ORIGINAL REPORT
GOAL ATTAINMENT AFTER TREATMENT WITH ABOBOTULINUMTOXINA AND A TAILORED HOME THERAPY PROGRAMME IN CHILDREN WITH UPPER LIMB SPASTICITY: DESCRIPTIVE, EXPLORATORY ANALYSIS OF A LARGE RANDOMIZED, CONTROLLED STUDY
Jorge CARRANZA-DEL RÍO, MD1, Nigar DURSUN, MD2, Cigdem CEKMECE, PHD2, Marcin BONIKOWSKI, MD3, Weronika PYRZANOWSKA, PHD3, Edward DABROWSKI, MD4, Ann TILTON, MD5, Joyce OLESZEK, MD6, Magali VOLTEAU, PHD7, Simon PAGE, PHD8, Angela SHIERK, PHD9 and Mauricio R. DELGADO, MD9
From the 1Hospital San José Celaya, Celaya, Guanajuato, Mexico, 2Kocaeli University Faculty of Medicine Department of Physical Medicine and Rehabilitation, Turkey, 3Mazovian Neuropsychiatry Centre, Warsaw, Poland, 4Beaumont Health, Oakland University School of Medicine, Grosse Pointe, MI, 5LSU Health Sciences Center and Children’s Hospital New Orleans, New Orleans, LA, 6Children’s Hospital Colorado, Aurora, CO, USA, 7Ipsen, Les Ulis, France, 8Ipsen, Bath Road, Slough, UK and 9University of Texas Southwestern Medical Center and Scottish Rite Hospital for Children, Dallas, TX, USA
Objective: This exploratory analysis of a large, randomized, double-blind study (NCT02106351) describes the effect of treatment with abobotulinumtoxinA followed by a tailored home exercises therapy programme in enabling children with upper limb spasticity due to cerebral palsy to achieve their functional goals using goal attainment scaling (GAS).
Methods: Children with cerebral palsy and spasticity in ≥ 1 upper limb received up to 4 injection cycles of abobotulinumtoxinA (2 U/kg (cycle 1 only), 8U/kg and 16U/kg) into the elbow and wrist flexors and other upper limb muscles selected to support individual treatment goals. Children followed a home exercises therapy programme, which included stretches and exercises specifically chosen to facilitate goal achievement and engagement in activities.
Results: For cycle 1, most children had active function goals set as their primary goal (69.7% vs 19.2% passive function goals). GAS T-scores and goal responder rates at week 16 indicated that most types of primary goal were achieved at least as expected during cycle 1 (all groups). Primary goal GAS T-scores were generally maintained for the first 3 abobotulinumtoxinA treatment cycles.
Conclusion: Most children with upper limb spasticity treated with repeat cycles of abobotulinumtoxinA supported by an individualized home exercises therapy programme achieved their functional goals.
LAY ABSTRACT
Treatment with botulinum toxins (such as abobotulinumtoxinA; aboBoNT-A) is often recommended to treat spasticity of the upper limb to help children with cerebral palsy improve their hand skills. In this large study, children with cerebral palsy were treated with up to 4 aboBoNT-A injection cycles followed by a home exercises programme that was specifically made for each child to help them meet their treatment goals. This study aimed to explore the types of goals the children wanted to achieve with this treatment and the factors that influence goal attainment.
Most children in this study had “active function” goals set, including “involving the affected arm more in daily activities” and improving “reaching”, “use of limb as a helping hand” and “grasp and release”. Combined treatment with aboBoNT-A and the exercise programme helped most children achieve their goals, but it was difficult to discern any differences in efficacy between the aboBoNT-A doses used in the study. The authors suggest that the high rates of goal achievement in this study indicate that botulinum toxin should not usually be given without a physiotherapy programme.
Key words: abobotulinumtoxin A; cerebral palsy; goal attainment scaling; physical therapies; upper limb.
Citation: J Rehabil Med 2022; 54: jrm00349. DOI: http://dx.doi.org/10.2340/jrm.v54.2540
Copyright: © Published by Medical Journals Sweden, on behalf of the Foundation for Rehabilitation Information. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/)
Accepted: Oct 03, 2022; Epub ahead of print: Oct 28, 2022; Published: Dec 09, 2022
Correspondence address: Mauricio R. Delgado, Scottish Rite Hospital for Children, 2222 Welborn Street, Dallas, 75219 TX, USA. E-mail: mdelgado@tsrh.org
Competing interests and funding: The authors have no conflicts of interest to declare.
*Supplementary materials have been published as submitted. Table SI and Fig. S1 have not been copyedited, typeset or checked for scientific content by Journal of Rehabilitation Medicine.
Up to 70% of children with cerebral palsy (CP) have some form of upper limb impairment with significant impact on activities of daily living (1, 2). Depending on the size and location of the brain lesion, children can have a combination of spasticity, weakness, dystonia, limited range of motion and other upper motor neurone syndrome signs and symptoms that all contribute to difficulties in reaching, grasping, releasing, and manipulating objects (2, 3). The inability to fully use the affected arm(s) for bimanual activities hinders the development of independent functioning in daily life, and the ability to fully engage in social, educational and leisure roles (4). When spasticity is a major contributing factor to the impairment, botulinum toxin injections are often used to produce a selective reduction in muscle tone while optimizing the potential for occupational therapies to improve range of motion and enhance motor ability and functional skills (5).
Rehabilitation plans need to be comprehensive and consider the needs of the child and their family. There is now a lot of evidence supporting the usefulness of collaborative goal-setting as part of the communication and decision-making process. For example, it is a basic tenet that goals should be amenable and appropriate to the intervention, and the process of goal negotiation helps set realistic family expectations and to actively engage them in the treatment plan (6, 7). Good goal-setting within an International Classification of Functioning, Disability and Health (ICF) framework enables consideration of how treatment can improve activity and participation (8). From the clinician’s perspective, goal-setting can help decide which treatments (pharmacological and non-pharmacological) are used and reviewing how well a child achieves their individual treatment goals is an important part of follow-up (9). In the context of a clinical trial, methods such as goal attainment scaling (GAS) assimilate achievement in a number of individually set goals into a single “goal attainmenT-score” that can be analysed as a measure of efficacy (10).
We have previously reported the primary efficacy analyses from this large, international phase III study, which showed that treatment with aboBoNT-A at doses of 8 U/kg or 16 U/kg in the affected upper limb significantly reduces spasticity in children with CP compared with the 2 U/kg low-dose control, and was generally well tolerated (11, 12). A key feature of the study design was the inclusion of a tailored home exercise therapy programme (HETP) that was specifically developed for the study to maximize the benefits of goal-directed treatment with aboBoNT-A, and which all children followed (13). When taken overall, treatment (i.e. aboBoNT-A plus HETP) was associated with global improvement and high goal attainment. During cycle 1, ≥ 70% of children across the 3 treatment groups achieved their primary goals at week 6, with no significant difference between groups (11).
We describe here the types of upper limb goals chosen and the effect of treatment on goal attainment and achievement according to goal domain. To better illustrate how study treatment was tailored towards the achievement of these goals, we also provide real examples from the study, including the goals set and home exercises prescribed for each child based on their clinical and personal situation.
METHODS
Study design and participants
This was a double-blind, randomized, repeat treatment, phase III study (NCT02106351), full details of which have been previously published (11). Institutional review boards at the participating sites approved the protocol, and the trial was executed in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines.
In brief, this multicentre study included 212 children (aged 2–17 years, weighing ≥ 10 kg) with a diagnosis of CP and increased muscle tone/spasticity in at least 1 upper limb (modified Ashworth Scale (MAS) score ≥ 2 in the primary targeted muscle group (PTMG; elbow or wrist flexors)). The study included children with a broad range of disease severity, from Gross Motor Function Classification System (GMFCS) level I to IV. Children could be botulinum toxin-naïve or previously treated, but the last botulinum toxin injection for any condition must have been ≥ 6 months prior to study entry. Any physiotherapy or occupational therapy had to have been initiated ≥ 30 days before the baseline visit and continued over the injection cycle. Key exclusion criteria included a fixed contracture in the PTMG (range of motion angle of < 40°), choreoathetoid/dystonic movements, previous/planned surgery of the PTMG, and phenol/alcohol injections within the past year (11).
During cycle 1, children were randomized (1:1:1) using computer-generated lists to receive double-blind treatment with aboBoNT-A at doses of 2 U/kg, 8 U/kg, and 16 U/kg across the PTMG and other upper limb muscles that were selected based on clinical presentation and to support the individualized treatment goals that were agreed upon by the children and their families at baseline. Treatment goals could be renegotiated and the PTMG could change in cycles 2–4 (injection intervals ≥ 16 weeks). The allocated dose remained double-blind; children previously randomized to the 2 U/kg dose were re-randomized to either 8 U/kg or 16 U/kg.
Children were to follow an individualized HETP, which included stretches and strengthening exercises (for appropriate muscle groups) as well as functional tasks and activities specifically chosen by the occupational therapist from the HETP manual to facilitate achievement of the chosen goals and enhance engagement in activities. Exercises could be adapted by the therapist throughout the study; for example, to aid in motivation, increase or decrease difficulty, or to better align with treatment goals as they changed over repeat cycles. The minimum expected requirement for the HETP was five 15-min sessions per week. Both caregivers/children and investigators were blinded to study treatment allocation.
Goal-setting and goal attainment scaling
The process for goal-setting and goal assessment was based on published GAS methodology, and available GAS materials were used for training (10). Before any treatment was decided, the treating team completed a comprehensive assessment, which included a family interview to identify the areas of concern, and a physical (body function/structure and activity) examination, which had to demonstrate that increased tone (MASPTMG score ≥ 2) was a contributing factor to goal attainment. All treatment goals (primary and secondary) had to be judged amenable and appropriate to the intervention, where relief of the hypertonia in the spastic muscles should underpin functional efficacy. To illustrate the goal-setting and exercise planning process more clearly, Box 1 provides real cases from the study demonstrating how goals were chosen and treatment tailored accordingly to individual children.
Box. 1. Case studies of goal-setting, goal-guided treatment, and goal attainment
Up to 3 goal statements per child were identified as part of the collaborative assessment prior to each treatment cycle. For the purposes of the main study analyses, all children had to have a primary (most important) goal defined for each treatment cycle. Goals were categorized according to a list of pre-defined goal domains applicable to this population and treatment programme (13) (Table I) and were individually rated for importance and difficulty. Based on clinical assessment with caregiver input, investigators rated achievement on a predefined 5-point scale (–2 = much less than expected, –1 = somewhat less than expected, 0 = expected outcome, +1 = somewhat more than expected, and +2 = much more than expected).
| mITT | Completers* | ||||
| All children (mITT) (n = 208) | Received 1 cycle (n = 22) | Received 2 cycles (n = 63) | Received 3 cycles (n = 43) | Received 4 cycles (n = 52) | |
| Age (years); mean (SD) | 9.1 (4.4) | 8.7 (4.0) | 8.7 (4.2) | 8.9 (4.6) | 9.6 (4.6) |
| 2–9 years, n (%) | 118 (57) | 15 (68) | 37 (59) | 25 (58) | 26 (50) |
| 10–17 years, n (%) | 90 (43) | 7 (32) | 26 (41) | 18 (42) | 26 (50) |
| Sex, n (%) | |||||
| Female | 125 (60) | 11 (50) | 20 (32) | 16 (37) | 22 (42) |
| Male | 83 (40) | 11 (50) | 43 (68) | 27 (63) | 30 (58) |
| Weight, (kg); mean (SD) | 32.4 (16.9) | 32.1 (16.2) | 31.9 (16.3) | 35.4 (19.7) | 29.4 (14.6) |
| GMFCS level, n (%) | |||||
| I | 94 (45) | 18 (82) | 30 (48) | 21 (49) | 18 (35) |
| II | 62 (30) | 4 (18) | 23 (36) | 12 (28) | 14 (27) |
| III | 11 (5) | 0 | 2 (3) | 1 (2) | 6 (11) |
| IV | 41 (20) | 0 | 8 (13) | 9 (21) | 14 (27) |
| MAS; mean (SD) | |||||
| PTMG | 3.1 (0.4) | 3.1 (0.2) | 3.0 (0.2) | 3.1 (0.6) | 3.2 (0.4) |
| Elbow | 2.8 (0.8) | 2.3 (1.3) | 2.7 (0.7) | 2.9 (0.7) | 2.9 (0.8) |
| Wrist | 2.5 (1.1) | 2.4 (0.9) | 2.5 (0.9) | 2.5 (1.3) | 2.9 (0.8) |
| Finger | 2.3 (1.1) | 1.8 (0.7) | 2.4 (0.9) | 2.5 (1.2) | 2.4 (1.6) |
| *Completers are defined as those children who had a week 16 assessment in the given cycle. SD: standard deviation; mITT: modified intention-to-treat; GMFCS: Gross Motor Function Classification System; MAS: modified Ashworth Scale; PTMG: primary targeted muscle group. |
|||||
Statistical analysis
The overall analyses of GAS were performed on the modified intention-to-treat population (mITT), including all randomized participants who received ≥ 1 injection of study treatment and had recorded MAS scores (primary outcome measure) at baseline and week 6 of cycle 1. Raw GAS scores were transformed into a standardized measure (T-score), which has a mean of 50 and an SD of 10 (14). In this system, a GAS T-score of 50 represents goals achieved as expected; scores below 50 reflect under attainment of goals, and scores greater than 50 represent over-attainment of goals. GAS T-scores for overall goal attainment during cycles 1–4 (predefined exploratory outcome), and for primary goals at weeks 6 and 16 of cycle 1 for each predefined goal domain (post-hoc analysis) were reviewed. Rates of goal achievement (defined as the percentage of goals achieved at least as expected; score ≥ 0), were also reviewed for all goals (i.e. primary and secondary goals combined) by predefined goal domain and overall.
In addition, to try to better understand why overall goal attainment and achievement was different in cycle 4 compared with earlier cycles (11), a post-hoc subset analysis was performed to review the baseline characteristics and primary goal attainment (all doses) of those children who required 4 cycles of aboBoNT-A treatment during the study (and had week 16 data from cycle 4 available).
Aside from the previously published secondary efficacy analysis of primary goal attainment during cycle 1 (11), all GAS statistics presented here were descriptive and performed using SAS software version 9.4 or later (SAS Institute, Cary, NC, USA).
RESULTS
Patient disposition
The first child was enrolled on 10 April 2014, and the last visit was completed on 4 September 2018. The mITT population included 208 (aboBoNT-A 2 U/kg, n = 69, 8 U/kg, n = 69; 16 U/kg, n = 70) of the 212 children randomized; 2 children did not receive treatment and 2 did not have post-baseline MASPTMG scores recorded. Overall, 180 children completed the study per protocol and were included in the post-hoc analysis where children were categorized by the number of treatment cycles they completed.
Baseline characteristics per dose group have been presented previously (11) and are shown in Table I for the overall cohort and categorized by number of treatment cycles completed. Compliance with the HETP during cycle 1 was high. Overall, 195 children practiced their HETP between baseline and week 6, with 56% (n = 109) performing the exercises daily, 35% (n = 68) performing the exercises 5–6 times per week and 5% (n = 10) performing them 4 times per week; 8 children performed their exercises ≤ 3 times per week.
Baseline goal choice
For cycle 1, the primary goal for all 3 treatment groups was most commonly related to active function (69.7%). Across the study sample, most frequent primary goals were “involving the affected arm more in daily activities” (29.8%) followed by “reaching” (19.7%) (Table II). Similarly, when considering all goals set (i.e. primary or secondary goals), active goals were also more commonly chosen than passive goals.
Goal attainment in cycle 1
As published previously, all 3 groups attained their cycle 1 primary goals on average at least as expected (secondary endpoint: LS mean GAS T-scores at week 6 of 52.1 for the 2 U/kg group and 52.6 for both the 8 and 16 U/kg groups), with no significant difference between groups (11). When analysed by domain, GAS T-scores at week 16 indicated that most types of primary goal were achieved as expected (score of 50.0) or overachieved (score > 50.0) (Fig. 1). The only exception was the passive goal of “being dressed” (i.e. ease of caregiver dressing the child), where the GAS T-score indicated underachievement in the 2 U/kg group (GAS T-score of 45.7), albeit only a small proportion of children had this as a primary goal (n = 9 children).
Fig. 1. Primary goal attainment by goal domains at week 16 of cycle 1 (modified intention-to-treat (mITT) population).
Goal responder rates (primary and secondary goals) also showed high rates of goal achievement per domain (Fig. 2).
Fig. 2. Rates of goal achievement at week 16 of cycle 1 by goal domain (including primary and secondary goals, modified intention-to-treat (mITT) population). Goal achievement defined as goal attainment scaling (GAS) score ≥ 0.
Goal attainment across cycles 1–4
Primary goal GAS T-scores were generally maintained for the first 3 aboBoNT-A treatment cycles and were generally similar between the aboBoNT-A 8 and 16 U/kg treatment groups (Table SI). As in cycle 1, GAS T-scores were generally slightly higher at week 16 compared with week 6 (Fig. 3a). However, overall GAS T-scores were below 50 in cycle 4 and responder analyses at week 16 showed that fewer children achieved their goals in this cycle than in the early cycles (Fig. 3b).
Fig. 3. (a) Goal attainment and (b) goal achievement at weeks 6 and 16 across cycles 1–4 (aboBoNT-A 8 and 16 U/kg combined). Responders were defined as the proportion of primary goals achieved where goal achievement was defined as goal attainment scaling (GAS) score ≥ 0.
To better understand why the overall goal attainment and achievement appeared to be lower in this final cycle, we reviewed the baseline characteristics of the small subset of children (n = 52) who required 4 treatment cycles within the study period (i.e. more frequent injections) and evaluated their goal attainment throughout the study. Post-hoc analysis revealed that this subset was slightly older and had a higher GMFCS score than children who required only 1 or 2 cycles (Table I). For example, all children with a GMFCS score of III or IV required at least 2 cycles of treatment, and these children were more heavily represented in the subsets of children who required 3 or 4 treatment cycles. Analysis of week 16 goal attainment for this subset showed that their goal attainment was as expected during cycle 1 (GAS T-score of 50.8), slightly overachieved during cycle 2 (GAS T-score of 51.6), and then slightly underachieved for cycles 3 and 4 (GAS T-scores of 47.3 and 49.6, respectively) (Fig. S1). Whereas 18 children (35%) in this subset did not change their goal domain over the study, the majority (65%) showed a change or progression of goal-setting over repeat cycles (e.g. from improving range of movement and reaching in cycles 1 and 2 to involving the affected arm more in cycles 3 and 4).
DISCUSSION
The results of these secondary and exploratory analyses of goal attainment support the overall findings of treatment efficacy (11) and confirm that most children achieved their goals following comprehensive treatment with aboBoNT-A followed by an individualized HETP. GAS responder rates were generally higher at week 16, indicating a time lag from peak aboBoNT-A effect on hypertonia to goal attainment, which may be expected as children require time for motor learning and task practice to complete their functional goals with reduced spasticity and improved biomechanics.
Most children in this population had active treatment goals. This probably reflects the high proportion of children with hemiplegia (and lower GMFCS scores with75% GMFCS I and II) and other demographic factors, such as the fact that most children were of school age. Per protocol, the most frequently injected muscles were the elbow flexors (brachialis and brachioradialis) and wrist flexors (flexor carpi radialis and flexor carpi ulnaris). However, a wide variety of other upper limb muscles were also injected, as physicians tailored injection patterns to individual patients (12). For example, the most chosen goal domain was to involve the affected arm more in daily activities. This included specific goals, such as carrying cups of water, opening a container, or holding plates of food safely with both hands. For these kinds of goals, wrist flexors were often chosen as the PTMG and the HETP exercises typically focused on strengthening. Although any conclusions on goal achievement by domain are limited by the small numbers of goals in certain domains, analysis of GAS T-scores showed considerable overachievement in most goal areas.
Investigators in this study were well experienced in the use of aboBoNT-A for upper limb spasticity and using GAS as an outcome measure, and there were extensive efforts made to provide training on appropriate goal-setting for children in this study. Thus, we would have expected scores closer to 50 (achievement as expected) and the higher scores might possibly indicate that the goals set, particularly in cycle 1, were not challenging enough (10). Another possible explanation of this notable overachievement of goals is the almost universal compliance with the individualized HETP, which was specifically designed for this study based on motor learning principles to harness neuroplasticity and produce long-term gains (13, 15). As highlighted in the commentary by Novak (15), the treating team worked with the children and families to devise a programme that included activities that were task-specific, with an intensity that should induce plasticity, and timed such that the exercises took full advantage of the window of opportunity for improving movement that was created by aboBoNT-A injections. It is also important to note that most children in the 2 U/kg group also benefited from clinically relevant tone reduction (albeit significantly less than the 8 U/kg and 16 U/kg groups) (11). Many potential reasons have been proposed to explain the efficacy of the low-dose treatment regimen in cycle 1. However, the very high level of compliance (both to treatment and to the HETP) seen in the study makes it challenging to disentangle the effects of toxin from physical therapy. Nevertheless, in terms of translation to the clinic, the current study reinforces the notion that botulinum toxin (BoNT-A) injections should not usually be considered a stand-alone treatment, but rather should be part of a holistic therapy programme that includes a carefully designed, goal-specific, and regularly reviewed physiotherapy programme. Of course, exceptions to this rule do exist and could include pain management and some aesthetic goals.
One striking observation was that children who required more cycles (i.e. the subset of children who required a fourth treatment cycle within the study timeframe) tended to have lower rates of goal achievement at cycle 4. Whereas the gradual lowering of overall GAS T-scores across the 4 consecutive treatment cycles may partly reflect the continual learning process where the treating team and families better understand what is possible (and adjust the difficulty of goals accordingly), the lower-than-expected goal attainment in the subset of children who required 4 treatment cycles may also reflect increased complexity of care or a gradual progression to more difficult goals. For example, the baseline characteristics of this subset appears to support a greater complexity, in that the children who required 4 treatment cycles were more likely to have a higher GMFCS score (GMFCS III or IV) than those who only required 1 or 2 treatment cycles. However, while not all children changed their overall goal domains, there is evidence that some of these children progressed to more difficult goals over the 2 years which may partly explain the reductions in overall goal attainment.
While classifications of manual ability are missing, the skew to higher GMFCS levels in the cycle 4 subset serves to highlight the need to better understand upper limb goal-setting for children with bilateral CP (who are more likely to be GMFCS III and IV) who were less well represented in this study (80% of children in this study had hemiplegia) (11). A recent review of interventions to improve upper limb function in children with bilateral CP identified a scarcity of information and little-to-no information on the types of goals set for these children (16). Prospective observational studies of goal-setting and attainment, such as those already conducted in the adult population (17), would provide much needed information on the evolution of goal-setting in these children. Such observational “real-life” data would also overcome another key limitation of this study, which was the prospective randomization of patients to 2, 8 or 16 U/kg and fixed requirements for injection into the PTMG irrespective of the patient’s presentation. The ability to tailor doses is particularly important in the management of upper limb spasticity where fine functional adjustments require very precise treatment and dose adjustments. Other limitations of this study include the fact that physicians and families were aware that the children would all receive aboBoNT-A in this industry sponsored study, which could have affected expectations and therefore assessment of goal outcomes. Indeed, it was the same therapists who set the goals and evaluated outcomes. The small number of children who had pain, hygiene or ease of care goals limits any conclusions on treatment efficacy in these specific domains. While we have information on overall goal domains, we do not have consistent information on the precise goals set within each domain, and the case studies were therefore chosen from the authors’ own investigational sites.
In conclusion, this is the first phase III study to demonstrate that repeat treatment with aboBoNT-A (8 or 16 U/kg) significantly improves the ability of children with upper limb spasticity to achieve their functional upper limb goals that are important to the children and their families. The process of goal-setting (and subsequent evaluation of outcomes using GAS) was found to be useful in guiding the development of an individualized exercise programme that optimized goal attainment following injection of aboBoNT-A and has the potential to significantly improve current practice.
ACKNOWLEDGEMENTS
The authors thank all the children, families and investigators who participated in this trial. We also thank Benjamin Regnault (Ipsen) for statistical support and Anita Chadha-Patel, PhD, of ACP Clinical Communications Ltd (Hertfordshire, UK) for providing medical writing support, which was funded by Ipsen (Paris, France) in accordance with Good Publication Practice guidelines.
This study was funded by Ipsen Pharma. Authors employed or contracted by Ipsen (SP, and MMV) were involved in interpretation of the data; and in review, approval of, and decision to submit the manuscript. The funder had no other role in study conduct or preparation of this report. JCdR, ND, AT, MB, ED, JO and MRD were investigators in Ipsen-sponsored clinical trials and they or their institutions have received payment for participation. In addition, JCdR reports personal fees for consultancy and speaking from Ipsen. ND reports research support from Ipsen, Allergan, and Merz and personal fees for consultancy and speaking from Ipsen and Allergan. MB reports research support from Ipsen, Allergan, and Merz and personal fees for consultancy and speaking from Ipsen and Allergan. ED reports personal fees from Ipsen and Allergan for speaking, Solstice Neurosciences for consultancy and serves on a US speaker bureau. AT and AS report research support and educational grants from Ipsen and personal fees for consultancy from Ipsen. JO reports consultancy fees for Ipsen and Allergan. MRD reports personal fees from Ipsen, Allergan and Kashiv Pharma for consultancy. CC and WP have no conflicts of interest to declare.
Ipsen will share aggregated data that underlie the results reported in this article 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.
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