Conditions: Spasticity in Participants With Multiple Sclerosis
Keywords: spasticity multiple sclerosis nabiximols adjunctive therapy velocity-dependent muscle tone
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 68
Healthy volunteers: no

Brief summary:
This study will be conducted to evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Modified Ashworth Scale Lower Limb Muscle Tone-6 \[MAS LLMT-6\]) in participants with multiple sclerosis (MS) who have not achieved adequate relief from spasticity with other antispasticity medications.

Detailed description:
Each period of this multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover trial includes a 7-day Baseline period, a 3-week treatment period (comprising a 2-week titration phase and a 1-week maintenance phase).

Eligible participants will enter the 7-day baseline period of each treatment period. During baseline, participants will maintain their optimized oral MS antispasticity medication regimen and record their 11-point NRS spasticity score and spasm count using an electronic daily diary. On Day 1, eligible participants will be randomized to 1 of 2 treatment sequences, each composed of 2 treatment periods, with administration of multiple doses of nabiximols or placebo in a 1:1 ratio.

Participants will be advised to titrate the investigational medicinal product (IMP), beginning with 1 spray/day, to an optimized dose or to a maximum of 12 sprays/day over the first 14 days of treatment. Participants should continue at the same dose level achieved at the end of the titration phase ±1 spray divided into a morning dose and an evening dose for the remainder of the treatment period.

Lower limb muscle tone, health-related quality of life, safety, tolerability, and pharmacokinetics will be evaluated during the treatment period.

Participants who complete the trial will participate for a maximum of 90 days, which consists of a maximum 29-day screening period and a maximum 61-day treatment period (s), including washout between periods, and safety follow-up.

Arms:
arm 1: Nabiximols is a complex botanical medicine formulated from extracts of the cannabis plant that contains the principal cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) and also contains minor constituents, including other cannabinoid and non-cannabinoid plant components, such as terpenes, sterols, and triglycerides. Each spray delivers 100 microliters (μL) of nabiximols.

Nabiximols will be self-administered by participants as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks. arm 2: Placebo to match nabiximols will be presented as an oromucosal spray containing the excipients ethanol and propylene glycol (50% v/v) with colorings and flavored with peppermint oil (0.05% v/v). Each spray will deliver 100 μL containing no active ingredients.

Placebo will be self-administered by participants as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks.

Interventions: intervention 1: Nabiximols intervention 2: Placebo
Intervention descriptions: intervention 1: oromucosal spray intervention 2: oromucosal spray

Protocol document:
Prot_000.pdf: 
Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
Confidential 
 Page 1 of 105 
 
Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
A Randomized, Double-blind, Placebo-controlled, 2-way Crossover 
Trial to Evaluate the Effect of Nabiximols Oromucosal Spray on 
Clinical Measures of Spasticity in Patients with Multiple Sclerosis 
 
Study Code: GWSP19066 
EudraCT Number: 2019-002625-29 
CLINICAL PROTOCOL 
 
GW Pharma Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: +44 (0) 1223 266 800 
Fax: +44 (0) 1223 235 667 
 
 
 
Confidentiality Statement 
This document contains confidential information of GW Pharma Ltd (GW) that must 
not be disclosed to anyone other than the recipient trial staff and members of the 
institutional review board or independent ethics committee.  This information cannot 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW. 


Study Code: GWSP19066
SPONSOR: GW PHARMA LIMITED
EudraCT Number: 2019-002625-29
Protocol V4 02 September 2021
Confidential
Page 2 of 105
Clinical Protocol Template (Phase 2–4)
V1, 24Sep15
Investigator Agreement
I have read the attached clinical protocol entitled “A Randomized, Double-blind, 
Placebo-controlled, 2-way Crossover Trial to Evaluate the Effect of Nabiximols 
Oromucosal Spray on Clinical Measures of Spasticity in Patients with Multiple 
Sclerosis,” dated 02 September 2021 and agree to abide by all provisions set forth 
therein.
I agree to comply with applicable regulatory requirement(s); the US Food and Drug 
Administration (FDA) regulations relating to Good Clinical Practice (GCP) and 
clinical trials, the European Union (EU) Clinical Trials Directive (2001/20/EC), the 
EU GCP Directive (2005/28/EC) and subsequent applicable regulatory/statutory 
instruments, or the International Conference on Harmonisation Tripartite Guidelines 
for GCP where the EU Clinical Trials and GCP Directives do not apply, and to 
complete Form FDA 1572, if required.  I accept responsibility for the overall medical 
care of patients during the trial and for all trial-related medical decisions.
I am not aware that any conflicts of interest, financial or otherwise, exist for myself, 
my spouse [or legal partner] and dependent children and agree to confirm this in 
writing if required and update as necessary.
I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of GW.
GW Authorization
Print name:
Date:
Vice President, 
Therapeutic Area Head
Clinical Development, Neuroscience
Jazz Pharmaceuticals
(D
Signature:
Trial site No:
Print name:
Date:
Principal investigator
(DD Month YYYY)
Signature:
PI
PI


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
Confidential 
 Page 3 of 105 
 
Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
1 
PROTOCOL SYNOPSIS 
Trial Title 
A Randomized, Double-blind, Placebo-controlled, 2-way 
Crossover Trial to Evaluate the Effect of Nabiximols 
Oromucosal Spray on Clinical Measures of Spasticity in 
Patients with Multiple Sclerosis  
Clinical Trial Type Phase 3 
Indication 
Symptomatic treatment of spasticity in patients with multiple 
sclerosis (MS) 
Primary Objective To evaluate the effect of multiple doses of nabiximols as 
adjunctive therapy compared with placebo on a clinical measure 
of velocity-dependent muscle tone in the lower limbs 
(Lower Limb Muscle Tone-6; LLMT-6) in patients with MS 
who have not achieved adequate relief from spasticity with 
other antispasticity medications 
Secondary 
Objectives 
x To evaluate the effect of multiple doses of nabiximols as 
adjunctive therapy compared with placebo on a clinical 
measure of velocity-dependent muscle tone in the lower 
limbs (Lower Limb Muscle Tone 4; LLMT-4) in patients 
with multiple sclerosis (MS) who have not achieved 
adequate relief from spasticity with other antispasticity 
medications 
x To evaluate the safety and tolerability of nabiximols after 
administration of multiple doses 
x To evaluate the pharmacokinetic (PK) profile of nabiximols 
after administration of multiple doses 
Exploratory 
Objectives 
x To evaluate the effect of nabiximols after administration of 
multiple doses on walking using the Timed 25-Foot Walk 
(T25FW) test 
x To evaluate the effect of nabiximols after administration of 
multiple doses on the following patient-reported outcomes: 
 The 11-point Numerical Rating Scale (NRS) spasticity 
score 
 Daily spasm count 
 The MS Spasticity Scale (MSSS-88) total and 
subdomain scores 
Trial Design 
This multicenter, randomized, double-blind, placebo-controlled, 
2-treatment, 2-period, Phase 3 crossover trial is being conducted 
to evaluate the effect of multiple doses of nabiximols as 
adjunctive therapy on clinical measures in the symptomatic 
treatment of patients with MS who have not achieved adequate 
relief from spasticity with other antispasticity medications. 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
Confidential 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Patients with MS who are naïve to treatment with nabiximols 
for spasticity will participate in a screening period of up to 
28 days; no changes in the dose of the patients’ current 
MS antispasticity medications will be made during this period. 
As part of the baseline period of each treatment period, patients 
will keep an electronic diary to record 11-point NRS spasticity 
score, spasm count, and use of antispasticity medications once 
daily, around the same time each day, preferably in the evening 
before retiring to sleep, for at least 7 days prior to Visits 2 and 
6.  At Visit 2, in the morning of Day 1, eligible patients will be 
randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences, 
each composed of 2 treatment periods, with administration of 
multiple doses of nabiximols or placebo. 
Patients randomized will complete 2 treatment periods with 
administration of investigational medicinal product (IMP) for 
21 days per treatment period.  Each treatment period will consist 
of a dose-titration phase of approximately 14 days, followed by 
a maintenance-dose phase of approximately 7 days, where the 
individually determined optimized dose level remains 
unchanged for the remainder of each treatment period after 
titration.  Doses greater than 1 spray/day will be divided into a 
morning dose and an evening dose. 
Throughout both treatment periods, patients will initiate IMP 
treatment as a single spray in the clinic in the morning of 
Visits 2 (Day 1) and 6 (Day 31) of each treatment period.  
Patients will gradually titrate their daily dose by 1 to 
2 additional sprays/day to an optimized dose or to a maximum 
of 12 sprays/day over the first approximately 14 days of 
treatment with an approximately 15-minute interval between 
sprays.  Patients should complete titration within approximately 
14 days of their first dose of IMP in each treatment period and 
should continue at the same dose level achieved at the end of 
the titration phase (i.e., their daily optimized dose) ± 1 spray 
divided into a morning dose and an evening dose for the 
remainder of the treatment period.  Once a stable daily dose has 
been reached, patients should gradually decrease the interval 
between sprays to a target interval of approximately 1 minute 
between sprays.  Patients will be advised to administer IMP at 
approximately the same time each day in a consistent manner in 
relation to food consumption.  Morning and evening doses 
should be administered around the same time within 30 minutes 
after starting a snack or meal. 
On the days of scheduled Modified Ashworth Scale (MAS) 
assessments other than Visit 1 (i.e., Visits 2, 5, 6, and 9), 
patients will attend the trial site without having administered 
any IMP in the morning.  On the day of MAS assessment, 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
Confidential 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
patients who are taking baclofen and/or tizanidine as part of 
their optimized antispasticity therapy should take their regular 
morning dose of either or both medication(s) at least 1 hour 
before the administration of IMP.  Administration of the 
morning dose of IMP with a standardized snack containing at 
least 300 kcal (of which approximately 30 kcal is composed of 
fat) will occur at the trial site under the supervision of site staff; 
MAS assessments will occur at scheduled time points before 
(Visits 2 and 6 [predose]) and after (Visits 2, 5, 6, and 9 
[3 hours ± 15 minutes postdose]) IMP administration. 
A washout period of at least 7 days will separate the 2 treatment 
periods.  During the washout period, patients will continue to 
take their current MS antispasticity medications without any 
changes in dose. 
Patients who complete the 2 treatment periods will complete an 
End of Treatment Visit (Visit 9).  Patients who discontinue IMP 
early will be encouraged to remain in the study for the duration 
of the treatment period in which they discontinue IMP and will 
complete an End of Treatment Visit (Visit 9) at the end of that 
period.  A Safety Follow-up Visit (Visit 10) will occur 
7 (+3) days after the last dose of IMP or after the 
End-of-Treatment visit (Visit 9), whichever is later, for all 
patients. 
Primary Endpoint 
Change in Lower Limb Muscle Tone-6 (LLMT-6; defined as 
the average of the 6 individual MAS transformed scores of knee 
flexors, knee extensors, and plantar flexors on both sides of the 
body) from Day 1 predose to Day 21 and from Day 31 predose 
to Day 51 
The MAS scores are transformed using the following algorithm: 
MAS untransformed [to MAS transformed] scores; 0[0], 1[1], 
1+[2], 2[3], 3[4], and 4[5]. 
Secondary 
Endpoints 
Efficacy:  
x Change in Lower Limb Muscle Tone-4 (LLMT-4; 
defined as the average of the 4 individual MAS 
transformed scores of knee flexors and knee extensors 
on both sides of the body) from Day 1 predose to Day 21 
and from Day 31 predose to Day 51 
Safety: 
x Frequency of treatment-emergent adverse events 
(TEAEs) 
x Change from baseline to each assessment timepoint by 
treatment period for the following: 
x Clinical laboratory parameters 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
x Vital signs 
x Physical examination procedures 
x 12-lead electrocardiograms (ECGs) 
x Columbia-Suicide Severity Rating Scale (C-SSRS) at 
screening, and at each subsequent timepoint with 
reference to the last assessment (since last visit) 
Pharmacokinetics: 
x 3ODVPDFRQFHQWUDWLRQVIRUǻ9-tetrahydrocannabinol 
(THC) and its relevant metabolites 
(11-hydroxy-ǻ9-tetrahydrocannabinol and 
11-carboxy-ǻ9-tetrahydrocannabinol) and 
cannabidiol (CBD) and its relevant metabolites 
(7-hydroxy-cannabidiol and 7-carboxy-cannabidiol) at 
distinct time points during each treatment period 
(Visits 2, 4, 5, 6, 8, and 9) 
Exploratory 
Endpoints 
Efficacy: 
x Difference between treatments in the change in 
Timed 25-Foot Walk (T25FW) test from Day 1 predose 
to Day 21 and from Day 31 predose to Day 51 
x Difference between treatments in average 11-point NRS 
spasticity score over the last 7 days of each double-blind 
treatment period 
x Difference between treatments in average daily spasm 
count over the last 7 days of each double-blind treatment 
period 
x Difference between treatments in total and subdomain 
scores of the MSSS-88 at the end of the 
maintenance-dose phase of each double-blind treatment 
period 
Sample Size 
The trial will consist of 2 treatment sequences.  A total of 
approximately 52 patients will be required.  Approximately 
26 patients will be randomly assigned to each treatment 
sequence to ensure that at least 46 patients in total complete the 
2 treatment periods.  If more than 6 patients withdraw from the 
trial, additional patients will be enrolled to have 46 completers. 
Assuming a standard deviation of the paired differences 
between nabiximols and placebo of 0.71 and a treatment 
difference of í0.30, 46 patients will provide 80% power using a 
5% significance level and a two-sided test.  Adjusting for 10% 
dropout, a total of approximately N=52 patients is required. 
A blinded assessment of the estimate of the variability of the 
treatment difference will be conducted during the study and the 
sample size recalculated based on this blinded estimate.  The 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
blinded sample size re-estimation (at 50% completers) may 
inform an increase in sample size while the trial is ongoing 
without the need for a protocol amendment, provided that the 
total sample size does not increase more than 2-fold over the 
number of enrolled currently specified in the protocol.  The 
power may be increased up to 90% depending upon the sample 
size re-assessment. 
Summary of 
Patient Eligibility 
Criteria 
Inclusion Criteria 
Screening (Visit 1) 
For inclusion in the trial, patients must fulfill ALL of the 
following criteria: 
x Male or female, aged 18 years or above. 
x Willing and able to give informed consent for 
participation in the trial. 
x Willing and able (in the investigator’s opinion) to 
comply with all trial requirements. 
x Has had a diagnosis with any disease subtype of MS, by 
revised 2017 McDonald criteria, for at least 12 months 
prior to Visit 1 and is expected to remain stable for the 
duration of the trial. 
x Has an MAS untransformed score of at least 2 in 2 or 
more of 6 muscle groups (right knee flexors, left knee 
flexors, right knee extensors, left knee extensors, right 
plantar flexors, or left plantar flexors) at Visit 1. 
x Currently receiving optimized treatment with at least 
1 oral antispasticity drug (baclofen, tizanidine, and/or 
dantrolene) that has been stable for at least 30 days prior 
to Visit 1.  Despite optimization, the patient does not 
have adequate relief of spasticity symptoms, including 
muscle spasms.  Optimization of antispasticity 
medications is defined as having reached the most 
efficacious and best tolerated dose according to the 
relevant local prescribing information.  The patient must 
be willing to maintain the same antispasticity medication 
and not plan to initiate a new course of physiotherapy 
for the duration of the trial. 
x If currently receiving an approved MS 
disease-modifying therapy, it must be at a stable dose for 
at least 3 months prior to Visit 1 and be expected to 
remain stable for the duration of the trial.  
x If currently receiving dalfampridine or fampridine, it 
must be at a stable dose for at least 3 months prior to 
Visit 1 and is expected to remain stable for the duration 
of the trial. 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
x Willing to allow the responsible authorities to be 
notified of participation in the trial, if mandated by local 
law. 
x Willing to allow his or her primary care practitioner (if 
he or she has one) and/or treating neurologist (if he or 
she has one) to be notified of participation in the trial, if 
the primary care practitioner/treating neurologist is 
different from the investigator. 
 
Additional Inclusion Criteria at Randomization (Visit 2) 
Patients are eligible for randomization in the trial if, in addition 
to continuing to meet the Screening (Visit 1) inclusion criteria, 
they also meet the following criterion prior to Visit 2 (Day 1): 
x Completed at least 5 of 7 days of their electronic diary 
reporting during the 7 days immediately preceding 
Visit 2 (Day 1). 
 
Exclusion Criteria 
The patient may not enter the trial if ANY of the following 
apply: 
x Has taken nabiximols, cannabis, or a cannabis-derived 
product for medicinal or recreational purposes in the 
30 days prior to Visit 1 and unable to abstain for the 
duration of the study. 
x Did not tolerate or did not respond adequately to 
treatment with nabiximols or another cannabis-based 
medication if exposed at any time before the 30-day 
period prior to Visit 1. 
x Any concomitant disease or disorder that has 
spasticity-like symptoms or that may influence the 
patient’s level of spasticity. 
x Medical history suggests that relapse/remission is likely 
to occur during the trial, which, in the opinion of the 
investigator, is expected to influence the patient’s 
spasticity. 
x Has had a relapse of MS within the 60 days prior to 
Visit 1. 
x Currently using botulinum toxin injection for the relief 
of spasticity (within 6 months of Visit 1) and is 
unwilling to abstain for the duration of the trial. 
x Currently taking antipsychotic medication. 
x Currently taking benzodiazepines unless doses and 
dosing regimen have been stable for at least 30 days 
prior to Visit 1. 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
x Clinically suspected to have a contracture in one of the 
muscle groups of the lower limbs, preventing assessment 
with the MAS. 
x Has any known or suspected hypersensitivity to 
cannabinoids or any of the excipients of the IMP. 
x Has experienced myocardial infarction or clinically 
significant cardiac dysfunction within the 12 months 
prior to Visit 1 or has a cardiac disorder that, in the 
opinion of the investigator, would put the patient at risk 
of a clinically significant arrhythmia or myocardial 
infarction. 
x Has a diastolic blood pressure of < 50 mmHg or 
> 105 mmHg or systolic blood pressure < 90 mmHg or 
>150 mmHg (when measured in a sitting position at rest 
for 5 minutes) or a postural drop in the systolic blood 
pressure of > 20 mmHg at Visit 1 or Visit 2.  All 
measurements will be performed singly and can be 
repeated once, if any are outside the reference range but 
not considered clinically significant. 
x Has clinically significant impaired renal function at 
Visit 1, as evidenced by an estimated creatinine 
clearance lower than 50 mL/min.  All measurements will 
be performed singly and can be repeated once, if any are 
outside the reference range but not considered clinically 
significant. 
x Has moderately impaired hepatic function at Visit 1, 
defined as serum alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) > 2 × upper limit of 
normal (ULN).  All measurements will be performed 
singly and can be repeated once, if any are outside the 
reference range but not considered clinically significant. 
x Male and fertile (i.e., after puberty unless permanently 
sterile by bilateral orchiectomy) unless willing to ensure 
that he uses male contraception (condom or vasectomy) 
or remains sexually abstinent during the trial and for 
3 months thereafter. 
x Female and of childbearing potential (i.e., following 
menarche and until becoming postmenopausal for 
 12 consecutive months unless permanently sterile by 
hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) unless willing to ensure that she uses a 
highly effective method of birth control (e.g., 
intrauterine device/hormone-releasing system, bilateral 
tubal occlusion, vasectomized partner, or sexual 
abstinence) during the trial and for 3 months thereafter.  
Patients using combined hormonal methods or a 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
progestogen-only pill or injection or implant should use 
an additional barrier method such as a male condom or 
diaphragm during the trial and for 3 months thereafter. 
x Female and pregnant (positive pregnancy test at Visit 1 
or Visit 2), lactating, or planning pregnancy during the 
course of the trial or within 3 months thereafter. 
x Has received an IMP within the 30 days prior to Visit 1. 
x Has any other clinically significant disease or disorder 
(including seizure disorder) that, in the opinion of the 
investigator, may put the patient, other patients, or site 
staff at risk because of participation in the trial, 
influence the interpretation of trial results, or may affect 
the patient’s ability to take part in the trial. 
x Has any abnormalities identified following a physical 
examination, clinical laboratory, serology, or other 
applicable screening procedures that, in the opinion of 
the investigator, would jeopardize the safety of the 
patient or the conduct of the study if he or she took part 
in the trial. 
x Has any history of suicidal behavior in the 5 years prior 
to Visit 1 or a score of 3, 4, or 5 on the C-SSRS in the 
month prior to Visit 1. 
x Has donated blood during the 3 months prior to Visit 1 
and is unwilling to abstain from donation of blood 
during the trial. 
x Has been previously randomized into this trial. 
x Has any known or suspected history of alcohol or 
substance abuse (including opiate abuse) or dependence 
within 1 year prior to Visit 1. 
x Currently using an illicit drug or current nonprescribed 
use of any prescription drug. 
x Has a history of psychiatric or neurologic disorder that, 
in the opinion of the investigator, may interfere with trial 
participation, data interpretation, or conduct of trial 
procedures. 
x Has a history of severe psychiatric disorder that may be 
exacerbated by the use of a cannabinoid-containing 
product. 
x Has any planned clinical interventions or intends to 
change any or all medications that may have an effect on 
spasticity or MS during the trial. 
x Currently taking drugs that are solely metabolized by 
UGT1A9 and UGT2B7. 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
x 
Currently taking strong CYP3A4 inducers (e.g., 
rifampicin, carbamazepine, phenytoin, phenobarbital, 
St John's Wort). 
Criteria for 
Withdrawal 
The patient must be withdrawn from the trial if any of the 
following apply: 
x Administrative decision by the investigator, GW Pharma 
Ltd, or regulatory authority 
x Withdrawal of patient consent 
x Lost to follow-up 
The patient must cease IMP and should remain in the trial if any 
of the following apply: 
x Pregnancy 
x Protocol deviation that is considered to potentially 
compromise the safety of the patient 
x Suicidal behavior or ideation of type 4 or 5 during the 
treatment period, as evaluated with the C-SSRS 
x ALT or AST > 3 × ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (> 5%) 
x ALT or AST > 5 × ULN 
x ALT or AST > 3 × ULN and (total bilirubin 
[TBL] > 2 × ULN or international normalized ratio 
[INR] > 1.5) 
The patient may be required to cease IMP at the discretion of 
the investigator and should remain in the trial for any of the 
following reasons: 
x Did not meet eligibility criteria 
x Patient noncompliance 
x AE (including clinically significant laboratory result) 
that, in the opinion of the investigator, would 
compromise the continued safe participation of the 
patient in the trial 
x Any evidence of drug abuse or diversion 
x Disease progression (defined as a relapse of MS 
requiring a change in treatment) 
x A positive Coronavirus disease 2019 (COVID-19) test 
result after randomization 


Study Code: GWSP19066 
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Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Investigational 
Medicinal Product: 
Formulation, 
Mode of 
Administration, 
Dose and Regimen 
Nabiximols oromucosal spray is a mixture of THC and CBD 
extracts derived from Cannabis sativa L.  Each of the botanical 
extracts contains a cannabinoid as the major constituent 
(i.e., THC or CBD) and minor constituents including other 
cannabinoid and non-cannabinoid plant components, such as 
terpenes, sterols, and triglycerides. 
Nabiximols is presented as an oromucosal spray containing 
THC (27 mg/mL):CBD (25 mg/mL) dissolved in 
ethanol:propylene glycol (50% v/v) excipients with peppermint 
oil (0.05% v/v) flavoring.  Each 100 μL spray delivers 2.7 mg 
THC and 2.5 mg CBD. 
Placebo to match nabiximols is presented as an oromucosal 
spray containing the excipients ethanol and propylene glycol 
(50% v/v) with colorings and flavored with peppermint oil 
YY(DFKVSUD\GHOLYHUVȝ/FRQWDLQLQJQRDFWLYH
ingredients. 
Treatment will be initiated in the clinic in the morning of 
Visits 2 (Day 1) and 6 (Day 31) of each treatment period.  The 
total daily dose should be administered as a morning dose and 
an evening dose, which may be composed of a different number 
of sprays during titration.  Patients will be advised to administer 
IMP at approximately the same time each day in a consistent 
manner in relation to food consumption.  Morning and evening 
doses should be administered around the same time within 30 
minutes after starting a snack or meal.  Patients will gradually 
titrate their daily dose to the maximally acceptable dose, 
balancing efficacy and tolerability, or to a maximum number of 
12 sprays/day.  During the titration phase, there should be an 
approximately 15-minute interval between sprays. 
Patients should complete titration within approximately 14 days 
of their first dose of IMP in each treatment period and should 
continue at the same dose level achieved at the end of titration 
phase (i.e., their daily optimized dose) ± 1 spray / day divided 
into a morning dose and an evening dose for the remainder of 
the treatment period. 
Once a stable daily dose has been reached, patients should 
gradually decrease the interval between sprays to a target 
interval of approximately 1 minute between sprays. 
Throughout each treatment period, patients will be advised to 
administer IMP at approximately the same time each day in a 
consistent manner in relation to food consumption. 
Control Arm 
All patients enrolled in the trial will receive both nabiximols 
and placebo during the 2-way crossover treatment period. 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Procedures 
Assessments/procedures at the trial site include the following: 
x Informed consent, demographics, previous cannabis use, 
medical history, electronic diary training, and blood THC 
test (Visit 1) 
x Eligibility check and urine drug screen (including THC) 
(Visits 1 and 2 [predose]) 
x Randomization and IMP dosing training (Visit 2 [predose]) 
x Concomitant medications review, AE review, and vital signs 
measurement (Visits 1, 2, 4, 5, 6, 8, 9, and 10) 
x Physical examination (including height measurement at 
Visit 1 only), 12-lead ECG, and clinical laboratory blood 
sampling (hematology and biochemistry) (Visits 1, 5, and 9) 
x Examination of oral mucosa (Visits 1, 2 [predose], 4, 5, 
6 [predose], 8, 9, and 10) 
x Body weight measurement (Visits 1, 2 [predose], 
6 [predose], and 10) 
x Dipstick urinalysis and serum pregnancy test (if appropriate) 
(Visits 1 and 10) 
x Urine pregnancy test (if appropriate) (Visits 2 and 6 
[predose]) 
x PK blood sampling (IMP) at distinct time points (Visits 2, 4, 
5, 6, 8, and 9) 
x MAS assessment (Visits 1, 2 [predose and at 
3 hours ± 15 minutes postdose], 5 [3 hours ± 15 minutes 
after the first spray of the morning dose], 6 [predose and at 
3 hours ± 15 minutes postdose], and 9 [3 hours ± 15 minutes 
after the first spray of the morning dose]) 
x MSSS-88 assessment (Visits 5 and 9) 
x T25FW test (Visits 2 [predose], 5, 6 [predose], and 9) 
x C-SSRS assessment (Visits 1, 2 [predose], 4, 5, 6 [predose], 
8, 9, and 10) 
x IMP dosing at the investigational site (Visits 2, 5, 6, and 9) 
x IMP dispensing (Visits 2, 4, 6, and 8) 
x IMP collection and compliance review (Visits 4, 5, 8, and 9) 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Additional procedures to screen for the presence of or immunity 
against infectious diseases may be conducted according to local 
guidance and policy.  In cases where patients are not able to 
attend study visits due to the presence of an infectious disease or 
other transmissible condition, the investigator will discuss with 
the Sponsor potential mitigation approaches. 
Scheduled Phone Calls 
Site staff will call patients 7 ± 1 days after the first dose of IMP 
during each treatment period (Visits 3 and 7) to monitor 
adherence with IMP administration and advise on dose titration 
if required.  Concomitant medications and AEs will be collected 
during this call. 
Patient Electronic Diary Assessments 
Patients will complete their electronic diary once daily, around 
the same time each day, preferably in the evening before retiring 
to sleep, for at least the 7 days prior to Visits 2 and 6 and 
throughout the trial until Visit 9, unless otherwise indicated, and 
the following assessments will be conducted: 
x 11-point NRS for spasticity 
x Spasm count 
x Use of antispasticity medications 
x IMP dosing record (Visits 2 through 9) 
x Dosing in relation to food (the day before Visits 4, 5, 8, and 
9 only) 
Statistical 
Considerations 
The Lower Limb Muscle Tone-6 (LLMT-6) will be derived as 
the average of individual MAS transformed scores (of left knee 
flexors, right knee flexors, left knee extensors, right knee 
extensors, left plantar flexors, and right plantar flexors) for each 
patient.  The change from baseline in LLMT-6 in treatment 
period 1 for each patient will be derived as LLMT-6 at Day 21 
minus LLMT-6 at Day 1 predose) and the change from baseline 
in LLMT-6 in treatment period 2 for each patient will be 
derived as LLMT-6 at Day 51 minus LLMT-6 at Day 31 
predose). 
 
The primary estimand is the mean treatment difference between 
the mean change from baseline in LLMT-6 while on nabiximols 
and the mean change from baseline in LLMT-6 while on 
placebo.  The changes from baseline in LLMT-6 will be 
analyzed using a linear mixed effects model for crossover data.  
The model will include a period level baseline covariate and 
treatment, period, and treatment sequence as fixed effects and 
patient nested within treatment sequence as a random effect. 
 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Secondary endpoints and exploratory endpoints will be analyzed 
based on the statistical analysis plan. 
Statistical hypothesis testing will be 2-tailed and carried out at 
the 5% level of significance.  Testing will be performed on the 
primary endpoint, secondary endpoints, and exploratory 
endpoints as appropriate. 
To control for Type 1 error, the primary efficacy endpoint and 
the secondary efficacy endpoint will be tested hierarchically, 
starting with the primary efficacy endpoint and followed by the 
secondary efficacy endpoint.  No adjustments for multiplicity 
will be made for the other secondary or exploratory endpoints. 
Safety data will be summarized using appropriate statistical 
methods. 
Sponsor 
GW Pharma Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
 
 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Figure 1-1 
Trial Design and Treatment Schematic 
 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Table of Contents 
Title Page ........................................................................................................ 1 
1 
PROTOCOL SYNOPSIS .................................................................... 3 
Table of Contents ......................................................................................... 17 
List of Appendices ....................................................................................... 22 
List of In-text Tables ................................................................................... 23 
List of In-text Figures .................................................................................. 24 
List of Abbreviations ................................................................................... 25 
Definition of Terms ...................................................................................... 27 
2 
OBJECTIVES ..................................................................................... 28 
2.1 
Objectives and Endpoints ................................................................................. 28 
3 
BACKGROUND AND RATIONALE .............................................. 31 
3.1 
Disease .............................................................................................................. 31 
3.2 
Nabiximols Background ................................................................................... 32 
3.3 
Rationale ........................................................................................................... 32 
3.4 
Clinical Hypothesis ........................................................................................... 33 
4 
EXPERIMENTAL PLAN ................................................................. 34 
4.1 
Trial Design ...................................................................................................... 34 
4.2 
Number of Sites ................................................................................................ 35 
4.3 
Number of Patients ........................................................................................... 36 
5 
INVESTIGATIONAL MEDICINAL PRODUCT .......................... 37 
5.1 
Nabiximols ........................................................................................................ 37 
5.2 
Placebo .............................................................................................................. 37 
5.3 
Packaging, Storage, and Drug Accountability .................................................. 37 
5.3.1 
Packaging and Labeling ................................................................................. 37 
5.3.2 
Storage ............................................................................................................ 38 
5.3.3 
Supply and Return of Investigational Medicinal Product .............................. 38 
5.3.4 
Investigational Medicinal Product Accountability ......................................... 39 
5.3.5 
Posttrial Provision .......................................................................................... 40 


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Clinical Protocol Template (Phase 2–4)  
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6 
PATIENT ELIGIBILITY .................................................................. 41 
6.1 
Inclusion Criteria .............................................................................................. 41 
6.2 
Exclusion Criteria ............................................................................................. 42 
7 
PATIENT ENROLLMENT .............................................................. 46 
7.1 
Treatment Assignment ...................................................................................... 46 
7.2 
Randomization .................................................................................................. 46 
8 
TREATMENT PROCEDURES........................................................ 47 
8.1 
Investigational Medicinal Product Dosage, Administration, and 
Schedule ............................................................................................................ 47 
8.1.1 
Dose Administration ...................................................................................... 47 
8.1.2 
Dose Escalation and Dose Adjustments ......................................................... 48 
8.2 
Washout Period ................................................................................................. 49 
8.3 
Concomitant Therapy........................................................................................ 49 
8.3.1 
Concomitant Optimized Multiple Sclerosis Antispasticity 
Medications .................................................................................................... 49 
8.4 
Prohibited Therapy During Trial Period ........................................................... 50 
8.5 
Compliance in Investigational Medicinal Product Administration .................. 50 
8.6 
Access to Blinded Treatment Assignment ........................................................ 51 
9 
TRIAL PROCEDURES ..................................................................... 52 
9.1 
Trial Procedures by Visit .................................................................................. 52 
9.1.1 
Screening (Visit 1 [Days -28 to -1]) ............................................................... 52 
9.1.1.1 
Screening Failures ...................................................................................... 53 
9.1.2 
Treatment Period 1 (Visits 2 to 5 [Days 1 to 21]) .......................................... 54 
9.1.2.1 
Visit 2 (Day 1) ............................................................................................ 54 
9.1.2.2 
Visit 3 (Day 8, Phone Call) ........................................................................ 56 
9.1.2.3 
Visit 4 (Day 15) and Visit 5 (Day 21) ........................................................ 56 
9.1.3 
Washout Period (Days 22 to 30) .................................................................... 57 
9.1.4 
Treatment Period 2 (Visits 6 to 9 [Days 31 to 51]) ........................................ 57 
9.1.4.1 
Visit 6 (Day 31) .......................................................................................... 58 
9.1.4.2 
Visit 7 (Day 38, Phone Call) ...................................................................... 59 
9.1.4.3 
Visit 8 (Day 45) and Visit 9 (Day 51, End of Treatment) .......................... 59 


Study Code: GWSP19066 
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EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
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9.1.5 
Safety Follow-up Visit (Visit 10 [Day 58]) ................................................... 61 
9.2 
Trial Procedure Listing ..................................................................................... 61 
9.2.1 
Informed Consent ........................................................................................... 61 
9.2.2 
Contraception Requirements .......................................................................... 62 
9.2.3 
Demographics ................................................................................................. 62 
9.2.4 
Previous Cannabis Use ................................................................................... 62 
9.2.5 
Medical History .............................................................................................. 63 
9.2.6 
Concomitant Medication ................................................................................ 63 
9.2.7 
Physical Examination ..................................................................................... 63 
9.2.8 
Examination of Oral Mucosa ......................................................................... 63 
9.2.9 
Body Weight Measurements .......................................................................... 63 
9.2.10 
Vital Signs ...................................................................................................... 63 
9.2.11 
12-Lead Electrocardiogram ............................................................................ 64 
9.2.12 
Clinical Laboratory Sampling ........................................................................ 64 
9.2.12.1 
Pharmacokinetic Blood Sampling .............................................................. 65 
9.2.13 
Interactive Response Technology .................................................................. 66 
9.2.14 
Electronic Patient Diary ................................................................................. 66 
9.2.14.1 
Electronic Diary Training ........................................................................... 67 
9.2.14.2 
Spasticity Numerical Rating Scale ............................................................. 67 
9.2.14.3 
Use of Antispasticity Medications and Investigational Medicinal 
Product Dosing Record ............................................................................... 67 
9.2.15 
Questionnaires and Assessments Completed at Scheduled Visits ................. 68 
9.2.15.1 
Modified Ashworth Scale ........................................................................... 68 
9.2.15.2 
Multiple Sclerosis Spasticity Scale ............................................................. 68 
9.2.15.3 
Columbia-Suicide Severity Rating Scale ................................................... 69 
9.2.15.4 
Timed 25-Foot Walk .................................................................................. 69 
9.2.16 
Investigational Medicinal Product Accountability ......................................... 69 
9.2.17 
Adverse Events ............................................................................................... 70 
9.2.18 
Special Circumstances .................................................................................... 70 
10 
WITHDRAWAL ................................................................................ 71 
11 
URGENT SAFETY MEASURES ..................................................... 73 


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EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
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12 
ADVERSE EVENT REPORTING ................................................... 74 
12.1 
Definitions......................................................................................................... 74 
12.1.1 
Adverse Event ................................................................................................ 74 
12.1.2 
Investigator ..................................................................................................... 74 
12.2 
Serious Adverse Events .................................................................................... 74 
12.3 
Reporting Procedures for Serious Adverse Events ........................................... 75 
12.4 
Pregnancy .......................................................................................................... 76 
12.5 
Causality Assessment........................................................................................ 76 
12.6 
Reporting Procedures for All Adverse Events .................................................. 77 
12.7 
Follow-up Procedures for Adverse Events ....................................................... 79 
12.8 
Potential Cases of Drug-induced Liver Injury .................................................. 79 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities, and Institutional Review Boards/Independent Ethics 
Committees ....................................................................................................... 80 
13 
STATISTICAL CONSIDERATIONS ............................................. 82 
13.1 
Sample Size, Power, and Significance Levels .................................................. 82 
13.2 
Interim Analysis ................................................................................................ 82 
13.3 
Analysis Sets ..................................................................................................... 82 
13.3.1 
Protocol Deviations ........................................................................................ 83 
13.4 
General Considerations ..................................................................................... 83 
13.5 
Accountability and Background Characteristics ............................................... 84 
13.5.1 
Enrollment and Disposition ............................................................................ 84 
13.5.2 
Baseline and Demographic Characteristics .................................................... 84 
13.5.3 
Medical History .............................................................................................. 84 
13.5.4 
Concomitant Medication ................................................................................ 84 
13.6 
Endpoints and Statistical Methods .................................................................... 84 
13.6.1 
Evaluable Period ............................................................................................ 85 
13.6.2 
Primary Endpoint ........................................................................................... 85 
13.6.3 
Secondary Efficacy Endpoint ......................................................................... 85 
13.6.4 
Exploratory Efficacy Endpoints ..................................................................... 86 
13.6.5 
Pharmacokinetics ........................................................................................... 86 


Study Code: GWSP19066 
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EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
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13.6.6 
Safety .............................................................................................................. 86 
13.6.6.1 
Treatment Compliance and Extent of Treatment Exposure ....................... 87 
13.6.6.2 
Adverse Events ........................................................................................... 87 
13.6.6.3 
Clinical Laboratory Data ............................................................................ 87 
13.6.6.4 
Vital Signs, 12-Lead Electrocardiogram, Physical Examination, 
and Other Safety Data ................................................................................. 88 
14 
DATA SAFETY MONITORING COMMITTEE .......................... 89 
15 
REGULATORY AND ETHICAL OBLIGATIONS ...................... 90 
15.1 
Declaration of Helsinki ..................................................................................... 90 
15.2 
Informed Consent.............................................................................................. 90 
15.3 
Institutional Review Board/Independent Ethics Committee ............................. 90 
15.4 
Pretrial Documentation Requirements .............................................................. 91 
15.5 
Patient Confidentiality ...................................................................................... 92 
16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................... 93 
16.1 
Protocol Amendments and End of Trial or Termination .................................. 93 
16.2 
Trial Documentation and Storage ..................................................................... 93 
16.3 
Trial Monitoring and Data Collection ............................................................... 94 
16.4 
Quality Assurance ............................................................................................. 95 
16.5 
Compensation ................................................................................................... 95 
16.6 
Publication Policy ............................................................................................. 96 
16.7 
Intellectual Property Rights .............................................................................. 96 
16.8 
Confidential Information .................................................................................. 96 
17 
REFERENCES ................................................................................... 97 
 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
List of Appendices 
Appendix 1 
SCHEDULE OF ASSESSMENTS ..................................... 99 
Appendix 2 
TRIAL PERSONNEL ....................................................... 103 
Appendix 2.1 
Investigator Details ............................................................................ 103 
Appendix 2.2 
Sponsor Contact Details .................................................................... 103 
Appendix 2.3 
Contract Research Organizations ...................................................... 103 
Appendix 3 
QUESTIONNAIRES/ASSESSMENTS ............................ 104 
Appendix 4 
PROHIBITED MEDICATIONS SOLELY 
METABOLIZED BY UGT1A9 AND UGT2B7 .............. 105 
Appendix 4.1 
Prohibited Medications Metabolized Solely by UGT1A9 ................ 105 
Appendix 4.2 
Prohibited Medications Metabolized Solely by UGT2B7 ................. 105 
 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
List of In-text Tables 
Table 2-1 
Objectives and Endpoints ........................................................ 28 
Table 8.1.2-1 
Example Titration Schedule .................................................... 48 
Table 9.2.12-1 
Biochemistry, Hematology, Urinalysis, Pregnancy Test, and 
Drug Screen ............................................................................. 64 
Table 9.2.12.1-1 
Pharmacokinetic Blood Sampling Schedule ........................... 66 
 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
List of In-text Figures 
Figure 1-1 
Trial Design and Treatment Schematic ................................... 16 
 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
List of Abbreviations 
11-COOH-THC 11-carboxy-ǻ9-tetrahydrocannabinol 
11-OH-THC 
11-hydroxy-ǻ9-tetrahydrocannabinol 
7-COOH-CBD 
7-carboxy-cannabidiol  
7-OH-CBD 
7-hydroxy-cannabidiol 
AD 
Assistive device 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BDS 
Botanical drug substance 
CBD 
Cannabidiol 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GW 
GW Pharma Ltd 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 


Study Code: GWSP19066 
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Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
IRT 
Interactive response technology 
LLMT-4 
Lower Limb Muscle Tone-4 
LLMT-6 
Lower Limb Muscle Tone-6 
MAS 
Modified Ashworth Scale 
MS 
Multiple sclerosis 
MSSS-88 
Multiple Sclerosis Spasticity Scale 
NRS 
Numerical Rating Scale 
PD 
Pharmacodynamics 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRN 
As-needed 
PT 
Preferred term 
PVD 
Pharmacovigilance department 
QoL 
Quality of life 
R2 
Relaxation Index 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
T25FW 
Timed 25-Foot Walk 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
THC 
ǻ9-Tetrahydrocannabinol 
ULN 
Upper limit of normal 
US 
United States 
 


Study Code: GWSP19066 
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EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Definition of Terms 
Term 
Definition 
Clonus 
A clinical manifestation of spasticity described as 
self-sustained rhythmic involuntary muscular contractions and 
relaxations in response to a muscle stretch 
Completer 
A patient who completes both treatment periods 
Day 1 
The day a patient first receives investigational medicinal 
product in this trial 
End of trial 
Last patient last visit or last contact, whichever occurs last 
Enrolled patient 
Any patient who has provided written informed consent to 
take part in the trial 
International 
normalized ratio 
A calculation made to standardize prothrombin time 
Investigational 
medicinal product 
Term used to describe both investigational active product and 
reference therapy (placebo) 
Investigator 
Trial principal investigator or a formally delegated trial 
physician 
Lower Limb Muscle 
Tone-4 
A measure of velocity-dependent muscle tone in the lower 
limbs consisting of the average of the 4 individual MAS 
transformed scores of knee flexors and knee extensors on both 
sides of the body 
Lower Limb Muscle 
Tone-6 
A measure of velocity-dependent muscle tone in the lower 
limbs consisting of the average of the 6 individual MAS 
transformed scores of knee flexors, knee extensors, and plantar 
flexors on both sides of the body 
Spasm 
A clinical manifestation of spasticity described as a sudden, 
involuntary contraction of a muscle 
Spasticity 
A velocity-dependent increase in muscle tone resulting from 
an upper motor neuron lesion.  Clinically, spasticity manifests 
as muscle stiffness or tightness, increased tendon reflexes, 
clonus, and flexor and extensor spasms 
Standardized snack 
A meal containing at least 300 kcal (of which approximately 
30 kcal is composed of fat) 


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Clinical Protocol Template (Phase 2–4)  
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2 
OBJECTIVES 
2.1 
Objectives and Endpoints 
An overview of objectives and endpoints is shown in Table 2-1. 
Table 2-1 
Objectives and Endpoints 
Primary Objective 
Primary Endpoint  
x To evaluate the effect of 
multiple doses of nabiximols 
as adjunctive therapy 
compared with placebo on a 
clinical measure of 
velocity-dependent muscle 
tone in the lower limbs 
(Lower Limb Muscle Tone-6; 
LLMT-6) in patients with 
multiple sclerosis (MS) who 
have not achieved adequate 
relief from spasticity with 
other antispasticity 
medications 
x 
Change in Lower Limb Muscle Tone-6 
(LLMT-6; defined as the average of the 
6 individual MAS transformed scores of knee 
flexors, knee extensors, and plantar flexors on 
both sides of the body) from Day 1 predose to 
Day 21 and from Day 31 predose to Day 51 
 
Secondary Objectives 
Secondary Endpoints 
x To evaluate the effect of 
multiple doses of nabiximols 
as adjunctive therapy 
compared with placebo on a 
clinical measure of 
velocity-dependent muscle 
tone in the lower limbs 
(Lower Limb Muscle Tone-4; 
LLMT-4) in patients with 
multiple sclerosis (MS) who 
have not achieved adequate 
relief from spasticity with 
other antispasticity 
medications 
x Change in Lower Limb Muscle Tone-4 
(LLMT-4; defined as the average of the 
4 individual MAS transformed scores of knee 
flexors and knee extensors on both sides of the 
body) from Day 1 predose to Day 21 and from 
Day 31 predose to Day 51 


Study Code: GWSP19066 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
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Table 2-1 
Objectives and Endpoints 
x To evaluate the safety and 
tolerability of nabiximols 
after administration of 
multiple doses 
x Frequency of treatment-emergent adverse 
events (TEAEs) 
x Change from baseline to each assessment 
timepoint by treatment period for the 
following: 
 Clinical laboratory parameters 
 Vital signs 
 Physical examination procedures 
 12-lead electrocardiograms (ECGs) 
x Columbia-Suicide Severity Rating Scale 
(C-SSRS) at screening, and at each subsequent 
timepoint with reference to the last assessment 
(since last visit) 
x To evaluate the 
pharmacokinetic (PK) profile 
of nabiximols after 
administration of multiple 
doses 
x Plasma concentrations for 
ǻ9-tetrahydrocannabinol (THC) and its 
relevant metabolites 
(11-hydroxy-ǻ9-tetrahydrocannabinol and 
11-carboxy-ǻ9-tetrahydrocannabinol) and 
cannabidiol (CBD) and its relevant metabolites 
(7-hydroxy-cannabidiol and 
7-carboxy-cannabidiol) at distinct time points 
during each treatment period (Visits 2, 4, 5, 6, 
8, and 9) 
Exploratory Objectives 
Exploratory Endpoints 
x To evaluate the effect of 
nabiximols after 
administration of multiple 
doses on walking using the 
Timed 25-Foot Walk 
(T25FW) test 
x Difference between treatments in the change in 
Timed 25-Foot Walk (T25FW) test from Day 1 
predose to Day 21 and from Day 31 predose to 
Day 51 
x To evaluate the effect of 
nabiximols after 
administration of multiple 
doses on the following 
patient-reported outcomes: 
 The 11-point Numerical 
Rating Scale (NRS) 
spasticity score 
x Difference between treatments in average 
11-point NRS spasticity score over the last 
7 days of each double-blind treatment period 
x Difference between treatments in average daily 
spasm count over the last 7 days of each 
double-blind treatment period 
x Difference between treatments in total and 
subdomain scores of the MSSS-88 at the end 


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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Table 2-1 
Objectives and Endpoints 
 Daily spasm count 
 The MS Spasticity Scale 
(MSSS-88) total and 
subdomain scores 
of the maintenance-dose phase of each 
double-blind treatment period 
Primary Estimand: the mean treatment difference (nabiximols í placebo) in the 
change in Lower Limb Muscle Tone-6 (LLMT-6) from Day 1 (predose) to Day 21 
and from Day 31 (predose) to Day 51 for all randomized patients. 


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Clinical Protocol Template (Phase 2–4)  
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3 
BACKGROUND AND RATIONALE 
3.1 
Disease 
Multiple sclerosis is a progressive, chronic, immune-mediated disease of the central 
nervous system1,2, diagnosed predominantly in young adults, with more than 2.3 million 
people affected worldwide3.  It is the most common neurological disease in young and 
middle-aged adults, resulting in marked physical disability, inability to work or early 
retirement, significantly impaired quality of life (QoL), and a substantial burden on 
society in terms of associated costs as the disease evolves4,5.  Multiple sclerosis is 
clinically characterized by a broad range of signs and symptoms, the most common being 
restricted mobility, spasticity, fatigue, sensory deficits, weakness, pain, bladder 
dysfunction, cognitive dysfunction, and visual impairment6,7. 
The pathology of MS is characterized by autoimmune damage of neuronal axons and 
destruction of the protective myelin sheath (demyelination).  Several signs and symptoms 
may occur as a consequence of the nerve damage; muscle spasticity (a velocity-
dependent increase in muscle tone resulting from an upper motor neuron lesion) is one of 
the most common manifestations of MS, affecting more than 80% of patients with MS 
during the course of the disease6,8,9.  Multiple sclerosis spasticity clinically manifests as 
symptoms, such as muscle stiffness or tightness, and signs including increased tendon 
reflexes, clonus, and flexor and extensor spasms mainly in the extensor muscles of the 
lower limbs and flexor muscles of the upper limbs.  On a daily basis, severity may be 
exacerbated by a range of concurrent medical conditions, such as urinary infections.  The 
QoL of patients with MS worsens as spasticity severity increases5,10,11. 
The most important goals in the treatment of patients with MS-induced spasticity are to 
avoid or eliminate triggers that may elicit spasms or enhance spasticity, to reduce pain 
and symptoms of spasticity, to improve or maintain functional abilities and QoL, and to 
facilitate nursing.  If physiotherapy, as a generally accepted first basic treatment option, is 
not sufficient, antispasticity medications should be tried12.  Depending on the severity of 
generalized spasticity, drug treatment varies widely, reliant on approved drugs that may 
differ between geographical regions.  Commonly used medications such as baclofen, 
tizanidine, or dantrolene are taken orally.  Their mode of action varies, but all cause 
muscle relaxation. 


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Both incidence and severity of MS spasticity increase as the disease evolves, appearing in 
more than 80% of patients with MS and reaching a moderate or severe intensity in over a 
third of cases despite available treatments6,13,14.  Multiple sclerosis spasticity of at least 
moderate severity is present in approximately a third of patients with a 10-year history of 
the disease14. 
3.2 
Nabiximols Background 
The investigational medicinal product (IMP) nabiximols (named Sativex® in Canada, 
Spain, and the United Kingdom and also named Sativex oromucosal spray; United States 
[US] Adopted Name: Nabiximols; World Health Organization Anatomical Therapeutic 
Chemical Code: N02BG10) is formulated from 2 genetically distinct varieties of the 
Cannabis sativa L. plant, which are defined by their chemical profiles (chemotypes).  
GW Pharma Ltd (GW) produces chemotypes of Cannabis sativa L. that contain 
principally 1 RIWKHPDMRUFDQQDELQRLGVǻ9-tetrahydrocannabinol (THC) or cannabidiol 
(CBD).  Production under controlled conditions ensures consistency in the starting 
materials.  Dried plant material is extracted and further processed to yield the THC 
botanical drug substance (BDS) and CBD BDS.  The extracts also contain smaller 
amounts of minor cannabinoids and other plant-derived compounds. 
Nabiximols contains amounts of both THC BDS and CBD BDS to yield similar 
concentrations of THC and CBD, dissolved in the excipients ethanol and propylene 
glycol and delivered as an oromucosal spray.  Peppermint oil is used in the spray 
preparation as a flavoring agent to mask the taste and odor of plant-based components 
present in the product.  The oromucosal spray is administered under the tongue or inside 
the cheeks and delivers 2.7 mg THC and 2.5 mg CBD per 100 ȝ/ spray. 
For more information, refer to the Investigator’s Brochure (IB)15. 
3.3 
Rationale 
The efficacy of nabiximols in the symptomatic treatment of spasticity associated with MS 
was originally demonstrated in trials with a primary endpoint based on a patient-reported 
outcome measure, the 11-point NRS for spasticity.  Data indicating efficacy of 
nabiximols on objective measures of spasticity was limited to change in the MAS, which 
formed the basis for secondary endpoints in the SAVANT trial and in an investigator-
initiated trial16.  Trial GWSP19066 is being conducted to further evaluate the potential 
effect of nabiximols on clinical measures of velocity-dependent muscle tone, which may 


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be considered more objective, and more proximate to the pathophysiology of spasticity in 
patients with MS than the 11-point NRS for spasticity.  This trial may support the 
authorization of nabiximols for the symptomatic treatment of spasticity in additional 
markets where nabiximols is not currently authorized. 
3.4 
Clinical Hypothesis 
The primary clinical hypothesis is that after administration of multiple doses, there will 
be a difference between nabiximols and placebo for change in velocity-dependent muscle 
tone in the lower limbs as measured by the Lower Limb Muscle Tone-6 (LLMT-6) from 
predose to end of treatment of each treatment period. 


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4 
EXPERIMENTAL PLAN 
4.1 
Trial Design 
This multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, 
Phase 3 crossover trial is being conducted to evaluate the effect of multiple doses of 
nabiximols as adjunctive therapy on clinical measures in the symptomatic treatment of 
patients with MS who have not achieved adequate relief from spasticity with other 
antispasticity medications. 
Patients with MS who are naïve to treatment with nabiximols for spasticity will 
participate in a screening period of up to 28 days; no changes in the dose of the patients’ 
current MS antispasticity medications will be made during this period. 
As part of the baseline period of each treatment period, patients will keep an electronic 
diary to record 11-point NRS spasticity score, spasm count, and use of antispasticity 
medications once daily, around the same time each day, preferably in the evening before 
retiring to sleep, for at least 7 days prior to Visits 2 and 6.  At Visit 2, in the morning of 
Day 1, eligible patients will be randomly assigned in a 1:1 ratio to 1 of 2 treatment 
sequences, each composed of 2 treatment periods, with administration of multiple doses 
of nabiximols or placebo. 
Patients randomized will complete 2 treatment periods with administration of IMP for 
21 days per treatment period.  Each treatment period will consist of a dose-titration phase 
of approximately 14 days, followed by a maintenance-dose phase of approximately 
7 days, where the individually determined optimized dose level remains unchanged for 
the remainder of each treatment period after titration.  Doses greater than 1 spray/day will 
be divided into a morning dose and an evening dose. 
Throughout both treatment periods, patients will initiate IMP treatment as a single spray 
in the clinic in the morning of Visits 2 (Day 1) and 6 (Day 31) of each treatment period.  
Patients will gradually titrate their daily dose by 1 to 2 additional sprays/day to an 
optimized dose or to a maximum of 12 sprays/day over the first approximately 14 days of 
treatment with an approximately 15-minute interval between sprays.  Patients should 
complete titration within approximately 14 days of their first dose of IMP in each 
treatment period and should continue at the same dose level achieved at the end of the 
titration phase (i.e., their daily optimized dose) ±1 spray divided into a morning dose and 
an evening dose for the remainder of the treatment period.  Once a stable daily dose has 
been reached, patients should gradually decrease the interval between sprays to a target 


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interval of approximately 1 minute between sprays.  Patients will be advised to 
administer IMP at approximately the same time each day in a consistent manner in 
relation to food consumption.  Morning and evening doses should be administered around 
the same time within 30 minutes after starting a snack or meal. 
On the days of scheduled MAS assessments other than Visit 1 (i.e., Visits 2, 5, 6, and 9), 
patients will attend the trial site without having administered any IMP in the morning.  
On days of MAS assessment, patients who are taking baclofen and/or tizanidine as part of 
their optimized antispasticity therapy should take their regular morning dose of either or 
both medication(s) at least 1 hour before the administration of IMP.  Administration of 
the morning dose of IMP with a standardized snack containing at least 300 kcal (of which 
approximately 30 kcal is composed of fat) will occur at the trial site under the supervision 
of site staff; MAS assessments will occur at scheduled time points before (Visits 2 and 6 
[predose]) and after (Visits 2, 5, 6, and 9 [3 hours ± 15 minutes postdose]) IMP 
administration. 
A washout period of at least 7 days will separate the 2 treatment periods.  During the 
washout period, patients will continue to take their current MS antispasticity medications 
without any changes in dose. 
Patients who complete the 2 treatment periods will complete an End of Treatment Visit 
(Visit 9).  Patients who discontinue IMP early will be encouraged to remain in the study 
for the duration of the treatment period in which they discontinue IMP and will complete 
an End of Treatment Visit (Visit 9) at the end of that period.  A Safety Follow-up Visit 
(Visit 10) will occur 7 (+3) days after the last dose of IMP or after the End of Treatment 
visit (Visit 9), whichever is later, for all patients. 
A schematic (Figure 1-1), presented at the end of Section 1, depicts the overall trial 
design.  More detailed information on treatment and trial procedures is provided in 
Section 8 and Section 9, respectively. 
4.2 
Number of Sites 
Approximately 20 sites are expected to participate in this trial. 


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4.3 
Number of Patients 
Twenty-six patients will be randomly assigned to each treatment sequence (nabiximols 
followed by placebo or placebo followed by nabiximols) to ensure that at least 46 patients 
in total complete the 2 treatment periods.  If more than 6 patients withdraw from the trial, 
additional patients will be enrolled to have 46 completers. 
 
 
 


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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
Please refer to the separate pharmacy manual for more detailed information on the IMP. 
5.1 
Nabiximols 
Product code: GW-1000-02 
Nabiximols is presented as an oromucosal spray containing THC (27 mg/mL):CBD 
(25 mg/mL) dissolved in ethanol:propylene glycol (50% v/v) excipients with peppermint 
oil (0.05% v/v) flavoring.  Each 100-μL spray delivers 2.7 mg THC and 2.5 mg CBD. 
5.2 
Placebo 
Placebo to match nabiximols is presented as an oromucosal spray containing the 
excipients ethanol and propylene glycol (50% v/v) with colorings (FD&C Yellow No.5 
[0.0260% v/v], FD&C Yellow No.6 [0.0038% v/v], FD&C Red No.40 [0.0033% v/v], 
and FD&C Blue No.1 [0.00058% v/v]) and flavored with peppermint oil (0.05% v/v).  
(DFKVSUD\GHOLYHUVȝ/FRQWDLQLQJQRDFWLYHLQJUHGLHQWV. 
5.3 
Packaging, Storage, and Drug Accountability 
5.3.1 
Packaging and Labeling 
The IMP will be manufactured, packaged, labeled, and/or distributed by GW or delegated 
contractors.  The IMP will be presented as an oromucosal spray in a plastic-coated, amber 
glass vial.  The IMP will be dispensed at each relevant visit.  A unique identification 
number will be used to identify each box and the IMP it contains.  The unique 
identification number, together with the packaging reference number, will permit full 
traceability of manufacture, pack, and label activities conducted at or on behalf of GW 
and the IMP information held on the interactive response technology (IRT).  GW will 
ensure that all IMP provided is fully labeled and packaged. 
Label text will include the following information, as a minimum: 
x Sponsor’s name and address 
x Product identification (e.g., “Nabiximols or Placebo”) 
x Product details 
x Dose and potency 
x Vial number 
x Batch number 


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x Trial code 
x Site details 
x Expiry date 
x Storage conditions 
x Instruction: “For clinical trial use only” 
x Instruction: “Keep out of the sight and reach of children” 
x Any other information required by local regulatory authorities 
In addition, any local country requirements in accordance with local drug law or 
regulatory requirement will be included in the final label text. 
Directions for use and the name, address, and telephone number of the investigator (of 
the main contact for information about the product or the clinical trial) will be provided 
separately to the patient. 
5.3.2 
Storage 
The IMP must be stored in compliance with the local regulations for a controlled drug (if 
applicable to country).  The sponsor must approve storage location and facilities.  
Temperature storage and monitoring must be done in accordance with the study 
Pharmacy Manual. 
Should storage conditions deviate from the specified requirements, the GW trial monitor 
must be contacted immediately to confirm if the IMP remains suitable for use.  The IMP 
must be placed under quarantine until written confirmation is received that the IMP is 
suitable for use. 
Patients should be instructed to store IMP in a refrigerator (2ºC to 8ºC).  Once the spray 
container is opened and in use, refrigerated storage is not necessary, but the IMP should 
not be stored above 25ºC.  The spray container should be stored upright.  Patients will be 
provided with instructions regarding home storage requirements for the IMP. 
5.3.3 
Supply and Return of Investigational Medicinal Product 
The IMP will be transported to approved country depots and trial sites in compliance with 
good distribution practice guidelines.  All IMP will be shipped with a product release 
certificate that includes a physical description of the product for confirmation of identity 
on receipt. 


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Once a site has been activated via the IRT at trial initiation, IMP will be shipped to the 
identified responsible person, such as the pharmacist, at the investigator’s site, who will 
check the amount received (against the IRT Shipment Request) and condition of the drug 
(i.e., integrity, physical appearance, and temperature during transit).  Details of the IMP 
received will be recorded in the IMP accountability record (see Section 5.3.4).  The site 
will acknowledge the IMP receipt via the IRT and will complete any receipt forms 
required.  The IMP will be dispensed and returned as detailed in Section 8.5 with further 
IMP shipments to be initiated by IRT.  As directed, all supplies, including unused, 
partially used, or empty containers, will be returned to GW/depot. 
5.3.4 
Investigational Medicinal Product Accountability 
The investigator has overall responsibility for the accountability of all used and unused 
IMP.  A drug accountability record for the IMPs must be kept current and must contain 
the following: 
x Trial code 
x Batch number/packaging reference number, date of receipt, and quantity of IMP 
received 
x Patient’s trial identification number 
x Date and quantity of IMP dispensed 
x The initials of the dispensing/dosing party 
x Date and quantity of IMP returned to the investigator 
x IMP expiry dates 
The IMP will be dispensed at Visits 2, 4, 6, and 8.  Patients will be asked to return all 
IMP (used and unused) at each subsequent visit (Visits 4, 5, 8, and 9).  The trial site will 
check the returned IMP against the usage recorded in the electronic diary.  Any 
discrepancies will be discussed with the patient at the time of the visit and documented 
accordingly within the patient’s source documents. 
The investigator must inform GW promptly of all missing or unaccounted IMP. 
A record of returned IMP must be completed and included in the shipment of used and 
unused IMP to the relevant drug distribution depot.  At the end of the trial, a 
record/statement of reconciliation must be completed and provided to GW. 
These inventories must be made available for inspection by an authorized GW 
representative and local officials or regulatory agency inspectors. 


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Please refer to the separate pharmacy manual for more detailed information on the IMP. 
5.3.5 
Posttrial Provision 
There will be no posttrial provision of nabiximols. 
A summary of the results of this trial will be made available on 
http://www.clinicaltrials.gov as required by US law and on 
http://www.clinicaltrialsregister.eu/ of the European Union (EU) Clinical Trials Register. 


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6 
PATIENT ELIGIBILITY 
Investigators are responsible for confirming patient eligibility and will be required to 
maintain a log that includes limited information about all screened patients (initials, age, 
race, and sex; as allowed per local regulations) and outcome of screening. 
6.1 
Inclusion Criteria 
Screening (Visit 1) 
For inclusion in the trial, patients must fulfill ALL of the following criteria: 
6.1.1 Male or female, aged 18 years or above. 
6.1.2 Willing and able to give informed consent for participation in the trial (see 
Section 15.2). 
6.1.3 Willing and able (in the investigator’s opinion) to comply with all trial 
requirements. 
6.1.4 Has had a diagnosis with any disease subtype of MS, by revised 
2017 McDonald criteria, for at least 12 months prior to Visit 1 and is expected 
to remain stable for the duration of the trial. 
6.1.5 Has an MAS untransformed score of at least 2 in 2 or more of 6 muscle 
groups (right knee flexors, left knee flexors, right knee extensors, left knee 
extensors, right plantar flexors, or left plantar flexors) at Visit 1. 
6.1.6 Currently receiving optimized treatment with at least 1 oral antispasticity drug 
(baclofen, tizanidine, and/or dantrolene) that has been stable for at least 
30 days prior to Visit 1.  Despite optimization, the patient does not have 
adequate relief of spasticity symptoms, including muscle spasms.  
Optimization of antispasticity medications is defined as having reached the 
most efficacious and best tolerated dose according to the relevant local 
prescribing information.  The patient must be willing to maintain the same 
antispasticity medication and not plan to initiate a new course of 
physiotherapy for the duration of the trial. 
6.1.7 If currently receiving an approved MS disease-modifying therapy, it must be 
at a stable dose for at least 3 months prior to Visit 1 and is expected to remain 
stable for the duration of the trial.  


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6.1.8 If currently receiving dalfampridine or fampridine, it must be at a stable dose 
for at least 3 months prior to Visit 1 and is expected to remain stable for the 
duration of the trial. 
6.1.9 Willing to allow the responsible authorities to be notified of participation in 
the trial, if mandated by local law. 
6.1.10 Willing to allow his or her primary care practitioner (if he or she has one) 
and/or treating neurologist (if he or she has one) to be notified of participation 
in the trial, if the primary care practitioner/treating neurologist is different 
from the investigator. 
Additional Inclusion Criteria at Randomization (Visit 2) 
Patients are eligible for randomization in the trial if, in addition to continuing to meet the 
Screening (Visit 1) inclusion criteria, they also meet the following criterion prior to 
Visit 2 (Day 1): 
x Completed at least 5 of 7 days of their electronic diary reporting during the 7 days 
immediately preceding Visit 2 (Day 1). 
6.2 
Exclusion Criteria 
The patient may not enter the trial if ANY of the following apply: 
6.2.1 Has taken nabiximols, cannabis, or a cannabis-derived product for medicinal 
or recreational purposes in the 30 days prior to Visit 1 and unable to abstain 
for the duration of the study. 
6.2.2 Did not tolerate or did not respond adequately to treatment with nabiximols or 
another cannabis-based medication if exposed at any time before the 30-day 
period prior to Visit 1. 
6.2.3 Any concomitant disease or disorder that has spasticity-like symptoms or that 
may influence the patient’s level of spasticity. 
6.2.4 Medical history suggests that relapse/remission is likely to occur during the 
trial, which, in the opinion of the investigator, is expected to influence the 
patient’s spasticity. 
6.2.5 Has had a relapse of MS within the 60 days prior to Visit 1. 
6.2.6 Currently using botulinum toxin injection for the relief of spasticity (within 
6 months of Visit 1) and is unwilling to abstain for the duration of the trial. 
6.2.7 Currently taking antipsychotic medication. 


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6.2.8 Currently taking benzodiazepines unless doses and dosing regimen have been 
stable for at least 30 days prior to Visit 1. 
6.2.9 Clinically suspected to have a contracture in one of the muscle groups of the 
lower limbs, preventing assessment with the MAS. 
6.2.10 Has any known or suspected hypersensitivity to cannabinoids or any of the 
excipients of the IMP. 
6.2.11 Has experienced myocardial infarction or clinically significant cardiac 
dysfunction within the last 12 months prior to Visit 1 or has a cardiac disorder 
that, in the opinion of the investigator, would put the patient at risk of a 
clinically significant arrhythmia or myocardial infarction. 
6.2.12 Has a diastolic blood pressure of < 50 mmHg or > 105 mmHg or systolic 
blood pressure < 90 mmHg or > 150 mmHg (when measured in a sitting 
position at rest for 5 minutes) or a postural drop in the systolic blood pressure 
of > 20 mmHg at Visit 1 or Visit 2.  All measurements will be performed 
singly and can be repeated once, if any are outside the reference range but not 
considered clinically significant. 
6.2.13 Has clinically significant impaired renal function at Visit 1, as evidenced by 
an estimated creatinine clearance lower than 50 mL/min.  All measurements 
will be performed singly and can be repeated once, if any are outside the 
reference range but not considered clinically significant. 
6.2.14 Has moderately impaired hepatic function at Visit 1, defined as serum alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit 
of normal (ULN).  All measurements will be performed singly and can be 
repeated once, if any are outside the reference range but not considered 
clinically significant. 
6.2.15 Male and fertile (i.e., after puberty unless permanently sterile by bilateral 
orchiectomy) unless willing to ensure that he uses male contraception 
(condom or vasectomy) or remains sexually abstinent during the trial and for 
3 months thereafter. 
6.2.16 Female and of childbearing potential (i.e., following menarche and until 
EHFRPLQJSRVWPHQRSDXVDOIRUFRQVHFXWLYHPRQWKVXQOHVVSHUPDQHQWO\
sterile by hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) 
unless willing to ensure that she uses a highly effective method of birth 
control (e.g., intrauterine device/hormone-releasing system, bilateral tubal 


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occlusion, vasectomized partner, or sexual abstinence) during the trial and for 
3 months thereafter.  Patients using combined hormonal methods or a 
progestogen-only pill or injection or implant should use an additional barrier 
method such as a condom or diaphragm during the trial and for 3 months 
thereafter (see Section 9.2.2). 
6.2.17 Female and pregnant (positive pregnancy test at Visit 1 or Visit 2), lactating, 
or planning pregnancy during the course of the trial or within 3 months 
thereafter. 
6.2.18 Has received an IMP within the 30 days prior to Visit 1. 
6.2.19 Has any other clinically significant disease or disorder (including seizure 
disorder) that, in the opinion of the investigator, may put the patient, other 
patients, or site staff at risk because of participation in the trial, may influence 
the interpretation of trial results, or may affect the patient’s ability to take part 
in the trial. 
6.2.20 Has any abnormalities identified following a physical examination, clinical 
laboratory, serology, or other applicable screening procedures that, in the 
opinion of the investigator, would jeopardize the safety of the patient or the 
conduct of the study if he or she took part in the trial. 
6.2.21 Has any history of suicidal behavior in the 5 years prior to Visit 1 or a score of 
3, 4, or 5 on the C-SSRS in the month prior to Visit 1. 
6.2.22 Has donated blood during the 3 months prior to Visit 1 and is unwilling to 
abstain from donation of blood during the trial. 
6.2.23 Has been previously randomized into this trial. 
6.2.24 Has any known or suspected history of alcohol or substance abuse (including 
opiate abuse) or dependence within 1 year prior to Visit 1. 
6.2.25 Currently using an illicit drug or current nonprescribed use of any prescription 
drug. 
6.2.26 Has a history of psychiatric or neurologic disorder that, in the opinion of the 
investigator, may interfere with trial participation, data interpretation, or 
conduct of trial procedures. 
6.2.27 Has a history of severe psychiatric disorder that may be exacerbated by the 
use of a cannabinoid-containing product. 


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6.2.28 Has any planned clinical interventions or intends to change any or all 
medications that may have an effect on spasticity or MS during the trial. 
6.2.29 Currently taking drugs that are solely metabolized by UGT1A9 and UGT2B7 
(see Appendix 4). 
6.2.30 Currently taking strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, 
phenytoin, phenobarbital, St John's Wort). 


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7 
PATIENT ENROLLMENT 
Before patients may be entered into the trial, GW requires a copy of the relevant site’s 
institutional review board (IRB) or independent ethics committee (IEC) written approval 
of the protocol, informed consent form (ICF), and other patient information material.  
Patients will be considered enrolled in the trial from the time of providing written 
informed consent.  All patients must personally sign and date the consent form prior to 
any procedures being performed (refer to Section 9.2.1 and Section 15.2). 
7.1 
Treatment Assignment 
At the start of Visit 1, enrolled patients will be allocated a unique patient number in a 
sequential order by trial site.  Following randomization, GW will provide all IMP in a 
packed and labeled state, and the IRT will identify the pack number to be dispensed to 
the patient at each relevant visit according to the treatment sequence assigned in the 
randomization schedule. 
7.2 
Randomization 
The allocation of IMP to treatment number will be done according to a randomization 
schedule produced by an independent statistician.  The randomization schedule will be 
held centrally on the IRT and not divulged to any other person involved in the trial until 
the database has been locked and unblinding authorized by the relevant GW personnel.  
For access to blinded treatment assignment, see Section 8.6.  If more than 6 patients 
withdraw from the trial, additional patients will be enrolled to have 46 completers. 


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8 
TREATMENT PROCEDURES 
8.1 
Investigational Medicinal Product Dosage, Administration, and 
Schedule 
The IMP will be presented as a pump oromucosal spray.  Nabiximols oromucosal spray is 
a mixture of THC and CBD extracts derived from Cannabis sativa L.  Each of the 
botanical extracts contains a cannabinoid as the major constituent (i.e., THC or CBD) and 
minor constituents, including other cannabinoid and non-cannabinoid plant components, 
such as terpenes, sterols, and triglycerides. 
The use of placebo in the current trial is deemed necessary to determine the efficacy or 
safety of the current intervention(s), since the best proven intervention has already been 
tried/is being given as background treatment and has failed to/does not fully alleviate the 
patient’s symptoms.  Placebo to match nabiximols is presented as an oromucosal spray 
containing excipients, coloring, and flavoring, with no active ingredients. 
For details regarding IMP formulations, see Section 5. 
8.1.1 
Dose Administration 
For all treatment sequences, IMP will be administered by the patient via a pump actuation 
of oromucosal spray.  The IMP will be self-administered to the oral mucosa.  Patients 
will receive IMP dosing training from site staff on Visit 2 (Day 1 predose).  Patients will 
be advised to administer IMP at approximately the same time each day in a consistent 
manner in relation to food consumption.  Morning and evening doses should be 
administered around the same time within 30 minutes after starting a snack or meal.  
Patients should divide doses greater than 1 spray/day into a morning dose and an evening 
dose.  On the days of scheduled MAS assessments other than Visit 1 (i.e., Visits 2, 5, 6, 
and 9), patients will attend the trial site without having administered any IMP in the 
morning.  On the days of MAS assessment, patients who are taking baclofen and/or 
tizanidine as part of their optimized antispasticity therapy should take their regular 
morning dose of either or both medication(s) at least 1 hour before the administration of 
IMP.  Administration of the morning dose of IMP with a standardized snack containing at 
least 300 kcal (of which approximately 30 kcal is composed of fat) will occur at the trial 
site under the supervision of site staff. 
Following the titration phase (see Section 8.1.2), IMP will be administered as 1 spray 
(100 ȝ/ per spray) with a target interval of approximately 1 minute, until the patient’s 


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specific optimized dose has been administered.  Patients should be advised to direct each 
spray at a different site on the oromucosal surface, changing the application site for each 
spray of the IMP.  If lesions are observed or persistent soreness is reported, the IMP 
administration must be interrupted until complete resolution occurs.  Events of this nature 
are to be recorded according to the adverse event (AE) procedures (see Section 12). 
8.1.2 
Dose Escalation and Dose Adjustments 
Site staff will demonstrate proper dosing and then observe dosing by the patient at Visit 2 
(Day 1) and verify that IMP was correctly administered.  Patients will initiate IMP 
treatment as a single spray in the clinic in the morning of Visits 2 (Day 1) and 6 (Day 31) 
of each treatment period.  Patients will gradually titrate their daily dose to the maximally 
acceptable dose, balancing efficacy and tolerability, or to a maximum number of 
12 sprays/day.  During the titration phase, there should be an approximately 15-minute 
interval between sprays.  Patients may temporarily pause or slightly reduce the number of 
sprays upon the emergence of adverse events; the titration may be resumed when the AEs 
resolve.  No further dose adjustments should take place after 14 days unless advised by 
the investigator.  An example titration schedule is presented in Table 8.1.2-1. 
Patients should not take more than 12 sprays/day of IMP at any time during the trial.  
Patients should consult the dosing instructions provided and contact the investigational 
site when in doubt about changes in the daily dose of IMP at any time during the study.   
Table 8.1.2-1 
Example Titration Schedule 
Day 
Number of Sprays in the 
Morning 
Number of Sprays in the 
Evening 
Total Number of 
Sprays/Day 
1 
1 
0 
1 
2 
1 
1 
2 
3 
1 
2 
3 
4 
2 
2 
4 
5 
3 
2 
5 
6 
3 
3 
6 
7 
4 
3 
7 
8 
4 
4 
8 
9 
5 
4 
9 
10 
5 
5 
10 
11 
6 
5 
11 
12 
6 
6 
12 
13 
6 
6 
12 
14 
6 
6 
12 
 


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Patients should complete titration within approximately 14 days of their first dose of IMP 
in each treatment period and should continue at the same dose level achieved at the end 
of the titration phase (i.e., their daily optimized dose) ±1 spray /day divided into a 
morning dose and an evening dose for the remainder of the treatment period.  This 
guidance applies unless patients agree with the investigator to lower the dose of IMP to 
address poor tolerability.  Once a stable daily dose has been reached, patients should 
gradually decrease the interval between sprays to a target interval of approximately 
1 minute between sprays. 
The total daily dose should be administered as a morning dose and an evening dose, 
which may be comprised of a different number of sprays during titration.  During the 
period of stable dosing following titration, patients should attempt to achieve a balance in 
the number of sprays administered as part of the morning and evening doses of IMP.   
8.2 
Washout Period 
Following the final dose of IMP in Treatment Period 1, in the morning of Visit 5 
(Day 21), patients will discontinue treatment with IMP for at least 7 days prior to Visit 6 
(Day 31).  This represents the washout period between the 2 treatment periods of this 
crossover trial. 
8.3 
Concomitant Therapy 
From Screening (Visit 1) forward, any new treatments taken or any change to ongoing 
medications during the patient’s participation in the trial will be recorded on the 
appropriate electronic case report form (eCRF) page by the investigator or designee.  
Similarly, any ongoing physiotherapy as part of the management of spasticity at the time 
of enrollment will be documented on a separate eCRF page as well as any changes in 
physiotherapy regimen that occur in the course of the study (e.g., discharge from 
physiotherapy). 
For details about the potential for interactions from initiating IMP with prior medications, 
refer to the guidance for the investigator and potential drug interactions within the IB15. 
8.3.1 
Concomitant Optimized Multiple Sclerosis Antispasticity 
Medications 
As nabiximols is being investigated as therapy in patients with spasticity due to MS, all 
patients must currently be taking at least 1 optimized oral MS antispasticity medication.  
Optimized oral MS antispasticity medications will include at least baclofen, tizanidine, 


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and/or dantrolene (monotherapy or combination therapy).  Their MS antispasticity 
medication must have been stable for at least 30 days prior to Screening (Visit 1) and the 
medication is expected to remain stable throughout the duration of the trial.  However, 
despite this optimization, eligible patients do not have adequate relief of their spasticity, 
including muscle spasms.  Optimization of antispasticity medications is defined as having 
reached the most efficacious and best tolerated dose according to the relevant local 
prescribing information.  The patient must be willing to maintain the same antispasticity 
therapy for the duration of the trial. 
Benzodiazepines use is allowed if doses and dosing regimen have been stable for at least 
30 days prior to Visit 1. 
If the patient is currently receiving an approved MS disease-modifying therapy or 
dalfampridine or fampridine, it must be at a stable dose for at least 3 months prior to 
Visit 1 and is expected to remain stable for the duration of the trial. 
8.4 
Prohibited Therapy During Trial Period 
The following medications are prohibited for the duration of the trial: 
x Cannabis use for medical or recreational purposes or any cannabinoid-based 
medication within 30 days of Visit 1 and for the duration of the trial 
x Botulinum toxin injection for the relief of spasticity within 6 months of Visit 1 
and for the duration of the trial 
x Antipsychotic medication 
x Any benzodiazepines use on an as-needed (PRN) basis 
x Drugs that are solely metabolized by UGT1A9 and UGT2B7 (see Appendix 4). 
x Strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, 
phenobarbital, St John's Wort) 
Any patients taking these medications after Visit 1 may be considered for withdrawal 
from IMP. 
8.5 
Compliance in Investigational Medicinal Product Administration 
The patient will record the number of sprays administered on each treatment day in the 
electronic diary. 
Patients should return all IMP (used and unused) at each of Visits 4, 5, 8, and 9.  The 
electronic diary-reported dosing information and any discrepancies discussed with the 


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patient at the time of the visit will be checked and documented accordingly within the 
patient’s source documents. 
Records of IMP accountability will be maintained according to Section 5.3.4. 
8.6 
Access to Blinded Treatment Assignment 
The identity of IMP assigned to patients will be held by the IRT.  The principal 
investigator (PI) at each site, or his or her designee, is responsible for ensuring that 
information on how to access the IRT for an individual patient is available to the relevant 
staff in case of an emergency and unblinding is required.  A patient’s treatment 
assignment should only be unblinded when knowledge of the treatment is essential to 
make a decision on the medical management of the patient.  Unblinding for any other 
reason will be considered a protocol deviation. 
The investigator is encouraged to contact GW to discuss the rationale for unblinding prior 
to doing so.  However, to prevent delays to the investigator or medical personnel 
responding to a potentially emergent situation, unblinding of IMP will not be dependent 
on the investigator receiving approval from GW (i.e., the investigator will be able to 
obtain the code break information independent of contacting GW). 
If the investigator does unblind, he or she must contact GW within 1 working day of the 
event and must document the time, date, and reason(s) for unblinding in the patient’s 
medical notes and on the eCRF. 


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9 
TRIAL PROCEDURES 
A list of the required trial procedures is provided in the subsections that follow; refer also 
to the schedule of assessments (Appendix 1).  Assessments or tests that are not done and 
examinations that are not conducted must be reported as such on the eCRF. 
Additional procedures to screen for the presence of or immunity against infectious 
diseases (such as body temperature, sampling of nasal or pharyngeal mucosa or serology) 
may be conducted at screening, at the beginning of each visit or as needed, according to 
local guidance and policy. 
The location of the source data for the following procedures will be documented, per site, 
in a signed source data verification plan; for further details, see Section 16.2.  
In cases where patients are not able to attend study visits due to the presence of an 
infectious disease or other transmissible condition, the investigator will discuss with the 
Sponsor potential mitigation approaches (including but not limited to extending the visit 
window, conducting evaluations via video link or phone call, allowing for safety 
procedures to be conducted at the patient’s home or local facility, or implementing 
potential mitigation approaches for IMP dispensing, secure delivery, and collection).  The 
rationale (e.g., the specific limitation imposed by the infectious disease that led to the 
inability to perform the protocol-specified assessment) and outcome of the discussion 
will be documented in the medical record. 
9.1 
Trial Procedures by Visit 
Patients will be invited to take part in the trial and will be issued with the patient 
information and informed consent.  Following adequate time to discuss the trial with the 
investigator, nurse, relatives, or caregiver, as wished, patients who provide written 
informed consent will be screened for entry into the trial. 
9.1.1 
Screening (Visit 1 [Days -28 to -1]) 
Informed consent (see Section 9.2.1) must be obtained from the patient prior to beginning 
any trial-related procedures. 
The following assessments/procedures will be performed: 
x Eligibility check (Section 6) 
x Demographics (Section 9.2.3) 
x Previous cannabis use (Section 9.2.4) 


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x Medical history (Section 9.2.5) 
x Electronic diary training (Section 9.2.14.1) 
x Concomitant medications review (Section 9.2.6) 
x AE review (Section 9.2.17) 
x Physical examination (including height measurement; Section 9.2.7) 
x Oral mucosa examination (Section 9.2.8) 
x Body weight measurement (Section 9.2.9) 
x Vital signs measurement (Section 9.2.10) 
x 12-lead ECG (Section 9.2.11) 
x Clinical laboratory blood sampling (hematology and biochemistry) 
(Section 9.2.12) 
x Dipstick urinalysis (Section 9.2.12) 
x Urine drug screen (including THC) (Section 9.2.12) 
x Serum pregnancy test (if appropriate) (Sections 9.2.2 and 9.2.12) 
x Blood THC test (Section 9.2.12) 
x MAS assessment (Section 9.2.15.1) 
x C-SSRS assessment (Section 9.2.15.3) 
The investigator should review the laboratory results as soon as these become available.  
If the results show that a patient is ineligible, the patient will fail screening. 
Following Visit 1, there will be no changes in the dose of the patient’s current oral MS 
antispasticity medications. 
Patients who satisfy all of the inclusion criteria and none of the exclusion criteria 
specified in Section 6 will enter a baseline period of at least 7 days prior to Visit 2, during 
which they will be required to take their optimized oral MS antispasticity medication 
(that must include at least 1 of baclofen, tizanidine, or dantrolene) and complete an 
electronic daily diary to record their 11-point NRS spasticity score, spasm count, and use 
of antispasticity medications once daily, around the same time each day, preferably in the 
evening before retiring to sleep. 
9.1.1.1 
Screening Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently randomly assigned to trial intervention.  A minimal set of screen 
failure information is required to ensure transparent reporting of individuals who failed 
screening in order to meet the Consolidated Standards of Reporting Trials publishing 


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requirements and to respond to queries from regulatory authorities.  The minimal 
information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) for 
reasons such as fever due to a brief acute upper respiratory illness, having taken a 
prohibited over-the-counter medication within the excluded period, recent blood 
donation, or who could not be enrolled within the screening window for logistical 
reasons, may be allowed one opportunity to be rescreened at the discretion of the 
investigator or designee.  The rescreened patient will be assigned a new patient number 
and all screening assessments will be repeated.  Patients will not be rescreened more than 
once. 
9.1.2 
Treatment Period 1 (Visits 2 to 5 [Days 1 to 21]) 
This treatment period will consist of a dose-titration phase of approximately 14 days 
followed by a maintenance-dose phase of approximately 7 days, where the individually 
determined optimized dose level remains unchanged for the remainder of the treatment 
period after titration.  On the days of scheduled MAS assessments other than Visit 1 
(i.e., Visits 2 and 5), patients will attend the trial site without having administered any 
IMP in the morning.  On the days of MAS assessment, patients who are taking baclofen 
and/or tizanidine as part of their optimized antispasticity therapy should take their regular 
morning dose of either or both medication(s) at least 1 hour before administration of 
IMP.  Patients will continue to take their current oral MS antispasticity medications 
without any changes in dose. 
9.1.2.1 
Visit 2 (Day 1) 
Patients will return to the site in the morning of Day 1 when eligibility will be confirmed 
and patients will be randomized. 
The following assessments/procedures will be performed on Day 1 predose: 
x Eligibility check  
x Randomization (Section 7.2) 
x Concomitant medications review 
x AE review 
x Examination of oral mucosa 
x Body weight measurement 


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x Vital signs measurement 
x Urine drug screen (including THC) 
x Urine pregnancy test (if appropriate) 
x PK blood sampling for IMP (Section 9.2.12.1) 
x MAS assessment 
x T25FW test (Section 9.2.15.4) 
x C-SSRS assessment 
x IMP dosing training (Section 9.2.14.3) 
x IMP dispensing 
Following predose assessments and after IMP dosing training and dispensing, site staff 
will observe dosing by the patient and verify that IMP was correctly administered.  
Patients will administer a single dose of IMP with a standardized snack containing at 
least 300 kcal (of which approximately 30 kcal is composed of fat) at the trial site under 
the supervision of site staff. 
The following assessments/procedures will be performed 2 to 4 hours postdose: 
x MAS assessment (3 hours ± 15 minutes postdose) 
x AE review 
x Vital signs measurement 
x PK blood sampling for IMP (Section 9.2.12.1) 
The patient will be provided dosing instructions and advised to contact the investigational 
site when in doubt about changes in the daily dose of IMP.  The patient will be instructed 
to record IMP doses administered in the patient electronic diary. 
The exact time of PK blood sampling and the time of the patient’s snacks and meals 
should be recorded.   
Following Visit 2, patients will titrate their daily dose of IMP for approximately 14 days 
until they achieve an optimized dose with an approximately 15-minute interval between 
sprays; patients should divide doses greater than 1 spray/day into a morning dose and an 
evening dose.  Administration of the morning and evening doses of IMP should be 
maintained around the same time each day in a consistent manner in relation to food 
consumption, i.e., within 30 minutes after starting a snack or meal.   
Patients should be reminded to record their 11-point NRS spasticity score, spasm count, 
and use of antispasticity medications in the electronic diary once daily, around the same 
time each day, preferably in the evening before retiring to sleep.  In addition, on the day 


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before Visits 4 and 5, patients will be prompted to record whether they started their 
morning and evening doses of IMP within 30 minutes of a snack or meal. 
Each site will have the option to follow up with the patient through telephone calls during 
the titration phase to monitor the patient’s titration, safety and tolerance, and electronic 
daily diary reporting. 
9.1.2.2 
Visit 3 (Day 8, Phone Call) 
Visit 3 will occur 7 days after the first dose of IMP and will consist of a phone call from 
site staff to patients to monitor adherence with IMP administration and advise on dose 
titration if required.  Concomitant medications and AEs will be collected during this call. 
9.1.2.3 
Visit 4 (Day 15) and Visit 5 (Day 21) 
Visits 4 and 5 will occur 14 and 20 days after the first dose of IMP, respectively.  A visit 
window of ±1 and ±2 days, respectively, from the scheduled visit date is permitted, but it 
is preferred that the visit is performed on the scheduled visit day, where possible. 
Once a stable daily dose has been reached, patients should gradually decrease the interval 
between sprays to a target interval of approximately 1 minute between sprays.  Patients 
should continue IMP administration at the same dose level achieved at the end of titration 
(i.e., their daily optimized dose) ±1 spray divided into a morning dose and an evening 
dose for approximately 7 days (maintenance-dose phase).  Administration of the morning 
and evening doses of IMP should be maintained around the same time of each day in a 
consistent manner in relation to food consumption, i.e., within 30 minutes after starting a 
snack or meal.   
On Visit 5, patients will administer their morning dose of IMP with a standardized snack 
containing at least 300 kcal (of which approximately 30 kcal is composed of fat) at the 
trial site under the supervision of site staff.  The IMP will not be administered in the 
evening of Visit 5 (Day 21). 
The following assessments/procedures will be performed at these visits, unless otherwise 
indicated: 
x MAS assessment (Visit 5 [3 hours ± 15 minutes after the first spray of the 
morning dose] only) 
x T25FW test (Visit 5 only) 
x Concomitant medications review 
x AE review 


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x Physical examination (Visit 5 only) 
x Examination of the oral mucosa 
x Vital signs measurement 
x 12-lead ECG (Visit 5 only) 
x Clinical laboratory sampling (hematology and biochemistry) (Visit 5 only) 
x PK blood sampling for IMP (Section 9.2.12.1) 
x MSSS-88 assessment (Visit 5 only) 
x C-SSRS assessment 
x IMP dosing at the investigational site (Visit 5 [morning] only) 
x IMP dispensing (Visit 4 only) 
x IMP collection and compliance review (Section 9.2.16) 
The exact time of PK blood sampling and the time of the patient’s snacks and meals 
should be recorded.   
Patients should be reminded to record their 11-point NRS spasticity score, spasm count, 
use of antispasticity medications, and IMP dosing in the electronic diary once daily, 
around the same time each day, preferably in the evening before retiring to sleep. 
9.1.3 
Washout Period (Days 22 to 30) 
A washout period of at least 7 days will separate the 2 treatment periods.  Following the 
final dose of IMP in Treatment Period 1, in the morning of Visit 5 (Day 21), patients will 
discontinue treatment with IMP for the 7 days prior to Visit 6 (Day 31).  Patients will 
continue to take their current optimized oral MS antispasticity medications without any 
changes in dose.  Patients should be reminded to record their 11-point NRS spasticity 
score, spasm count, and use of antispasticity medications in the electronic diary once 
daily, around the same time each day, preferably in the evening before retiring to sleep, 
for at least 7 days prior to Visit 6. 
9.1.4 
Treatment Period 2 (Visits 6 to 9 [Days 31 to 51]) 
This treatment period will consist of a dose-titration phase of approximately 14 days 
followed by a maintenance-dose phase of approximately 7 days, where the individually 
determined optimized dose level remains unchanged for the remainder of the treatment 
period after titration.  On the days of scheduled MAS assessments other than Visit 1 
(i.e., Visits 6 and 9), patients will attend the trial site without having administered any 
IMP in the morning.  On the days of MAS assessment, patients who are taking baclofen 
and/or tizanidine as part of their optimized antispasticity therapy should take their regular 


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morning dose of either or both medication(s) at least 1 hour before administration of 
IMP.  Patients will continue to take their current optimized oral MS antispasticity 
medications without any changes in dose. 
9.1.4.1 
Visit 6 (Day 31) 
Visit 6 will occur 30 days after the first dose of IMP.  A visit window of ±1 day from the 
scheduled visit date is permitted, but it is preferred that the visit is performed on the 
scheduled visit day, where possible. 
The following assessments/procedures will be performed on Day 31 predose: 
x Concomitant medications review 
x AE review 
x Examination of oral mucosa 
x Body weight measurement 
x Vital signs measurement 
x Urine pregnancy test (if appropriate) 
x PK blood sampling for IMP (Section 9.2.12.1) 
x MAS assessment 
x T25FW test 
x C-SSRS assessment 
x IMP dispensing 
Following predose assessments and IMP dispensing, patients will administer a single 
dose of IMP with a standardized snack containing at least 300 kcal (of which 
approximately 30 kcal is composed of fat) at the trial site under the supervision of site 
staff.   
The following assessments/procedures will be performed 2 to 4 hours postdose: 
x MAS assessment (3 hours ± 15 minutes postdose) 
x AE review 
x Vital signs measurement 
x PK blood sampling for IMP (Section 9.2.12.1) 
The patient will be provided dosing instructions and advised to contact the investigational 
site when in doubt about changes in the daily dose of IMP.  The patient will be instructed 
to record IMP doses administered in the patient electronic diary. 


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The exact time of PK blood sampling and the time of the patient’s snacks and meals 
should be recorded. 
Following Visit 6, patients will titrate their daily dose of IMP for approximately 14 days 
until they achieve an optimized dose with an approximately 15-minute interval between 
sprays; patients should divide doses greater than 1 spray/day into a morning dose and an 
evening dose.  Administration of the morning and evening doses of IMP should be 
maintained around the same time each day in a consistent manner in relation to food 
consumption, i.e., within 30 minutes after starting a snack or meal.   
Patients should be reminded to record their 11-point NRS spasticity score, spasm count, 
and use of antispasticity medications in the electronic diary once daily, around the same 
time each day, preferably in the evening before retiring to sleep.  In addition, on the day 
before Visits 8 and 9, patients will be prompted to record whether they started their 
morning and evening doses of IMP within 30 minutes of a snack or meal. 
Each site will have the option to follow up with the patient through telephone calls during 
the titration phase to monitor the patient’s titration, safety and tolerance, and electronic 
daily diary reporting. 
9.1.4.2 
Visit 7 (Day 38, Phone Call) 
Visit 7 will occur 7 days after the first dose of IMP during Period 2 and will consist of a 
phone call from site staff to patients to monitor adherence with IMP administration and 
advise on dose titration if required.  Concomitant medications and AEs will be collected 
during this call. 
9.1.4.3 
Visit 8 (Day 45) and Visit 9 (Day 51, End of Treatment) 
Visits 8 and 9 will occur 44 and 50 days after the first dose of IMP, respectively.  A visit 
window of ±1 and ±2 days, respectively, from the scheduled visit date is permitted, but it 
is preferred that the visit is performed on the scheduled visit day, where possible. 
Once a stable daily dose has been reached, patients should gradually decrease the interval 
between sprays to a target interval of approximately 1 minute between sprays.  Patients 
should continue IMP administration at the same dose level achieved at the end of titration 
(i.e., their daily optimized dose) ±1 spray divided into a morning dose and an evening 
dose for approximately 7 days (maintenance-dose phase).  Administration of the morning 
and evening doses of IMP should be maintained around the same time of each day in a 


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consistent manner in relation to food consumption, i.e., within 30 minutes after starting a 
snack or meal.   
On Visit 9, patients will administer the morning dose of IMP with a standardized snack 
containing at least 300 kcal (of which approximately 30 kcal is composed of fat) at the 
trial site under the supervision of site staff.  The IMP will not be administered in the 
evening of Visit 9 (Day 51). 
The following assessments/procedures will be performed at these visits, unless otherwise 
indicated: 
x MAS assessment (Visit 9 [3 hours ± 15 minutes after the first spray of the 
morning dose] only) 
x T25FW test (Visit 9 only) 
x Concomitant medication review 
x AE review 
x Physical examination (Visit 9 only) 
x Examination of the oral mucosa 
x Vital signs measurement 
x 12-lead ECG (Visit 9 only) 
x Clinical laboratory sampling (hematology and biochemistry) (Visit 9 only) 
x PK blood sampling for IMP (Section 9.2.12.1) 
x MSSS-88 assessment (Visit 9 only) 
x C-SSRS assessment 
x IMP dosing at the investigational site (Visit 9 [morning] only) 
x IMP dispensing (Visit 8 only) 
x IMP collection and compliance review 
The exact time of PK blood sampling and the time of the patient’s snacks and meals 
should be recorded.   
Patients should be reminded to record their 11-point NRS spasticity score, spasm count, 
use of antispasticity medications, and IMP dosing in the electronic diary once daily, 
around the same time each day, preferably in the evening before retiring to sleep. 
If the decision is made to discontinue IMP early, the patient concerned will be 
encouraged to remain in the study for the duration of the treatment period in which they 
discontinue IMP and will complete an End of Treatment Visit (Visit 9) at the end of that 
period. 


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9.1.5 
Safety Follow-up Visit (Visit 10 [Day 58]) 
The Safety Follow-up Visit will occur 7 days after the last dose of IMP or after the 
End of Treatment visit (Visit 9), whichever is later.  A visit window of +3 days from the 
scheduled visit date is permitted, but it is preferred that the visit is performed on the 
scheduled visit day, where possible. 
The following assessments/procedures will be performed: 
x Concomitant medication review 
x AE review 
x Examination of oral mucosa 
x Body weight measurement 
x Vital signs measurement 
x Dipstick urinalysis 
x Serum pregnancy test (if appropriate) 
x C-SSRS assessment 
9.2 
Trial Procedure Listing 
9.2.1 
Informed Consent 
Adult patients with an adequate level of understanding must personally sign and date the 
IRB/IEC-approved ICF before any trial-specific procedures are performed or any 
patient-related data are recorded for the trial.  If an adult patient is unable to read 
(illiterate or visually impaired), or is physically unable to speak or write, an impartial 
witness should be present during the entire informed consent discussion.  After the ICF is 
read and explained to the patient and after the patient has orally consented to participation 
in the trial and has signed and dated the ICF (if capable of doing so), the witness should 
also sign and personally date the ICF.  By signing the ICF, the witness attests that the 
information in the ICF was accurately explained to and apparently understood by the 
patient and that informed consent was freely given by the patient (as outlined in the 
International Council for Harmonisation [ICH] Tripartite Guideline for Good Clinical 
Practice [GCP] Topic E6(R2), Section 4.8.9). 
If the patient cannot write, they can give consent by “making their mark” on the consent 
form (e.g., writing an “X”). 
The original signed ICF should be retained, and a copy should be provided to the patient.  
For further details regarding the informed consent, see Section 15.2. 


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9.2.2 
Contraception Requirements 
To be eligible for the trial, female patients of childbearing potential (i.e., following 
PHQDUFKHDQGXQWLOEHFRPLQJSRVWPHQRSDXVDOIRU 12 consecutive months unless 
permanently sterile by hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) 
must have agreed that they are willing to use highly effective contraception for the 
duration of the trial and for 3 months thereafter.  Highly effective methods of birth 
control are defined as those, alone or in combination, that result in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly.  Such methods include 
an intrauterine device/hormone-releasing system, bilateral tubal occlusion, vasectomized 
partner (provided that partner is the sole sexual partner of the trial patient and that the 
vasectomized partner has received medical assessment of the surgical success), or sexual 
abstinence.  Due to the possible interaction of the IMP with contraceptive steroids, the 
use of hormonal contraception must be supplemented with a barrier method (preferably 
male condom or diaphragm). 
To be eligible for the trial, male patients who are fertile (i.e., after puberty unless 
permanently sterile by bilateral orchiectomy) must have agreed that they are willing to 
use male contraception (condom or vasectomy) or remain sexually abstinent during the 
trial and for 3 months thereafter. 
Abstinence, as referenced above, is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic abstinence (calendar, 
symptothermal, and postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and the lactational amenorrhea method are not acceptable methods of contraception. 
9.2.3 
Demographics 
At screening (Visit 1), the following information will be obtained for each patient: date of 
birth, sex, and race (if allowed per local regulations). 
9.2.4 
Previous Cannabis Use 
At Screening (Visit 1), any intermittent or regular previous use of cannabis or 
cannabinoid products for medical or recreational purposes will be recorded. 


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9.2.5 
Medical History 
Relevant, significant medical history will be obtained at Screening (Visit 1) and is 
defined as any condition or disease that meets any of the following criteria: 
x May affect the condition under study in this trial 
x Is ongoing on entry into the trial 
x Has occurred within 1 year prior to Screening (Visit 1) 
x Suspected or confirmed Coronavirus disease 2019 (COVID-19) infection (or 
other significant communicable diseases) within one year prior to screening 
9.2.6 
Concomitant Medication 
Details of all current medications will be recorded.  Any changes in concomitant 
medication during the trial must be recorded on the eCRF at trial visits.  Patients should 
stop taking any prohibited therapy prior to Screening (Visit 1), as defined in Section 8.4. 
Please note: Any vaccination related to COVID-19 that was received within the last 
12 months prior to screening should be recorded as a concomitant medication.  The 
information recorded should include the vaccine manufacturer and the dates of 
administration; with differing start and end dates if more than one dose is received. 
9.2.7 
Physical Examination 
A full physical examination will be performed at the timepoints specified in the Schedule 
of Assessments (see Appendix 1); height will be recorded at Screening (Visit 1) only. 
9.2.8 
Examination of Oral Mucosa 
Examination of the oral mucosa will occur at relevant visits (see Appendix 1). 
9.2.9 
Body Weight Measurements 
Body weight measurements will be recorded at relevant visits (see Appendix 1). 
9.2.10 
Vital Signs 
As part of the screening procedures at Visit 1, vital signs (systolic and diastolic blood 
pressure and pulse rate) will first be measured after the patient assumed a supine position 
for 5 minutes.  Vital signs will then be measured within 2 minutes of assuming a standing 
position in ambulatory patients only.  At all subsequent time points, vital sign 


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measurements will be completed in a sitting position at rest for 5 minutes.  Blood 
pressure should be recorded using the same arm throughout the trial, where possible.  
Additional vital signs measurements may be taken during the trial if clinically indicated. 
9.2.11 
12-Lead Electrocardiogram  
A 12-lead ECG will be performed after 5 minutes in a supine position.  A physician must 
review the ECG (annotated, signed, and dated) and any abnormal findings considered to 
indicate significant medical history or AEs must be recorded appropriately on the eCRF.  
Additional ECG measurements can be taken at any time during the trial, if clinically 
indicated. 
9.2.12 
Clinical Laboratory Sampling 
The investigator and trial monitor will be provided with a list of the normal ranges used 
by the central clinical laboratory for all variables assayed during the trial and a statement 
of accreditation (or similar) for the laboratory.  Clinical laboratory sample parameters are 
detailed in Table 9.2.12-1. 
All clinical blood samples other than PK sampling will be analyzed at a central clinical 
laboratory.  Urine samples for biochemistry will be analyzed at the trial site by use of a 
dipstick.  In cases where samples cannot be analyzed at the site due to local regulations, a 
full set of urine samples should be sent to the central clinical laboratory for analysis.  
Urine sample volume requirements and processing procedures will be detailed in a 
separate laboratory manual. 
Table 9.2.12-1 
Biochemistry, Hematology, Urinalysis, Pregnancy Test, and 
Drug Screen 
Biochemistry 
(Serum¹) 
Hematology 
(Whole Blood¹) 
Urinalysis 
(Urine²) 
Pregnancy Test 
(Serum¹/ 
Urine²) 
Drug Screen 
(Serum¹/ 
Urine3) 
Alanine 
aminotransferase 
Hematocrit 
Blood 
Serum and urine THC 
Albumin 
Hemoglobin 
Glucose 
 
Drugs of 
abuse 
Alkaline phosphatase 
Mean cell volume 
Nitrites 
 
 
Aspartate 
aminotransferase 
Mean corpuscular 
hemoglobin 
pH 
 
 
Calcium 
Platelets 
Protein 
 
 
Creatinine 
Red blood cell count 
White blood cells  
 
Gamma-glutamyl 
transferase 
White blood cell count 
with automated 
differential 
Specific gravity 
 
 


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Table 9.2.12-1 
Biochemistry, Hematology, Urinalysis, Pregnancy Test, and 
Drug Screen 
Biochemistry 
(Serum¹) 
Hematology 
(Whole Blood¹) 
Urinalysis 
(Urine²) 
Pregnancy Test 
(Serum¹/ 
Urine²) 
Drug Screen 
(Serum¹/ 
Urine3) 
Potassium 
 
Ketones 
 
 
Sodium 
 
Urobilinogen 
 
 
Total bilirubin 
 
Bilirubin 
 
 
Total protein 
 
 
 
 
Urea (blood urea 
nitrogen) 
 
 
 
 
Prothrombin time 
(plasma4) 
 
 
 
 
¹Analyzed at a central laboratory. 
²Analyzed at the trial site by use of a dipstick (if allowed per local regulations). 
3The standard drugs of abuse screen, including THC, will be analyzed by use of a urine dipstick at 
Visits 1 and 2.  Patients will undergo a separate blood THC test at Visit 1 only. 
4Analyzed at Screening (Visit 1) only. 
 
All laboratory results will be reviewed, and the reports signed and dated by an 
investigator.  Any results considered to be of clinical significance must be addressed and 
followed up as clinically appropriate.  The results of blood THC testing at Screening 
(Visit 1) will be reported back to the trial site for confirmation of eligibility.  All 
laboratory results considered to represent an AE must be documented on the eCRF.  For 
reporting and follow-up of potential cases of drug-induced liver injury, see Section 12.8. 
Repeat samples will be taken, if required, for clinical follow-up or if the sample is lost or 
damaged.  Any abnormal end of treatment clinical laboratory result of clinical 
significance must be repeated at regular intervals until it returns to normal or until an 
investigator is satisfied that the abnormality is not related to the IMP and needs no further 
investigation.  Blood sample volume requirements and processing procedures will be 
detailed in a separate laboratory manual; the maximum amount of blood taken during the 
course of the trial, including PK blood samples, will be approximately 126 mL, taking 
into account possible repeat tests.  If deemed necessary by the investigator or the sponsor, 
the number and/or volume of blood samples per assessment may be increased as long as 
the total volume of blood drawn for a subject does not surpass 500 mL (except when 
extra blood samples need to be taken for safety reasons). 
9.2.12.1 
Pharmacokinetic Blood Sampling 
Plasma concentrations will be obtained for THC and its relevant metabolites 
(11-OH-THC and 11-COOH-THC) and CBD and its relevant metabolites (7-OH-CBD 
and 7-COOH-CBD) at distinct time points (Visits 2, 4, 5, 6, 8, and 9).  The exact time of 


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PK blood sampling and the time of the patient’s snacks and meals should be recorded.  
On the day before PK blood sampling at Visits 4, 5, 8, and 9, patients will be prompted to 
record whether they started their morning and evening doses of IMP within 30 minutes of 
a snack or meal.  The PK blood sampling schedule is presented in Table 9.2.12.1-1. 
Table 9.2.12.1-1 
Pharmacokinetic Blood Sampling Schedule 
Visit / Day 
Time Points 
Visit 2 / Day 1 
Predose and at 0-2 and 2-4 hours postdose 
Visit 4 / Day 15 
0-2 and 2-4 hours postdose 
Visit 5 / Day 21 
Predose and at 0-1 and 2-3 hours postdose 
Visit 6 / Day 31 
Predose and at 0-2 and 2-4 hours postdose 
Visit 8 / Day 45 
0-2 and 2-4 hours postdose 
Visit 9 / Day 51 
Predose and at 0-1 and 2-3 hours postdose 
 
Analysis of all PK samples will be conducted at a central bioanalytical laboratory.  Blood 
sample volume requirements and processing procedures will also be detailed in a separate 
laboratory manual; the maximum amount of blood taken for PK analyses during the 
course of the trial will be approximately 75 mL, taking into account possible repeat tests.  
The patient must be advised that it may not be safe for the patient to undertake further 
blood tests within 1 month of any trial-related blood draws and to inform the investigator 
if they suffered any blood loss during the 1-month period leading up to a planned blood 
draw. 
9.2.13 
Interactive Response Technology 
The IRT will be used to assign patients to treatment sequences, manage IMP supply, and 
to provide treatment allocation information in the event of patient unblinding. 
A member of the trial team must contact the IRT at each clinic visit in order to perform 
the following: 
x Randomize a patient (Visit 2) 
x Obtain IMP dispensing information (Visits 2, 4, 6, and 8) 
x Provide completion/early withdrawal information (Visit 9) 
Training will be given to all sites prior to the start of the trial. 
9.2.14 
Electronic Patient Diary 
As part of the baseline period of each treatment period, patients will record their 11-point 
NRS spasticity score, spasm count, and use of antispasticity medications in the electronic 


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diary once daily, around the same time each day, preferably in the evening before retiring 
to sleep, for at least 7 days prior to Visits 2 and 6. 
Throughout the trial, the patient will complete an electronic diary once daily, around the 
same time each day, preferably in the evening before retiring to sleep, to record 11-point 
NRS spasticity score, spasm count, use of antispasticity medications, and IMP dosing.  In 
addition, on the day before PK blood sampling at Visits 4, 5, 8, and 9, patients will be 
prompted to record whether they started their morning and evening doses of IMP within 
30 minutes of a snack or meal. 
9.2.14.1 
Electronic Diary Training 
Patients will be trained by the site staff on the use of the electronic diary at Screening 
(Visit 1) and will be instructed to record their 11-point NRS spasticity score, spasm 
count, and use of antispasticity medications once daily, around the same time each day, 
preferably in the evening before retiring to sleep, throughout the baseline period of at 
least 7 days prior to Visits 2 and 6 and throughout the trial until Visit 9.  Following 
randomization during Visit 2, patients will be instructed to log their daily IMP dosing in 
the electronic diary throughout the 2 treatment periods until Visit 9. 
9.2.14.2 
Spasticity Numerical Rating Scale 
The 11-point NRS is considered a valid and reliable method to assess overall spasticity in 
patients with MS.  It is the standardized patient-related outcome that best identifies a 
clinically important difference and a minimum clinically important difference. 
Patients will be asked to make a daily assessment, at bedtime, to read the question, and to 
tick the most appropriate number to indicate the severity of his or her spasticity over the 
last 24 hours.  The patients will be given a definition of spasticity and the question will be 
phrased as follows: 
On a scale of 0 to 10, please indicate your level of spasticity over the last 24 hours, 
considering 0 as “No spasticity” and 10 as “Worst possible spasticity.” 
This information will be recorded in the patient electronic diary. 
9.2.14.3 
Use of Antispasticity Medications and Investigational Medicinal 
Product Dosing Record 
Patients will be instructed to record their use of antispasticity medications, including their 
use of baclofen and/or tizanidine as part of their optimized oral antispasticity therapy, and 
their IMP dosing daily in their electronic diary. 


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9.2.15 
Questionnaires and Assessments Completed at Scheduled Visits  
Questionnaires should be completed by the patient, unless otherwise specified.  The same 
person should administer/complete the questionnaires/assessments in order to maintain 
consistency, unless otherwise stated. 
9.2.15.1 
Modified Ashworth Scale 
The MAS is one of the most widely used methods of measuring spasticity, due in a large 
part to the simplicity and reproducible method17 and reflects the findings of a trained 
observer and not the patients’ perception of symptoms. 
The MAS has 6 categories to classify muscle spasticity and will be conducted and scored 
by a blinded, independent, trained, and certified healthcare professional (i.e., one not 
otherwise involved in the care of the patient within or outside this trial - while the patient 
is participating in the trial) as follows: 
0) No increase in muscle tone 
1) Slight increase in muscle tone, manifested by a catch and release or minimal 
resistance at end of the range of motion when affected part(s) are moved in flexion or 
extension 
1+) Slight increase in muscle tone, manifested by a catch, followed by minimal 
resistance throughout the remainder (less than half) of the range of movement (ROM) 
2) More marked increase in muscle tone through most of the ROM, but affected 
part(s) easily moved 
3) Considerable increase in muscle tone, passive movement is difficult 
4) Affected part rigid in flexion or extension 
The blinded, independent, trained, and certified healthcare professional will perform the 
MAS assessment, specifically the following 10 muscle groups: hip flexors and adductors, 
knee flexors and extensors, and plantar flexors on both sides of the body at each time 
point at specified visits.  The same assessor should administer the MAS throughout the 
trial where possible. 
9.2.15.2 
Multiple Sclerosis Spasticity Scale 
The MSSS-88 is a patient self-report measure of the impact of spasticity (muscle stiffness 
and spasms) in MS.  This 88-item scale captures the patient experience and impact of 


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spasticity, including muscle stiffness, pain and discomfort, muscle spasms, effect on daily 
activities, ability to walk, body movement, patient feelings, and social functioning.  
Responses to individual questions can range from “not at all bothered” to “extremely 
bothered.” 
9.2.15.3 
Columbia-Suicide Severity Rating Scale 
The definitions of behavioral suicidal events used in this scale are based on those used in 
the Columbia Suicide History Form.  Questions are asked on suicidal behavior, suicidal 
ideation, and intensity of ideation.  At Screening (Visit 1), questions will be in relation to 
lifetime experiences (baseline).  Questioning at all subsequent visits will be in relation to 
the last assessment (since last visit). 
The C-SSRS is to be administered by the investigator or his or her qualified designee at 
Visits 1 through 10 as indicated in the schedule of assessments (see Appendix 1); 
“qualified designee” is defined as anyone who has completed the C-SSRS training within 
the past 2 years or has continually administered C-SSRS assessments throughout the trial 
since obtaining the training certificate.  The survey should be completed by the same 
assessor, where possible, throughout the trial.  Assessments will be conducted only if 
patients are capable of understanding and answering the questions, in the investigator’s 
opinion. 
9.2.15.4 
Timed 25-Foot Walk 
The T25FW is a quantitative measure of lower extremity function.  A blinded, 
independent, trained, and certified healthcare professional will perform the T25FW.  The 
same assessor should administer the T25FW test throughout the trial where possible.  If 
ambulatory, the patient will be instructed to begin at one end of a clearly marked 25-foot 
course.  They will be instructed to walk the 25 feet as quickly as possible, but safely, and 
to not slow down until after they have passed the finish line.  The task will be 
immediately administered a second time following the first trial by having the patient 
walk back the same distance. 
Patients will be permitted to use their customary, nonmotorized assistive device (AD) 
(cane, walking sticks, walker, and rollator) during the T25FW test.  The same AD must 
be used at each assessment and its use documented in the patient record. 
9.2.16 
Investigational Medicinal Product Accountability 
Records of IMP accountability will be maintained according to Section 5.3.4. 


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9.2.17 
Adverse Events 
Refer to Section 12 for definitions, procedures, and further information on AE reporting. 
9.2.18 
Special Circumstances 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied.  In cases where participants are not able to perform 
all protocol-defined assessments due to special circumstances, the investigator must 
discuss with the medical monitor potential mitigation approaches.  
For the duration of such special circumstances, the following measures may be 
implemented for enrolled subjects:  
x Safety follow-up may be done by a telephone call, other means of virtual contact 
or home visit, if appropriate.  
x An alternative approach for IMP dispensing, secure delivery and collection may 
be sought. 
x Biological samples may be collected and analyzed at a different location than 
defined in the protocol.  Biological samples should not be collected if they cannot 
be processed in a timely manner or appropriately stored until shipping/processing.  
x If it is not possible to collect the biological samples or safety assessments (e.g., 
ECG, vital signs) within the interval predefined in the protocol (see the SoA in 
Appendix 1), then the interval may be extended up to a maximum duration of 
3 days. 
x If a safety assessment cannot be performed within the modified window, the 
investigator must review the benefit-risk for patient continuation in the study and 
record this in the medical records. 
The rationale (e.g., the specific reasons behind the changes) and outcome of the 
discussion with the medical monitor will be documented in the medical record.  
Information on how each visit was performed will be recorded in the eCRF. 


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10 
WITHDRAWAL 
In accordance with the Declaration of Helsinki, the ICH Tripartite Guideline for GCP 
Topic E6(R2), the US Food and Drug Administration (FDA) regulations relating to GCP 
and clinical trials, the EU Clinical Trials Directive, the EU GCP Directive, and/or other 
applicable regulations, a patient has the right to withdraw from the trial at any time and 
for any reason, with no obligation to provide a reason, and without prejudice to his or her 
future medical care by the physician or at the institution. 
The patient must be withdrawn from the trial if any of the following apply: 
x Administrative decision by the investigator, GW, or a regulatory authority 
x Withdrawal of patient consent 
x Lost to follow-up 
The patient must cease IMP and should remain in the trial if any of the following apply: 
x Pregnancy 
x Protocol deviation that is considered to potentially compromise the safety of the 
patient 
x Suicidal behavior or ideation of type 4 or 5 during the treatment period, as 
evaluated with the C-SSRS 
x ALT or AST > 3 u ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
x ALT or AST > 5 u ULN 
x ALT or AST > 3 u ULN and (total bilirubin [TBL] > 2 u ULN or international 
normalized ratio [INR] > 1.5) 
The patient may be required to cease IMP at the discretion of the investigator and should 
remain in the trial for any of the following reasons: 
x Did not meet eligibility criteria 
x Patient noncompliance 
x AE (including clinically significant laboratory result) that, in the opinion of the 
investigator, would compromise the continued safe participation of the patient in 
the trial 
x Any evidence of drug abuse or diversion 
x Disease progression (defined as a relapse of MS requiring a change in treatment) 
x A positive COVID-19 test result after randomization 


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Participants who are withdrawn from the study, including for reasons of a COVID-19 
infection, may be replaced following discussion between the investigator and the sponsor.  
The decision regarding the replacement of these participants will be documented. 
Should a patient request or decide to withdraw from the trial, all efforts must be made to 
complete and report the observations as thoroughly as possible up to the date of 
withdrawal.  Patients withdrawing due to an AE should be followed up according to 
Section 12.7.  All information should be reported on the applicable eCRF pages (refer to 
Section 9.2).  A Safety Follow-up Visit should take place 7 (+3) days after last dose of 
IMP or after the End of Treatment visit (Visit 9), whichever is later (refer to 
Section 9.1.5).  If withdrawing patients decline to give a reason for withdrawal of 
consent, the investigator must respect the patients’ wishes. 


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11 
URGENT SAFETY MEASURES 
The sponsor and investigator may take appropriate urgent safety measures in order to 
protect the patients of a clinical trial against any immediate hazard to their health or 
safety.  If such measures are taken by the investigator, they must notify GW immediately 
or at least within 24 hours of awareness.  GW will report urgent safety measures to 
regulatory authorities and will provide a written report to the regulatory authorities and 
IRB/IEC within 3 days. 


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12 
ADVERSE EVENT REPORTING 
12.1 
Definitions 
12.1.1 
Adverse Event 
For the purposes of this trial, an AE is defined as follows: 
Any new unfavorable/unintended signs/symptoms (including abnormal laboratory 
findings when relevant) or diagnosis or worsening of a preexisting condition that occurs 
following Screening (Visit 1) and at any point up to the posttreatment Safety Follow-up 
Visit (Visit 10), which may or may not be considered to be related to the IMP.  Any event 
that is the result of a trial procedure must be recorded as an AE. 
Surgical/investigational procedures are not AEs.  The medical reason for the procedure is 
the AE.  Elective hospitalizations for pretrial existing conditions or elective procedures 
are not AEs.  An exception may be if the patient has an AE during hospitalization that 
prolongs his or her scheduled hospital stay, in which case it would be considered a SAE 
(refer to Section 12.2). 
If reporting a fatal event, the SAE term should be the underlying cause of the death 
(e.g., disease or medical condition leading to death). 
12.1.2 
Investigator 
The term investigator refers to the trial PI or a formally delegated trial physician. 
12.2 
Serious Adverse Events 
During clinical investigations, AEs may occur that, if suspected to be IMP related, might 
be significant enough to lead to important changes in the way the IMP is developed 
(e.g., change in dose, population, monitoring need, or consent forms).  This is particularly 
true for events that threaten life or function.  Such SAEs will be reported promptly to 
regulatory authorities, applicable IRBs/IECs, and investigators (expedited reporting) by 
GW. 
An AE must only be classed as serious, i.e., an SAE, when the event falls into one of the 
following criteria: 
x Results in death 
x Is life-threatening* 
x Requires inpatient hospitalization or prolongation of existing hospitalization 


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x Results in persistent or significant disability/incapacity 
x Is a congenital anomaly/birth defect 
x Is medically significant** 
*The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event that, 
hypothetically, might have caused death if it were more severe. 
**Medical and scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations.  Important medical events may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These should also usually be considered serious.  Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
development of drug dependency or drug abuse, or positive COVID test. 
12.3 
Reporting Procedures for Serious Adverse Events 
All SAEs occurring during the trial must be reported to GW with any other supporting 
information and recorded in the AE section of the eCRF.  Any ongoing SAEs should be 
followed up until resolution wherever possible.  For all deaths, the working diagnosis or 
cause of death as stated on a death certificate, available autopsy reports, and relevant 
medical reports should be sent to GW promptly. 
All SAEs must be recorded in the eCRF within 24 hours of discovery or notification 
of the event.  The GW Pharmacovigilance Department (PVD) will be automatically 
notified that an SAE has been recorded.  Any additional information required for a case 
(follow-up or corrections to the original case) will be requested by GW PVD through 
eCRF queries. 
The investigator is not obliged to actively monitor for any new SAEs that occurred after 
the last formal Safety Follow-up Visit (Visit 10).  However, if the investigator becomes 
aware of any deaths or a new IMP-related SAE occurring within 28 days of the final dose 
of IMP, these should be reported to the GW PVD. 
Any other problem discovered after Visit 10 that is deemed to be an unexpected safety 
issue and is likely to have an impact on patients who have taken part in the trial must be 
treated as an SAE and reported to the GW PVD.  Such posttrial SAEs do not need to be 


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recorded on the patient’s eCRF if editing rights to the eCRF have been removed due to 
final trial database lock.  GW PVD may request safety follow-up information after the 
final trial visit in order to investigate a potential safety issue. 
Contact details for the GW PVD are provided at the front of the site files for all trial site 
and upon completion of the GW SAE report form. 
12.4 
Pregnancy 
Any patient, or patient’s partner, who has become pregnant while receiving the IMP, or 
within 3 months of the last dose of IMP, must be reported to the GW PVD.  Where 
possible, the investigator should provide the outcome of the pregnancy. 
All pregnancies must be recorded in the eCRF within 24 hours of awareness.  The GW 
PVD will be automatically notified that a pregnancy has been recorded.  Any additional 
information required for a case (follow-up or corrections to the original case) will be 
requested by GW PVD through eCRF queries. 
The investigator is not obliged to actively monitor for any pregnancies that commence 
more than 3 months after the final dose of IMP.  However, if the investigator becomes 
aware of a new pregnancy outside this time limit, then he/she should report it as above.  
The GW PVD will follow up for all pregnancy outcomes. 
12.5 
Causality Assessment 
Causality assessment is required for all AEs and SAEs.  Causality assessment must only 
be assigned by the investigator.  All cases judged as having a reasonable suspected causal 
relationship to the IMP must be reported as such.  The expression “reasonable causal 
relationship” is meant to convey in general that there are facts (evidence) or arguments to 
suggest a causal relationship. 
The following question, which must be answered by the investigator for all AEs, is used 
to capture the reasonable causal relationship of an event to the IMP: 
“In your opinion, is there a plausible relationship to the IMP?” The answer is either 
“yes” or “no.” 
Events that start before the first dose of IMP (pretreatment) should be considered as not 
causally related.  Where a pretreatment event worsens in severity following the first dose 
of IMP, a new event record should be entered into the eCRF. 


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Considering the explanation given above, investigators are strongly encouraged to 
express their opinion on what the cause of an AE might be.  For individual patients, the 
investigator is usually in the best position to assess the underlying suspected cause of an 
AE.  For all AEs and especially SAEs, it is important that the investigator assess not only 
the possible role of the IMP but also other potential contributing factors.  Factors for 
consideration of the underlying cause may include the following: 
x Medical and disease history 
x Lack of efficacy/worsening of treated condition 
x Concomitant or previous treatment 
x Withdrawal of IMP 
x Protocol-related procedure 
12.6 
Reporting Procedures for All Adverse Events 
All AEs (including SAEs) occurring during the trial will be reported on the running logs 
in the AE section of the eCRF.  This includes all events from the time following 
Screening (Visit 1) up to and including the Safety Follow-up Visit (Visit 10), whether or 
not attributed to IMP and observed by the investigator or patient. 
The following information will need to be provided for all AEs: 
A) 
Adverse Event (Diagnosis or Syndrome if Known or Signs and Symptoms) 
Where the investigator cannot determine a diagnosis, signs or symptoms should be 
recorded in the AE section of the eCRF.  Once a diagnosis has been determined, the AE 
section of the eCRF must be updated to reflect the diagnosis in replacement of the 
original symptoms.  In circumstances where only a provisional diagnosis is possible 
(working diagnosis), the eCRF must be updated to reflect the provisional diagnosis in 
replacement of the original symptoms.  In some circumstances, it may be relevant for the 
investigator to include the symptoms alongside the diagnosis in the verbatim event 
description.  However, the diagnosis (full or provisional) should be clearly stated, 
e.g., symptom due to disease (i.e., weakness due to cancer, tremor due to MS, headache 
and fever due to pneumonia, and generalized weakness due to hepatic cancer 
progression). 
B) 
Adverse Event Start Date and Stop Date 
The start and stop dates of the event must be provided.  All AEs require these fields to be 
completed in full.  Partial dates or missing dates are not normally acceptable, and 


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significant effort must be undertaken to obtain any unknown information.  If a precise 
date is not known, an estimated date should be provided instead.  When a complete date 
cannot be given, much information as possible (i.e., month and year or, in exceptional 
circumstances, just year) should be recorded.  When the actual start date becomes known, 
the eCRF must be updated to replace the previously recorded date. 
C) 
Outcome 
The outcome of the event must be recorded accurately and classified into one of the 
following categories: 
x Recovered/Resolved 
x Recovered/Resolved with Sequelae 
x Not Recovered/Not Resolved 
x Fatal 
D) 
Severity 
When describing the severity of an AE, the terms mild, moderate, or severe should be 
used.  Clinical judgment should be used when determining which severity applies to any 
AE. 
If the severity of an AE fluctuates day-to-day, e.g., a headache or constipation, the 
change in severity should not be recorded each time; instead, only the worst observed 
severity should be recorded with AE start and stop dates relating to the overall event 
duration, regardless of severity. 
A severe AE is not the same as an SAE.  For example, a patient may have severe 
vomiting, but the event does not result in any of the SAE criteria above.  Therefore, it 
should not be classified as serious. 
E) 
Causality 
See Section 12.5 above. 
F) 
Action Taken with Trial Medication 
This question refers to the action taken with the IMP due to an AE.  The action with the 
IMP must be classed as follows: 
x Dose Not Changed 
x Dose Reduced 
x Drug Interrupted 
x Drug Withdrawn 


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12.7 
Follow-up Procedures for Adverse Events 
The investigator may be asked to provide follow-up information to the GW PVD for any 
AEs reported or during the investigation of potential safety issues.  Such requests for 
additional safety information may occur after Visit 10, after the trial. 
AEs considered related to the IMP by the investigator or the sponsor should be followed 
up until resolution or the event is considered stable. 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the patient’s withdrawal from treatment.  A patient may also 
voluntarily withdraw from treatment due to what he or she perceives as an intolerable 
AE.  Further details of withdrawal are presented in Section 10.  If either of these occurs, 
the patient must undergo an end-of-treatment assessment and be given appropriate care 
under medical supervision until symptoms cease or the condition becomes stable.  If a 
safety concern is identified following withdrawal of a patient, GW may contact the 
investigator for additional follow-up information. 
12.8 
Potential Cases of Drug-induced Liver Injury 
All trial sites are required to submit to the GW PVD the laboratory results of any patient 
after randomization who meets the criteria for the following selected laboratory 
parameters:  
x ALT or AST > 3 u ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
x ALT or AST > 8 u ULN 
x ALT or AST > 5 u ULN for more than 2 weeks 
x ALT or AST > 3 u ULN and (TBL > 2 u ULN or INR > 1.5 
These reports must be sent to the GW PVD via email within 24 hours of awareness of the 
results (see Appendix 2 for GW PVD contact details).  In addition, a copy of the patient’s 
baseline laboratory results together with all reports must be sent to the GW PVD.  Any 
laboratory results that constitute an AE in the investigator’s opinion must be recorded in 
the eCRF.  Where the results are considered to be SAEs, these must be recorded in the 
eCRF within 24 hours of becoming aware of the result, in line with reporting procedures 
for SAEs (Section 12.3). 
Abnormal values in AST and/or ALT concurrent with abnormal elevations in TBL that 
meet the criteria outlined above are considered potential cases of drug-induced liver 


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injury and will be considered as protocol-defined criteria for IMP discontinuation and 
important medical events.  The investigator will arrange for the patient to return to the 
trial site as soon as possible (within 24 hours of notice of abnormal results) for repeat 
assessment of ALT, AST, TBL, alkaline phosphatase, gamma-glutamyl transferase, INR, 
and hematology parameter levels; detailed history; and physical examination.  Patients 
should be followed this way until all abnormalities have normalized (in the investigator’s 
opinion) or returned to the baseline state. 
Elevations in ALT or AST > 3 × ULN or TBL > 2 × ULN alone are not considered 
potential cases of drug-induced liver injury, but will be followed as detailed above, 
within 72 hours’ notice of abnormal results.  If the patient cannot return to the trial site, 
repeat assessments may be done at a local laboratory and the results sent to GW PVD. 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities, and Institutional Review Boards/Independent Ethics 
Committees 
In accordance with the EU Clinical Trials Directive, relevant parts of the FDA Code of 
Federal Regulations, and any national regulations, GW will inform investigators, 
regulatory authorities, and relevant IRBs/IECs of all relevant safety information.  This 
will include the reporting of relevant SAEs and all suspected unexpected serious adverse 
reactions (SUSARs). 
This information will be provided through 3 sources: 
1) IB15: this document is a compilation of the clinical and nonclinical safety data 
available on the IMP that are relevant to the trial.  The IB is updated annually. 
2) Development core safety information: this document forms the safety section of 
the IB15 or is updated as an addendum to the IB15.  This document is revised, if 
necessary, when new important safety information becomes available. 
3) Council for International Organizations of Medical Sciences (CIOMS) reports: 
these reports are issued every time a SUSAR is reported to GW.  These provide 
information on individual case reports and are sent to all the regulatory 
authorities, the relevant central ethics committees that have approved the trial, and 
the investigators.  As required, the investigator should notify their regional 
IRBs/IECs of SAEs or SUSARs occurring at their trial site and other AE reports, 
i.e., CIOMS reports and any additional safety documentation received from GW, 
in accordance with local procedures. 


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In the US, investigators are normally required to report promptly to their IRBs all 
unanticipated problems involving risks to patients or others, including AEs that should be 
considered unanticipated problems.  Based on current FDA guidance, the following 
clarification is provided in determining what constitutes an unanticipated problem: 
In general, an AE observed during the conduct of a trial should be considered an 
unanticipated problem involving risk to patients and reported to the IRB only if it were 
unexpected, serious, and would have implications for the conduct of the trial 
(e.g., requiring a significant, and usually safety-related, change in the protocol such as 
revising inclusion/exclusion criteria or including a new monitoring requirement, informed 
consent, or IB).  An individual AE occurrence ordinarily does not meet these criteria 
because, as an isolated event, its implications for the trial cannot be understood. 
The FDA guidance states that, accordingly, to satisfy the investigator’s obligation to 
notify the IRB of unanticipated problems, any investigators participating in a multicenter 
trial may rely on the sponsor’s assessment and provide to the IRB a report of the 
unanticipated problem prepared by the sponsor. 
GW will inform investigators, regulatory authorities, and relevant IRBs/IECs of any 
safety issues or case reports that are considered to be unanticipated and provide such 
reports as mentioned above.  It should be noted that a single SUSAR report notified to 
investigators in the trial does not necessarily constitute an unanticipated problem unless 
identified by GW in the submission cover letter. 
As a minimum, the recipient will be sent all of the above and relevant updates between 
the period from ethical approval and final database lock. 


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13 
STATISTICAL CONSIDERATIONS 
Further details of the proposed statistical analysis will be documented in a statistical 
analysis plan (SAP), which will be produced prior to unblinding of the trial.  Any 
deviations from the original SAP will be described in the final clinical study report. 
13.1 
Sample Size, Power, and Significance Levels 
Approximately 26 patients will be randomly assigned to each treatment sequence to 
ensure that at least 46 patients in total complete the 2 treatment periods.  If more than 6 
patients withdraw from the trial, additional patients will be enrolled to have 46 
completers. 
The primary comparison will be the estimate of the mean treatment difference between 
nabiximols and placebo in the mean change from baseline in Lower Limb Muscle Tone-6 
(LLMT-6). 
Assuming a standard deviation of the paired differences between nabiximols and placebo 
of 0.71 and a treatment difference of í0.30, 46 patients will provide 80% power using a 
5% significance level and a two-sided test.  Adjusting for 10% dropout, a total of 
approximately N=52 patients is required. 
SAS software version 9.4 was used to perform the sample size calculations. 
13.2 
Interim Analysis 
A blinded assessment of the estimate of the variability of the treatment difference will be 
conducted during the study and the sample size recalculated based on this blinded 
estimate.  The blinded sample size re-estimation (at 50% completers) may inform an 
increase in sample size while the trial is ongoing without the need for a protocol 
amendment, provided that the total sample size does not increase more than 2-fold over 
the number of enrolled currently specified in the protocol.  The power may be increased 
up to 90% depending upon the sample size re-assessment. 
13.3 
Analysis Sets 
The following analysis sets will be used for the statistical analysis: 


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Full Analysis Set 
x All patients who signed the informed consent and were randomized, received at 
least 1 dose of IMP in the trial, and have post-baseline efficacy data will be 
included and analyzed according to their randomized treatment.   
x The Full Analysis Set (FAS) is the primary analysis set for all efficacy endpoints. 
Pharmacokinetic Analysis Set 
x All patients who have received at least 1 dose of IMP and provided sufficient 
bioanalytical data to calculate reliable (based on the judgement of the 
pharmacokineticist) estimates of the PK parameters will be included in the PK 
Analysis Set. 
Safety Analysis Set 
x All patients who received at least 1 dose of IMP in the trial will be included in the 
Safety Analysis Set and analyzed according to the treatment received.  Only 
patients for whom it has been confirmed that they did not take IMP will be 
excluded from the Safety Analysis Set.  The Safety Analysis Set will be used to 
report all safety data. 
Per Protocol Analysis Set 
If there are a sufficient number of significant protocol deviations in the trial, a Per 
Protocol (PP) Analysis Set may also be presented.  The PP Analysis Set is defined as 
follows: 
A subset of the FAS that includes all patients who have completed the trial with 
no major protocol deviations deemed to compromise the assessment of efficacy.  
Major protocol deviations will be identified and fully defined prior to unblinding 
of the trial.  The PP analysis will only be conducted on efficacy endpoints and 
patients analyzed according to their randomized treatment. 
13.3.1 
Protocol Deviations 
Protocol deviations will be listed, and reasons for exclusion from the analysis sets (for 
major protocol deviations) will be summarized. 
13.4 
General Considerations 
Unless stated otherwise, continuous variables will be summarized showing the number of 
non-missing values (n), mean, SD, median, minimum, and maximum.  Categorical 


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variables will be summarized showing the number and percentage of patients falling in 
each category. 
For patient electronic diary-based endpoints, baseline is defined as the average of the last 
7 days of electronic diary entries prior to randomization (Visit 2). 
For clinic-based endpoints, baseline is defined as the last record or measure collected 
prior to the first dose of IMP in each treatment period. 
13.5 
Accountability and Background Characteristics 
13.5.1 
Enrollment and Disposition 
All patients (screened, received IMP, prematurely terminated IMP, etc.) will be 
accounted for in the enrollment and disposition summary tables. 
13.5.2 
Baseline and Demographic Characteristics 
Age, sex, race (per local data protection laws), and other demographic or baseline 
characteristics will be summarized by treatment sequence using appropriate summary 
statistics.  There will be no formal comparison of baseline data. 
13.5.3 
Medical History 
Previous and current medical conditions will be summarized by system organ class 
(SOC) and preferred term (PT) by treatment sequence. 
13.5.4 
Concomitant Medication 
Prior medication will be summarized by treatment sequence and concomitant medications 
taken during the trial will be summarized by treatment period. 
13.6 
Endpoints and Statistical Methods 
The primary efficacy endpoint will be analyzed as detailed in Section 13.6.2.  The 
secondary efficacy endpoint will be analyzed as detailed in Section 13.6.3.  The 
exploratory efficacy endpoints will be analyzed as detailed in Section 13.6.4.  The PK 
data will be summarized as detailed in Section 13.6.5.  Safety endpoints will be 
summarized as detailed in Section 13.6.6. 


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13.6.1 
Evaluable Period 
The evaluable period starts on the day of randomization.  The end of the evaluable period 
is defined as the Safety Follow-up Visit (Visit 10). 
13.6.2 
Primary Endpoint 
The primary endpoint is the change in LLMT-6 from Day 1 predose to Day 21 and from 
Day 31 predose to Day 51.  The MAS scores are transformed using the following 
algorithm: MAS untransformed [to MAS transformed] scores; 0[0], 1[1], 1+[2], 2[3], 
3[4], and 4[5]. 
The primary estimand is the mean treatment difference (nabiximols í placebo) in the 
mean change from baseline in LLMT-6 from Day 1 (predose) to Day 21 and from Day 31 
(predose) to Day 51 for all randomized patients. 
For any given patient, at a given visit, the LLMT-6 will be set to missing if individual 
MAS transformed scores are missing for 3 or more of the 6 specified muscle groups. 
The change from baseline in LLMT-6 will be analyzed using a linear mixed-effects 
model for crossover data.  The model will include a period level LLMT-6 baseline 
covariate, and treatment, period, and treatment sequence as fixed effects, and patient 
nested within treatment sequence as a random effect.  Mean change from baseline in 
LLMT-6 will also be summarized by treatment sequence, over time. 
The least squares mean estimates for each treatment, along with the standard error and 
95% confidence intervals (CIs), will be presented.  In addition, estimate of the mean 
treatment difference in change from baseline in LLMT-6 will be presented along with 
standard errors of the difference and 95% CIs. 
If the data appear to not be normally distributed, alternative approaches such as 
transformation of the data and nonparametric analyses may be considered to express 
treatment effects.  This will be specified in detail in the SAP. 
Further details of statistical analyses will be elaborated in the SAP. 
13.6.3 
Secondary Efficacy Endpoint 
The change in Lower Limb Muscle Tone-4 (LLMT-4; defined as the average of the 
4 individual MAS transformed scores of knee flexors and knee extensors on both sides of 
the body) from Day 1 predose to Day 21 and from Day 31 predose to Day 51 will be 
analyzed in a similar way to the primary endpoint. 


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For any given patient, at a given visit, the LLMT-4 will be set to missing if individual 
MAS transformed scores are missing for 2 or more of the 4 specified muscle groups.  To 
control for Type 1 error, the primary efficacy endpoint and the secondary efficacy 
endpoint will be tested hierarchically, starting with the primary efficacy endpoint and 
followed by the secondary efficacy endpoint.  No adjustments for multiplicity will be 
made for other secondary or exploratory endpoints. 
13.6.4 
Exploratory Efficacy Endpoints 
The exploratory endpoints are as follows: 
x Difference between treatments in the change in Timed 25-Foot Walk (T25FW) 
test from Day 1 predose to Day 21 and from Day 31 predose to Day 51 
x Difference between treatments in average 11-point NRS spasticity score over the 
last 7 days of each double-blind treatment period 
x Difference between treatments in average daily spasm count over the last 7 days 
of each double-blind treatment period 
x Difference between treatments in total and subdomain scores of the MSSS-88 at 
the end of the maintenance-dose phase of each double-blind treatment period 
 
These endpoints will be analyzed using the methods used for the primary endpoint 
described in Section 13.6.2 and this will be detailed in the statistical analysis plan. 
13.6.5 
Pharmacokinetics 
Plasma concentration for THC and its relevant metabolites (11-OH-THC and 
11-COOH-THC) and CBD and its relevant metabolites (7-OH-CBD and 7-COOH-CBD) 
will be summarized by treatment period together with any estimates of PK parameters. 
This data will undergo a population PK analysis and will be presented in a stand-alone 
report. 
13.6.6 
Safety 
The safety endpoints are listed below and will be compared with placebo as detailed in 
the following subsections:  
x Frequency of TEAEs 


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x Change from baseline to each assessment timepoint by treatment period for the 
following: 
x Clinical laboratory parameters 
x Vital signs 
x Physical examination procedures 
x 12-Lead ECGs 
x Columbia-Suicide Severity Rating Scale (C-SSRS) will be summarized at 
screening, and at each subsequent timepoint with reference to the last assessment 
(since last visit) 
13.6.6.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized. 
13.6.6.2 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 
A TEAE is one that started, or worsened in severity or seriousness, following the first 
dose of IMP. 
Descriptive presentations of TEAEs will be given by PT and SOC for the Safety Analysis 
Set.  The number of patients reporting at least 1 TEAE will be provided. 
The following summaries will be produced at a minimum: 
x All-causality TEAEs 
x Treatment-related TEAEs 
x All-causality TEAEs by maximal severity 
x All-causality serious TEAEs 
x Treatment-related serious TEAEs 
x TEAEs reported as leading to permanent cessation of IMP 
x Fatal TEAEs 
13.6.6.3 
Clinical Laboratory Data 
Clinical laboratory data at Screening, during, and at the end of treatment and the change 
from baseline to end of treatment will be summarized for the Safety Analysis Set using 
appropriate summary statistics.  Categorical shift tables will also be presented showing 


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the numbers of patients with values outside the normal range.  Changes from baseline to 
each visit will be summarized. 
13.6.6.4 
Vital Signs, 12-Lead Electrocardiogram, Physical Examination, 
and Other Safety Data 
Vital signs, 12-lead ECG, physical examination, and C-SSRS data will be summarized 
for the Safety Analysis Set at screening, baseline, and each time point during the 
treatment period using appropriate summary statistics, as applicable.  Changes in vital 
signs from baseline to each assessment post-baseline will also be summarized. 


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14 
DATA SAFETY MONITORING COMMITTEE 
There will not be a data safety monitoring committee involved in this trial. 


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15 
REGULATORY AND ETHICAL OBLIGATIONS 
15.1 
Declaration of Helsinki 
The investigator will ensure that this trial is conducted in full conformity with the current 
version and subsequent amendments of the Declaration of Helsinki, the ICH Tripartite 
Guideline for GCP Topic E6(R2), the EU Clinical Trials Directive, the EU GCP 
Directive, and the clinical trial regulations adopting European Commission Directives 
into national legislation. 
15.2 
Informed Consent 
Initial master informed consent will be prepared by GW and provided to the investigator, 
who will tailor this for their trial site by adding the site’s contact details and by using 
headed paper.  The GW clinical manager will communicate updates to the template by 
letter.  The written informed consent document should be prepared in the language(s) of 
the potential patient population. 
Before a patient’s involvement in the trial, the investigator is responsible for obtaining 
written informed consent from the patient after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the trial and before any 
trial-specific procedures are performed or any patient-related data are recorded for the 
trial.  The patient must have ample time to consider the information provided before 
giving written consent.  More specific definitions of “ample time” may be in force if 
required by IRBs/IECs or local regulations. 
The acquisition of informed consent must be documented in the patient’s medical 
records, and the ICF must be signed and personally dated by the patient and by the person 
who conducted the informed consent discussion.  The original signed ICF should be 
retained and a copy should be provided to the patient. 
15.3 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICFs, master ICF, other patient information material, 
any proposed advertising material, and any further documentation requested must be 
submitted to the IRB/IEC for written approval.  GW must receive a copy of the written 
approval of the appropriate version of the protocol and ICF before recruitment of patients 
into the trial and shipment of IMP. 


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The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent document.  
The investigator must notify the IRB/IEC of deviations from the protocol, SAEs 
occurring at the trial site, and other AE reports received from GW, in accordance with 
local procedures. 
The investigator will be responsible for obtaining ongoing IRB/IEC approval/renewal 
throughout the duration of the trial.  Copies of the investigator’s reports and the IRB/IEC 
continuance of approval must be sent to GW. 
15.4 
Pretrial Documentation Requirements 
The investigator is responsible for forwarding the following documents to GW for review 
before allowing any patients to consent for entry into the trial: 
x Signed and dated protocol signature page 
x Copy of IRB/IEC-approved ICF (including version number and date) and other 
patient information material 
x Copy of the IRB/IEC approval of the protocol, ICF (including version number 
and date), and other patient information material 
x Up-to-date curricula vitae and medical licenses (per local regulations) of the PI 
and all subinvestigators 
x The IRB/IEC composition and/or written statement of the IRB/IEC in compliance 
with the FDA regulations relating to GCP and clinical trials, the EU Clinical 
Trials Directive, the EU GCP Directive, or the ICH Tripartite Guideline for GCP 
Topic E6(R2), where the EU Clinical Trials and GCP Directives do not apply 
x Signed and dated laboratory normal ranges and documentation of laboratory 
certification (or equivalent) unless using central laboratory arranged by GW 
x Signed and dated clinical trial agreement (including patient/investigator indemnity 
insurance and financial agreement) 
x Form FDA 1572, if required 
x Drug Enforcement Administration license (where applicable) 
x Completed financial disclosure statements for the PI and all subinvestigators, if 
relevant 
GW will ensure that the trial site is informed of when screening of patients can 
commence.  


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15.5 
Patient Confidentiality 
The investigator must ensure that the patient’s anonymity is maintained.  In the eCRFs 
and within electronic data capture databases used to collect the trial data or other 
documents submitted to GW, patients should be identified by their initials and race (if 
allowed per local regulations) and their trial screening number only.  Documents that are 
not for submission to GW, e.g., signed ICFs, should be kept in strict confidence by the 
investigator. 
In compliance with the FDA regulations relating to GCP and clinical trials and the EU 
Clinical Trials Directive/ICH Tripartite Guideline for GCP Topic E6(R2), it is required 
that the investigator and institution permit authorized representatives of the company, the 
regulatory authorities, and the IRB/IEC to have direct access to review the patient’s 
original medical records for verification of trial-related procedures and data.  Direct 
access includes examining, analyzing, verifying, and reproducing any records and reports 
that are important to the evaluation of the trial.  The investigator is obligated to inform 
the patient that his or her trial-related records will be reviewed by the above-named 
representatives without violating the confidentiality of the patient. 
All information concerning the IMP and operations of GW such as patent applications, 
formulae, manufacturing processes, basic scientific data, or formulation information 
supplied to the investigator by the company and not previously published is considered 
confidential by the company and shall remain the sole property of the company.  The 
investigator will agree to use this information only in accomplishing the trial and will not 
use it for any other purposes without the written consent of the company. 


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Clinical Protocol Template (Phase 2–4)  
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16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
16.1 
Protocol Amendments and End of Trial or Termination 
Protocol amendments must be made only with the prior approval of GW.  Agreement 
from the investigator must be obtained for all protocol amendments and amendments to 
the informed consent document.  The IRB/IEC and regulatory authorities must be 
informed of all amendments and give approval for any substantial amendments.  
Amendments for administrative changes can be submitted to the IRB/IEC for information 
only.  The investigator must send a copy of the approval letter from the IRB/IEC to GW. 
Both GW and the investigator reserve the right to terminate the trial according to the 
clinical trial agreement.  The investigator must notify the IRB/IEC in writing of the trial’s 
completion or early termination and send a copy of the notification to GW. 
16.2 
Trial Documentation and Storage 
The investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated trial duties.  All persons authorized to make entries in and/or corrections to 
eCRFs will be included on the GW Delegation of Authority and Signature form. 
Source documents are original documents, data and records containing all 
protocol-specified information from which the patient’s eCRF data are obtained.  These 
include, but are not limited to, hospital records, clinical and office charts, laboratory and 
pharmacy records, diaries, microfiches, radiographs, and correspondence.  A source data 
verification plan, identifying the source for each data point at each trial site, will be 
agreed upon with each trial site prior to patient recruitment.  In the rare situations of data 
being recorded directly into the eCRF in error, then the source data from the eCRF should 
be transcribed into the patient’s notes with appropriate signature and date to provide a full 
audit trail. 
The investigator and trial staff are responsible for maintaining a comprehensive and 
centralized filing system of all trial-related, essential documentation (as outlined in the 
ICH Tripartite Guideline for GCP Topic E6(R2), Section 8.2), suitable for inspection at 
any time by representatives from GW and/or applicable regulatory authorities.  Elements 
should include the following: 
x Patient files containing completed eCRFs, ICFs, and supporting copies of source 
documentation 


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x Trial files containing the protocol with all amendments, IB, copies of pretrial 
documentation (see Section 15.4), and all correspondence to and from the 
IRB/IEC and GW 
x Enrollment log of all patients who consented to take part in the trial 
x Screening and recruitment log of all patients screened and whether or not they 
were recruited into the trial (i.e., randomized and/or dosed with IMP) 
x Proof of receipt, IMP accountability record, return of IMP for destruction, final 
IMP reconciliation statement, and all drug-related correspondence 
In addition, all original source documents supporting entries in the eCRFs and electronic 
diary data must be maintained and be readily available. 
Following completion or termination of a clinical trial, GW will initiate proper archive of 
clinical trial-related documentation and electronic records generated by the investigator 
and/or GW.  All clinical trial-related documents and electronic records will be retained 
within an archiving system for a period dependent on need and for a minimum of 
25 years.  Essential documents must be retained until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the IMP.  These 
documents must be retained for a longer period, however, if required by the applicable 
regulatory requirements or if needed by GW. 
GW will inform the investigators for each trial site in writing of the need for record 
retention.  No trial document may be destroyed without prior written agreement between 
GW and the investigator.  Should the investigator wish to assign the trial records to 
another party or move them to another location, he/she must notify GW in writing of the 
new responsible person and/or the new location. 
16.3 
Trial Monitoring and Data Collection 
The GW representative and regulatory authority inspectors are responsible for contacting 
and visiting the investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the trial, e.g., eCRFs and other pertinent data, provided 
that patient confidentiality is respected. 
The GW trial monitor, or designee, is responsible for inspecting onsite or remotely the 
eCRFs and available electronic diary data at regular intervals throughout the trial to 
verify adherence to the protocol, completeness, accuracy, and consistency of the data and 


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Clinical Protocol Template (Phase 2–4)  
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adherence to local regulations on the conduct of clinical research.  The trial monitor must 
have direct or remote access to patient medical records and other trial-related records 
needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the trial monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
To ensure the quality of clinical data across all patients and sites, a clinical data 
management review will be performed on patient data received at GW or a contract 
research organization (CRO).  During this review, patient data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol and FDA regulations, ICH Tripartite Guideline for 
GCP Topic E6(R2), and all other applicable regulatory requirements.  To resolve any 
questions arising from the clinical data management review process, data queries and/or 
site notifications will be sent to the trial site for completion and then returned to GW or 
the CRO, as applicable. 
16.4 
Quality Assurance 
In accordance with the FDA regulations, EU Clinical Trials Directive/ICH Tripartite 
Guideline for GCP Topic E6(R2), and the sponsor’s audit plans, representatives from 
GW’s Clinical Quality Assurance Department may select this trial for audit.  Inspection 
of site facilities (e.g., pharmacy, drug storage areas, and laboratories) and review of 
trial-related records will occur to evaluate the trial conduct and compliance with the 
protocol, the EU Clinical Trials Directive/ICH Tripartite Guideline for GCP Topic 
E6(R2), and applicable regulatory requirements. 
16.5 
Compensation 
GW will indemnify the investigator and the trial site in the event of any claim in respect 
of personal injury arising due to a patient’s involvement in the trial providing that the 
trial protocol has been adhered to.  This would include claims arising out of or relating to 
the administration of the IMP or any clinical intervention or procedure provided for or 
required by the protocol to which the clinical trial patient would not otherwise have been 
exposed, providing there is no evidence of negligence on behalf of the investigator or 
their team.  GW will not be liable for any claims arising from negligence on the part of 
the investigator or their team. 


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Clinical Protocol Template (Phase 2–4)  
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16.6 
Publication Policy 
GW recognizes that there is a responsibility under the regulatory guidelines to ensure that 
results of scientific interest arising from this clinical trial are appropriately published and 
disseminated.  They will coordinate this dissemination and may solicit input and 
assistance from the chief/PIs.  A summary of the results of this trial will be made 
available on http://www.clinicaltrials.gov and http://www.clinicaltrialsregister.eu/ (as 
applicable), as required by US and EU laws, respectively. 
Any publication of the trial data will be made in accordance with the terms of the 
Clinical Trial Agreement. 
All publications, e.g., manuscripts, abstracts, oral/slide presentations, or book chapters, 
based on this trial must be submitted to the GW Medical Writing Department and, as 
applicable, GW Publication Committee for corporate review before release.  To ensure 
adequate time for GW to make comments and suggestions where pertinent, all such 
material should be submitted to them at least 60 days prior to the date for submission for 
publication, public dissemination, or review by a publication committee.  The PIs must 
then incorporate all reasonable comments made by GW into the publication. 
GW also reserves the right to delay the submission of such information by a period of up 
to 6 months from the date of first submission to them in order to allow them to take steps 
to protect proprietary information where applicable. 
16.7 
Intellectual Property Rights 
All intellectual property rights owned by or licensed to either GW or the PIs, other than 
those arising from the clinical trial, will remain their property.  All intellectual property 
rights arising out of the clinical trial will vest in or be exclusively licensed to GW and, as 
such, the PI must promptly disclose all knowledge to GW and refrain from using such 
knowledge without the prior written consent of GW. 
16.8 
Confidential Information 
GW and the PI must ensure that only personnel directly concerned with the trial are party 
to confidential information and that any information coming to either party about the 
other during the course of the trial must be kept strictly confidential and must not be 
disclosed to any third party or made use of without the prior written consent of the other. 


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Clinical Protocol Template (Phase 2–4)  
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17 
REFERENCES 
1 
Zettl UK, Stüve O, Patejdl R.  Immune-mediated CNS diseases:  a review on 
nosological classification and clinical features.  Autoimmun Rev.  2012;11:167-73. 
2 
Kutzelnigg A, Lassmann H.  Pathology of multiple sclerosis and related inflammatory 
demyelinating diseases.  Handb Clin Neurol.  2014;122:15-58. 
3 
Browne P, Chandraratna D, Angood C, et al.  Atlas of Multiple Sclerosis 2013:  A 
growing global problem with widespread inequity.  Neurology 2014;83:1022-4. 
4 
Zettl UK, Henze T, Essner U, Flachenecker P.  Burden of disease in multiple sclerosis 
patients with spasticity in Germany:  mobility improvement study (Move 1).  Eur J 
Health Econ.  2013;15:953-66. 
5 
Svensson J, Borg S, Nilsson P.  Costs and quality of life in multiple sclerosis patients 
with spasticity.  Acta Neurol Scand.  2014;129:13-20. 
6 
Rizzo MA, Hadjimichael OC, Preiningerova J, Vollmet TL.  Prevalence and 
treatment of spasticity reported by multiple sclerosis patients.  Mult Scler.  
2004;10:589-95. 
7 
Goldenberg MM.  Multiple sclerosis review.  P T.  2012;37:175-84. 
8 
Barnes MP, Kent RM, Semlyen JK, McMullen KM.  Spasticity in multiple sclerosis.  
Neurorehabil Neural Repair.  2003;17:66-70. 
9 
Beard S, Hunn A, Wight J.  Treatments for spasticity and pain in multiple sclerosis:  a 
systematic review.  Health Technology Assessment.  2003;7:1-111. 
10 Flachenecker P, Henze T, Zettl UK.  Spasticity in patients with multiple sclerosis 
clinical characteristics, treatment and quality of life.  Act Neurol Scand.  
2004;129:154-62. 
11 Arroyo R, Massana M, Vila C.  Correlation between spasticity and quality of life in 
patients with multiple sclerosis:  the CANDLE study.  Int J Neurosci.  2013;123:850-
8. 
12 Henze T, Rieckmann P, Toyka KV.  Symptomatic treatment of multiple sclerosis.  
Multiple Sclerosis Therapy Consensus Group (MSTCG) of the German Multiple 
Sclerosis Society.  Eur Neurol.  2006;56:78-105. 
13 Kister I, Bacon TE, Chamot E, et al.  Natural history of multiple sclerosis symptoms.  
Int J MS Case.  2013;15:146-58. 
14 Arroyo R, Vila C, Clissold S.  Retrospective observational study of the management 
of multiple sclerosis patients with resistant spasticity in Spain:  the '5E' study.  Expert 
Rev Pharmacoecon Outcomes Res.  2011;11:205-13. 
15 Investigator's Brochure:  Sativex Oromucosal Spray.  GW Pharma Ltd.  Edition 22.1 
and Addendum 1, January 2020. 


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16 Leocani L, Nuara A, Houdayer E, et al.  Sativex and clinical-neurophysiological 
measures of spasticity in progressive multiple sclerosis.  J Neurol.  
2015;262(11):2520-7. 
17 Ansari NN, Naghdi S, Arab TK, Jalaie S.  The interrater and intrarater reliability of 
the Modified Ashworth Scale in the assessment of muscle spasticity:  limb and 
muscle group effect.  NeuroRehabilitation.  2008;23:231-7. 
 


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Clinical Protocol Template (Phase 2–4)  
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Appendix 1 
SCHEDULE OF ASSESSMENTS 
Period 
Screening 
Treatment Period 1 
Treatment Period 2 
Safety 
Follow-up 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
(Phone 
Call) 
Visit 4 
Visit 5a 
Visit 6 
Visit 7 
(Phone 
Call) 
Visit 8 
Visit 9 
Visit 10 
(or 7 days 
after 
final IMP 
dose or 
ET visit) 
Day/Hour  
Days -28 
to -1 
Day 1 
predose 
Day 1 
2-4 hrs 
postdose 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 21 
(±2 days) 
Day 31 
predose 
(±1 day) 
Day 31 
2-4 hrs  
postdose 
Day 38 
(±1 day)  
Day 45 
(±1 day) 
Day 51 
(±2 days) 
End of 
Treatment 
Visit 
Day 58 
(+3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Previous cannabis 
use 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Electronic diary 
training 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
Assessed at each visit 
AEs 
Assessed at each visit 
Physical 
examinationb 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Examination of 
oral mucosa 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 


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Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
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Period 
Screening 
Treatment Period 1 
Treatment Period 2 
Safety 
Follow-up 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
(Phone 
Call) 
Visit 4 
Visit 5a 
Visit 6 
Visit 7 
(Phone 
Call) 
Visit 8 
Visit 9 
Visit 10 
(or 7 days 
after 
final IMP 
dose or 
ET visit) 
Day/Hour  
Days -28 
to -1 
Day 1 
predose 
Day 1 
2-4 hrs 
postdose 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 21 
(±2 days) 
Day 31 
predose 
(±1 day) 
Day 31 
2-4 hrs  
postdose 
Day 38 
(±1 day)  
Day 45 
(±1 day) 
Day 51 
(±2 days) 
End of 
Treatment 
Visit 
Day 58 
(+3 days) 
Body weight 
measurement 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Clinical laboratory 
blood sampling 
(hematology and 
biochemistry) 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Dipstick urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
X 
Urine drug screen 
(including THC) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Serum/urine 
pregnancy test (if 
appropriate)c 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Blood THC test 
X 
 
 
 
 
 
 
 
 
 
 
 
PK blood sampling 
(IMP)d 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 


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Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
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Period 
Screening 
Treatment Period 1 
Treatment Period 2 
Safety 
Follow-up 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
(Phone 
Call) 
Visit 4 
Visit 5a 
Visit 6 
Visit 7 
(Phone 
Call) 
Visit 8 
Visit 9 
Visit 10 
(or 7 days 
after 
final IMP 
dose or 
ET visit) 
Day/Hour  
Days -28 
to -1 
Day 1 
predose 
Day 1 
2-4 hrs 
postdose 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 21 
(±2 days) 
Day 31 
predose 
(±1 day) 
Day 31 
2-4 hrs  
postdose 
Day 38 
(±1 day)  
Day 45 
(±1 day) 
Day 51 
(±2 days) 
End of 
Treatment 
Visit 
Day 58 
(+3 days) 
Electronic daily diary 
11-Point NRS 
spasticitye 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
Daily spasm 
counte 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
Use of 
antispasticity 
medicationse 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
IMP dosing 
recorde 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
MASf 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
MSSS-88 
 
 
 
 
 
X 
 
 
 
 
X 
 
T25FW testg 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
C-SSRS 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
IMP dosing 
training 
 
X 
 
 
 
 
 
 
 
 
 
 
IMP dosingh 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
IMP dispensingi 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
IMP collection and 
compliance review 
 
 
 
 
X 
X 
 
 
 
X 
X 
 


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EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
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AE = adverse events; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; IMP = investigational medicinal product; MAS = Modified Ashworth 
Scale; MS = multiple sclerosis; MSSS-88 = Multiple Sclerosis Spasticity Scale; NRS = Numerical Rating Scale; PK = pharmacokinetics; T25FW = Timed 25-Foot Walk; 
THC = ǻ9-tetrahydrocannabinol. 
a A washout period of at least 7 days will separate the 2 treatment periods.  Following the final dose of IMP in Treatment Period 1, in the morning of Visit 5 (Day 21), patients 
will discontinue treatment with IMP for the 7 days prior to Visit 6 (Day 31).  During the washout period, patients will continue to take their current MS antispasticity 
medications without any changes in dose. 
b A comprehensive physical examination, including an assessment of height, will be completed at Screening (Visit 1) only; subsequent physical examinations will be 
symptom-directed. 
c Serum pregnancy test at Visits 1 and 10; urine pregnancy test at Visits 2 and 6 (predose).  
d On the day before PK blood sampling at Visits 4, 5, 8, and 9, patients will be prompted to record whether they started their morning and evening doses of IMP within 
30 minutes of a snack or meal.  On the day of PK blood sampling, the exact time and date of PK blood sampling and the time of the patient’s snacks and meals should be 
recorded.  See Section 9.2.12.1 for the PK blood sampling schedule.  Please note that more than one PK sample may be collected at distinct time points during a single 
visit. 
e Patients will record their 11-point NRS spasticity score, spasm count, and use of antispasticity medications in an electronic diary once daily, around the same time each day, 
preferably in the evening before retiring to sleep, for at least 7 days prior to Visits 2 and 6 and throughout the trial until Visit 9.  Investigational medicinal product dosing 
will be recorded by the patient in an electronic diary from Visits 2 through 9. 
f MAS assessments will occur at Visit 1 (Screening) and at scheduled time points before (Visits 2 and 6 [predose]) and after (Visits 2, 5, 6, and 9 [3 hours ± 15 minutes 
postdose]) IMP administration; for Visits in which the morning dose consists of more than 1 spray (Visits 5 and 9), postdose assessments will occur 3 hours ± 15 minutes 
after the first spray of the morning dose. 
g Non-ambulatory patients are not expected to perform the T25FW test. 
h IMP administration of the morning dose will occur at the trial site within 30 minutes after a standardized snack containing at least 300 kcal (of which approximately 30 kcal is 
composed of fat) under the supervision of site staff.  On the days of scheduled MAS assessments other than Visit 1, patients who are taking baclofen and/or tizanidine as part 
of their optimized antispasticity therapy should take their regular morning dose of either or both medication(s) at least 1 hour before administration of IMP.  IMP will not be 
administered in the evening of Days 21 and 51. 
i In cases where patients are not able to attend study visits due to the presence of an infectious disease or other transmissible condition, the investigator will discuss with the 
Sponsor potential mitigation approaches for IMP dispensing, secure delivery, and collection. 
 


Study Code: GWSP19066 
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EudraCT Number: 2019-002625-29 
Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
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Appendix 2 
TRIAL PERSONNEL 
Appendix 2.1 
Investigator Details 
At the time of protocol production, the participating investigators have not been 
confirmed.  A list of all investigators will be maintained within the GW master files 
(electronically and added to the trial master file at the end of the trial). 
Appendix 2.2 
Sponsor Contact Details 
Pharmacovigilance Department 
Email: pvd@gwpharm.com 
Fax: +44 (0)1223 233 319 
USA Toll-free Fax: 
+1-866-234-1751 
Tel: +44 (0)1223 233 410 
Sponsor: 
GW Pharma Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
Tel: +44 (0) 1223 266 800 
Fax: +44 (0) 1223 235 667 
Medical Advisor & Clinical Project 
Manager: 
Please refer to the Sponsor and 
Related Contact Details form in the 
trial site file. 
Clinical Trial Supplies: 
G-Pharm Ltd 
Tel: +44 (0) 1795 435 029 
Fax: +44 (0) 1795 475 439 
 
Appendix 2.3 
Contract Research Organizations 
At the time of protocol production, the contract research organizations, and the central 
and bioanalytical laboratories for the trial had not been confirmed.  A corresponding 
list will be maintained within the GW master files (electronically and added to the 
trial master file at the end of the trial). 
 
 


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Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Appendix 3 
QUESTIONNAIRES/ASSESSMENTS 
At the time of protocol finalization, questionnaire/assessment licensing has not yet 
been obtained.  Copies of the questionnaires/assessments will be made available to all 
investigators. 
 
 


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Protocol V4 02 September 2021 
 
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Clinical Protocol Template (Phase 2–4)  
V1, 24Sep15 
Appendix 4 
PROHIBITED MEDICATIONS SOLELY 
METABOLIZED BY UGT1A9 AND UGT2B7 
Examples of medications that are solely metabolized by UGT1A9 and UGT2B7 and 
prohibited for the duration of the trial are provided in the sections below. 
Appendix 4.1 
Prohibited Medications Metabolized Solely by 
UGT1A9 
x Flavopiridol 
x Propofol 
 
Appendix 4.2 
Prohibited Medications Metabolized Solely by 
UGT2B7 
x Benoxaprofen 
x Carbamazepine 
x Codeine 
x Cyclosporin A 
x Epirubicin 
x Indomethacin 
x Tacrolimus 
x Tiaprofenic acid 
x Zaltoprofen 
x Zomepirac 
x Zidovudine 

SAP_001.pdf: 
Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 1 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
Statistical Analysis Plan (SAP)
Protocol Title:
Randomized, Double-blind, Placebo-controlled, 2-way Crossover Trial 
to Evaluate the Effect of Nabiximols Oromucosal Spray on Clinical 
Measures in Patients with Multiple Sclerosis 
Protocol Version No./Date:
V4.0 / 02-Sept-2021
CRF Version No./Date:
V4.1 / 28-April-2022
SAP Version No./Date:
Final / 06-June-2022
Approvals
Sponsor
Sponsor Name:
GW PHARMA LIMITED
Representative / Title:
Contract Statistician
Signature / Date:
Representative / Title:
Senior Medical Director
Signature / Date:
PRA
Biostatistician / Title:
 Senior Principal Biostatistician
Signature / Date:
(NOTE: Electronic Signatures should only be used if all parties have the ability to eSign.)
PI
PI
PI
PI
PI
PI
PI


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 2 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
Change History
Version/Date
Change Log
1.0
Created as new
2.0
Added clarification to efficacy models as to model checking technique by reduction to 
using only unstructured/compound symmetry covariance structures.
Final
1) Updated to clarify tipping point instructions
2) eGFR to be presented as collected on eCRF and derivation removed
3) Section 12.3.1.2 MP dosing additional summaries added to titration phase and 
maximal presentation change to mode.
4) Overall combine (titration + maintenance) summary added


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 3 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
Table of Contents, List of Tables and Figures
Table of Contents
Approvals
1
Change History .................................................................................................................................2
Table of Contents, List of Tables and Figures ..................................................................................3
Table of Contents....................................................................................................................................3
3.1 List of Tables.......................................................................................................................................5
3.2 List of Figures......................................................................................................................................5
Purpose
6
Scope
6
Introduction
6
6.1 Timings of Analyses............................................................................................................................6
6.2 Changes from Protocol .......................................................................................................................6
Study Objectives ...............................................................................................................................7
7.1 Primary Objectives..............................................................................................................................7
7.2 Secondary Objectives .........................................................................................................................7
7.3 Exploratory Objectives ........................................................................................................................7
Study Design7
8.1 General Design ...................................................................................................................................7
8.2 Sample Size Considerations.............................................................................................................14
8.3 Randomization ..................................................................................................................................14
Study Endpoints, Variables and Covariates ...................................................................................15
9.1 Overview ...........................................................................................................................................15
9.2 Predetermined Covariates and Prognostic Factors and other Analyzed Factors.............................16
9.3 Analysis Sets.....................................................................................................................................17
9.3.1 Treatment Arm .....................................................................................................................17
9.3.2 Definition of Analysis Sets....................................................................................................17
Conventions and Derivations ........................................................................................................18
10.1 Study Period, Reference Day, Study Day, Analysis Day and Visit Window ...................................18
10.1.1 Study Periods.....................................................................................................................18
10.1.2 Reference Day and Study Day ..........................................................................................18
10.1.3 Target Days and Visit Window...........................................................................................19
10.2 Baseline ..........................................................................................................................................23
10.3 Change from Baseline.....................................................................................................................23
10.4 Percentage Change from Baseline.................................................................................................23
10.5 Time Conversion.............................................................................................................................23
10.6 Patient Disposition ..........................................................................................................................23
10.7 Duration of Treatment .....................................................................................................................24
10.8 IMP Dosing......................................................................................................................................24
10.8.1 Study Phases Start and Stop Dates used to summarize IMP Dosing ...............................24
10.8.2 Number of Sprays Summary..............................................................................................25
10.9 Compliance .....................................................................................................................................26
10.10 Age................................................................................................................................................26
10.11 Body Mass Index...........................................................................................................................27
10.12 Disease History.............................................................................................................................27
10.13 Renal Function Formula................................................................................................................28
10.14 Prior and Concomitant Medication Start/Stop Date Imputation Rule............................................28
10.15 Mobile Health Data handling.........................................................................................................29
10.16 Modified Ashworth Scale (MAS) Transformed Score ...................................................................29
10.17 Timed 25-Foot Walk......................................................................................................................30
10.18 11-point Numerical Rating Scale Score (NRS-Spasticity Score)..................................................30
10.19 Daily Spasm Count .......................................................................................................................31
10.20 Multiple Sclerosis Spasticity Scale (MSSS-88).............................................................................31


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10.21 Adverse Events.............................................................................................................................32
10.21.1 Start and Stop Date Imputation........................................................................................32
10.21.2 COVID-19 AE...................................................................................................................33
10.21.3 Time to First Onset of AE.................................................................................................33
10.21.4 AE Duration......................................................................................................................33
10.22 Laboratory data.............................................................................................................................34
10.23 Columbia Suicide Severity Rating Scale (C-SSRS) .....................................................................34
Interim Analyses............................................................................................................................35
11.1 Blinded Sample Size Reassessment..............................................................................................35
11.2 Other Analyses................................................................................................................................36
Statistical Methods........................................................................................................................36
12.1 Patient Disposition ..........................................................................................................................37
12.2 Demographic and Baseline Characteristics....................................................................................38
12.2.1 Demographics Characteristics ...........................................................................................38
12.2.2 Baseline Physical Examination ..........................................................................................39
12.2.3 Baseline Vital Signs ...........................................................................................................39
12.2.4 Medical History...................................................................................................................39
12.2.5 Disease Characteristics .....................................................................................................39
12.2.6 Baseline Efficacy Endpoints...............................................................................................40
12.2.7 Baseline Safety Endpoints .................................................................................................41
12.3 Treatments ......................................................................................................................................41
12.3.1 Extent of Exposure.............................................................................................................41
12.3.2 Prior, Concomitant and Prohibited Therapies....................................................................43
12.4 Important Protocol Deviations.........................................................................................................46
12.5 Efficacy Analysis .............................................................................................................................47
12.5.1 Hypothesis Testing Strategy and Multiplicity .....................................................................47
12.5.2 Primary Endpoint................................................................................................................47
12.5.3 Secondary Endpoint...........................................................................................................55
12.5.4 Other Analyses based on MAS..........................................................................................56
12.5.5 Exploratory Efficacy Analysis.............................................................................................58
12.6 Pharmacokinetics............................................................................................................................61
12.7 Safety Analyses ..............................................................................................................................61
12.7.1 Adverse Events ..................................................................................................................62
12.7.2 Death, Serious Adverse Events and Other Significant Adverse Events............................64
12.7.3 Laboratory Data .................................................................................................................66
12.7.4 Vital Signs ..........................................................................................................................67
12.7.5 Physical Examination, ECGs and other Observation Related to Safety............................68
References 71
Glossary of Abbreviations .............................................................................................................72
Appendix 1
Classification of Protocol Deviations.........................................................................76
Appendix 2
Clinical laboratory parameters ..................................................................................78
Appendix 3
Unscheduled Clinical laboratory parameters ............................................................79
Appendix 4
Toxicity Criteria for Laboratory Hematology and coagulation Parameters based on 
CTCAE version 5.0 ...............................................................................................................................81
Appendix 5
Toxicity Criteria for Laboratory Biochemistry Parameters based on CTCAE version 5.0
82
Appendix 6
Abnormality Criteria...................................................................................................83
Appendix 7
Prohibited medication solely metabolized by UGT1A9 and UGT2B7 and determination 
criteria
85
Appendix 8
Prohibited medications strong CYP3A4 inducers and determination criteria ...........86
Appendix 9
Other Prohibited medications and determination criteria..........................................87
Appendix 10
Medications used in MS and determination criteria ..................................................88
Appendix 11
Adverse Drug Reaction of Special Interest – AE selections .....................................89
Appendix 12
Category of Adverse Events of Special Interest .......................................................90


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Appendix 13
Modify registry of severe cutaneous adverse reaction criteria for Drug reaction with 
eosinophilia and systemic systems (DRESS) .......................................................................................90
Appendix 13.1
Acute skin reaction......................................................................................................90
Appendix 13.2
Involvement of at least 1 internal organ ......................................................................92
Appendix 13.3
Enlarged lymph nodes of at least 2 sites ....................................................................99
Appendix 13.4
One of the following blood count abnormalities ..........................................................99
Appendix 13.5
Fever above 38 degrees Celsius ................................................................................99
Appendix 14
Overview of primary, secondary and exploratory efficacy objectives .....................100
3.1 List of Tables
Table 6.2-1 Change from protocol ................................................................................................................6
Table 8.1-1 Schedule of Assessments .......................................................................................................10
Table 8.1-2 Pharmacokinetic Blood Sample Schedule...............................................................................14
Table 9.1-1 Objectives and Endpoints ........................................................................................................15
Table 9.1-2 Estimands ................................................................................................................................16
Table 10.1-1 Longitudinal Assessment –  Analysis Day and Target Day...................................................19
Table 10.1-2 Longitudinal Assessment – Target Day and Visit Window – Part 1 ......................................21
Table 10.1-3 Longitudinal Assessment –Target Day and Visit Window – Part 2 .......................................22
Table 10.9-1 Optimized Daily Dose and Allowed Optimized Dose Range .................................................26
Table 10.14-1 Imputation Rules for Partial Medication Dates (D = day, M = month, Y = year)..................28
Table 10.16-1 Lower Limb Muscle Tone - Missing Data Handling .............................................................30
Table 10.20-1 Multiple Sclerosis Spasticity Scale - Missing Data Handling...............................................32
Table 10.21-1 Imputation Rules for Partial Adverse Events Start/Stop Dates ...........................................32
Table 12.1-1 Subgroups Applied to Patient Disposition .............................................................................37
Table 12.5-1 Scenarios for Methods of Imputation when Data are not Collected ......................................48
Table 12.5-2 Subgroup Analyses of Primary Efficacy Endpoint .................................................................54
Table 12.7-1 Subgroups applied to Safety Analysis ...................................................................................61
3.2 List of Figures
Figure 8.1-1 Trial Design and Treatment Schematic ....................................................................................9


Statistical Analysis Plan Final
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Purpose
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under GW PHARMA LIMITED Protocol GWSP19066 V4.0 dated 2nd Sept 2021.
Scope
This plan supplements the study protocol for statistical analysis related aspects.
The SAP outlines the following:
x
Study Objectives,
x
Study Design,
x
Endpoints to be Analyzed and the Analysis sets,
x
Estimands,
x
Applicable Study Definitions,
x
Statistical Methods.
Introduction
This SAP should be read in conjunction with the study protocol V4.0 2nd Sept 2021 and case report form 
(CRF) V4.1 28th April 2022. Any further changes to the protocol or CRF may necessitate updates to the 
SAP.
Final approval of the SAP by the GW and PRA statisticians will occur prior to database lock and unblinding 
of the study treatment. 
6.1 Timings of Analyses
When at least 50% (24 patients) of the patients have completed both treatment periods and before database 
lock and unblinding, a blinded estimate of the pooled variability for the primary endpoint treatment difference 
will be conducted and sample size may be re-evaluated.
Analyses of efficacy, safety, and pharmacokinetics/pharmacodynamics will be performed after all patients 
complete or terminate early from the study following database lock and unblinding.
6.2 Changes from Protocol
Table 6.2-1 Change from protocol
Section of SAP 
Affected
Type of Change
Rationale
Section 9.6.2.3,
Section 11.0, and 
Section 12.5
Change to the definition of the 
Full Analysis Set (FAS) that is
detailed in protocol Section 
13.3 
The FAS includes all patients who have taken a dose of 
investigational medicinal product (IMP). Per our specified 
estimand, patients should continue Period 1 despite 
stopping IMP. Hence, if a patient withdraws from the 
study, they should be handled as a missing data problem 
and will be imputed per this analysis plan.
Since IMP was taken, withdrawal may have been due to 
IMP and hence it may be important to include this patient 
in the analysis.
Section 7.3,
Section 9.1,
Section 10.15, and
Section 12.5
Addition of an exploratory 
objective/ endpoint, the Lower 
Limb Muscle Tone-10 to those 
presented in Protocol Section 
2 and Section 13.6.2
Since hip flexors and hip adductors are being collected 
the Lower Limb Muscle Tone-10 was added as 
exploratory endpoints 


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Study Objectives
7.1 Primary Objectives
To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on a 
clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle Tone-6; 
LLMT-6) in patients with multiple sclerosis (MS) who have not achieved adequate relief from spasticity with 
other antispasticity medications.
7.2 Secondary Objectives
x
To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on 
a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle 
Tone-4; LLMT-4) in patients with MS who have not achieved adequate relief from spasticity with other 
antispasticity medications.
x
To evaluate the safety and tolerability of nabiximols after administration of multiple doses.
x
To evaluate the pharmacokinetic (PK) profile of nabiximols after administration of multiple doses.
7.3 Exploratory Objectives
x
To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on 
a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle 
Tone-10; LLMT-10) in patients with MS who have not achieved adequate relief from spasticity with 
other antispasticity medications.
x
To evaluate the effect of nabiximols after administration of multiple doses on walking using the Timed 
25-Foot Walk (T25FW) test.
x
To evaluate the effect of nabiximols after administration of multiple doses on the following 
patient-reported outcomes:
o
The 11-point Numerical Rating Scale (NRS) spasticity score,
o
Daily spasm count,
o
The MS Spasticity Scale (MSSS-88) total and subdomain scores
Study Design
8.1 General Design
This multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, Phase 3 crossover 
trial is being conducted to evaluate the effect of multiple doses of nabiximols as adjunctive therapy on 
clinical measures in the symptomatic treatment of patients with MS who have not achieved adequate relief 
from spasticity with other antispasticity medications.
Patients with MS who are naïve to treatment with nabiximols for spasticity will participate in a screening 
period of up to 28 days; no changes in the dose of the patients’ current MS antispasticity medications will 
be made during this period.
As part of the baseline period of each treatment period, patients will keep an electronic diary (eDiary) to 
record 11-point NRS spasticity score, spasm count, and use of antispasticity medications once daily, around 
the same time each day, preferably in the evening before retiring to sleep, for at least 7 days prior to Visits 
2 and 6. At Visit 2, in the morning of Day 1, eligible patients will be randomly assigned in a 1:1 ratio to 1 of 
2 treatment sequences, each composed of 2 treatment periods, with administration of multiple doses of 
nabiximols or placebo.


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Patients randomized will complete 2 treatment periods with administration of IMP for 21 days per treatment 
period.  Each treatment period will consist of a dose-titration phase of approximately 14 days, followed by 
a maintenance-dose phase of approximately 7 days, where the individually determined optimized dose 
level remains unchanged for the remainder of each treatment period after titration.  Doses greater than 1
spray/day will be divided into a morning dose and an evening dose.
Throughout both treatment periods, patients will initiate IMP treatment as a single spray in the clinic in the 
morning of Visits 2 (Day 1) and 6 (Day 31) of each treatment period.  Patients will gradually titrate their daily 
dose by 1 to 2 additional sprays/day to an optimized dose or to a maximum of 12 sprays/day over the first 
approximately 14 days of treatment with an approximately 15-minute interval between sprays. Patients 
should complete titration within approximately 14 days of their first dose of IMP in each treatment period 
and should continue at the same dose level achieved at the end of the titration phase (i.e., their daily 
optimized dose) ± 1 spray divided into a morning dose and an evening dose for the remainder of the 
treatment period. Once a stable daily dose has been reached, patients should gradually decrease the 
interval between sprays to a target interval of approximately 1 minute between sprays. Patients will be 
advised to administer IMP at approximately the same time each day in a consistent manner in relation to 
food consumption. Morning and evening doses should be administered around the same time within 30 
minutes after starting a snack or meal.
Table 8.1-1   Example Titration Schedule
Day
Number of Sprays in 
the Morning
Number of Sprays in 
the Evening
Total Number of 
Sprays/Day
1
1
0
1
2
1
1
2
3
1
2
3
4
2
2
4
5
3
2
5
6
3
3
6
7
4
3
7
8
4
4
8
9
5
4
9
10
5
5
10
11
6
5
11
12
6
6
12
13
6
6
12
14
6
6
12
The patient’s first dose of IMP will be administered in the clinic. 
On the days of scheduled Modified Ashworth Scale (MAS) assessments other than Visit 1 (i.e., Visits 2, 5, 
6, and 9), patients will attend the trial site without having administered any IMP in the morning. On the day 
of MAS assessment, patients who are taking baclofen and/or tizanidine as part of their optimized 
antispasticity therapy should take their regular morning dose of either or both medication(s) at least 1 hour 
before the administration of IMP. Administration of the morning dose of IMP with a standardized snack 
containing at least 300 kcal (of which approximately 30 kcal is composed of fat) will occur at the trial site 
under the supervision of site staff; MAS assessments will occur at scheduled time points before (Visits 2 
and 6 [pre-dose]) and after (Visits 2, 5, 6, and 9 [3 hours ± 15 minutes post-dose]) IMP administration


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A washout period of at least 7 days will separate the 2 treatment periods.  During the washout period, 
patients will continue to take their current MS antispasticity medications without any changes in dose.
Patients who complete the 2 treatment periods will complete an End of Treatment Visit (Visit 9). Patients 
who discontinue IMP early will be encouraged to remain in the study for the duration of the treatment period 
in which they discontinue IMP and will complete an End of Treatment Visit (Visit 9) at the end of that period.  
A Safety Follow-up Visit (Visit 10) will occur 7 (+3) days after the last dose of IMP or after the 
End-of-Treatment visit (Visit 9), whichever is later, for all patients. 
The total daily dose should be administered as a morning dose and an evening dose, which may be 
comprised of a different number of sprays during titration.  During the period of stable dosing following 
titration, patients should attempt to achieve a balance in the number of sprays administered as part of the 
morning and evening doses of IMP.
The study overview is specified in Figure 8.1-1.
The schedule of study events is specified in Table 8.1-1 and in Table 8.1-2.
Figure 8.1-1 Trial Design and Treatment Schematic


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Table 8.1-1 Schedule of Assessments
Period
Screening
Treatment Period 1
Treatment Period 2
Safety 
Follow-up
Visit Number
Visit 1
Visit 2
Visit 3 
(Phone Call)
Visit 4
Visit 5a
Visit 6
Visit 7
(Phone 
Call)
Visit 8
Visit 9
Visit 10
(or 7 days 
after 
final IMP dose 
or ET visit)
Day/Hour
Days -28 
to -1
Day 1
Pre-
dose
Day 1
2-4 hrs 
Post-
dose
Day 8
(±1 day)
Day 
15
(±1 
day)
D21
(±2
days)
Day 31
Pre-
dose
(±1 
day)
Day 31
2-4 hrs
Post-
dose
Day 38
(±1 day)
Day 45
(±1 day)
Day 51
(±2 days)
End of 
Treatment 
Visit
Day 58
(+3 days)
Informed consent
X
Eligibility check
X
X
Demographics
X
Previous cannabis 
use
X
Medical history
X
Electronic diary 
training
X
Randomization
X
Concomitant 
medications
Assessed at each visit
AEs
Assessed at each visit
Physical 
examinationb
X
X
X
Examination of oral 
mucosa
X
X
X
X
X
X
X
X
Body weight 
measurement
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X


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Period
Screening
Treatment Period 1
Treatment Period 2
Safety 
Follow-up
Visit Number
Visit 1
Visit 2
Visit 3 
(Phone Call)
Visit 4
Visit 5a
Visit 6
Visit 7
(Phone 
Call)
Visit 8
Visit 9
Visit 10
(or 7 days 
after 
final IMP dose 
or ET visit)
Day/Hour
Days -28 
to -1
Day 1
Pre-
dose
Day 1
2-4 hrs 
Post-
dose
Day 8
(±1 day)
Day 
15
(±1 
day)
D21
(±2
days)
Day 31
Pre-
dose
(±1 
day)
Day 31
2-4 hrs
Post-
dose
Day 38
(±1 day)
Day 45
(±1 day)
Day 51
(±2 days)
End of 
Treatment 
Visit
Day 58
(+3 days)
12-lead ECG
X
X
X
Clinical laboratory 
blood sampling 
(hematology and 
biochemistry)
X
X
X
Dipstick urinalysis
X
X
Urine drug screen 
(including THC)
X
X
Serum/urine 
pregnancy test (if 
appropriate)c
X
X
X
X
Blood THC test
X
PK blood sampling 
(IMP)d
X
X
X
X
X
X
X
X
Electronic daily diary
11-Point 
NRS 
spasticitye
X
X
X
X
X
X
X
Daily spasm 
counte
X
X
X
X
X
X
X
Use of 
antispasticity 
medicationse
X
X
X
X
X
X
X


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Period
Screening
Treatment Period 1
Treatment Period 2
Safety 
Follow-up
Visit Number
Visit 1
Visit 2
Visit 3 
(Phone Call)
Visit 4
Visit 5a
Visit 6
Visit 7
(Phone 
Call)
Visit 8
Visit 9
Visit 10
(or 7 days 
after 
final IMP dose 
or ET visit)
Day/Hour
Days -28 
to -1
Day 1
Pre-
dose
Day 1
2-4 hrs 
Post-
dose
Day 8
(±1 day)
Day 
15
(±1 
day)
D21
(±2
days)
Day 31
Pre-
dose
(±1 
day)
Day 31
2-4 hrs
Post-
dose
Day 38
(±1 day)
Day 45
(±1 day)
Day 51
(±2 days)
End of 
Treatment 
Visit
Day 58
(+3 days)
IMP dosing 
recorde
X
X
X
X
X
X
MASf
X
X
X
X
X
X
X
MSSS-88
X
X
T25FW testg
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
IMP dosing training
X
IMP dosingh
X
X
X
X
IMP dispensingi
X
X
X
X
IMP collection and 
compliance review
X
X
X
X
AE = adverse events; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; IMP = investigational medicinal product;
MAS = Modified Ashworth Scale; MS = multiple sclerosis; MSSS-88 = Multiple Sclerosis Spasticity Scale; NRS = Numerical Rating Scale; 
PK = pharmacokinetics; T25FW = Timed 25-Foot Walk; THC = Δ9-tetrahydrocannabinol.
a A washout period of at least 7 days will separate the 2 treatment periods.  Following the final dose of IMP in Treatment Period 1, in the morning 
of Visit 5 (D21), patients will discontinue treatment with IMP for the 7 days prior to Visit 6 (Day 31).  During the washout period, patients will 
continue to take their current MS antispasticity medications without any changes in dose.
b A comprehensive physical examination, including an assessment of height, will be completed at Screening (Visit 1) only; subsequent physical 
examinations will be symptom-directed.
c Serum pregnancy test at Visits 1 and 10; urine pregnancy test at Visits 2 and 6 (pre-dose). 
d On the day before PK blood sampling at Visits 4, 5, 8, and 9, patients will be prompted to record whether they started their morning and evening 
doses of IMP within 30 minutes of a snack or meal. On the day of PK blood sampling, the exact time and date of PK blood sampling and the time 


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of the patient’s snacks and meals should be recorded for the PK blood sampling schedule (see Table 8.1-2). Please note that more than one PK 
sample may be collected at distinct time points during a single visit.
e Patients will record their 11-point NRS spasticity score, spasm count, and use of antispasticity medications in an electronic diary once daily,
around the same time each day, preferably in the evening before retiring to sleep, for at least 7 days prior to Visits 2 and 6 and throughout the 
trial until Visit 9. Investigational medicinal product dosing will be recorded by the patient in an electronic diary from Visits 2 through 9.
f MAS assessments will occur at Visit 1 (Screening) and at scheduled time points before (Visits 2 and 6 [pre-dose]) and after (Visits 2, 5, 6, and 
9 [3 hours ± 15 minutes post-dose]) IMP administration; for Visits in which the morning dose consists of more than 1 spray (Visits 5 and 9), post-
dose assessments will occur 3 hours ± 15 minutes after the first spray of the morning dose.
g Non-ambulatory patients are not expected to perform the T25FW test.
h IMP administration of the morning dose will occur at the trial site within 30 minutes after a standardized snack containing at least 300 kcal (of 
which approximately 30 kcal is composed of fat) under the supervision of site staff. On the days of scheduled MAS assessments other than Visit 
1, patients who are taking baclofen and/or tizanidine as part of their optimized antispasticity therapy should take their regular morning dose of 
either or both medication(s) at least 1 hour before administration of IMP.  IMP will not be administered in the evening of Days 21 and 51.
i In cases where patients are not able to attend study visits due to the presence of an infectious disease or other transmissible condition, the 
investigator will discuss with the Sponsor potential mitigation approaches for IMP dispensing, secure delivery, and collection.


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Table 8.1-2 Pharmacokinetic Blood Sample Schedule
Visit/Day
Period /Day 
Timepoints
Visit 2 / Day 1
Period 1 Day 1
Pre-dose and 0-2 and 2-4 hours post-dose
Visit 4 / Day 15
Period 1 Day 15
0-2 and 2-4 hours post-dose
Visit 5 / D21
Period 1 D21
Pre-dose and 0-1 and 2-3 hours post-dose
Visit 6  / Day 31
Period 2 Day 1
Pre-dose and 0-2 and 2-4 hours post-dose
Visit 8 / Day 45
Period 2 Day 15
0-2 and 2-4 hours post-dose
Visit 9 / Day 51
Period 2 D21
Pre-dose and 0-1 and 2-3 hours post-dose
8.2 Sample Size Considerations
Approximately 26 patients will be randomly assigned to each treatment sequence to ensure that at least 46
patients in total complete the 2 treatment periods. The primary comparison will be the estimate of the mean 
treatment difference between nabiximols and placebo in the mean change from baseline in LLMT-6.
Assuming a standard deviation of the paired differences between nabiximols and placebo of 0.71 and a 
treatment difference of −0.30, 46 patients will provide 80% power using a 5% significance level and a 
two-sided test. Adjusting for 10% dropout, a total of approximately N=52 patients are required. If more than 
6 patients withdraw from the trial, additional patients will be enrolled to have 46 completers.
A blinded sample size re-estimation was conducted based on methodology in section 11.1 and the 
estimated standard deviation of the pooled treatment period differences (treatment period 2 – treatment 
period 1) in changes from baseline to D21 in MAS was larger than 0.71 (the assumed standard deviation 
of the treatment differences at design stage). Using this new standard deviation as the estimate of the
standard deviation of the treatment differences (nabiximols – placebo) of the changes from baseline to D21
in MAS, the sample size was recalculated. In a blinded sample size re-estimation committee meeting dated 
30th November 2021, the committee recommended increasing the sample size to 68 completers. This new 
sample size will result in at least 80% power for this study if the new observed blinded standard deviation
were the true unblinded standard deviation, and greater than 90% power if the true unblinded standard 
deviation was exactly 0.71.
SAS software version 9.4 was used to perform the sample size calculations.
8.3 Randomization
At Visit 2, in the morning of Day 1, eligible patients will be randomly assigned in a 1:1 ratio to 1 of 2 treatment 
sequences, each composed of 2 treatment periods, with administration of multiple doses of nabiximols or 
placebo following the randomization schedule generated and kept by Endpoint.
Enrolled patients will be allocated a unique patient number in a sequential order by trial site. Following 
randomization, GW Pharma Limited will provide all IMP in a packed and labelled state, and the Interactive 
Web Response Technology (IRT) will identify the pack number to be dispensed to the patient at each 
relevant visit according to the treatment sequence assigned in the randomization schedule.


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Study Endpoints, Variables and Covariates
9.1 Overview
An overview of objectives and endpoints is shown in Table 9.1-1 and an overview of estimands is shown 
in Table 9.1-2.
Table 9.1-1 Objectives and Endpoints
Objectives and Endpoints
Primary Objective 
Primary Endpoint 
x
To evaluate the effect of multiple doses of nabiximols 
as adjunctive therapy compared with placebo on a 
clinical measure of velocity-dependent muscle tone in 
LLMT-6 in patients with MS who have not achieved 
adequate relief from spasticity with other antispasticity 
medications 
x
Change in LLMT-6; defined as the average of the 6 
individual MAS transformed scores of knee flexors, 
knee extensors, and plantar flexors on both sides of the 
body, from Day 1 pre-dose to D21 and from Day 31 pre-
dose to Day 51 
Secondary Objectives 
Secondary Endpoints 
x
To evaluate the effect of multiple doses of nabiximols 
as adjunctive therapy compared with placebo on a 
clinical measure of velocity-dependent muscle tone in 
the lower limbs in LLMT-4 in patients with multiple 
sclerosis (MS) who have not achieved adequate relief 
from spasticity with other antispasticity medications 
x
Change in LLMT-4; defined as the average of the 4 
individual MAS transformed scores of knee flexors and 
knee extensors on both sides of the body, from Day 1 
pre-dose to D21 and from Day 31 pre-dose to Day 51 
x
To evaluate the safety and tolerability of nabiximols 
after administration of multiple doses 
x
Frequency of treatment-emergent adverse events 
(TEAEs) 
x
Change from baseline to each assessment timepoint by 
treatment period for the following: 
o
Clinical laboratory parameters
o
Vital signs
o
Physical examination procedure
o
12-Lead electrocardiograms (ECGs)
x
Columbia-Suicide Severity Rating Scale (C-SSRS) at 
screening, and at each subsequent timepoint with 
reference to the last assessment (since last visit)
x
To evaluate the PK profile of nabiximols after 
administration of multiple doses 
x
Plasma concentrations for Δ9-tetrahydrocannabinol 
(THC) and its relevant metabolites (11-hydroxy-Δ9-
tetrahydrocannabinol and 11-carboxy-Δ9-
tetrahydrocannabinol) and cannabidiol (CBD) and its 
relevant metabolites (7-hydroxy-cannabidiol and 7-
carboxy-cannabidiol) at distinct time points during each 
treatment period (Visits 2, 4, 5, 6, 8, and 9) 
Exploratory Objectives 
Exploratory Endpoints 
x
To evaluate the effect of multiple doses of nabiximols 
as adjunctive therapy compared with placebo on a 
clinical measure of velocity-dependent muscle tone in 
the lower limbs in LLMT-10 in patients with multiple 
sclerosis (MS) who have not achieved adequate relief 
from spasticity with other antispasticity medications
x
Difference between treatment arm in change in LLMT-
10; defined as the average of the 10 individual MAS 
transformed scores of knee flexors, knee extensors; 
plantar flexors, hip flexors and hip adductors on both 
sides of the body, from Day 1 pre-dose to D21 and from 
Day 31 pre-dose to Day 51
x
To evaluate the effect of nabiximols after administration 
of multiple doses on walking using the T25FW test 
x
Difference between treatments in the change in T25FW 
test from Day 1 pre-dose to D21 and from Day 31 pre-
dose to Day 51 
x
To evaluate the effect of nabiximols after administration 
of multiple doses on the following patient-reported 
outcomes: 
o
The
11-point Numerical Rating Scale (NRS) 
spasticity score
o
Daily spasm count
o
The MS Spasticity Scale (MSS-88) total and 
subdomain scores
x
Difference between treatments in average 11-point NRS 
spasticity score over the last 7 days of each double-blind 
treatment period 
x
Difference between treatments in average daily spasm 
count over the last 7 days of each double-blind treatment 
period 
x
Difference between treatments in total and subdomain 
scores of the MSSS-88 at the end of maintenance-dose 
phase of each double-blind treatment period


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Table 9.1-2 Estimands
Estimands
Primary Estimand
The primary estimand for this study is defined by the following 4 components: 
x
Population: Patients with MS, naïve to treatment with nabiximols who have not achieved adequate relief from spasticity 
with other antispasticity agents but have optimized treatment with at least 1 oral antispasticity drug.
x
Treatment:
x
Endpoint: Change in LLMT-6 from Day 1 pre-dose to D21 and from Day 31 pre-dose to Day 51.
x
Intercurrent events: 
o
Treatment-policy: Intercurrent events of non-adherence with IMP, use of prohibited medications, or other protocol 
deviations will be handled following a ‘treatment-policy’ strategy. Study data will continue to be collected and 
analyzed following the occurrence of the intercurrent event, i.e., the measure of effect is regardless of non-
compliance, use of prohibited medications, or other protocol deviations. For patients who discontinue IMP, only the 
period in which this intercurrent event occurs will follow a treatment-policy strategy. Data will continue to be collected 
and analyzed following the occurrence of the intercurrent event up to the end of the period.
o
Hypothetical strategy: For patients who discontinue IMP during Period 1, their Period 2 data will be assumed to 
follow a hypothetical strategy, i.e., patients will be assumed to follow a similar pattern of data in Period 2 to those 
patients in the same Period 2 treatment arm who did not experience this intercurrent event during Period 1. For 
these patients, Period 2 data will not be collected, and these data will be imputed according to Table 9.1-3. 
Summary Measure: Mean difference in ‘change from period level baseline to 21 days of the period assigned to nabiximols’ 
compared to ‘change from period level baseline to 21 days of the period assigned to placebo’ regardless of treatment 
compliance and change of other antispasticity medications; following a treatment policy and hypothetical strategy for 
handling intercurrent events (as described above). 
Secondary Estimand
The secondary estimand for this study is defined by the following 4 components: 
x
Population: Patients with MS, naïve to treatment with nabiximols who have not achieved adequate relief from spasticity 
with other antispasticity agents but have optimized treatment with at least 1 oral antispasticity drug.
x
Treatment:
x
Endpoint: Change in LLMT-4 from Day 1 pre-dose to D21 and from Day 31 pre-dose to Day 51.
x
Intercurrent events: 
o
Treatment-policy: Intercurrent events of non-adherence with IMP, use of prohibited medications, or other protocol 
deviations will be handled following a ‘treatment-policy’ strategy. Study data will continue to be collected and 
analyzed following the occurrence of the intercurrent event, i.e., the measure of effect is regardless of non-
compliance, use of prohibited medications, or other protocol deviations. For patients who discontinue IMP, only the 
period in which this intercurrent event occurs will follow a treatment-policy strategy. Data will continue to be collected 
and analyzed following the occurrence of the intercurrent event up to the end of the period.
o
Hypothetical strategy: For patients who discontinue IMP during Period 1, their Period 2 data will be assumed to 
follow a hypothetical strategy, i.e., patients will be assumed to follow a similar pattern of data in Period 2 to those 
patients in the same Period 2 treatment arm who did not experience this intercurrent event during Period 1. For 
these patients, Period 2 data will not be collected, and these data will be imputed according to Table 9.1-4.
Summary Measure: Mean difference in ‘change from period level baseline to 21 days during period assigned to 
nabiximols’ compared to ‘change from period level baseline to 21 days during period assigned to placebo’ regardless of 
treatment compliance and change of other antispasticity medications; following a treatment policy and hypothetical strategy 
for handling intercurrent events (as described above).
9.2 Predetermined Covariates and Prognostic Factors and other Analyzed 
Factors
The following factors will be adjusted for as covariates and used in the analysis models as fixed effect:
x
Treatment sequence, which has two levels: nabiximols/placebo (coded as 1) and placebo/nabiximols 
(coded as 2),
x
Treatment period, which has two levels: Period 1 (coded as 1) and Period 2 (coded as 2),
x
Baseline / Period baseline (as continuous covariates)


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9.3 Analysis Sets
9.3.1 Treatment Arm
The “as randomized” treatment arm called the “planned treatment arm” is defined as the treatment 
allocated at each treatment period according to the randomization scheme.
The “as treated” treatment arm also called “actual treatment arm” is defined as the treatment received 
for the longest period of time within each treatment period.
9.3.2 Definition of Analysis Sets
9.3.2.1 Screening Analysis Set
All patients who signed the inform consent and have performed Visit 1 (screening).
9.3.2.2 Randomized Analysis Set
All patients who signed the informed consent and were randomized by IRT will be included and analysed 
according to their randomized treatment arm / treatment sequence.
9.3.2.3 Full Analysis Set
All patients who signed the informed consent and are randomized and received at least 1 dose of IMP in 
the trial, will be included and analyzed according to their randomized treatment. The Full Analysis Set is 
the primary analysis set for all efficacy endpoints and patient reported outcome (PRO) assessment.
9.3.2.4 Safety Analysis Set
All patients from the Screening Analysis Set, who received at least 1 dose of IMP in the trial will be included 
in the Safety Analysis Set and analysed according to the treatment received. Only patients for whom it has 
been confirmed that they did not take IMP will be excluded from the Safety Analysis Set. The Safety 
Analysis Set will be used to report all safety data using the actual treatment arm.
9.3.2.5 Study Completer Analysis Set
All patients from the FAS who have completed the trial (completed both treatment period 1 and treatment 
period 2), regardless whether they have permanently withdrawn from study drug. The analyses on the 
Study Completer Analysis Set will only be conducted on efficacy endpoints and patients analyzed according 
to their randomized treatment arm. 
9.3.2.6 Per Protocol Analysis Set
The Per Protocol (PP) Analysis Set is defined as follows: a subset of the FAS that includes all patients who 
have completed the trial with no major important protocol deviations deemed to compromise the 
assessment of efficacy. Major important protocol deviations will be identified as a subset of the important 
protocol deviations and fully defined prior to unblinding of the trial. The PP analysis will only be conducted 
on efficacy endpoints and patients analyzed according to their randomized treatment arm. 
9.3.2.7 Pharmacokinetic Analysis Set
All patients who have received at least 1 dose of IMP and provided sufficient bioanalytical data to calculate 
reliable (based on the judgement of the pharmacokineticist) estimates of the PK parameters of THC, CBD, 
and their metabolites will be included in the PK Analysis Set. This analysis set cannot be determined before 
unblinded analysis.


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Conventions and Derivations
10.1 Study Period, Reference Day, Study Day, Analysis Day and Visit Window
10.1.1 Study Periods
For each patient, there will be a screening period, an evaluable period composed of a treatment period 1, 
a washout period, and a treatment period 2, and a safety follow-up period.
The Screening period starts on the day of the informed consent signature and ends on Day 1 (as defined 
on in Section 10.1.2) before 1st IMP intake.
The evaluable period starts on the day of randomization and ends the day of the safety follow-up visit.
x
The 51-day efficacy period which starts on the first day of IMP administration and ends at the end of 
treatment date.
o
This period will be composed of:
x
The 21-day on-treatment efficacy Period 1 which starts the day of first IMP intake during 
Period 1 and ends the earliest between end of Period 1 D21 date and permanent end of 
treatment date;
x
The on-treatment wash-out period which begins the day following the end of the 21-day on-
treatment efficacy Period 1 and ends the day before the beginning of the 21-day on-treatment 
efficacy Period 2; 
x
The 21-days on-treatment efficacy Period 2 which starts the day of IRT call for Period 2 
and ends on the end of treatment date. This period is only defined for patients exposed to 
IMP during Period 2.
o
It will be used for efficacy analyses using the Full Analysis Set.
x
The 51-day safety period which starts on the first day of IMP administration and ends at the end of
treatment date (+ x days).
o
This period will be composed of:
x
The 21 day on-treatment Safety Period 1 which starts the day of first IMP intake during 
Period 1 and ends the earliest between end of the wash out period date, the day before the 
date of IRT call for Period 2, the day before Visit 6 date and permanent end of treatment date 
+ x days.
x
The 21 day on-treatment Safety Period 2 which starts the earliest between date of Visit 6, 
day of IRT on treatment safety period call for Period 2 date, and ends on the end of treatment 
day date + x days.
o
x will be equal to 14 days for Adverse events, 4 days for C-SSRS and 0 days otherwise.
o
it will be used for safety analyses using the Safety Analysis Set (unless otherwise specified).
x
The Follow-up period which starts the day following the 51-day on-treatment safety period and ends 
on the end of study date.
10.1.2 Reference Day and Study Day
The reference day (Day 1) will be the day of the first dose of study drug administration.
For a patient who was randomized but not exposed, the reference day date will be imputed by the 
randomization date.
The reference day for Period 1 (Period 1 Day 1) will be the reference day.


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The reference day for Period 2 (Period 2 Day 1) will be the first day of IMP administration during 
Period 2. For a patient who entered the second period but was not exposed during this period, this reference 
day date will be imputed by the date of Visit 6 IRT call, if any, or the Visit 6 date.
The study day is defined relative to the reference day date. For assessments that occur after this visit date, 
the study day is calculated as (assessment date – reference day date + 1). For assessments that occur 
prior to first dose date, study day will be calculated as (assessment date – reference day date).
For the analyses being done by treatment arm, an analysis day will need to be derived for each treatment 
period as described in Table 10.1-1. The analysis day is defined relative to the date of reference day of 
each study period. 
For assessments that occur prior to reference day date, analysis day will be calculated as (assessment 
date – reference day date); 
For assessments that occur on or after the Period 1 reference day date until the end of the wash-out period, 
analysis day will be calculated as (assessment date – Period 1 reference day date +1);
For assessments that occur on or after Period 2 reference day date the analysis day will be calculated as 
(assessment date – Period 2 reference day date +1);
Thus, there is no study day or analysis day referring to Day 0. 
10.1.3 Target Days and Visit Window
Visit windows are summarized in Table 10.1-3 for efficacy data and urine drug screen collection and, in
Table 10.1-2 for all other safety endpoints.
When there are multiple observations within a visit window, the value closest to the target day will be 
analyzed (as described in Table 10.1-1).
For safety assessments, on-treatment assessments will be preferred to off-treatment ones.
In case of ties between observations located on different sides of the target, the observation with the earliest 
date/time will be used. In case of ties between observations located on the same side of the target, (i.e., 
more than one value for the same day but at different time), the observation with the earliest date/time will 
be used. However, in case of non-respect of wash-out period, the one done at least 7 days after last 
Period 1 dosing date will be preferred.
For efficacy, PRO endpoints visit windowing will apply whether patient is on or off treatment.
Table 10.1-1 Longitudinal Assessment –  Analysis Day and Target Day
Treatment 
Period
Visit / Day
Analysis 
visit
Target Day 
(defined by 
period)
Observation used for 
analysis, if more than 
one exists
Screening 
Visit 1 / Day -28 to -1
Screening
Day -28 to -1
Latest value
Period 1
Visit 2 / Day 1
Day 1
Day 1*
Closest to Target Day
But Day 1 H0 should be 
before 1st IMP intake and 
D1H3 should be post IMP 
intake
Visit 3 / Day 8
Day 8
Day 8
Closest to Target Day
Visit 4 / Day 15
Day 15
Day 15
Closest to Target Day
Visit 5 / D21
D21
D21
Closest to Target Day 
Period 2
Visit 6 / Day 31 
Day 1
Day 1*
Closest to Target Day
But Day 1 H0 should be 
before 1st IMP intake and 


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Treatment 
Period
Visit / Day
Analysis 
visit
Target Day 
(defined by 
period)
Observation used for 
analysis, if more than 
one exists
D1H3 should be post IMP 
intake. 
Visit 7 / Day 38
Day 8
Day 8
Closest to Target Day
Visit 8 / Day 45
Day 15
Day 15
Closest to Target Day
Visit 9 / Day 51
D21
D21
Closest to Target Day
Follow-up
Visit 10 / Day 58
Day 28
Day 28**
Closest to Target Day
H = Hours; IMP = Investigational medical product.
* Day 1 is based on the date of IRT call within each period
** Day 28 relative to the period where IMP is permanently discontinued thus visit is expected between 
Day 25 and Day 31


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Table 10.1-2 Longitudinal Assessment – Target Day and Visit Window – Part 1
Treatment 
Period
Visit / Day
Target Day 
(defined 
by period)
Physical 
examination /
12-lead ECG /
Clinical 
laboratory blood 
sampling
Examination of 
oral mucosa /
C-SSRS
Body weight /
Serum urine 
pregnancy test
Vital signs
Dipstick urine
Screening 
Visit 1 / Day -
28 to -01
Day -28 to -
01
Day-28 – D1H0
Day -28 to -01
Day -28 to -01
Day -28 to -01
Day-28 – D1H0 
(before 1st IMP 
dosing)
Period 1
Visit 2 / Day 
1H0
Day 1*
Day 1H0 *
Day 1 H0 (before P1 
IMP intake)
Day 1 H0 (before P1 
IMP intake)
Visit 2 / Day 1
Day 1 H2-
H4*
Day 1 post dose (the 
day of 1st P1 IMP 
intake)
Visit 4 / Day 
15
Day 15
Day 1 post dose to 
Day 18
Day 2 (day following 
IMP intake) – Day 
18
Visit 5 / D21
D21
Day 1 post dose to
LP1V
Day 19 to LP1V
Day 19 to LP1V
Wash-out
Period 2
Visit 6 / Day -
31 
Day 1H0*
Day 1 – 4 days to 
D1H0 *
D1H0 (before  P2 
IMP intake)
Day 1 – 4 days to 
D1H0
Visit 6 / Day -
31 
Day 1H2-
H4*
Day 1 post dose (the 
day of 1st P2 IMP 
intake)
Visit 8 / Day 
45
Day 15
Day 1 post dose to 
Day 18
Day 2 (day following 
IMP intake) – Day 
18
Visit 9 / Day 
51
D21
Day 1 post dose to 
LP2V
Day 19 to LP2V
Day 19 to LP2V
Follow-up
Visit 10 / Day 
58
Day 28***
after last IMP dosing
After last IMP dosing
Day 1 post 1st IMP 
dosing to after last 
IMP dosing
H = Hour; P = Period; LP1V = Last visit during Period 1, LP2V = Last visit during Period 2, IMP = Investigational Medical Product; IRT = Interactive response 
technology; ECG = Electrocardiogram; C-SSRS = Columbia-Suicide Severity Rating Scale.
* 
Day 1 is based on the date of IRT call within each period.
*** Day 28 relative to the period where IMP is permanently discontinued.


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Table 10.1-3 Longitudinal Assessment –Target Day and Visit Window – Part 2
Treatment 
Period
Visit / Day
Target Day 
(defined 
by period)
Urine drug 
screen
11-point NRS 
spasticity / Daily 
spasm count
MAS
MSSS-88
T25FW test
Screening 
Visit 1 / Day -
28 to -01
Day -28 to -
01
Day -28 to -01
Day -28 to -01
Day -28 to -01
Period 1
Visit 2 / Day 
1H0
Day 1*
Day 1 H0 (before P1 
IMP intake)
Day1H0 (before P1 
IMP intake) *
Day1H0 (before P1 
IMP intake)
Day 1H0 (before P1
IMP intake)
Visit 2 / Day 1
Day 1 H2-
H4**
Day1 post dose (the 
day of 1st P1 IMP 
intake)** up to Day 18
Visit 4 / Day 
15
Day 15
Day 2 (day following 
IMP intake) – Day 
18 (or the first day of 
maintenance phase)
Visit 5 / D21
D21***
Day 19 up to LP1V
Day 19 up to LP1V
Day 1 post dose 
of 1st IMP intake 
up to LP1V
Day 1 post dose of 
1st IMP intake up to 
LVP1
Wash out 
period
Period 2
Visit 6 / Day 
31 
Day 1H0*
Day 1 – 4 days to 
D1H0 *
Day 1H0 (before P2 
IMP intake)
Day 1H0 (before P2 
IMP intake)
Visit 6 / Day 
31 
Day 1H2-
H4**
Day 1 post dose (the 
day of 1st P2 IMP 
intake)** up to Day 18
Visit 8 / Day 
45
Day 15
Day 2 (day following 
IMP intake) – Day 
18 (or the first day of 
maintenance phase)
Visit 9 / Day 
51
D21***
Day 19 to LP2V
Day 19 to LP2V
Day 1 post dose 
of Period 2 1st IMP 
intake up to LP2V
Day 1 post dose of 
Period 2 1st IMP  
intake up to LVP2
Follow-up
Visit 10 / Day 
58
Day 28****
After last IMP dosing
H = Hours, P = Period; LP1V = Last visit during Period 1, LP2V = Last visit during Period 2, IMP = Investigational Medicinal Product, NRS = Numerical Rating 
Scale; IRT = Interactive Response System; MAS = Modified Ashworth Scale,.MSSS-88 = Multiple Sclerosis Spasticity Scale; T25FW = Timed 25-Foot Walk.
* 
Day 1 is based on the date of IRT call within each period.
**   D1H2-H4 for sensitivity analysis purpose only assessments collected between at H3 (+/- 15 min) post first IMP morning spray will be considered. Should be 
collected during the titration phase
*** D21 should be collected during the maintenance phase (including off-treatment days).
**** Day 28 relative to the period where IMP is permanently discontinued.


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For patient electronic diary-based endpoints (NRS-spasticity and spasm count), baseline is defined as 
the weekly average of daily electronic diary entries over the last 7 days prior to randomization (Visit 2, 
Period 1 Day 1H0).
In case of missing assessments within the 7 days preceding Period1 Day1 H0
x
For 11-point NRS spasticity scale, the weekly average will be set to missing if scores are missing for 
4 days in total or for 3 consecutive days within the 7-days period.
x
For daily spasm count, the weekly average will be derived as detailed in Section 10.19) and will be set 
to missing if spasm count is not collected during 4 days out of 7 or for 3 consecutive days during the 
last 7 days preceding Day 1H0.
For clinic-efficacy based endpoints, baseline is defined as the last record or measure collected prior to 
the first dose of IMP in each treatment period.
However, if deemed necessary the baseline will be defined for each period as described in Section 10.1.2
as:
x
the reference day for Period 1,
x
the reference day for Period 2,
For clinic-safety based endpoints, baseline is defined as the last record or measure collected prior to the 
first dose of IMP or if deemed necessary as the reference day as described in Section 10.1.2.
10.3 Change from Baseline
Change from baseline (CFB) will be calculated as:
(post-baseline – baseline).
CFB will be calculated for patients with both a baseline and post-baseline value as applicable.
10.4 Percentage Change from Baseline
Percent CFB will be calculated, where applicable, as:
(CFB/baseline)*100.
If a baseline value has not been recorded for a parameter, then percent CFB will be missing for that 
parameter.
If baseline and post baseline are rates the following formula will be used: 
((ܲ݋ݏݐܾܽݏ݈݁݅݊݁ݏܿ݋ݎ݁/ܿ݋ݑ݊ݐ∗ܾܽݏ݈݁݅݊݁݀ݑݎܽݐ݅݋݊
ܤܽݏ݈݁݅݊݁ݏܿ݋ݎ݁/ܿ݋ݑ݊ݐ∗݌݋ݏݐܾܽݏ݈݁݅݊݁݀ݑݎܽݐ݅݋݊−1) × 100)
10.5 Time Conversion
Time conversion will follow the rules described below:
x
1 week = 7 days,
x
1 Month = 30.4375 days,
x
1 year = 365.25 days.
10.6 Patient Disposition
The time to treatment discontinuation expressed in day is defined as:
x
the date of last administration – the date of 1st IMP spray intake +1 day.


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The time to study discontinuation expressed in day is defined as:
x
End of study day – date of randomization + 1 day.
Where the date of the 1st IMP spray intake (e.g., IMP start date) will be retrieved from the eCRF “PK sample 
collection form” and, if missing, from the eDiary first spray date for Period 1 whereas, the end of treatment 
date will be the latest date between the end of treatment date coming from eCRF “End of treatment Period 
1” form and “End of treatment Period 2” form.
Censoring rules for time to event analysis are defined in Section 12.1.
10.7 Duration of Treatment
The duration of study drug exposure expressed in days will be defined for each study drug as:
x
the date of last administration – the first day of administration +1 day.
The mean duration of study drug exposure expressed in patient-time will be defined as follows:
x
The mean duration (patient-year) = (∑
ܦ݅
௜ୀ௡
௜ୀଵ
) /365.25
x
The mean duration (patient-week) = (∑
ܦ݅
௜ୀ௡
௜ୀଵ
) /7
With n being the number of patients within the Safety Analysis Set and i=1,2, 3,…,n, and, with Di being the 
duration of treatment (in days) for patient i.
The IMP start date will be retrieved from the eCRF “PK sample collection form” for each treatment period
whereas the end of treatment date for each period will respectively be coming from eCRF “End of treatment 
Period 1” form and “End of treatment Period 2” form. However, if the information is missing on the eCRF 
“PK sample collection”, the first IMP spray date will be retrieved from the eDiary first spray date of each 
treatment period.
10.8.1 Study Phases Start and Stop Dates used to summarize IMP Dosing
The titration phase
x
Start of the titration phase during Period 1 is defined as:
Min(randomization date, 1st IMP dosing date)
x
Start of the titration phase during Period 2 is defined as:
Min(the date of IRT call for Period 2, Visit 6 date)
x
End of the titration phase during Period 1 is defined as:
Min(the day preceding Visit 4 date, the last dose date during Period)
x
End of the titration phase during Period 2 is defined as:
Min(the day preceding Visit 8 date, the last dose date during Period 2)
The maintenance phase 
x
Start of the of the maintenance phase during Period 1 is defined as:
the date of Visit 4,
x
Start of the of the maintenance phase during Period 2 is defined as:
the date of Visit 8,
x
End date of the maintenance phase during Period 1 is defined as:
Min(Visit 5 date, the date of the last dose of study drug)


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x
End date of the maintenance phase during Period 2 is defined as:
the date of the last dose of study drug
10.8.2 Number of Sprays Summary
For each parameter presented in this section,
x
The start and stop date of each studied period is defined in Section 10.8.1. These studied periods
are defined for Period 1 and Period 2 to allow summaries by treatment arm.
x
The duration of each studied period will then be derived using the appropriate treatment phase
(titration, maintenance) for each treatment period as: Date of stop – date of start + 1 day
x
eDiary information will be used to retrieve the total daily number of sprays taken by a given patient
x
A non-missing diary day is defined as any day where the eDiary is filled but IMP dosing information 
are fully included or partial (missing morning or evening dose) or totally missing.
x
A missing diary day is defined as any day where the eDiary is not filled
x
Imputation rule: for a non-missing diary day where IMP dosing information is partial or missing the 
number of sprays taken on that missing morning or evening administration will be imputed to “0” to 
derive the total daily number of spray taken.
The mean number of sprays is defined for each treatment arm as the total number of sprays taken during 
the studied period divided by the number of patients within the studied period regardless intermittent IMP 
discontinuation.
The patient mean number of daily sprays a patient has taken on a daily basis is calculated for each 
studied period as the total number of sprays taken divided by the number of non-missing diary days for 
each patient.
Based on the above the patient mean number of daily sprays (also called mean use of IMP) will also be
categorized as follows:
x
≤ 6 sprays,
x
> 6 sprays and ≤ 12 sprays,
x
> 12 sprays.
The total number of daily sprays is referring to the total number of sprays a patient has taken on a daily 
basis for a studied period.
The patient median number of daily sprays refers to is referring to the median number of sprays a patient 
has taken on a daily basis for a studied period.
The patient mode number of daily sprays refers to more frequently occurring number of sprays a patient 
has taken on a daily basis for a studied period. If a patient has more than one mode or no mode determined 
then the patient has a ‘missing’ mode.
The patient maximal number of daily sprays refers to the maximal number of sprays a patient has taken 
on a daily basis for a studied period.
The patient percentage of imputed diary days is derived for each patients as the number of non-missing
diary days where morning and/or evening number of sprays are imputed to ‘0’ to calculate the total daily 
dose divided by the number of non-missing diary days for a studied period and multiply by 100.


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10.9 Compliance
Compliance will be derived, for each patient, during the maintenance phase, based on optimized and 
amended doses information as reported in the “Dose amendment” eCRF form and the total daily number 
of sprays derived from the eDiary as the sum of morning and evening number sprays applying missing data 
rule imputation on non-missing diary days as described in Section 10.8.2.
A compliant day, is defined for each patient as a day when the total number of sprays taken is
x
Within +/- 1 (and between 1 and 12) of the patients’ optimized dose range as defined in Table 10.9-1
when sprays are taken outside of an amended dose period,
x
Equal to the amended dose +/- 1 spray (and between 1 and 12) when sprays are taken between start 
and stop date of an amended dose period as collected in the eCRF.
The compliance will then be defined as 
100*( 
୬୳୫ୠୣ୰୭୤ୡ୭୫୮୪୧ୟ୬୲ୢୟ୷ୱ
୬୳୫ୠୣ୰୭୤ୢୟ୷ୱ୵୧୲୦୬୭୬ି୫୧ୱୱ୧୬୥୲୭୲ୟ୪ୢୟ୧୪୷ୢ୭ୱୣ୧୬୤୭୰୫ୟ୲୧୭୬୵୧୲୦୧୬୲୦ୣୱ୲୳ୢ୷୮ୣ୰୧୭ୢ)
Table 10.9-1 Optimized Daily Dose and Allowed Optimized Dose Range 
Optimized dose
Maximal allowed dose
Minimal Allowed dose
1
2
1
2
3
1
3
4
2
4
5
3
5
6
4
6
7
5
7
8
6
8
9
7
9
10
8
10
11
9
11
12
10
12
12
11
The rate of “0” total daily spray is defined at patient level as 
100*( 
୬୳୫ୠୣ୰୭୤ୢୟ୷ୱ୵୧୲୦୲୭୲ୟ୪ୢୟ୧୪୷ୢ୭ୱୣୀ଴
ୱ୲୳ୢ୷୮ୣ୰୧୭ୢୢ୳୰ୟ୲୧୭୬∗
)
The rate of “> 12” total daily spray is defined at patient level as
100*( 
୬୳୫ୠୣ୰୭୤ୢୟ୷ୱ୵୧୲୦୲୭୲ୟ୪ୢୟ୧୪୷ୢ୭ୱୣ୧ୱவଵଶ
ୱ୲୳ୢ୷୮ୣ୰୧୭ୢୢ୳୰ୟ୲୧୭୬∗
)
The rate of missing diary day IMP information is defined for each patient as: 
100*( 
୬୳୫ୠୣ୰୭୤ୢୟ୷ୱ୵୧୲୦୫୧ୱୱ୧୬୥ୢ୧ୟ୰୷ୢ୭ୱ୧୬୥୧୬୤୭୰୫ୟ୲୧୭୬
ୱ୲୳ୢ୷୮ୣ୰୧୭ୢୢ୳୰ୟ୲୧୭୬∗
)
Using missing morning and/or evening number of sprays information from either missing diary day and non-
missing diary day (as defined in Section 10.8.2)
* The study period duration refers to either the titration phase duration or the maintenance phase duration 
for period.
10.10 Age
The age at consent will be determined as follows:


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x
If age is recorded in the eCRF then this will be the one used for analysis
x
If only year of birth is known, Date of Birth is imputed to the 15 June of the year of birth and age is 
derived as: 
Age at Informed Consent (years) = (Date of Informed Consent – Date of Birth + 1)/365.25
However, if derived age is resolved to 17-year-old and inclusion criteria 6.1.1 is met then age will be set to 
18 years.
Based on the above age will also be categorized as ≤18, > 18 to ≤45, > 45 to ≤ 65 and > 65 years old and 
labelled ≤18, > 18 to ≤45, ≥46 to ≤ 65 and > 65 years, respectively.
10.11 Body Mass Index
At each weight measurement, the Body Mass Index (BMI) will be derived using height collected at 
screening.
It is calculated using the following formula: 
BMI (kg/m²) = Weight (kg) / [Height (cm)]) x0.01]2
Based on the above value BMI will also be categorized as follows:
x
< 18.5 as underweight; 
x
≥ 18.5 and < 25.0 as normal or healthy weight; 
x
≥ 25.0 and < 30.0 as overweight; 
x
≥ 30.0 as obese.
10.12 Disease History
As part of Disease history description, the following parameters will be derived:
x
Time since diagnosis of MS (years)
(Date of Informed consent – Date of MS diagnosis + 1) / 365.25;
x
Age at diagnosis of MS (years)
(year of MS diagnosis – year of Birth + 1)
x
Time since onset of spasticity due to MS (years)
(Date of Informed consent – Date of onset of spasticity due to MS + 1) / 365.25;
x
Age at onset of spasticity due to MS (years)
(year of onset of spasticity due to MS – year of Birth + 1);
x
Time between MS diagnosis and onset of spasticity due to MS (years)
(Date of onset of spasticity due to MS - Date of MS diagnosis + 1) / 365.25;
x
Time between MS diagnosis and onset of spasticity due to MS (months)
(Date of onset of spasticity due to MS - Date of MS diagnosis + 1) / 30.4375.
The following conversion will be applied as appropriate:
x
Time since last relapse (months) = Time since last relapse (years) * 12,
x
Time since last relapse (months) = Time since last relapse (days) / 30.4375.
Age at diagnosis of MS and age at onset of spasticity due to MS are only using year because only year of 
birth is planned to be collected.
If date of MS diagnosis and/or date of onset of spasticity due to MS are unknown or partial, they will be
imputed as follow:


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x
if only day is missing, it will be imputed to the 15th of the month,
x
If day and month are missing, they will be imputed to the 30 June of the year,
x
However, if any of these dates fall after the informed consent date, they will be set to the informed 
consent date. If the date of onset of spasticity due to MS before the date of MS diagnosis due to 
imputation rule, it will be set to the date of MS diagnosis. 
10.13 Renal Function Formula 
Estimated Glomerular filtration rate (eGFR)
For the purpose of summary, the eGFR collected by central laboratory will be used.
eGFR will also be categorized as follows:
x
≥ 90 as normal,
x
>= 60 and < 90 as mild reduction,
x
>= 30 and < 60 as moderate reduction,
x
>= 15 and < 30 as severe reduction,
x
<15 as end stage kidney failure.
10.14 Prior and Concomitant Medication Start/Stop Date Imputation Rule
Table 10.14-1 Imputation Rules for Partial Medication Dates (D = day, M = month, Y = year)
Parameter
Missing
Additional Conditions
Imputation
Start date for 
concomitant 
meds
D only
M and Y same as M and Y of first dose
of study drug
Date of first dose of study drug
M and/or Y not same as date of first dose 
of study drug
First day of month but should fall on or 
after first study drug intake or if impossible 
after informed consent date
M and D
Y same as Y of first dose of study drug 
intake during Period 1 and 2
Date of first dose of study drug
Y after Y of first dose of study intake 
during period 1 but same Y as 1st study 
drug intake during Period 2
Date of first drug intake during period 2
Y after Y of last study drug intake
The earliest date between date of last 
study drug intake and end of study date
M, D, and Y
Not allowed by the system
Not applicable
Stop date for 
concomitant 
meds
D only
M and Y same as M and Y of last dose of 
study drug
The earliest date between date of last 
dose of study drug and end of study date
M and/or Y not same as date of last
dose of study drug
The earliest date between last day of 
month and end of study date
M and D
Not allowed by the system
Not applicable
M, D, and Y
Not allowed by the system
Not applicable
Meds = Medications.
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop 
date month.
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the 
start day month.


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10.15 Mobile Health Data handling
Data downloaded from the Mobile Health platform (MHP) such has number of morning and evening sprays 
administered, NRS scales, number of spasm counts, C-SSRS questionnaire, MSSS-88 questionnaire have 
specific information to link the date MHP data were submitted to the date the data are referring to which 
have to be reported in SDTM and ADAM as detailed in Table . In practice, any time the variable XGRID 
contains the term “Late” the date to be used refers to the day before the one coming from MHP.
Table 10.15-1 MHP data - Date Handling
XPGRID 
Explanation
Initial on time Diary
Served from 6:00pm to 11:59 pm to the day a participant is moved to screening
Initial late Diary
Served from 12:00 am to 03:05 pm the next morning when the initial On Time Diary 
was NOT completed the previous day
On time diary
Served from 6:00pm to 11:59 pm when the Initial On Time, On time, or Missed On 
Time Diary was completed the previous day
Late diary
Served from 12:00 am to 03:05 pm when On Time Diary was NOT completed the 
previous day
Missed on time
Served from 6:00pm to 11:59 pm when an Initial Late, or Missed Late Diary was 
served on the same day
Missed late
Served from 12:00 am to 03:05 pm when the Missed On Time Diary was Not 
completed the previous day
10.16 Modified Ashworth Scale (MAS) Transformed Score
The MAS will be conducted and scored on 10 lower limb muscle groups (hip flexors and adductors, knee 
flexors and extensors, and plantar flexors) on the left and the right side of the body at Screening, Day 1 H0, 
D1H3 and D21 each treatment period.
For the purpose of the analysis, the result of each of the 10 MAS scores will be transformed using the 
following algorithm: MAS untransformed [to MAS transformed] scores; 0[0], 1[1], 1+[2], 2[3], 3[4] and 4[5].
Each MAS transformed score is ranging from ‘0’ (No increase in muscle tone) to ‘5’ (Affected part rigid in 
flexion or extension).
These scores will then be used to derive 3 mean Lower Limb Muscle Tone (LLMT) measures at D1H0, 
D1H3 and D21 of each treatment period.
x
The LLMT-6: defined as the average of the 6 individual MAS transformed scores of knee flexors, knee 
extensors, and plantar flexors on both sides of the body. For any given patient, at a given visit, the 
LLMT-6 will be set to missing if individual MAS transformed scores are missing for 3 or more of the 
6 specified muscle groups (as described in Table 10.16-1),
x
The LLMT-10: defined as the average of the 10 individual MAS transformed scores of knee flexors, 
knee extensors, plantar flexors, hip flexors and hip adductors on both sides of the body. For any given 
patient, at a given visit, the LLMT-10 will be set to missing if individual MAS transformed scores are 
missing for 5 or more of the 10 specified muscle groups (as described in Table 10.16-1),
x
The LLMT-4 defined as the average of the 4 individual MAS transformed scores of knee flexors, knee 
extensors on both sides of the body. For any given patient, at a given visit, the LLMT-4 will be set to 
missing if individual MAS transformed scores are missing for 2 or more of the 4 specified muscle groups
(as described in Table 10.16-1).
In addition, LLMT-6/LLMT-4/LLMT-10 scores derived with individual MAS transformed score missing in at 
least one muscle group will be identified.


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Table 10.16-1 Lower Limb Muscle Tone - Missing Data Handling
Parameter
Number of items (muscle groups)
included in score derivation
Minimum number of muscle group
scores required for score derivation (at 
least 50%)
LLMT-4
4
3
LLMT-6
6
4
LLMT-10
10
6
LLMT-4 = Lower Limb Muscle Tone-4; LLMT-6 = Lower Limb Muscle Tone-6; LLMT-10 = Lower Limb 
Muscle Tone-10.
The change and percentage change from baseline will then be calculated (as respectively described in 
Section 10.3 and in Section 10.4) for each LLMT score. 
The percentage change from baseline values will also be categorized as ≤- 20%, ≤ -30%, ≤ -40% and 
≤ -50% to assess an improvement of respectively ≥20%, ≥30%, ≥40% and ≥50%
Although unlikely to occur as per inclusion criteria 6.1.5, if a baseline LLMT score is equal to 0, the 
percentage change from baseline will be imputed using the following formula:
x
Percentage change from baseline =(x+1)*100, where x is the post baseline value .
Missing LLMT scores will be considered as not having met any of the improvement criteria (imputed as 
failure).
10.17 Timed 25-Foot Walk
The T25FW is the time needed for a patient to walk 25-feet and will be performed at Day 1 H0 and D21 of 
each treatment period. The test consists of two trials separated by a 5-minute rest period. The maximum 
duration of each trial is set to 3 minutes (180 seconds).
The average T25FW (expressed in seconds) will be derived for each patient as the average of the two 
trials..
If a patient only performs 1 of the 2 trials at a given analysis day, the unperformed trial will be imputed using
the highest T25FW (180 seconds) to perform the main analysis. An exploratory analysis will also be 
conducted without imputing unperformed trial as missing thus, leading to a missing average T25FW.
If a patient is not using the same device or is introducing a device within a given treatment period, the 
average T25FW will be set to missing.
The change and percentage change from baseline will then be calculated (as respectively described in 
Section 10.3 and in Section 10.4).
The percentage change from baseline will be categorized as ≤= -20% and > -20% to assess respectively 
≥20% improvement (as response) and < 20% improvement (as non–response) using imputed T25FW (as 
described above).
Missing average T25FW will be considered as not having met the improvement criteria (imputed as failure).
10.18 11-point Numerical Rating Scale Score (NRS-Spasticity Score)
The 7-day average 11-point NRS spasticity score will be derived for each patient as the mean NRS-
spasticity score recorded in the eDiary during the last 7 days preceding Period 1 Day 1 H0 (Baseline), and 
Day 15 and D21 of each treatment period as follows:
ܵݑ݉݋݂ݐℎܴ݁ܰܵݏ݌ܽݏݐ݅ܿ݅ݐݕݏܿ݋ݎ݁ݏ݀ݑݎ݅݊݃ݐℎ݁7 −݀ܽݕ݌݁ݎ݅݋݀
ܰݑܾ݉݁ݎ݋݂݀ܽݕݏ݅݊ݓℎ݅ܿℎݐℎ݁daily diary ݓܽݏܿ݋݉݌݈݁ݐ݁݀݀ݑݎ݅݊݃ݐℎ݁7 −݀ܽݕ݌݁ݎ݅݋݀
For each assessment timepoint, the 7-day average 11-point NRS-spasticity score will be set to missing if 
scores are missing for 4 days or more in total or for 3 consecutive days within each 7-day period.


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In case of the diary data are available but the visit does not take place the target visit date will be used.
On-treatment / off-treatment assessment
A 7-day average 11-point NRS spasticity score will be considered on-treatment if derived using only post 
baseline daily scores collected on or before the date of IMP discontinuation and will be considered 
off-treatment otherwise.
In case of IMP discontinuation, if possible with regards to missing data rule specified just above, the 7-day 
average 11-point NRS spasticity score considered on-treatment will also be derived using only 
post-baseline scores collected on or before the date of IMP discontinuation.
The change from baseline will then be calculated (as respectively described in Section 10.3).
10.19 Daily Spasm Count
The 7-day average daily spasm count will be derived for each patient using the number of spasms recorded 
in the eDiary during the last 7 days preceding Period 1 Day 1 H0 (Baseline), and Day 15 and D21 of each 
treatment period as follow:
ܶ݋ݐ݈ܽݏ݌ܽݏ݉ܿ݋ݑ݊ݐ݀ݑݎ݅݊݃ݐℎ݁7 −݀ܽݕ݌݁ݎ݅݋݀
ܰݑܾ݉݁ݎ݋݂݀ܽݕݏ݅݊ݓℎ݅ܿℎݐℎ݈݁݀ܽ݅ݕ݀݅ܽݎݕݓܽݏܿ݋݉݌݈݁ݐ݁݀݀ݑݎ݅݊݃ݐℎ݁7 −݀ܽݕ݌݁ݎ݅݋݀
For each analysis timepoint, the 7-day average daily spasm count will be set to missing if spasm counts 
are not collected during 4 days or more in total or for 3 consecutive days during the 7-day period.
In case of the diary data are available but the visit does not take place the target visit date will be used.
On-treatment / off-treatment assessment
A 7-days average daily spasm count will be considered on-treatment if derived using only post-baseline 
daily records collected on or before the date of IMP discontinuation and will be considered off-treatment 
otherwise.
In case of IMP discontinuation, if possible with regards to missing data rule specified just above, the 7-day 
average daily spasm count considered on-treatment will also be derived using only post- baseline spasm 
counts collected on or before the date of IMP discontinuation.
Missing daily spasm count information
If for a given day, the spasm count is missing whereas the eDiary has been filled by the patient, the number 
of spasms will be imputed to “0” to derive the 7-days average daily spasm count.
The change from baseline will then be calculated (as respectively described in Section 10.3).
10.20 Multiple Sclerosis Spasticity Scale (MSSS-88)
The MSSS-88 will be completed at D21 of each period, and 8 sub-scales representing 8 domains along 
with a total score will be derived by summing each of the constitutive items provided that at least 50% of 
the items are answered. Missing responses will be replaced by the mean score of the items completed.
The questions will be grouped as follows:
x
3 spasticity specific symptoms
o
Muscle Stiffness: sum of questions 1 to 12,
o
Pain and Discomfort: sum of questions 13 to 21,
o
Muscle Spasms: sum of questions 22 to 35,
x
3 areas of physical functioning
o
Activity of Daily living (ADL): sum of questions 36 to 46,


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o
Ability to Walk: sum of questions 47 to 56,
o
Body Movement: sum of questions 57 to 67,
x
2 area of psychosocial impact
o
Emotional health: sum of questions 68 to 80,
o
Social Functioning: sum of questions 81 to 88,
x
Total score
o
Sum of the 8 non-missing sub-scales after missing data rule has been applied for each subscale, 
otherwise set to missing if any of the sub-scales is missing.
Table 10.20-1 Multiple Sclerosis Spasticity Scale - Missing Data Handling
Subscale and total score
Number of questions included 
in subscale and total score
Minimum number of questions required 
for score derivation (at least 50%)
Muscle Stiffness
12
6
Pain and Discomfort
9
5
Muscle Spasms
14
7
Activity of Daily living 
11
6
Ability to Walk
10
5
Body Movement
11
6
Emotional health
13
7
Social Functioning 
8
4
10.21 Adverse Events
10.21.1 Start and Stop Date Imputation
Table 10.21-1 Imputation Rules for Partial Adverse Events Start/Stop Dates 
Parameter
Missing
Additional Conditions
Imputation
Start date for AEs
D
M and Y same as M and Y of first dose of 
study drug
Date of first dose of study drug
M and/or Y not same as date of first dose 
of study drug
First day of month but should fall after 
1st study drug intake or if impossible 
after informed consent date
D and M
Y same as Y of first dose of study drug 
intake during period 1 and 2
Date of first dose of study drug
Y after Y of first dose of study intake 
during Period 1 but same Y as 1st study 
drug intake during Period 2
Date of first drug intake during period 2
Y prior to Y of first dose of study drug but 
same as Y of informed consent date
Date of informed consent
Y after Y of last study drug intake
The earliest date between date of last 
study drug intake + 14 days and end of 
study date
D, M, Y
Not allowed by the system
Not applicable
Stop date for AEs
D
M and Y same as M and Y of last dose
of study drug
The earliest date between date of last 
dose of study drug and end of study date
M and/or Y not same as date of last dose 
of study drug
The earliest date between last day of 
month and end of study date
D and M
Not allowed by the system
Not applicable
D, M, Y
Not allowed by the system
Not applicable
AE = Adverse events; D = day; M = month; Y = year
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month.
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month.


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10.21.2 COVID-19 AE
A confirmed or suspected COVID-19 AE will be any adverse event for which the AE term or the preferred 
term include the character “COVID-19” but should not be “COVID-19 ELISA test negative”.
For instance, confirmed COVID-19 TEAE will be reported as:
x
COVID-19 infection,
x
COVID-19 disease,
x
COVID-19 pneumonia,
x
COVID-19 respiratory infection,
x
Asymptomatic COVID-19,
whereas suspected COVID-19 AE will be coded as Suspected COVID-19.
10.21.3 Time to First Onset of AE
The time to first onset of AE will be defined by study period as:
x
AE start date – IMP start date in the studied period
For AEs with an onset date occurring during the 21-days on-treatment safety Period 1 (as defined in 
Section 10.1.1) the IMP start date refers to the date of 1st IMP spray intake during Period 1.
For AEs with onset date occurring during the 21-days on-treatment safety Period 2 (as defined in 
Section 10.1.1), the IMP start date refers to Period 2 start date provided that the patient is exposed during 
Period 2. 
Based on the above value time to first onset of AE will be categorized as:
x
1-7 days, 
x
8 to 14 days, 
x
15 to 21 days, 
x
> 21 days.
If onset time is shorter as 1 day, it will be included in the 1-7 days category.
For the purpose of time-to-event analysis, censoring rules are defined in Section 12.7.2.3.
10.21.4 AE Duration
The AE duration (expressed in days) will be defined as:
x
AE stop date – AE start date + 1 day.
The duration will not be derived in case of partial or missing start or stop date.
Based on the above value the AE duration will also be categorized as follows:
x
1-7 days,
x
8 to 14 days,
x
15 to 28 days,
x
28 to 42 days,
x
43 to 61 days,
x
> 61 days,
x
Ongoing,
x
Indeterminate.


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If AE stop date is missing and the outcome of the AE is “Not recovered, Not resolved”, the AE will be 
categorized as “Ongoing”.
If the AE start date is partial or missing and the AE is not considered as “Ongoing”, the AE will be classified 
as “Indeterminate”.
If AE duration is less than 1 day, the AE will be counted in the 1-7 days category.
10.22 Laboratory data
Strip-sign handling
In cases a hematology or chemistry value is recorded as ‘>x’ or ‘<x’, the value will be imputed as “x” to 
perform summary statistics but the strip sign will be presented in individual data listings.
10.23 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS scale is composed of 11 items answered Yes or No. Ten of them are ordered in categories 
as described below to determine the studied endpoints.
5 subtypes of suicidal ideation:
x
Category 1 – Wish to be Dead,
x
Category 2 – Non-specific Active Suicidal Thoughts,
x
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act,
x
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan,
x
Category 5 – Active Suicidal Ideation with Specific Plan and Intent.
5 subtypes of suicidal behavior:
x
Category 6 – Preparatory Acts or Behavior,
x
Category 7 – Aborted Attempt,
x
Category 8 – Interrupted Attempt,
x
Category 9 – Actual Attempt (non-fatal),
x
Category 10 – Completed Suicide.
Last item:
x
Self-injurious behavior without suicidal intent.
The C-SSRS also includes a suicidal ideation intensity rating from 1 (least severe) to 5 (most severe).
The following composite endpoints will be assessed based on the categories described above:
x
Suicidal ideation (Yes/No): is Yes if one of the categories from 1 to 5 is answered Yes,
x
Suicidal behavior (Yes/No): is Yes if one of the categories from 6 to 10 is answered Yes,
x
Suicidal ideation or behavior (Yes/ No): is Yes if one of the categories from 1 to 10 is answered Yes,
x
Self-injurious behavior without suicidal intent (Yes /No): is Yes if this question is answered Yes.
The following scores will be derived as follows:
x
Suicidal ideation score is rating from 1 to 5 the most severe suicidal ideation category answered Yes 
and is assigned to 0 if categories 1 to 5 are answered No,


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x
Suicidal ideation intensity rating score (0 to 25) will be defined as the sum of the 5 features described 
below (ranging from 0 to 5, 0 being the least severe and 5 being the most severe) rated with respect 
to the most severe type of ideation category,
o
Frequency,
o
Duration,
o
Controllability,
o
Deterrents,
o
Reason for ideation. 
Comparative endpoints will also be defined as described below:
Treatment emergent outcomes will include any events that first emerge of worsen, whereas emergent
outcomes will refer to outcomes that first emerge.
x
Treatment-emergent suicidal ideation compared to recent history (not using C-SSRS taken during 
screening): 
o
Increase from baseline in suicidal ideation score,
o
Increase from last on-treatment visit to follow-up (FU) visit,
x
Treatment-emergent serious suicidal ideation compared to recent history (not using C-SSRS taken 
during screening):
o
Increase in suicidal ideation score from a baseline (0-3) to (4-5),
o
Increase in suicidal ideation score from last on-treatment visit (0-3) to FU visit (4-5),
x
Emergence of a serious suicidal ideation compared to recent history (not using C-SSRS taken during 
screening):
o
Increase in suicidal ideation score from baseline (0) to (4-5),
o
Increase in suicidal ideation score from last on-treatment visit (0) to FU visit (4-5),
x
Emergence of suicidal behavior compared to all prior (using C-SSRS taken at and post screening 
assessments): 
o
Occurrence of suicidal behavior (categories 6-10) post baseline with no screening or baseline 
suicidal behavior,
No imputation should be done with regards to missing data.
Interim Analyses
No interim analysis will be conducted. 
However, a blinded assessment of the estimate of the variability of the treatment difference will be 
conducted during the study and the sample size recalculated using this blinded estimate. The study will still 
be ongoing at time of these blinded analyses and the decision whether or not to increase the sample size 
will be based on the Sponsor judgment.
This blinded review of the data will take place once, using the first 50% of the patients, from FAS, having 
completed both treatment periods, and for whom all MAS assessment data are cleaned (no open queries), 
coded and reconciled.
11.1 Blinded Sample Size Reassessment
The sample size estimate as described in Section 8.2 was assuming mean treatment difference of -0.30 
and a standard deviation of paired difference of 0.71.


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Let ݀௜denote the difference between Period 2 and Period 1 for Patient ݅(݅= 1 to n) when n is the number 
of patients, at the interim analysis, having completed Period 1 and Period 2 on-treatment  and for whom 
LLMT-6 score (as described in Section 10.16) can be derived for both treatment periods.
Let ݀̅ is the overall mean of all ݀௜
When the ݊patients complete the assessment on the primary endpoint, the variability is estimated by 
pooling all the patients as follows 
ߪොௗ௜௙௙
ଶ
=
1
(݊−1) ෍൫݀௜−݀̅൯²
௡
௜
The re-calculated sample size is given by 
ܰ෡= ൫ݐଵିఈ+ ݐଵିఉ൯
ଶ
ߜଶ
ߪොௗ௜௙௙
ଶ
That is,
ܰෝ= ൫ݐ1−ߙ+ ݐ1−ߚ൯
2
ߜ2
1
(݊−1) ෍(݀݅−݀ത)²
݊
݅
where ߜis the target treatment effect size. This re-calculated sample size will be provided to the sponsor
to aid decision-making; however the sponsor has the final decision as to whether to increase the sample 
size and to what number.
11.2 Other Analyses
Baseline efficacy endpoints will be summarised and no other additional analyses are planned during the 
blinded sample size reassessment. 
Statistical Methods
All analyses will use SAS® version 9.4 or higher. However, pharmacokinetic analyses may be performed 
using a dedicated software as mentioned in Section 12.6.
Standard Summary Statistics for Continuous and Discrete Variables. 
Summaries will be tabulated either per treatment arm or per treatment sequence, and overall (when 
deemed appropriate), unless otherwise specified.
Unless otherwise noted, categorical variables will be summarized using non-missing counts and 
percentages. Percentage will be using the number of patients (or the number of patients at risk) in the 
treatment arm/treatment sequence and as appropriate in the analyzed categories as denominator. 
Percentages will be rounded to one decimal place, except 100% will be displayed without any decimal 
places and percentages will not be displayed for zero counts.
Odd ratios (ORs) will be provided as appropriate. Odd ratios will be presented with 2 decimal places
Continuous data will be summarized using the number of non-missing observations (n), mean, standard 
deviation (SD), median, first quartile (Q1), third quartile 3 (Q3), minimum (Min), and maximum (Max). 
Minimum and maximum, will be rounded to the precision of the original value. Mean, median, Q1 and Q3
will be rounded to 1 decimal place greater than the precision of the original value. The SD will be rounded 
to 2 decimal places greater than the precision of the original value. Confidence intervals (CIs), LS means,
standard error (SE), geometric mean, geometric SD and coefficient of variation (CV) (%) will be provided 
as appropriate. Confidence intervals, LS means and geometric mean will be presented with the same 
precision as the mean value whereas SE and geometric SD will be presented with the same precision as 
SD and the CV (%) will be presented with 1 decimal place.


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Inferential Statistics
P-values will be rounded to 4 decimal places. P-values less than 0.0001 will be presented as “<0.0001” 
and p-values greater than 0.9999 will be presented as “>0.9999.”
Statistical hypothesis testing will be 2-tailed and carried out at the 5% level of significance. Testing will 
be performed on the primary endpoint and secondary endpoint as appropriate. 
To control for Type 1 error at a 2-sided alpha of 0.05, the primary endpoint and key secondary endpoint 
will be tested hierarchically, starting with the primary endpoint and followed by the secondary endpoint. No 
additional adjustments for multiplicity will be made for the other secondary endpoints and for exploratory 
endpoints although nominal p-values will be presented.
Individual Data Listings
All the listings will be displayed sorted by treatment sequence, patient identifier and date of assessment. 
They will present age, sex, race and country.
For those listings presenting on-treatment assessment post randomization, treatment arm along with the 
treatment period will also be displayed. A flag informing whether or not the data are impacted by 
COVID-19 may also be added.
12.1 Patient Disposition
The number and percentage of patients screened, re-screened, randomized and not randomized along with 
reason of screen failure will be presented using the Screening Analysis Set.
The number of patients randomized, randomized and treated, randomized and not treated, and the number 
of patients in each analysis set will be summarized per treatment sequence for the Randomized Analysis
set. 
The number and percentage of patients will also be summarized for the following patient disposition 
categories:
1.
Completed study drug treatment per protocol 
2.
Discontinued study drug early and the reason for discontinuation
3.
Completed the study including follow-up period
4.
Discontinued from the study early and the reason for discontinuation
The table will be presented by treatment sequence, per period and overall using the Randomized Analysis
Set and will be repeated for the different subgroups presented in Table 12.1-1.
Table 12.1-1 Subgroups Applied to Patient Disposition
Group Variables
Subgroup
Comments
Sex
Male
Female
Age group
x
<= 18 years
x
> 18 and ≤ 45
x
≥ 46 to ≤ 65
x
> 65
According to patient ‘s distribution within age, 
age group may be differently defined
Detailed derivation is given in Section 10.10
Race
White
Black or African American
Asian
American India or Alaska Native
Native Hawaiian or Other Pacific Islander
Other
According to patient’s distribution within race 
some races may be grouped together
Prior cannabis 
use
Yes
No


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Number of current 
antispasticity 
medication
0
1
2
≥3
A cumulative incidence plot of permanent IMP discontinuation due to any reason will be provided by 
treatment sequence on the Safety Analysis Set. The Time to treatment discontinuation (in days) is defined 
as the number of days from 1st IMP intake until permanent treatment discontinuation (as detailed in Section
10.6). Patients who will not permanently withdraw from study drug will be censored to the earliest of last 
contact date and their date of completion of Period 2,whereas patients lost to follow-up will be censored at 
their last contact date.
A cumulative incidence plot of study discontinuation due to any reason will be provided by treatment 
sequence on the Randomized Analysis Set. The Time to study discontinuation (in days) is defined as the 
number of days from randomization until study discontinuation (as detailed in Section 10.6). Patients who 
will not permanently withdrawn from study drug, or lost to follow-up will be censored at their last contact 
date.
Each cumulative incidence plot will only be provided if more than 5 patients are presenting an event in each 
treatment sequence (i.e., premature end of treatment, premature study discontinuation).
A tabulation based on the Randomized Analysis Set of the number and percentage of patients randomized 
at country and center will be presented per randomization sequence and overall.
All patient’s disposition data will be listed by treatment sequences.
12.2 Demographic and Baseline Characteristics
For all demographic and baseline characteristics assessments presented below the baseline is defined as 
the last available assessment collected before the first administration of study drug. Further details are 
given in Section 10.2.
Demographic and baseline characteristics will be summarized by treatment sequence and overall using 
appropriate summary statistics as described in Section 12.0 in the FAS and the Randomized Analysis Set
if different from FAS.
If deemed appropriate (i.e., more than 20 % of the randomized patients experiencing at least one major 
protocol deviation, as defined in Appendix 1), demographic and selected baseline characteristics will also 
be summarized using the PP Analysis Set, and may also be summarized on the Study Completer Analysis 
Set.
All summaries for continuous parameters will be based on non-missing observation. For categorical 
variables, the percentage will be based on the total number of patients, within the studied dataset, overall 
and per treatment sequence (i.e., each denominator includes the number of patients with missing/unknown 
value for this parameter). 
Demographic, baseline characteristics, and disease history data will also be listed with a flag identifying 
those belonging to the FAS, the PP Analysis Set, the Study Completer Analysis Set, and the Safety Analysis 
Set.
All baseline safety and efficacy parameters (apart those presented below) are presented along with 
summary statistics in the safety and the efficacy sections, respectively (Section 12.7 and Section 12.5).
12.2.1 Demographics Characteristics
As defined in Section 10.10, the following demographic and baseline characteristics will be summarized:
x
Age (years),
x
Age groups ( ≤18,> 18 to ≤ 45; ≥ 46 to ≤ 65; > 65 years old),
x
Sex (Male, Female),


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x
Race (White, Black or African American, Asian, American India or Alaska Native, Native Hawaiian or 
Other Pacific Islander, other) (per legal data protection law),
x
Country (Poland, Czech Republic),
12.2.2 Baseline Physical Examination
As defined in Section 10.11. the following baseline physical examination will be summarized.
x
Baseline height (cm),
x
Baseline weight (kg),
x
Baseline BMI (kg/m²),
x
Baseline BMI category (< 18.5 as underweight; ≥ 18.5 and < 25.0 as normal or Healthy Weight; 
≥25.0 and < 30.0 as overweight; ≥ 30 as obese),
12.2.3 Baseline Vital Signs
The following baseline vital signs including postural drop assessment will be summarized.
x
Baseline Supine Systolic blood pressure (SBP) (mmHg), 
x
Baseline Orthostatic SBP (mmHg)
Orthostatic SBP being defined as supine SBP- Standing SBP,
x
Baseline Orthostatic SBP ≥- 20 mm Hg,
x
Baseline Supine Diastolic blood pressure (DBP) (mmHg), 
x
Baseline Orthostatic DBP (mmHg)
Orthostatic DBP being defined as supine DBP- Standing DBP,
x
Baseline Orthostatic DBP ≥- 10 mm Hg,
x
Baseline Supine Heart Rate (HR) (Beats/min), 
x
Baseline Orthostatic HR (Beats/min)
Orthostatic HR being defined as supine HR- Standing HR,
x
Proportion of patients who meet criteria for orthostatic hypotension.
defined as either drop in SBP of 20 mmHg or greater or drop in DBP of 10 mmHg or greater.
12.2.4 Medical History
Previous and current medical conditions (medical history) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 24.0 or higher and will be summarized by system organ class 
(SOC) and preferred term (PT) per treatment sequence and overall in the FAS.
12.2.5 Disease Characteristics
The following disease characteristics will be summarized.
Multiple sclerosis diagnosis
As defined in Section 10.12:
x
MS subtype (primary progressive, secondary progressive, relapsing-remitting),
x
Time since diagnosis of MS (years),
x
Age at diagnosis of MS (years),
x
Time since onset of spasticity due to MS (expressed in months or years as appropriate),
x
Age at onset of spasticity due to MS (years),
x
Time between MS diagnosis and onset of spasticity due to MS (months or years as appropriate),


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o
also presenting the number and percentage of patients experiencing spasticity before MS 
diagnosis,
x
Time between MS diagnosis and onset of spasticity due to MS (years),
x
Number of relapses in the past 12 months,
x
Time since last relapse (months or years as appropriate),
Current MS medications
As defined in Section 12.3.2, the following summaries relative to current MS medications will be provided:
x
At least 1 MS medication
o
At least 1 antispasticity medication
x
Baclofen,
x
Tizanidine,
x
Dantrolene,
x
Benzodiazepine,
x
Muscle relaxants,
x
Botulinum toxin,
x
Gabapentin,
x
Pregabalin,
x
Other.
o
Number of antispasticity medications used
x
0,
x
1,
x
2,
x
>= 3.
o
At least 1 MS disease modifying drug (DMD),
o
At least 1 medication to treat other MS Symptoms,
x
Dalfampridine,
x
Fampridine.
Current MS medications are those taken at time of randomization/1st IMP dosing as described in 
Section 12.3.2). They will be determined based on information retrieved from eCRF concomitant medication 
form; further determination criteria being given in Appendix 10.
Prior use of cannabis or cannabinoid
At Screening (Visit 1), any intermittent or regular previous use of cannabis or cannabinoid products for 
medical or recreational purposes will be recorded. 
Prior use of cannabis or cannabinoid will be summarized for the following
x
Prior use of cannabis or cannabinoid
o
Medicinal use,
o
Recreational use.
12.2.6 Baseline Efficacy Endpoints
The following endpoints derived from MAS transformed scores (as defined in Section 10.16) will be 
summarized:
x
Baseline Lower Limb Muscle Tone-6,


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x
Baseline Lower Limb Muscle Tone-4,
x
Baseline Lower Limb Muscle Tone-10,
x
Other Baseline Efficacy Endpoints
The following other endpoint will be summarized:
Baseline 7-day average NRS Spasticity Score
12.2.7 Baseline Safety Endpoints
The following baseline safety endpoints linked to renal function and C-SSRS will be summarized
x
Renal function (as defined in Section 10.13)
o
Baseline eGFR (ml/min/1.73m²),
o
Baseline eGFR category (ml/min/1.73m²): ≥ 90 as normal, ≥ 60 and < 90 as mild reduction, ≥ 30 
and < 60 as moderate reduction, ≥ 15 and < 30 as severe reduction, <15 as end-stage kidney 
failure.
x
C-SSRS (as defined in Section 10.23)
o
Baseline Suicidal Ideation Score,
o
Baseline Suicidal Behavior.
12.3 Treatments
12.3.1 Extent of Exposure
Exposure to study drug, IMP dosing, treatment compliance and drug accountability will be presented using 
the Safety Analysis set.
12.3.1.1 Duration of Therapy
The extent of exposure will be for each study drug (e.g., nabiximols or placebo) the total number of days of 
administration of IMP, ignoring temporary drug discontinuation, within the designated treatment period.
The duration of exposure (as defined in Section 10.7) will be summarized descriptively as quantitative 
variable (number, mean, SD, median, Q1, Q3, minimum and maximum) but also presenting the total 
number of days and the mean number of days (expressed in patient-week) as defined in Section 10.7.
The number and percentage of patients with an extent of exposure within a predefined study day range will 
also be presented for each of the following categories and the cumulative distribution according to these 
categories:
x
Day 1 to 7,
x
Day 8 to 14, 
x
Day 15 to 21,
x
> D21.
Extend to exposure will also be summarized per treatment arm by subgroups of interest as presented in 
Table 12.1-1.
12.3.1.2 IMP Dosing
Patients are expected to record, daily, the number of morning and evening spray(s) they have taken in their 
eDiary. This information will be integrated in the eCRF.
At Day 15 of each treatment period (at the end of the titration phase), the daily number of sprays to be 
taken by each patient defined as the optimized dose will be reported in the eCRF “Dose adjustment” form. 


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Whenever a patient has taken an amended dose, this will also be reported in the eCRF “Dose adjustment” 
form along with start and stop date of each amended dose and the reason why the optimized dose was 
amended (e.g., adverse event, insufficient therapeutic effect, other).
During the Titration Phase (up to Day 14)
The number of sprays taken will be summarized by day as quantitative variable (n, mean, SD, median, Q1, 
Q3, min and max) but also presenting per day, the number of sprays administered as a categorical variable.
Additionally,
x
the rate of missing diary day information (%),
x
the patient percentage of imputed diary days (%),
x
the patient total number of daily sprays,
x
the patient  mean number of daily sprays,
x
the patient  mode number of daily sprays,
x
the patient  median number of daily sprays,
x
the rate of ”0” total daily sprays (%),
x
the rate of “>12” total daily sprays (%),
as defined in Section 10.8.2 and Section 10.9, will be summarized per treatment arm as quantitative 
variable (n, mean, SD, median, Q1, Q3, min and max).
During the Maintenance Phase (Day 15 to D21) 
As defined in Section 10.8.2,
x
the patient total number of daily sprays,
x
the patient mean number of daily sprays,
x
the patient mode number of daily sprays,
x
the patient median number of daily sprays
Combined: During the Titration Phase (up to Day 14) + Maintenance Phase (Day 
15 to D21)
x
the rate of ”0” total daily sprays (%),
x
the patient maximal number of daily sprays
will be summarized as quantitative variable (n, mean, SD, median, Q1, Q3, min and max).
In addition, the patient mean number of daily sprays used by patient will be categorized as ≤6 sprays; > 6
to ≤ 12 sprays and >12 sprays and summarized.
As defined in Section 10.9,
x
the rate of missing diary day information (%),
x
the patient percentage of imputed diary days (%),
x
the rate of “0” total daily sprays (%),
x
the rate of >12 total daily sprays (%)
will be summarized per treatment arm as quantitative variable (n, mean, SD, Median, Q1, Q3 min and max).
These four parameters are also part of compliance assessment (as presented in Section 12.3.1.3). 
Graphical Representations


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The mean (± SD) number of sprays will also be presented by day using a line plot by treatment arm.
The patient mean number of daily sprays during the titration phase, during the maintenance phase and 
overall will also be presented by treatment arm using a cumulative distribution function.
12.3.1.3 Compliance
Compliance
Based on the total daily number of sprays taken recorded by the patient on the eDiary and on the optimized 
dose defined at Day 15 of each treatment period and collected on the eCRF “Dose adjustment” form the 
compliance to study drug will be assessed, during the maintenance phase of each treatment period, by the 
means of the 4 below parameters:
x
The compliance (%),
x
The rate of “0 total daily spray (%),
x
The rate of “> 12” total daily sprays (%),
x
The rate of missing diary day IMP information (%),
which will be summarized by treatment arm.
Detailed calculation along with missing data handling is described in Section 10.9.
Furthermore, the percentage of patients meeting study drug compliance will be presented in the following 
categories of days in the allowed dose range (coded as yes/no): < 80%, ≥ 80% to < 90%, ≥ 90% to < 100 % 
and = 100%.
Additionally, the patient percentage of imputed diary days (as defined in Section 10.8.2) which 
represents the percentage of days where missing morning and/or evening number of sprays taken have 
been imputed to ‘0’ to derive the total daily IMP dose and thus compliance is based on imputed total number 
of sprays taken that day will be described by treatment arm.
Optimized Dose
The optimized dose will be summarized as quantitative and categorical variable per treatment arm. The 
need of optimized dose adjustment will also be described along with reason for dose adjustment.
12.3.1.4 Drug Accountability
Study drug accountability including volume dispensed (mm), residual volume (mm), volume used (mm),
number of sprays taken and eDiary sprays accountability (%) will be listed.
12.3.2 Prior, Concomitant and Prohibited Therapies
For any medications / non-drug therapies initiated or ongoing since Visit 1 (Screening), the start and stop 
date, dose, unit, frequency, route of administration, and indication will be recorded respectively in the 
‘Concomitant Medication’ eCRF page and in the ‘Concomitant Physiotherapy’ eCRF page.
As nabiximols is being investigated as therapy in patients with spasticity due to MS, all patients must 
currently be taking at least 1 optimized oral MS antispasticity medication. Optimized oral MS antispasticity 
medications will include at least baclofen, tizanidine, and/or dantrolene (monotherapy or combination 
therapy). Their MS antispasticity medication must have been stable for at least 30 days prior to Screening 
(Visit 1) and the medication is expected to remain stable throughout the duration of the trial.
All medications will be categorized by medication anatomic and therapeutic class (ATC) according to the 
most current version of World Health Organization-Drug Dictionary (WHO-DD) global March 2021
Dictionary Version B3 or higher according to the version in used at time of database lock.
Medication used for MS will also be categorized according to information recorded in the CRF as:


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x
Disease modifying drug,
x
Antispasticity drug (baclofen, tizadinidine, dentrolene, benzodiazepine, muscle relaxants, botulinum 
toxin, gabapentin, pregabalin),
x
Other MS symptoms.
Whereas physiotherapy used will be categorized according to the reason as recorded in CRF as:
x
Spasticity,
x
Adverse events (other than spasticity),
x
Other MS symptoms,
x
Other symptoms not associated with MS.
Patients should stop taking any prohibited therapy prior to Screening (Visit 1) and, within 30 days of Visit 1
regarding use of cannabis for medical or recreational purposes or any cannabinoid-based medication. 
These medications are prohibited for the duration of the trial.
Prohibited medications are categorized as:
x
Nabiximols, cannabis or cannabinoid-based derived products,
x
Botulinum toxin injections,
x
Antipsychotic medications,
x
Benzodiazepines (if not following protocol requirements),
x
Medications that are solely metabolized by UGT1A9 (see Appendix 8),
x
Medications that are solely metabolized by UGT2B7 (see Appendix 8),
x
Strong CYP3A4 inducers (e.g., rifampicine, carbamazepine, phenytoin, phenobarbital, St John’s 
Wort) (see Appendix 8).
In order to flag prohibited medications taken in the study, each medication taken will be compared against 
a pre-specified list of all prohibited medications as presented in Appendix 7, Appendix 8 and Appendix 9
along with their determination criteria. 
All medications / non-drug therapies (e.g., physiotherapies) will be classified as follows:
x
Prior medications are those the patient used prior to the first IMP intake. Prior medications can be 
discontinued before first administration or can be ongoing during the treatment periods (and wash-out 
period).
x
Current medications are those the patient used at time of randomization and at the same time as 
study drug intake. This classification will mainly be used to summarize MS medications.
x
Concomitant medications are any medications / non-drug therapies that are ongoing at the time of 
each study medication (e.g., nabiximols, placebo) intake; these medications can be initiated
o
Before first intake of study medication.
o
At the same time of study medication.
Medications concomitant the Period 1 study medication are those:
o
Initiated before first intake of study medication,
o
Initiated and /or taken at the same time of Period 1 study medication,
o
Initiated and /or taken during the wash-out period.
Medications concomitant the Period 2 study medication are those:
o
Initiated before first intake of Period 2 study medication,
o
Initiated and /or taken at the same time of Period 2 study medication,


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x
Post treatment medications (FU medications) are any medications / non-drug therapies initiated 
following last IMP intake.
To classify each therapy in case of missing / partial start and /or stop date, imputation rules as described 
in Section 10.14 will be applied.
All medications / non-drug therapies (including physiotherapies) taken during the trial will be summarized 
in the Safety Analysis Set. If it appears that the randomized treatment arm is different from the actual 
treatment arm (for summary by treatment arm) and/or if patients belonging to the Safety Analysis Set are 
different from those belonging to the FAS, medication summaries will be presented using both study 
populations.
The number and percentage of patients using each medication along with the number and percentage of 
patients using at least one medication within each medication group will be summarized. For each summary
by treatment arm, a patient can be counted in both treatment arms for instance if:
x
A patient stops one medication on or before the wash-out period and initiates a new one belonging to 
the same ATC class
x
A patient is taking a medication concomitant to both Period 1 and Period 2.
All medications and all physiotherapy will be separately listed.
12.3.2.1 Non-MS Medications
Prior medications: The number and percentage of patient taking each non-MS prior medication will be 
summarized by treatment sequence and overall according to the first digit of the ATC class (anatomic 
category), first 3 digits of the ATC class (pharmacological category) and standard medication name.
Concomitant medications: The number and percentage of patient taking each non-MS concomitant 
medication will be summarized by treatment arm according to the first digit of the ATC class (anatomic 
category), first 3 digits of the ATC class (pharmacological category) and standard medication name.
Post-treatment medications: The number and percentage of patient taking each non-MS post-treatment 
medication will be summarized by treatment sequence according to the first digit of the ATC class (anatomic 
category) and first 3 digits of the ATC class (pharmacological category) and standard medication name.
Tables for non-MS prior and post-treatment medications will be sorted by decreasing frequency of anatomic 
class followed by pharmacological class, followed by standard medication name based on overall incidence. 
In case of equal frequency, the alphabetic order will be used.
Tables for non-MS concomitant medications will be sorted by decreasing frequency of anatomic class 
followed by pharmacological class, followed by standard medication name based on the incidence in the 
nabiximols treatment arm. In case of equal frequency, based on decreasing frequency in the placebo arm 
then in case of equal frequency the alphabetic order will be used.
12.3.2.2 Medications Used for MS
Prior medications: The number and percentage of patient taking each MS prior medication will be 
summarized by treatment sequence and overall according to the predefined categories and standard 
medication name.
Concomitant medications: The number and percentage of patient taking each MS concomitant 
medication will be summarized by treatment arm according to the predefined categories and standard 
medication name. 
Post-treatment medications: The number and percentage of patient taking each MS post-treatment 
medication will be summarized by treatment sequence according to the predefined categories and standard 
medication name.


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Tables for MS prior and post-MS medications will be sorted by decreasing frequency of standard medication 
name within each predefined category based on overall incidence. In case of equal frequency, the 
alphabetic order will be used.
Tables for MS concomitant medications will be sorted by decreasing frequency of standard medication 
name based on the incidence within each predefined category in the nabiximols treatment arm. In case of 
equal frequency, based on decreasing frequency in the placebo arm then in case of equal frequency the 
alphabetic order will be used.
12.3.2.3 Non-Antispasticity Medications and Antispasticity Medications
Prior medications: The number and percentage of patient taking either antispasticity medications or 
non-antispasticity medications will be separately summarized by treatment sequence and overall according 
to the first 2 digits of the ATC class (therapeutic category) and standard medication name.
Concomitant medications: The number and percentage of patient taking either antispasticity medications 
or non-antispasticity medications will be separately summarized by treatment arm according to the first 
2 digits of the ATC class (therapeutic category) and standard medication name.
Post-treatment medications: The number and percentage of patient taking either antispasticity 
medications or non-antispasticity medications will be separately summarized by treatment sequence 
according to the two first digits of the ATC class (therapeutic category) and standard medication name.
Tables for prior and post-treatment antispasticity or non-antispasticity medications will be sorted by 
decreasing frequency in by therapeutic class, followed by standard medication name based on overall 
incidence. In case of equal frequency, the alphabetic order will be used.
Tables for concomitant medications antispasticity or non-antispasticity medications will be sorted by 
decreasing frequency of therapeutic class, followed by standard medication name based on the incidence 
in the nabiximols treatment arm. In case of equal frequency, based on decreasing frequency in the placebo 
arm then in case of equal frequency the alphabetic order will be used.
12.3.2.4 Prohibited Medication 
Prior medications: The number and percentage of patient taking prohibited prior medications will be 
summarized by treatment sequence and overall according to the predefined categories and standard 
medication name. 
Concomitant medications: The number and percentage of patient taking prohibited concomitant 
medications will be summarized by treatment arm according to the predefined categories and standard 
medication name. 
Tables for prohibited prior medications will be sorted by decreasing frequency of standard medication name 
within each predefined category based on overall incidence. In case of equal frequency, the alphabetic 
order will be used.
Tables for prohibited concomitant medications will be sorted by decreasing frequency of standard 
medication name based on the incidence within each predefined category in the nabiximols treatment arm. 
In case of equal frequency, based on decreasing frequency in the placebo arm then in case of equal 
frequency, the alphabetic order will be used.
12.3.2.5 Physiotherapy
Summary of use of Physiotherapy will be summarized for each predefined category using the same 
approach as the one used for MS medication.
12.4 Important Protocol Deviations
All important protocol deviations (IPDs) are defined in a study specific protocol deviation guidance and 
classified as presented in Appendix 1. The IPDs that are determined to affect the primary efficacy results 


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will be classified as major IPDs as reported in Appendix 1Error! Reference source not found.. The 
occurrence of major IPDs will identify which patients maybe excluded from PP Analysis Set. 
IPDs linked to COVID-19 will be identified. Patients for which at least one IPD has been identified, will be 
listed along with their deviation reason; demographics and treatment sequence for inclusion in the clinical 
study report (CSR) based on the deviation data will be entered into the clinical trial management system
(CTMS).
The study team and the Sponsor will conduct ongoing reviews of the deviation data from both an internal 
system of record named Predictive Study Operations (PSO) and any other additional major IPDs that were 
missed and now identified through SAS programming of the blinded ADaM datasets, and the resulting set 
of evaluable patients throughout the study, adjusting the deviation criteria as seems appropriate. The PP 
Analysis Set must be finalized at the post-freeze data review meeting (or earlier), prior to database lock 
and unblinding. However, in case a patient is receiving a treatment kit he/she is not allocated to, this will be 
considered as a major IPD before unblinding but the impact on the PP Analysis Set will only be determined
following unblinding. This particular case will clearly be identified prior to database lock.
Based on the Randomized Analysis Set, the number and percentage of patients with important protocol 
deviations by category, as well as the number and percentage of patient with IPDs linked to COVID-19, by 
category, will be summarized by treatment sequence and overall.
Based on the FAS, the number and percentage of patients with at least one major IPD and the number and 
percentage of patients with major IPDs linked to COVID-19 will also be summarized by treatment sequence
and overall.
Using the Randomized Analysis Set and the Safety Analysis Set (if deemed necessary to account for any 
patients exposed out of randomization) IPDs will be listed by treatment sequence and patient identifier and 
flagged for belonging to FAS and Safety Analysis Set. In this listing major IPDs, and IPDs linked to 
COVID-19 will be identified.
Furthermore, a COVID-19 deviation listing identifying COVID-19-related IPDs will be issued including date 
of the deviation and duration of the impact.
12.5 Efficacy Analysis
All efficacy analyses, unless otherwise specified will be performed on the FAS during the 51-day 
randomized efficacy period (as defined in Section 10.1) regardless of treatment compliance and permanent 
treatment discontinuation.
To assess robustness of the results with regard to intercurrent events some efficacy analyses may be 
repeated, for instance:
x
During the 51-day on-treatment efficacy period (as defined in Section 10.1) using only on-treatment 
assessments (assessments obtained post treatment being set to missing);
x
During the 51-days randomized period (as defined in Section 10.1) using the PP analysis set, If more 
than 20% of patients from FAS are excluded from the PP Analysis Set;
x
During the 51-days randomized period using the Study Completer Analysis Set.
x
During the 51-days randomized period excluding patients having at least one efficacy assessment 
impacted by COVID-19.
12.5.1 Hypothesis Testing Strategy and Multiplicity
To control for Type 1 error at a 2-sided alpha of 0.05, the primary endpoint and key secondary efficacy 
endpoint will be tested hierarchically, starting with the primary endpoint and followed by the key secondary 
endpoint. No adjustments for multiplicity will be made for other secondary or exploratory endpoints.
12.5.2 Primary Endpoint
The primary endpoint is the estimated mean treatment difference between nabiximols and placebo on the 
estimated change from baseline to D21 on LLMT-6 score (as defined in Section 10.16), where MAS scores 


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are collected during the 51-day randomized efficacy period, for all randomized patients belonging to the 
FAS.
The comparison between nabiximols and placebo treatment arm will be performed at a type I error level of 
0.05 (two-sided).
12.5.2.1 Primary Efficacy Analysis
The primary analysis on the primary estimand (see Section 9.1), the change from baseline to D21 of each 
treatment period (as defined in Section 10.2 and Section 10.3) in LLMT-6 (as defined in Section 10.16) will 
be analyzed using a linear mixed-effects (LME) model for crossover data (as detailed in Section 12.5.2.1.8)
performed following a multiple imputation strategy applied to missing data (as presented in Section 
12.5.2.1.6 and summarized in Table 12.5-1) during the 51-day randomized efficacy period using FAS.
12.5.2.1.1 Missing Data Handling
As stated in Section 9.1, under the hypothetical strategy for handling intercurrent events, Period 2 data will 
not be collected when patients discontinue IMP during Period 1. In addition, missing data within a single 
period only may arise if patients decide to withdraw from the study or are lost to follow-up.
For patients who discontinue study before entering Period 2,
x
Not collected Period 1 data will be imputed under the missing at random (MAR) assumption if the
patient withdraws from the study due to a reason relative to COVID-19 or if the patient is randomized 
to the placebo/nabiximols treatment sequence and will be imputed under the control-based missing 
not at random (MNAR) assumption otherwise (i.e., patient lost to follow up or prematurely withdraws
from the study and randomized to nabiximols/placebo treatment sequence),
x
Not collected Period 2 data will be imputed under the MAR assumption whether or not missing data 
arise under the hypothetical strategy and whatever the treatment sequence the patient is randomized 
to.
For patients who discontinue study but enter in Period 2 not collected Period 2 data will be imputed,
x
under the MAR assumption if the patient withdraws from study due to a reason relative to COVID-19 
and/or is randomized to the placebo/nabiximols treatment sequence,
x
under the control-based MNAR assumption otherwise.
Under this framework, for those patients having their missing scores assumed MNAR, their mean profile 
will be assumed to be the same as those patients in the placebo treatment arm for the period containing 
the missing data. Details regarding missing data handling are given in Table 12.5-1 below.
Table 12.5-1 Scenarios for Methods of Imputation when Data are not Collected
Scenario
Missing Data
Period 1 Imputation
Period 2 Imputation
1. Data not collected 
under the hypothetical 
strategy for handling 
intercurrent events
Period 2 data not collected due 
to patients who discontinue 
IMP or withdraw during Period 
1/washout
N/A
Within treatment arm under 
MAR
2. Missing data arising 
due to reasons related to 
COVID-19, (and/or for 
patients assigned to 
placebo/nabiximols 
treatment sequence 
assignment)
Period 1 post baseline missing 
data but patient continues in 
study at least up to Period 2
baseline
Within treatment arm under 
MAR
Within treatment arm under 
MAR
Period 1 withdrawal
Within treatment arm under 
MAR
Within treatment arm under 
MAR (Scenario 1)
Period 2 post-baseline missing 
data/withdrawal
N/A
Within treatment arm under 
MAR


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3. Missing data arising 
due to reasons not related 
to COVID-19, and not 
from the 
placebo/nabiximols 
treatment sequence 
assignment
Period 1 post-baseline missing 
data but patient continues in 
study
Control-based imputation 
under MNAR
Control-based imputation 
under MNAR
Period 1 withdrawal
Control-based imputation 
under MNAR
Within treatment arm under 
MAR (Scenario 1)
Period 2 post-baseline missing 
data/withdrawal
N/A
Control-based imputation 
under MNAR
These scenarios will be applied to the monotone datasets as described in Section 12.5.2.1.6.
12.5.2.1.2 Indicator Variables
The following indicator variables will be used to allow inclusion of qualitative variables in the imputation 
models or to select  the imputation strategy as described in Table 12.5-1.
x
Treatment arm will be coded as:
o
DTRTP=1 for Nabiximols treatment arm,
o
DTRTP=0 for Placebo treatment arm.
x
Treatment sequence will be coded as:
o
DTRTSEQP=1 for Nabiximols/Placebo treatment sequence,
o
DTRTSEQP=0 for Placebo/Nabiximols treatment sequence.
x
Impact of COVID-19 on MAS score will be coded as:
o
COVID1=1 if at least score is impacted by the COVID-19 and/or at least one visit impacted by 
COVID-19 is missed or performed remotely during Period 1 or if the patient withdraws study 
during Period 1 due to COVID-19;
o
COVID1=0 if no scores are impacted by the COVID-19 and /or no visits are impacted by 
COVID-19 during Period 1, or if the patient withdraws study during Period 1 not due to COVID-19;
o
COVID2=1 if at least score is impacted by the COVID-19 or at least one visit impacted by 
COVID-19 is missed or performed remotely during Period 2 or if the patient withdraws study 
during Period 2 due to COVID-19;
o
COVID2=0 if no scores are impacted by the COVID-19 and /or no visits are impacted by 
COVID-19 during Period 2, or if the patient withdraws study during Period 2 not due to COVID-19.
12.5.2.1.3 Missing Data Description 
Description of missing data patterns will present the number and percentage of patients within each 
missing data pattern by treatment sequence and overall for the LLMT-6 score and the 6 individual muscle 
group scores composing the LLMT-6 score (as defined in Section 10.16).
Description of LLMT-6 score monotone missing pattern will be performed by treatment arm and 
COVID-19 impact (using indicator variable for COVID-19 impact as defined in Section 12.5.2.1.2), 
presenting the number and percentage of patients within each of the following monotone missing data 
pattern.
x
Pattern 1: Patient with no baseline nor post baseline LLMT-6 scores,
x
Pattern 2: Patient with a baseline LLMT-6 score but no post baseline LLMT-6 scores,
x
Pattern 3: Patient with a baseline LLMT-6 score and LLMT-6 scores up to Day 1H3 only,
x
Pattern 4: Patient with a baseline LLMT-6 score and LLMT-6 scores up D21.
This summary will also provide Mean (SD) at Baseline, D1H3 and D21 of each treatment period for each 
monotone missing data pattern.


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12.5.2.1.4 MI Models - General Consideration 
Each imputation model will use a common random seed value of 20210714 and any imputed value > 5 
will be set to 5 whereas any imputed value below 0 will be set to 0 to account for LLMT score ranging from 
0 to 5.
Post Period 1 baseline missing LLMT-6 scores (see Section 10.16), will be imputed using the strategy 
described in Section 12.5.2.1.6.
12.5.2.1.5 Monotone data pattern
Prior to performing any imputation methods as described below, intermittent missing scores as well as 
missing period 2 baseline score will be imputed under a MAR model using a Markov Chain Monte Carlo 
(MCMC) method to generate monotone missing data patterns within each treatment period.
This will be performed using the MCMC method in conjunction with the IMPUTE = MONOTONE option of 
the SAS® MI procedure.
First, for patients with no missing Period 1 baseline score but missing Period 2 baseline score, missing 
Period 2 baseline score will be imputed using a REGRESSION method in conjunction with the MONOTONE 
statement of the SAS® MI procedure using a model with indicator variables representing treatment 
sequence, Period 1 baseline score and Period 2 baseline score to create 300 imputed datasets.
Second, for each of the 300 imputed datasets and separately for each treatment period, intermittent missing 
score (missing period D1H3 score) will be imputed using a MCMC method in conjunction with the IMPUTE
= MONOTONE option of the SAS® MI procedure to create 300 monotone datasets. The model will include 
in the following indicator variable representing treatment sequence, and continuous variables for Period i 
baseline, Period i D1H3, and Period i D21 where i = 1,2.
Details regarding indicator variables are described in Section 12.5.2.1.2.
12.5.2.1.6 Pattern Mixture Model Placebo-based Multiple Imputation Method
The Pattern mixture placebo-based multiple imputation method which is a “copy to reference method” will 
be implemented using baseline to predict D1H3 and D21 values in a MNAR model with indicator variables 
for treatment period, treatment sequence, and treatment.
For each of the 300 monotone by treatment period datasets generated as described in Section 12.5.2.1.5, 
the remaining missing data will be imputed separately for each treatment period within each treatment arm
using the REGRESSION method in conjunction with the MONOTONE statement and either MNAR or MAR 
statement (as described in Table 12.5-1) of the SAS® MI procedure.
x
Step1, the imputation model will create 300 monotone by treatment period datasets, as described in 
Section 12.5.2.1.5.
x
Step 2a applied to Period 1 scores,
o
For patients on placebo treatment arm (i.e. placebo/nabiximols treatment sequence) and/or due to 
COVID-19 with non-missing LLMT-6 baseline score, LLMT-6 scores will be imputed sequentially at 
each post period baseline assessment (D1H3, D21) using a MAR imputation based on all non-
missing LLMT-6 scores. Therefore, the models used to generate each post period baseline LLMT-
6 scores are:
x
placebo LLMT-6 Period 1 D1H3 = placebo LLMT-6 Period 1 baseline score.
x
placebo LLMT-6 Period 1 D21 = placebo LLMT-6 Period 1 baseline score and placebo Period 
1 D1H3 LLMT-6 score.
o
For patients on nabiximols treatment arm (i.e. nabiximols/placebo treatment sequence) with non-
missing LLMT-6 baseline score, LLMT-6 scores will be imputed sequentially at each post period 
baseline assessment (D1H3, D21) using a MNAR imputation based on all non-missing LLMT-6 
scores. Therefore, the models used to generate each post period baseline LLMT-6 scores are:


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x
nabiximols LLMT-6 Period 1 D1H3 = placebo LLMT-6 Period 1 baseline score.
x
nabiximols LLMT-6 Period 1 D21 = placebo LLMT-6 Period 1 baseline score and placebo
Period 1 D1H3 LLMT-6 score.
x
Step 2b applied to Period 2 scores,
o
For patients on nabiximols treatment arm (i.e. placebo/nabiximols treatment sequence) and/or due 
to COVID-19 with non-missing LLMT-6 baseline score, LLMT-6 scores will be imputed sequentially 
at each post period baseline assessment (D1H3, D21) using a MAR imputation based on all non-
missing LLMT-6 scores. Therefore, the models used to generate each post period baseline LLMT-
6 scores are:
o
For patients on placebo treatment arm (i.e. nabiximols/placebo treatment sequence) with non-
missing LLMT-6 baseline score, LLMT-6 scores will be imputed sequentially at each post period 
baseline assessment (D1H3, D21) based on all non-missing LLMT-6 scores. 
x
If data is missing due to Period 1 withdrawal the procedure will use a MAR imputation and the 
models used to generate each post period baseline LLMT-6 scores are:

placebo LLMT-6 Period 1 D1H3 = placebo LLMT-6 Period 1 baseline score.

placebo LLMT-6 Period 1 D21 = placebo LLMT-6 Period 1 baseline score and placebo
Period 1 D1H3 LLMT-6 score.
x
If data is missing due to not due to Period 1 withdrawal the procedure will use a MNAR
imputation and the models used to generate each post period baseline LLMT-6 scores are:

placebo LLMT-6 Period 1 D1H3 = placebo LLMT-6 Period 1 baseline score.

placebo LLMT-6 Period 1 D21 = placebo LLMT-6 Period 1 baseline score and placebo
Period 1 D1H3 LLMT-6 score.
x
Step 3, Each of the 300 LLMT-6 scores generated from the fit of 300 placebo-based imputation 
models for each missing LLMT-6 score generated in Step 2 will correspond to a unique imputation 
number, and combination of imputed and non-missing LLMT-6 scores for each result in 300 complete 
datasets.
x
Step 4: Imputed values from each of the 300 imputation datasets selected from step 3 and non-
missing LLMT-6 scores will be analyzed by a linear mixed-effects model for crossover data applied to 
D21 as described in Section 12.5.2.1.8.
x
Step 5: Result from each linear mixed-effects model for crossover data will be combined as described 
in Section 12.5.2.1.7.
12.5.2.1.7 Combining multiple imputation results
The analysis models will be evaluated in each imputed dataset and, the point estimates and SEs will be 
combined using Rubin’s rules to produce valid global estimates with corresponding CIs and p-values. SAS®
MIANALYZE procedure will be used for this purpose (Rubin, 1976).
12.5.2.1.8 Linear Mixed-effects Model for Crossover Data
The primary analysis model will be selected before multiple imputation and all subsequential statistical 
analysis conducted on this final model. The final selected model (after convergency and residual 
diagnostics and outlier searches, see below) will be fitted to each of the 300 imputed datasets. The model 
selection process will NOT be reconducted for each imputed dataset. 
The change from baseline to D21 of each treatment period (as defined in Section 10.2 and Section 10.3)
in LLMT-6 (as defined in Section 10.16) will be analyzed with a LME model for crossover data using the 
SAS® GLIMMIX procedure with an identity link function and a normal distribution. The change from period 
level baseline to D21 in LLMT-6 score will be included as the dependent variable. Hence, each patient will
contribute two measurements to the model, one for each period of the study.


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The preferred model will include a period level LLMT-6 baseline (pre-dose measurement) covariate, 
period level treatment arm, treatment period, and treatment sequence as fixed effects). An unstructured 
(UN) covariance structure will be used for the repeated LLMT-6 measurements of the changes from 
baseline in each treatment period and the denominator degrees of freedom will be calculated according to 
the Kenward-Roger method (e.g., KR2, 2009 version)
In case of non-convergence of the preferred model or memory space issue, the compound symmetry
covariance structure will be applied to the preferred model described above.
This model will provide the least squares mean estimates for each treatment arm, along with the SEs and 
95% CIs as well as, the least squares mean (LS mean) estimate of the mean treatment difference between
nabiximols and placebo in change from baseline in LLMT-6 along with SE of the difference, 95% CI and 
associated nominal p-values will be presented. 
In addition, this model will present the LSmeans estimates along with 95% CIs for each treatment period 
and treatment sequence, as well as the difference between treatment periods and treatment sequences 
and associated nominal p-values.
12.5.2.1.9 Model Assumption Assessment
Potential Period and Sequence effects
To assess potential period and sequence effects, using the primary efficacy model the following outputs 
will be presented:
x
The combined estimates, 95% confidence intervals, and corresponding p-values for each treatment 
period and each treatment sequence, as well as the difference between treatment periods and between 
treatment sequences (representing the period term and sequence term combined estimates).
x
A plot of the LLMT-6 mean change from baseline at D21 of each treatment arm by treatment period.
In addition, summaries of the pre-dose baseline values for each treatment period (e.g., period baseline 
values) and overall per treatment arm will be explored from the descriptive statistics table presented in 
Section 12.5.2.3.3.
Distribution of Residual and Outliers search
The distribution of residuals as well as the search for potential outliers will be based on the analysis of 
primary endpoint using a LME model for cross-over data (as described in Section 12.5.2.1.8) but using 
observed cases LLMT-6 scores (not following any missing data MI strategy).
Distribution of the residuals will be assessed, based on outcome of the primary efficacy endpoint as 
follows:
x
The normality of the residuals will be graphically assessed presenting boxplot, histogram, QQ-plots
and scatterplot of residual versus linear predictors, based on studentized residuals obtained from the 
primary efficacy model.
x
The distribution of the residuals obtained from the primary efficacy model will also be assessed using 
boxplots with each category of the fixed effect (treatment arm, treatment sequence and treatment 
period) 
If the residuals appear not to be normally distributed, alternative approaches such as transformation of the 
data and nonparametric analyses may be considered to express treatment effect.
Outliers search: Outliers will be identified based on diagnosis performed from primary outcome measure
using boxplot, and scatterplot of residual versus linear predictors,
If outliers are present, additional sensitivity analyses may be conducted with outliers excluded to assess 
their impact on the results.


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12.5.2.2 Sensitivity Analysis – Tipping Point
The primary efficacy analysis assumes data are either missing at random or missing not at random as per 
missing data handling strategy described in Section 12.5.2.1.6
To assess the robustness of the treatment effect with regard to missing data, a sensitivity analysis based 
on a tipping point analysis will be performed for the primary efficacy endpoint to assess the impact of 
missing data assumed MNAR on the primary estimand.
This analysis will impute missing nabiximols D21 data under a Missing Not at Random assumption, using 
the FAS, during the 51-day randomized efficacy period (see Section 10.1).
Thus, when no penalty is added the tipping point analysis is the equivalent to the primary efficacy analysis.
Tipping point analyses
Using monotone datasets generated as described in Section 12.5.2.1.5, the remaining missing data will be 
imputed separately for each treatment period and each treatment arm using the REGRESSION method in 
conjunction with the MONOTONE statement and either MNAR statements (for nabiximols treatment arm 
following imputation strategy described in Table 12.5-1) or MAR statement (for either placebo treatment 
arm or nabiximols treatment arm following imputation strategy described in Table 12.5-1) of the SAS® MI 
procedure.
x
Step1, the imputation model will create 300 monotone datasets, as described in Section 12.5.2.1.5
x
Step 2
o
Step2a for Period 1 - first model 
Imputed missing D21 LLMT-6 scores for patients on placebo treatment arm with non-
missing baseline score and missing D21 LLMT-6 score as well as for patients on 
nabiximols treatment arm with non-missing baseline LLMT-6 score and missing D21 LLMT-
6 scores due to COVID-19 will remain MAR (no delta addition) and MI will follow the same 
approach as the one described in Section 12.5.2.1.6 Step 2a
The first imputation model (e.g., delta=0) to impute missing D21 LLMT-6 scores for patients 
on nabiximols treatment arm with non-missing baseline scores and missing LLMT-6 scores 
not due to COVID-19 will follow the same MNAR placebo-based MI approach as the one 
described in Section 12.5.2.1.6 Step 2a.
o
Step2b for Period 2 - first model
I
Imputed missing D21 LLMT-6 scores for patients on placebo treatment arm with missing 
D21 LLMT-6 score as well as for patients on nabiximols treatment arm with either missing 
D21 LLMT-6 scores due to COVID-19 for those entered in Period 2 or due to study 
withdrawal during Period 2 will remain MAR (no delta addition) and MI will follow the same 
approach as the one described in Section 12.5.2.1.6 Step 2b;
The first imputation model (e.g., delta=0) to impute missing D21 LLMT-6 scores for patients 
on nabiximols treatment arm entered in Period 2 with missing D21 LLMT-6 scores not due 
to COVID-19 will follow the same MNAR placebo-based MI approach as the one described 
in Section 12.5.2.1.6 Step 2b.
o
Step2c subsequent models
Separately for each treatment period, missing D21 LLMT-6 scores imputed under MAR at 
Step 2a or Step 2b will remain MAR (no delta addition) whereas for D21 LLMT-6 scores 
imputed under MNAR at Step 2a or Step 2b, in subsequent models, a common (non-zero) 
delta value (where delta value represents LLMT-6 score ranging from 0.12 to 5) will be 
added following MNAR imputation to each imputed value. Delta addition will be obtained 
using the DELTA option of the MNAR statement of the SAS® MI procedure.
For the first imputation model (delta=0)  300 imputed datasets will be generated at Step 
2a and Step 2b. For the subsequent models (delta >0), the same monotone datasets as 
those used for first imputation model (delta=0) will be retrieved.


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o
Step 3, the 300 imputation datasets generated from each delta values will be analyzed by a LME
model for crossover data applied to D21 as described in Section 12.5.2.1.8.
o
Step 4, for each value of delta, results from each LME model for crossover data as described in 
Section 12.5.2.1.8 will be combined as described in Section 12.5.2.1.7.
x
Step 5, the tipping point will correspond to the first instance where the primary inference changes (i.e., 
p>=0.05 for between treatment arm difference in LSmeans). Consequently, the testing (Step 2 to Step 
4) will be repeated for a plausible nabiximols value using a grid search method. Firstly, larger changes in 
delta values (delta will range from 0 to 5 by increments of 5/6 where 5/6 represents the maximum effect 
of an individual MAS transformed score on LLMT-6) will be used. If the primary inference changes, then 
smaller changes in delta values (1/6 representing the change of 1 in LLMT-6) will be used to identify a 
more accurate tipping point between the last two delta values which were using larger changes (ie. last 
delta value with p<0.05 and first delta value with p>=0.05).
x
Step 6, results corresponding to each delta values will be presented within a summary table including 
combined LS mean estimate and corresponding SE and 95% CI for each treatment arm along with the 
combined LS mean estimate of the difference versus placebo along with its corresponding SE and 
confidence interval. The tipping point will be identified.
12.5.2.3 Supplementary Analyses Based on LLMT-6
12.5.2.3.1 Subgroup Analysis for Primary Endpoint
The treatment effect across the different subgroups indicated in Table 12.5-2 will be explored on the primary 
efficacy endpoint: LLMT-6.
Table 12.5-2 Subgroup Analyses of Primary Efficacy Endpoint
Group variables
Subgroup
Comments
Sex
Male
Female
Prior cannabis use
Yes
No
Baseline LLMT-6 
category (cut off=2)
Period 1 baseline LLMT-6<=2
Period 1 baseline LLMT-6 >2
Baseline LLMT-6 categories refers to 
period 1 baseline score
Baseline LLMT-6 
category (cut off=3)*
Period 1 baseline LLMT-6<=3
Period 1 baseline LLMT-6 >3
If the value of a group variable cannot be determined, the patient will be excluded from the corresponding 
subgroup analysis.
The treatment arm-by-subgroup interaction will be assessed for the primary efficacy endpoint using the 300
imputation
datasets 
derived 
to 
perform 
the 
primary 
efficacy 
analysis 
as 
described 
in 
Section 12.5.2.1.6. Each imputed dataset will be analysed using linear mixed-effects model for crossover 
data as described in Section 12.5.2.1.8 with subgroup and subgroup-by-period level treatment arm 
interaction, as 2 additional fixed effects. Result from each linear mixed-effects model for crossover data will 
then be combined as described in Section 12.5.2.1.7.
For each subgroup analyses, the following estimates will be presented. Within each subgroup; (i) the 
combined adjusted LS mean (SEs and 95% CIs) of the change from period baseline to D21 for nabiximols 
and placebo will be presented, (ii) the combined difference in LS means (nabiximols–placebo) together with 
SEs and 95% CIs as well as the nominal p-value will be presented.  The subgroup-by-treatment arm 
interaction nominal p-value will be presented. In addition, frequency count and descriptive statistics for each 
subgroup will be presented in a separate table. Forest plots will be used to present subgroup analyses 
results. The forest plot created from subgroup analyses will display number of patients, all combined 
estimates (i, ii),including combined 95% CI for (ii) and interaction p-values.
If, in each treatment arm by subgroup, the number of patients is less than 5, only summary statistics will be 
displayed and no subgroup analyses will be conducted.


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As the study is not stratified by site it is not planned to explore the impact of site on the treatment effect. 
However, if deemed necessary the impact of MAS assessors on LLMT-6 will be looked at.
12.5.2.3.2 Response Analyses Based on LLMT-6
The reduction from baseline to D21 of respectively >=20%, >=30%, >=40%, >=50% (as described in 
Section 10.16) will be analyzed using a logistic regression applied to crossover design using a generalized 
estimating equation (GEE). The models will be analyzed using the SAS® GLIMMIX procedure with a logit 
link function and a binary distribution. The marginal log likelihood will be approximated with an adaptive 
Gauss-Hermite quadrature (obtained using the EMPIRICAL option of the SAS® GLIMMIX procedure) using 
a likelihood-based sandwich estimator.
The preferred model will include a period level LLMT6 baseline covariate, treatment arm, treatment period, 
and treatment sequence as fixed effect.
An unstructured covariance will be used to model the residual errors between LLMT-6 scores within the 
same patient across period. The denominator degrees of freedom will be calculated according to the
Kenward-Roger method (e.g. KR2, 2009 version).
This model will provide, for each response analysis, at D21, the estimate of the odds ratios (OR) 
representing the odds in nabiximols treatment arm versus placebo treatment arm and corresponding 95% 
CI and nominal p-value. These parameters will be summarized by treatment arm along with number of 
responders and associated crude response rates.
If less than 5 patients in either treatment arm are considered as responders, only descriptive statistics will 
be conducted presenting the number and percentage of responders by treatment arm.
In case of non-convergence, appropriate model will be applied. 
12.5.2.3.3 Summary Descriptions and Listings
LLMT-6 values, change from baseline and percentage change from baseline in LLMT-6 will be summarized 
by treatment arm, per treatment period and overall, over time.
Mean ± SD LLMT-6 values and change from baseline by visit and treatment arm will be plotted.
Scatterplots of the change from baseline to D21 and percentage change from baseline to D21 in LLMT-6 
against the baseline LLMT-6 will also be produced.
Spaghetti plots presenting baseline, D1H3 and D21 LLMT-6 sores from both treatment periods will be 
plotted for each patient by treatment arm. Paneled by treatment period and the treatment received in that 
period differentiated by line pattern.
Cumulative distribution functions on change from baseline and relative change from baseline to D21 in 
LLMT-6 will be plotted by treatment arm.
A by-patient listing will be provided for LLMT-6 observed, change and relative change from baseline along 
with responder status (as defined in Section 12.5.2.3.2).
12.5.3 Secondary Endpoint
12.5.3.1 Secondary Efficacy Endpoint
For comparison of nabiximols treatment arm versus placebo treatment arm, if primary endpoint is 
significant, the statistical test will be performed on the secondary endpoint. The Type I error rate for 
comparing nabiximols treatment arm to placebo treatment arm for the secondary endpoint will be controlled 
at 0.05 level (2-sided) and inference will be provided. Otherwise, if primary endpoint does not reach the 
statistical significance at the nominal Type I error rate, nominal p-value for the secondary endpoint will be 
calculated but no claim could be made based on that p-value as per testing strategy described above.


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The secondary endpoint change from baseline to D21 of each treatment period (as defined in Section 10.2
and Section 10.3) in LLMT-4 (as defined in Section 10.16) will be analyzed in a similar way to the primary 
efficacy endpoint (see Section 12.5.2.1), during the 51-day randomized efficacy period using FAS . The 
comparison between nabiximols treatment arm and placebo treatment arm will be performed following the 
testing procedure outline just above and is assessing the secondary estimand (as defined in Section 9.1).
12.5.3.2 Sensitivity Analysis: Tipping Point
The primary efficacy analysis on secondary endpoint assumes data are either missing at random or missing 
not at random as per missing data handling strategy described in Section 12.5.2.1.3.
To assess the robustness of the treatment effect with regard to missing data, sensitivity analyses based on 
a tipping point analysis will be performed for the secondary efficacy endpoint to assess the impact of the 
missing data assumed MNAR on the secondary estimand.
This analysis will impute missing nabiximols D21 data under a Missing Not at Random approach, using the 
FAS during the 51-day randomized efficacy period (see Section 10.1).
Thus, when no penalty is added the tipping point analysis is equivalent to the primary analysis of the 
secondary endpoint.
This analysis will be conducted using the same approach as the one described for primary efficacy endpoint 
(see Section 12.5.2.2). However, as LLMT-4 score is based on 4 muscle groups (and not 6 muscle groups 
as LLMT-6)as described in Section 12.5.2.2,the Step 5 (Step 2 to Step 4 will be repeated for a plausible 
nabiximols value using a grid search method. Firstly larger changes in delta values (delta will range from 0 to 
5 by increments of 5/4 where 5/4 represents the maximum effect of an individual MAS transformed score 
on LLMT-4) will be used. If the inference changes, then smaller changes in delta values (1/4 representing 
the change of 1 of  LLMT-4 score) will be used to identify a more accurate tipping point between the last 
two delta values which were using larger changes (ie. last delta value with p<0.05 and first delta value with 
p>=0.05).
The same tables, figures and listing as those performed for LLMT-6 (as described in Section 12.5.2.3.3) 
will be provided for LLMT-4.
12.5.4 Other Analyses based on MAS 
12.5.4.1 Analysis based on LLMT-10
The exploratory efficacy analysis associated with the LLMT-10 endpoint is defined as the estimated 
mean treatment difference between nabiximols and placebo on the estimated change from baseline to D21
on the LLMT-10 score (as defined in Section 10.16) where MAS scores are collected during the 51-day 
randomized efficacy period, for all randomized patients belonging to the FAS. The comparison between 
nabiximols and placebo will be performed at a type I error level of 0.05 (two-sided) and nominal p-values 
will be provided. No adjustments for multiplicity will be made on that endpoint and no claim could be made 
based on that p-value as per testing procedure outline in Section 12.5.1.
The same analyses as those conducted for LLMT-4 will be performed (see Section 12.5.3.1 ) apart from
the tipping point analysis.
12.5.4.2 MI followed by Linear mixed-effect model with repeated measures for 
crossover data
Model Selection Before Multiple Imputations (MI)
The model will be selected before MI and all subsequent statistical analyses conducted on this model. The 
model selection process will NOT be reconducted for each imputed dataset.


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The change from baseline to D21 of each treatment period (as defined in Sections 10.2 and 10.3) in LLMT-
6, LLMT-4 and LLMT-10 scores (as defined in Section 10.16) will be analyzed using a linear mixed-effects 
model with repeated measures for crossover data using the SAS® GLIMMIX procedure with an identity link 
function and a normal distribution performed on each multiple imputed dataset. This model is an extension 
of the primary efficacy analysis by including the D1H3 post-dose timepoint.
The model will include period level LLMT-X* baseline covariate, period level treatment arm, treatment 
sequence, treatment period, visit, visit-by-period level LLMT-X* baseline covariate interaction and visit-by-
period level treatment arm interaction as fixed effects. An unstructured covariance structure will be used to 
model the residual errors between LLMT-X* scores within the same patient across visit and period and the 
denominator degrees of freedom will be calculated according to the Kenward-Roger method (e.g. KR2, 
2009 version). In case of non-convergence of the preferred model or memory space issues the compound 
symmetry (CS) covariance structure will be used. The final selected model from this process will be fitted 
to each of the 300 imputed datasets. Note: The model selection process will NOT be reconducted for each 
imputed dataset.
Pattern Mixture Model Placebo-based Multiple Imputation
Using the 300 imputed datasets obtained while performing primary analysis of LLMT-X* scores (see 
methodology in Section 12.5.2.1.6), each imputed dataset will be analyzed using a LME repeated 
measures for crossover data (described in Section 12.5.4.2). The result of each of these models will then 
be combined as described in Section 12.5.2.1.7 to produce for each post-dose assessment (D1H3, 
D21), valid combined estimates for each treatment arm with corresponding SEs and 95% CIs as well as 
combined valid estimates of treatment difference in change from baseline in LLMT-X* with corresponding 
SEs, 95% CIs and nominal p-value for treatment arm comparison at D1H3 and D21.
Combined LS means change from period baseline and 95% CI will be plotted by timepoint per treatment 
arm.
Linear Mixed-effect Model with Repeated Measure for Crossover Data
The model fitted to the data will be the one selected in the ‘Model Selection Before Multiple Imputations 
(MI) section above.
12.5.4.3 Impact of Intercurrent Events
12.5.4.3.1 Impact of Missing individual transformed MAS muscle score
To assess the robustness of LLMT-6, LLMT-4 and LLMT-10 scores to missing individual muscle scores,
the change from baseline to D21 of each treatment period (as defined in Section 10.2 and Section 10.3) for
LLMT-6, LLMT-4 and LLMT-10 scores will be analyzed using the same approach as the one described 
respectively in Section 12.5.2.1 in Section 12.5.3.1Error! Reference source not found. and in Section 
12.5.4.1 (LME model for crossover data applied to MI imputed datasets). The analyses will be conducted 
on FAS during the 51-days randomized period but only using LLMT-6, LLMT-4 and LLMT-10 scores derived 
without any missing individual MAS transformed muscle score.
12.5.4.3.2 Impact of Study/Treatment Discontinuation
To assess the robustness of the MAS scores results with regard to permanent premature treatment 
discontinuation and/or study withdrawal, the change from baseline to D21 of each treatment period (as 
defined in Section 10.2 and Section 10.3) for LLMT-6, LLMT-4 and LLMT-10 scores will be analyzed by 
means of a linear mixed-effects model for crossover data applied on MI datasets using the approach 
described respectively in Section 12.5.2.1, Section 12.5.3.1 and in Section 12.5.4.1 but conducted:
x
during the 51-day on-treatment efficacy period (as defined in Section 10.1) using only on-treatment 
assessments (assessments obtained post treatment discontinuation are excluded from the analysis),


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during the 51-day randomized period using the Study Completer Analysis Set.
12.5.4.3.3 Impact of Major Important Protocol Deviations and Deviations from Predefined 
Time Windows
If more than 20% of patients from FAS are excluded in the PP Analysis Set; the robustness of the MAS 
scores results with regard to major IPDs will be assessed as described just above.
The change from baseline to D21 of each treatment period (as defined in Section 10.2 and Section 10.3)
in LLMT-6, LLMT-4 and LLMT-10 scores will be analyzed with a linear mixed-effects model for crossover 
data applied to MI datasets using the approach described in respectively Section 12.5.2.1, Section 12.5.3.1
and in Section 12.5.4.1 during the 51-day randomized period using the PP Analysis Set.
Furthermore, to also assess the impact on deviation from predefined time window at D1H3, the change 
from baseline to D21 of each treatment period (as defined in Section 10.2 and Section 10.3) in LLMT-6
score will be analyzed by means of a linear mixed-effects model with repeated measures for crossover data
applied to MI dataset using the approach described in Section 12.5.4.2, but during the 51-day on-treatment 
efficacy period. For this analysis any D1H3 MAS assessment not having taken place within 3 hours (± 15 
minutes) post first morning dosing spray will be excluded from the analysis.
If more than 20% patients from FAS are excluded in the PP analysis set this analysis will be conducted on
the PP analysis set, otherwise the FAS will be used.
12.5.4.3.4 Impact of COVID-19
If at least 5 patients have at least one visit where MAS scores are impacted by COVID-19, as assessed by 
the investigator, the impact of COVID-19 on the treatment effect will be assessed on MAS scores as 
described just below.
The change from baseline to D21 of each treatment period (as defined in Sections 10.2 and 10.3) in LLMT-
6, LLMT-4 and LLMT-10 scores will be analyzed by the mean of a linear mixed-effects model for crossover 
data applied on MI datasets using the approach described respectively in Section 12.5.2.1, Section 12.5.3.1
and in Section 12.5.4.1 but removing the patients having at least one MAS assessment impacted by 
COVID-19.
12.5.4.4 Other Summaries and Listings based on MAS
An histogram presenting combined LS mean change from baseline to D21 estimates in LLMT-6, LLMT-4 
and LLMT-10 along with their corresponding 95% CIs will be provided by treatment arm using combined
LS means and 95% CIs coming from the linear mixed-effects model for crossover data applied to MI 
datasets used to analyze these 3 efficacy endpoints (as respectively described in Section 12.5.2.1,  Section 
12.5.3.1 and Section 12.5.4.1).
Descriptive statistics will be provided for each of the 10 individual muscle group MAS scores, presenting 
observed values along with change from baseline and percentage change from baseline score per 
treatment arm by treatment period and overall.
A by-patient listing will be provided for observed and derived variables presenting each of the 10 individual 
MAS scores along with LLMT-4, LLMT-6 and LLMT-10 scores.
12.5.5 Exploratory Efficacy Analysis
All exploratory efficacy analyses will be conducted among the full analysis set during the 51-day efficacy 
randomized period.
If more than 20% of patients from FAS are excluded in the PP Analysis Set; the analyses may be repeated 
using the PP analysis set as described in Section 12.5.
The exploratory efficacy analyses based on LLMT-10 are described in Section 12.5.5.


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If at least 5 patients have at least one visit where the studied endpoint is impacted by the COVID-19, as 
assessed by the investigator, the analysis of that endpoint will be repeated excluding the concerned patients
as described below:
x
For the average 25-foot walk time (as described in Section 10.2 and in Section 10.17) if during 
Period 1 and/or Period 2, D21 visit, T25FW trials are impacted by COVID-19,
x
For the 7-day average NRS spasticity score (as described in Section 10.2 and in Section 10.18) if 
during Period 1 and/or Period 2, Day 15 or D21 visits are impacted by COVID-19 and patient is
infected*,
x
For the 7-days average daily spasm counts (as described in Section 10.2 and in Section 10.19) if 
during Period 1 and/or Period 2, Day 15 or D21 visits are impacted by COVID-19 and patient is
infected*,
x
For MSSS-88 total and sub-scales scores (as described in Section 10.20) if during Period 1 and/or 
Period 2 at D21 Visit MSSS-88 scoring is impacted by COVID-19.
* For eDiary endpoints, impact on COVID-19 is assessed based on information collected on the “Visit 
COVID-19 Impact” eCRF form. Thus if reason is due to “Caregiver or family member infected with COVID-
19” but not to “Patient infected by COVID-19” the assessment will not be discarded.
12.5.5.1 Timed 25-Foot Walk (T25FW)
A decrease in average time to complete the two trials will show an improvement.
The difference between treatment arms in the change from baseline to D21 in average 25-foot walk time
(as defined in Section 10.17) will be analyzed using the same LME model for crossover data as the one 
used for the primary analysis of the primary efficacy endpoint (as described in Section 12.5.2.1.8).
As a sensitivity analysis, the same analysis will be repeated using non-imputed average 25-foot walk times 
(as defined in Section 10.17).
If model diagnostics suggests that the residuals are not normality distributed a non-parametric analysis will 
be conducted.
A >=20% reduction from baseline to D21 of in average time (as described in Section 10.17) will be analyzed 
using a logistic regression applied to crossover design using a GEE (as described in Section 12.5.2.3.2).
A histogram presenting LS means change from baseline estimates along with their corresponding 95% CI 
will be provided by treatment arm.
Descriptive statistics for the average T25FW values change from baseline and percentage change from 
baseline by treatment arm will be provided; as well as a by-patient listing presenting observed and derived 
variables.
12.5.5.2 11-point Numerical Rating Scale Score (NRS-spasticity score)
The 11-point NRS spasticity scale is composed of 11 items ranging from 0 (no spasticity) to 10 (maximal 
spasticity) to assess the overall spasticity in patients with MS during the last 24 hours.
The difference between treatment arms in the 7-day average NRS spasticity score over the last 7 day 
preceding D21 of each period (as defined in Section 10.18) will be analyzed using a linear mixed model for 
crossover data using the SAS® GLIMMIX procedure with an identity link function and a normal distribution. 
The 7-day average NRS spasticity D21 score will be included as the dependent variable. Hence, each 
patient will contribute two measurements to the model, one for each period of the study.
The preferred model will include period level treatment arm, treatment period, and treatment sequence as 
fixed effects. Unstructured (UN) covariance structure will be used to model the repeated 7-day average 
NRS spasticity scores. The denominator degrees of freedom will be calculated according to Kenward-Roger 
method (e.g., KR2, 2009 version).


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In case of non-convergence of the preferred model or memory space issue the, the compound symmetry
covariance structure will be applied to the preferred model described above.
This model will provide the LS mean estimates for each treatment arm, along with the SEs and 95% CIs as 
well as, the LS mean treatment difference between nabiximols and placebo in NRS spasticity score along 
with the SE , 95% CI and the nominal p-value for treatment arm comparison. 
In addition, this model will present the LSmeans estimates along with 95% CIs for each treatment period 
and treatment sequence, as well as the difference between treatment periods and treatment sequences 
and nominal p-values for treatment sequence and treatment period comparison.
The 7-day average NRS spasticity scores will be summarized at baseline, Day 15 and D21 per treatment 
arm and, per treatment period and overall.
Mean ± SD 7-day average NRS spasticity score will be plotted per treatment arm by 7-day period.
Furthermore, a histogram presenting LS means estimates and corresponding 95% CIs will be plotted per 
treatment arm.
A by-patient listing presenting 7-day average NRS spasticity score along with the corresponding score per 
day will be provided.
12.5.5.3 Daily Spasm Count
The 7-day average daily spasm count is derived from spasm counts recorded daily by the patients in the 
eDiary.
The difference between treatment arms in the average daily spasm count over the last 7 day preceding 
D21 of each period (as defined in Section 10.19) will be analyzed using the same approach as the one 
used to analyze 7-day average NRS-spasticity score (as described in Section 12.5.5.2).
The 7-day average daily spasm count will be summarized at baseline, Day 15 and D21 per treatment arm 
and, per treatment period and overall.
Mean ± SD 7-days average daily spasm will be plotted per treatment arm by 7-day period.
Furthermore, a histogram presenting LS means estimates along with their corresponding 95% CIs will be 
provided by treatment arm.
A by-patient listing presenting 7-day average daily spasm count along with the corresponding count per 
day will be provided.
12.5.5.4 The MS Spasticity Scale
The MSSS-88 is a patient self-report measure of the impact of spasticity (muscle stiffness and spasms) in 
MS. It is composed of 88 items ranging from 1 (not at all bothered) to 4 (extremely bothered).
These items are grouped to derive 8 subscales (as defined in Section 10.20) within 3 different categories 
which are composed of: 3 spasticity symptoms (i.e., muscle stiffness, pain and discomfort, muscles 
spasms), 3 areas of physical functioning (i.e., effects on daily activities, ability to walk, body movement) 
and 2 areas of psychosocial impact (i.e., emotional health, social functioning).
Difference between treatment arms in total and subdomain scores of the MSSS-88 at the end of the 
maintenance-dose phase (D21) of each double-blind treatment period will be analyzed using the same 
approach as the one used to analyze the 7-day average NRS-spasticity score (as described in Section 
12.5.5.2).
A histogram presenting LS means estimates along with their corresponding 95% CIs will be provided for
respectively for the 8 subscale scores and for the total score.


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The 88 items as well as subscales and total sores will be summarized by treatment arm.
A by-patient listing presenting the total score along with the 8 subscales scores will be provided
12.6 Pharmacokinetics 
Plasma concentrations will be obtained for THC and its relevant metabolites (11-hydroxy-Δ9-
tetrahydrocannabinol and 11-carboxy-Δ9-tetrahydrocannabinol) and CBD and its relevant metabolites 
(7-hydroxy-cannabidiol and 7-carboxy-cannabidiol) at distinct time points (as described in Table 8.1-2) on 
Day 1, Day 15 and D21 of each treatment period.
Concentration data will be summarized per treatment arm, treatment period and overall, by analysis day 
(as defined in Table 10.1-1) and hours (see Table 8.1-2) since last dose for post-baseline samples of THC 
and its relevant metabolites and of CBD and its relevant metabolites. Concentrations that are below the 
limit of quantitation (BLQ) will be excluded from the computation of descriptive statistics but the number of
patients presenting a concentration below the limit of quantification will be presented at each time point. 
The number of observations, mean, standard deviation, geometric mean, geometric standard deviation,
coefficient of variation (%), median, minimum, maximum values will be displayed 
Individual data will be presented in listing.
If concentration data show that sufficient systemic exposure for THC or one or more of the metabolites is 
available, relevant PK parameters may be calculated using a population PK model. In that case, PK results 
will be presented in a stand-alone report. This report might also include a post hoc PK/PD analysis on the 
basis of PK and pharmacodynamics (PD) data collected in the study.
12.7 Safety Analyses
The safety analyses will be conducted during the 51-day on-treatment safety period (as described in 
Section 10.1) by actual treatment arm. As appropriate, the safety analyses will also be conducted during 
the follow-up period (as described in Section 10.1) by treatment sequence. All the safety analyses will be 
conducted using the Safety Analysis Set.
Some analyses of adverse events and laboratory parameters will assess the potential impact of the study 
drug among the subgroups presented in Table 12.7-1.
Table 12.7-1 Subgroups applied to Safety Analysis
Group Variables
Subgroup
Comments
Sex
Male
Female
Age group
≤18,
> 18 and ≤ 45
≥46 to ≤ 65
> 65
According to patient ‘s distribution 
within age, age group may be 
differently defined
Detailed derivation is given in 
Section 10.10
Race
White
Black or African American
Asian
American India or Alaska Native
Native Hawaiian or Other Pacific 
Islander
Other
According to patient’s distribution 
within race some races may be 
grouped together
Prior cannabis use
Yes
No
If it appears that one patient has 
missing prior cannabis use 
information, the missing category 
will be added for AE summary
Number of current antispasticity 
medication
0
1
2
≥3


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Patient mean number of daily
sprays
≤ 6 sprays,
> 6 sprays and ≤ 12 sprays,
> 12 sprays.
This is referring to “Patient means 
number of daily spray” taken during 
the maintenance phase (derivation 
as described in Section 10.8.2)
12.7.1 Adverse Events
Adverse events (AEs) will be coded using MedDRA 24.0 or higher according to the version in use at time 
of database lock. All safety analyses of AEs will be performed by actual treatment arm and reported using 
the Safety Analysis Set. An AE will be considered a TEAE if it first occurs or worsens in severity or 
seriousness after the first dose of IMP intake and before the last dose date + 15 days. 
All AEs will be classified during the pre-treatment period, the 51-day safety on-treatment period or during 
the follow-up period as follows:
x
Events that occurred before first IMP intake without worsening or becoming serious after the first IMP 
dose are classified as pre-treatment AEs; 
x
Events that occurred or worsens between first IMP dose and 14 days after IMP last dose are 
classified as on-treatment AE and are defined as treatment-emergent AEs (TEAEs);
o
TEAE occurring during 21-day on-treatment safety Period 1 will be considered emergent to actual 
treatment received during Period 1 (as defined in Section 10.1.1).
o
TEAE occurring during 21-day on-treatment safety Period 2 will be considered emergent to actual 
treatment received during Period 2 (as defined in Section 10.1.1).
x
Events occurring more than 15 days after last dose are classified as follow-up AEs. 
Consequently, TEAEs will be summarized by treatment arm using the actual treatment received at each 
given period. Any adverse event occurring during the wash-out period will be linked to the actual treatment 
arm defined for Period 1, whereas any AEs occurring after last IMP dose will be linked to the actual arm 
defined at time of permanent study drug discontinuation. 
The following events will not be identified as AEs in this study: 
x
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, etc.). The condition (the 
“triggering event”) that leads to the procedure are adverse events and will be reported as such. 
x
Pre-existing conditions present or detected prior to the first dose of study drug that do not worsen 
during the study. 
Counting rules
For incidence reporting, if a patient reported more than one AE that was coded to the same preferred 
term/system organ class within a given treatment arm, the patient will be counted only once for that specific 
preferred term/system organ class by treatment arm and the rules defined below will be applied.
For TEAEs presented by action taken on study drug, the worst action taken among the events with same 
SOC/PT emergent to the same treatment arm will be selected for each patient. If action taken is missing 
for a TEAE, the action taken “drug withdrawn” will be assigned considering the AE leads to permanent IMP 
discontinuation. The imputed values for action taken will be used for incidence summaries, while the actual 
values will be used in data listings.
For TEAEs presented by severity, the worst severity among the events with same SOC/PT emergent to the 
same treatment arm will be selected for each patient. If the severity is missing for a TEAE, then a severity 
of “Severe” will be assigned. The imputed values for severity assessment will be used for incidence 
summaries, while the actual values will be used in data listings.
For TEAEs presented by relationship to study drug, the relationship to study drug, as assigned by the 
investigator, for each event during the clinical trial will be presented for each patient. If the relationship to 


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investigational product is missing for a TEAE, a causality of “Related” will be assigned. The imputed values 
for relationship assessment will be used for incidence summaries, while the actual values will be presented 
in data listings.
For TEAEs presented by categories for time of first onset of AE, if the AE start date is missing ,it will be 
imputed as specified in Table 10.21-1 for AE analysis or summary but actual values will be presented in 
data listing. 
Summary of Adverse Events
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be imputed as specified 
in Table 10.21-1. No duration will be calculated for adverse events with incomplete start-or stop dates, or 
for ongoing adverse events.
For summary by SOC and PT the denominator to derive the percentage will be the number of patients at
risk in the treatment arm.
For subgroup analysis by SOC and PT the denominator to calculate the percentage will be the number 
of patients at risk in the treatment arm and in the category of the analyzed subgroup.
For summary by SOC and PT and category of time to first onset of AE the denominator to derive the 
percentage will be the number of patients at risk in the treatment arm in each time interval category.
For summary by SOC and PT and category of duration of AE the denominator to derive the percentage 
will be the number of patients in the corresponding treatment arm having experienced a TEAE 
corresponding to the SOC or PT being summarized.
The number of patients at risk in the treatment arm is defined as the number of patients having taken at 
least 1 spray of respectively nabiximols or placebo in the actual treatment arm (as defined in Section 9.3.1) 
linked to either the 21-day safety period 1 or the 21-day safety period 2 (as defined in Section 10.1.1).
All summary by SOC and PT will be sorted by descending frequency of nabiximols for SOC and by 
descending frequency of nabiximols for PT within SOC.
Listing of Adverse Events
All AEs, SAEs, AEs leading to study drug discontinuation, AE with outcome of death; AE of special interest
will be listed.
The listings will include Subject ID, actual treatment received, SOC, preferred term, investigator term, start 
and stop date of the AE, whether or not the AE was treatment emergent, duration, frequency, severity, 
relatedness, action taken, outcome, and seriousness of the AE. Imputed start or stop dates will not be 
displayed in listings of AEs. These listings will be sorted by treatment sequence, subject ID and onset of 
adverse events.
12.7.1.1 Overall Adverse Event Summary
An overall adverse event summary will provide, by treatment arm, the number and percentage of patients 
with at least:
x
One TEAE,
x
One TEAE related to IMP,
x
One confirmed or suspected COVID-19 TEAE (as defined in Section 10.21.2),
x
One TEAE leading to permanent IMP discontinuation,
x
One TEAE related to IMP leading to permanent IMP discontinuation,
x
One serious TEAE,


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x
One serious TEAE related to IMP,
x
One TEAE with outcome of death,
x
One AE with outcome of death related to IMP,
x
One TEAE of special interest.
This table will also present the number of TEAEs and the number of TEAE of special interest by treatment 
arm.
12.7.1.2 All-causality Treatment-emergent Adverse Event Summary
Descriptive presentations of TEAEs will be given by PT and SOC for the Safety Analysis Set. The 
number and percentage of patients reporting at least one TEAE within a given treatment arm will be 
provided as described below
x
*All TEAEs by SOC and PT,
x
*All TEAEs by SOC, PT and subgroups (as described in Table 12.7-1),
x
Most common TEAEs (incidence ≥ 5% in either treatment arm) by SOC and PT,
x
Most common TEAEs (incidence ≥ 2 patients in either treatment arm) by SOC and PT,
x
Most common TEAEs (incidence ≥ 2 patients in either treatment arm) by SOC, and PT and 
subgroups (as described in Table 12.7-1),
x
All TEAEs by SOC, PT and maximum severity,
x
All TEAEs by SOC, PT and worst action taken on study drug,
x
All TEAEs by SOC, PT and time of first onset of AE categorized as:
1-7 day, 8 to 14 days, 15 to 21 days and > 21 days (as described in Section 10.21.3),
x
All TEAEs by SOC, PT and AE duration, categorized as:
1-7 day, 8 to 14 days, 15 to 28 days, 29 to 42 days ,43 to 61 days ,> 61 days, ongoing, indeterminate 
(as described in Section 10.21.4),
x
All TEAEs by SOC, PT and relationship to IMP,
x
All treatment-related TEAEs by SOC and PT and maximum severity,
x
*All treatment-related TEAEs by SOC and PT and subgroups (as described in Table 12.7-1),
x
*All treatment-related TEAEs leading to permanent IMP discontinuation by SOC and PT,
x
*All TEAEs leading to permanent IMP discontinuation by SOC and PT,
x
*All TEAEs leading to permanent IMP discontinuation by SOC and PT and subgroups (as described 
in Table 12.7-1),
x
All treatment-related TEAEs leading to permanent IMP discontinuation by SOC and PT and maximum
severity,
x
All non-serious TEAEs by SOC and PT,
x
All most common non-serious TEAEs (incidence ≥ 5% in either treatment arm) by SOC and PT.
*These tables will also present the total number of AEs by treatment arm and as appropriate by 
category of subgroup.
12.7.2 Death, Serious Adverse Events and Other Significant Adverse Events
12.7.2.1 Death
All deaths recorded in the EDC as adverse events, as the result of an adverse event or as fatal outcome of 
an adverse event will be listed and summarized as described in Section 12.7.1 and described in depth as 
narrative.


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Descriptive presentations of fatal TEAEs will be given by PT and SOC for the Safety Analysis Set. The 
number and percentage of patients reporting at least one fatal TEAE within a given treatment arm will be 
provided as described below:
x
All TEAEs leading to death by SOC and PT (if at least 2 patients experienced a fatal issue TEAE),
x
All treatment-related TEAEs leading to death by SOC and PT (if at least 2 patients experienced a 
fatal issue TEAE related to study drug).
These tables will also present the total number of AEs by treatment arm.
12.7.2.2 Serious Adverse Events
Descriptive presentations of serious TEAEs will be given by PT and SOC for the Safety Analysis Set. 
The number and percentage of patients reporting at least one serious TEAE within a given treatment arm 
will be provided as described below:
x
All serious TEAEs by SOC and PT,
x
All serious TEAEs by SOC, PT and subgroups (as described in Table 12.7-1),
x
All serious TEAEs leading to permanent IMP discontinuation by SOC and PT,
x
All serious treatment-related TEAEs by SOC and PT,
x
All serious treatment-related TEAEs by SOC and PT leading to permanent IMP discontinuation by 
SOC and PT,
These tables will also present the total number of AEs by treatment arm and as appropriate by category of 
subgroup.
12.7.2.3 Adverse Events of Special Interest
An adverse events of special interest (AESI) is any adverse event of scientific or medical interest to the
study medication. The types of AESIs which will be analyzed are presented in Descriptive presentations 
of AESIs will be given for each AESI category on the safety analysis set presenting:
x
The number and percentage of patients with at least one treatment-emergent AESI,
x
The number and percentage of patients with at least one treatment-emergent AESI by SOC and PT,
x
The number and percentage of patients with at least one severe treatment-emergent AESI,
x
The number and percentage of patient with at least one serious treatment-emergent AESI,
x
The number of and percentage of patients with at least one treatment-emergent AESI leading to 
permanent IMP discontinuation,
x
The number of treatment-emergent AESI,
x
The number of severe treatment-emergent AESI,
x
The number of serious treatment-emergent AESI,
x
The number of treatment-emergent AESI leading to permanent IMP discontinuation,
x
The number of unique* treatment-emergent AESI,
x
The number of unique* severe treatment-emergent AESI,
x
The number of unique* serious treatment-emergent AESI,
x
The number of unique* treatment-emergent AESI leading to permanent IMP discontinuation,
x
The time to first onset of treatment-emergent AESI categorized as :1-7 day, 8 to 14 days, 15 to 
21 days, 21 to 28 days and > 28 days (as described in Section 10.21.3),
*Unique AESI is defined as any AESI coded with the same PT and having the same date of onset.
Analysis of time to first onset of AESIs will be conducted by actual treatment arm on the Safety Analysis 
SAS using the SAS® LIFEEST procedure.


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Assuming no carry over effect, Kaplan-Meier plots (estimates) of cumulative incidence of first onset of AESI
will be provided by actual treatment arm on the Safety analysis set. The time to AESI onset (in days) is 
defined as the number of days from 1st IMP intake of the treatment arm (e.g., nabiximols, placebo) the AESI 
is emergent to (as defined in Section 12.7.1) until the onset of the AESI (see detailed in Section 10.21.4).
For patients not known to have experienced an AESI during respectively Period 1 and Period 2:
x
Period 1 censoring day is the date of 1st IMP intake during Period 2 minus 1 day for those patients 
continuing in Period 2 and, the end of study date for those patients who discontinued before Period 2,
x
Period 2 censoring day is the end of study date in the period.
Additionally, for lost to follow-up patients:
x
Period 1 censoring day is the earliest date between end of study date in the period and the planned 
Visit 6 day minus 1 day (Day 30),
x
Period 2 censoring day is the earliest date between end of study date in the period and the planned 
Visit 10 day (Day 58).
To accompany the Kaplan-Meier (KM) plots, summary tables will display the KM estimates of cumulative 
probabilities (with 95% CI calculated based on the Greenwood method when applicable).
x
of patients with on event at a specific time point such as 7, 14, 21, 28 (if applicable) days after 1st
IMP intake in the studied period;
x
time to first event based on the 10th, 20th, 30th, 40th, 50th (median) and 75th percentiles.
If the estimate of lower bound of the 95% CI is below ‘0’ or the estimate of the upper bound of the 95% CI
is over ‘1’, then it will be respectively restricted to ‘0’ and ‘1’.
The number of patients at risk along with the number and percentage of patients censored and with an 
event, using the number of patients at risk as denominator to calculate the percentage will also be displayed.
Each Kaplan-Meier plot (estimates) will only be provided if more than 5 patients are presenting an event in 
each treatment arm.
12.7.3 Laboratory Data
The clinical safety laboratory data (hematology and biochemistry) are planned to be collected at Screening 
and D21 of each treatment period. In case of premature end of treatment the latest assessment collected 
on-treatment will be used as described in Table 10.1-1.
For the purposes of summarization in both the tables and listings, all laboratory values will be converted to 
standardized units. The investigator and medical monitor will be provided with a list of the normal ranges
used by the central clinical laboratory for all variables assayed during the trial and a statement of 
accreditation (or similar) for the laboratory. However, AST, ALT, GGT, ALP and total bilirubin will be 
summarized using SI units.
Only scheduled laboratory parameters defined in Appendix 2 and those derived from them as eGFR (as 
defined in Section 10.13) will be included in summary tables and figures. However unscheduled laboratories 
values (coming from central or local laboratories) will be used in abnormality summary tables and will be 
presented in listings (using categories as defined in Appendix 6).
Baseline (Screening), D21 of each treatment period and the change from baseline to D21 (end of the
treatment) will be summarized using the safety analysis set, by treatment arm, separately for red blood cells 
parameters and white blood cells parameters, hepatobiliary parameters, renal parameters, coagulation 
parameters and electrolytes and proteins (as described in Appendix 2). Furthermore, AST, ALT, GGT, ALP 
and total bilirubin will also be summarized as a multiple of the upper limit of normal (ULN).


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Laboratory hematology and biochemistry (as described in Appendix 2) abnormalities will be evaluated, on 
patients from the Safety Analysis Set using shift tables at D21 according to baseline status with categories 
based on:
x
reference ranges as either normal, below the lower limit of normal (LLN) as “Low” or above the ULN 
as “High”,
x
based on CTCAE toxicity grade using version 5.0 or higher (as defined in Appendix 4 for hematology 
parameters and in Appendix 5 for biochemistry parameters),
presented by treatment arm.
Shift tables based on reference ranges will also be repeated for the subgroups presented in Table 12.7-1. 
Furthermore, a summary of patients with laboratory values outside the reference ranges at baseline and 
during each 21-day on-treatment safety period (as defined in Section 10.1.1) will be presented  for 
scheduled parameter including either scheduled visit only or scheduled and unscheduled visits, by 
treatment arm.
Scatterplot presenting baseline against last on-treatment value within each treatment period will be 
presented by treatment arm for scheduled biochemistry and hematological parameters of interest.
Regarding AST, ALT, GGT, ALP and total bilirubin these parameters will be summarized by treatment arm 
within the Safety Analysis Set for D21 of each treatment period using SI units and as a proportion of the 
population with no missing assessment if abnormal values with reference to ULN are presented using the 
All laboratory values will be listed and all test values outside the normal range will be flagged.
Urinalysis results will be summarized and listed.
12.7.3.1 Potential Drug-induced Liver Injury (DILI)
Liver function test data will also be provided in separate listings for:
x
Patients who possibly met Hy’s Law criteria (i.e., had any elevated ALT or AST of > 3 x ULN, and 
increase in total bilirubin >= 2 x ULN, at the same visit)
x
Patients who met any one or more of the following criteria at any post-baseline visit (list laboratory 
parameters ALT, AST, and total bilirubin only)
x
ALT or AST > 3 u ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (> 5%)
x
ALT or AST > 8 u ULN
x
ALT or AST > 5 u ULN for more than 2 weeks
x
ALT or AST > 3 u ULN and (TBL > 2 u ULN or INR > 1.5)
A summary table will also be provided by treatment arm for number of patients who met any of the criteria 
specified above at any post-baseline visit. Any elevation during the wash-out period will be linked to the 
actual treatment arm received during Period 1 whereas any elevation observed permanent treatment 
discontinuation will be linked to the last treatment received. 
A drug-induced serious hepatotoxicity (DISH) plot will display, for each patient during each 21-day on-
treatment safety period (as defined in Section 10.1.1) the maximal total bilirubin value (expressed as a 
multiple of the ULN) against the maximal ALT value (expressed multiple of the ULN) to identify possible 
Hy’s Law range or Temple’s Corollary.
All post-baseline potential drug-induced liver injury laboratory data will be listed.
12.7.4 Vital Signs
Vital signs will include sitting SBP and DBP and pulse rate which are planned to be measured at Day 1 H0, 
D1H3, Day 15 and D21 of each treatment period as well as during the screening and the FU visit.


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Vital signs parameters will be summarized on the Safety Analysis Set as described below.
Observed and change from baseline value in vital signs measures at each scheduled timepoint
(D1H3, Day 15, D21) will we summarized by treatment arm.
The number and percentage of patients with any clinically significant abnormal value and change in vital 
signs (as defined in Appendix 6) within each treatment period will be summarized by treatment arm within 
the Safety Analysis Set.
Observed and change from baseline (Screening) to FU will also be summarized by treatment sequence.
All vital signs data will be listed.
12.7.5 Physical Examination, ECGs and other Observation Related to Safety 
12.7.5.1 Physical Examination: Weight and BMI
Weight is planned to be measured at Screening, Day 1H0 of each period and at follow-up visit.
Based on the Safety Analysis Set, weight and BMI (as defined in Section 10.11), observed and change 
from baseline value at each scheduled timepoint (Period 2 Day 1 H0, D21) will we summarized by treatment 
arm.
Observed and change from Screening to FU will also be summarized by treatment sequence.
The number and percentage of patients meeting a clinically significant change in weight (as defined in
Appendix 6 at any time during within each treatment period will be summarized by treatment arm. All 
measurements (scheduled or unscheduled) will be used to determine if any abnormality criteria is met(as 
determined in Appendix 6).
Weight and BMI will be listed.
12.7.5.2 Electrocardiogram Results
Based on the safety analysis set, 12-lead ECG parameters (Heart rate (beats/min), PR interval (msec), 
QRS duration (msec), QT Interval (ms), QTc B Interval (Bazett’s formula) (msec), QTcF (Fridericia’s 
formula) Interval (msec) will be summarized by treatment arm. All ECG results will be listed.
ECG results will be summarized for continuous variables and will be presented for the absolute result and 
change from baseline (Screening) to D21. 
The number and percentage of patient with any abnormal QTcF (as detailed in Appendix 6) values or any 
other clinically significant ECG abnormality (as defined in Appendix 6) at baseline and within each treatment 
period will be summarized by treatment arm within the Safety Analysis Set.
12.7.5.3 Columbia-Suicide Severity Rating Scale
The Columbia-Suicide Severity Rating Scale is a patient questionnaire that evaluates suicidal ideation and 
behaviors. In this study, the C-SSRS is assessed at Screening using the “Baseline/Screening Version” and 
at subsequent timepoints using the “Since Last Visit” version. At the Screening visit, patient eligibility will 
be assessed with respect to suicidal ideation during the past month and suicidal behavior during the past 
5 years.
The C-SSRS questionnaire is planned to be administered by the investigator (or designee) at Screening, 
Day 1 H0, Day 15 and D21 of each treatment period and at FU. 
To analyze these questionnaires, events will be considered associated with:
x
Nabiximols, if collected between first and last date of nabiximols intake.
x
Placebo, if collected between first and last date of placebo intake.
x
Any unscheduled C-SSRS questionnaire taken during the wash-out period will be linked to the actual 
treatment arm defined during Period 1.


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x
FU if collected after last IMP intake and only the latest one will be used for summary.
Derived parameters are presented in Section 10.23.
On treatment and by timepoints assessments
The number and percentage of patients who have answer “Yes” to each of the 5 suicidal ideation subtypes
and each of the 5 suicidal behavior subtypes along with the number and percentage of patients presenting:
x
A suicidal ideation, 
x
A suicidal behavior,
x
A suicidal ideation or behavior,
x
A self-injurious behaviour without suicidal intent.
will be summarized at baseline, for each scheduled on-treatment timepoint, for the 51-day safety 
on- treatment period, for last on-treatment assessment and for the Follow-up assessment by treatment arm.
For this summary FU assessments will be linked to the last treatment received.
Shift table from baseline to maximal suicidal ideation score as well as a shift table for change in category 
(no suicidal ideation or behavior, suicidal ideation [without suicidal behavior], suicidal behavior) will also be 
summarized by treatment arm for patients having a baseline and at least 1 post baseline on-treatment 
assessment.
The number and percentage of patients presenting a suicide-related treatment-emergent event defined as:
x
A treatment emergent suicidal ideation (without suicidal behavior) compared to recent history,
x
A treatment emergent serious suicidal ideation compared to recent history,
x
An emergence of serious suicidal ideation compared to recent history,
x
An emergence of suicidal behavior compared to all prior history,
will be summarized by treatment arm.
Observed scores and changes from baseline in Suicidal ideation score and in Suicidal intensity rating score 
will be summarized at baseline and for each scheduled on-treatment timepoint, for the last on-treatment 
assessment and for the worst on-treatment score and for the follow-up assessment, by treatment arm using 
n, mean, median, SD, Q1, Q3, min and max.
Cumulative distribution function on change from baseline to last on-treatment value will be plotted by 
treatment arm. This will be displayed as an increasing CDF.
Withdrawal assessment from last on-treatment visit
The number and percentage of patients presenting:
x
An emergence of suicidal ideation without suicidal behavior,
x
An emergence of serious suicidal ideation,
x
An emergence of suicidal behaviour.
From last on treatment assessment to FU will be summarized by treatment arm according to last treatment 
received.
Observed at last on-treatment assessment and FU along with change from last on-treatment assessment 
in Suicidal intensity rating score will be summarized by treatment group using n, mean, median, SD, Q1, 
Q3, min and max. A shift table of from last on-treatment to FU score will also be displayed.
For patients with any post-baseline suicidal ideation or suicidal behavior, listings will be prepared including 
all C-SSRS scores for these patients.
12.7.5.4 Drug of Abuse Screen
Drug of abuse screen is planned to be collected at Screening and Period 1 Day 1 H0.


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A by-patient listing presenting all THC measures along with urinary drug screen results will also be provided.
12.7.5.5 Pregnancies
Any reported positive pregnancy results or reported pregnancies will be listed.
12.7.5.6 Examination of Oral Mucosa
Based on the Safety Analysis Set, results of oral mucosa examination (normal, abnormal NCS and 
Abnormal CS) planned to be performed at Screening, Day 1 H0, Day 15 and D21 of each period and during 
the follow-up visit will be described by treatment arm according to baseline status. 
Each patient presenting at least one abnormal assessment will be listed.
12.7.5.7 Covid-19 Impact
The impact of COVID-19 on each visit will be summarized by treatment arm and a by-patient listing 
presenting patients impacted by COVID-19 during the conduct of the trial will be provided.


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References
SAS Institute Inc. 2015. Base SAS 9.4 Procedures Guide. 5th ed. Cary, NC: SAS Institute Inc. 
Mary E. Nilsson, Shailaja Suryawanshi. Cristiana Gassmann-Mayer, Sarah Dubrava, Paul McSorley, and 
Kaihong Jiang Columbia-Suicide Severity Rating Scale Scoring and Analysis guide -  Version 2.0 FEB 2013
Jill S. Fischer, Amy J. Jak, Judith E. Kniker, Richard A, Rudick, Gary Cutter, Multiple sclerosis functional 
composite (MSFC) administration – administration and scoring manual. Revised, October 2001. 2011..
Grayling MJ, Mander AP, Wason JMS. Blinded and unblinded sample size reestimation in crossover trials 
balanced for period. Biometrical Journal. 2018;60:917-933
Daniel G, Tim F, Meinhard K, Blinded sample size re-estimation in crossover bioequivalence trials
Byron Jones, Michael G. Kenward, Design and analysis of cross-over trials, ed 1,1988: 43-45 
Rubin, D. (1976). Inference and Missing Data. Biometrika, 63(3), 581-592.


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Glossary of Abbreviations
Glossary of Abbreviations:
11-COOH-THC
11-carboxy-Δ9-tetrahydrocannabinol
11-OH-THC
11-hydroxy-Δ9-tetrahydrocannabinol
7-COOH-CBD
7-carboxy-cannabidiol 
7-OH-CBD
7-hydroxy-cannabidiol
ADaM
Analysis dataset model
ADL
Activity of Daily Living
AE
Adverse event
AESI
Adverse events of special interest
ATC
Anatomic Therapeutic Class
ET visit
End of Treatment visit
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
AST
Aspartate aminotransferase
BLQ
Below Limit of Quantification
BDZ
Benzodiazepine
BMI
Body Mass Index
bpm
Beats per minutes
CBD
Cannabidiol
CDF
Cumulative distribution function
CFB
Change from baseline
CI
Confidence interval
CRF
Case report form
CS
Compound symmetry
CS
Clinically significant
CSR
Clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology criteria for adverse events
CTMS
Clinical Trial Management System
CV
Coefficient of variation
D
Day
DBP
Diastolic blood pressure
DILI
Drug-Induced Liver Injury
DISH
drug-induced serious hepatotoxicity


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DMD
Disease Modifying Drug
DRESS
Drug reaction with eosinophilia and systemic systems
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
eDiary
Electronic diary
eGRF
Estimated Glomerular filtration rate
FAS
Full Analysis Set
FU
Follow-up
GEE
Generalized estimating equation
GGT
Gamma-glutamyl transferase
GW
GW Pharma Ltd / GW Pharma Limited 
H
Hour
HLGT
High Level Group Term
HLT
High Level Term
HR
Heart rate
hrs
hours
ICF
Informed consent form
ICH
International Council for Harmonisation
IES
Intercurrent event(s) strategy
IMP
Investigational medicinal product
INR
International normalized ratio
IPD
Important protocol deviation
IRT
Interactive response technology
kcal
Kilo calories
KM
Kaplan-Meier
KR
Kenward-Roger
KR2
Kenward-Roger method (e.g., KR2, 2009 version)
LLMT
Lower Limb Muscle Tone
LLMT-4
Lower Limb Muscle Tone-4
LLMT-6
Lower Limb Muscle Tone-6
LLMT-10
Lower Limb Muscle Tone-10
LLN
Lower Limit of Normal
LME
Linear mixed-effects 
LS mean
Least square mean


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LSMD
Least square mean difference
M
Month
MAR
Missing at Random
MAS
Modified Ashworth Scale
Max
Maximum
MCMC
Markov Chain Monte Carlo
MDRD
Modification of Diet Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MHP
Mobile Health Platform
MI
Multiple Imputation
Min
Minimum
MNAR
Missing Not At Random
MS
Multiple sclerosis
msec
millisecond
MSSS-88
Multiple Sclerosis Spasticity Scale
NC
Not Calculated
NCS
Not Clinically significant
NRS
Numerical Rating Scale
OR
Odds ratio
P
Period
PD
Pharmacodynamic
PK
Pharmacokinetic
PLS
Population-level summary
PP
Per Protocol
PRA
Pharmaceutical Research Associates
PRN
pro re nata (meaning as-needed)
PRO
Patient reported outcome
PSO
Predictive Study Operations
PT
Preferred term
Q1
First Quartile / Quartile 1
Q3
Third Quartile / Quartile 3
QTc B
QT corrected Bazett’s formula
QTc F
QT corrected Fridericia’s formula
SAE
Serious adverse event
SAP
Statistical analysis plan


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SBP
Systolic Blood Pressure
SD
Standard deviation
SDTM
Study data tabulation model
SE
Standard error 
SI
Standard International
SOC
System organ class
T25FW
Timed 25-Foot Walk
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
THC
Δ9-Tetrahydrocannabinol
UK
United Kingdom
ULN
Upper limit of normal
UN
Unstructured 
WHO-DD
World Health Organization-Drug Dictionary
Y
Year


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Appendix 1
Classification of Protocol Deviations
List of Important Protocol Deviation Category
Number
IPD category
01
Inclusion criteria
02
Exclusion criteria
03
Study drug
04
Assessment safety
05
Efficacy/pharmacodynamic endpoint
06
Visit window
07
Prohibited co-medication
08
Others
List of Major Important Protocol Deviations
Number
Major IPD 
category
Major IPD criteria
01
Inclusion criteria
Patient was not diagnosed with any disease subtype of MS, by revised 2017 
McDonald criteria, for at least 12 months prior to Visit 1.
02
Inclusion criteria
Does not have a MAS untransformed score of at least 2 in 2 or more of six 
muscle groups (right knee flexors, left knee flexors, right knee extensors, left 
knee extensors, right plantar flexors, or left plantar flexors) at Visit 1.
03
Inclusion criteria
Subject was not receiving optimized treatment with at least 1 oral antispasticity 
drug (baclofen, tizanidine, and/or dantrolene) that has been stable for at least 
30 days prior to Visit 1.
04
Exclusion criteria
Has taken nabiximols, cannabis, or a cannabis-derived product for medicinal or 
recreational purposes in the 30 days prior to Visit 1 and unable to abstain for 
the duration of the trial.
05
Exclusion criteria
Did not respond adequately to treatment with nabiximols or another 
cannabis-based medication if exposed at any time before the 30-day period 
prior to Visit 1.
06
Exclusion criteria
Any concomitant disease or disorder that has spasticity-like symptoms or that 
may influence the patient’s level of spasticity.
07
Exclusion criteria
Has had a relapse of MS within the 60 days prior to Visit 1.
08
Exclusion criteria
Clinically suspected to have a contracture in one of the muscle groups of the 
lower limbs, preventing assessment with the MAS.
09
Exclusion criteria*
Has any other clinically significant disease or disorder (including seizure 
disorder) that, in the opinion of the investigator, may put the patient at risk 
because of participation in the trial, influence the interpretation of trial results, 
or may affect the patient’s ability to take part in the trial.
For certain disorders, determined with medical monitor
10
Study drug
Subject taking more than 13 sprays per day at any time during each treatment 
phase.
11
Study drug
Patient randomized but not exposed to study drug.
12
Study drug
Subject not receiving at least 1 spray in the morning on the last day during 
maintenance phase.
13
Study drug
Subject receiving IMP during the washout period.
14
Study drug
Subject not exposed to IMP during at least 1 day during titration or the 
maintenance phase.
15
Study drug
Subject not exposed to IMP during at least 1 day in either treatment period.
16
Study drug
Patient receiving a kit number not allocated by IXRS which is not the treatment 
he/she was allocated to by IXRS during this period.
17
Efficacy endpoint
Missing evaluable MAS LLMT-6 pre-dose assessment.
18
Efficacy endpoint
Missing evaluable MAS LLMT-4 pre-dose assessment.
19
Efficacy endpoint
Missing evaluable MAS LLMT-6 at endpoint. (D21 or Day 51)
20
Efficacy endpoint
Missing evaluable MAS LLMT-4 at endpoint. (D21 or Day 51)
21
Visit window
Wash-out duration of less than 7 days.
22
Visit window
During maintenance phase:
Visit 4 occurred +/- 2 days out of window


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Number
Major IPD 
category
Major IPD criteria
Visit 5 occurred +/- 3 days out of window
Visit 6 occurred +/- 2 days out of window
Visit 8 occurred +/- 2 days out of window
Visit 9 occurred +/- 3 days out of window
23
Prohibited co-
medication
Patient taking antipsychotic medication at any time during the trial.
24
Prohibited co-
medication
Patient taking benzodiazepine on an as needed (PRN) basis during the trial.
25
Prohibited co-
medication
Patient taking commercial cannabis or any cannabinoid medication during the 
trial.
26
Prohibited co-
medication
Patient taking botulinum injection during the trial.
27
Prohibited co-
medication
Initiation or changes in the dose of MS disease modifying therapy any time 
after randomization at Visit 2
28
Prohibited co-
medication
Patient taking drugs solely metabolized by UGT1A9 and UGT2B7 during the 
trial
29
Prohibited co-
medication
Patient taking strong CYP3A4 inducer during the trial
30
Prohibited co-
medication
Initiation of a new course of physiotherapy any time after randomization at 
Visit 2
31
Prohibited co-
medication
Patient changing dose or introducing antispasticity medication (baclofen, 
tizanidine, dantrolene)
32
Prohibited co-
medication
Patient changing dose or introducing dalfampridine or fampridine
MS = Multiple sclerosis; MAS = Modified Ashworth Scale, IMP = Investigational Medicinal Product; 
IXRS = Interactive x Response System; LLMT-6 = Lower Limb Muscle Tone-6, LLMT-4 = Lower Limb 
Muscle Tone-6, PRN = pro re nata meaning as needed.
* Refers to important protocol which may or not be considered as major important deviation


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Appendix 2
Clinical laboratory parameters
Biochemistry (Serum¹)
Hematology (Whole Blood¹)
Urinalysis
(Urine²)
Category
Parameters
Category
Parameters
Parameters
Hepatobiliary 
Alanine 
aminotransferase
Red blood cells 
Hematocrit
Blood
Hepatobiliary 
Albumin
Red blood cells
Hemoglobin
Glucose
Hepatobiliary 
Alkaline phosphatase
Red blood cells
Mean cell volume
Nitrites
Hepatobiliary 
Aspartate 
aminotransferase
Red blood cells
Mean corpuscular 
hemoglobin
pH
Electrolytes 
and proteins
Calcium
Coagulation parameter
Platelets
Protein
Renal 
Creatinine
Red blood cells
Red blood cell count
White blood cells
Hepatobiliary 
Gamma-glutamyl 
transferase
White blood cells 
parameters
White blood cell count 
with automated 
differential
Specific gravity
Electrolytes 
and proteins
Potassium
Ketones
Electrolytes 
and proteins
Sodium
Urobilinogen
Hepatobiliary 
Total bilirubin
Bilirubin
Electrolytes 
and proteins
Total protein
Renal 
Urea (blood urea 
nitrogen)
Coagulation 
parameters
Prothrombin time 
(plasma4)
¹Analyzed at a central laboratory.
²Analyzed at the trial site by use of a dipstick (if allowed per local regulations).
3The standard drugs of abuse screen, including THC, will be analyzed by use of a urine dipstick at 
Visits 1 and 2. Patients will undergo a separate blood THC test at Visit 1 only.
4Analyzed at Screening (Visit 1) only.


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Appendix 3
Unscheduled Clinical laboratory parameters 
Biochemistry (Serum¹)
Hematology (Whole Blood¹)
Urinalysis
(Urine²)
Category
Parameters
Category
Parameters
Parameters
Hepatobiliary 
Alanine 
aminotransferase
Red blood cells 
Hematocrit
Blood
Hepatobiliary 
Albumin
Red blood cells
Hemoglobin
Glucose
Hepatobiliary 
Alkaline phosphatase
Red blood cells
Mean cell volume
Nitrites
Hepatobiliary 
Aspartate 
aminotransferase
Red blood cells
Mean corpuscular 
hemoglobin
pH
Electrolytes, 
proteins and 
creatinine 
kinase
Calcium
Coagulation parameter
Platelet count
Protein
Renal 
Creatinine
Red blood cells
Red blood cell count
White blood cells
Hepatobiliary 
Gamma-glutamyl 
transferase
White blood cells 
parameters
White blood cell count 
Specific gravity
Electrolytes, 
proteins and 
creatinine 
kinase
Potassium
White blood cells 
parameters
Total neutrophil count
Ketones
Electrolytes, 
proteins and 
creatinine 
kinase
Sodium
White blood cells 
parameters
Monocyte count
Urobilinogen
Hepatobiliary 
Total bilirubin
White blood cells 
parameters
Lymphocyte count
Bilirubin
Electrolytes, 
proteins and 
creatinine 
kinase
Total protein
White blood cells 
parameters
Basophil count
Squamous 
epithelial cells
Renal 
Urea (blood urea 
nitrogen)
White blood cells 
parameters
Eosinophil count
Mucus
Coagulation 
parameters
Prothrombin time 
(plasma4)
Microscopy 
Hepatobiliary
Amylase
Leucocyte esterase
Electrolytes, 
proteins and 
creatinine 
kinase
chloride
Color
Electrolytes, 
proteins and 
creatinine 
kinase
Bicarbonate
Appearance
Lipids
HDL-Cholesterol
Bacteria


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Biochemistry (Serum¹)
Hematology (Whole Blood¹)
Urinalysis
(Urine²)
Lipids
LDL-Cholesterol
Lipids
Total Cholesterol
Lipids
Triglycerides
Hepatobiliary
Lipase
Electrolytes 
and proteins
Magnesium
Electrolytes, 
proteins and 
creatinine 
kinase 
Phosphorus
Renal
Creatinine clearance
Endocrinology
Insulin-like growth 
factor-1
Endocrinology
Prolactin
Renal
Estimate glomerular 
filtration rate
Coagulation
INR
Endocrinology
Glucose
Electrolytes, 
proteins and 
creatinine 
kinase
Creatinine Kinase 
Immunology
HBaAg
Immunology
HCV
Immunology
HIV


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Appendix 4
Toxicity Criteria for Laboratory Hematology and 
coagulation Parameters based on CTCAE version 5.0 
Laboratory 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematology 
Anemia 
(Hemoglobin 
Decreased)
<LLN – 6.2 mmol/L 
<LLN - 100 g/L 
<LLN – 10.0 g/L
<6.2 – 4.9 mmol/L
<100 - 80 g/L
<10.0 to 80.0 g/dL
<4.9 mmol/L 
<80 g/L
<8.0 g/dL
Hemoglobin 
increased 
Increase in >0 - 2 
g/dL 
Increase in >2 - 4 g/dL
Increase in >4 g/dL 
White Blood Cells
Decreased 
<LLN – 3000/mm3 
<LLN – 3.0 x 109/L 
<3000 - 2000/mm3 
<3.0 – 2.0 x 109/L 
<2000 - 1000/mm3 
<2.0 – 1.0 x 109/L 
<1000/mm3 
<1.0 x 109/L 
Neutrophils count 
Decreased 
<LLN – 1500/mm3 
<LLN – 1.5 x 109/L 
<1500 - 1000/mm3 
<1.5 – 1.0 x 109/L 
<1000 - 500/mm3 
<1.0 – 0.5 x 109/L 
<500/mm3 
<0.5 x 109/L 
Lymphocytes count  
Decreased 
<LLN – 800/mm3 
<LLN – 0.8 x 109/L 
<800 – 500/mm3 
<0.8 – 0.5 x 109/L 
<500 - 200/mm3 
<0.5 – 0.2 x 109/L 
<200/mm3 
< 0.2 x 109/L 
Lymphocyte count 
increased 
>4000/mm3-20,000/mm3
>4 - 20 x 109/L
>20,000/mm3 
> 20 x 109/L
Platelets count
Decreased 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109/L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109/L 
<50,000 – 25,000/mm3 
<50.0 – 25.0 x 109/L 
<25,000/mm3 
<25.0 x 109/L 
Activated partial 
thromboplastin time 
prolonged (aPTT)
>ULN – 1.5 x ULN
>1.5 – 2.5 x ULN
>2.5 ULN °


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Appendix 5
Toxicity Criteria for Laboratory Biochemistry
Parameters based on CTCAE version 5.0 
Laboratory 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistry 
Sodium Increased 
(Hypernatremia)
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L 
>160 mmol/L 
Sodium Decreased 
(Hyponatremia)
<LLN - 130 mmol/L 
<130 - 120 mmol/L 
<120 mmol/L 
Potassium Increased 
(Hyperkaliemia)
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L; 
Potassium Decreased
(Hypokaliemia) 
<LLN - 3.0 mmol/L 
<LLN - 3.0 mmol/L 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
Calcium Increased 
(Hypercalcemia)
>ULN - 11.5 mg/dL;
>ULN - 2.9 mmol/L 
Ionized calcium 
>ULN - 1.5 mmol/L
>11.5 - 12.5 mg/dL; 
>2.9 - 3.1 mmol/L 
Ionized calcium 
>1.5 - 1.6 mmol/L
>12.5 - 13.5 mg/dL; 
>3.1 - 3.4 mmol/L; 
Ionized calcium >1.6 -
1.8 mmol/L
>13.5 mg/dL;
>3.4 mmol/L; 
Ionized calcium 
>1.8 mmol/L
Calcium Decreased  
(Hypocalcemia)
<LLN - 8.0 mg/dL;
<LLN - 2.0 mmol/L; 
Ionized calcium 
<ULN – 1.0 mmol/L
<8.0 - 7.0 mg/dL;
<2.0 - 1.75 mmol/L 
Ionized calcium 
<1.0 - 0.9 mmol/L
<7.0 - 6.0 mg/dL; <1.75 -
1.5 mmol/L; 
Ionized calcium 
<0.9-0.8 mmol/L
<6.0 mg/dL;
<1.5 mmol/L; 
Ionized calcium 
<0.8 mmol/L
Albumin Decreased 
(hypoalbuminemia)
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL; 
<30 - 20 g/L 
<2 g/dL; <20 g/L 
Alkaline Phosphatase 
increased 
>ULN - 2.5 x ULN if 
baseline normal
2.0 - 2.50 x baseline if 
baseline abnormal
>2.5 - 5.0 x ULN if 
baseline normal
>2.5 – 5.0 x baseline 
if baseline abnormal
>5.0 - 20.0 x ULN if 
baseline normal
>5.0 – 20.0 x baseline if 
baseline abnormal
>20.0 x ULN if 
baseline normal
20.0 x baseline if 
baseline abnormal  
Alanine amino 
transferase increased 
>ULN - 3.0 x ULN if 
baseline normal
1.5 - 3.0 x baseline if 
baseline abnormal
> 3.0 - 5.0 ULN if 
baseline normal
>3.0 - 5.0 x baseline 
if baseline abnormal 
>5.0 – 20.0 x ULN if 
baseline normal
>5.0 - 20.0 x baseline if 
baseline abnormal
>20.0 x ULN if 
baseline normal
> 20.0 x baseline if 
baseline abnormal
Aspartate amino 
transferase increased 
>ULN - 3.0 x ULN if 
baseline normal
1.5 - 3.0 x baseline if 
baseline abnormal
> 3.0 - 5.0 ULN if 
baseline normal
>3.0 - 5.0 x baseline 
if baseline abnormal 
>5.0 – 20.0 x ULN if 
baseline normal
>5.0 - 20.0 x baseline if 
baseline abnormal
>20.0 x ULN if 
baseline normal
> 20.0 x baseline if 
baseline abnormal
Blood Bilirubin 
Increased 
>ULN – 1.5 x ULN if 
baseline normal
>1.0-1.50 x baseline if 
baseline abnormal
>1.5 – 3.0 x ULN if 
baseline normal
>1.5-3.0 x baseline if 
baseline abnormal
>3.0 – 10.0 x ULN if 
baseline normal
>3.0- 10.0 x baseline if 
baseline abnormal
>10.0 x ULN if 
baseline normal
> 10.0 x baseline if 
baseline abnormal
Gamma Glutamyl 
Transferase Increased 
>ULN - 2.5 x ULN if 
baseline normal
2.0 - 2.5 x baseline if 
baseline abnormal
>2.5 - 5.0 x ULN if 
baseline normal
>2.5 - 5.0 x  baseline 
if baseline abnormal
>5.0 - 20.0 x ULN if 
baseline normal
>5.0 - 20.0 x  baseline if 
baseline abnormal
>20.0 x ULN if 
baseline normal
>20.0 x ULN if 
baseline abnormal
Creatinine Increased 
>ULN – 1.5 x ULN 
>1.5 - 3.0 x baseline;
>1.5 – 3.0 x ULN 
>3.0 baseline; 
>3.0 – 6.0 x ULN 
>6.0 x ULN 


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Chronic Kidney 
Disease 
eGFR (estimated 
Glomerular Filtration 
Rate) or CrCl 
(creatinine 
clearance)
<LLN - 60 
ml/min/1.73 m2 or 
proteinuria 2+ 
present; urine 
protein/creatinine 
>0.5 
eGFR or CrCl 59 -
30 ml/min/1.73 m2 
eGFR or CrCl 29 - 15 
ml/min/1.73 m2 
eGFR or CrCl <15 
ml/min/1.73 m2 
Hypoalbuminemia 
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL; 
<30 - 20 g/L 
<2 g/dL; 
<20 g/L
Proteinuria
1+ proteinuria
2+ and 3+ 
proteinuria
4+ proteinuria
Appendix 6
Abnormality Criteria 
Hepatic abnormality criteria
Hepatic laboratory Parameters
Abnormality criteria
ALT 
> 3 x ULN
>5 x ULN 
> 8 x ULN
> 10 x ULN
> 20 x ULN
AST 
> 3 x ULN
>5 x ULN 
> 8 x ULN
> 10 x ULN
> 20 x ULN
ALP
> 1.5 x ULN
> 2 x ULN
> 3 x ULN
Total bilirubin
> 1.5 x ULN
> 2 x ULN
> 3 x ULN
> 5 x ULN
GGT
> 1 x ULN
Blood pressures and pule rate abnormality criteria
Blood pressures and pulse rate 
criteria
Abnormality criterion value
Abnormality criterion on change from 
baseline
SBP
> 180 mmHg
≥20 mmHg increase from baseline


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< 90 mmHg
≥20 mmHg decrease from baseline
DBP
> 105 mmHg
≥15 mmHg increase from baseline
< 50 mmHg
≥15 mmHg decrease from baseline
Pulse rate
> 120 bpm
≥10 bpm increase from baseline
< 50 bpm
≥10 bpm decrease from baseline
Weight Abnormality Criteria
Weight criteria
Abnormality criteria
Weight (kg)
≥7% increase from baseline
≥7% decrease from baseline
ECG abnormality criteria
ECG criteria
Abnormality criteria
QTcF interval prolongation*
> 450 msec
> 480 msec
> 500 msec
Change from baseline in QTcF interval* 
> 30 msec increase from baseline
> 60 msec increase from baseline
PR interval
< 120 msec
> 200 msec
QRS complex
< 80 msec
> 120 msec
HR
< 60 bpm 
> 100 bpm
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase; 
GGT= gamma-glutamyl transferase; SBP = Systolic blood pressure; DBP = diastolic blood pressure; 
bpm=beats per minutes to be classified as potentially clinically significant, the measurement must 
satisfy both criteria: the criterion for the value and the criterion for the change relative to baseline.
*Abnormal QTcF interval categories as defined in ICH Guidelines E14
Any patients fulfilling at least one ECG abnormality criteria (as described in Appendix 6) or having at least 
one abnormal ECG assessed as significant by the investigator will be listed presenting all his/her ECG 
information.


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Appendix 7
Prohibited medication solely metabolized by UGT1A9 
and UGT2B7 and determination criteria
Examples of medications that are solely metabolized by UGT1A9 and UGT2B7 and prohibited for the 
duration of the trial are provided below.
Medications solely 
metabolized by UGT1A9 
Medications solely metabolized by UGT2B7
Medication 
name
ATC code
Medication 
name
ATC code
Comments
Flavopiridol
Benoxaprofen
M01AE06
Propofol
N01AX10
Carbamazepine
N03AF01
Codeine
R05DA12
R05DA04
N02AJ01
N02AJ02
N02AJ03
N02AJ07
N02AJ08
N02AJ09
N02AA08
N02AA58
N02AA59
N02AA79
Cyclosporin A
L04AD01,
S01XA18
Epirubicin
L01DB03
Indomethacin
C01EB03
M01AB01
M01AB51
M02AA23
S01BC01
S01CC02
S01CC02 also contains anti-infective 
medications
Tacrolimus
D11AH01
L04AD02
Tiaprofenic acid
M01AE11
Zaltoprofen
Not popped up in ATC code list.
Zomepirac
M01AB04
Zidovudine
J05AF01


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J05AR01
J05AR04
J05AR05
Combination product
Combination product
Combination product
ATC = Anatomic Therapeutic Class
Appendix 8
Prohibited medications strong CYP3A4 inducers and 
determination criteria
Strong CYP3A4 inducers
Medication name
ATC code
Comments
Rifampicin
J04AB02
J04AB03
J04AM02
J04AM05
J04AM06
J04AM07
A07AA13*
D06AX15*
S01AA16*
S02AA12*
This is a list on rifampicin only but also on products 
which contain rifampicin
* refers to rifamycin
carbamazepine
N03AF01
phenytoin
N03AB02
N03AB04
N03AB05
N03AB52
phenobarbital,
N03AA01
N03AA02
Primidone
N03AA03
St John’s Wort (hypericum perforatum)
Not popped up in ATC code list.
ATC = Anatomic Therapeutic Class


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Appendix 9
Other Prohibited medications and determination 
criteria
Other prohibited medication
Medication name
ATC code
Verbatim code
Comments
Nabiximols, cannabis 
or cannabinoid-based 
derived product
N03AX24
N02BG10
N03AX24: group of other anti-
epileptics and cannabidiol is one of 
them
This is the greater group of 
analgesics, and N02BG10 is a 
cannabinoid
Botulinum toxin 
injections,
M03AX01
Contains:
‘BO’ and ‘Tox’
‘“Dysport
‘Xeomin
Muscle relaxant products
Antipsychotic 
medications,
N05A 
apart from N05AN (Lithium)
Including N05AH02 (BDZ)
Benzodiazepines (if 
not following protocol 
requirements)
N03AE
N05BA
N05CD
M03BX07
N03AE: clonazepam
N05BA: broader group of anxiolytics 
contain the main used BDZ
N05CD broader group of hypnotics 
but also contains melatonin for 
instance.
M03BX07: tetrazepam
BDZ=Benzodiazepines


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Appendix 10
Medications used in MS and determination criteria
Any medication used for MS along with its category will be retrieved from the eCRF Concomitant medication 
form. However, the information in the table below will be used to define subcategory of interest.
MS 
medications 
type
WHO-DD 
Therapeutic 
class
Standardized 
Medication 
name 
ATC code
Verbatim term
Comments
Antispasticity 
medication
Muscle relaxant 
(M03)
Baclofen
M03BX01
Contains: 
x
‘‘BACLOFEN”’
Tizanidine
M03BX02
Contains: 
x
‘‘TIZANIDINE”’
Dantrolene
M03CA
Contains: 
x
‘DANTROLENE’
Tetrazapam 
(BDZ)
M03BX07
Not considered as a 
BDZ in the coding of 
ATC, but as a 
centrally acting 
muscle relaxant.
Botulinum toxin
M03AX01
Contains:
x
‘BO’ and ‘Tox’
x
Dysport’
x ‘Xeomin’
Others
M03B and 
M03C  apart 
those 
mentioned 
above
Refers to the 
broader group of 
muscle relaxants
Antiepileptic (N03)
Clonazepam 
N03AE
N03AE is a BDZ
Gabapentin
N03AX12
Pregabaline
N03AX16
Cannabinidiol
N03AX24
Not allowed per 
protocol
Psychoanaleptic 
(N05)
Clozapine (BDZ)
N05AH02
Benzodiazepines
N05BA
N05CD
N05BA and N05CD 
refers to a list of 
BDZ
Medication to 
treat other MS 
symptoms
Other system 
nervous system 
drug (N07)
Dalfampridine
N07XX007
Fampridine
N07XX007
MS=Multiple sclerosis; ATC= Anatomic Therapeutic Class; BDZ=Benzodiazepines


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Appendix 11
Adverse Drug Reaction of Special Interest – AE 
selections
Adverse drug of special interest type
AESI search
Falls and injuries
PT from either:
SOC “Injury, Poisoning, and procedural complications” 
Accidents and injuries (SMQ) [20000135] 
Drug reaction with eosinophilia and systemic 
systems (DRESS)
See Appendix 13
Disorientation and confusion
Confusion and disorientation High Level Term (HLT) [10010301] 
Driving and road traffic accident
Impaired driving ability (PT) [10049564] 
Road traffic accident (PT) [10039203] 
Impaired ability to use machinery (PT) (10077474) 
Accident – for machinery (PT) (10000369) 
Abuse liability
Drug abuse, dependence and withdrawal (SMQ) [20000100] 
Euphoric mood (PT) [10015535] 
Abnormal liver adverse events
Drug related hepatic disorders – comprehensive search (SMQ) [20000006] 
Drug related hepatic disorders – severe events only (SMQ) [20000007] 
Somnolence and sedation
Somnolence (PT) [10041349] 
Hypersomnia (PT) [10020765] 
Sedation (PT) [10039897] 
Fatigue and lethargy
Fatigue (PT) [10016256] 
Lethargy (PT) [10024264] 
Suicidal ideation and behavior
Suicide/self-injury (SMQ) [20000037] 
AEs will also be searched using the following search term string of 
suicidality-related terms (Bangs, 2008): accident, asphyxiation, burn, cut, 
drown, firearm, die, dying, gas, gun, hang, hung, immolat, injur, jump, 
attempt, kill, monoxide, mutilate, overdos, poison, self-damag, self-harm, 
self injur, shoot, slash, suffocation, and suic.
Significant cardiovascular (CVD) disease
Cardiac arrhythmias (SMQ) [20000049] 
Cardiac failure (SMQ) [20000004] 
Cardiomyopathy (SMQ) [20000150] 
Hypertension (SMQ) [20000147] 
Ischaemic heart disease (SMQ) [20000043] 
Pulmonary hypertension (SMQ) [20000130] 
Cognitive function
Cognitive and attention disorders and disturbances High Level Group Term 
(HLGT) [10009841] 
Depression and depressed mood
Depression (excl. suicide and self-injury) (SMQ) [20000167] 
Psychosis and psychotic disorders
Psychosis and psychotic disorders (SMQ) [20000117] 
Disturbances in thinking and perception (HGLT) [1001351] 
Seizures
Convulsions (SMQ) [20000079] (includes Seizure [PT]) [10039906]


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Appendix 12
Category of Adverse Events of Special Interest
List number
Category of adverse events of special interest
01
Falls and injuries
02
Drug reaction with eosinophilia and systemic systems
03
Disorientation and confusion
04
Driving and road traffic accident
05
Abuse liability
06
Abnormal liver adverse events
07
Somnolence and sedation
08
Fatigue and lethargy
09
Suicidal ideation and behavior
10
Significant cardiovascular disease
11
Cognitive function
12
Depression and depressed mood
13
Psychiatric disorders
14
Seizures
Appendix 13
Modify registry of severe cutaneous adverse reaction 
criteria for Drug reaction with eosinophilia and systemic systems
(DRESS)
Only patients meeting the criteria will be presented.
At least 3 of the following criteria should be present for hypersensitivity syndrome or DRESS: 
x
1. Acute skin rash 
x
2. Involvement of at least 1 internal organ 
x
3. Enlarged lymph nodes of at least 2 sites 
x
4. One of the following blood count abnormalities (limits provided by laboratory): 
o
lymphocytes above or below the laboratory limits 
o
eosinophils above the laboratory limits (in % or absolute count) 
o
platelets below the laboratory limits 
x
5. Fever above 38 degrees Celsius
The adverse events should occur within 30 days of each other (There should be temporal proximity for the 
onset of these AEs.). Some PTs may be mentioned in more than one SOC. (within 1 month of each other).
Appendix 13.1
Acute skin reaction
Search in ‘Skin and subcutaneous tissue disorders’ SOC the following preferred term: 
x
Dermatitis (any Preferred Term that includes the word “dermatitis”) 
x
Drug eruption 
x
Eczema 
x
Erythema multiforme 
x
Erythema nodosum 


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x
Rash (any PT that includes the word “rash”) 
x
Skin lesion 
x
Skin reaction 
x
Skin exfoliation 
x
Stevens-Johnson Syndrome 
x
Toxic epidermal necrolysis 
x
Toxic skin eruption 
x
Urticaria


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Appendix 13.2
Involvement of at least 1 internal organ
Blood and lymphatic system 
disorders SOC
Cardiac disorders SOC:
Endocrine disorders SOC:
Agranulocytosis 
Aplastic anemia 
Aplasia pure red cell 
Autoimmune lymphoproliferative 
syndrome 
Autoimmune neutropenia 
Autoimmune pancytopenia 
Blood disorder 
Bone marrow disorder 
Bone marrow failure 
Bone marrow toxicity 
Coagulopathy
Disseminated intravascular 
coagulation 
Disseminated intravascular 
coagulation in newborn 
Drug reaction with eosinophilia and 
systemic symptoms 
Eosinophilia 
Febrile neutropenia 
Granulocytopenia 
Haemolytic anemia 
Hemolysis 
Hypereosinophilic syndrome 
Leukemoid reaction 
Leukopenia 
Lymphocytosis 
Lymphopenia 
Hypersensitivity vasculitis 
Lymphadenitis 
Lymphadenopathy 
Lymphoma 
Monocytosis 
Mononucleosis 
Neutropenia 
Pancytopenia 
Platelet disorder 
Platelet toxicity 
Splenitis 
Splenomegaly 
Splenosis 
Thrombocytopenia
Autoimmune myocarditis 
Cardiomyopathy
Endocarditis 
Eosinophilic myocarditis 
Myocarditis 
Pericarditis 
Pericardial effusion 
Pericardial disease 
Pleuropericarditis
Adrenalitis 
Autoimmune thyroiditis 
Thyroiditis


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Eye disorders SOC
Gastrointestinal disorders 
SOC
Hepatobiliary disorders SOC
Eye allergy 
Eye swelling 
Iritis 
Iridocyclitis 
Optic neuritis 
Retinitis 
Uveitis 
Vitritis 
Scleritis
Allergic colitis 
Colitis 
Eosinophilic colitis 
Eosinophilic oesophagitis 
Gastritis 
Gingival edema 
Gingival swelling 
Gingivitis 
Glossitis
Enteritis 
Mouth ulceration 
Mesenteritis 
Edema mouth 
Oropharyngeal swelling 
Parotitis 
Pancreatitis 
Periodontitis 
Sialadenitis 
Stomatitis 
Swollen tongue 
Tongue oedema 
Vasculitis gastrointestinal
Autoimmune hepatitis 
Amylase increased 
Blood trypsin increased 
Cholangitis 
Cholecystitis 
Hepatic failure 
Hepatic functional abnormal 
Hepatic encephalopathy 
Hepatic infiltration eosinophilic 
Hepatitis 
Hepatitis acute 
Hepatitis toxic 
Hepatocellular injury 
Hepatomegaly 
Hepatosplenomegaly 
Hepatorenal failure 
Hepatorenal syndrome
Hepatotoxicity 
Hyperbilirubinemia 
Hyperbilirubinemia neonatal 
Hyperlipidemia 
Jaundice 
Jaundice neonatal 
Liver disorder 
Lipase abnormal 
Lipase increased 
Edema due to hepatic disease 
Edematous pancreatitis 
Pancreatic enzymes increased 
Pancreatic hemorrhage 
Pancreatic necrosis 
Pancreatitis (any PT that includes 
the word “pancreatitis”) 
Pancreatorenal syndrome 
Peripancreatic fluid collection 
Swollen tongue


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General disorders and 
administration site conditions 
SOC:
Immune system disorders 
SOC (Part 1)
Immune system disorders 
SOC (Part 2)
Influenza like illness 
Malaise 
Multi-organ failure 
Neonatal multi-organ failure
Allergic bronchitis 
Allergic cough 
Allergic cystitis 
Allergic keratitis 
Allergic oedema 
Allergic sinusitis
Alveolitis allergic 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactoid reaction 
Anaphylactoid shock 
Asthma 
Angioedema 
Antiphospholipid syndrome 
Autoimmune disorder 
Autoimmune hepatitis 
Biliary cirrhosis primary 
Biliary cirrhosis 
Bronchospasm 
Circumoral edema 
Cholangitis sclerosing 
Dermatomyositis 
Drug hypersensitivity 
Drug reaction with eosinophilia 
and systemic symptoms 
Encephalitis 
Encephalopathy allergic 
Eyelid edema 
Eosinophilic fasciitis 
Face edema 
Hypersensitivity 
Immune thrombocytopenic 
purpura 
Glomerulonephritis 
Laryngeal edema 
Lip edema 
Lip swelling
Myasthenia Gravis
Myositis 
Nephrogenic systemic fibrosis 
Edema mouth 
Panniculitis 
Pemphigus 
Pemphigoid 
Periorbital edema 
Pruritus allergic 
Polymyositis 
Reaction to drug excipients 
Sarcoidosis 
Serum sickness 
Systemic lupus erythematosus 
Systemic sclerosis 
Type IV hypersensitivity reaction 
Vitiligo


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Investigations SOC:
Hematologic
Investigations SOC: 
Immunologic
Investigations SOC: others
Any PT that reflects increased, 
decreased or abnormal MedDRA 
Hematology investigations (incl 
blood groups) HLGT 
Any PT that reflects increase or 
abnormal under MedDRA 
Hepatobiliary investigations HLGT
Any PT that reflects a positive or 
abnormal result under MedDRA 
Immunology and allergy 
investigations HLGT, and 
Investigations, imaging and 
histopathology procedures NEC, 
HLGT
Alanine aminotransferase 
Amylase 
Aspartate aminotransferase 
Bilirubin conjugated 
Blood amylase 
Blood bilirubin 
Blood bilirubin unconjugated 
Gamma-glutamyltransferase 
increased
Lipase 
Liver function test 
Transaminases 
Biopsy liver abnormal
Lung 
Biopsy lung abnormal 
Renal 
Blood creatinine increased 
Blood creatinine abnormal 
Blood urea increased 
Blood urea abnormal 
Creatinine renal clearance 
decreased 
Glomerular filtration rate 
decreased 
Blood urine 
Cells in urine 
Eosinophils urine 
Protein urine 
Red blood cells urine 
Urinary casts 
Urinary casts present 
Biopsy kidney abnormal 
Skin 
Biopsy skin abnormal


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Musculoskeletal and 
connective tissue disorders 
SOC:
Neoplasms benign, 
malignant and unspecified 
(including cysts and 
polyps) SOC
Nervous system disorders SOC
Arthralgia 
Arthritis
Arthroplasty 
Ankle arthroplasty 
Hip arthroplasty 
Joint arthroplasty 
Knee arthroplasty 
Shoulder arthroplasty 
Joint swelling 
Joint warmth 
Lupus-like syndrome 
Myopathy 
Myositis 
Polyarthritis 
Tendonitis 
Tenosynovitis 
Synovitis 
Any PT under the MedDRA 
Connective tissue disorders (excl 
congenital) HLGT.
Lymphoma (any PT that includes 
the word “lymphoma”)
Pseudolymphoma 
Acoustic neuritis 
Arachnoiditis 
CNS inflammation 
CNS ventriculitis 
Spinal cord infection 
Encephalitis (all PTs under 
Encephalitis NEC, HLT) 
Encephalopathy 
Leukoencephalopathy 
Leukoencephalomyelitis
Meningitis (all PTs under 
Meningitis NEC, HLT) 
Myelitis 
Neuritis cranial 
Neuropathy peripheral 
Polyneuropathy 
Reye’s syndrome 
Toxic optic neuropathy 
Vasculitis cerebral


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Renal and urinary disorders 
SOC:
Respiratory, thoracic and 
mediastinal disorders SOC:
Vascular disorders SOC:
Anuria 
Cardiorenal syndrome 
Dialysis 
Eosinophilic cystitis 
Hematuria 
Hemodialysis 
Hemolytic uremic syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Pancreatorenal syndrome 
Peritoneal dialysis 
Edema due to renal disease 
Renal disorder 
Renal failure 
Renal impairment 
Nephropathy toxic 
Any PT under MedDRA 
Nephropathies HLGT
Allergic bronchitis 
Acute interstitial pneumonitis 
Asthma
Allergic granulomatous angiitis 
Alveolitis 
Alveolitis allergic 
Angiolymphoid hyperplasia with 
Eosinophilia 
Eosinophilic bronchitis 
Eosinophilia myalgia syndrome 
Eosinophilic pneumonia 
Interstitial lung disease 
Pleural effusion 
Pleurisy 
Pleurisy viral 
Pleuropericarditis 
Pneumonitis 
Pulmonary eosinophilia 
Pulmonary vasculitis 
Pulmonary toxicity
Arteritis (any PT that includes the 
word “arteritis”) 
Capillaritis 
Vasculitis (any PT that includes 
the word “vasculitis”)


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Renal and urinary disorders 
SOC:
Respiratory, thoracic and 
mediastinal disorders SOC:
Vascular disorders SOC:
Anuria 
Cardiorenal syndrome 
Dialysis 
Eosinophilic cystitis 
Hematuria 
Hemodialysis 
Hemolytic uremic syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Pancreatorenal syndrome 
Peritoneal dialysis 
Edema due to renal disease 
Renal disorder 
Renal failure 
Renal impairment 
Nephropathy toxic 
Any PT under MedDRA 
Nephropathies HLGT
Allergic bronchitis 
Acute interstitial pneumonitis 
Asthma
Allergic granulomatous angiitis 
Alveolitis 
Alveolitis allergic 
Angiolymphoid hyperplasia with 
Eosinophilia 
Eosinophilic bronchitis 
Eosinophilia myalgia syndrome 
Eosinophilic pneumonia 
Interstitial lung disease 
Pleural effusion 
Pleurisy 
Pleurisy viral 
Pleuropericarditis 
Pneumonitis 
Pulmonary eosinophilia 
Pulmonary vasculitis 
Pulmonary toxicity
Arteritis (any PT that includes the 
word “arteritis”) 
Capillaritis 
Vasculitis (any PT that includes 
the word “vasculitis”)


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Appendix 13.3
Enlarged lymph nodes of at least 2 sites 
Search for PT including the word “Lymphadenopathy” alone or as part of another PT
Such as some examples are given below:
x
Lymphadenopathy Mediastinal 
x
Paratracheal Generalized
x
Retroperitoneal 
x
Vaccination site
Search for other PT that could reflect lymphadenopathy
x
Benign lymph node neoplasm 
x
Lymph node palpable
x
Lymph node scan abnormal
Appendix 13.4
One of the following blood count abnormalities 
The search will use laboratory blood sample values along with their corresponding reference ranges
x
Lymphocytes above or below lab limits
x
Eosinophils above the lab limits
x
Platelets below lab limits
Appendix 13.5
Fever above 38 degrees Celsius
The following selection will be performed based on AE
x
Hyperthermia
x
Hyperpyrexia
x
Pyrexia 
x
Febrile bone marrow aplasia (and all PTs that include the word “febrile”) 
x
Body temperature increased
x
Body temperature abnormal


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Appendix 14
Overview of primary, secondary and exploratory
efficacy objectives
Objective
Clinical Category
Statistical 
Category
Estimand/Variable
Primary Objective: To evaluate the effect of multiple doses of nabiximols as adjunctive therapy 
compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs 
(Lower Limb Muscle Tone-6; LLMT-6) in patients with multiple sclerosis (MS) who have not achieved 
adequate relief from spasticity with other antispasticity medications.
LLMT-6
P1, Primary
Variable: Change from period baseline in LLMT-6 at D21
Population: FAS
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-6 with placebo-based MI 
under MNAR assumption. 
P1, SA1 
(Sensitivity)
Variable: Change from period baseline in LLMT-6 at D21
Population: FAS
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-6 with MI under MNAR 
assumption. Tipping point analysis  
P1, SUP1
(Supplementary , 
Subgroup)
Subgroup analyses based on same estimand as primary endpoint
P1, SUP2 
(response 
analyses)
Variable: proportion of patients with LLMT-6 score reduction 
criterion cut-offs defined by different percentages of >=20%, 
>=30%, >=40%, >=50% from period baseline in LLMT-6 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless COVID-19 impact
PLS: Odd ratio in nabiximols versus placebo
Analysis: OR from logistic regression model for crossover data 
adjusted on period baseline LLMT-6.  Single imputation: Missing 
D21 values are imputed a failure.


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 101 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
P1, SUP 3 
(Repeated 
measure 
analysis)
Variable: Change from period baseline in LLMT-6 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless deviation from time window at D1H3
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model with 
repeated measure for crossover data adjusted on period baseline 
LLMT-6 with placebo-based MI under MNAR assumption.
P1, SUP4 
(Supplementary 
without missing 
individual muscle 
group MAS score 
Variable: Change from period baseline in LLMT-6 at D21
Population: Study completer analysis set
IES: 
Regardless permanent treatment discontinuation
Without premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
Excluding LLMT-6 score derived with missing individual muscle 
group MAS score
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-6 with placebo-based MI 
under MNAR assumption.
P1, SUP5 
(Supplementary 
without premature 
study 
discontinuation
Variable: Change from period baseline in LLMT-6 at D21
Population: Study completer analysis set
IES: 
Regardless permanent treatment discontinuation
Without premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-6 with placebo-based MI 
under MNAR assumption.
P1, SUP6 
(Supplementary 
on-treatment 
assessment)
Variable: Change from period baseline in LLMT-6 at D21
Population: FAS
IES: 
Prior permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-6 with placebo-based MI 
under MNAR assumption.


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 102 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
P1, SUP7 
(Supplementary 
without major IPD 
impact) 
Variable: Change from period baseline in LLMT-6 at D21
Population: PP analysis set
IES: 
Regardless permanent treatment discontinuation
Prior to major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-6 with placebo-based MI 
under MNAR assumption.
P1, SUP8 
(Supplementary 
without major IPD 
impact and 
without deviation 
from time 
window)
Variable: Change from period baseline in LLMT-6 at D21
Population: PP analysis set
IES: 
Prior permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Without deviation from time window at D1H3
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model with 
repeated measure for crossover data adjusted on period baseline 
LLMT-6 with placebo-based MI under MNAR assumption.
P1, SUP9 
(Supplementary 
without COVID-
19 impact)
Variable: Change from period baseline in LLMT-6 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Without COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-6 with placebo-based MI 
under MNAR assumption.
Secondary objective (efficacy): To evaluate the effect of multiple doses of nabiximols as adjunctive therapy 
compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb 
Muscle Tone 4; LLMT-4) in patients with multiple sclerosis who have not achieved adequate relief from spasticity 
with other antispasticity medications.
LLMT-4
S1, Primary
Variable: Change from period baseline in LLMT-4 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-4 with placebo-based MI 
under MNAR assumption.


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 103 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
S1, SA1
(Sensitivity)
Variable: Change from period baseline in LLMT-4 at D21
Population: FAS
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-4 with MI under MNAR 
assumption. Tipping point analysis  
S1, SUP1
(Repeated 
measure 
analysis)
Variable: Change from period baseline in LLMT-4 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless deviation from time window at D1H3
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model with 
repeated measure for crossover data adjusted on period baseline 
LLMT-4 with placebo-based MI under MNAR assumption.
S1, SUP2 
(Supplementary 
without missing 
individual muscle 
group MAS score 
Variable: Change from period baseline in LLMT-4 at D21
Population: Study completer analysis set
IES: 
Regardless permanent treatment discontinuation
Without premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
Excluding LLMT-4 score derived with missing individual muscle 
group MAS score
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-4 with placebo-based MI 
under MNAR assumption.
S1, SUP3
(Supplementary 
without premature 
study 
discontinuation
Variable: Change from period baseline in LLMT-4 at D21
Population: Study completer analysis set
IES: 
Regardless permanent treatment discontinuation
Without premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-4 with placebo-based MI 
under MNAR assumption.


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 104 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
S1, SUP4
(Supplementary 
on-treatment 
assessment)
Variable: Change from period baseline in LLMT-4 at D21
Population: FAS
IES: 
Prior permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-4 with placebo-based MI 
under MNAR assumption.
S1, SUP5
(Supplementary 
without major IPD 
impact) 
Variable: Change from period baseline in LLMT-4 at D21
Population: PP analysis set
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-4 with placebo-based MI 
under MNAR assumption.
S1, SUP6
(Supplementary 
without COVID-
19 impact)
Variable: Change from period baseline in LLMT-4 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Without COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-4 with placebo-based MI 
under MNAR assumption.
Exploratory objective: To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with 
placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle Tone-10; 
LLMT-10) in patients with multiple sclerosis who have not achieved adequate relief from spasticity with other 
antispasticity medications
LLMT-10
E1, Primary
Variable: Change from period baseline in LLMT-10 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-10 with placebo-based MI 
under MNAR assumption.


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 105 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
E1, SUP1
Repeated 
measure 
analysis)
Variable: Change from period baseline in LLMT-10 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless deviation from time window at D1H3
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model with 
repeated measure for crossover data adjusted on period baseline 
LLMT-10 with placebo-based MI under MNAR assumption
E1, SUP2
(Supplementary 
without missing 
individual muscle 
group MAS score 
Variable: Change from period baseline in LLMT-10 at D21
Population: Study completer analysis set
IES: 
Regardless permanent treatment discontinuation
Without premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
Excluding LLMT-10 score derived with missing individual muscle 
group MAS score
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-10 with placebo-based MI 
under MNAR assumption.
E1, SUP3
(Supplementary 
without premature 
study 
discontinuation
Variable: Change from period baseline in LLMT-10 at D21
Population: Study completer analysis set
IES: 
Regardless permanent treatment discontinuation
Without premature study discontinuation
Regardless major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-10 with placebo-based MI 
under MNAR assumption.
E1, SUP4
(Supplementary 
on-treatment 
assessment)
Variable: Change from period baseline in LLMT-10 at D21
Population: FAS
IES: 
Prior permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-10 with placebo-based MI 
under MNAR assumption.


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 106 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
E1, SUP5
(Supplementary 
without major IPD 
impact) 
Variable: Change from period baseline in LLMT-10 at D21
Population: PP analysis set
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Accounting for COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-10 with placebo-based MI 
under MNAR assumption.
E1, SUP6
(Supplementary 
without COVID-
19 impact)
Variable: Change from period baseline in LLMT-10 at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Without COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline LLMT-10 with placebo-based MI 
under MNAR assumption.
Exploratory Objective: To evaluate the effect of nabiximols after administration of multiple doses on walking using 
the Timed 25-Foot Walk (T25FW) test.
T25FW
E2,Primary
Variable: Change from period baseline in average 25-foot walk 
time at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline average T25FW. Single 
imputation at trial level: missing  trial time are imputed to 180 
seconds under MAR assumption


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 107 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
E2, S1 (without 
missing trial time 
imputation)
Variable: Change from period baseline in average 25-foot walk 
time at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline average T25FW. No imputation 
under MAR assumption
E2, SUP1 
(response 
analysis)
Variable: proportion of patients with a 20% decrease from period 
baseline in average T25FW at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless COVID-19 impact
PLS: Odd ratio in nabiximols versus placebo
Analysis: OR from logistic regression model for crossover data 
adjusted on period baseline average T25FW. Single imputation: 
Missing D21 values are imputed a failure.
E2, SUP2 
(Supplementary 
without major IPD 
impact) 
Variable: Change from period baseline in average 25-foot walk 
time at D21
Population: PP analysis set
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline average T25FW. No imputation 
under MAR assumption
E2, SUP3 
(Supplementary 
without COVID-
19 impact)
Variable: Change from period baseline in average 25-foot walk 
time at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Without COVID-19 impact.
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from CFB linear mixed-effect model for crossover 
data adjusted on period baseline average T25FW. No imputation 
under MAR assumption


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 108 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
Exploratory Objectives: To evaluate the effect of nabiximols after administration of multiple doses on the following 
patient-reported outcomes: the 11-point Numerical Rating Scale (NRS) spasticity score, Daily spasm count as well 
as the MS Spasticity Scale (MSSS-88) total and subdomain scores.
11-point NRS-spasticity 
score
E3,Primary
Variable: 7-day average NSR spasticity score at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for crossover data. No imputation under MAR assumption
E3, SUP1 
(Supplementary 
without major IPD 
impact) 
Variable: 7-day average NSR spasticity score at D21
Population: PP analysis set
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for cross over data. No imputation under MAR assumption
E3, SUP2 
(Supplementary 
without COVID-
19 impact)
Variable: 7-day average NSR spasticity score at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Without COVID-19 impact.
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for crossover data. No imputation under MAR assumption
7-days average daily 
spasm count
E4,Primary
Variable: 7-days average daily spasm count at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for crossover data. No imputation under MAR assumption


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 109 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
E4, SUP1 
(Supplementary 
without major IPD 
impact) 
Variable: 7-days average daily spasm count at D21
Population: PP analysis set
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for crossover data. No imputation under MAR assumption
E4, SUP2 
(Supplementary 
without COVID-
19 impact)
Variable: 7-days average daily spasm count at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Without COVID-19 impact.
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for crossover data. No imputation under MAR assumption
MSSS-88 total and sub 
scale scores
E5,Primary
Variable: Score at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for crossover data. No imputation under MAR assumption
E5, SUP1 
(Supplementary 
without major IPD 
impact) 
Variable: Score at D21
Population: PP population
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Without major IPD
Regardless COVID-19 impact
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for crossover data. No imputation under MAR assumption


Statistical Analysis Plan Final
Version Date: 6th-June-2022
Sponsor: GW PHARMA LIMITED
Protocol no: GWSP19066
PRA-QMS-02745 9.0
Page 110 of 110
Strictly Confidential.  © 2022, PRA Health Sciences.  All rights reserved.
E5, SUP2 
(Supplementary 
without COVID-
19 impact)
Variable: Score at D21
Population: FAS
IES: 
Regardless permanent treatment discontinuation
Regardless premature study discontinuation
Regardless major IPD
Without COVID-19 impact.
PLS: Mean difference between nabiximols and placebo
Analysis: LSMD from observed value linear mixed-effect model 
for crossover data. No imputation under MAR assumption
P = Primary – S=Secondary - SA= Sensitivity analysis – SUP=Supplementary analysis
E=Exploratory analysis
FAS = Full analysis set – PP = Per Protocol
PLS = Population-level summary.
IES = Intercurrent event(s) strategy – IPD = Important protocol deviation;
CFB = Change from baselines analysis. - OR= odds ratio -  LSMD = Least square mean difference.
MI = Multiple Imputation
MAR = Missing at Random – MNAR = Missing not a random.
MS = Multiple Sclerosis – NRS= Numerical rating scale
LLMT-6 = Lower Limb Muscle Tone-6 - LLMT-4 = Lower Limb Muscle Tone-4
LLMT-10 = Lower Limb Muscle Tone-10
T25FW = Timed 25-foot walk