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
Phase: PHASE3
Conditions: Spasticity in Participants With Multiple Sclerosis
Sponsor: Jazz Pharmaceuticals

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 
 Page 4 of 105 
 
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 
 Page 5 of 105 
 
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 
 
Confidential 
 Page 6 of 105 
 
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 
 
Confidential 
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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 
 
Confidential 
 Page 8 of 105 
 
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 
 
Confidential 
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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 
 
Confidential 
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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 
 
Confidential 
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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 
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 
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 
 
Confidential 
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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)  
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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 

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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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 
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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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 
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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 
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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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 
 
Confidential 
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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 
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 
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 
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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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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EudraCT Number: 2019-002625-29 
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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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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 
 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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Clinical Protocol Template (Phase 2–4)  
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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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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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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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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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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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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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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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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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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. 
 

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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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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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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