Objectives: Describe data on real-life clinical practice and patient-centered goal attainment for integrated management of upper limb spasticity (ULS), including repeated botulinum toxin A (BoNT-A) injections.
Design: ULIS-III was a prospective, observational, longitudinal (2-year) cohort study (NCT02454803) of integrated ULS management, including BoNT-A, starting January 2015 and completing December 2019. Eligible participants were ≥18 years with ULS in whom a decision had already been made to inject BoNT-A. The study was the first to use the Upper Limb Spasticity Index (ULSI), an assessment battery including a structured approach to goal attainment scaling (GAS) alongside a set of standardized measures. Participants continued with their usual concomitant therapies, which were recorded in the Upper Limb Focal Spasticity Therapy Recording Schedule (ULSTR) to document the number/duration/type of therapies related to specific goals.
Results: A total of 1004 participants from 14 countries were enrolled. Interim data for Treatment Cycle 1 (n=807) are reported here. 60.4% of participants saw a therapist after BoNT-A treatment: the most frequent therapy interventions were passive stretch (69.4%), splinting (25.7%) and strength-training (24.8%). Mean [95%CI] overall GAS T-scores were 49.9 [49.4, 50.5] at end of cycle;69.4% of participants met their first primary treatment goal, with highest rates of achievement for primary goals related to passive (75.0%) vs. active function (52.1%). Standardised measures of spasticity, pain, involuntary movements, active and passive function all improved over the treatment cycle.
Conclusions: The ULIS-III is the first study to use the ULSI in the assessment of BoNT-A effectiveness for upper-limb spasticity. Data captured in the ULSTR describe how therapies are used alongside BoNT-A treatment. First cycle data indicate that nearly 70% patients achieved their primary goal. Final analyses at 2 years will provide insights in how integrated treatment and treatment goals evolve, and how this impacts goal achievement over time.
Background: Large, international, observational studies are well placed to understand the complexities of how BoNT-A is used in routine clinical practice. The Upper Limb International Spasticity Study (ULIS) programme represents a series of large international observational studies to describe current clinical practice in the application of BoNT-A in upper limb spasticity. The programme started in 2008 and has taken an iterative approach to trial design. The results informed the third stage of the programme (ULIS-III).
Design: ULIS-III is an ongoing 2-year observational, prospective, longitudinal cohort study conducted at 57 study centres across 14 countries. The inclusion criteria required patients to be consenting adults ≥18 years with post-stroke upper limb spasticity in whom a decision had already been made to inject BoNT-A (patients could be new to BoNT-A treatments or previously treated). In accordance with the observational nature of this study, clinicians were free to choose the targeted muscles, BoNT-A preparation, and injection parameters in accordance with their usual practice. The ULIS-III study is the first to use the Upper Limb Spasticity Index (ULS Index) to record patient-centred goals and standardised outcomes directed by priority goal areas. Standardized outcomes include: the Modified Ashworth Scale (MAS), pain score, Associated Reaction Rating Scale (ARRS), upper limb spasticity adapted Neurological Impairment Scale (ULS-NIS), Arm Activity Measure (ArmA) and Functional Ambulation Category (FAC). While the goal-directed approach to selection of targeted standardised measures is novel, the measures themselves are well-validated tools and are suitable for use in routine practice. The timing of follow up was based on their usual practice and the nature of the goals set, usually between Month 3 and Month 5. Subjects participated in concomitant therapies as per usual practice, and all activities were recorded in the Upper Limb Focal Spasticity Therapy Recording Schedule (ULSTR), which records the number, duration and types of therapies related to specific goals.
Results: Across 14 countries,1004 subjects were enrolled, of which 807 had validated data for Treatment Cycle 1. The mean±SD age was 54.4±15.2 years, 56.4% were male. Most subjects (82.9%) had spasticity due to a vascular event (infarct or haemorrhage). The mean±SD time since onset of event was 7.71±9.16 years. 475 subjects (59.3%) saw a therapist at baseline of Treatment Cycle 1; 89.3% saw a physiotherapist, 37.5% an occupational therapist, 5.1% a therapy assistant and 9.7% another allied professional. Approximately two-thirds (n=537; 66.5%) had previously received BoNT-A in the upper limb, the median duration of treatment being 2.31 years (IQR 4.72); but some had had treatment spanning up to 21 years. A median of five muscles were injected (range: 1−15), most commonly in the forearm with very wide variation in the total dose. The most frequent therapy interventions were passive stretch (69.4%), splinting (25.7%) and strength-training (24.8%).Overall 69.4% [95%CI: 66.1%, 72.5%] of subjects met their primary treatment goal during Treatment Cycle 1. Mean [95%CI] GAS T scores increased from 36.9 [36.7, 37.2] at start of Cycle 1 to 49.9 [49.4, 50.5] at end of cycle (a score of 50 indicates that, overall, goals were attained as expected). Rates of goal achievement were highest for the goal domains of ‘involuntary movements’ (76.3% of set goals), range of movement (74.9%), passive function (73.8%) and pain (67.6%) and lower for active function (49.8% of set goals). Based on standard assessments, subjects generally showed a clinically relevant reduction in spasticity as evidenced by a mean ±SD reduction in MAS-Total score of -1.7±2.5 points. For patients with pain goals (n=284), mean±SD pain scores decreased from 6.7±1.8 at baseline to 3.8±2.2 at end of cycle (mean change of -2.9±2.0 points). For those with goals of reduce involuntary movements (n=182), ARRS Total scores decreased from 7.2±2.3 at baseline to 5.7±2.5 at end of cycle (mean±SD change of -1.5±2.4 points). ArmA scores also decreased over the treatment cycle; for patients with goals in passive function (n=368) ArmA passive scores decreased from 13.9±5.3 at baseline to 10.5±5.8 at end of cycle (mean±SD change of -3.4±5.3 points). For those with goals in active function (n=176) ArmA active scores decreased from 39.3±11.0 at baseline to 35.9±11.5 at end of cycle (mean±SD change of -3.2±7.0 points).
Conclusions: This is the first presentation of a broad range of clinical results from the ULIS-III study.The ULIS-III study is the first to study to use the ULSI in the assessment of BoNT-A effectiveness for upper-limb spasticity. The findings from this large prospective international cohort study confirm the overall good response rates to BoNT-A injection delivered in the context of routine clinical practice for the management of upper limb spasticity as previously seen in the ULIS-II study (Turner-Stokes et al, 2013). Data captured in the ULSTR provide important insights into how therapies are used alongside BoNT-A treatment. First cycle data indicate that overall goals were achieved as expected – 69.4% of patients achieved their primary goal. The overall success in goal achievement mirrored the changes observed in the standard outcome measures used to monitor the changes produced in the different aspects of symptoms, activity and function, which underpin the validity of GAS in demonstrating change. Final analyses at 2 years will provide insights in how integrated treatment and treatment goals evolve, and how this impacts goal achievement, over time.
Lynne Turner-Stokes– Herbert Dunhill Chair of Rehabilitation, Kings College London
Andreas Lysandropoulos– Medical Advisor, Ipsen Pharma
Stephen Ashford– Senior Clinical Lecturer and Consultant Physiotherapist, King’s College London
Klemens Fheodoroff– Senior Physician, Gailtal-Klinik Hermagor
Jorge Jacinto– Centro de Medicina de Reabilitaçãode Alcoitão, Serviço de Reabilitação de adultos 3, Consultant
Allison Brashear– Dean, University of California Davis School of Medicine
Pascal Maisonobe– Director of Biometrics, Ipsen Bioscience