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International Journal of Neuroscience
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: http://www.tandfonline.com/loi/ines20
Sativex® as Add-on therapy Vs. further optimized
first-line ANTispastics (SAVANT) in resistant
multiple sclerosis spasticity: a double-blind,
placebo-controlled randomised clinical trial
Jolana Markovà, Ute Essner, Bülent Akmaz, Marcella Marinelli, Christiane
Trompke, Arnd Lentschat & Carlos Vila Silván
To cite this article: Jolana Markovà, Ute Essner, Bülent Akmaz, Marcella Marinelli, Christiane
Trompke, Arnd Lentschat & Carlos Vila Silván (2018): Sativex® as Add-on therapy Vs. further
optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-
blind, placebo-controlled randomised clinical trial, International Journal of Neuroscience, DOI:
10.1080/00207454.2018.1481066
To link to this article: https://doi.org/10.1080/00207454.2018.1481066
Accepted author version posted online: 24
May 2018.
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Publisher: Taylor & Francis
Journal: International Journal of Neuroscience
DOI: https://doi.org/10.1080/00207454.2018.1481066
Sativex® as Add-on therapy Vs. further optimized first-line
ANTispastics (SAVANT) in resistant multiple sclerosis
spasticity: a double-blind, placebo-controlled randomised
clinical trial
Jolana Markovàa, Ute Essnerb, Bülent Akmazc, Marcella Marinellid, Christiane Trompkec, Arnd
Lentschatc, Carlos Vila Silváne
a Neurology Department, Thomayer's Hospital, Praha, Czech Republic
b O. Meany Consultancy GmbH, Hamburg, Ohkamp 26, Germany
c International Clinical Trial Managers, Almirall Hermal GmbH, Scholtzstraβe 3, Reinbeck, Germany
d Clinical Statistics, Almirall S.A., Laureà Miró, 408 08980 Sant Feliu de Llobregat, Barcelona, Spain
e Neurology Medical Manager, Global Medical Affairs, Almirall S.A., Barcelona, Spain
Correspondence:
Jolana Markovà
Thomayer's Hospital
Vídeňská 800
Praha 4 - 140 59 Czech Republic
jolana.markova@ftn.cz
Word count (body): ~3870 to end of Discussion
Figures: 4; Tables: 4; References: 22
Language: British English
Keywords: Multiple sclerosis; spasticity; Sativex; THC; CBD; nabiximols
Abstract
Purpose/aim: To evaluate the efficacy of tetrahydrocannabinol [THC]:cannabidiol [CBD] oromucosal
spray (Sativex®) as add-on therapy to optimized standard antispasticity treatment in patients with
moderate to severe multiple sclerosis (MS) spasticity.
Methods: Sativex as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) was a
two-phase trial. In Phase A, eligible patients received add-on THC:CBD spray for 4 weeks to identify
initial responders (≥ 20% improvement from baseline in spasticity 0-10 numerical rating scale [NRS]
score). Following washout, eligible initial responders were randomised to receive THC:CBD spray or
placebo for 12 weeks (double-blinded, Phase B). Optimization of underlying antispasticity
medications was permitted in both groups across all study periods.
Results: Of 191 patients who entered Phase A, 106 were randomised in Phase B to receive add-on
THC:CBD spray (n = 53) or placebo (n = 53). The proportion of clinically-relevant responders after 12
weeks (≥ 30% NRS improvement; primary efficacy endpoint) was significantly greater with THC:CBD
spray than placebo (77.4 vs 32.1%; P < 0.0001). Compared with placebo, THC:CBD spray also
significantly improved key secondary endpoints: changes in mean spasticity NRS (P < 0.0001), mean
pain NRS (P = 0.0013), and mean modified Ashworth’s scale (P = 0.0007) scores from Phase B
baseline to week 12. Adverse events, when present, were mild/moderate and without new safety
concerns.
Conclusions: Add-on THC:CBD oromucosal spray provided better and clinically relevant
improvement of resistant MS spasticity compared with adjusting first-line antispasticity medication
alone.
Introduction
Spasticity is a common chronic symptom in patients with multiple sclerosis (MS) which increases in
prevalence and severity as the disease progresses [13]. It is frequently accompanied by pain,
spasms, mobility restrictions, sleep disturbances, and/or bladder dysfunction and is strongly
associated with fatigue, anxiety, and depression [4,5]. Patients’ quality of life worsens as spasticity
severity increases [68].
Interventional procedures (e.g. physiotherapy) and pharmacological therapy are the main
approaches for treating MS spasticity. Baclofen and tizanidine are recommended first-line
pharmacological options in the European Union (EU) [4,9], and dantrolene is indicated in certain
countries (albeit used less often). However, treatment with these conventional oral antispasticity
medications is often limited by undesired adverse effects, including effects on the central nervous
system (CNS), increased risk of falls, and/or by a waning effect as MS progresses [10]. About one-
third of MS patients continue to experience moderate to severe spasticity despite first-line
treatment [1113], and a relevant proportion of patients and physicians are dissatisfied with
standard antispasticity medications [7].
Randomised clinical trials [1416] and observational studies conducted in routine clinical practice
[17,18] have shown that an oromucosal spray of tetrahydrocannabinol (THC) and cannabidiol (CBD)
(Sativex®, Nabiximols USAN name) is an effective and well-tolerated option for treating resistant MS
spasticity. THC:CBD spray is approved in several countries (e.g. Canada, Germany, Italy, Spain, UK)
and across Europe it is indicated as add-on therapy for patients with moderate to severe MS
spasticity who have not responded adequately to first-line antispasticity medications [19]. This
indication has raised a clinical question in terms of how much greater the benefits of THC:CBD spray
might be compared with those achieved by attempting to further optimize standard first-line oral
antispasticity therapy.
Herein, we report results from the Sativex as Add-on therapy Vs. further optimized first-line
ANTispastics (SAVANT) randomised, placebo-controlled trial which was designed to evaluate the
therapeutic efficacy of add-on THC:CBD spray compared with further optimization of standard
antispasticity therapy in patients with moderate to severe MS spasticity who were not achieving
adequate symptomatic relief after use of two or more optimized first-line antispasticity medications.
Methods
Design and participants
SAVANT was a prospective, randomised, parallel group, double-blind, placebo-controlled two-phase
trial. Patients were enrolled at 15 sites, 14 in the Czech Republic and 1 in Austria.
Main inclusion criteria were: adults ≥ 18 years of age, with a diagnosis of MS and existing MS
spasticity symptoms for at least 12 months; moderate to severe MS spasticity defined as a score of ≥
4 on the MS spasticity 0-10 numerical rating scale (NRS) scale; previous treatment with at least two
different optimized oral MS spasticity therapies which included oral baclofen and/or oral tizanidine
(as monotherapy or in combination therapy); currently receiving optimized treatment with one or
more oral antispasticity drugs (baclofen and/or tizanidine and/or dantrolene as monotherapy or in
combination therapy) for at least 3 months prior to screening without adequate relief of MS
spasticity symptoms. Optimization was defined as reporting achievement of the most effective and
best tolerated dose possible according to approved labelling. Patients provided written informed
consent to participate.
Exclusion criteria included prior administration of THC:CBD spray; current consumption of cannabis
herb or other cannabinoid-based drugs within 30 days prior to study entry; treatment with
botulinum toxin injection for spasticity relief within the previous 6 months; medical history or family
history of major psychiatric disorders other than depression; known or suspected history of a
dependence disorder or heavy alcohol consumption; possibility of pregnancy or lactation; history of
myocardial infarction or clinically significant cardiac dysfunction; clinically significant impaired renal
function or impaired hepatic function.
The study design is illustrated in Figure 1. In a single-blind, 4-week, trial period (Phase A), patients
received THC:CBD spray as add-on therapy to optimized standard antispasticity medication. Patients
up-titrated the dosage of THC:CBD spray to a maximum of 12 sprays/day according to posology in
the approved label [19] until optimized symptom relief was achieved. Initial responders were
identified based on having achieved a Minimal Clinically Important Difference (MCID) in MS
spasticity, defined as ≥ 20% improvement from baseline in the MS spasticity 0-10 NRS score, which
was rounded up from the 18% improvement calculated as a MCID [20]. Non-responders were
removed from the study. Initial responders at 4 weeks entered a 1 to 4 week washout phase
designed to minimize carry-over effects, during which THC:CBD spray was withdrawn but underlying
standard antispasticity treatment was continued. Initial responders whose improvement in the MS
spasticity NRS score during Phase A was reduced by ≥ 80% during the washout period were eligible
for Phase B. In Phase B, patients were randomised in a double-blind manner to treatment with
THC:CBD spray or placebo for 12 weeks. Patients were advised to re-up-titrate their study
medication to the optimal individual dose identified in Phase A, then to maintain the study
treatment at this dose while allowing for adjustments according to the patient’s needs. Optimization
of underlying antispasticity medications was permitted across all study periods.
The study comprised seven clinic visits: screening (Visit 1); start of single-blind THC:CBD spray trial
period in Phase A (Baseline visit, Visit 2); start of washout phase (Visit 3); start of randomised
double-blind treatment in Phase B (Visit 4); then at 4-weekly intervals during the 12-week treatment
period (Visits 5 until 7, end of treatment). Patients therefore participated in the study for a
maximum total duration of 18 to 22 weeks (Figure 1).
The study was conducted in accordance with the recommendations set out in the Declaration of
Helsinki (Seoul 2008) and in compliance with the ICH Consolidated Guideline for Good Clinical
Practice and applicable local laws and regulations.
The EudraCT allocated number was 2015-004451-40.
Outcomes
The primary efficacy endpoint was the proportion of responders after 12 weeks of randomised
treatment in Phase B, where responder was defined as a patient who achieved ≥ 30% improvement
(i.e. a clinically important difference [CID]) in the MS spasticity 0-10 NRS score from Phase B baseline
[20].
Secondary efficacy variables were measures of spasticity and associated symptoms during the 12-
week randomised treatment period (Phase B). Changes referred to values at study end compared
with values at Phase B baseline:
Change from baseline in MS spasticity 0-10 NRS score
Change from baseline in pain 0-10 NRS score
Change from baseline in modified Ashworth scale (MAS) score
Change from baseline in Expanded Disability Status Scale (EDSS) score.
Other secondary efficacy endpoints were: frequency and severity of spasms; sleep disruption 0-10
NRS score; modified Ashworth scale score per muscular group; Barthel activities of daily living (ADL)
index; short form 36 quality of life (QoL) health survey (SF-36); global assessment of clinical change
(GIC) by subject (SGIC) and physician (PGIC); and timed 10-metre walk test. Safety and tolerability
outcomes were collected during the Phase A, washout, and Phase B periods and assessed separately.
The number of patients with adverse events (AEs) and serious adverse events (SAEs); the numbers of
AEs, SAEs, and treatment interruptions related to AEs; and discontinuation rates and the reasons for
discontinuation were also recorded. AEs were assessed for their intensity (mild, moderate, severe)
and causal relationship with study treatment.
AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA; version 19.1) and
tabulated by system organ class (SOC) and preferred term (PT).
Statistical analysis
A sample size of 82 randomised (1:1 ratio) evaluable patients in Phase B was estimated to provide
90% power to detect a difference of 35% between arms in the primary endpoint. A blinded interim
analysis was performed to ensure adequacy of the sample size calculation.
Analysis of the primary endpoint was performed for the Phase B intention-to-treat (ITT) population.
An analysis was performed using the Phase B per protocol (PP) population to assess the robustness
of the trial. All other efficacy variables were analysed using both the ITT and PP populations. Safety
outcomes were analysed for the safety population.
The Phase B primary efficacy variable was analysed using a logistic regression model, with
baseline value as a covariate and treatment group as factor. Missing data were handled
using Last Observation Carried Forward (LOCF) and Generalized Linear Mixed Models
(GLMM) methods for binary repeated data with GLIMMIX SAS procedure as a sensitivity
analysis.
All secondary continuous efficacy variables with repeated measures were analysed by
means of a mixed model for repeated measures (MMRM). The dependent variable was the
change from baseline to each scheduled post-baseline visit (encompassing all available
measurements in a patient) during the treatment period. The model adjusted for baseline
value as covariate and treatment, visit and treatment-by-visit interaction as fixed effect
factors.
Treatment effects and treatment comparisons were estimated by Least Square (LS) means
and differences in LS means on the treatment-by-visit interaction at the corresponding
visits, along with standard errors (SE) and 95% confidence intervals (CIs), and the p-value
corresponding to the between-treatment group difference.
Finally, secondary binary efficacy variables with repeated measures were analysed using a
GLMM model for binary repeated data with GLIMMIX SAS procedure. All secondary
variables or other outcomes with one post-baseline assessment were analysed using an
observed cases approach.
Continuous data were summarised using descriptive statistics and categorical data are
presented using frequency (n) and percentage (%). All statistical hypotheses were tested at
the two-sided 5% significance level (α=0.05), and corresponding 95% CIs are reported as
appropriate.
Other secondary endpoints, exploratory endpoints and safety endpoints are presented using
descriptive statistics.
Statistical analyses were performed using SAS statistical analysis software Version 9.1.3 or higher
(SAS Institute Inc., Cary, NC, USA).
Results
The demographic and clinical characteristics of patients entering the Phase A trial period (n = 191)
are summarised in Table 1. The population was predominantly female (70.2%) with a mean (SD) age
of 51.3 ± 10.2 years. Most patients had secondary progressive MS (n = 92; 48.2%) or relapsing
remitting MS (n = 78; 40.8%). At baseline, patients had significant disability (mean EDSS score 5.9)
and moderate to severe MS spasticity (mean NRS score 6.4). Patients had a long history of MS and of
MS spasticity with a mean duration of 14.2 and 7.8 years, respectively.
Most patients in the Phase A safety population had received baclofen (99.0%) and/or tizanidine
(89.0%) as prior antispasticity medication, and 77.5% had taken a combination of baclofen and
tizanidine. No patient had received dantrolene as prior antispasticity medication. Other previous
antispasticity medications taken by patients included other centrally acting agents (14.6%) and
benzodiazepine derivatives (8.4%). At Phase A baseline, 82.2% of patients were receiving baclofen
and 34.5% were receiving tizanidine (inclusive of patients receiving combination therapy). The
demographic and clinical characteristics of Phase B patients were similar to those in the Phase A
population. At Phase B baseline, 84.9% of patients were receiving baclofen, 31.1% were receiving
tizanidine, and 16.0% were receiving combination therapy.
Patient disposition during all phases of the study is shown in Figure 2. Following trial therapy with
THC:CBD spray in Phase A, 134 patients (70.5%) were initial responders (≥ 20% NRS improvement).
Of these, 106 patients (i.e. 55.5% of 191 Phase A patients) had a ≥ 80% reduction of their Phase A
NRS improvement during the washout period and were eligible for randomization into Phase B. A
total of 50/53 patients (94.3%) allocated to THC:CBD spray and 46/53 patients (88.8%) allocated to
placebo completed 12 weeks of double-blind treatment.
Efficacy
The primary efficacy endpoint, the proportion of MS spasticity 0-10 NRS CID responders after 12
weeks of randomised treatment, was significantly higher in the THC:CBD oromucosal spray group
(41/53; 77.4%) than in the placebo group (17/53; 32.1%), with an adjusted Odds Ratio of 7.0 (95% CI:
2.95 – 16.74; P < 0.0001; ITT population; Figure 3).
At week 4 in Phase B, 81.1% of patients allocated to THC:CBD spray had reached the initial response
threshold of ≥ 20% NRS improvement versus 45.3% in the placebo group (P = 0.0007).
The mean (SD) number of sprays/day of THC:CBD spray was 7.7 (3.0) at week 4 of Phase A (n =188)
and 7.5 (2.6) at week 4 of randomised Phase B (n = 102). At the week 12 final visit (study end), the
mean (SD) number of sprays/day was 7.3 (2.7) for THC:CBD spray (n = 48) and 8.5 (3.0) for placebo (n
= 46).
Mean (SD) doses of underlying antispasticity study medication were 35.8 (25.5) mg for baclofen and
5.2 (3.0) for tizanidine in Phase A and 35.4 (25.5) mg for baclofen and 5.1 mg (2.9) for tizanidine in
Phase B. During Phase B, seven patients (two in the THC:CBD oromucosal spray group and five in the
placebo group) re-adjusted their baclofen doses.
The results of secondary efficacy outcomes are shown in Table 2. At week 12 in Phase B, significant
reductions were observed with THC:CBD spray versus placebo in the mean MS spasticity 0-10 NRS
score (P < 0.0001; Figure 4), mean pain 0-10 NRS score (P < 0.0013), and mean 0-4 MAS score (P <
0.0007). The difference between THC:CBD spray and placebo in the change of mean MS EDSS scores
from Phase B baseline to week 12 was not significant. Among other secondary efficacy assessments,
THC:CBD spray was significantly superior to placebo for spasms severity (P = 0.0001), sleep
disruption (P = 0.0006), and MAS scores for seven of 10 tested muscular groups (elbow flexor,
extensor and pronator, hip adductor, knee flexor and extensor and foot plantar).
Statistically significant improvements in SGIC and PGIC were reported for THC:CBD vs. placebo after
4 weeks, but tended to decrease at follow up visits (Table 2). Most other secondary efficacy
endpoints changes were in favour of THC:CBD oromucosal spray but comparisons did not reach
statistical significance.
Safety
Features of treatment emergent adverse events (TEAEs) occurring in the Phase A and washout
period safety population (n = 191) and Phase B safety population (n = 106) are shown in Tables 3 and
4, respectively.
In Phase A, 75 AEs (28 moderate, 47 mild) were reported in 46 patients (24.1%), of which 64 events
in 37 patients (19.4%) were considered to be related to study medication (Table 3). The three SAEs
which occurred in two patients (erysipelas; olecranon bursitis and MS relapse) were considered
unrelated to study treatment. There were 54 AE-related treatment interruptions in 29 patients
(15.2%) and five AEs in four patients (2.1%) which led to withdrawal.
The most frequently reported TEAEs during Phase A were: vertigo (15 TEAEs in 14 patients [7.3%]),
somnolence (six TEAEs in three patients [1.6%]), dizziness (four TEAEs in four patients [2.1%]),
diarrhoea (four TEAEs in four patients [2.1%]) and nausea (four TEAEs in four patients [2.1%]). All
TEAEs except one event of vertigo were assessed as related to study treatment.
In the washout phase, 20 TEAEs in 12 patients were ongoing (i.e. carried over from Phase A or
started during washout phase), of which 12 TEAEs in six patients (carried over from Phase A) were
assessed as related to study medication. All TEAEs ongoing during washout were mild or moderate in
intensity. The most frequently reported TEAEs were classified in the SOC Nervous system disorders
(four TEAEs in four patients). All TEAEs were reported by single patients, except for dry mouth, dry
throat and hypertension, which were reported by two patients.
During the 12-week randomised treatment phase (Phase B), no major or new safety concerns were
identified for THC:CBD spray (Table 4).
There was no statistically significant difference between treatment groups in the number of patients
with TEAEs (including SAEs) during Phase B: 19 TEAEs in 12 patients in the active group and 8 TEAEs
in 7 patients in the placebo group. All TEAEs were of either mild or moderate intensity except for
one severe SAE reported in the placebo group.
There was no statistically significant difference between treatment groups in the number of patients
with SAEs during Phase B: one SAE (haematuria of moderate severity) in one patient in the active
group and one SAE (tubulointerstitial nephritis of severe intensity) in one patient in the placebo
group, both of which began and ended in Phase B and were assessed as not related to study
medication.
There was no statistically significant difference between treatment groups in the number of patients
with TEAEs related to study medication during Phase B: seven TEAEs in five patients in the active
group and one TEAE in one patient in the placebo group. All related TEAEs in the active group were
of mild intensity, except for one event of vertigo which was of moderate intensity. Of TEAEs deemed
related to THC:CBD spray, five TEAEs in three patients were classified in the SOC Nervous system
disorders (PT: somnolence, hypoaesthesia, hypogeusia and psychomotor skills impaired). There were
three treatment interruptions related to AEs in two patients (3.8%) in the active group and none in
the placebo group.
Discussion
In patients with moderate-to-severe resistant MS spasticity who initially responded to THC:CBD
spray during a 4-week trial period, adding THC:CBD spray to already-optimized antispasticity
treatment is a better alternative to readjusting the first-line antispasticity medication alone. After 12
weeks’ treatment, a significantly greater proportion of patients treated with add-on THC:CBD spray
than placebo achieved clinically relevant improvement (≥ 30% NRS improvement) in MS spasticity,
with the difference representing a +45.3% therapeutic gain in favour of THC:CBD oromucosal spray.
Compared with placebo, THC:CBD spray also produced significantly greater reductions in key
secondary efficacy measures including MS spasticity 0-10 NRS, pain 0-10 NRS, and MAS scores. Other
secondary efficacy measures significantly in favour of THC:CBD spray included spasms severity, sleep
disruption, and MAS for seven of 10 tested muscular groups. Although improvement was observed
in the physical activity subscale of the SF-36 in the group treated with THC:CBD spray, overall QoL
scores did not differ significantly between treatment groups, probably due to underlying MS and the
presence of other MS-related symptoms (e.g. fatigue).
In accordance with standard procedures for pre-approval regulatory studies in which changes in
factors other than target medication must be kept to a minimum, no alterations to underlying
antispasticity medications were permitted in previous clinical development trials of THC:CBD spray
[15,16,21]. However, daily clinical experience with THC:CBD spray indicates that patients can adapt
their underlying antispasticity medications according to individual needs and, indeed, continuous
optimization is viewed as an integral component of gaining maximum benefit from a given
treatment. The current study therefore set out to evaluate the efficacy of add-on THC:CBD spray
under conditions closer to daily clinical practice by explicitly allowing optimization of patients’
underlying antispasticity therapy throughout all phases of the study and also ensuring that all
participants had tried and failed at least two first-line antispasticity drugs.
The demographic and clinical characteristics of the patient population were comparable to those in
previous clinical trials and observational studies of THC:CBD spray in resistant MS spasticity [1618],
allowing meaningful comparisons to be made between the studies.
At the end of the 4-week trial period of THC:CBD spray, 70.5% of patients (134/190) were initial
responders (≥ 20% NRS improvement). This was higher than the initial response rate of 47%
(272/572 patients) reported in the enriched-design phase 3 clinical trial of THC:CBD spray [16] but
identical to the initial response rate of 70.5% reported in the Italian health authorities prospective e-
registry study of THC:CBD spray (n = 1615) [18]. The washout period eliminated 28 initial responders
(20.9%) who failed to show ≥ 80% reduction in their Phase A NRS improvement. The inclusion of a
washout period, and requirement for patients’ spasticity levels to return to near pre-treatment
levels, is the main point of difference between our study and that of Novotna et al. [16] and ensured
that treatment effects observed in Phase B were not confounded by any ‘carryover’ or other effects
of THC:CBD spray from Phase A.
After 12 weeks of randomised treatment in initial responders, the CID responder rate was
significantly in favour of THC:CBD spray over placebo (77.4 vs 32.1%; p<0.0001), demonstrating a
broad therapeutic gain despite having allowed for dosage adjustments of underlying antispasticity
medication in both groups. This result compares favourably with respective values of 74% and 51%
(OR: 2.73; 95% CI 1.59 to 4.69; P = 0.0003) reported in the pivotal trial of Novotna et al. (2011)
where the absence of a washout period between Phases A and B may have contributed to a more
pronounced placebo effect [16].
Among study participants who were initial responders to THC:CBD spray in Phase A and met
eligibility criteria after washout for randomization in Phase B, 77.4% of those allocated to THC:CBD
spray in Phase B achieved the CID threshold of ≥ 30% NRS improvement [20]. Thus, the probability of
becoming a CID responder to THC:CBD spray upon starting treatment (start of trial period) was 43%,
which is similar to the 36% reported in the phase 3 trial [16] and to the 41% reported in the Mobility
ImproVEment (MOVE) 2 observational study in Germany [17].
Secondary effectiveness measures in favour of THC:CBD spray, specifically changes from Phase B
baseline to study end in MS spasticity 0-10 NRS, pain 0-10 NRS, and MAS scores, further support the
difference observed between THC:CBD spray and placebo in the responder rate at 12 weeks
(primary endpoint) and are consistent with or superior to results reported for these endpoints in the
previous enriched design trial and observational studies of THC:CBD spray conducted under
approved conditions [16,17]. Although no changes were observed with THC:CBD spray or placebo on
the MS EDSS, this is not surprising given that the EDSS is linked to underlying overall MS evolution, is
largely ambulation driven, and has been shown to have low sensitivity to alterations in MS spasticity
severity [22]. Other efficacy secondary endpoints showed trends in favour of THC:CBD spray but
without reaching statistical significance. This might relate to the study power (the sample size was
calculated for the primary endpoint) and also to the parameters per se and the nature of MS
spasticity as being one of many symptoms of MS [3].
Mean daily use of THC:CBD spray was 7.7 sprays/day at the end of Phase A and 7.3 sprays/day
(versus 8.5 sprays/day for placebo) at the end of 12 weeks’ treatment in Phase B. This level of usage
is lower than that reported in the largest pivotal phase 3 clinical trial of THC:CBD spray (8.3
sprays/day) [16], and consistent with that reported in observational studies in daily practice (6.7-6.8
sprays/day) [17,18]. Evidence is accumulating to suggest that patients receiving THC:CBD spray in
daily practice gain sufficient benefit at a mean dosage of about 7 sprays/day.
THC:CBD spray was well tolerated during both the trial and treatment phases of the study. In line
with observational studies of THC:CBD spray [17,18], incidences of treatment-related AEs were low
overall and any AEs reported were mainly mild or moderate in intensity and not different from those
reported in the previous studies (e.g. dizziness, somnolence). The incidence of AEs related to
THC:CBD spray decreased from 19.4% of patients in Phase A to 9.4% of patients in Phase B, likely
reflecting accustomisation by patients during continued use, which was further supported by a
decrease in the incidence of treatment interruptions related to AEs in THC:CBD spray-treated
patients, from 15.2% of patients in Phase A to 3.8% of patients in Phase B.
The design of this study, especially the inclusion of a washout period to avoid carryover and other
effects of THC:CBD spray during the randomised treatment phase, allowed us to better evaluate its
true therapeutic effect. Under these conditions, THC:CBD spray at an average dose of about 7
sprays/day produced clinically meaningful improvement of resistant MS spasticity in more than
three-quarters of initial responders, thus proving to be a more efficacious alternative to readjusting
underlying antispasticity drugs.
Acknowledgements
The authors wish to express their sincere thanks for the collaboration of participating patients and
investigators *CZ: Y. Benešová (Brno), M. Dufek (Brno), P. Hradílek (Havířov), L. Janů (Plzeň), H.
Lachmann (Prague), B. Luběnová (Olomouc), E. Meluzínová (Prague), I. Nováková (Prague), O. Škoda
(Pelhřimov), I. Štětkářová (Prague), R. Taláb (Hradec Králové), M. Vachová (Teplice), M. Vališ
(Choceň); AT: M. Guger (Linz)+, all team members at study sites, Easthorn CRO, and Almirall S.A.
Writing assistance was provided by Content Ed Net (Madrid, Spain), with funding from Almirall S.A.
(Barcelona, Spain).
Disclosure statement
J Markovà has received fees as consultant or investigator in projects sponsored by Almirall, Amgen,
Biogen, Merck, Novartis, Pfizer, Teva and other pharmaceutical companies.
U Essner and A Lenschat are consultants for Almirall Hermal GmbH.
B Akmaz and C Trompke are fulltime employees of Almirall Hermal GmbH.
M Marinelli and C Vila are fulltime employees of Almirall S.A.
Funding details
This study was sponsored by Almirall Hermal GmbH and Almirall S.A.
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Figures
Figure 1. Overview of study design. Non-returners were initial responders who failed to show a ≥
80% reduction of their Phase A NRS improvement during washout.
Figure 2. Patient disposition. Abbreviations: IMP: Investigational Medicinal Product; NRS, Numerical
Rating Scale.
Figure 3. Primary endpoint: proportion of MS spasticity 0-10 NRS CID responders (≥ 30%
improvement from baseline) after 12 weeks’ randomised double-blind treatment with THC:CBD
oromucosal spray or placebo. CI, Confidence interval; CID, Clinically important difference; NRS,
Numerical rating scale. OR, Odds ratio.
Figure 4. Change in MS spasticity 0-10 NRS score (measured in Least Squares [LS] means) from Phase
B baseline (week 1) through to week 12 of randomised double-blind treatment with THC:CBD
oromucosal spray (n = 53) or placebo (n = 53) in the intent-to-treat population.
Tables
Table 1. Demographic and clinical characteristics of patients entering the Phase A trial
period (n = 191).
Characteristic
Value
Gender: female/male: n (%)
134 (70.2%) / 57 (29.8%)
Age: mean (SD)
51.3 (10.2)
MS classification: n (%)
Primary progressive MS
Secondary progressive MS
Relapsing remitting MS
21 (11.0%)
92 (48.2%)
78 (40.8%)
MS disease history, years: mean (SD)
14.2 (8.4)
EDSS score: mean (SD)
5.9 (1.1)
Disease modifiers use n (%):
Past
Present
191 (100%)
190 (99.5%)
MS spasticity history, years: mean (SD)
7.8 (5.3)
NRS spasticity score: mean (SD)
6.4 (1.2)
Pain NRS: mean (SD)
5.5 (1.9)
Table 2. Secondary efficacy endpoints: least squares (LS) means for change in measures of spasticity
and associated symptoms from Phase B baseline to week 12.
Endpoint
THC:CBD
oromucosal spray
(mean) (n = 53)
Placebo
(mean)
(n = 53)
Treatment
difference
P-value
Spasticity NRS score, 0-10
scale
-3.5
-1.6
-1.9
< 0.0001
Pain NRS score, 0-10 scale
-3.2
-1.8
-1.4
< 0.0013
MAS score, 6-point ordinal
scale
-0.30
-0.06
-0.24
< 0.0007
MS EDSS score, 0-10 scale
-0.02
-0.01
-0.01
< 0.6529
Spasms frequency, n
-20.58
-17.75
-2.83
ns
Spasms severity, 0-3 scale
-0.72
-0.38
-.34
0.0001
Sleep disruption NRS score, 0-
10 scale
-3.21
-1.78
-1.43
0.0006
MAS score per muscular
group, 0-4 scale
Elbow flexor
Elbow extensor
Elbow pronator
Elbow supinator
Wrist flexor
Finger flexor
Hip adductor
Knee flexor
Knee extensor
-0.28
-0.31
-0.23
-0.16
-0.16
-0.16
-0.43
-0.47
-0.51
-0.33
-0.03
-0.01
-0.02
-0.02
-0.04
-0.02
-0.09
-0.11
-0.13
-0.10
-0.24
-0.30
-0.20
-0.14
-0.12
-0.14
-0.34
-0.36
-0.38
-0.22
0.0044
0.0004
0.0327
ns
ns
ns
0.0007
0.0016
0.0004
0.0119
Foot plantar
Barthel ADL index
0.04
0.11
-0.07
ns
SF-36 (General Health)
0.31
1.90
-1.59
ns
Timed 10-meter walk,
seconds
-2.79
-1.08
-1.71
0.11
SGIC, adjusted odds ratio and
P-value THC:CBD vs. placebo
Week 4 2.852, P=0.0035 Week 8 1.823, P=0.1331
Week 12 1.384, P=0.3515
PGIC, adjusted odds ratio and
P-value THC:CBD vs. placebo
Week 4 3.972, P=0.00005 Week 8 2.418, P=0.0260
Week 12 1.623, P=0.1615
ADL, Activities of daily living; EDSS: Expanded Disability Status Scale; MAS: modified Ashworth scale;
MS, Multiple sclerosis; NRS: Numerical rating scale; ns, Not significant; PGIC, Physician’s global
impression of change; SF-36: 36-Item Short Form health survey; SGIC: Subject’s/patient’s global
impression of change.
Table 3: Treatment-emergent adverse events (TEAEs) in the Phase A and washout safety population.
Total (n = 191)
n (%)
Events
Phase A
Serious adverse events (SAEs)
2 (1.0%)
3
Adverse events (AEs)
46 (24.1%)
75
Relationship to IMP
Not related to IMP
9 (4.7%)
11
Related to IMP
37 (19.4%)
64
Intensity
Mild
34 (17.8%)
47
Moderate
13 (6.8%)
28
Number of treatment interruptions*
related to AEs
29 (15.2%)
54
Adverse events leading to withdrawal
4 (2.1%)
5
Adverse events leading to death
0
0
Washout
SAEs
0
0
AEs
12 (6.3%)
20
Relationship to IMP
Not related
6 (3.1%)
8
Related
6 (3.1%)
12
Intensity
Mild
6 (3.1%)
10
Moderate
6 (3.1%)
10
Number of treatment interruptions*
related to AEs
6 (3.1%)
12
Adverse events leading to withdrawal
1 (0.5%)
1
Adverse events leading to death
0
0
IMP: Investigational medicinal product.
*Treatment interruptions includes the following action taken with study treatment: drug withdrawn,
dose reduced, or dose increased.
An adverse event that has a start and stop date in different study phases has been presented in all
phases that the event was ongoing.
Table 4. Treatment-emergent adverse events (TEAEs) during the 12-week double-blind treatment
period (Phase B), in the Phase B safety population.
THC:CBD oromucosal
spray
(n = 53)
Placebo
(n = 53)
n (%)
Events
n (%)
Events
Serious adverse events
(SAEs)
1 (1.9%)
1
1 (1.9%)
1
Adverse events (AEs)
including SAEs
12 (22.6%)
19
7 (13.2%)
8
Relationship to IMP
Not related to IMP
8 (15.1%)
12
6 (11.3%)
7
Related to IMP
5 (9.4%)
7
1 (1.9%)
1
Intensity
Moderate
6 (11.3%)
6
0
0
Mild
7 (13.2%)
13
6 (11.3%)
7
Severe
0
0
1 (1.9%)
1
Number of treatment
interruptions related to
AEs
2 (3.8%)
3
0
0
IMP: Investigational medicinal product.
*Treatment interruptions includes the following action taken with study treatment: drug withdrawn,
dose reduced, or dose increased.
An adverse event that has a start and stop date in different study phases has been presented in all
phases that the event was ongoing.
