Patient-reported benefits from nabiximols treatment in multiple sclerosis-related spasticity exceed conventional measures

Nabiximols oromucosal spray (Sativex^®) is approved as add-on treatment for patients with moderate-to-severe treatment-resistant multiple sclerosis (MS) spasticity who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy [1]. The active ingredients of nabiximols in a 1:1 ratio are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) extracted from cloned herbal cannabis plants [2].

Enriched-design clinical trials of nabiximols in MS spasticity indicated that 35–40% of initial responders (i.e., those with ≥20% improvement from baseline in their 0–10 numerical rating scale [NRS] score) might expect to achieve clinically meaningful (≥30% NRS response) and durable symptomatic improvement beyond 4 weeks [3,4]. Similar responder rates were reported in large observational studies of nabiximols in routine practice during up to 1 year's observation [5–7]. Notably, clinically relevant improvements were also observed in spasticity-associated symptoms such as pain and sleep disturbances [3–5].

Besides relief of spasticity and associated symptoms, patients with MS spasticity also aim for treatment to provide a better quality of life (QoL) and facilitate their ability to perform activities of daily living (ADL). However, scales commonly used to measure QoL and ADL may not reflect a patient's individual needs and can fail to detect improvement despite a reduction in spasticity symptoms [8]. The goal attainment scale (GAS) is a method used to assess a person's achievement of personalized goals during or following an intervention. Patients identify their own goals and set an achievement level based on their current and expected levels of performance [9]. GAS has been applied as an outcome metric in a range of rehabilitation settings in patients with MS [10–12]; in the pharmacological treatment of spasticity with botulinum toxin [13–19]; and during treatment with nabiximols for MS spasticity [19].

The aim of this study was to investigate the effectiveness of nabiximols in a real-world setting for the treatment of MS spasticity using GAS as a primary measure of treatment success. The effectiveness and tolerability of nabiximols was also evaluated using a range of clinical tools to assess MS spasticity and associated symptoms.

Methods

This was an open-label, prospective, single cohort, multicenter, phase IV, noninterventional (as per § 4 Para.23 of the German Medicinal Products Act [Arzneimittelgesetz]), 12-week study of adult patients with MS spasticity who started treatment with nabiximols oromucosal spray according to the Summary of Product Characteristics (SmPC) [1] in routine clinical practice in Germany. Patients were considered for enrollment only after the treatment decision was made and established.

Patients

Included were adults aged ≥18 years with MS spasticity who began treatment with nabiximols. All patients were required to provide written informed consent for study participation. Patients with any of the following contraindications, as defined in the Sativex Oromucosal Spray SmPC [1], were excluded from the study: hypersensitivity to cannabinoids or any study drug excipient; known or suspected history or family history of schizophrenia or other psychotic disease; history of severe personality disorder or other significant psychiatric disorder other than depression associated with the underlying condition and/or breast-feeding women.

Treatment & data collection

As per the nabiximols SmPC [1], patients were instructed to titrate the dose of nabiximols until optimum symptom relief was achieved (maximum of 12 sprays/day) and to maintain the optimum dose. Physicians were at liberty to prescribe any medication and/or continue existing treatments within approved labels for MS spasticity and concomitant conditions. Data were collected using an electronic case report form (eCRF) and entered into a project-specific database via the eCRF by the study team at each participating center. Data collection timepoints were at baseline (Visit 1), week 4 (Visit 2) and week 12 (Visit 3) of nabiximols treatment, or at an early termination visit.

Goal attainment scale score

The primary objective of the study was to assess patients' achievement of individual GAS treatment goals during treatment with add-on nabiximols. In brief, goal attainment scaling is a mathematical technique to quantify the level of achievement of the set goal. Patients establish a set of priority goal areas. Goals are weighted according to their perceived importance (rather important = +1, very important = +2, extremely important = +3) and the anticipated probability of achievement (probable = +1, possible = +2, and uncertain = +3). GAS is scored on a 5-point scale based on the anticipated level of treatment outcome: much worse than expected (-2), somewhat worse than expected (-1), as expected (0), somewhat better than expected (+1) and much better than expected (+2). The composite GAS score (the sum of attainment levels × relative weights for each goal) is then transformed into a standard variable (T score) with a mean of 50 and a standard deviation (SD) of 10. GAS scores range from 0 and 100, with higher values indicating a better outcome. Individualized outcome measures are scored in a standardized manner to enable statistical analysis.

At baseline, each patient was asked to select and rate five individual MS spasticity-related goals from a list of 33 possible goals generated from publications applying GAS scoring in MS or spasticity [10,15,20,21] (Supplementary File 1). At clinic visits on week 4 and week 12, patients assessed their goal attainment using a self-administered questionnaire.

End points

The primary end point was change in the mean overall GAS score after 12 weeks' observation compared with baseline. Secondary end points were clinical measures of MS spasticity and associated symptoms.

At baseline and week 4, physicians assessed spasticity severity on the spasticity 0–10 NRS to identify nabiximols responders and nonresponders as per the approved label [1]; and assessed gait speed using the timed 25-feet walk (T25-FW) test.

At baseline, week 4 and week 12, patients completed questionnaires to record a range of outcomes: spasticity severity within the last 24 h on the spasticity 0–10 NRS; spasticity-related pain severity within the last 24 h on the pain 0–10 NRS; if spasticity-related pain was present (NRS >0), general wellbeing was assessed on the 7-item Marburg questionnaire on habitual health (MFHW), which rates the extent to which a statement applies using a 6-point Likert scale ranging from 0 (does not apply at all) to 5 (fully applies) [22]; spasticity-related sleep impairment within the last 24 h on the sleep quality 0–10 NRS; spasticity-related bladder function impairment within the last 24 h on the bladder function 0–10 NRS; patient's global impression of nabiximols tolerability; patient's global impression of change in spasticity (PGIC-S) since the start of treatment.

Safety was assessed according to the occurrence of adverse drug reactions (ADRs), serious ADRs, adverse events (AEs) and serious AEs during the observation period. Events were categorized using MedDRA (version 25.1) by system organ class and preferred term, and by special situations (e.g., ineffectiveness, overdose).

Statistical analysis

Statistical analysis used mainly descriptive methods. Continuous variables are summarized by mean and standard deviation (SD) and categorical variables are summarized by number and frequency of cases. Changes in the GAS score over time were analyzed statistically. After application of the Shapiro-Wilk test, normally distributed data were analyzed by the Student's t-test, and non-normally distributed data by the Wilcoxon rank-sum test. The significance level threshold was 0.05. Regression analysis was performed to investigate any dependency between the GAS score and PGIC-S by assigning numerical values to PGIC-S responses: very much worse (-3), much worse (-2), slightly worse (-1), no change (0), slightly improved (+1), much improved (+2) and very much improved (+3). All statistical analyses were performed using SAS 9.4 (SAS/STAT 14.3) for Windows (Statistical Analysis System, SAS Institute, NC, USA).

Results

The study was conducted from 2 December 2021 to 26 January 2023 at 17 centers in Germany. A total of 68 patients were recruited by physicians of whom 54 (79.4%) were included in the statistical analysis. Reasons for exclusion (n = 14) were no use of nabiximols (n = 2), nabiximols treatment prior to study start (n = 10) and loss to follow-up (n = 2).

Of 54 included patients, 49 (90.7%) showed clinically significant improvement in spasticity after 4 weeks of nabiximols therapy (≥20% NRS improvement) and were eligible for continued treatment (as per the approved label [1]). Five patients (9.3%) failed to respond sufficiently after 4 weeks' therapy. Nabiximols was terminated in three non-responders and was continued in two non-responders. The main analysis set comprised 51 patients. Patient demographics and baseline clinical characteristics are presented in Table 1. Most patients were female (60.8%) and mean ± SD age was 51.4 ± 11.1 years. Mean time since initial MS diagnosis was 14.9 ± 9.8 years and mean time since onset of spasticity symptoms was 6.1 ± 6.3 years. The median Expanded Disability Status Scale (EDSS) score at baseline was 4.0. Spasticity severity on the physician-rated modified Ashworth Scale was graded most frequently as 1+ (33.3%) or 2 (27.5%). Previous therapy for spasticity was documented for most patients (86.3%) and was mainly baclofen (66.7%).

Reasons to begin nabiximols were ineffectiveness of previous treatment (72.5%), intolerance to previous therapy (17.6%) and ‘other’ (19.6%) which included experiencing pain due to spasticity (7.8%). At baseline, concomitant therapy for spasticity was recorded in 27 patients (52.9%), most (82.5%) of whom received nabiximols in combination with baclofen. Nabiximols therapy was terminated early in 6 patients (11.8%). Reasons for discontinuation (multiple reasons were possible) were lack of acceptance (n = 3), ineffectiveness (n = 2), nontolerability (n = 2) and patient's decision (n = 1). The mean nabiximols dose was 5.3 ± 3.2 (range 1–12) sprays/day at week 4 and 5.9 ± 3.4 (range 1–15) sprays/day at week 12.

Primary effectiveness variable

At baseline, patients selected five goals each for a total of 255 MS spasticity-related goals. The most frequent goals were less pain (Goal 8) selected by 35 patients (68.6%); improvement of physical fitness – walking (Goal 2c) selected by 27 patients (52.9%); improvement of sleep (Goal 7) selected by 25 patients (49.0%) and less discomfort due to stiffness (Goal 9) selected by 21 patients (41.2%) (Figure 1). Overall, attainment goals were rated as being extremely important (23.1%), very important (41.6%) and rather important (35.3%). The probability of goal attainment was rated as possible (63.1%), probable (27.5%) and uncertain (9.4%).

Goal attainment at week 4 and week 12 is summarized in Figure 2. At week 4, approximately half (50.6%) of selected goals were achieved, and this increased to 62.2% at week 12. Approximately two-thirds of patients indicated that the goals achieved at week 12 were as expected (28.0%), more than expected (15.1%) or much more than expected (19.1%).

The mean overall GAS score (primary end point) increased significantly from baseline to week 12 (35.2 vs 51.4; p < 0.001; Table 2), equating to a 46% increase.

Secondary end points

The evolution in physician- and patient-assessed secondary end points is presented in Table 3.

Physician-assessed end points

Physician-assessed mean ± SD 0–10 NRS spasticity scores were 4.5 ± 1.8 at baseline and 3.5 ± 2.0 at week 4 of nabiximols treatment, representing a 23.2% mean reduction.

Among patients who undertook the T25-FW test, physician-assessed mean ± SD gait speed was 17.3 ± 27.9 sec at baseline (n = 30) and decreased to 13.2 ± 9.8 sec at week 4 (n = 31) and 13.2 ± 7.0 sec at week 12 (n = 32), equivalent to a mean improvement of 23.7% at each timepoint.

Patient-assessed end points

Patient-assessed spasticity severity improved over time with spasticity 0–10 NRS scores reduced from 5.2 ± 1.9 at baseline to 3.0 ± 2.2 at week 4 and 2.6 ± 1.9 at week 12, representing mean reductions from baseline of 45.5 and 52.7%, respectively.

Spasticity-related pain improved over time with pain 0–10 NRS scores reduced from 4.9 ± 2.3 at baseline to 3.3 ± 2.3 at week 4 and 2.3 ± 1.5 at week 12, equivalent to reductions of 32.7 and 53.1%, respectively. Among patients with spasticity-associated pain who completed the MFHW, the mean ± SD total MFHW score decreased from 15.8 ± 7.7 at baseline to 14.5 ± 8.0 at week 12.

Spasticity-related sleep impairment improved over time with sleep quality 0–10 NRS scores reduced from 5.5 ± 2.4 at baseline to 2.9 ± 2.0 at week 4 and 2.2 ± 1.7 at week 12, representing respective changes of 47.3 and 60.0%.

Spasticity-related bladder function impairment improved over time with urinary bladder function 0–10 NRS scores reduced from 4.5 ± 2.8 at baseline to 3.2 ± 2.3 at week 4 and 2.4 ± 2.2 at week 12, representing reductions of 28.9 and 46.7%, respectively.

Among 35 patients who completed an end points questionnaire at week 4, most (91.4%) rated nabiximols tolerability as ‘very good’ (20.0%) or ‘good’ (71.4%). Corresponding figures for 29 patients who completed the end points questionnaire at week 12 were 48.3% (‘very good’) and 41.4% (‘good’).

Among 35 patients who completed the PGIC-S questionnaire at week 4, most (91.4%) reported that their spasticity was ‘very much improved’ (14.3%), ‘much improved' (45.7%) or ‘slightly improved' (31.4%) since the start of nabiximols treatment. At week 12, all 29 respondents (100%) reported that their spasticity was very much (13.8%), much (65.5%) or slightly (20.7%) improved. Regression analyses indicated a low correlation between GAS and PGIC-S scores at week 4 (R² = 0.212) and week 12 (R² = 0.148).

A total of 11 AEs were reported in nine patients consisting of insufficient ineffectiveness of nabiximols (four patients), fatigue (two patients), dizziness (two patients), balance disorder (one patient), cardiac insufficiency (one patient) and mood swings (one patient). All events were assessed as mild (71.4%) or moderate (28.6%) and no event was deemed to be serious. Seven of the nine patients with AEs discontinued nabiximols following the event. A suspected causal relationship with nabiximols (i.e., an ADR) was recorded for seven events in five patients.

Discussion

This 12-week study assessed the effectiveness of nabiximols add-on therapy in patients with MS spasticity in routine clinical practice in Germany by evaluating the evolution of GAS scores as the main end point. Given the heterogeneous clinical expression of spasticity and its related symptoms in patients with MS [23], GAS scoring is a useful method to determine whether an intervention addresses a patient's individual treatment-related goals as these can vary widely per person.

Based on other real-world data indicating that common spasticity-associated symptoms are pain, sleep disturbances, spasm/involuntary movements and difficulty walking/climbing stairs, it seemed reasonable to ask patients to select five treatment goals since any more than five might be difficult for patients to assess at the end of treatment. MS spasticity-related attainment goals selected at baseline by at least 25% of the study population were less pain, better walking, better sleep, less discomfort due to stiffness, better able to climb stairs, better range of movement, less fatigue, and less involuntary movements/spasms, clearly reflecting the burden of MS spasticity on patients' everyday lives. Along with better bladder functioning (selected by 21.6% of patients), several of these goals are among the cluster of symptoms described as the ‘spasticity-plus syndrome’ [24]. At week 12, nearly two-thirds (62%) of selected goals were achieved ‘as expected' or ‘better than expected’ which is useful insight for clinicians with regard to setting realistic expectations with patients prior to the start of nabiximols treatment.

The statistically significant and clinically meaningful 46% improvement in the mean overall GAS score observed during 12 weeks of nabiximols therapy is highly relevant to daily practice. The positive change in GAS scores indicates that the benefits of nabiximols extend beyond a nonspecific enhancement in quality of life or wellbeing as per a ‘lifestyle’ drug but, rather, offer a therapeutic solution for individual problems from the large spectrum of spasticity-associated symptoms in MS. The GAS goals selected by patients reflect common MS spasticity-associated symptoms that had not been resolved adequately with previous antispasticity therapies.

The mean 23.3% reduction in the physician-assessed spasticity 0–10 NRS score from baseline to week 4 of treatment met the threshold for an acceptable initial response to nabiximols [1]. The physician-assessed 90.7% responder rate at 4 weeks exceeded that reported in comparable real-world studies of nabiximols (67–80%) [25,26] possibly because, with cumulative experience, clinicians have learned to identify patients with a better capacity to respond. Two of the five non-responders at 4 weeks continued nabiximols treatment. In routine practice, physicians may consider it useful to persevere with nabiximols if the reduction in spasticity severity is approaching the 20% NRS threshold or if patients perceive benefits in spasticity-associated symptoms if not spasticity itself. Nabiximols has been shown to improve spasticity-related symptoms even in patients who fail to meet current thresholds for a spasticity NRS response [26,27]. The patient-reported reductions in mean spasticity 0–10 NRS scores of 45.5 and 52.7% at 4 weeks and 12 weeks, respectively, emphasize the importance of patient-rated outcome measures to evaluate the effectiveness of an intervention since patients will perceive their symptom burden differently from physicians. The reduction in spasticity severity was reflected by a near 25% improvement in gait speed at week 4 which was maintained at week 12. Other studies using gait analyses in patients with MS spasticity have reported improvements with nabiximols in walking ability and various gait parameters [28,29].

Despite a patient-reported 50% reduction in spasticity-related pain from baseline to week 12, there was no associated improvement in patients' wellbeing according to the MFHW, possibly because the instrument is insufficiently sensitive to detect a change in spasticity-associated pain in the setting of a multisymptomatic disease such as MS. Wellbeing is a highly complex concept that encompasses an individual's physical, mental, social and environmental status. Each aspect interacts with the other and each has a different level of importance and impact per individual [30]. In our cohort, patients assigned scale values of mostly 1 or 2 to the MFHW statements, indicating low applicability to their situation.

In addition to relief of spasticity and pain, patients perceived clinically relevant improvement from baseline in spasticity-related sleep impairment and bladder function impairment at weeks 4 and 12 of nabiximols treatment. The findings are consistent with real-world Italian Medicines Agency e-Registry analyses showing amelioration of spasms, pain, sleep disturbances and bladder dysfunction in MS patients newly started on nabiximols [26,27]. A therapeutic invention that provides integrated symptom management across multiple domains may, to some extent, limit the polypharmacy that is common in patients with MS [31] and minimize or even avoid side effects and/or drug–drug interactions [32].

Patients viewed the overall change in spasticity since the start of nabiximols treatment positively, with 45% of patients at week 4 and 65% at week 12 rating their spasticity as ‘much improved’. However, only minimal dependency was found between the change in GAS score and patients' assessment of the change in their spasticity.

The mean dose of nabiximols at 4 and 12 weeks (5.3 and 5.9 sprays/day, respectively), was similar to doses reported in other real-world studies of nabiximols in patients with MS spasticity [5–7] suggesting that treatment goals can be achieved at ‘typical’ optimal doses that patients find sufficient for symptomatic relief of spasticity and related symptoms.

The majority of patients (91%) rated the tolerability of nabiximols as good or better, and this was reflected in the safety data. Few AEs were reported and most were known adverse effects of nabiximols [1]. No new safety concerns were reported.

Limitations of noninterventional studies include possible selection bias, lack of a control group and missing or incomplete data. Specific to this study, the relatively small sample size represents a key study limitation. Because most eligible patients at participating study centers were already receiving nabiximols, the planned threshold of 200 patients newly started on nabiximols could not be reached. This, combined with the limited number of participating centers, restricts the generalizability of the results. Additionally, the results of patient-assessed end points may not truly reflect the study population as a whole since not all patients completed end point questionnaires at baseline (70.6% of cohort), week 4 (68.6%) and week 12 (56.9%), although this is not unusual for an observational study in patients with a chronic disease.

Conclusion

In this real-world study of MS spasticity involving nabiximols responders according to the spasticity 0–10 NRS threshold, the mean GAS score increased by 46% from baseline to 12 weeks and 60% of treatment goals were achieved ‘as expected’ or ‘better than expected’ at 12 weeks. These findings were accompanied by positive changes from baseline in physician- and patient-assessed measures of MS spasticity and spasticity-associated symptoms. Nabiximols was well tolerated. Nabiximols is a useful therapeutic option for patients with MS spasticity who fail to gain adequate symptom relief with conventional antispasticity therapy or are poorly tolerable to conventional antispasticity therapy. Nabiximols nonresponders (<20% NRS improvement) may show sufficient improvement in spasticity-associated symptoms to warrant continued treatment.