The survey was conducted in France, Germany, Italy, Spain, the United Kingdom, and the United States between November 10, 2017, and February 28, 2018, using an established online approach [30-32]. Patients or caregivers of patients with spasticity who were members of the Carenity platform were invited by email to complete a questionnaire, presented in the local language, translated by a specialized agency and reviewed by local Carenity community managers. The study methodology and questionnaire were validated by 3 neurologists (from Canada, Spain, and the United States) and 1 rehabilitation physician (from the United States). To ensure language suitability, a patient who matched the study inclusion criteria was selected via the Carenity platform and asked to proofread the questionnaire.

All questions were the same between countries except for those relating to BoNT-A formulation brand names, which were removed from the Spanish questionnaire to comply with Spanish regulations. The study had a prespecified target of 600 respondents: included 300 from the United States and 300 from Europe, determined using the Cochran formula, with p set at 0.5 (maximum variability), the confidence level at 95%, and a maximum margin of error between 5% and 6% for each region.

The questionnaire comprised multiple-choice, sliding-scale, or free-text answers and consisted of 4 sections (Multimedia Appendix 1). For caregivers, some questions related to the patient they cared for, whereas others related specifically to their caregiver experiences. The first section of questions collected information on the patient’s/caregiver's profiles (sex, age, spasticity diagnosis and symptoms, treatments for spasticity, duration of BoNT-A treatment, BoNT-A formulation, relationship to patient, duration and frequency of caregiving). Respondents were screened out of the survey at this stage if the eligibility criteria were not met. In countries other than Spain, patients selected the BoNT-A formulation from the following list: Dysport (aboBoNT-A), Xeomin (incobotulinumtoxinA, incoBoNT-A), Botox (onabotulinumtoxinA; onaBoNT‑A), or “not known.” Patients in Spain were asked to state the BoNT-A treatment they were receiving (if known) in a free-text field.

The second section collected information on the impact of spasticity on the ability to work, functioning, and QoL. The third section collected information on BoNT-A treatment behavior (goals, number of injections, and retreatment) and the impact of BoNT-A injections on patients' and caregivers' QoL. The final section collected information on the potential impact of reduced BoNT-A injection frequency on patients and caregivers (assuming efficacy was maintained). The sliding-scale questions in these sections are shown in Multimedia Appendix 1.

The responses provided by the patients or caregivers regarding the patients' condition were self-reported and were not verified by an independent rater or reviewer. Free-text responses were categorized both automatically and manually (as appropriate) by Carenity personnel, who also developed a tool to program and code the questionnaire.

Eligible participants were adult patients (≥18 years old) who self-reported as having spasticity and receiving treatment with BoNT-A for ≥1 year, and caregivers of patients meeting the survey criteria (caregivers were not those of the participating patients). Spasticity had to be due to MS, stroke, traumatic brain injury, spinal cord injury, cerebral palsy, brain tumor, or spastic paraplegia. Patients treated with oral antispasticity medications (eg, baclofen) or receiving concurrent physiotherapy (at home or in hospital) were permitted to participate.

Descriptive analyses are presented: categorical variables are presented as frequency counts and percentages. Differences in reported burden, treatment behavior, and perceived benefits of fewer injections are compared between patients by limbs affected, level of difficulty experienced due to spasticity, symptoms experienced, and treatment received (number of injections).

The study was conducted in accordance with Good Pharmacovigilance Practices Modules IV and VIII in compliance with relevant codes of conduct and data protection legislation, with no approval from the Clinical Research Ethics Committee or Independent Review Board required. All participants provided informed consent to participate and were made aware that the research was sponsored by a pharmaceutical company that manufactures a product approved for the treatment of spasticity.

This study was sponsored by Ipsen. Where patient data can be anonymized, Ipsen will share all data that underlie the results reported in this paper with qualified researchers who provide a valid research question. Study documents, such as the study protocol and clinical study report, are not always available. Proposals should be submitted to DataSharing@Ipsen.com and will be assessed by a scientific review board. Data are available beginning 6 months and ending 5 years after publication; after this time, only raw data may be available.

Carenity invited 16,494 members (who had agreed to receive invitations to participate in questionnaires) from their community of members affected by spasticity or one of the targeted diseases to complete the survey and, of these, 3548 members started the survey (Figure 1). Participants were screened out of the study if they did not meet the eligibility criteria (n=2,659), and 274 participants did not complete the questionnaire.

In total, 615 participants completed the survey (427 patients and 188 caregivers), and the survey was closed (United States, 300/615, 49%; Europe, 315/615, 51%; Table 1). Patients had a mean age of 41.7 (95% CI 40.6-42.8) years; 48% (206/427) were women, 51% (216/427) were men, and 1% (5/427) were transgender.

The mean age at diagnosis was 33.5 (95% CI 32.3-34.7) years, and the mean time since diagnosis was 8.3 (95% CI 7.4-9.3) years. More patients had spasticity due to MS (199/427, 47%) than other conditions (Table 1). The proportion of patients with MS was lower in the United States (65/178, 37%) than in Europe (134/249, 54%; Multimedia Appendix 2). The most frequent symptoms of spasticity were muscle spasms, stiffness/rigidity, and muscle pain (Table 1).

The current BoNT-A treatment was onaBoNT-A for most patients (237/427, 56%), with 18% (75/427) receiving aboBoNT-A and 11% (48/427) receiving incoBoNT-A (Table 1). The mean time since the first BoNT-A treatment was 3.5 (95% CI 3.0-3.9) years, suggesting an average gap of 4.8 years between diagnosis and BoNT-A initiation. More patients from the participating European countries did not know which formulation they were taking (21% vs 6% for the United States; Multimedia Appendix 2). In total, 60% (256/427) of patients were receiving concurrent oral medication (eg, muscle relaxants or baclofen), 69% (297/427) were receiving physiotherapy (35% at home, 34% in hospital), 11% (45/427) had received phenol, 9% (40/427) had received botulinum neurotoxin type B injections, and 7% (29/427) had received alcohol (Table 1).

The mean age of caregivers was 38.6 (95% CI 36.9-40.2) years; 55% (104/188) were women and 45% (84/188) were men (Table 1). The mean duration of caregiving was reported as 4.9 (95% CI 4.1-5.7) years, with 12% (22/188) providing care for ≥10 years. Most caregivers (147/188, 78%) provided care either every day (85/188, 45%) or for ≥4 days a week (62/188, 33%). The patient was a parent of the caregiver in 40% (76/188) of cases, with the remainder being another family member, a friend, a partner, a neighbor, or other. The mean age of caregivers was highest in those providing care for patients with stroke (41.7 years; 95% CI 38.7-44.7) and lowest for traumatic brain injury (35.2 years; 95% CI 30.2-40.2). For MS—the most common cause of spasticity in this study—caregivers had a mean age of 37.6 (95% CI 34.7-40.6) years.

Caregiver profiles were similar in Europe and the United States, although the latter appeared to spend more time each week in their caregiving role (Multimedia Appendix 2).

Evidence-based medicine for the treatment of spasticity requires the patient perspective on the burdens of symptoms and receiving treatment, for which there is a knowledge gap. The present survey, which was self-reported by over 600 patients and caregivers in the international Carenity online community, is, to our knowledge, the largest of its kind for those affected by spasticity. The results presented here supplement efficacy and safety data from clinical trials of BoNT-A treatment for spasticity with information on treatment benefits to patients, the effects of symptoms on everyday life, and practical issues associated with treatment. Such insights can inform the development of new patient-reported outcome measures and help guide more effective management of spasticity in clinical practice, thus informing the development of new therapeutics.

The use of online communities is becoming increasingly popular, as they can encourage patients to educate themselves about their condition, motivate patients to participate in clinical research, and are easily accessible; FDA guidance for collecting information from patients who are members of these communities is now available [1,2]. Online communities also offer methodological advantages by providing quick access to a specific patient population, supporting hypothesis generation, improving sociodemographic representativeness, and providing insights into the feasibility of a study and recruitment for future studies [2]. In this study, only one-fifth of people who had agreed to receive Carenity survey invitations actually participated in our survey, and information regarding the eligibility of those who did not participate is not available, highlighting the challenge of patient and caregiver engagement when using online platforms. However, a high response rate was still achievable as a result of the very large size of the online international community involved.

The presented results confirm that spasticity, irrespective of etiology, has a clear and negative effect on patients' and caregivers' lives. Specifically, patients reported the impact of spasticity on the ability to conduct routine, everyday activities like walking and driving, and on various aspects of QoL. Many patients also reported that spasticity affected their ability to work; among those aged <65 years, 22% changed to part-time working and 22% gave up work completely. In caregivers of working age, the corresponding values were 21% and 8%, respectively. These results are consistent with data from several studies showing that spasticity has a substantial impact on patients' activities of daily living, QoL, and independent living [14,33-35]. They also confirm the results of a study evaluating work restrictions faced by caregivers of patients with spasticity [36].

All the surveyed patients had received treatment with BoNT-A for ≥1 year. Patients and caregivers reported that treatment improved the ability to conduct daily tasks and aspects of QoL that are affected by spasticity, increasing patients' overall satisfaction with life. Despite its well-established efficacy for spasticity, there was an average gap of 4.8 years between diagnosis and BoNT-A treatment initiation in the population surveyed. However, for conditions such as MS, spasticity may not be present at the initial diagnosis, appearing only later in the disease course. In a previous internet survey among patients with spasticity, almost 50% had to wait 1 year before BoNT was started, and 23% waited >3 years. The authors propose that this may reflect the cost of treatment to health care providers or patients, or a lack of experienced injectors [14]. Regarding costs, reimbursement for BoNT-A by health insurance providers has been decreasing year after year in many countries [37]. In our survey, most patients and caregivers incurred costs at each BoNT-A injection, with >50% of patients reporting an annual expenditure of >500€.

Many patients reported practical issues with BoNT-A treatment, including the availability of timely appointments and the frequency of injections. On average, patients received 4.4 injections per year, irrespective of BoNT-A formulation, and, although most planned their visits, some reported scheduling earlier appointments for emergent spasticity symptoms. It is important to note that this was an international study, and treatment intervals were largely dependent on each participating country's health care insurance authorization; therefore, the number of injections per year may be more reflective of this rather than the duration of efficacy or physician guidance. Additionally, these results are dependent on the participant being able to accurately remember how many injections they received per year, and therefore, may be affected by memory bias.

When first asked whether reducing BoNT-A injection frequency (without reducing efficacy) would provide any benefits, 86% (368/427) of patients and 87% (163/188) of caregivers reported that it would, citing factors such as better QoL and fewer logistical constraints. Participants were later asked the same question alongside a prespecified list, from which they had to select the 3 most important benefits of less frequent injections. Only 3% (13/427) of patients and 3% (6/188) of caregivers responded that they would not experience benefits, which suggests that providing a list of potential benefits influenced responses, most likely by enabling participants to envisage benefits they had not been able to foresee previously. Importantly, the 3 most selected benefits (longer periods of improved mobility, not worrying about symptoms, and self-confidence) were related to prolonged symptom relief rather than a reduced number of injections.

These data collectively suggest that the option of a longer-acting BoNT-A formulation would be favorably received by patients and their caregivers, to provide sustained relief from spasticity symptoms and to overcome practical issues associated with more frequent treatment, as suggested in another patient survey [38]. A recent clinical review indicates that aboBoNT-A treatment may allow long intervals between injections, suggesting long-term symptom relief [39]. These data appear to be corroborated by real-world evidence [40] and may be explained by recent preclinical research showing that aboBoNT-A contains more active neurotoxin at licensed doses than other BoNT products [41].

The ability to reduce injection frequency depends on the duration of the effect of the BoNT-A injection. This, in turn, depends on several factors, including dose, muscle mass, and depth of injection [42]. In a model designed to assess the pharmacodynamic effects of aboBoNT-A and onaBoNT‑A, the former had a significantly longer duration of action [43]. A Phase 3 trial of aboBoNT-A in patients with lower limb spasticity post-stroke or post-traumatic brain injury permitted retreatment (per the investigator's judgment) at Weeks 12, 16, 20, or 24 [44]. The percentages of patients re-injected at week 16 or later were 20% during the first cycle, 32% during the second cycle, and 15% during the third cycle, indicating that some patients required ≤3 aboBoNT‑A injections per year. The authors concluded that the long duration of aboBoNT-A may reduce the burden associated with injection frequency [44], which is consistent with the anticipated benefits of less frequent administration in the current study.

This study has several limitations. No formal prespecified statistical evaluation took place, and recruitment was conducted via the Carenity website, meaning results may not be representative of the general population of patients with spasticity and their caregivers. The proportion of patients with MS in this survey was higher than would be expected in the general population; in the United States, for example, the incidence of MS is surpassed by both stroke and traumatic brain injury [45]. This survey system self-selected for engaged participants who were familiar with social media and internet platforms. This may explain the relatively large proportion of patients aged under 40 years and patients with MS as a primary etiology for their spasticity, as these patients have been shown to be well-informed and engaged in their condition management, and thus are very active on these platforms [46]. Patients with stroke are typically older (aged >65 years) and may be less likely to engage with online surveys. In addition, it should be considered that caregiver burden may vary with etiology. As discussed, MS was the most common cause of spasticity in this study; however, strokes typically affect older populations and, consequently, patients may have older caregivers, which could potentially cause a higher degree of burden. In this study, there was an age range of 4.1 years between the caregivers of patients with stroke and MS, which does not suggest a greater degree of burden on caregivers of patients with stroke due to older age. However, this small age range may be reflective of the social media aspect of this system, as mentioned previously, rather than the real-world situation. Other limitations were the lack of severity assessment of the patients' spasticity, and that data reflect patients' and caregivers' perceptions of treatment effectiveness rather than accepted clinical endpoints. Additionally, a large proportion of patients received concomitant physiotherapy and oral medications during treatment with BoNT-A; as a result of the nature of this patient survey, it is not possible to deduce how these confounding factors affected patients' and caregivers' perceptions of the efficacy of BoNT-A treatment.

From the patient and caregiver's perspectives elucidated in this study, spasticity represents a great burden on many aspects of their lives, including the ability to work, QoL, and difficulties with daily living. Several challenges were identified with receiving BoNT-A treatment for spasticity, predominantly around scheduling and the associated costs of injections. Despite these challenges, it was established that patients and caregivers perceive that BoNT‑A improves patients' lives, with high levels of overall satisfaction reported. However, patients and caregivers reported that providing efficacy was maintained, BoNT-A injections of reduced frequency would alleviate practical issues associated with treatment and, more importantly, provide prolonged symptom relief. Using an online community enabled more rapid recruitment to the study and data collection regarding patient and caregiver perspectives than would have been possible in a clinical trial or a validation study of patient-reported outcomes.