have this done yearly, 19.5% 6 monthly, 10.5% every 2 months and 22.7% monthly (see Additional file 6: Table S5 for by-condition and subgroup breakdown).
In order to explore factors influencing willingness to undergo IT drug administration, we split the responses to the question into two groups: those who would be willing to have IT drug administration every 6 months or more frequently, and those who would never or only on a yearly basis. A binary logistic regression analysis was then conducted, using age groups, sex, condition, ambulatory status and whether or not they were interested in participating in a future trial as variables. Respondents who were interested in participating in a future trial were more likely to accept an LP every 6 months or more frequently (OR = 5.118, 95% CI 2.72, 9.450, p < 0.001). Other variables influencing willingness to undergo IT drug administration that displayed a trend towards significance were a diagnosis of FRDA (OR = 2.463, 95% CI 0.948, 6.401, p = 0.064) and using walking aids (OR = 2.140, 95% CI 0.962, 4.760, p = 0.062).
Total time patients are prepared to dedicate to a clinical trial
Amongst respondents interested in taking part in a future trial (n = 178), we sought to determine the total amount of time which they would be willing to dedicate to it. To do this, we summed the amount of time respondents were willing to spend travelling to and from hospital, the amount of time they were willing to spend in hospital at each visit and multiplied this by the number of times they were willing to come to hospital in one year. This resulted in a mean (SD) value of 251.7 (181.6) hours. To investigate factors influencing this time dedication, we performed a multiple linear regression with dummy coding to allow for nominal variables. A model with the variables, age, sex, ambulatory status, condition and previous trial participation gave an R2 = 0.273 (F (12, 162) = 5.059, p < 0.001). Significant contributors to the model were having participated in more than 1 trial (B = 193.8, p < 0.001), age 26–35 (B = 96.49, p = 0.038), age 36–45 (B = 97.69, p = 0.035) and age 46–55 (B = 94.72, p = 0.037). Thus, those who had participated in more than one trial or were aged between 26 and 55 years would be willing to dedicate more time to a trial.
Procedures patients are willing to undergo during a trial
Most procedures were deemed acceptable by more than 70% of respondents with the exceptions of fasting (< 6 h = 68.6%, > 6 h = 53.2%), scans longer than one hour (64.5%), overnight stay in hospital (59.8%), muscle biopsy (49.2%) and lumbar puncture (42.7%) (Additional file 7: Table S6).
Reporting back trial results
Finally, we asked respondents to rate how important it was for them to have the results of any trial they participated in reported back to them and how they would prefer this to be done. Overall, 83.3% of respondents felt that it was either very or extremely important to have results reported back to them, with the most popular modes being through meeting with a physician (64.4%), and receiving a lay summary (54.2%) (Table 2).
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