Clinical trial NCT04203498
Conditions: Multiple Sclerosis (MS)
Keywords: Spasticity
Sponsor: Jazz Pharmaceuticals
Start date: 2020-10-01; Completion date: 2023-02-28
Enrollment: 139 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is being conducted to demonstrate the efficacy of nabiximols, compared with placebo, when added to standard of care, in the treatment of muscle spasms associated with multiple sclerosis (MS).

Detailed description:
This multicenter, double-blind, placebo-controlled trial includes a 28-day Baseline period, a 12-week treatment period (comprising a 2-week titration phase and a 10-week maintenance phase), and 2-week follow-up period.

Eligible participants will enter the 28-day baseline period. During baseline, participants will maintain their optimized oral MS antispasticity medication regimen and record spasm count using an electronic daily diary. At screening (Day 1), eligible participants will be randomized to either nabiximols or placebo in a 1:1 ratio.

Participants will be advised to titrate the investigational medicinal product (IMP), beginning with 1 spray/day, to an optimized dose or to a maximum of 12 sprays/day over the first 14 days of treatment. Participants may leave a gap between sprays of approximately 15 minutes. Participants should continue at the same dose level achieved at the end of the titration phase ±1 spray divided into a morning dose and an evening dose for the remainder of the treatment period.

Daily spasm count, the participant's symptom experiences, clinician's assessment of spasticity, functional outcomes, health-related quality of life, changes in mood, safety, tolerability, and pharmacokinetics will be evaluated during the treatment period.

Participants who complete the trial will participate for a total of approximately 18 weeks (127 days), including the 28-day baseline period. Participants will have a maximum duration of 85 (±7) days on IMP treatment.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Nabiximols intervention 2: Placebo
Intervention descriptions: intervention 1: Nabiximols is a complex botanical medicine formulated from extracts of the cannabis plant that contains the principal cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) and also contains minor constituents, including other cannabinoid and non-cannabinoid plant components, such as terpenes, sterols, and triglycerides.Nabiximols will be self-administered by participants as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks. intervention 2: Placebo to match nabiximols will be presented as an oromucosal spray containing the excipients ethanol and propylene glycol (50% v/v) with colorings and flavored with peppermint oil (0.05% v/v). Each spray will deliver 100 microliters (μL) containing no active ingredients. Placebo will be self-administered by participants as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks.

Protocol documents:
Prot_000.pdf: 
Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 1 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
A Double-blind, Randomized, Placebo-controlled, Parallel-group 
Trial of the Efficacy and Safety of Nabiximols Oromucosal Spray as 
Add-on Therapy in Patients with Spasticity Due to Multiple Sclerosis 
Study Code: GWSP18023 
EudraCT Number: 2019-002623-14 
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. 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
Approved


Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 2 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Investigator Agreement 
I have read the attached clinical protocol entitled “A Double-blind, Randomized, 
Placebo-controlled, Parallel-group Trial of the Efficacy and Safety of Nabiximols 
Oromucosal Spray as Add-on Therapy in Patients with Spasticity Due to Multiple 
Sclerosis”, dated 01Jun2021 and agree to abide by all provisions set forth therein. 
I agree to comply with applicable regulatory requirement(s), the United States 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 Council for Harmonisation (ICH) Harmonised 
Guideline: Integrated Addendum to ICH E6(R1):  Guideline for GCP E6(R2) 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. 
Trial site No:  
  
 
 
 
  
 
Print name: 
 
 Date:  
 
Principal investigator 
  
(DD Month YYYY) 
Signature: 
 
  
 
 
GW Authorization 
Print name: 
 
 Date:  
 
Clinical Operations Director 
  
(DD Month YYYY) 
Signature: 
  
 
01-Jul-2021 | 21:27 PDT
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
Approved
CCI
CCI


Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 3 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
1 
PROTOCOL SYNOPSIS 
Trial Title 
A Double-blind, Randomized, Placebo-controlled, Parallel-group 
Trial of the Efficacy and Safety of Nabiximols Oromucosal Spray 
as Add-on Therapy in Patients with Spasticity Due to Multiple 
Sclerosis 
Clinical Trial 
Type 
Phase 3 
Indication 
Symptomatic treatment of spasticity in patients with multiple 
sclerosis (MS) 
Primary 
Objective 
To establish the efficacy of nabiximols relative to placebo in 
reducing spasm count as part of the presentation of spasticity when 
used as adjunctive therapy in patients with MS who have not 
achieved adequate relief from other antispasticity agents 
Secondary 
Objective(s) 
• To evaluate the effect of nabiximols relative to placebo using 
the following patient-reported outcome measure of spasticity: 
− The MS Spasticity Scale (MSSS-88) total score 
• To evaluate the safety and tolerability of nabiximols 
• To evaluate the pharmacokinetics (PK) of nabiximols 
Exploratory 
Objective(s) 
To evaluate the effect of nabiximols relative to placebo using the 
following patient-reported outcome measures and 
clinician-administered assessments of spasticity: 
− The 8 MS Spasticity Scale (MSSS-88) subscale scores 
− The 11-point Numerical Rating Scale (NRS) for spasm 
severity 
− The 11-point NRS for spasticity 
• To evaluate the effect of nabiximols relative to placebo on 
health-related quality of life (QoL), as reflected by the 36-Item 
Short Form Health Survey (SF-36) 
• To evaluate the effect of nabiximols relative to placebo on 
functional outcome as reflected by walking ability using the 
Timed 25-Foot Walk (T25FW) test 
Trial Design 
This multicenter, double-blind, placebo-controlled trial includes a 
28-day baseline period, a 12-week treatment period (comprising a 
2-week titration phase and a 10-week maintenance phase), and 
2-week follow-up period. 
Eligible patients will enter a 28-day baseline period.  During 
baseline, patients will maintain their optimized oral antispasticity 
medication regimen (that must include at least 1 of baclofen, 
tizanidine or dantrolene) and record spasm count, 11-point NRS 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 4 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
spasm severity score, 11-point NRS spasticity score, and use of 
antispasticity medications once daily, around the same time of day, 
preferably in the evening before retiring to sleep, using an 
electronic daily diary.  At Visit 2 (Day 1), eligible patients will be 
randomized to either nabiximols or placebo in a 1:1 ratio. 
Patients will initiate investigational medicinal product (IMP) 
treatment as a single spray in the evening on the first day of the 
titration phase.  Patients will be advised to titrate IMP, beginning 
with 1 spray/day, to an optimized dose or to a maximum of 
12 sprays/day over the first 14 days of treatment.  Patients may 
leave a gap between sprays of approximately 15 minutes.  Patients 
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.  For the first 14 days of administering stable 
doses of IMP following titration, patients should be instructed to 
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. 
Daily spasm count, the patient’s symptom experiences, functional 
outcomes, health-related quality of life, safety, tolerability, and PK 
will be evaluated during the treatment period. 
Following randomization (Visit 2 [Day 1]), patients will attend the 
trial site on Visit 3 (Day 15), Visit 4 (Day 29), and Visit 5 
(Day 57).  The End of Treatment Visit (Visit 6) will occur on 
Day 85 (± 7 days).  Participants who are permanently discontinued 
from receiving IMP will be recommended to continue the study 
and follow the original visit schedule and requirements (e.g. 
eDiary data entry) without taking IMP.  
If a participant discontinues from the IMP and is unwilling or 
unable to follow the original visit schedule and requirements 
without taking IMP, he or she should be asked, at the discretion of 
the investigator, to return to the study site for the Early Withdrawal 
Visit (see Schedule of Assessment table). Where possible, the 
Early Withdrawal Visit should be within 14 days from last IMP 
dose, unless consent is withdrawn from further study participant, 
or the participant is lost to follow-up. 
A Safety Follow-up Visit (Visit 7 [Day 99]) will take place 
14 (± 4) days after the End of Treatment Visit or Withdrawal Visit 
for all patients. 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 5 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Patients who complete the trial will participate for a total of 
approximately 18 weeks (127 days), including the 28-day baseline 
period.  Patients will have a maximum duration of 85 (± 7) days on 
IMP treatment. 
Primary 
Endpoint 
Change from baseline in the average daily spasm count (from 
Days 57 to 84 compared to the average daily spasm count for the 
baseline period). 
Secondary 
Endpoints 
Efficacy: 
• 
Change from baseline in total score of the MSSS-88 at Visit 6 
Safety: 
• Frequency of treatment-emergent adverse events (AEs) 
• Change from baseline to each assessment timepoint by 
treatment arm for the following: 
− Clinical laboratory tests 
− Vital signs 
− 12-lead electrocardiograms (ECGs) 
Columbia-Suicide Severity Rating Scale (C-SSRS) at screening, 
and at each subsequent timepoint with reference to the last 
assessment (since last visit) 
Pharmacokinetics: 
• Plasma concentrations for Δ9-tetrahydrocannabinol (THC) and 
its relevant metabolites (11-hydroxy-Δ9-tetrahydrocannabinol 
[11-OH-THC] and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol 
[11-COOH-THC]) and cannabidiol (CBD) and its relevant 
metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 
7-carboxy-cannabidiol [7-COOH-CBD]) at Visits 2 (predose), 
3, 4, 5, and 6 
Exploratory 
Endpoints 
Efficacy: 
• Change from baseline in the 8 subscale scores of the MSSS-88 
at Visit 6 
• Change from baseline in average daily 11-point NRS spasm 
severity score to Days 57 to 84 
• Change from the last 7 days of baseline in average daily 
11-point NRS spasticity score to Days 78 to 84 
• Change from baseline in the SF-36 total score at Visit 6 
(Day 85) 
• Change from baseline in Timed 25-Foot Walk (T25FW) test at 
Visit 6 (Day 85) 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 6 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Sample Size 
The trial will consist of 2 treatment arms:  a nabiximols treatment 
arm and a placebo treatment arm. 
446 patients (223 patients per treatment arm) will be randomized to 
nabiximols or placebo in a 1:1 ratio. 
Summary of 
Patient 
Eligibility 
Criteria 
Inclusion Criteria 
Screening (Visit 1) 
For inclusion in the trial, patient must fulfill ALL of the following 
criteria: 
• Male or female aged 18 years or above 
• Willing and able to give informed consent for participation in 
the trial 
• Willing and able (in the investigator’s opinion) to comply with 
all trial requirements.  (With the exception of the T25FW test, 
if the patient is non-ambulatory) 
• 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 
• Has had treatment with at least 1optimized oral antispasticity 
therapy prior to Visit 1 that must include either oral baclofen or 
oral tizanidine (monotherapy or combination therapy) 
• Currently receiving optimized treatment with at least 1 oral 
antispasticity medication (baclofen, tizanidine or dantrolene) 
and has been stable for at least 30 days prior to Visit 1.  
Despite optimization, the patient does not have adequate relief 
of spasticity signs and 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 
• If currently receiving an 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 
• 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 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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Page 7 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
• Willing to allow the responsible authorities to be notified of 
participation in the trial, if mandated by local law 
• 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 than the 
investigator 
Additional Inclusion Criteria at Randomization (Visit 2) 
The patient is eligible for randomization in the trial if, in addition 
to continuing to meet the Screening (Visit 1) inclusion criteria, 
they also meet ALL of the following criteria during the first 
28 days of the baseline period (Note: patients are expected to start 
completing their electronic diary in the evening of their screening 
visit): 
• In the opinion of the investigator, the patient is able to interpret 
and report spasm count data accurately 
• Completed their electronic diary for at least 25 of the first 
28 days of the baseline period 
• Has an average daily spasm count of ≥ 4 during the first 
28 days of the baseline period, as recorded by the patient 
• Has no more than 35 spasms on any single day of the first 28 
days of the baseline period, as recorded by the patient 
• Does not have > 7 consecutive days without experiencing any 
spasm during the first 28 days of the baseline period 
If, for any reason, the patient is unable to attend the site for 
randomization within the visit window, the site should contact the 
Medical Monitor or the sponsor to discuss. 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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Page 8 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
In addition to meeting the Screening (Visit 1) inclusion criteria and 
additional inclusion criteria above, any patient with more than 
28 days between Visit 1 and Visit 2 would need to meet ALL of 
the following criteria prior to randomization: 
• Completed their electronic diary for at least 85% of days 
between Visit 1 and Visit 2 
• Has an average daily spasm count of ≥ 4 between Visit 1 and 
Visit 2 (randomization), as recorded by the patient 
• Has no more than 35 spasms on any single day between Visit 1 
and Visit 2, as recorded by the patient 
• Does not have > 7 consecutive days without experiencing any 
spasm between Visit 1 and Visit 2 
Exclusion Criteria 
The patient may not enter the trial if ANY of the following apply: 
• Previously participated in a clinical trial of nabiximols or has 
had a poor previous response or intolerance to nabiximols or 
other cannabinoid-containing products used for therapeutic 
purposes 
• Any concomitant disease or disorder that has spasticity-like 
symptoms or that may influence the patient’s level of spasticity 
• 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 
• Has had a relapse of MS within the 60 days prior to Visit 1 
• Has taken cannabis, or a cannabis-derived product for 
medicinal or recreational use within the 30 days prior to 
screening (Visit 1) or a positive blood drug test for THC at 
screening (Visit 1)  
• Is unwilling to abstain from use of cannabis, or 
a cannabis-derived product for medicinal or recreational 
purposes for the duration of the trial 
• Currently using botulinum toxin injection for the relief of 
spasticity (within 6 months of Visit 1) 
• Is unwilling to abstain from the use of botulinum toxin 
injection for the relief of spasticity for the duration of the trial 
• Currently taking antipsychotic medication 
• Currently taking benzodiazepines, unless the doses and dosing 
regimen have been stable for at least 30 days prior to Visit 1 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 9 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
• Has any known or suspected hypersensitivity to cannabinoids 
or any of the excipients of the IMP 
• 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 
• Has a diastolic blood pressure of < 50 mmHg or > 105 mmHg 
or systolic blood pressure < 90 mmHg or > 150 mmHg (when 
measured in a supine position at rest for 5 minutes), or a 
postural drop in the systolic blood pressure of ≥ 20 mmHg or in 
diastolic blood pressure of ≥ 10 mmHg at Visit 1.  All 
measurements will be performed singly and can be repeated 
once, if any are outside the reference range but not considered 
clinically significant 
• 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 
• 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 
• 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 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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Page 10 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
• Female and of childbearing potential (i.e., following menarche 
and until becoming postmenopausal for ≥ 12 consecutive 
months with a follicle stimulating hormone (FSH) 
≥ 30 mIU/mL 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, other 
highly effective hormonal methods 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 
• Female and pregnant (positive pregnancy test at Visit 1 or 
Visit 2 [predose]), lactating, or planning pregnancy during the 
course of the trial or within 3 months thereafter 
• Received an IMP within the 30 days prior to Visit 1 
• 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 
• Has any abnormalities identified following a physical 
examination, clinical laboratory, serology, or other applicable 
screen 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 
• Has any history of suicidal behavior in the 5 years prior to 
Visit 1 or a suicidal ideation score of 3, 4, or 5 on the C-SSRS 
in the month prior to Visit 1 
• Has a history of severe psychiatric disorder that may be 
exacerbated by the use of a cannabinoid-containing product 
• Has donated blood during the 3 months prior to Visit 1 and is 
unwilling to abstain from donation of blood during the trial 
• Has been previously randomized into this trial 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
• Has any known or suspected history of alcohol or substance 
use disorder within 1 year prior to Visit 1.  Patients with 
nicotine use disorder are allowed to enroll 
• Currently using an illicit drug or current nonprescribed use of 
any prescription drug.  A positive drug test at Visits 1 or 2 for a 
prescribed medication is not exclusionary at the investigator’s 
discretion.  A positive drug test at Visit 1 or predose at Visit 2 
for illicit drugs may be repeated locally at the investigator’s 
discretion 
• 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 
• Currently taking drugs that are solely metabolized by UGT1A9 
and UGT2B7 
• Currently taking strong CYP3A4 inducers (e.g., rifampicin, 
carbamazepine, phenytoin, phenobarbital, St John's Wort) 
• There is an expectation that the participant will require a new 
course of treatment with strong CYP3A4 inhibitors during the 
study duration (e.g., participant with recurrent fungal infections 
requiring intermittent treatment with itraconazole) 
• Patients who receive a positive coronavirus disease 2019 
(COVID-19) antigen test result, potentially suggesting 
infective status, before randomization may be screen failed, at 
the discretion of the investigator 
Individuals who do not meet the criteria for participation in this 
trial (screen failure) because of, for example, fever due to a brief 
acute upper respiratory illness, having taken a prohibited over the 
counter medication within the excluded period, recent blood 
donation, due to the inclusion criterion related to the ability to 
interpret and report spasm count data accurately, or who could not 
be randomized for logistical reasons, can be rescreened once, at the 
discretion of the investigator or designee, with sponsor approval.  
Rescreened participants should be assigned a new screening 
number. 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Criteria for 
Withdrawal 
The patient must be withdrawn from the trial if any of the 
following apply: 
• Administrative decision by the investigator, GW Pharma Ltd, 
or regulatory authority 
• Withdrawal of patient consent 
• Lost to follow-up 
The patient must cease IMP and should remain in the trial if any of 
the following apply: 
• Pregnancy 
• Protocol deviation that is considered to potentially compromise 
the safety of the patient 
• Suicidal behavior, or a suicidal ideation score of 4 or 5 during 
the treatment period, as evaluated with the C-SSRS 
• ALT or AST > 3 × ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%) 
• ALT or AST > 5 × ULN 
• ALT or AST > 3 × ULN and (total bilirubin [TBL] > 2 × ULN 
or international normalized ratio [INR] > 1.5)  
• Any prohibited medication after Visit 1 
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: 
• Did not meet eligibility criteria 
• Patient noncompliance 
• 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 
• Any evidence of drug abuse or diversion 
• Disease progression (defined as a relapse of MS requiring a 
change in treatment) 
• A positive COVID-19 test result after randomization 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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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 (GW-1000-02) 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 noncannabinoid 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 (0.05% v/v).  Each 
spray delivers 100 μL containing no active ingredients. 
Treatment will be initiated as a single spray in the evening on the 
first day of the titration phase (normally the day of Visit 2 
[Day 1]).  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 by 1 additional spray/day to an individually determined 
optimized dose, balancing efficacy and tolerability, or to a 
maximum number of 12 sprays/day.  Patients may leave a gap 
between sprays of approximately 15 minutes. 
Patients should complete titration within 14 days of their first dose 
of IMP and should continue 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 the remainder of the 
treatment period.  For the first 14 days of administering stable 
doses of IMP following titration, patients should be instructed to 
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 composed of a different number of 
sprays.  Patients may take their morning dose spread out during the 
morning and their evening dose spread out during the evening, 
with a minimum interval between sprays as specified above (i.e., 
15 minutes during the titration phase and a target of approximately 
1 minute during the maintenance phase). 
Control Arm 
The control arm will receive matching placebo (excipients alone). 
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Page 14 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Procedures 
Assessments/procedures include the following: 
• Informed consent, demographics, previous cannabis use, 
medical history, and electronic diary training (Visit 1) 
• Eligibility check and urine drug screen (Visit 1 and 2) 
• Blood THC test (Visit 1) 
• Randomization, urine pregnancy test (if appropriate), and IMP 
dosing training (Visit 2 [predose]) 
• Concomitant medications review, AE review, and vital signs 
measurement (Visits 1 through 7) 
• Physical examination (including height measurement at Visit 1 
only) (Visits 1, 2 [predose], and 6) 
• Examination of oral mucosa and C-SSRS assessment (Visits 1 
through 6) 
• Body weight measurement, 12-lead ECG, and clinical 
laboratory blood sampling (hematology and biochemistry) 
(Visits 1, 2 [predose], 4, and 6) 
• Dipstick urinalysis and serum pregnancy test (if appropriate) 
(Visits 1 and 6) 
• PK blood sampling – patients can choose the sparse PK 
sampling option or the semi-intensive PK sampling option:   
o Sparse option (Visit 2 [predose], and one sample will be 
collected at any time during Visits 3, 4, 5, and 6) 
o Semi-intensive option (Visit 2 [predose] and at just one 
of Visits 3, or 4, or 5 but not during Visit 6, at predose 
[collected upon arrival], and then at 2, 4, and 6 hours 
postdose during the clinic visit). 
• MSSS-88 assessment (Visits 2 [predose], 5, and 6) 
• T25FW test in ambulatory patients, and SF-36 assessment 
(Visits 2 [predose] and 6) 
• Medication Use Survey (Visit 6) 
• IMP dispensing (Visits 2 [predose], 3, 4, and 5) 
• IMP collection and compliance review (Visits 3, 4, 5, and 6) 
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Protocol V5 01Jun2021 
 
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Page 15 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Electronic Patient Diary 
Patients will complete their electronic diary once daily, around the 
same time each day, during the baseline period prior to Visit 2 and 
throughout the trial until Visit 7, unless otherwise indicated, and 
the following assessments will be conducted: 
• Spasm count 
• 11-point NRS for spasm severity 
• 11-point NRS for spasticity 
• Use of antispasticity medications 
• IMP dosing record (Visits 2 through 6) 
• Dosing in relation to food intake (applicable only to the days 
preceding Visits 3, 4, 5, and 6) 
• 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 (such as 
COVID-19/other pandemic restrictions), the investigator will 
discuss with the Sponsor potential mitigation approaches. 
Statistical 
Considerations 
The primary and secondary endpoints will be compared between 
treatment arms, using appropriate statistical methods, through the 
12-week double-blind treatment period. 
Statistical hypothesis testing will be 2-sided and carried out at the 
5% level of significance. 
To control for Type 1 error, the primary endpoint and secondary 
efficacy endpoints will be tested hierarchically, starting with the 
primary endpoint, then the change from baseline in total score of 
MSSS-88.  No additional adjustments for multiplicity will be made 
for the 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 
 
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 16 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Figure 1-1 
Trial Design and Treatment Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Group 1: 
Nabiximols (N = 223)
Group 2: 
Placebo (N = 223) 
Titration 
Phase
Visit 5 
Day 57 (±  7)  
28 to 30 days 
14 days
14 days 
Visit 6* 
Day 85 (±  7)  
Visit 7 
Day 99 (±   4 )  
Visit 3 
Day 15 (±  3)   
Visit 2 
Day 1
Visit 1 
Days 
-30 to -28  
Visit 4 
Day 29 (±  3)  
28 days 
Baseline 
Period
28 days 
*End of Treatment Visit or Withdrawal Visit for those who withdraw from the study early 
  
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Page 17 of 106 
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 ................................................................................ 35 
5 
INVESTIGATIONAL MEDICINAL PRODUCT .................. 36 
5.1 
Nabiximols ............................................................................................ 36 
5.2 
Placebo .................................................................................................. 36 
5.3 
Packaging, Storage, and Drug Accountability ...................................... 36 
5.3.1 
Packaging and Labeling ................................................................... 36 
5.3.2 
Storage .............................................................................................. 37 
5.3.3 
Supply and Return of Investigational Medicinal Product ................ 37 
5.3.4 
Investigational Medicinal Product Accountability ........................... 38 
5.3.5 
Post-trial Provision ........................................................................... 39 
6 
PATIENT ELIGIBILITY .......................................................... 40 
6.1 
Inclusion Criteria ................................................................................... 40 
6.2 
Exclusion Criteria .................................................................................. 41 
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EudraCT Number: 2019-002623-14 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
7 
PATIENT ENROLLMENT ...................................................... 45 
7.1 
Treatment Assignment........................................................................... 45 
7.2 
Randomization ....................................................................................... 45 
8 
TREATMENT PROCEDURES ............................................... 46 
8.1 
Investigational Medicinal Product Dosage, Administration, and 
Schedule ............................................................................................ 46 
8.1.1 
Dose Administration ......................................................................... 46 
8.1.2 
Dose Escalation and Dose Adjustments ........................................... 46 
8.2 
Concomitant Therapy ............................................................................ 48 
8.2.1 
Concomitant Optimized Multiple Sclerosis Antispasticity 
Medications ................................................................................. 48 
8.3 
Prohibited Therapy During Trial Period ................................................ 48 
8.4 
Compliance in Investigational Medicinal Product Administration ....... 49 
8.5 
Access to Blinded Treatment Assignment ............................................ 49 
9 
TRIAL PROCEDURES ............................................................. 50 
9.1 
Trial Procedures by Visit ....................................................................... 50 
9.1.1 
Visit 1 (Days −30 to −28, Screening) ............................................... 50 
9.1.1.1 
Screen Failures ........................................................................... 52 
9.1.2 
Visit 2 (Day 1, Randomization) ....................................................... 52 
9.1.3 
Visit 3 (Day 15), Visit 4 (Day 29), and Visit 5 (Day 57) ................. 53 
9.1.4 
Visit 6 (Day 85, End of Treatment Visit/Withdrawal Visit) ............ 54 
9.1.5 
Visit 7 (Day 99, Safety Follow-up Visit) ......................................... 55 
9.2 
Trial Procedure Listing .......................................................................... 55 
9.2.1 
Informed Consent ............................................................................. 55 
9.2.2 
Contraception Requirements ............................................................ 56 
9.2.3 
Demographics ................................................................................... 56 
9.2.4 
Previous Cannabis Use ..................................................................... 56 
9.2.5 
Medical History ................................................................................ 57 
9.2.6 
Concomitant Medication .................................................................. 57 
9.2.7 
Physical Examination ....................................................................... 57 
9.2.8 
Examination of Oral Mucosa ........................................................... 57 
9.2.9 
Body Weight Measurements ............................................................ 57 
9.2.10 
Vital Signs ........................................................................................ 57 
9.2.11 
12-Lead Electrocardiogram .............................................................. 58 
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EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
9.2.12 
Clinical Laboratory Sampling .......................................................... 58 
9.2.12.1 
Pharmacokinetic Blood Sampling .............................................. 59 
9.2.13 
Interactive Response Technology .................................................... 60 
9.2.14 
Electronic Patient Diary ................................................................... 61 
9.2.14.1 
Electronic Diary Training ........................................................... 61 
9.2.14.2 
Spasm Severity Numerical Rating Scale .................................... 61 
9.2.14.3 
Spasticity Numerical Rating Scale ............................................. 61 
9.2.14.4 
Use of Antispasticity Medications and Investigational Medicinal 
Product Dosing Record .......................................................... 62 
9.2.15 
Questionnaires and Assessments Completed at Scheduled Visits ... 62 
9.2.15.1 
Multiple Sclerosis Spasticity Scale ............................................ 62 
9.2.15.2 
Columbia-Suicide Severity Rating Scale ................................... 62 
9.2.15.3 
Timed 25-Foot Walk .................................................................. 63 
9.2.15.4 
Medication Use Survey .............................................................. 63 
9.2.15.5 
36-Item Short Form Health Survey ............................................ 63 
9.2.16 
Investigational Medicinal Product Accountability ........................... 63 
9.2.17 
Adverse Events ................................................................................. 63 
9.2.18 
Monitoring of Drug Abuse Liability ................................................ 64 
9.2.18.1 
Monitoring of Adverse Events (Abuse Liability) ....................... 66 
9.2.18.1.1 
List of Triggering Adverse Events of Interest (Abuse 
Liability) .......................................................................... 66 
9.2.18.1.2 
Supplemental Adverse Event Form (Abuse Liability) ......... 66 
9.2.18.2 
Monitoring Drug Accountability Discrepancies (Abuse Liability)
 ............................................................................................... 67 
9.2.18.2.1 
List of Triggering Drug Accountability Discrepancies (Abuse 
Liability) .......................................................................... 67 
9.2.18.2.2 
Supplemental Drug Accountability Form (Abuse Liability) 67 
9.2.18.3 
Site Classification Form (Abuse Liability) ................................ 68 
9.2.18.4 
Adjudication Committee: Assessment of Abuse Potential of 
Nabiximols ............................................................................. 68 
10 
WITHDRAWAL ........................................................................ 69 
11 
URGENT SAFETY MEASURES ............................................. 71 
12 
ADVERSE EVENT REPORTING ........................................... 74 
12.1 
Definitions ............................................................................................. 74 
12.1.1 
Adverse Event .................................................................................. 74 
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Study Code: GWSP18023 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
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 ............................................ 78 
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 ................................... 83 
13.5.1 
Enrollment and Disposition .............................................................. 83 
13.5.2 
Baseline and Demographic Characteristics ...................................... 83 
13.5.3 
Medical History ................................................................................ 84 
13.5.4 
Concomitant Medication .................................................................. 84 
13.6 
Endpoints and Statistical Methods ........................................................ 84 
13.6.1 
Primary Endpoint ............................................................................. 84 
13.6.1.1 
Sensitivity Analyses for the Primary Efficacy Analysis ............ 85 
13.6.1.2 
Supplemental Analyses .............................................................. 85 
13.6.2 
Secondary Endpoint(s) ..................................................................... 85 
13.6.3 
Exploratory Endpoints ...................................................................... 86 
13.6.4 
Pharmacokinetics .............................................................................. 86 
13.6.5 
Safety ................................................................................................ 87 
13.6.5.1 
Treatment Compliance and Extent of Treatment Exposure ....... 87 
13.6.5.2 
Adverse Events ........................................................................... 87 
13.6.5.3 
Clinical Laboratory Data ............................................................ 87 
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Study Code: GWSP18023 
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EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 21 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
13.6.5.4 
Vital Signs, 12-lead Electrocardiogram, Physical Examination, 
and Other Safety Data ............................................................ 88 
13.6.6 
Handling of Missing 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 
Pre-trial Documentation Requirements ................................................. 91 
15.5 
Patient Confidentiality ........................................................................... 91 
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 .................................................................................. 95 
16.7 
Intellectual Property Rights ................................................................... 96 
16.8 
Confidential Information ....................................................................... 96 
REFERENCES .................................................................................... 97 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
Approved


Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 22 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
List of Appendices 
Appendix 1 
SCHEDULE OF ASSESSMENTS ............................................... 99 
Appendix 2 
TRIAL PERSONNEL ................................................................. 104 
Appendix 2.1 
Investigator Details ...................................................................... 104 
Appendix 2.2 
Sponsor Contact Details .............................................................. 104 
Appendix 2.3 
Contract Research Organizations ................................................ 104 
Appendix 3 
QUESTIONNAIRES/ASSESSMENTS ...................................... 105 
Appendix 4 
PROHIBITED MEDICATIONS SOLELY METABOLIZED 
BY UGT1A9 AND UGT2B7 ...................................................... 106 
Appendix 4.1 
Prohibited Medications Metabolized by UGT1A9 ..................... 106 
Appendix 4.2 
Prohibited Medications Metabolized Solely by UGT2B7 .......... 106 
 
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Study Code: GWSP18023 
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EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 23 of 106 
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 .......................................................... 47 
Table 9.2.12-1 
Biochemistry, Hematology, Urinalysis, Pregnancy Test, and 
Drug Screen ................................................................................... 58 
Table 11-1 
Assessments Required at Minimum in the Event of Pandemic 
Conditions ..................................................................................... 73 
 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
Approved


Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 24 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
List of In-text Figures 
Figure 1-1 
Trial Design and Treatment Schematic ......................................... 16 
Figure 9.2.18-1 
Flow Diagram for Identifying and Evaluating Clinical Trial 
Adverse Event Data through Systematic Categorization, 
Tabulation, and Analysis which can Illuminate an Abuse 
Potential Signal .............................................................................. 65 
 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 25 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
List of Abbreviations 
11-COOH-THC 
11-nor-9-carboxy-Δ9-tetrahydrocannabinol 
11-OH-THC 
11-hydroxy-Δ9-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 
CYP3A4 
Cytochrome P450 3A4 
ECG 
12-lead electrocardiogram 
EDSS 
Expanded Disability Status Scale 
eCRF 
Electronic case report form 
EU 
European Union 
FAS 
Full analysis set 
FDA 
US Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GW 
GW Pharma Ltd 
IB 
Investigator’s 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 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 26 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
IRT 
Interactive response technology 
MAR 
Missing at random 
MedDRA 
Medical dictionary for regulatory activities 
MMRM 
Mixed model repeated measures 
MNAR 
Missing not at random 
MS 
Multiple sclerosis 
MSSS-88 
Multiple Sclerosis Spasticity Scale 
MUS 
Medication Use Survey 
NRS 
Numerical Rating Scale 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per protocol 
PRN 
As-needed 
PT 
Preferred term 
PVD 
Pharmacovigilance department 
QoL 
Quality of life 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-36 
36-Item Short Form Health Survey 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
T25FW 
Timed 25-Foot Walk 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
THC 
Δ9-tetrahydrocannabinol 
ULN 
Upper limit of normal 
US 
United States 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
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EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 27 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Definition of Terms 
Term 
Definition 
Baseline period 
The 28 (+2)-day period from screening (Visit 1 
[Day -28(-2)] to the day before randomization 
(Visit 2 [Day 1]). 
Clonus 
A clinical manifestation of spasticity described as 
self-sustained rhythmic involuntary muscular 
contractions and relaxations in response to a 
muscle stretch. 
Day 1 
The day a patient is randomized and 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. 
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. 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Study Code: GWSP18023 
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EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
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  
• To establish the efficacy of 
nabiximols relative to placebo in 
reducing spasm count as part of the 
presentation of spasticity when used 
as adjunctive therapy in patients with 
multiple sclerosis (MS) who have not 
achieved adequate relief from other 
antispasticity agents 
• 
Change from baseline in average daily 
spasm count (from Days 57 to 84 
compared to the average daily spasm 
count for the baseline period) 
Secondary Objectives 
Secondary Endpoints 
The secondary endpoints are change in MS Spasticity Scale (MSSS-88) total score, 
safety, tolerability, and pharmacokinetics (PK). 
• To evaluate the effect of nabiximols 
relative to placebo using the 
following patient-reported outcome 
measure of spasticity: 
o The MSSS-88 total score 
Efficacy: 
• Change from baseline in total score of 
the MSSS-88 at Visit 6 
• To evaluate the safety and tolerability 
of nabiximols 
The following outcomes will be assessed at 
distinct time points during the 12 weeks of 
the double-blind treatment period. 
• Frequency of treatment-emergent 
adverse events (TEAEs) 
• Change from baseline to each 
assessment timepoint by treatment arm 
for the following: 
o Clinical laboratory tests 
o Vital signs 
o 12-lead electrocardiograms (ECGs) 
• Columbia-Suicide Severity Rating 
Scale (C-SSRS) at screening, and at 
each subsequent timepoint with 
reference to the last assessment (since 
last visit) 
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Protocol V5 01Jun2021 
 
Confidential 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Table 2-1 
Objectives and Endpoints 
• To evaluate the PK of nabiximols 
• Plasma concentrations for THC and its 
relevant metabolites (11-hydroxy-Δ9-
tetrahydrocannabinol [11-OH-THC] 
and 11-nor-9-carboxy Δ9 
tetrahydrocannabinol 
[11-COOH-THC]) and CBD and its 
relevant metabolites 
(7-hydroxy-cannabidiol [7-OH-CBD] 
and 7-carboxy-cannabidiol 
[7-COOH-CBD]) at Visits 2 (predose), 
3, 4, 5, and 6 
Exploratory Objectives 
Exploratory Endpoints 
• To evaluate the effect of nabiximols 
relative to placebo using the 
following patient-reported outcome 
measures and clinician-administered 
assessments of spasticity: 
o The 8 MS Spasticity Scale 
(MSSS-88) subscale scores 
o The 11-point Numerical Rating 
Scale (NRS) for spasm severity 
o The 11-point NRS for spasticity 
• To evaluate the effect of nabiximols 
relative to placebo on health-related 
QoL, as reflected by the 36-Item 
Short Form Health Survey (SF-36) 
• To evaluate the effect of nabiximols 
relative to placebo on functional 
outcome as reflected by walking 
ability using the Timed 25-Foot Walk 
(T25FW) test 
• The change from baseline in the 
8 subscale scores of the MSSS-88 at 
Visit 6  
• Change from baseline in average daily 
11-point NRS spasm severity score to 
Days 57 to 84 
• Change from the last 7 days of baseline 
in average daily 11-point NRS 
spasticity score to Days 78 to 84 
• Change from baseline in the SF-36 
total score at Visit 6 (Day 85) 
• Change from baseline in Timed 
25-Foot Walk (T25FW) test at Visit 6 
(Day 85) 
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Table 2-1 
Objectives and Endpoints 
Primary Estimand: 
The primary estimand for this study is defined by the following 3 components: 
• Target population:  patients with spasticity due to MS who have not achieved 
adequate relief from other antispasticity agents but have optimized treatment 
• Endpoint:  change from baseline in average daily spasm frequency count (from 
Days 57 to 84 compared to the average daily spasm count for the baseline period) 
• Measure of intervention effect:  mean difference in change from baseline between 
patients randomized to nabiximols compared to patients randomized to placebo, 
regardless of treatment compliance and change of other antispasticity medications; 
following a treatment policy strategy for handling intercurrent events. 
All randomized patients and all measurements collected after treatment discontinuation 
and after change in antispasticity medication will be included in the primary analysis. 
 
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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 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. 
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 
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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 (GW-1000-02) (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 of the 2 major cannabinoids, Δ9-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 μL spray. 
For details on the pharmacological activity of nabiximols, please refer to the 
investigator’s brochure (IB)15. 
3.3 
Rationale 
Nabiximols is currently authorized across 28 countries for the symptomatic improvement 
of patients with moderate to severe spasticity due to MS who have not responded 
adequately to other antispasticity medications on the basis of favorable treatment effects 
on the NRS spasticity compared to placebo.  The data to establish a favorable benefit-risk 
ratio for nabiximols and to support the registration for this indication globally were 
generated in a series of Phase 3 trials with and without enrichment design, with change 
from baseline in NRS spasticity score at the end of treatment as the primary endpoint. 
The effects of nabiximols on muscle spasms were evaluated in some of the pivotal trials; 
however, changes in spasms were not the main focus of these trials.  Hence, different 
outcome measures were used for the assessment of spasm frequency across trials, and 
data were collected with different means (e.g., paper diary and interactive voice response 
system).  There was evidence of efficacy of nabiximols in reducing spasm frequency 
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based on post-hoc analyses; however, no nabiximols trial evaluated the effect on muscle 
spasms as a primary or secondary endpoint.  Muscle spasms are quantifiable and 
represent 1 of the 3 cardinal features of spasticity in patients with MS (i.e., increase in 
muscle tone, spasms, and clonus).  Demonstration of efficacy in reducing spasm count 
should support the overall benefit-risk ratio of nabiximols in the treatment of spasticity 
associated with MS. 
Trial GWSP18023 is being conducted to demonstrate the efficacy of nabiximols in the 
treatment of muscle spasms associated with MS and the data generated may support 
registration or labeling of nabiximols worldwide. 
3.4 
Clinical Hypothesis 
The primary clinical hypothesis is that there will be a difference between nabiximols and 
placebo in their effect on spasm count as measured by the change from baseline in the 
average daily spasm count from Days 57 to 84 relative to the average daily spasm count 
for the baseline period. 
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4 
EXPERIMENTAL PLAN 
4.1 
Trial Design 
This multicenter, double-blind, placebo-controlled trial includes a 28-day baseline period, 
a 12-week treatment period (comprising a 2-week titration phase and a 10-week 
maintenance phase), and a 2-week follow-up period. 
Eligible patients will enter a 28-day baseline period.  During baseline, patients will 
maintain their optimized oral antispasticity medication regimen (that must include at least 
1 of baclofen, tizanidine, or dantrolene) and record spasm count, 11-point NRS spasm 
severity score, 11-point NRS spasticity score, and use of antispasticity medications once 
daily, around the same time of day, preferably in the evening before retiring to sleep, 
using an electronic daily diary.  At Visit 2 (Day 1), eligible patients will be randomized to 
either nabiximols or placebo in a 1:1 ratio. 
Patients will initiate IMP treatment as a single spray in the evening on the first day of the 
titration phase.  Patients will be advised to titrate IMP, beginning with 1 spray/day, to an 
optimized dose or to a maximum of 12 sprays/day over the first 14 days of treatment.  
Patients may leave a gap between sprays of approximately 15 minutes.  Patients 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.  For the first 14 days of administering stable doses of 
IMP following titration, patients should be instructed to 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. 
Daily spasm count, the patient’s symptom experiences, functional outcomes, 
health-related QoL, safety, tolerability, and PK will be evaluated during the treatment 
period. 
Following randomization (Visit 2 [Day 1]), patients will attend the trial site on Visit 3 
(Day 15), Visit 4 (Day 29), and Visit 5 (Day 57).  The End of Treatment Visit (Visit 6) 
will occur on Day 85 (±7 days).  Participants who are permanently discontinued from 
receiving IMP will be recommended to continue the study and follow the original visit 
schedule and requirements (e.g., eDiary data entry) without taking IMP.  
If a participant discontinues from the IMP and is unwilling or unable to follow the 
original visit schedule and requirements without taking IMP, he or she should be asked, 
at the discretion of the investigator, to return to the study site for the Early Withdrawal 
Visit (see Schedule of Assessment table [APPENDIX 1]).  Where possible, the Early 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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Withdrawal Visit should be within 14 days from last IMP dose, unless consent is 
withdrawn from further study participant, or the participant is lost to follow-up. 
A Safety Follow-up Visit (Visit 7 [Day 99]) will take place 14 (± 4) days after the End of 
Treatment Visit or Withdrawal Visit for all patients. 
Patients who complete the trial will participate for a total of approximately 18 weeks 
(127 days), including the 28-day baseline period.  Patients will have a maximum duration 
of 85 (± 7) days on IMP treatment. 
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 65 sites (US and Europe) are expected to participate in this trial.  
Additional trial sites may be used in order to supplement recruitment. 
4.3 
Number of Patients 
A total of 446 patients (223 patients per treatment arm) will be randomized to nabiximols 
or placebo in a 1:1 ratio. 
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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 [0.038% 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).  Each 
spray delivers 100 μL containing no active ingredients. 
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 brown 
plastic-coated, 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: 
• Sponsor’s name and address 
• Product identification (e.g., “Nabiximols or Placebo”) 
• Product details 
• Dose and potency 
• Vial number 
• Batch number 
• Trial code 
• Site details 
• Expiry date 
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EudraCT Number: 2019-002623-14 
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• Storage conditions 
• Instruction: “For clinical trial use only” 
• Instruction: “Keep out of the sight and reach of children” 
• 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 (or 
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 records of the trial site storage location must be maintained (recording a 
minimum of Monday through Friday, excluding public holidays) from the date of receipt 
of first shipment until the end of the trial dispensing period at each site.  These records 
must contain at least the minimum and maximum daily temperatures and must be made 
available to the appropriate GW personnel for review throughout the trial.  Temperature 
during transit of IMP to the trial site must be checked on receipt and 
compliance/noncompliance to the minimum and maximum recorded. 
Should storage conditions deviate from these 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 will be instructed to store IMP in a refrigerator (2°C to 8°C).  Once the spray 
container is opened and in use, refrigerated storage is not necessary, but the IMP should 
not be stored above 25°C.  The spray container should be stored upright.  Patients will be 
provided with further instructions regarding home storage requirements for the IMP. 
5.3.3 
Supply and Return of Investigational Medicinal Product 
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. 
Once a trial 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 
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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 8.4 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 or destroyed at a GW 
approved site if agreed in writing by the trial monitor. 
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: 
• Trial code 
• Packaging reference number, date of receipt, and quantity of IMP received 
• Patient’s trial unique patient number and/or treatment number 
• Date and quantity of IMP dispensed 
• The initials of the dispensing/dosing party 
• Date and quantity of IMP returned to the investigator 
• IMP expiry dates 
IMP will be dispensed at Visits 2, 3, 4, and 5.  Patients will be asked to return all IMP 
(used and unused) at each subsequent visit (Visits 3, 4, 5, and 6).  The trial site will check 
the returned IMP against the usage recorded in the electronic diary via electronic Clinical 
Report Form (eCRF) accountability calculations.  Any discrepancies will be discussed 
with the patient at the time of the visit and documented accordingly within the patient’s 
source documents.  Refer to Section 9.2.18.2.1 for the list of triggering drug 
accountability discrepancies associated with monitoring of drug abuse liability. 
The investigator must inform GW promptly of all missing or unaccountable 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. 
Please refer to the separate pharmacy manual for more detailed information on the IMP. 
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5.3.5 
Post-trial Provision 
There will be no post-trial provision of nabiximols. 
A summary of the results of this trial will be made available on 
https://www.clinicaltrials.gov as required by US law and on 
https://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, patient must fulfill ALL of the following criteria: 
1. 
Male or female aged 18 years or above. 
2. 
Willing and able to give informed consent for participation in the trial (see 
Section 15.2). 
3. 
Willing and able (in the investigator’s opinion) to comply with all trial 
requirements.  (With the exception of the T25FW test, if the patient is non-
ambulatory). 
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. 
5. 
Has had treatment with at least 1 optimized oral antispasticity therapy prior to 
Visit 1 that must include either oral baclofen or oral tizanidine (monotherapy 
or combination therapy). 
6. 
Currently receiving optimized treatment with at least 1 oral antispasticity 
medication (baclofen, tizanidine, or dantrolene) and has been stable for at 
least 30 days prior to Visit 1.  Despite optimization, the patient does not have 
adequate relief of spasticity signs and 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. 
7. 
If currently receiving an 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. 
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. 
9. 
Willing to allow the responsible authorities to be notified of participation in 
the trial, if mandated by local law. 
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 
than the investigator. 
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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 ALL of the following criteria during 
the first 28 days of the baseline period.  (Note: patients are expected to start completing 
their electronic diary in the evening of their screening visit): 
11. 
In the opinion of the investigator, the patient is able to interpret and report 
spasm count data accurately 
12. 
Completed their electronic diary for at least 25 of the first 28 days of the 
baseline period 
13. 
Has an average daily spasm count of ≥ 4 during the first 28 days of the 
baseline period, as recorded by the patient 
14. 
Has no more than 35 spasms on any single day of the first 28 days of the 
baseline period, as recorded by the patient 
15. 
Does not have > 7 consecutive days without experiencing any spasm during 
the first 28 days of the baseline period 
If, for any reason, the patient is unable to attend the site for randomization within the visit 
window, the site should contact the Medical Monitor or the sponsor to discuss.  
In addition to meeting the Screening (Visit 1) inclusion criteria and additional inclusion 
criteria 11 to 14, any patient with more than 28 days between Visit 1 and Visit 2 would 
need to meet ALL of the following criteria prior to randomization: 
 
16. 
Completed their electronic diary for at least 85% of days between Visit 1 and 
Visit 2 
17. 
Has an average daily spasm count of ≥ 4 between Visit 1 and Visit 2 
(randomization), as recorded by the patient 
18. 
Has no more than 35 spasms on any single day between Visit 1 and Visit 2, as 
recorded by the patient 
19. 
Does not have > 7 consecutive days without experiencing any spasm between 
Visit 1 and Visit 2 
 
6.2 
Exclusion Criteria 
The patient may not enter the trial if ANY of the following apply: 
1. 
Previously participated in a clinical trial of nabiximols or has had a poor 
previous response or intolerance to nabiximols or other 
cannabinoid-containing products used for therapeutic purposes. 
2. 
Any concomitant disease or disorder that has spasticity-like symptoms or that 
may influence the patient’s level of spasticity. 
3. 
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. 
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4. 
Has had a relapse of MS within the 60 days prior to Visit 1. 
5. 
Has taken cannabis, or a cannabis-derived product for medicinal or 
recreational use within the 30 days prior to screening (Visit 1) or a positive 
blood drug test for THC at screening (Visit 1). 
6. 
Is unwilling to abstain from use of cannabis, or a cannabis-derived product for 
medicinal or recreational purposes for the duration of the trial. 
7. 
Currently using botulinum toxin injection for the relief of spasticity (within 
6 months of Visit 1) 
8. 
Is unwilling to abstain from the use of botulinum toxin injection for the relief 
of spasticity for the duration of the trial. 
9. 
Currently taking antipsychotic medication. 
10. 
Currently taking benzodiazepines, unless doses and dosing regimen have been 
stable for at least 30 days prior to Visit 1. 
11. 
Has any known or suspected hypersensitivity to cannabinoids or any of the 
excipients of the IMP. 
12. 
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. 
13. 
Has a diastolic blood pressure of < 50 mmHg or > 105 mmHg or systolic 
blood pressure < 90 mmHg or > 150 mmHg (when measured in a supine 
position at rest for 5 minutes), or a postural drop in the systolic blood pressure 
of ≥ 20 mmHg or in diastolic blood pressure of ≥ 10 mmHg at Visit 1.  All 
measurements will be performed singly and can be repeated once, if any are 
outside the reference range but not considered clinically significant. 
14. 
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. 
15. 
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. 
16. 
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. 
17. 
Female and of childbearing potential (i.e., following menarche and until 
becoming postmenopausal for ≥ 12 consecutive months with a follicle 
stimulating hormone (FSH) ≥ 30 mIU/mL 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, other highly effective hormonal methods or sexual 
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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). 
18. 
Female and pregnant (positive pregnancy test at Visit 1 or Visit 2 [predose]), 
lactating, or planning pregnancy during the course of the trial or within 
3 months thereafter. 
19. 
Received an IMP within the 30 days prior to Visit 1. 
20. 
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. 
21. 
Has any abnormalities identified following a physical examination, clinical 
laboratory, serology, or other applicable screen 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. 
22. 
Has any history of suicidal behavior in the 5 years prior to Visit 1 or a suicidal 
ideation score of 3, 4, or 5 on the Columbia Suicide Severity Rating Scale 
(C-SSRS) in the month prior to Visit 1. 
23. 
Has a history of severe psychiatric disorder that may be exacerbated by the 
use of a cannabinoid-containing product. 
24. 
Has donated blood during the 3 months prior to Visit 1 and is unwilling to 
abstain from donation of blood during the trial. 
25. 
Has been previously randomized into this trial. 
26. 
Has any known or suspected history of alcohol or substance use disorder 
within 1 year prior to Visit 1.  Patients with nicotine use disorder are allowed 
to enroll. 
27. 
Currently using an illicit drug or current nonprescribed use of any prescription 
drug.  A positive drug test at Visits 1 or 2 for a prescribed medication is not 
exclusionary at the investigator’s discretion.  A positive drug test at Visit 1 or 
predose at Visit 2 for illicit drugs may be repeated locally at the investigator’s 
discretion. 
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. 
29. 
Currently taking drugs that are solely metabolized by UGT1A9 and UGT2B7 
(see APPENDIX 4). 
30. 
Currently taking strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, 
phenytoin, phenobarbital, St John's Wort). 
31. 
There is an expectation that the participant will require a new course of 
treatment with strong CYP3A4 inhibitors during the study duration (e.g., 
participant with recurrent fungal infections requiring intermittent treatment 
with itraconazole). 
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32. 
Patients who receive a positive coronavirus disease 2019 (COVID-19) antigen 
test result, potentially suggesting infective status, before randomization may 
be screen failed, at the discretion of the investigator. 
Individuals who do not meet the criteria for participation in this trial (screen failure) 
because of, for example, fever due to a brief acute upper respiratory illness, having 
taken a prohibited over the counter medication within the excluded period, recent 
blood donation, due to the inclusion criterion related to the ability to interpret and 
report spasm count data accurately, or who could not be randomized for logistical 
reasons, can be rescreened once, at the discretion of the investigator or designee with 
sponsor approval.  Rescreened participants should be assigned a new screening 
number. 
 
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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 arm 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 treatment allocation schedule will 
have balanced randomly permuted blocks, stratified by region (US versus non-US) and 
prior cannabis use defined as any pattern of recreational or medicinal use, which would 
typically exclude isolated, unintentional, or passive exposures.  Investigator judgment 
should be applied during the clinical interview to determine if there is a history of 
intentional, repeated use of cannabis or cannabinoid products.  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 8.5.  Patients 
who withdraw from the trial will not be replaced. 
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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 noncannabinoid 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 arms, IMP will be administered by the patient via a pump 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. 
Following the titration phase (see Section 8.1.2), IMP will be administered as 1 spray 
(100 μL per spray) with a target interval of approximately 1 minute until the patient’s 
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, and patients should divide doses greater than 2 sprays/day into a 
morning dose and an evening dose.  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 
After IMP dosing training and IMP dispensing, site staff will provide patients with an 
example titration schedule and instructions to record IMP dosing information in the 
patient electronic diary.  Patients will initiate IMP treatment as a single spray in the 
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evening on the first day of the titration phase.  Patients will be advised to titrate IMP, to 
the maximally acceptable dose, balancing efficacy and tolerability, beginning with 
1 spray/day, to an optimized dose or to a maximum number of 12 sprays/day over the 
first 14 days of treatment.  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 AEs, 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 regimen 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 
0 
1 
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 
Patients should complete titration within 14 days of their first dose of IMP and should 
continue 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 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 that emerges during the period of 
stable dosing.  For the first 14 days of administering stable doses of IMP following 
titration, patients should be instructed to 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 composed of a different number of sprays.  Patients may take their 
morning dose spread out during the morning and their evening dose spread out during the 
evening, with a minimum interval between sprays as specified above (i.e., 15 minutes 
during the titration phase and a target of approximately 1 minute during the maintenance 
phase). 
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8.2 
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 in the eCRF 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. 
8.2.1 
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 antispasticity medication.  
Optimized oral antispasticity medications will include at least baclofen, tizanidine, or 
dantrolene (monotherapy or combination therapy).  Their antispasticity medication must 
have been stable for at least 30 days prior to Screening (Visit 1) and the medication is 
expected to remain stable through the duration of the trial.  However, despite this 
optimization, eligible patients do not have adequate relief of their 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 
therapy for the duration of the trial. 
Benzodiazepine 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 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. 
8.3 
Prohibited Therapy During Trial Period 
The following medications are prohibited for the duration of the trial: 
• 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 
• Botulinum toxin injection for the relief of spasticity within 6 months of Visit 1 
and for the duration of the trial 
• Antipsychotic medication 
• Any benzodiazepines use on an as-needed (PRN) basis 
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• Drugs that are solely metabolized by UGT1A9 and UGT2B7 (See APPENDIX 4) 
• Strong CYP3A4 inhibitors or inducers (e.g., rifampicin, carbamazepine, 
phenytoin, phenobarbital, St John's Wort) 
Any patient taking these medications after Visit 1 must cease IMP and should remain in 
the trial. 
The use of psychotropic medications other than those specified above would be allowed 
provided the medication is used on a daily basis, has been at a stable dose for at least 
30 days or 5 half-lives (whichever is longer) prior to Visit 1 and is expected to remain 
stable throughout the trial. 
8.4 
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 3, 4, 5, and 6.  The 
electronic diary-reported dosing information will be checked and any discrepancies 
discussed with the patient at the time of the visit and documented accordingly within the 
patient’s source documents.  Refer to Section 9.2.18.2.1 for the list of triggering drug 
accountability discrepancies associated with monitoring of drug abuse liability. 
Records of IMP accountability will be maintained according to Section 5.3.4. 
8.5 
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/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 trial medication will not be 
dependent upon 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 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 (such as COVID-19/other pandemic 
restrictions), 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. 
In keeping with ICH Good Clinical Practice (ICH GCP) E6 Guideline, it is the 
investigator’s responsibility to provide oversight of data provided by patients, including 
daily spasm count entered in the eDiary, to ensure completeness and reliability.  If the 
investigator has concerns about the reliability of the spasm count data, they may discuss 
this with the sponsor or sponsor’s representative. 
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 
Visit 1 (Days −30 to −28, Screening) 
Informed consent (see Section 9.2.1) must be obtained from the patient prior to beginning 
any trial-related procedures. 
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The following assessments/procedures will be performed: 
• Eligibility check (Section 6) 
• Demographics (Section 9.2.3) 
• Previous cannabis use (Section 9.2.4) 
• Medical history (Section 9.2.5), including current Expanded Disability Status 
Scale (EDSS) score (if known) or ambulatory status 
• Electronic diary training (Section 9.2.14.1) 
• Concomitant medications review (Section 9.2.6) 
• AE review (Section 9.2.17) 
• Physical and oral mucosa examinations (including height measurement) 
(Section 9.2.7 & 9.2.8) 
• Body weight measurement (Section 9.2.9) 
• Vital signs measurement (Section 9.2.10) 
• 12-lead ECG (Section 9.2.11) 
• Clinical laboratory blood sampling (hematology and biochemistry) 
(Section 9.2.12) 
• Dipstick urinalysis (Section 9.2.12) 
• Urine drug screen (including THC) (Section 9.2.12) 
• Serum pregnancy test (if appropriate) (Sections 9.2.2 and 9.2.12) 
• Confirmatory FSH test for postmenopausal state (see Sections 6.2 and 9.2.2) 
• Blood THC test (Section 9.2.12) 
• 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 
antispasticity medications.  Patients will enter a 28-day baseline period, during which 
they will be required to take their optimized oral antispasticity medication (that must 
include at least 1 of baclofen, tizanidine, or dantrolene) and complete an electronic daily 
diary to record spasm count, 11-point NRS spasm severity score, 11-point NRS spasticity 
score, and use of antispasticity medications once daily, around the same time of day, 
preferably in the evening before retiring to sleep.  Patients are expected to start 
completing their electronic diary in the evening of their screening visit (first day of the 
28-day baseline period). 
At the discretion of the investigator, patients who receive a positive COVID-19 antigen 
test result, suggesting potentially infective status, before randomization may be screen 
failed.  At the discretion of the investigator, patients who receive a positive COVID-19 
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test result after randomization may be discontinued from IMP but kept in the trial.  See 
Section 9.2.6 for the data to be collected from those patients who received a COVID-19 
vaccination in the 12 months prior to Screening. 
9.1.1.1 
Screen Failures 
Screen failures are defined as individuals 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 
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). 
Rescreening of Participants: 
Individuals who do not meet the criteria for participation in this trial (screen failure) 
because of, for example, fever due to a brief acute upper respiratory illness, having taken 
a prohibited over the counter medication within the excluded period, recent blood 
donation, due to the inclusion criterion related to the ability to interpret and report spasm 
count data accurately, or who could not be randomized within the screening window for 
logistical reasons, can be rescreened once, at the discretion of the investigator or designee 
with sponsor approval.  Rescreened participants should be assigned a new screening 
number. 
9.1.2 
Visit 2 (Day 1, Randomization) 
Following the 28-day baseline period, patients will attend the site for Visit 2 on Day 29, a 
visit window of +2 days is permitted but it is preferred that the visit is performed on the 
scheduled visit day, where possible.  If, for any reason, the patient is unable to attend the 
site for randomization within the visit window, the site should contact the Medical 
Monitor or the sponsor to discuss; please note the eligibility criteria the patient needs to 
meet should this occur. 
The following assessments/procedures will be performed: 
• Eligibility check 
• Randomization (Section 7.2) 
• Concomitant medications review 
• AE review 
• Physical and oral mucosa examinations 
• Body weight measurement 
• Vital signs measurement 
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• 12-lead ECG 
• Clinical laboratory blood sampling (hematology and biochemistry) 
• Urine drug screen (including THC) 
• Urine pregnancy test (if appropriate) 
• PK blood sampling (Section 9.2.12.1) 
• MSSS-88 assessment (Section 9.2.15.2) 
• C-SSRS assessment 
• T25FW test (Section 9.2.15.4) 
• SF-36 assessment (Section 9.2.15.6) 
• IMP dosing training and dispensing (Section 9.2.14.4) 
Following predose assessments and after IMP dosing training and IMP dispensing, site 
staff will provide patients with an example titration schedule and instructions to record 
IMP dosing information in the patient electronic diary.  Patients will take the first dose of 
IMP on the evening of Visit 2 (Day 1).  
See Section 8.1.1 and Section 8.1.2 for IMP dosing and administration information.   
Patients should be reminded to record their spasm count, 11-point NRS spasm severity 
score, 11-point NRS spasticity score, and use of antispasticity medications in the 
electronic diary once daily, around the same time of the day, preferably in the evening 
before retiring to sleep.  In addition, on the day before Visits 3, 4, and 5 patients will be 
prompted to record whether they started their morning and evening doses of IMP within 
30 minutes of a 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. 
9.1.3 
Visit 3 (Day 15), Visit 4 (Day 29), and Visit 5 (Day 57) 
Visits 3, 4, and 5 will occur 14, 28, and 56 days after the first dose of IMP, respectively.  
A visit window of ± 3 days for Visits 3 and 4 and ± 7 days for Visit 5 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 at these visits, unless otherwise 
indicated: 
• Concomitant medications review 
• AE review 
• Oral mucosa examination 
• Body weight measurement (Visit 4 only) 
• Vital signs measurement 
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• 12-lead ECG (Visit 4 only) 
• Clinical laboratory blood sampling (hematology and biochemistry) (Visit 4 only) 
• PK blood sampling (see Section 9.2.12.1) 
• MSSS-88 assessment (Visit 5 only) 
• C-SSRS assessment 
• IMP collection and compliance review (Section 8.4) 
• IMP dispensing 
See Section 8.1.1 and Section 8.1.2 for IMP dosing and administration information. 
Patients should be reminded to record their spasm count, 11-point NRS spasm severity 
score, 11-point NRS spasticity score, use of antispasticity medications, and IMP dosing 
in the electronic diary once daily, around the same time of the day, preferably in the 
evening before retiring to sleep.  In addition, on the day before Visit 6, patients will be 
prompted to record whether they started their morning and evening doses of IMP within 
30 minutes of a meal. 
9.1.4 
Visit 6 (Day 85, End of Treatment Visit/Withdrawal Visit) 
This visit will occur 84 days after the first dose of IMP or earlier, if the patient withdraws 
from the trial.  A visit window of ± 7 days from the scheduled visit date is permitted, but 
it is preferred that the visit is performed on the scheduled visit day, where possible. 
Patients who discontinue IMP treatment early will be encouraged to continue (off 
treatment) in the trial and to complete all remaining trial procedures to Visit 6 (Day 85), 
where possible. 
The following assessments/procedures will be performed: 
• Concomitant medications review 
• AE review 
• Physical and oral mucosa examinations 
• Body weight measurement 
• Vital signs measurement 
• 12-lead ECG 
• Clinical laboratory blood sampling (hematology and biochemistry) 
• PK blood sampling (see Section 9.2.12.1) 
• Dipstick urinalysis 
• Serum pregnancy test (if appropriate) 
• MSSS-88 assessment 
• C-SSRS assessment 
• T25FW test  
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• Medication Use Survey (MUS [Section 9.2.15.5]) 
• SF-36 assessment 
• IMP collection and compliance review 
Patients should be reminded to record their spasm count, 11-point NRS spasm severity 
score, 11-point NRS spasticity score, and use of antispasticity medications in the 
electronic diary once daily, around the same time of the day, preferably in the evening 
before retiring to sleep. 
9.1.5 
Visit 7 (Day 99, Safety Follow-up Visit) 
The Safety Follow-up Visit will occur 14 days after the End of Treatment Visit or 
Withdrawal Visit.  A visit window of ± 4 days from the scheduled visit date is permitted, 
but it is preferred that the visit is performed on the scheduled visit day, where possible.  
Patients who discontinue IMP but complete scheduled trial visits are not required to 
complete the Safety Follow-up Visit. 
The following assessments/procedures will be performed: 
• Concomitant medications review 
• AE review 
• Vital signs measurement 
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] Harmonised Guideline:  Integrated 
Addendum to ICH E6(R1):  Guideline for Good Clinical Practice [GCP] E6(R2), 
Section 4.8.9). 
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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 provided to the patient.  Patients 
will be given the option of being informed about the summary outcome and results of the 
trial as part of the ICF.  For further details regarding the informed consent, see 
Section 15.2. 
9.2.2 
Contraception Requirements 
To be eligible for the trial, female patients of childbearing potential (i.e., following 
menarche and until becoming postmenopausal for ≥ 12 consecutive months with a FSH 
≥ 30 mIU/mL 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 hormonal contraception, 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 (as 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 medicinal or recreational purposes will be recorded. 
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9.2.5 
Medical History 
Relevant, significant medical history, including current EDSS score (if known) or 
ambulatory status, will be obtained at Screening (Visit 1) and is defined as any condition 
or disease that: 
• May affect the condition under study in this trial 
• Is ongoing on entry into the trial 
• Has occurred within 1 year prior to Screening (Visit 1) 
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 8.3. 
Please note: Any vaccination related to COVID-19, that was received within the 
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; differing start and end dates denoting two doses being received, if 
applicable. 
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.  Where postural blood pressure is required at Visit 1 it should be measured 
within 2 minutes of assuming a standing position in ambulatory patients only.  At all 
subsequent time points, vital sign measurements will be completed in a sitting position at 
rest for 5 minutes.  Blood pressure must be recorded using the same arm throughout the 
trial, where possible. 
Additional vital signs measurements may be taken during the trial if clinically indicated. 
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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 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 with any relevant findings being sent for further urinalysis at the central 
laboratory (urinalysis, microscopy, culture and sensitivity, as applicable).  In cases where 
samples cannot be analyzed at the trial 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 
 
 
Follicle stimulating 
hormone 
 
 
Serum4 
 
Gamma-glutamyl 
transferase 
White blood cell 
count with automated 
differential 
Specific gravity 
 
 
Potassium 
 
Ketones 
 
 
Prothrombin time 
(plasma)5 
 
 
 
 
Sodium 
 
Urobilinogen 
 
 
Total bilirubin 
 
Bilirubin 
 
 
Total protein 
 
 
 
 
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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) 
Urea (blood urea nitrogen) 
 
 
 
 
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.  All patients will undergo a separate blood THC test at Visit 1. 
4Confirmatory test for postmenopausal state. 
5Analyzed as Screening (Visit 1) only. 
Investigators at trial sites will be notified of safety laboratory test results.  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 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 67 mL, taking into 
account possible repeat tests. 
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).  There will be 2 options for the collection of PK samples: 
1) For patients choosing the sparse PK sampling option, blood samples will be taken 
as follows: 
• Visit 2 – 1 sample predose 
• Visits 3, 4, 5, and 6 – 1 sample collected at any time during the visit 
• During the visits, the exact time of PK blood sampling and the time of the 
patient’s snacks and meals should be recorded 
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2) For patients choosing the semi-intensive PK sampling option, blood samples will 
be taken as follows: 
• Visit 2 – 1 sample predose 
• At 1 visit (either Visit 3, 4, or 5): 
o 1 sample predose (i.e., prior to administration of IMP at the 
investigational site) 
o 1 sample between 2 and 3 hours postdose 
o 1 sample between 4 and 6 hours postdose 
o 1 sample between 6 and 8 hours postdose 
• There must be a minimum period of at least 2 hours between each of the 
4 blood sampling time points 
• The predose sample will be taken prior to the morning IMP dose.  On the 
day of the semi-intensive PK sampling the patient must bring their study 
medication with them to the visit and not take their morning IMP dose until 
instructed to do so by the site staff 
• During the visits the exact time of PK blood sampling and the time of the 
patient’s snacks and meals should be recorded 
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 30 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 arms, 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: 
• Randomize a patient (Visit 2) 
• Obtain IMP dispensing information (Visits 2, 3, 4, and 5) 
• Provide completion/premature termination information (Visit 6) 
Training will be given to all sites prior to the start of the trial. 
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9.2.14 
Electronic Patient Diary 
As part of the baseline period, patients will record their spasm count, 11-point NRS 
spasm severity score, 11-point NRS spasticity score, and use of antispasticity medications 
in the electronic diary once daily, around the same time each day, during the baseline 
period prior to Visit 2 and throughout the trial until Visit 7, unless otherwise indicated.  
Patients are expected to start completing their electronic diary in the evening of their 
screening visit (first day of the 28-day baseline period). 
In addition, on the day before PK blood sampling, patients will be prompted to record 
whether they started their morning and evening doses of IMP within 30 minutes of a 
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 on how to record their spasm count, 11-point NRS spasm 
severity score, 11-point NRS spasticity score, and use of antispasticity medications once 
daily, around the same time of day, preferably in the evening before retiring to sleep, 
during the baseline period prior to Visit 2 and throughout the trial until Visit 7.  
Following randomization during Visit 2, patients will be instructed to log their daily IMP 
dosing in the electronic diary throughout the treatment period until Visit 6. 
9.2.14.2 
Spasm Severity 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 spasms over the last 
24 hours.  The patients will be given a definition of spasm and the question will be 
phrased as follows: 
On a scale of 0 to 10, how severe were your spasms on average over the last 24 hours? 
Considering 0 as “No spasms” and 10 as “Worst possible spasms”. 
This information will be recorded in the patient electronic diary. 
9.2.14.3 
Spasticity Numerical Rating Scale 
Patients will be asked to make a daily assessment, at bedtime, to read the instruction, 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: 
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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. 
9.2.14.4 
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, tizanidine or dantrolene as part of their optimized oral antispasticity 
therapy, and their IMP dosing daily in their electronic diary. 
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.  The C-SSRS and T25FW will be administered by a 
trained assessor. 
9.2.15.1 
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 
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.” 
9.2.15.2 
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/her qualified designee at 
Visits 1 through 6 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. 
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9.2.15.3 
Timed 25-Foot Walk 
The T25FW is a quantitative measure of lower extremity function and should be 
performed by a trained assessor.  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. 
9.2.15.4 
Medication Use Survey 
This form consists of 18 questions regarding the use of the IMP.  The trained investigator 
or trial coordinator will complete this survey as an interview with the patient at the End 
of Treatment Visit or Withdrawal Visit (Visit 6). 
The MUS will be completed for all patients in the trial and not only those who have 
reported a triggering AE or drug accountability discrepancy, although only those with 
triggering AEs/drug accountability events will be adjudicated for abuse potential (see 
Section 9.2.18). 
9.2.15.5 
36-Item Short Form Health Survey 
The SF-36 is a generic multipurpose, short-form QoL health survey comprising 
36 questions self-reported by the patient.  It yields an 8-scale profile of functional health 
and well-being scores as well as psychometrically based physical and mental health 
summary measures and a preference-based health utility index17. 
The SF-36 differentiates between physical and mental health and consists of 8 different 
dimensions (physical functioning, vitality, bodily pain, general health perceptions, 
physical role functioning, emotional role functioning, social role functioning, and mental 
health) and is validated for bodily pain and physical function. 
The SF-36 scores for each dimension can range between 0 and 100, where higher scores 
indicate better functional health and well-being. 
9.2.16 
Investigational Medicinal Product Accountability 
Records of IMP accountability will be maintained according to Section 5.3.4. 
9.2.17 
Adverse Events 
Refer to Section 12 for definitions, procedures, and further information on AE reporting. 
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Refer to Section 9.2.18.1.1 for the list of triggering AEs of interest associated with 
monitoring of drug abuse liability. 
9.2.18 
Monitoring of Drug Abuse Liability 
There are 2 triggers that will require the investigator or trial coordinator to discuss abuse 
potential signals with the patient.  These are either AEs of interest that may be reported 
by the patient or drug accountability issues regarding overuse of the IMP or missing 
vials.  Different questionnaires will be completed by the trial site depending upon which 
trigger occurs (see Figure 9.2.18-1).  Irrespective of the above, all patients will be 
interviewed at the End of Treatment Visit or Withdrawal Visit (Visit 6) and a MUS will 
be completed by the investigator or trial coordinator (see Section 9.2.15.4).  Investigators 
and trial coordinators will be provided with training on how to complete and perform the 
processes outlined in this section.  This training must be completed and documented by 
the relevant site staff prior to implementation at the trial site. 
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Figure 9.2.18-1 
Flow Diagram for Identifying and Evaluating Clinical Trial 
Adverse Event Data through Systematic Categorization, 
Tabulation, and Analysis which can Illuminate an Abuse 
Potential Signal 
 
 
Stage 1 
Patients with ‘Triggering Adverse 
Event of Interest’ 
Patients with ‘Triggering Drug 
Accountability Discrepancy’ 
All 
patients  
When a Triggering Adverse Event of 
Interest is identified, a patient 
interview is conducted with the 
Supplemental Adverse Event Form 
and, if applicable, the Supplemental 
Drug Accountability Form. 
When a Triggering Drug 
Accountability discrepancy is 
identified, a patient interview is 
conducted with the Supplemental 
Drug Accountability Form and, if 
applicable, the Supplemental 
Adverse Event Form. 
Investigator completes a Site Classification Form after supplemental 
information is collected, drug accountability evaluated, and the patient 
evaluated.  One Site Classification Form is completed per Supplemental 
Adverse Event Form or Drug Accountability Form. 
Stage 2 
Stage 3 
Site completes Medication Use Survey at end of dosing. 
Stage 4 
Adjudication Committee 
Evaluates all of the information collected (as detailed above in Stages 1–4) in the 
assessment of the abuse potential of nabiximols and completes a report. 
Committee submits a report to GW. 
Stage 5 
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9.2.18.1 
Monitoring of Adverse Events (Abuse Liability) 
AE information will be collected according to Section 12.6. 
9.2.18.1.1 
List of Triggering Adverse Events of Interest (Abuse Liability) 
During the collection of AEs, if the patient reports an AE consistent with any of the 
following categories, then the investigator or trial coordinator is required to complete a 
Supplemental Adverse Event Form (see Section 9.2.18.1.2) and a Site Classification 
Form (investigator only; see Section 9.2.18.3) following further discussion of the event(s) 
with the patient.  The categories are: 
• Addiction 
• Disturbance in cognition, memory, or attention 
• Drug abuse 
• Drug withdrawal or drug withdrawal syndrome 
• Drunk, high or intoxicated 
• Euphoria or inappropriate elation 
• Hallucinations (visual or auditory), dissociations, disorientation, agitation 
• Inappropriate laughter or exhilaration 
• Misuse of IMP 
• Mood changes 
• Overdose 
• Thoughts of suicide, attempted suicide, or suicide 
An AE that is consistent with the above categories will be known as a ‘triggering AE of 
interest’ for the purposes of this trial. 
9.2.18.1.2 
Supplemental Adverse Event Form (Abuse Liability) 
This form consists of 12 questions regarding the AE and the use of IMP.  It is completed 
as part of an interview with the patient when a triggering AE of interest is reported.  It is 
important that this is completed by a trained investigator or trial coordinator with the 
patient present.  The answers on the Supplemental Adverse Event Form will then be 
entered into the patient’s eCRF for the trial.  If the Supplemental Adverse Event Form 
cannot be completed at the time the triggering AE of interest is reported, then the trial site 
should contact the patient to obtain the required answers as soon as possible.  The time 
and date of collection must be recorded in the patient’s notes and on the eCRF. 
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9.2.18.2 
Monitoring Drug Accountability Discrepancies (Abuse Liability) 
Any time after randomization until final collection of trial data, drug accountability 
discrepancies are monitored as follows: 
• At routine drug accountability collection times (i.e., Visits 3, 4, 5, and 6) 
o The site personnel will collect the IMP clinical supplies and make sure the 
usage is in line with the expectations reported within the electronic diary 
• At any time that the trial site is informed by the patient about any overuse of IMP, 
suspected misuse, abuse, or diversion 
9.2.18.2.1 
List of Triggering Drug Accountability Discrepancies (Abuse 
Liability) 
If there are any discrepancies in drug accountability as outlined by the criteria below, 
known as ‘triggering drug accountability discrepancies’, then the trained investigator or 
trial coordinator will complete a Supplemental Drug Accountability Form (see 
Section 9.2.18.2.2) and a Site Classification Form (investigator only; see 
Section 9.2.18.3) following further discussion of the event(s) with the patient.  The 
triggering drug accountability discrepancies are as follows: 
• Compliance issues where 1 or more vials are used compared to the expected use, 
according to the electronic diary entries and drug accountability calculations in 
eCRF 
• Greater than the target daily dose as recorded in the electronic diary 
• Missing vial(s) 
• Returned IMP supply with evidence of tampering 
9.2.18.2.2 
Supplemental Drug Accountability Form (Abuse Liability) 
This form consists of 10 questions regarding various aspects of drug accountability and 
patient usage.  It is completed as part of an interview with the patient when a triggering 
drug accountability discrepancy is identified.  It is important that this is completed by a 
trained investigator or trial coordinator with the patient present.  The answers on the 
Supplemental Drug Accountability Form will then be entered into the patient’s eCRF for 
the trial.  The accountability reporting procedures will still occur (see Section 5.3.4).  If 
the Supplemental Drug Accountability Form cannot be completed at the time the 
triggering drug accountability discrepancy is identified, then the trial site should contact 
the patient by telephone to obtain the required answers as soon as possible.  (Note: IMP 
refers to nabiximols or placebo, not other concomitant medications). 
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9.2.18.3 
Site Classification Form (Abuse Liability) 
The investigator should review the applicable Supplemental Adverse Event Form or 
Supplemental Drug Accountability Form, and should then complete the Site 
Classification Form.  For each Supplemental Adverse Event Form or Supplemental Drug 
Accountability Form completed, there should be an associated Site Classification Form. 
The Site Classification Form requires the investigator to assign the finding to an 
appropriate classification and then to also assign the possible relationship to the IMP.  
The investigator is also required to indicate the level of certainty of the classification.  
The answers from the Site Classification Form will then be entered into the patient’s 
eCRF for the trial. 
9.2.18.4 
Adjudication Committee: Assessment of Abuse Potential of 
Nabiximols 
A formal adjudication committee will be appointed and assigned to this initiative to 
classify triggered cases.  The adjudication committee will meet on a periodic basis to 
review and assess all of the information collected on triggered cases.  Only data from 
patients who have completed the trial will be assessed. 
A detailed charter will be agreed, which will describe the roles, responsibilities, and 
duties of the members of adjudication committee.  The adjudication committee will 
review all of the information collected in the process and in the assessment of the abuse 
potential of nabiximols, such as: 
• Additional information from trial site(s) as requested by the adjudication 
committee 
• All triggering AE information 
• All triggering drug accountability discrepancies 
• Site Classification Form 
• MUS 
• Supplemental Adverse Event Form (if applicable) 
• Supplemental Drug Accountability Form (if applicable) 
The adjudication committee will assess all of the information.  It will form an opinion on 
the classification of each event and will write a trial-related report, detailing the 
conclusions and recommendations. 
The overall process is summarized in Figure 9.2.18-1. 
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10 
WITHDRAWAL 
In accordance with the Declaration of Helsinki, the ICH Harmonised Guideline: 
Integrated Addendum to ICH E6(R1): Guideline for GCP E6(R2), the US 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: 
• Administrative decision by the investigator, GW, or a regulatory authority 
• Withdrawal of patient consent 
• Lost to follow-up 
The patient must cease IMP and should remain in the trial if any of the following apply: 
• Pregnancy 
• Protocol deviation that is considered to potentially compromise the safety of the 
patient 
• Suicidal behavior, or suicidal ideation score of 4 or 5 during the treatment period, 
as evaluated with the C-SSRS 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
• ALT or AST > 5 × ULN  
• ALT or AST > 3 × ULN and (total bilirubin [TBL] > 2 × ULN or international 
normalized ratio [INR] > 1.5)  
• Any prohibited medication after Visit 1 
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: 
• Did not meet eligibility criteria 
• Patient noncompliance 
• 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 
• Any evidence of drug abuse or diversion 
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• Disease progression (defined as a relapse of MS requiring a change in treatment) 
• A positive COVID-19 test result after randomization 
Should a patient request or decide to withdraw consent 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 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 14 (± 4) days after the End of 
Treatment Visit (Visit 6) or Withdrawal Visit if the patient does not complete the 
remaining trial visits after discontinuing IMP (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. 
Patients who withdraw from the trial will not be replaced. 
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11 
URGENT SAFETY MEASURES 
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 patients:  
• Safety follow-up may be done by a telephone call, other means of virtual contact 
or home visit, if appropriate.  
• Patient and/or clinician-rated outcomes assessments may be done by 
videoconference, telephone call, other means of virtual contact, if possible. 
• An alternative approach for IMP dispensing, secure delivery and collection may 
be sought. 
• Visits may take place in a different location than defined in the protocol.  If this is 
not feasible, then the visit may take place virtually with documentation of the 
means of communication (e.g., phone call or videoconference). 
• 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.  
• 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 Schedule 
of Assessments in APPENDIX 1), then the interval may be extended up to a 
maximum duration of 3 days.  
• 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.  
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.  Exceptional measures 
taken in response to COVID-19/other pandemic conditions and their impact on study 
results, such as tests done in a local laboratory, will be justified, assessed, and reported in 
the clinical study report in keeping with ICH E3. 
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The remote visit should include all protocol assessments that can be performed remotely 
(see minimum requirements, Table 11-1) and should take place within the original visit 
window, if possible.  The investigator should make reasonable efforts to obtain these 
assessments which may include local clinicians, local laboratories and other resources.  If 
these assessments cannot be obtained within a reasonable time outside the window of the 
scheduled visit date, the benefit-risk ratio for the patient to continue in the study should 
be reassessed. 
The decision to replace a site visit with a remote visit will be made by the investigator, on 
a case-by-case basis, in consultation with GW, who should be informed of each visit to 
be rescheduled as early as possible. 
If a telephone contact takes place at the time of stopping IMP, all safety data which can 
be obtained remotely should be collected as close as possible to the time of stopping 
IMP. 
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Table 11-1 
Assessments Required at Minimum in the Event of 
Pandemic Conditions 
 
Visit 
2 
3 
4 
5 
6 
7 
Day 1 
(Randomization) 
Day 15 
 
14 days 
from 
Day 1 
(± 3 days) 
Day 29 
 
28 days 
from 
Day 1 
(± 3 days
) 
Day 57 
 
56 days 
from  
Day 1 
(± 7 days
) 
End of 
Treatment 
/Early 
Withdraw
al  
Day 85 
 
84 days 
from 
Day 1  
(± 7 days) 
Day 99 
 
14 days 
from 
Visit 6 
(± 4 days
) 
 
 
C-SSRS 
X 
X 
X 
X 
X 
 
Review of concomitant 
medications 
X 
X 
X 
X 
X 
X 
Review of AEs 
X 
X 
X 
X 
X 
X 
MSSS-88 
X 
 
 
  
X 
 
MUS 
 
 
 
 
X 
 
Clinical laboratory blood 
sampling (hematology and 
biochemistry) 
X 
 
X 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
X 
 
X 
 
Dipstick pregnancy test (if 
appropriate) 
X 
 
 
 
X 
 
eDiary completion 
X 
X 
X 
X 
X 
X 
IMP dosing training 
X 
 
 
 
 
 
IMP collection and 
compliance review 
 
X 
X 
X 
X 
 
IMP dispensing 
X 
X 
X 
X 
 
 
AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; COVID-19 = coronavirus 
disease 2019; ECG = 12-lead electrocardiogram; IMP = investigational medicinal product; 
MSSS-88 = Multiple Sclerosis Spasticity Scale; MUS = Medication Use Survey 
Notes:  
[1]  During pandemic conditions only, sites may use local laboratories for safety assessments noted 
above, following consultation with the Sponsor.  
[2]  Methodology for some assessments performed at locations other than the site (e.g., blood pressure 
cuff) will need to be pre-approved.   
[3]  Under pandemic conditions, an initial IMP dosing training would be given at the site at Visit 1, 
with a refresher training given remotely at Visit 2.  A training video would be supplied for IMP 
dosing training should pandemic conditions begin between Visits 1 and 2. 
[4]  In cases where patients are not able to attend study visits due to COVID-19/other pandemic 
restrictions, the investigator will discuss with the Sponsor potential mitigation approaches for IMP 
dispensing and collection. 
[5]  Data for the day of Visit 7 should not be entered in the electronic diary.  Site staff will confirm that 
data that relates to the day prior to attending the site for Visit 7 has been entered in the electronic 
diary prior to completion of the trial. 
 
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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 pre-existing condition, that 
occurs following Screening (Visit 1) and at any point up to the post-treatment Safety 
Follow-up Visit (Visit 7), which may or may not be considered 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 pre-trial existing conditions or elective procedures 
are not AEs.  An exception may be if the patient has an AE during hospitalization that 
prolongs his/her scheduled hospital stay, in which case it would be considered an 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, 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 classified as serious, i.e., an SAE, when the event falls into 1 of the 
following criteria: 
• Results in death 
• Is life-threatening* 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is medically significant** 
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*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, or 
development of drug dependency or drug abuse.  In addition, a positive test result for 
COVID-19 is to be recorded as an SAE. 
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 reported in the eCRF within 24 hours of discovery or notification 
of the event (see APPENDIX 2).  The GW Pharmacovigilance Department (PVD) will 
be automatically notified that an SAE has been recorded.  Any additional information 
required for a case (follow-up of 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 7).  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 7 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 post-trial SAEs do not need to be 
recorded on the patient’s eCRF if editing rights to the eCRF have been removed due to 
final trial data lock.  The 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 sites 
and on the GW SAE report form. 
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12.4 
Pregnancy 
Any patient, or patient’s partner, who becomes pregnant while receiving the IMP, or 
within 3 months of the last dose of IMP, must be reported to the GW PVD using the GW 
Pregnancy Monitoring forms provided.  Where possible, the investigator should provide 
the outcome of the pregnancy. 
All pregnancies must be recorded in the eCRF within 24 hours of becoming aware.  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 where data is entered in EDC. 
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 pre-treatment event worsens in severity following the first dose 
of IMP, a new event record should be entered into the eCRF. 
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: 
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• Medical and disease history 
• Lack of efficacy/worsening of treated condition 
• Concomitant or previous treatment 
• Withdrawal of IMP 
• 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 7), whether or 
not attributed to the 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 
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, as 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. 
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C) Outcome 
The outcome of the event must be recorded accurately and classified into 1 of the 
following categories: 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Not Recovered/Not Resolved 
• 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 classified as follows: 
• Dose Not Changed 
• Dose Reduced 
• Drug Interrupted 
• Drug Withdrawn 
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 7, after the trial. 
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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 discontinuation of 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 for any patient 
after randomization who meets the criteria for the following selected laboratory 
parameters:  
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
• ALT or AST > 8 × ULN 
• ALT or AST > 5 × ULN for more than 2 weeks 
• ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5) 
These reports must be sent to the GW PVD via email within 24 hours of becoming aware 
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 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 
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 in this way until all abnormalities have normalized (in the 
investigator’s opinion) or returned to the baseline state. 
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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 non-clinical 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.  They 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. 
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 
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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 
446 patients will be randomized to the nabiximols or placebo treatment arms on a 
1:1 basis. 
The following assumptions have been used for the sample size: 
• Common standard deviation of 6.5 for the change from baseline in average daily 
spasm count for nabiximols and placebo treatment arms 
• True mean difference of −2 between the mean change from baseline in average 
daily spasm count in the nabiximols treatment arm compared to the placebo 
treatment arm 
Using the above assumptions, the total sample size of 446 patients (223 patients per 
treatment arm) will have 90% power to detect a difference between treatment arms in 
change from baseline in average spasm count of −2 using a 2-sided hypothesis test at the 
5% significance level. 
13.2 
Interim Analysis 
No formal interim analysis is planned. 
13.3 
Analysis Sets 
The following analysis sets will be used for the statistical analysis: 
Full Analysis Set 
• All patients who sign the informed consent, and are randomized will be included 
and analyzed according to their randomized treatment arm 
• The full analysis set (FAS) is the primary analysis set for all efficacy endpoints 
Safety Analysis Set 
• All patients who receive 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.   
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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.   
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, standard deviation, median, minimum, and maximum.  
Categorical variables will be summarized showing the number and percentage of patients 
falling in each category. 
For the primary endpoint of spasm count and the exploratory endpoint of 11-point NRS 
spasm severity score, baseline is defined as the average of all data collected between 
Visit 1 and the day before Visit 2. 
For the exploratory endpoint of 11-point NRS spasticity score, baseline is defined as the 
average of the last 7 days of electronic diary entries prior to randomization. 
For clinic-based endpoints, baseline is defined as the last record or measure collected 
prior to the first dose of IMP. 
13.5 
Accountability and Background Characteristics 
13.5.1 
Enrollment and Disposition 
All patients (signed informed consent, 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 (as per local data protection laws), and other demographic or baseline 
characteristics will be summarized by treatment arm using appropriate summary 
statistics.  There will be no formal comparison of baseline data. 
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13.5.3 
Medical History 
Previous and current medical conditions will be coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class 
(SOC) and preferred term (PT) by treatment arm. 
13.5.4 
Concomitant Medication 
Concomitant medications taken prior to and during the trial will be summarized by 
treatment arm, medication class, and active ingredients. 
13.6 
Endpoints and Statistical Methods 
The primary endpoint will be analyzed as detailed in Section 13.6.1.  The secondary 
endpoints will be analyzed as detailed in Section 13.6.2.  The exploratory endpoints will 
be analyzed as detailed in Section 13.6.3.  PK data will be summarized as detailed in 
Section 13.6.4.  Safety endpoints will be summarized as detailed in Section 13.6.5. 
13.6.1 
Primary Endpoint 
The primary endpoint is the change from baseline in average daily spasm count (the 
average daily spasm count from Days 57 to 84 compared to the average daily spasm 
count for the baseline period) for all randomized patients regardless of treatment 
compliance. 
The average daily spasm count will be calculated for the baseline period and each 28-day 
period corresponding to Days 1 to 28, Days 29 to 56, and Days 57 to 84.  The change 
from baseline for average daily spasm count will be calculated for Days 1 to 28, Days 29 
to 56, and Days 57 to 84. 
Average daily spasm count for each period is defined as follows: 
 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑓𝑓𝑓𝑓𝑓𝑓 𝑡𝑡ℎ𝑒𝑒 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝑤𝑤ℎ𝑖𝑖𝑖𝑖ℎ 𝑡𝑡ℎ𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑡𝑡ℎ𝑒𝑒 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 
For post-randomization data, the average daily spasm count over the 28-day period will 
only be calculated if there are ≥ 15 days of non-missing data and < 10 consecutive days 
of missing data.  If there are < 15 days of non-missing data or ≥ 10 consecutive days of 
missing data then the average daily spasm count for the 28-day period will be set to 
missing. 
The average daily spasm count and change from baseline will be summarized by 
treatment for each 28-day period. 
The change from baseline will be analyzed using mixed model repeated measures 
(MMRM), using data for each 28-day period.  The model will include baseline average 
daily spasm count, prior cannabis use, region (US versus non-US), period, treatment arm, 
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period by treatment arm interaction, and period by baseline interaction as fixed effects.  
Period repeated within each patient will be included as a repeated effect.  Denominator 
degrees of freedom adjustment will be performed using the Kenward-Roger method.  
The within-patient correlation structure will be modelled using an unstructured 
covariance matrix.  If the model does not converge the following structures will be used 
in order of preference Toeplitz, first-order autoregressive and Compound symmetry. 
The least squares mean estimates for each treatment arm and period, along with the 
standard error and 95% confidence intervals (CIs), will be presented.  In addition, 
estimates of the treatment difference at each period in change from baseline will be 
presented along with standard errors of the difference and 95% CIs.  The primary 
comparison is the estimate of the treatment difference for the Days 57 to 84 period. 
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 along with other further 
details on the statistical analysis. 
13.6.1.1 
Sensitivity Analyses for the Primary Efficacy Analysis 
The following sensitivity analysis will be conducted for the primary endpoint to assess 
the impact on the primary estimand:  
• MMRM using multiple imputation to impute missing data under the missing not 
at random (MNAR) assumption.  MMRM assumes that missing data are missing 
at random (MAR), a pattern mixture model with control-based imputation using 
multiple imputation methodology will be used to assess the impact of MNAR on 
the MAR assumption.  Further details of this analysis will be specified in the 
SAP. 
13.6.1.2 
Supplemental Analyses 
• Primary efficacy analysis repeated for the PP analysis set 
Full details of the sensitivity and supplemental analyses and any further analyses deemed 
appropriate will be provided in the SAP. 
13.6.2 
Secondary Endpoint(s) 
The secondary efficacy endpoints are as follows: 
• Change from baseline in total score of the MSSS-88 at Visit 6 
Other secondary endpoints: 
• To evaluate the safety and tolerability of nabiximols 
To evaluate the PK of nabiximols 
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Total score of MSSS-88 will be analyzed using the MMRM methods used for the 
primary endpoint described in Section 13.6.1, using visit instead of period.  Patients who 
withdraw from the trial are required to complete the procedures scheduled for Visit 6 at 
the time of withdrawal.  For these patients, their Visit 6 data will be assigned to the 
nearest post-baseline Visit (for which the assessment is scheduled to be performed) based 
on the trial day of the visit.  Further details will be specified in the SAP. 
To control for Type 1 error, the primary endpoint and secondary efficacy endpoint will be 
tested hierarchically, starting with the primary endpoint, then the change from baseline in 
total score of MSSS-88.  No additional adjustments for multiplicity will be made for the 
exploratory endpoints. 
13.6.3 
Exploratory Endpoints 
The exploratory endpoints are as follows: 
• Change from baseline in the 8 subscale scores of the MSSS-88 at Visit 6 
• Change from baseline in average daily 11-point NRS spasm severity score to 
Days 57 to 84 
• Change from the last 7 days of baseline in average daily 11-point NRS spasticity 
score to Days 78 to 84 
• Change from baseline in the SF-36 total score at Visit 6 (Day 85) 
• Change from baseline in T25FW (measured in seconds) test at Visit 6 (Day 85) 
The NRS and MSSS-88 endpoints will be analyzed using the methods used for the 
primary endpoint described in Section 13.6.1 and secondary endpoints described in 
Section 13.6.2, respectively. 
The T25FW and SF-36 endpoints will be analyzed using analysis of covariance models 
with baseline as a covariate and treatment, prior cannabis use and region (US versus non-
US) effects. 
Each endpoint will be summarized by treatment arm and visit/period. 
13.6.4 
Pharmacokinetics 
Plasma concentrations 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 visit together with any estimates of PK parameters. 
This data will undergo a population PK analysis and will be presented in a stand-alone 
report. 
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13.6.5 
Safety 
The safety endpoints are listed below and will be compared with placebo as detailed in 
the following subsections:  
• Frequency of TEAEs 
• Change from baseline to each assessment timepoint by treatment arm for the 
following: 
− Clinical laboratory tests 
− Vital signs 
− 12-lead ECGs 
•  Columbia-Suicide Severity Rating Scale (C-SSRS) at screening, and at each 
subsequent timepoint with reference to the last assessment (since last visit) 
13.6.5.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized. 
13.6.5.2 
Adverse Events 
AEs will be coded according to the MedDRA. 
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: 
• All-causality TEAEs 
• Treatment-related TEAEs 
• All-causality TEAEs by maximal severity 
• All-causality serious TEAEs 
• Treatment-related serious TEAEs 
• TEAEs reported as leading to permanent cessation of IMP 
• Fatal TEAEs 
13.6.5.3 
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 
the numbers of patients with values outside the normal range.  Changes from baseline to 
each visit will be summarized. 
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13.6.5.4 
Vital Signs, 12-lead Electrocardiogram, Physical Examination, 
and Other Safety Data 
Vital signs, 12-lead ECG, and C-SSRS data will be summarized for the safety analysis 
set at screening, baseline, and at each time point during the treatment period using 
appropriate summary statistics, as applicable.  Changes in vital signs from baseline to the 
End of Treatment Visit or Withdrawal Visit (Visit 6) will also be summarized. 
13.6.6 
Handling of Missing Data 
Analyses using MMRM account for missing data under the assumption that the missing 
data are missing at random.  In addition, for the primary endpoint, a sensitivity analysis is 
proposed to impute missing data under the missing not at random assumption. 
Further details on handling of missing data will be provided in the SAP. 
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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 Harmonised 
Guideline:  Integrated Addendum to ICH E6(R1):  Guideline for GCP 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 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. 
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. 
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The investigator will be responsible for obtaining annual 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 
Pre-trial 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: 
• Signed and dated protocol signature page 
• Copy of IRB/IEC-approved ICF (including version number and date) and other 
patient information material 
• Copy of the IRB/IEC approval of the protocol, ICF (including version number 
and date), and other patient information material 
• Up-to-date curricula vitae and medical licenses (as per local regulations) of the PI 
and all subinvestigators 
• 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 Harmonised Guideline: 
Integrated Addendum to ICH E6(R1):  Guideline for GCP E6(R2), where the EU 
Clinical Trials and GCP Directives do not apply 
• Signed and dated laboratory normal ranges and documentation of laboratory 
certification (or equivalent) unless using central laboratory arranged by GW 
• Signed and dated clinical trial agreement (including patient/investigator indemnity 
insurance and financial agreement) 
• Form FDA 1572, if required 
• Drug Enforcement Administration license (where applicable) 
• 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. 
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 ICF, should be kept in strict confidence by the 
investigator. 
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In compliance with the FDA regulations relating to GCP and clinical trials and the EU 
Clinical Trials Directive/ICH Harmonised Guideline: Integrated Addendum to ICH 
E6(R1):  Guideline for GCP 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/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 will 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 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 Harmonised Guideline:  Integrated Addendum to ICH E6(R1):  Guideline for GCP 
Topic R6(R2), Section 8.2), suitable for inspection at any time by representatives from 
GW and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed eCRFs, ICFs, and supporting copies of source 
documentation 
• Trial files containing the protocol with all amendments, IB, copies of pre-trial 
documentation (see Section 15.4), and all correspondence to and from the 
IRB/IEC and GW 
• Enrollment log of all patients who consented to take part in the trial 
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• 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) 
• 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 upon 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 
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. 
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To ensure the quality of clinical data across all patients and trial 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 Harmonised Guideline: 
Integrated Addendum to ICH E6(R1): Guideline for GCP 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 Guideline: 
Integrated Addendum to ICH E6(R1): Guideline for GCP 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 Harmonised 
Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP 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. 
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. 
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 96 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
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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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 97 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
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 Brochure:  Sativex Oromucosal Spray.  GW Pharma Ltd.  Edition 22.1 
and Addendum 1, January 2020. 
16 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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SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 98 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
17 Angst F, Aeschlimann A, Stucki G.  Smallest detectable and minimal clinically 
important differences of rehabilitation intervention with their implications for 
required sample sizes using WOMAC and SF-36 quality of life measurement 
instruments in patients with osteoarthritis of the lower extremities.  Arthritis and 
Rheum.  2001;45:384–91. 
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EudraCT Number: 2019-002623-14 
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Confidential 
Page 99 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
 Appendix 1 
SCHEDULE OF ASSESSMENTS 
 
Screening  
Treatment Period 
Safety Follow-up 
Period  
Visit  
1 
2 
3 
4 
5 
6 
7 
Day Number 
(Visit Window) 
Days -28  
Day 1/Randomizati
on1 
(+2) 
Day 15 
 
14 days 
from 
Day 1 
(± 3 days) 
Day 29 
 
28 days 
from 
Day 1 
(± 3 days) 
Day 57 
 
56 days 
from  
Day 1 
(± 7 days) 
End of 
Treatment 
/Early 
Withdrawal  
Day 85 
 
84 days from 
Day 1  
(± 7 days) 
Day 99 
 
14 days from 
Visit 6 
(± 4 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 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X2 
X 
 
 
 
X 
 
Examination of oral mucosa 
X 
X 
X 
X 
X 
X 
 
Body weight measurement 
X 
X 
 
X 
 
X 
 
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EudraCT Number: 2019-002623-14 
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Confidential 
Page 100 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
 
Screening  
Treatment Period 
Safety Follow-up 
Period  
Visit  
1 
2 
3 
4 
5 
6 
7 
Day Number 
(Visit Window) 
Days -28  
Day 1/Randomizati
on1 
(+2) 
Day 15 
 
14 days 
from 
Day 1 
(± 3 days) 
Day 29 
 
28 days 
from 
Day 1 
(± 3 days) 
Day 57 
 
56 days 
from  
Day 1 
(± 7 days) 
End of 
Treatment 
/Early 
Withdrawal  
Day 85 
 
84 days from 
Day 1  
(± 7 days) 
Day 99 
 
14 days from 
Visit 6 
(± 4 days) 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Postural changes in vital signs 
X 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
X 
 
X 
 
Clinical laboratory blood 
sampling (hematology and 
biochemistry) 
X 
X 
 
X 
 
X 
 
Dipstick urinalysis 
X 
 
 
 
 
X 
 
Urine drug screen (including 
THC)3 
X 
X 
 
 
 
 
 
Serum/urine pregnancy test (if 
appropriate)4 
X 
X 
 
 
 
X 
 
Blood THC test 
X 
 
 
 
 
 
 
PK blood sampling (IMP)5 
 
X 
X 
X 
X 
X 
 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 101 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
 
Screening  
Treatment Period 
Safety Follow-up 
Period  
Visit  
1 
2 
3 
4 
5 
6 
7 
Day Number 
(Visit Window) 
Days -28  
Day 1/Randomizati
on1 
(+2) 
Day 15 
 
14 days 
from 
Day 1 
(± 3 days) 
Day 29 
 
28 days 
from 
Day 1 
(± 3 days) 
Day 57 
 
56 days 
from  
Day 1 
(± 7 days) 
End of 
Treatment 
/Early 
Withdrawal  
Day 85 
 
84 days from 
Day 1  
(± 7 days) 
Day 99 
 
14 days from 
Visit 6 
(± 4 days) 
 
 
Electronic daily diary 
Spasm count6 
X 
X 
X 
X 
X 
X 
X7 
11-point NRS for 
spasm severity6 
X 
X 
X 
X 
X 
X 
X7 
11-point NRS for 
spasticity6 
X 
X 
X 
X 
X 
X 
X7 
Use of antispasticity 
medications6 
X 
X 
X 
X 
X 
X 
X7 
IMP dosing record6 
 
X 
X 
X 
X 
X 
 
Electronic Clinical 
Outcome Assessments 
MSSS-88 
 
X 
 
 
X 
X 
 
C-SSRS8 
X 
X 
X 
X 
X 
X 
 
SF-36 
 
X 
 
 
 
X 
 
MUS 
 
 
 
 
 
X 
 
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EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 102 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
 
Screening  
Treatment Period 
Safety Follow-up 
Period  
Visit  
1 
2 
3 
4 
5 
6 
7 
Day Number 
(Visit Window) 
Days -28  
Day 1/Randomizati
on1 
(+2) 
Day 15 
 
14 days 
from 
Day 1 
(± 3 days) 
Day 29 
 
28 days 
from 
Day 1 
(± 3 days) 
Day 57 
 
56 days 
from  
Day 1 
(± 7 days) 
End of 
Treatment 
/Early 
Withdrawal  
Day 85 
 
84 days from 
Day 1  
(± 7 days) 
Day 99 
 
14 days from 
Visit 6 
(± 4 days) 
 
 
Spasm count training 
X 
X 
X 
X 
X 
X 
X 
T25FW 
 
X 
 
 
 
X 
 
IMP dosing training 
 
X 
 
 
 
 
 
IMP collection and 
compliance review 
 
 
X 
X 
X 
X 
 
IMP dispensing9 
 
X 
X 
X 
X 
 
 
C-SSRS = Columbia-Suicide Severity Rating Scale; COVID-19 = coronavirus disease 2019; ECG = 12-lead electrocardiogram; FSH = follicle stimulating 
hormone; IMP = investigational medicinal product; MSSS-88 = Multiple Sclerosis Spasticity Scale; MUS = Medication Use Survey; NRS = Numerical 
Rating Scale; PK = pharmacokinetics; SF-36 = 36-Item Short Form Health Survey; T25FW = Timed 25-Foot Walk; THC = Δ9-tetrahydrocannabinol. 
1  Visit 2 will occur 28 days after Visit 1.  A visit window of +2 days is permitted but it is preferred that the visit is performed on the scheduled visit day, 
where possible. 
2  A comprehensive physical examination, including an assessment of height, will be completed at Screening (Visit 1) only, subsequent physical examinations 
will be symptom-directed. 
3 A positive urine drug screen at Visit 1or pre dose at Visit 2 for illicit drugs may be repeated locally at the investigator’s discretion.  Urine drug tests must 
not be performed once the patient has received IMP  
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Study Code: GWSP18023 
SPONSOR: GW PHARMA LIMITED 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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Page 103 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
4  Serum pregnancy test at Visits 1 and 6; urine pregnancy test before randomization at Visit 2.  Note that pregnancy testing is not required for females 
postmenopausal for ≥ 12 consecutive months with a FSH ≥ 30 mIU/mL.  
5  On the day before PK blood sampling, patients will be prompted to record whether they started their morning and evening doses of IMP within 30 minutes 
of a meal.  During the visits, the exact time of PK blood sampling and the time of the patient’s snacks and meals should be recorded.  There will be 
2 options for the collections of PK samples:  
Option 1: For patients choosing the sparse PK sampling option, blood samples will be taken as follows: Visit 2 – 1 sample predose; Visits 3, 4, 5, and 6 – 1 
sample collected at any time during the visit.  Option 2: For patients choosing the semi-intensive PK sampling option, blood samples will be taken as 
follows: Visit 2 – 1 sample predose; At 1 visit (either Visit 3, 4, or 5), – 1 sample predose (i.e., prior to administration of IMP at the investigational site), 
1 sample between 2 and 3 hours postdose, 1 sample between 4 and 6 hours postdose, and 1 sample between 6 and 8 hours postdose.  There must be a 
minimum period of at least 2 hours between each of the 4 blood-sampling time-points.  The predose sample will be taken prior to the morning IMP dose.  
On the day of the semi-intensive PK sampling, the patient must bring their study medication with them to the visit and not take their morning IMP dose 
until instructed to do so by the site staff. 
6  Patients will record their spasm count, 11-point NRS spasm severity score, 11-point NRS spasticity score, and use of antispasticity medications in an 
electronic diary once daily, around the same time of day, preferably in the evening before retiring to sleep, during the baseline period prior to Visit 2 and 
throughout the trial until Visit 7.  Patients are to be instructed to start completing their electronic diary in the evening of their screening visit.  IMP dosing 
will be recorded by the patient in the electronic diary from Visits 2 through 6. 
7  Data for the day of Visit 7 should not be entered in the electronic diary.  Site staff will confirm that data that relates to the day prior to attending the site for 
Visit 7 has been entered in the electronic diary prior to completion of the trial. 
8  C-SSRS: ‘Baseline’ version should be used at Visit 1, and ‘Since last visit’ version should be used at all subsequent visits. 
9  In cases where patients are not able to attend study visits due to the presence of an infectious disease or other transmissible condition (such as 
COVID-19/other pandemic restrictions), the investigator will discuss with the Sponsor potential mitigation approaches for IMP dispensing and collection. 
 
 
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SPONSOR: GW PHARMA LIMITED 
Study Code: GWSP18023 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 104 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
 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 — SAE 
Reporting: 
Email: 
 
Fax: 
 
USA Toll-free Fax: 
 
Tel: 
 
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: 
GW 
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 CROs 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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SPONSOR: GW PHARMA LIMITED 
Study Code: GWSP18023 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
Confidential 
Page 105 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
 Appendix 3 
QUESTIONNAIRES/ASSESSMENTS 
At the time of protocol finalization, questionnaire/assessment licensing has not yet 
been obtained.  Copies of the questionnaires/assessments will be made available to all 
investigators. 
 
 
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SPONSOR: GW PHARMA LIMITED 
Study Code: GWSP18023 
EudraCT Number: 2019-002623-14 
Protocol V5 01Jun2021 
 
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Page 106 of 106 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
 Appendix 4 
PROHIBITED MEDICATIONS SOLELY 
METABOLIZED BY UGT1A9 AND UGT2B7 
Examples of medications that are solely metabolized by UGT1A9 and UGT2B7 and 
prohibited for the duration of the trial are provided in the sections below.  
Appendix 4.1 
Prohibited Medications Metabolized by UGT1A9 
• Flavopiridol 
• Propofol 
Appendix 4.2 
Prohibited Medications Metabolized Solely by UGT2B7 
• Benoxaprofen 
• Carbamazepine 
• Codeine 
• Cyclosporin A 
• Epirubicin 
• Indomethacin 
• Tacrolimus 
• Tiaprofenic acid 
• Zaltoprofen 
• Zomepirac 
• Zidovudine 
GWSP18023___V4-PV5_01 Jun 2021_Protocol Amendment_ | VV-TMF-104819
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SAP_001.pdf: 
GW Pharma Limited 
Statistical Analysis Plan for Protocol GWSP18023 (22-MAR-2022) 
CONFIDENTIAL  
Page 1 of 78 
 
 
Statistical Analysis Plan (SAP) 
Protocol Title: 
A Double-blind, Randomized, Placebo-controlled, Parallel-group Trial 
of the Efficacy and Safety of Nabiximols Oromucosal Spray as Add-on 
Therapy in Patients with Spasticity Due to Multiple Sclerosis 
Study Code: 
GWSP18023 
Protocol Version No. /Date: 
V5.0 / 01JUN2021 
CRF Version No. / Date: 
V3.0 / 05NOV2021 
SAP Version No. / Date: 
V1.0 / 22MAR2022 
 
 Approvals 
Author / Title: 
 / Senior Manager, Biostatistics 
Signature / Date: 
NA - approved with eSignature 
 
Reviewer 
Biostatistician / Title: 
 / Associate Director, Biostatistics 
Signature / Date: 
NA - approved with eSignature 
 
Medical Monitor: 
 / Medical Director 
Signature / Date: 
NA - approved with eSignature 
 
 
GWSP18023___V1.0_22 Mar 2022_Statistical Analysis Plan_ | VV-TMF-117088
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CCI
CCI
CCI


GW Pharma Limited 
Statistical Analysis Plan for Protocol GWSP18023 (22-MAR-2022) 
CONFIDENTIAL  
Page 2 of 78 
 
 Change History 
Version/Date 
Change Log 
1.0 / 22MAR2022 
Created as new 
 
 
 
 
 
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Statistical Analysis Plan for Protocol GWSP18023 (22-MAR-2022) 
CONFIDENTIAL  
Page 3 of 78 
 
 Table of Contents, List of Tables and Figures  
3.1 Table of Contents 
 Approvals ............................................................................................................................................... 1 
 Change History ....................................................................................................................................... 2 
 Table of Contents, List of Tables and Figures ........................................................................................ 3 
3.1 Table of Contents ................................................................................................................................ 3 
3.2 List of Tables ....................................................................................................................................... 5 
3.3 List of Figures ...................................................................................................................................... 5 
 Purpose 
............................................................................................................................................... 6 
 Scope 
............................................................................................................................................... 6 
 Introduction ............................................................................................................................................. 6 
6.1 Timings of Analyses ............................................................................................................................ 6 
6.2 Changes from Protocol ....................................................................................................................... 6 
 Study Objectives ..................................................................................................................................... 6 
 Study Design ........................................................................................................................................... 6 
8.1 General Design ................................................................................................................................... 6 
8.2 Sample Size Considerations ............................................................................................................... 8 
8.3 Randomization .................................................................................................................................... 8 
8.4 Adjudication Committee ...................................................................................................................... 8 
 Study Endpoints, Variables, and Covariates .......................................................................................... 9 
9.1 Overview ............................................................................................................................................. 9 
9.2 Predetermined Covariates, Prognostic Factors, and other Analyzed Factors .................................. 12 
9.3 Subgroups ......................................................................................................................................... 12 
9.4 Population Sets ................................................................................................................................. 13 
9.4.1 Treatment Arm ........................................................................................................................... 13 
9.4.2 Analysis Sets .............................................................................................................................. 14 
9.4.3 Subsets ...................................................................................................................................... 14 
 Conventions and Derivations .............................................................................................................. 15 
10.1 Source of Key Dates ....................................................................................................................... 15 
10.2 Reference Day, Study Day, Study Periods and Analysis Visit Window .......................................... 15 
10.2.1 Reference Day and Study Day ................................................................................................ 15 
10.2.2 Study Periods ........................................................................................................................... 15 
10.2.3 Target Days and Analysis Visit Windows ................................................................................. 16 
10.2.4 Reporting of Longitudinal Safety Assessments ....................................................................... 18 
10.3 Rescreened Patients Data Handling ............................................................................................... 18 
10.4 Baseline .......................................................................................................................................... 18 
10.4.1 Diary Efficacy Based Endpoint ................................................................................................. 18 
10.4.2 Clinic Based Endpoint .............................................................................................................. 18 
10.5 Change from Baseline..................................................................................................................... 18 
10.6 Percent Change from Baseline ....................................................................................................... 19 
10.7 Time Conversion ............................................................................................................................. 19 
10.8 Patient Disposition and Treatment Duration ................................................................................... 19 
10.9 IMP Dosing – Number of Sprays Summary .................................................................................... 20 
10.10 Compliance, Optimized Dose and Drug Accountability ................................................................ 20 
10.11 Age ................................................................................................................................................ 21 
10.12 Body Mass Index ........................................................................................................................... 21 
10.13 Disease History ............................................................................................................................. 22 
10.14 Renal Function Formula ................................................................................................................ 22 
10.15 Prior and Concomitant Medication Start/Stop Date Imputation Rule ............................................ 23 
10.16 Mobile Health Platform Data Handling .......................................................................................... 23 
10.17 Daily Spasm Count ....................................................................................................................... 24 
10.18 Multiple Sclerosis Spasticity Scale (MSSS-88) ............................................................................. 25 
10.19 Numerical Rating Scale (NRS) for Spasm Severity ...................................................................... 26 
10.20 Numerical Rating Scale (NRS) for Spasticity ................................................................................ 26 
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CONFIDENTIAL  
Page 4 of 78 
 
10.21 Timed 25-Foot Walk ...................................................................................................................... 26 
10.22 36-Item Short Form Health Survey ............................................................................................... 27 
10.23 Adverse Events ............................................................................................................................. 28 
10.23.1 Start Date Imputation ............................................................................................................. 28 
10.23.2 COVID-19 Adverse event....................................................................................................... 28 
10.23.3 Time to First Onset of AE ....................................................................................................... 29 
10.23.4 AE Duration ............................................................................................................................ 29 
10.24 Laboratory Data ............................................................................................................................ 29 
10.24.1 Strip-sign Handling ................................................................................................................. 29 
10.24.2 Minimal, Maximal and Most Extreme Value for Laboratory Measurements .......................... 29 
10.25 Columbia Suicide Severity Rating Scale (C-SSRS) ..................................................................... 30 
 Interim Analyses .................................................................................................................................. 31 
 Statistical Methods .............................................................................................................................. 31 
12.1 Patient Disposition .......................................................................................................................... 32 
12.2 Demographic and Baseline Characteristics .................................................................................... 33 
12.2.1 Demographics Characteristics ................................................................................................. 33 
12.2.2 Baseline Physical examination ................................................................................................ 34 
12.2.3 Baseline Vital Signs ................................................................................................................. 34 
12.2.4 Medical History ......................................................................................................................... 34 
12.2.5 Disease Characteristics ........................................................................................................... 34 
12.2.6 Baseline Efficacy Endpoints ..................................................................................................... 35 
12.2.7 Baseline Safety Endpoints ....................................................................................................... 36 
12.3 Treatments ...................................................................................................................................... 36 
12.3.1 Extent of IMP Exposure ........................................................................................................... 36 
12.3.2 Prior, Concomitant and Prohibited Medications ....................................................................... 37 
12.4 Important Protocol Deviations ......................................................................................................... 40 
12.5 Efficacy Analyses ............................................................................................................................ 43 
12.5.1 Hypothesis Testing Strategy and Multiplicity ........................................................................... 43 
12.5.2 Primary Endpoint ...................................................................................................................... 43 
12.5.3 Secondary Efficacy Endpoint ................................................................................................... 50 
12.5.4 Exploratory Efficacy Analyses .................................................................................................. 53 
12.6 Quality of life ................................................................................................................................... 55 
12.6.1 36-items Short Form Survey (SF-36) ....................................................................................... 55 
12.7 PK Analyses .................................................................................................................................... 55 
12.8 Safety Analyses .............................................................................................................................. 56 
12.8.1 Adverse Events ........................................................................................................................ 56 
12.8.2 Death, Serious Adverse Events and Other Significant Adverse Events .................................. 58 
12.8.3 Laboratory Data ....................................................................................................................... 58 
12.8.4 Vital Signs ................................................................................................................................ 60 
12.8.5 Physical Examinations, ECGs, and other Observations Related to Safety ............................. 61 
12.8.6 Monitoring of Drug Abuse Liability ........................................................................................... 63 
 References .......................................................................................................................................... 64 
 Glossary of Abbreviations ................................................................................................................... 65 
 
Scheduled Clinical Laboratory Parameters ......................................................................... 69 
 
Unscheduled Clinical Laboratory Parameters ..................................................................... 70 
 
Toxicity Criteria for Laboratory Hematology and Coagulation Parameters based on CTCAE 
version 5.0 
............................................................................................................................................. 72 
 
Toxicity Criteria for Laboratory Biochemistry and Urinalysis Parameters based on CTCAE 
version 5.0 
............................................................................................................................................. 73 
 
Prohibited Medications Solely Metabolized by UGT1A9 and UGT2B7 and Determination 
Criteria 
............................................................................................................................................. 75 
 
Prohibited Medications Strong CYP3A4 Inducers and Determination Criteria ................... 76 
 
Other Prohibited Medications and Determination criteria ................................................... 77 
 
Medications used in MS and Determination Criteria ........................................................... 78 
 
 
 
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3.2 List of Tables 
Table 9.1-1 Objectives and Endpoints .......................................................................................................... 9 
Table 9.3-1 Subgroups Applied to Patient Disposition ............................................................................... 12 
Table 9.3-2 Subgroup analyses of Primary Efficacy Endpoint .................................................................... 13 
Table 9.3-3 Subgroups Applied to Safety Analysis ..................................................................................... 13 
Table 9.4-1 Analysis Set Definitions and Abbreviations ............................................................................. 14 
Table 9.4-2 Subset Definitions and Abbreviations ...................................................................................... 14 
Table 10.2-1 Longitudinal Efficacy and QoL Assessment – Target Day and Analysis Visit Window ......... 16 
Table 10.2-2 Semi-intensive PK Draw Assessment – Target Day and Time and Visit/Time Window ....... 17 
Table 10.2-3 Sparse PK Draw Assessment – Target Day and Analysis Visit Window .............................. 17 
Table 10.15-1 Imputation Rules for Partial Medication Dates .................................................................... 23 
Table 10.16-1 MHP data - Date Handling ................................................................................................... 24 
Table 10.18-1 Multiple Sclerosis Spasticity Scale - Missing Data Handling ............................................... 25 
Table 10.23-1 Imputation Rules for Partial Adverse Event Start Dates ...................................................... 28 
Table 12.4-1 List of Important Protocol Deviation Category ....................................................................... 41 
Table 12.4-2 List of Major Important Protocol Deviation Category ............................................................. 41 
Table 12.8-1 Hepatic Abnormality Criteria .................................................................................................. 59 
Table 12.8-2 Blood Pressures and Pulse Rate Abnormality Criteria .......................................................... 61 
Table 12.8-3 Weight Abnormality Criteria ................................................................................................... 61 
Table 12.8-4 ECG Abnormality Criteria ...................................................................................................... 62 
 
 
3.3 List of Figures 
 
Figure 8.1-1 Trial Design and Treatment Schematic .................................................................................... 7 
 
 
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 Purpose 
This Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Protocol GWSP18023 V5.0 dated 01JUN2021. 
 Scope 
This plan supplements the study protocol for statistical analysis related aspects. 
The SAP outlines the following: 
 
Study Objectives 
 
Study Design 
 
Estimands 
 
Applicable Study Definitions 
 
Statistical Methods  
 Introduction 
This SAP should be read in conjunction with the study protocol V5.0 01JUN2021 and Case Report Form 
(CRF) V3.0 05NOV2021. Changes to the protocol or CRF may necessitate updates to the SAP. 
Final approval of the SAP will occur prior to study unblinding. 
6.1 Timings of Analyses 
The primary analysis of safety, efficacy, and pharmacokinetics/pharmacodynamics will be performed 
following database lock and unblinding after all patients complete or discontinue study early. 
6.2 Changes from Protocol 
No change  
 Study Objectives 
An overview of objectives and endpoints is provided in Section 9.1. 
 Study Design 
8.1 General Design 
This multicenter, double-blind, placebo-controlled trial includes a 28-day baseline period, a 12week 
treatment period (comprising a 2-week titration phase and a 10-week maintenance phase), and a 2-week 
follow-up period. 
Eligible patients will enter a 28-day baseline period. During baseline, patients will maintain their optimized 
oral antispasticity medication regimen (that must include at least 1 of baclofen, tizanidine, or dantrolene) 
and record spasm count, 11-point NRS spasm severity score, 11-point NRS spasticity score, and use of 
antispasticity medications once daily, around the same time of day, preferably in the evening before retiring 
to sleep, using an electronic daily diary. At Visit 2 (Day 1), eligible patients will be randomized to either 
nabiximols or placebo in a 1:1 ratio. 
Patients will initiate investigational medicinal product (IMP) as a single spray in the evening on the first day 
of the titration phase. Patients will be advised to titrate IMP, beginning with 1 spray/day, to an optimized 
dose or to a maximum of 12 sprays/day over the first 14 days of treatment. Patients may leave a gap 
between sprays of approximately 15 minutes. Patients should continue at the same dose level achieved at 
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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. For the first 14 days of administering stable doses 
of IMP following titration, patients should be instructed to 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. No further dose adjustments should take place after 14 days unless advised by the investigator.  
Daily spasm count, the patient’s symptom experiences, functional outcomes, health-related quality of life, 
tolerability, and PK will be evaluated during the treatment period. 
Following randomization (Visit 2 [Day 1]), patients will attend the trial site on Visit 3 (Day 15),  
Visit 4 (Day 29), and Visit 5 (Day 57). The End of Treatment Visit (Visit 6) will occur on Day 85 (± 7 days). 
Patients who discontinue IMP early will be encouraged to continue (off treatment) in the trial and to complete 
all remaining trial procedures up to the End of Treatment/Early Withdrawal Visit (Visit 6 [Day 85]), where 
possible. 
A Safety Follow-up Visit (Visit 7 [Day 99]) will take place 14 (± 4) days after the End of Treatment Visit or 
Early Withdrawal Visit for all patients except those who discontinue IMP but complete scheduled trial visits. 
Patients who complete the trial will participate for a total of approximately 18 weeks (127 days), including 
the 28-day baseline period.  Patients will have a maximum duration of 85 (± 7) days on IMP. 
Approximately 65 sites (USA and Europe) are expected to participate in this trial. Additional trial sites may 
be used in order to supplement recruitment. Although no minimal number of patients are required to come 
from USA sites, the IRT was designed to make all efforts to have at least 100 US patients. 
The study overview is specified in Figure 8.1-1. 
The schedule of study events is specified in clinical protocol appendix 1. 
Figure 8.1-1 Trial Design and Treatment Schematic 
 
 
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8.2 Sample Size Considerations  
A total of 446 patients are planned to be randomized to the nabiximols or placebo treatment arms on a 1:1 
basis. 
The following assumptions have been used for the sample size: 
 
Common standard deviation of 6.5 for the change from baseline in average daily spasm count for 
nabiximols and placebo treatment arms 
 
True mean difference of −2 between the mean change from baseline in average daily spasm count in 
the nabiximols treatment arm compared to the placebo treatment arm 
Using the above assumptions, the total sample size of 446 patients (223 patients per treatment arm) will 
have 90% power to detect a difference between treatment arms in change from baseline in average spasm 
count of −2 using a 2-sided hypothesis test at the 5% significance level. 
8.3 Randomization 
Randomization will be conducted in the following manner: 
At Visit 2, in the morning of Day 1, eligible participants will be randomized by the Interactive Response 
Technology (IRT) using a pre-specified schedule generated and kept by Endpoint (IRT vendor), in a double-
blind manner to the nabiximols or placebo treatment arms on a 1:1 ratio, based on the stratification factors 
of region (USA versus non-USA) and prior cannabis use defined as any pattern of recreational or medicinal 
use, which would typically exclude isolated, unintentional, or passive exposures. 
The IRT will provide IMP kit numbers that contain the appropriate IMP (nabiximols or placebo) for 
dispensation to patients. 
At subsequent study visits, the investigator or designee will access the IRT to receive the corresponding kit 
numbers assigned to the participant for the purpose of dispensing IMP. 
8.4 Adjudication Committee 
A formal adjudication committee, blinded to treatment arm will classify triggered cases related to abuse 
potential, based on adverse events and drug accountability. 
A separate adjudication charter will define and describe the procedure for the handling, reporting, and 
classification of these events. 
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 Study Endpoints, Variables, and Covariates 
9.1 Overview 
An overview of objectives and endpoints is shown in Table 9.1-1. 
Table 9.1-1 Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Estimand(s) 
Primary Efficacy 
To establish the efficacy of nabiximols 
relative to placebo in reducing spasm 
count as part of the presentation of 
spasticity when used as adjunctive 
therapy in patients with MS who have 
not achieved adequate relief from other 
antispasticity agents 
Change from baseline in the average 
daily spasm count (from Days 57 to 84 
compared to the average daily spasm 
count for the baseline period) 
The primary efficacy estimand is defined as follows:  
 
Population: patients in the FAS with spasticity due 
to MS who have not achieved adequate relief from 
other antispasticity agents but have optimized 
treatment 
 
Endpoint: change from baseline in average daily 
spasm frequency count (from Days 57 to 84 
compared to the average daily spasm count for the 
baseline period) 
 
Treatment of interest: The randomized study 
treatment (nabiximols or placebo)  
 
Handling of intercurrent events: Intercurrent 
events of treatment compliance and changes of 
other antispasticity medications have been 
identified. A treatment policy strategy will be used 
for the handling of all intercurrent events. All 
observed values will be used regardless of 
occurrence of an intercurrent event.  
 
Summary Measure: mean difference in change 
from baseline in average daily spasm frequency 
count between patients randomized to nabiximols 
compared to patients randomized to placebo 
Secondary Efficacy 
To evaluate the effect of nabiximols 
relative to placebo using the following 
Change from baseline in total score of 
the MSSS-88 at Visit 6 
The secondary efficacy estimand is defined as follows: 
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patient-reported outcome measure of 
spasticity: 
 
The MS Spasticity Scale (MSSS-
88) total score 
 
Population: patients in the FAS with spasticity due 
to MS who have not achieved adequate relief from 
other antispasticity agents but have optimized 
treatment 
 
Endpoint: change from baseline to Visit 6 in MS 
Spasticity Scale (MSSS-88) total score 
 
Treatment of interest: The randomized study 
treatment (nabiximols or placebo)  
 
Handling of intercurrent events: Intercurrent 
events of treatment compliance and changes of 
other antispasticity medications have been 
identified. A treatment policy strategy will be used 
for the handling of all intercurrent events. All 
observed values will be used regardless of 
occurrence of an intercurrent event.  
 
Summary Measure: mean difference in change 
from baseline to Visit 6 in MS Spasticity between 
patients randomized to nabiximols compared to 
patients randomized to placebo. 
Safety 
To evaluate the safety and tolerability 
of nabiximols 
 
Frequency of treatment-emergent 
adverse events (AEs) 
 
Change from baseline to each 
assessment timepoint by treatment 
arm for the following: 
 
Clinical laboratory tests 
 
Vital signs 
 
12 lead electrocardiograms (ECGs) 
 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) at screening, and at 
each subsequent timepoint with 
reference to the last assessment 
(since last visit) 
Not applicable 
Pharmacokinetics 
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To evaluate the pharmacokinetics (PK) 
of nabiximols 
Plasma concentrations for 
Δ9-tetrahydrocannabinol (THC) and its 
relevant metabolites 
(11-hydroxy-Δ9-tetrahydrocannabinol [11-
OH-THC] and 11-nor-9-
carboxy-Δ9-tetrahydrocannabinol 
[11-COOH-THC]) and cannabidiol (CBD) 
and its relevant metabolites 
(7-hydroxy-cannabidiol [7-OH-CBD] and 
7-carboxy-cannabidiol [7-COOH-CBD]) at 
Visits 2 (predose), 3, 4, 5, and 6 
Not applicable 
Exploratory Efficacy 
To evaluate the effect of nabiximols 
relative to placebo using the following 
patient-reported outcome measures 
and clinician administered assessments 
of spasticity: 
 
The 8 MS Spasticity Scale (MSSS-
88) subscale scores 
 
The 11-point Numerical Rating 
Scale (NRS) for spasm severity 
 
The 11-point NRS for spasticity 
 
 Change from baseline in the 8 
subscale scores of the MSSS-88 at 
Visit 6 
 Change from baseline period in 
average daily 11-point NRS spasm 
severity score to Days 57 to 84 
 Change from the last 7 days of 
baseline in average daily 11-point 
NRS spasticity score to Days 78 to 84  
Not applicable 
To evaluate the effect of nabiximols 
relative to placebo on health-related 
quality of life (QoL), as reflected by the 
36-Item Short Form Health Survey (SF-
36) 
Change from baseline in the 36-Item 
Short Form Health Survey (SF-36) total 
score at Visit 6 
Not applicable 
To evaluate the effect of nabiximols 
relative to placebo on functional 
outcome as reflected by walking ability 
using the Timed 25-Foot Walk (T25FW) 
test 
Change from baseline in Timed 25-Foot 
Walk (T25FW) test at Day 85 Visit 6 
 
Not applicable 
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9.2 Predetermined Covariates, Prognostic Factors, and other Analyzed Factors 
The following factors will be adjusted as covariates: 
 
Treatment arm, which has two levels: nabiximols (coded as 1), and placebo (coded as 2) 
 
Randomization strata of “Prior cannabis use”, which has 2 levels: Yes (coded as Y) and No (coded 
as N) 
 
Randomization strata of region, which has two levels: USA (coded as 1) and non-USA (coded as 
2) 
 
Baseline (as continuous covariate) 
9.3 Subgroups 
 
Table 9.3-1 Subgroups Applied to Patient Disposition 
Group Variables 
Subgroup 
Comments 
Gender 
Male 
Female 
 
Age group 
<18 
≥ 18 to < 45 
≥ 45 to < 65 
 ≥ 65 
Depending on patient distribution, 
age groups may be differently 
defined 
Detailed derivation is given in 
Section 10.11 
Race 
White 
Black or African American 
Asian 
American India or Alaska Native 
Native Hawaiian or Other Pacific 
islander 
Other 
Depending on patient distribution; 
some 
races 
may 
be 
grouped 
together 
Randomization strata of prior 
cannabis use 
Yes 
No 
 
Number of current antispasticity 
medication 
0 
1 
2 
≥ 3 
 
Randomization strata of region  
USA 
Non-USA 
 
Country 
Poland 
Czech Republic 
Romania 
United Kingdom 
Ireland 
Canada 
New Zealand 
USA 
Depending on countries eventually 
participating into the study this list 
may be updated and grouping may 
be performed 
USA = United states of America 
 
 
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Table 9.3-2 Subgroup analyses of Primary Efficacy Endpoint 
Group variables 
Subgroup 
Gender 
Male 
Female 
Age group 
<45 
≥ 45 
Randomization strata of region 
USA 
Non-USA 
Randomization strata of prior cannabis use 
Yes 
No 
USA=United states of America 
 
Table 9.3-3 Subgroups Applied to Safety Analysis 
Group variables 
Subgroup 
Comments 
Gender 
Male 
Female 
 
Age group 
<18 
≥ 18 and < 45 
≥ 45 to < 65 
≥ 65 
Depending 
on 
patient  
distribution, age groups 
may 
be 
differently 
defined. 
Detailed 
derivation 
is 
given in Section 10.11 
Randomization strata of region 
USA 
Non-USA 
 
Randomization strata of prior cannabis use 
Yes 
No 
 
USA=United states of America 
9.4 Population Sets 
9.4.1 Treatment Arm 
The “as randomized” treatment arm is defined as the treatment arm allocated at randomization according 
to the randomization scheme (even if the treatment received is different). 
The “as treated” treatment arm also called “actual treatment arm” is defined as the longest duration of 
treatment received during the 12-week treatment period. 
 
 
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9.4.2 Analysis Sets 
 
Table 9.4-1 Analysis Set Definitions and Abbreviations  
Analysis Set 
Abbreviation (if 
applicable) 
Definition 
Screening 
Analysis Set 
 
 
All patients who signed the informed consent and have performed 
Visit 1 (Screening). 
Safety Analysis 
Set 
SAF 
All patients, from the Screening Analysis Set, who received at least 1 
dose of IMP in the trial.  Only patients for whom it has been confirmed 
that they did not take IMP will be excluded from the Safety Analysis 
Set, for example where this is reported as a protocol deviation 
Full Analysis Set 
FAS 
All patients from the SAF who signed the informed consent and are 
randomized by IRT. 
Pharmacokinetic 
Analysis Set 
PK Analysis Set 
All patients who have received at least 1 dose of nabiximols and 
provided sufficient bioanalytical data to calculate reliable (based on 
the judgement of the pharmacokineticist) estimates of the PK 
parameters of THC, CBD, and their metabolites.  For the purposes of 
biostatistics and programming team this will be patients who have 
taken at least one dose of nabiximols and have at least one PK 
parameter concentration and will be determined post unblinding; The 
final PK population being defined by the pharmacokineticist. 
9.4.3 Subsets 
 
Table 9.4-2 Subset Definitions and Abbreviations  
Analysis 
Set 
Abbreviation  
(if applicable) 
Definition 
Per Protocol 
Analysis Set 
PP Analysis Set 
Subset of the FAS that includes all patients who have completed the 
trial with no major important protocol deviations deemed to 
compromise the assessment of efficacy. Major protocol deviations will 
be identified as a subset of the important protocol deviation and fully 
defined prior to unblinding of the trial. 
Follow-up 
Analysis Set 
FUAS 
Subset of the FAS that includes all patients who have completed 
Week 12 on-treatment and have follow-up data. 
 
 
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 Conventions and Derivations 
10.1 Source of Key Dates 
 
The IMP Start Date will be assumed to be the first date of IMP dispense, which will be obtained 
from the IRT data.  If there is documented confirmation that patient did not take IMP eg where this 
is reported as a protocol deviation, the IMP Start Date will be set to missing.  
 
The IMP End Date will be taken from eCRF “End of treatment” form. 
 
The Last Day in Study will be taken from “Study Completion/Discontinuation Date” on the “End of 
study” form for patients that completed or discontinued early for any reason other than Lost to 
Follow-up. For patients Lost to Follow-up, the Last Day in Study will be their last contact date. 
10.2 Reference Day, Study Day, Study Periods and Analysis Visit Window 
10.2.1 Reference Day and Study Day 
The reference day (Study Day 1) will be the date of randomization. However, in the event that IMP is 
dispensed before randomization first date of IMP dispense will be used (see Section 10.1). 
The study day is defined relative to the reference day date.  
 
For assessments that occur on or after this date, the study day will be calculated as assessment 
date – reference day date +1.  
 
For assessment that occur prior to the reference day date, the study day will be calculated as 
assessment date – reference day date.  
Thus, there is no study day referring to Day 0. 
10.2.2 Study Periods 
The following study periods will be defined: 
 
Screening/baseline period: starting the day of the informed consent signature and ending  
 
For clinical based endpoints: on Day 1 (as defined in Section 10.2.1) before first IMP intake  
 
For eDiary based endpoints: the day prior to Day 1 
 
12-week randomized period: starting on Day 1 (as defined in Section 10.2.1) and ending the day of 
Visit 6 (end of treatment or early withdrawal visit). 
 
 For the eDiary endpoints of spasm count and NRS spasm severity this period will be split 
into three 4-week periods: 
 
Week 1 to 4; defined as Day 1 to Day 28 
 
Week 5 to 8; defined as Day 29 to Day 56  
 
Week 9 to 12; defined as Day 57 to Day 84  
 
For the eDiary endpoint of NRS spasticity this period will be split into twelve 1-week 
periods: 
 
Week 1; defined as Day 1 to Day 7  
 
Week 2; defined as Day 8 to Day 14 
 
Week 3; defined as Day 15 to Day 21 
… 
 
Week 12; defined as Day 78 to Day 84 
 
12-week on-treatment period: which starts on the IMP Start Date and ends on the IMP End Date(+ x 
days), where x will be equal to 30 days for safety assessment and medication, and 0 days for efficacy.  
See Section 10.1 for definitions of IMP Start Date and IMP End Date. 
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 
For IMP dosing summaries this period will be considered as follows: 
 
The titration period; defined as Day 1 to Day 14  
 
The maintenance period; defined as Day 15 to IMP End Date 
 
On-treatment period; defined as Day 1 to IMP End Date 
 
Follow-up period: for eDiary based endpoints this starts on the day after IMP End Date and ends 14 
days after IMP End Date. 
 
For the eDiary endpoint of NRS spasticity this period will be split into two 1-week periods:  
 
Follow-up Week 1; defined as the day after IMP End Date to the day 7 days after IMP 
End (inclusive) 
 
Follow-up Week 2; defined as the day 8 days after IMP End Date to the day 14 days 
after IMP End Date (inclusive) 
 
Follow-up baseline period: the baseline period for the follow-up analysis for eDiary based endpoints 
starts 13 days before IMP End Date and ends on IMP End Date, ie covers a 14-day period ending on 
IMP End Date. 
10.2.3 Target Days and Analysis Visit Windows 
Analysis visit windows are summarized in Table 10.2-1 for efficacy data, and on Table 10.2-2 and Table 
10.2-3 for pharmacokinetic data. 
When there are multiple observations within a visit window, the value closest to the target day will be 
analyzed, with the earliest date/time used in the event of ties.  
For visit based efficacy endpoints, visit windowing will apply whether patient is on- or off-treatment. 
 
Table 10.2-1 Longitudinal Efficacy and QoL Assessment – Target Day and Analysis Visit Window  
Visit / Day 
Analysis 
visit  
Target day  
MSSS-88 
T25FW 
SF-36 
Visit 2 / Day 1* 
Baseline 
1 (predose) 
-28 to 1 (predose) 
-28 to 1 (predose) 
Visit 3 / Day 15 
Week 2 
15 
NA 
NA 
Visit 4 / Day 29 
Week 4 
29 
NA 
NA 
Visit 5 / Day 57 
Week 8 
57 
2 to 71  
NA 
Visit 6 / Day 85** 
Week 12 
85  
72 to 92  
2 to 92 
Visit 7 / Day 99 *** 
Week 14 
99 
NA 
NA 
MSSS-88 = Multiple sclerosis spasticity scale; T25FW=Timed 25-foot walk; SF-36=36-items Short form 
health Survey; NA = Not applicable.  
* Day 1 is based on the date of randomization. 
** Will also be completed for those patients who permanently withdraw from the study. 
*** Follow-up visit is not required to be completed for any patient who discontinue IMP but continue off-
treatment provided that Visit 6 is completed. 
*** Follow-up visit is expected to be completed between 10 and 14 days following early study 
withdrawal. 
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Table 10.2-2 Semi-intensive PK Draw Assessment – Target Day and Time and Visit/Time Window  
Visit / Day 
Analysis visit  
Target 
day  
Day window 
Target time 
H0 
H2-H3 
H4-H6 
H6-H8 
Visit 2 / Day 1* 
Baseline 
1  
-28 to 1 
predose 
 
 
 
Visit 3 / Day 15 or 
Visit 4 / Day 29 or 
Visit 5 / Day 57 
Week 2 to Week 8 
15 
or  
29 
or  
57 
2 to 71 
predose 
H0 + 2 hours to 
H0 + 3 hours 
H2-H3 + 2 hours to 
H2-H3 + 4.5 hours 
H4-H6 + 2hours 
H5_H6 + 4.5 hours 
H=Hour; IMP=Investigational medicinal product 
* Day 1 is based on the date of first IMP spray administration 
 
 
Table 10.2-3 Sparse PK Draw Assessment – Target Day and Analysis Visit Window  
Visit / Day 
Analysis 
visit  
Target day  
Sparse PK sampling 
Visit 2 / Day 1* 
Baseline 
1 (predose) 
-28 to 1 (predose) 
Visit 3 / Day 15** 
Week 2 
15 
2 to 22 
Visit 4 / Day 29** 
Week 4 
29 
23 to 43 
Visit 5 / Day 57** 
Week 8 
57 
44 to 71  
Visit 6 / Day 85** 
Week 12 
85  
72 to 92  
PK=Pharmacokinetic. 
* Day 1 is based on the date of first IMP spray administration 
** Sample collected at any time during the visit  
 
 
 
 
 
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10.2.4 Reporting of Longitudinal Safety Assessments 
Physical examination, serum urine pregnancy test, dipstick urinalysis, examination of oral mucosa, vital 
signs, body weight, 12-lead ECG, clinical laboratory blood sampling, C-SSRS, MUS will be summarized 
using the nominal visit.  In case of repeat assessments, the original assessment will be used in summaries, 
but all assessments will be listed. 
For patients that discontinued IMP early but remained on study, assessments taken after IMP End Date will 
be assigned to the Follow-up visit, as long as they are within 30 days of IMP End Date. 
For examination of oral mucosa, vital signs, body weight, 12-lead ECG, clinical laboratory blood sampling 
and C-SSRS the last on-treatment assessment will also be identified.  The last on-treatment assessment 
is defined as the last scheduled assessment prior to IMP End Date, only assessments after the IMP Start 
Date will be considered (see Section 10.1 for source of dates). 
10.3 Rescreened Patients Data Handling 
A rescreened patient is defined as a patient who fails initial screening attempt because of eligibility criteria 
violation, is then screen failed and rescreened under a new patient identifier. Rescreened patients will be 
presented in outputs conducted on the Screening analysis set as two different patients. 
10.4 Baseline 
10.4.1 Diary Efficacy Based Endpoint 
For the primary endpoint of spasm count and the exploratory endpoint of NRS spasm severity score, the 
baseline is defined as the average of all data collected during the baseline period (as defined in Section 
10.2.2) immediately prior to the reference day (as defined in Section 10.2.1).  
For the exploratory endpoint of NRS spasticity score, baseline is defined as the average of the last 7 days 
of electronic diary entries immediately prior to the reference day (as defined in Section 10.2.1) ie from Study 
Day -1 to -7. 
The baseline for the follow-up analysis for spasm count and NRS spasm severity is defined as the average 
of all data collected during the baseline follow-up period (as defined in Section 10.2.2).  
The baseline for the follow-up analysis for NRS spasticity score is defined as the average of all data 
collected during the period of time starting 6 days before IMP End Date and ending on IMP End Date, ie 
covers a 7 day period ending on IMP End Date.  
10.4.2 Clinic Based Endpoint 
For visit based endpoints, the baseline is defined as the last assessment prior to IMP Start Date or prior to 
randomization if IMP Start Date is after the date of randomization.  
However, for C-SSRS, only the assessment carried out at Visit 2 should be used as the baseline 
assessment.  
10.5 Change from Baseline  
Change from baseline (CFB) is defined as: 
 post-baseline −baseline 
CFB will be calculated only for patients with both a baseline and post-baseline value. 
 
 
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10.6 Percent Change from Baseline 
Percent CFB is defined as: 
(
𝐶𝐹𝐵
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒) × 100% 
If baseline and post baseline are averages (derived using a known numerator and denominator) percent 
CFB will be derived as:  
((total post-baseline numerator × baseline denominator
total baseline numerator × post-baseline denominator) −1) × 100%  
Percent CFB will be calculated only for patients with both a baseline and post-baseline value.  
If the baseline is zero, then percent CFB will be derived as: 
((total post-baseline numerator
post-baseline denominator ) + 1) × 100%  
10.7 Time Conversion 
Time conversion will follow the rules described below: 
 
1 Week = 7 days 
 
1 Month = 30.4375 days 
 
1 Year = 365.25 days 
10.8 Patient Disposition and Treatment Duration 
The time in study expressed in days is defined as: 
(Last Day in Study −date of randomization) + 1 
See Section 10.1 for source of dates. 
The duration of IMP exposure expressed in days will be derived as: 
(IMP End Date −IMP Start Date) + 1 
See Section 10.1 for source of dates. 
Duration of IMP will also be categorized as follows: 
 
1 to 14 days 
 
15 to 28 days 
 
29 to 56 days 
 
57 to 84 days 
 
85 to 91 days 
 
> 91 days 
The treatment arm total duration of IMP exposure expressed in patient-years will be derived as follows: 
∑
𝐷𝑖
𝑖=𝑛
𝑖=1
365.25
 
With n being the number of patients within the treatment arm and SAF and i=1,2, 3,…,n, and, with Di 
being the duration of IMP exposure (in days) for patient i. 
 
 
 
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10.9 IMP Dosing – Number of Sprays Summary 
For each parameter presented in this section, 
 
The derivation will be carried out for the titration, maintenance and on-treatment periods (as 
defined in Section 10.2.2) 
 
eDiary information will be used to retrieve the total daily number of sprays taken by a given patient 
 
A missing diary day is defined as any day where the eDiary is not completed. 
The mean number of daily sprays a patient has taken will be calculated for each period as: 
total number of sprays taken during the period
the number of non-missing diary days during the period  
Based on the above the mean number of daily sprays will also be categorized as follows: 
 
≤ 6 sprays per day 
 
6 to ≤ 12 sprays per day 
 
> 12 sprays per day 
The modal number of sprays per patient 
 
refers to the most frequent number of sprays per day a patient has taken during the period. 
The maximum number of sprays per patient 
 
refers to the maximum number of sprays a patient has taken in a single day during the period. 
10.10 Compliance, Optimized Dose and Drug Accountability 
Percent compliance will be derived, for each patient, during the maintenance phase (as defined in Section 
10.2.2), based on optimized and amended doses information as reported in the “Dose amendment” eCRF 
form and the total daily number of sprays derived from the eDiary as the sum of morning and evening 
number sprays.  
A compliant day, is defined for each patient as a day when the total number of sprays taken is 
 
Within ± 1 (and between 1 and 12) of the patients’ optimized dose when sprays are taken 
outside of an amended dose period 
 
Equal to the amended dose ± 1 spray (and between 1 and 12) when sprays are taken between 
start and stop date of an amended dose period as collected in the eCRF. 
The percent compliance will then be defined as:  
100% × (
number of compliant days
the number of non-missing diary days during the period)  
The percent compliance will also be categorized as follows: 
 
< 80% 
 
≥ 80% to < 90% 
 
≥ 90% to < 100% 
 
= 100% 
The following will be derived for the titration, maintenance and on-treatment periods (as defined in Section 
10.2.2):  
 
 
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The percent of “0” total daily sprays is defined at patient level as:  
100% × (
the number of days where total daily dose is 0
the number of non-missing diary days during the period)  
The percent of “ > 12” total daily sprays is defined at patient level as: 
100% × (
the number of days where total daily dose is > 12
the number of non-missing diary days during the period)  
The percent of missing diary day IMP information is defined for each patient as:  
100% × (the number of diary days missing dosing information during the period
period duration
)  
The final optimized dose is defined as: 
 
The last amended dose in case of any dose adjustment 
 
The optimized dose if no dose adjustment 
Total IMP used (sprays) is defined as: 
total IMP used (mm) −37.698
−0.3468
  
10.11 Age 
The age at consent will be determined as follows: 
 
If age is recorded in the eCRF then this will be used for analysis 
 
If only year of birth is known, then age is derived as:  
(date of informed consent - date of birth) + 1
365.25
  
where date of birth is imputed to the 30th June of the year of birth. However, if derived age is 
resolved to 17 years and inclusion criteria 1 is met then age will be set to 18 years. 
 
Based on the above, age will also be categorized as: < 18, ≥ 18 to < 45, ≥ 45 to < 65 and ≥ 65 
years. 
10.12 Body Mass Index  
At each weight measurement, the Body Mass Index (BMI) will be derived using height collected at 
screening. 
BMI (kg/m²) is calculated using the following formula: 
Weight (kg)
(Height (cm)∗0.01)2  
BMI will be categorized as follows: 
 < 18.5; 
 ≥ 18.5 and < 25.0  
 ≥ 25.0 and < 30.0; 
 ≥ 30. 
 
 
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10.13 Disease History 
As part of disease history description, the following parameters will be derived: 
Time since diagnosis of multiple sclerosis (MS) (years): 
(Date of Informed Consent − Date of MS diagnosis) + 1
365.25
  
Age at diagnosis of MS (years): 
(Year of MS diagnosis − Year of Birth) + 1  
Time since onset of spasticity due to MS (years): 
(Date of Informed Consent − Date of Onset of Spasticity due to MS) + 1
365.25
  
Age at onset of spasticity due to MS (years): 
(Year of Onset of Spasticity due to MS − Year of Birth) + 1  
Time between MS diagnosis and onset of spasticity due to MS (years): 
(Date of onset of spasticity due to MS − Date of MS diagnosis) + 1
365.25
  
Time between MS diagnosis and onset of spasticity due to MS (months): 
(Date of onset of spasticity due to MS − Date of MS diagnosis) + 1
30.4375
  
The following conversion will be applied as appropriate: 
 Time since last relapse (month) = Time since last relapse (year) * 12, 
 Time since last relapse (month) = Time since last relapse (day) / 30.4375. 
Age at diagnosis of MS and age at onset of spasticity due to MS are only using year because only year of 
birth is planned to be collected. 
If date of MS diagnosis and/or date of onset of spasticity due to MS are unknown or partial, they will be 
imputed as follow: 
 if only day is missing, it will be imputed to the 15th of the month, 
 If day and month are missing, they will be imputed to the 30th June of the year, 
 However, if any of these dates fall after the informed consent date, they will be set to the informed 
consent date. If, due to imputation rule the date of onset of spasticity due to MS falls before the 
date of MS diagnosis, it will be set to the date of MS diagnosis. 
10.14 Renal Function Formula  
Estimated Glomerular filtration rate (eGFR) (mL/min/1.73m²) will be categorized as follows: 
 ≥ 90 as normal renal function, 
 ≥60 and < 90 as mild renal impairment, 
 ≥30 and < 60 as moderate renal impairment, 
 ≥15 and < 30 as severe renal impairment, 
 <15 as end stage kidney failure. 
 
 
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10.15 Prior and Concomitant Medication Start/Stop Date Imputation Rule 
 
Table 10.15-1 Imputation Rules for Partial Medication Dates 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
concomitant meds 
D only 
M and Y same as M and Y of IMP Start 
Date 
Date of IMP Start Date 
M or Y not same as date of IMP Start Date First day of month but should fall 
on or after IMP Start Date or if 
impossible after informed consent 
date 
M and D 
Y same as Y of IMP Start Date 
Date of IMP Start Date 
Y is after Y of IMP Start Date 
Use Jan 01 of Y  
Y is before Y of IMP Start Date  
Use the latest between Jan 01 of 
Y and informed consent date 
M, D, and Y 
Not allowed by the system 
Not applicable 
Stop date for 
concomitant meds 
D only 
M and Y same as M and Y of IMP End 
Date 
The earliest date between IMP 
End Date and Last Day in Study 
M or Y not same as IMP End Date 
The earliest between last day of 
month and Last Day in Study 
M and D 
Not allowed by the system 
Not applicable 
M, D, and Y 
Not allowed by the system 
Not applicable 
Meds = Medications; Jan = January; D = day; M = month; Y = year. 
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date 
month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start 
day month. 
10.16 Mobile Health Platform Data Handling 
Data downloaded from the Mobile Health platform (MHP) such as number of morning and evening sprays 
administered, NRS scales, number of spasm counts, C-SSRS questionnaire, MSSS-88 questionnaire, have 
specific information to link the date of MHP data to the date it is referring to which is to be reported in SDTM 
and ADaM as detailed in Table 10.16-1. In general, any time the variable XPGRPID contains the term “Late” 
the date to be used refers to the day before the one coming from MHP. 
An exception to this is data collected under the ‘Initial late’ prompt prior to December 2nd 2021 when the 
incorrect prompt “Enter the number of spasms you had since bedtime yesterday until now.” was given.  
Data collected under the Initial late diary (ie where variable XPTESTCD end in _117) using this prompt will 
not be included in the analysis.  Data collected under the Initial late diary using the prompt “Enter the 
number of spasms you had in the 24 hours before your bedtime yesterday.” will be included. 
 
 
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Table 10.16-1 MHP data - Date Handling 
XPGRPID  
Explanation 
Initial on time Diary 
Served from 6:00pm to 11:59 pm on the day a participant is moved to screening 
Initial late Diary 
Served from 12:00 am to 3:00 pm the next day when the initial On Time Diary was NOT 
completed the previous day 
On time diary 
Served from 6:00pm to 11:59 pm when the Initial On Time, On time, or Missed On Time 
Diary was completed the previous day 
Late diary 
Served from 12:00 am to 3:00 pm when On Time Diary was NOT completed the 
previous day 
Missed on time 
Served from 6:00pm to 11:59 pm when an Initial Late, or Missed Late Diary was served 
on the same day 
Missed late 
Served from 12:00 am to 3:00 pm when the Missed On Time Diary was Not completed 
the previous day 
10.17 Daily Spasm Count 
The spasm count is recorded daily via the eDiary. The average daily spasm count will be derived for each 
patient for the following periods: in the baseline period, the three 4-week periods in the randomized period 
(Week 1 to 4, Week 5 to 8 and Week 9 to 12), the follow-up baseline period and the follow-up period 
(definitions for the periods and baseline are described in Section 10.2.2 and Section 10.4.1). 
The average daily spasm count for each period is defined as follows: 
Total spasm count for the period
Number of days in which the daily diary was completed during the period 
The average daily spasm count value will be set to missing under the following conditions: 
 
if less (<) than 15 days with non-missing data and more than or equal to (≥) 10 consecutive days 
with missing data for the three 4-week periods in the randomized period.  
 
if less (<) than 7 days with non-missing data and more than or equal to (≥) 5 consecutive days with 
missing data for the follow-up period. 
The change from baseline will be calculated (as described in Section 10.5) for the three 4-week periods in 
the randomized period and the follow-up period. 
The percent change from baseline will be calculated (as described in Section 10.6) for the three 4-week 
periods in the randomized period. 
The percentage change from baseline values for the Week 9 to 12 period will be categorized using the 
following responder analysis cut-offs: 
 
20% improvement (≤ -20% vs > -20%) 
 
30% improvement (≤ -30% vs > -30%) 
 
40% improvement (≤ -40% vs > -40%) 
 
50% improvement (≤ -50% vs > -50%). 
Missing average daily spasm count will be considered as not having met any of the improvement criteria 
(imputed as failure) for the responder analysis. 
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On-treatment average daily spasm count will be derived for each patient for the three 4-week periods in the 
randomized period using the same derivation as for average daily spasm count detailed above but using 
only diary records before the IMP End Date. The same criteria for missing data will be applied. 
10.18 Multiple Sclerosis Spasticity Scale (MSSS-88) 
The MSSS-88 will be completed at Day 1 Visit (baseline), Visit 5 (Week 8) and Visit 6 (Week 12/early 
withdrawal). Eight sub-scales representing 8 domains will be derived by summing each of the constitutive 
items provided that at least 50% of the items are answered, items with a missing score will be replaced by 
the mean score of the items completed within the same domain for subscale scores.  The total score will 
only be calculated if, after applying the imputation, all 8 sub-scales have a score, otherwise will be set to 
missing. 
The questions will be grouped as follows: 
 
3 spasticity specific symptoms 
 
Muscle Stiffness: sum of questions 1 to 12 
 
Pain and Discomfort: sum of questions 13 to 21 
 
Muscle Spasms: sum of questions 22 to 35 
 
3 areas of physical functioning 
 
Activity of Daily living (ADL): sum of questions 36 to 46 
 
Ability to Walk: sum of questions 47 to 56 
 
Body Movement: sum of questions 57 to 67 
 
2 area of psychosocial impact 
 
Emotional health: sum of questions 68 to 80 
 
Social Functioning: sum of questions 81 to 88 
 
Total score 
 
 Sum of the 88 questions 
 
Table 10.18-1 Multiple Sclerosis Spasticity Scale - Missing Data Handling 
Subscale and total score 
Number of questions included in 
subscale and total score 
Minimum number of questions required 
for score derivation (at least 50%) 
Muscle Stiffness 
12 
6 
Pain and Discomfort 
9 
5 
Muscle Spasms 
14 
7 
Activity of Daily living (ADL) 
11 
6 
Ability to Walk 
10 
5 
Body Movement 
11 
6 
Emotional health 
13 
7 
Social Functioning  
8 
4 
Total score 
88 
NA will only be calculated if minimum 
number of questions met for each 
subscale 
 
 
 
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10.19 Numerical Rating Scale (NRS) for Spasm Severity 
The NRS spasm severity score is collected daily via eDiary and is on a scale from 0 to 10. The average 
NRS spasm severity score will be derived for each patient for the following periods: the baseline period, the 
three 4-week periods in the randomized period (Week 1 to 4, Week 5 to 8 and Week 9 to 12), the follow-up 
baseline period and the follow-up period (definitions for the periods and baseline are described in Section 
10.2.2 and Section 10.4.1). 
The average NRS spasm severity score for each period is defined as follows: 
Sum of the NRS spasm severity score for the period
Number of days in which the daily diary was completed during the period 
The average NRS spasm severity score will be set to missing under the following conditions: 
 
if less (<) than 15 days with non-missing data and more than or equal to (≥) 10 consecutive days 
with missing data for the three 4-week periods in the randomized period.  
 
if less (<) than 7 days with non-missing data and more than or equal to (≥) 5 consecutive days with 
missing data for the follow-up period. 
The change from baseline will then be calculated (as described in Section 10.5) for the three 4-week periods 
in the randomized period and the follow-up period. 
10.20 Numerical Rating Scale (NRS) for Spasticity 
The NRS spasticity score is collected daily via eDiary and is on a scale from 0 to 10. The average NRS 
spasticity score will be derived for each patient for the following periods: the baseline period, the twelve 1-
week periods in the randomized period, the follow-up baseline period and the two 1-week follow-up periods 
(definitions for the periods and baseline are described in Section 10.2.2 and Section 10.4.1). 
The average NRS spasticity score for each period is defined as follows: 
Sum of the NRS spasticity score for the period
Number of days in which the daily diary was completed during the period 
The non-baseline average NRS spasticity score will be set to missing under the following conditions: 
 
if less (<) than 3 days with non-missing data and more than or equal to (≥) 3 consecutive days with 
missing data. 
The change from baseline will then be calculated (as described in Section 10.5) for the twelve 1-week 
periods in the randomized period and the two 1-week periods in the follow-up period. 
10.21 Timed 25-Foot Walk  
The Timed 25-Foot Walk (T25FW) is the time needed for a patient to walk 25-feet. The test consists of two 
trials separated by a 5-minute rest period. The maximum duration of each trial is set to 3 minutes (180 
seconds).  
The average timed 25-foot walk (expressed in seconds) will be derived for each patient as the average of 
the two trials recorded at Day 1 Visit (baseline) and Visit 6 (Week12/early withdrawal). 
If a patient only performs 1 of the 2 trials at a given timepoint, the unperformed trial will be imputed as 180 
seconds.  
If a patient is not using the same assistive device or introduces a new assistive device between pre- and 
post-randomisation assessment, the post-randomisation average T25FW will be set to missing.  
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The change from baseline will then be calculated (as respectively described in Section 10.5 and in Section 
10.6). 
10.22 36-Item Short Form Health Survey 
The SF-36 is a 36-item instrument. Items are divided into eight concepts plus one health comparison 
question.  
The programming team will use the Enterprise Version of PRO CoRE software by Optum to score the SF-
36. 
The raw scale scores are computed by summing item responses within each concept after recoding the 
individual item if needed.  
The eight concepts to be scored are:  
 
Physical Functioning (PF) (items 3a-3j): The ten items are coded as 1-3. There is no recoding 
needed.  
The lowest possible raw score is 10, the highest is 30 and the range is 20. High score indicates 
better PF. 
 
Role-Physical (RP) (items 4a-4d): The items are coded as 1-5. There is no recoding needed.  
The lowest possible raw score is 4, the highest is 20 and the range is 16. High score indicates 
better Role- Physical function.  
 
Role-Emotional (RE) (items 5a-5c): The items are coded as 1-5. There is no recoding needed. 
The lowest possible raw score is 3, the highest is 15 and the range is 12. High score indicates 
better Role-Emotional function.  
 
Social Functioning (SF) (items 6, 10): The items are coded as 1-5. Item 6 is recoded as 5-1. Item 
10 does not require recoding value.  
The lowest possible raw score is 2, the highest is 10 and the range is 8. High score indicates 
better social functioning.  
 
Bodily Pain (BP) (items 7 & 8): This concept requires special coding. Item 7 is coded as 1-6 and 
is recoded as 6.0, 5.4, 4.2, 3.1, 2.2, 1.0. Item 8 is coded as 1-5 and is recoded as 6-1 if both item 
7 and item 8 are answered. If item 7 is not answered, item 8 is recoded as 6.0, 4.75, 3.5, 2.25, 
1.0.  
The lowest possible raw score is 2, the highest is 12 and the range is 10. High score indicates 
lack of bodily pain. 
 
Mental Health (MH) (items 9b, 9c, 9d, 9f & 9h). The items are coded as 1-5. Items 9b, 9c and 9f 
do not require recoding. Items 9d and 9h are recoded as 5-1.  
The lowest possible raw score is 5, the highest is 25 and the range is 20. High score indicates 
better mental health. 
 
Vitality (VT) (items 9a, 9e, 9g, 9i): The items are coded as 1-5. Items 9a and 9e are recoded as 
5-1. Items 9g and 9i do not require recoding.  
The lowest possible raw score is 4, the highest is 20, the range is 16. High score indicates more 
vitality. 
 
General Health (GH) (items 1, 11a-11d): The items are coded as 1-5. Items 11a and 11c do not 
require recoding. Items 11b and 11d are recoded as 5-1. 
Item 1 is recoded as 5.0, 4.4, 3.4, 2.0, 1.0.  
The lowest possible raw score is 5, the highest is 25 and the range is 20. High score indicates 
better general health perceptions. 
 
Reported Health Transition (HT) (item 2). Item 2 is coded as 1-5 and is recoded 5-1.  
 
In addition to the concepts above, the scoring software also provides results for two aggregate 
scores: 
 
Physical Component Summary (PCS) 
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 
Mental Component Summary (MCS). 
Any out-of-range value will be considered missing.  
Missing or blank values will be estimated using the Full missing score estimation (as defined in scoring 
PRO CoRE software manual). 
The formula for the transformed scale = [(actual raw score – lowest possible raw score)/Possible raw score 
range] x 100.The raw scores will be transformed to a 0 to 100 scale.  
10.23 Adverse Events 
Unless specified otherwise derivations will be applied to each adverse event (AE). 
10.23.1  Start Date Imputation 
Only start dates will be imputed. 
Table 10.23-1 Imputation Rules for Partial Adverse Event Start Dates  
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for AEs 
D 
M and Y same as M and Y of IMP Start 
Date 
Date of IMP Start Date 
M and/or Y not same as date of IMP Start 
Date 
First day of month but should fall on or 
after first IMP intake or if impossible 
after informed consent date 
D and M 
Y same as Y of IMP Start Date 
Date of IMP Start Date 
Y prior to Y of IMP Start Date but same 
as Y of informed consent date 
Date of informed consent 
Y after Y of IMP Start Date 
Use Jan 01 of Y 
D, M, Y 
Not allowed by the system 
Not applicable 
AE = Adverse events; Jan = January; D = day; M = month; Y = year  
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date 
month. 
10.23.2 COVID-19 Adverse event 
A confirmed or suspected COVID-19 adverse event will be any adverse event for which the AE term or the 
preferred term include the text “COVID-19” but should not be “COVID-19 ELISA test negative”. 
For instance, confirmed COVID-19 Treatment emergent adverse event (TEAE) will be reported as:  
 
COVID-19 infection 
 
COVID-19 disease 
 
COVID-19 pneumonia 
 
COVID-19 respiratory infection 
 
Asymptomatic COVID-19 
whereas a suspected COVID-19 AE will be coded as Suspected COVID-19. 
 
 
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10.23.3 Time to First Onset of AE 
The time to first onset of AE (expressed in days) will be defined as: 
(AE start date −IMP Start Date) + 1 
Based on the above value time to first onset of TEAE (as defined in Section 12.8.1.2) will be categorized 
as: 
 
1 to 7 days  
 
8 to 14 days  
 
15 to 28 days  
 
29 to 42 days 
 
43 to 84 days 
 
> 84 days. 
If onset time is shorter than 1 day, it will be included in the 1-7 days category. 
10.23.4 AE Duration 
The AE duration (expressed in days) will be defined as: 
(AE stop date −AE start date) + 1 
The duration will not be derived in case of partial or missing start or stop date. 
Based on the above value the AE duration will also be categorized as follows: 
 
1 to 7 days 
 
8 to 14 days 
 
15 to 28 days 
 
29 to 42 days 
 
43 to 84 days 
 
> 84 days 
 
Ongoing, 
 
Indeterminate. 
If AE stop date is missing and the outcome of the AE is “Not recovered, Not resolved”, the AE will be 
categorized as “Ongoing”. 
If the AE start date is partial or missing and the AE is not considered as “Ongoing”, the AE will be classified 
as “Indeterminate”. 
10.24 Laboratory Data 
10.24.1  Strip-sign Handling 
In cases a hematology or chemistry value has been recorded as ‘>x’, ‘≥x’, ‘≤x’ or ‘<x’, the value will be 
imputed as “x” to perform summary statistics but the strip sign will be presented in individual data listings. 
10.24.2  Minimal, Maximal and Most Extreme Value for Laboratory Measurements 
The minimal value is defined as the lowest value from assessments taken during the period of interest. 
The maximal value is defined as the highest value from assessments taken during the period of interest. 
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The most extreme (ME) value is defined as the furthest value from normal range in either direction collected 
during the period of interest. 
Let’s define for a given patient and a given parameter x: 
 
n: the number of observations collected during the studied period, 
 
i= 1, 2, 3,…,n  xi  the values of the study parameter for that patient during the studied period, 
 
LLN: the lower limit of normal range of the study parameter, 
 
ULN: the upper limit of normal range of the study parameter, 
 
ME: the most extreme value of the study parameter, 
 
i= 1,2, 3,…,n   yi the distance of each collected laboratory value xi to the reference range 
 
If the parameter has only a LLN then yi= LLN-xi 
 
If the parameter has only a ULN then yi= xi- ULN 
 
If the parameter has both a LLN and a ULN then yi= max (LLN-xi, xi- ULN)  
Consequently ME= xi such as yi=max (y1, y2,….y1,…yn). In case of ties, the measurement xi presenting 
the highest change from baseline in absolute values will be used. 
10.25 Columbia Suicide Severity Rating Scale (C-SSRS)  
The C-SSRS scale is composed of 11 items answered Yes or No. Ten of them are ordered in categories 
as described below to determine the studied endpoints. 
5 subtypes of suicidal ideation  
 
Category 1 – Wish to be Dead 
 
Category 2 – Non-specific Active Suicidal Thoughts 
 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent. 
5 subtypes of suicidal behavior  
 
Category 6 – Preparatory Acts or Behavior 
 
Category 7 – Aborted Attempt 
 
Category 8 – Interrupted Attempt, 
 
Category 9 – Actual Attempt (non-fatal) 
 
Category 10 – Completed Suicide. 
Last item  
 
Self-injurious behavior without suicidal intent 
The C-SSRS also includes a suicidal ideation intensity rating from 1 (least severe) to 5 (most severe). 
The following composite endpoints will be assessed based on the categories described above: 
 
Suicidal ideation (Yes/No): is Yes if one of the categories from 1 to 5 is answered Yes 
 
Suicidal behavior (Yes/No): is Yes if one of the categories from 6 to 10 is answered Yes 
 
Suicidal ideation or behavior (Yes/ No): is Yes if one of the categories from 1 to 10 is answered 
Yes 
 
Self-injurious behavior without suicidal intent (Yes /No): is Yes if this question is answered Yes. 
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The following scores will be derived as follow: 
 
Suicidal ideation score is rated from 1 to 5 according to the most severe suicidal ideation 
category answered Yes and is assigned to 0 if categories 1 to 5 are answered No, 
 
Suicidal ideation intensity rating score (0 to 25) will be defined as the sum of the 5 features 
described below (ranging from 0 to 5, 0 being the least severe and 5 being the most severe) 
rated with respect to the most severe type of ideation category 
 
Frequency 
 
Duration, 
 
Controllability 
 
Deterrents 
 
Reason for ideation.  
Comparative endpoints will also be defined as described below: 
Treatment emergent outcomes will include any events that first emerge or worsen whereas emergent 
outcomes will refer to outcome that first emerge. 
 
Treatment-emergent suicidal ideation compared to recent history (not using C-SSRS taken 
during screening):  
 
Increase from baseline in suicidal ideation score. 
 
Treatment-emergent serious suicidal ideation compared to recent history (not using C-SSRS 
taken during screening): 
 
Increase in suicidal ideation score from a baseline (0-3) to (4-5).  
 
Emergence of a serious suicidal ideation compared to recent history (not using C-SSRS taken 
during screening): 
 
Increase in suicidal ideation score from baseline (0) to (4-5).  
 
Emergence of suicidal behavior compared to all prior (using C-SSRS taken at and post 
screening assessments):  
 
Occurrence of suicidal behavior (categories 6-10) post baseline with no screening or 
baseline suicidal behavior. 
No imputation should be done with regards to missing data. 
 Interim Analyses 
Not applicable.  
 Statistical Methods 
All analyses will be performed in SAS® version 9.4 or higher.  
Standard summary statistics for continuous and discrete variables 
Summaries will be tabulated by treatment arm and overall, unless otherwise specified. 
Unless otherwise noted, categorical data will be summarized using non-missing counts and percentages. 
Percentage will be using with the number of patients (or the number of patients at risk) in the treatment arm 
and, as appropriate, in the analyzed categories as denominator. 
Percentages will be rounded to one decimal place except 100% which will be displayed without any decimal 
places and percentages which will not be displayed for zero counts. 
Ratios will be presented with 2 decimal places and adjusted proportions will follow percentage rules but 
could be rounded to 1 or 2 decimal places according to meaningful precision. 
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Continuous data will be summarized using the number of non-missing observations (n), mean, standard 
deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum (Min), and maximum (Max).  
Minimum and maximum will be rounded to the precision of the original value. Mean, median, Q1 and Q3 
will be rounded to 1 decimal place greater than the precision of the original value. The SD will be rounded 
to 2 decimal places greater than the precision of the original value. Confidence intervals (CIs), LS means, 
standard error (SE), geometric mean, geometric SD and coefficient of variation (CV) (%) will be provided 
as appropriate. Confidence intervals, LS means and geometric mean will be presented with the same 
precision as the mean value whereas SE and geometric SD will be presented with the same precision as 
SD and the CV (%) will be presented with 1 decimal place. 
Inferential statistics 
P-values will be presented to 4 decimal places. P-values less than 0.0001 will be presented as “<0.0001” 
and p-values greater than 0.9999 will be presented as “>0.9999”. 
Statistical hypothesis testing will be 2-sided and carried out at the 5% level of significance. Testing will be 
performed on the primary endpoint and secondary endpoints as appropriate.  
To control for Type 1 error, the primary endpoint and efficacy secondary endpoint will be tested 
hierarchically, starting with the primary endpoint, followed by the secondary endpoint. No additional 
adjustments for multiplicity will be made for the other secondary endpoints and for the exploratory endpoints 
although nominal p-values will be presented. 
Individual listings.  
All the listings will be displayed sorted by treatment arm, patient identifier and date of assessment. They 
will include age, gender, race, country and randomization strata (as needed). A flag informing whether or 
not the data are impacted by COVID-19 may also be added. 
Back-up model selection for the mixed model of repeated measure (MMRM) 
In case of non-convergence, back-up models will be used changing the method of degrees of freedom 
approximation, using another variance-covariance matrix or removing one or both randomization strata 
from the model, following the below steps until convergence is achieved.  
 
Step 1: Model including Unstructured (UN) covariance matrix and Kenward-Roger (KR) method 
of degrees of freedom approximation. 
 
Step 2: Replace Kenward-Roger (KR) method of degrees of freedom approximation with the 
Satterthwaite (SAT) approximation. 
 
Step 3: Repeat Steps 1 and 2 using the following covariance structures, instead of 
unstructured, in the order described below 
1. Toeplitz (TOEP) 
2. First order autoregressive (AR(1)) 
3. Compound symmetry (CS) 
 
Step 4: If convergence has still not been achieved, repeat Steps 1-3 including only the 
randomization strata of region. 
 
Step 5: If convergence has still not been achieved, repeat Steps 1-3 including only the 
randomization strata of prior cannabis use. 
 
Step 6: If convergence has still not been achieved, repeat Steps 1-3 with no randomization 
strata included. 
12.1 Patient Disposition 
All patient disposition outputs will be based on the FAS unless otherwise stated. 
The number and percentage of patients screened, rescreened, randomized and not randomized along with 
reason of screen failure will be presented using the Screening analysis set.   
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The number of patients randomized, randomized and treated, randomized and not treated, and the number 
of patients in the analysis sets will be summarized per treatment arm.  
The number and percentage of patients will also be summarized per treatment arm for the following patient 
disposition categories: 
 
Completed the study 
 
Completed treatment phase, 
 
Discontinued IMP early and the reason for discontinuation, 
 
Discontinued from the study early and the reason for discontinuation, 
 
Completed the follow-up visit. 
 
Descriptive statistics for time in study (as detailed in Section 10.8) will be provided by treatment arm.  
Summaries of patient disposition will be repeated for the different subgroups presented in Table 9.3-1.  
A tabulation of the number and percentage of patients randomized at each center will be presented by 
country per treatment arm and overall. 
The number and percentage of randomized patients will also be summarized by randomization strata as 
recorded by the IRT. Additionally, a description of each randomization strata will be presented by the strata 
entered into the eCRF (representing the actual stratification factor in case of mis-stratification) and overall. 
The number and percentage of randomized patients attending each scheduled visit will be summarized by 
treatment arm and overall. 
All patient’s disposition data will be listed, including membership of analysis sets.. 
12.2 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment arm and overall using 
appropriate summary statistics as described in Section 12.0 for the FAS and the SAF, unless otherwise 
stated. If the FAS and SAF are the same and actual treatment arm is the same as the randomized treatment 
arm for all patients then summaries will only be presented for the FAS. 
Definitions for baseline assessment are given in Section 10.4. 
Demographic information, baseline characteristics, and disease history data will be presented in data 
listings.  
12.2.1 Demographics Characteristics 
The following demographic and baseline characteristics will be summarized: 
 
Age (years), as a continuous variable (defined in Section 10.11) 
 
Age groups (< 18, ≥ 18 to < 45; ≥ 45 to < 65, ≥ 65) 
 
Gender (Male, Female) 
 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian 
or other Pacific Islander, other) 
 
Prior Cannabis Use (Yes, No) 
 
Region (USA and Non–USA) 
o 
Country (Poland, Czech Republic, Romania, United Kingdom, Ireland, Canada, New 
Zealand, USA) 
 
 
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12.2.2 Baseline Physical examination 
The following baseline physical examination will be summarized. 
 
Baseline weight (kg) 
 
Baseline BMI (kg/m2) 
 
Baseline BMI (kg/m2) category (< 18.5; ≥ 18.5 and < 25.0; ≥ 25.0 and < 30.0; ≥ 30) 
As defined in Section 10.12. 
12.2.3 Baseline Vital Signs 
The following baseline vital signs (collected at Screening) including with postural drop assessment will be 
summarized. 
 
Screening Supine Systolic blood pressure (SBP) (mmHg),  
 
Screening Orthostatic SBP (mmHg) 
Orthostatic SBP being defined as supine SBP- Standing SBP, 
 
Screening Orthostatic SBP ≤ - 20 mm Hg 
 
Screening Supine Diastolic blood pressure (DBP) (mmHg),  
 
Screening Orthostatic DBP (mmHg), 
Orthostatic DBP being defined as supine DBP- Standing DBP, 
 
Screening Orthostatic DBP ≤ - 10 mm Hg 
 
Screening Supine Heart Rate (HR) (Beats/min),  
 
Screening Orthostatic HR (Beats/min) 
Orthostatic HR being defined as supine HR- Standing HR, 
 
Proportion of patients who meet criteria for orthostatic hypotension defined as either drop in SBP 
of 20 mmHg or greater or drop in DBP of 10 mmHg or greater. 
12.2.4 Medical History 
Previous and current medical condition (medical history) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 23.0 or higher and summarized by system organ class (SOC) and 
preferred term (PT) per treatment arm and overall, in the FAS. 
12.2.5 Disease Characteristics 
The following disease characteristics will be summarized: 
Multiple sclerosis diagnosis 
 
MS subtype (primary progressive, secondary progressive, relapsing-remitting), 
 
Time since diagnosis of MS (year) 
 
Age at diagnosis of MS (year) 
 
Time since onset of spasticity due to MS (expressed in month or year as appropriate), 
 
Age at onset of spasticity due to MS (year) 
 
Time between MS diagnosis and onset of spasticity due to MS (expressed in month or year as 
appropriate) 
 
Also presenting the number and percentage of patients experiencing spasticity before MS 
diagnosis. 
 
Number of relapses in the past 12 months 
 
Time since last relapse (expressed in months or years as appropriate 
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 
Expanded Disability Status Scale (EDSS) score 
 
Ambulatory Status 
As defined in Section 10.13).  
Current MS medication  
The following summaries relating to current (are defined in Section 12.3.2) MS medications will be provided:  
 
At least 1 MS medication (y/n) 
 
Current use of antispasticity medication  
 
Baclofen (y/n) 
 
Tizanidine (y/n) 
 
Dantrolene (y/n) 
 
Benzodiazepine (y/n) 
 
Muscle relaxants (y/n) 
 
Botulinum toxin (y/n) 
 
Gabapentin (y/n) 
 
Pregabalin (y/n) 
 
Other (y/n) 
 
Number of antispasticity medications  
 
0 
 
1  
 
2  
 
≥ 3 
 
At least 1 MS disease-modifying drug (DMD) (y/n) 
 
Current use of medication to treat other MS Symptoms  
 
Dalfampridine (y/n) 
 
Fampridine (y/n) 
Current MS medications are those taken at time of randomization/1st IMP dosing as described in Section 
12.3.2). They will be determined based on information captured in the eCRF “Concomitant medication” 
form; further determination criteria being given in Appendix 8. 
Prior use of cannabis or cannabinoid products 
At Screening (Visit 1), any intermittent or regular previous use of cannabis or cannabinoid products for 
medical or recreational purposes will be recorded on the Prior Cannabis Use CRF form. 
Prior use of cannabis or cannabinoid products will be summarized for the following 
 
Prior use of cannabis or cannabinoid products (PUC) (y/n) 
 
For PUC = Y: Medicinal use (y/n) 
 
For PUC = Y: Recreational use (y/n) 
12.2.6 Baseline Efficacy Endpoints 
The following baseline efficacy endpoints will be summarized 
 
The baseline 28-day average daily spasm count 
 
The baseline 28-day average 11-point NRS spasm severity score 
 
The baseline MSSS-88 total score 
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 
The baseline MSSS-88 muscle spasms count score 
 
The baseline MSSS-88 muscle stiffness score 
 
The baseline MSSS-88 pain and discomfort score, 
 
The baseline 7-day average 11-point NSR spasticity score 
As defined in Section 10.17, Section 10.18, Section 10.19 and Section 10.20. 
12.2.7 Baseline Safety Endpoints 
The following baseline safety endpoints linked to renal function and C-SSRS will be summarized. 
 
Renal function (as defined in Section 10.14) 
 
Baseline eGFR (ml/min/1.73m²) 
 
Baseline eGFR category: ≥ 90 as normal, ≥ 60 and < 90 as mild reduction, ≥ 30 and < 60 
as moderate reduction, ≥ 15 and < 30 as severe reduction, <15 as kidney failure 
 
C-SSRS (as defined in Section 10.25) 
 
C-SSRS baseline Suicidal ideation score 
 
Baseline Suicidal Behavior (Yes/No) 
12.3 Treatments 
12.3.1 Extent of IMP Exposure 
Exposure to IMP, IMP dosing, treatment compliance and drug accountability will be presented by treatment 
arm using the SAF.  
12.3.1.1 Duration of Therapy 
The following parameters (as defined in Section 10.8) will be presented by treatment arm for the on-
treatment period. 
 
duration of exposure 
 
total exposure (patient-years) 
 
categorized duration of exposure (1 to 14 days, 15 to 28 days, 29 to 56 days, 57 to 84 days, 85 to 
91 days, > 91 days) 
 
cumulative duration of exposure (>= 1 day, > 14 days, > 28 days, > 56 days, > 84 days, > 91 days) 
12.3.1.2  IMP Dosing 
Patients are expected to record daily the number of morning and evening spray(s) they have taken in their 
eDiary.  
At Visit 3, Day 15 (end of the titration phase), the daily number of sprays to be taken by each patient, 
defined as the optimized dose, will be reported in the eCRF “Dose adjustment” form. 
Whenever a patient has taken an amended dose, this will also be reported in the eCRF “Dose adjustment” 
form along with start and stop date of each amendment dose and the reason why the optimized dose was 
amended (i.e., adverse event, insufficient therapeutic effect, other). 
The optimized dose will be summarized as quantitative and categorical variable per treatment arm. The 
need of optimized dose adjustment will also be described along with reason for adjustment. Furthermore, 
the final optimized dose (as described in Section 10.10 will also be described). 
The following parameters (as defined in Section 10.9 and Section 10.10) will be summarized by treatment 
arm for the titration, maintenance and on-treatment periods (as defined in Section 10.2.2) 
 
the percent of missing diary day information (%) 
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 
the percent of “0” total daily sprays (%) 
 
the percent of >12 total daily sprays (%) 
 
the mean number of daily sprays (maintenance and on-treatment periods only) 
 
categorized mean number of daily sprays (≤6 sprays, > 6 to ≤ 12 sprays and >12 sprays) 
(maintenance and on-treatment periods only) 
 
the maximum number of sprays 
 
the modal number of sprays (maintenance and on-treatment periods only) 
The mean (± SD) number of sprays will be presented by day using a line plot by treatment arm. 
12.3.1.3 Compliance 
The following parameters (as defined in Section 10.10) will be summarized by treatment arm for the 
maintenance period (as defined in Section 10.2.2): 
 
the percent compliance (%) 
 
the categorized percent compliance (< 80%, ≥ 80% to < 90%, ≥ 90% to < 100% and = 100%) 
12.3.1.4 Drug Accountability 
IMP accountability including IMP total dispensed (mm), total returned (mm), total IMP used (mm), total IMP 
used (sprays) (as defined in Section 10.10) will be listed. 
Additionally, patient will be triggered for drug accountability by the MADDERS® adjudication committee as 
described in Section 8.4. 
12.3.2 Prior, Concomitant and Prohibited Medications 
For any medications/nondrug therapies initiated or ongoing since Visit 1 (Screening), the start and stop 
date, dose, unit, frequency, route of administration, and indication will be recorded respectively in the 
‘Concomitant Medication’ eCRF page and in the ‘Concomitant Physiotherapy’ eCRF page. 
As nabiximols is being investigated as therapy in patients with spasticity due to MS, all patients must 
currently be taking at least 1 optimized oral MS antispasticity medication. Optimized oral MS antispasticity 
medications will include at least baclofen, tizanidine, and/or dantrolene (monotherapy or combination 
therapy). Their MS antispasticity medication must have been stable for at least 30 days prior to Screening 
(Visit 1) and the medication is expected to remain stable throughout the duration of the trial. 
All Medications will be categorized by medication anatomic and therapeutic class (ATC) according to the 
most current version of World Health Organization-Drug Dictionary (WHO-DD) global March 2020 
Dictionary Version B3 or higher according to the version in use at the time of database lock. 
Medication used for MS will also be categorized according to information recorded in the CRF as: 
 
Disease modifying drug, 
 
Anti-spasticity drug (baclofen, tizanidine, dantrolene, benzodiazepine, muscle relaxants, 
botulinum toxin, gabapentin, pregabalin), 
 
Other MS symptoms. 
Whereas physiotherapy used will be categorized according to the reason recorded in CRF as: 
 
Spasticity, 
 
Adverse events (other than spasticity), 
 
Other MS symptoms, 
 
Other symptoms not associated MS. 
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Patients should stop taking any prohibited therapy prior to Screening (Visit 1) and also within 30 days of 
Visit 1 for cannabis for medical or recreational purposes or any cannabinoid-based medication. These 
medications are prohibited for the duration of the trial.  
Prohibited medications are categorized as: 
 
Nabiximols, cannabis or cannabinoid-based derived product (see Appendix 7), 
 
Botulinum toxin injections (see Appendix 7), 
 
Antipsychotic medications (see Appendix 7), 
 
Benzodiazepines (if not following protocol requirements) (see Appendix 7), 
 
Medications that are solely metabolized by UGT1A9 (see Appendix 5), 
 
Medications that are solely metabolized by UGT2B7 (see Appendix 5), 
 
Strong CYP3A4 inducers or inhibitors (eg, rifampicine, carbamazepine, phenytoin, phenobarbital, 
St John’s Wort) (see Appendix 6). 
In order to flag prohibited medications taken in the study, each medication taken will be compared against 
a pre-specified list of all prohibited medications as presented in Appendix 5, Appendix 6 and Appendix 7 
along with their determination criteria. 
All medications/ non-drug therapy (eg, physiotherapy) will be classified as follows: 
 
Prior medications are those the patient used prior to the IMP Start Date and discontinued before 
first administration. 
 
Current medications are those that the patient used at time of randomization and at the same 
time as IMP intake. This classification will mainly be used to summarize MS medications. 
 
Concomitant medications are any medications / non-drug therapies that are ongoing at the time 
of first dose; these medications can be initiated 
 
Before first intake of study medication. 
 
At the same time of study medication. 
 
Post treatment medications (FU medications) are any medications /non-drug therapies initiated 
following IMP End Date. 
In order to classify each therapy in case of missing / partial start and /or stop date, imputation rules as 
described in Section 10.15 will be applied. 
All medications / non-drug therapies (including physiotherapies) taken during the trial will be summarized 
by treatment arm for the SAF. If it appears that the randomized treatment arm is different from the actual 
treatment arm and/or if patients belonging to the SAF are different from those belonging to the FAS. All the 
summaries will be presented using both study populations. 
The number and percentage of patients using each medication along with the number and percentage of 
patients using at least one medication within each medication group will be summarized. 
All medications and all physiotherapy will be separately listed. 
12.3.2.1 Non-MS medications 
Prior medications: The number and percentage of patient taking each non-MS prior medication will be 
summarized by treatment arm and overall, according to the first digit of the ATC class (anatomic category), 
first 3 digits of the ATC class (pharmacological category) and standard medication name. 
Concomitant medications: The number and percentage of patient taking each non-MS concomitant 
medication will be summarized by treatment arm according to the first digit of the ATC class (anatomic 
category), first 3 digits of the ATC class (pharmacological category) and standard medication name. 
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Post-treatment medications: The number and percentage of patient taking each non-MS post-treatment 
medication will be summarized by treatment arm according to the first digit of the ATC class (anatomic 
category) and first 3 digits of the ATC class (pharmacological category) and standard medication name. 
Tables for non-MS prior, concomitant and post-treatment medications will be sorted by decreasing 
frequency of anatomic class followed by pharmacological class, followed by standard medication name 
based on the incidence in the nabiximols treatment arm. In case of equal frequency, based on decreasing 
frequency in the placebo arm then in case of equal frequency, the alphabetic order will be used. 
12.3.2.2 Medication used for MS 
Prior medications: The number and percentage of patient taking each MS prior medication will be 
summarized by treatment arm and overall  
 
according to the predefined categories and standard medication name. 
 
according to the according to the first digit of the ATC class (anatomic category) and first 2 digits 
of the ATC class (therapeutic category) and standard medication name 
Concomitant medications: The number and percentage of patient taking each MS concomitant medication 
will be summarized by treatment arm  
 
according to the predefined categories and standard medication name.  
 
according to the according to the first digit of the ATC class (anatomic category) and first 2 digits 
of the ATC class (therapeutic category) and standard medication name 
Post-treatment medications: The number and percentage of patient taking each MS post-treatment 
medication will be summarized by treatment arm  
 
according to the predefined categories and standard medication name. 
 
according to the according to the first digit of the ATC class (anatomic category) and first 2 digits 
of the ATC class (therapeutic category) and standard medication name 
Tables for MS prior, concomitant and post-treatment medications based on predefined category will be 
sorted by decreasing frequency of standard medication name based on the incidence within each 
predefined category in the nabiximols treatment arm. In case of equal frequency, based on decreasing 
frequency in the placebo arm then in case of equal frequency, the alphabetic order will be used. 
Tables for MS prior, concomitant and post-treatment medications based on ATC will be sorted by 
decreasing frequency of anatomic class followed by therapeutic class, followed by standard medication 
name based on the incidence in the nabiximols treatment arm. In case of equal frequency, based on 
decreasing frequency in the placebo arm then in case of equal frequency, the alphabetic order will be used. 
12.3.2.3 Prohibited Medication  
Prior medications: The number and percentage of patient taking prohibited prior medication will be 
summarized by treatment arm and overall, according to the predefined categories and standard medication 
name.  
Concomitant medications: The number and percentage of patient taking prohibited concomitant medication 
will be summarized by treatment arm according to the predefined categories and standard medication 
name.  
Tables for prohibited prior medications will be sorted by decreasing frequency of standard medication name 
within each predefined category based on overall incidence. In case of equal frequency, the alphabetic 
order will be used. 
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Tables for prohibited concomitant medications will be sorted by decreasing frequency of standard 
medication name based on the incidence within each predefined category in the nabiximols treatment arm. 
In case of equal frequency, based on decreasing frequency in the placebo arm then in case of equal 
frequency the alphabetic order will be used. 
12.3.2.4 Physiotherapy 
Summary of use of Physiotherapy will be summarized for each category using the same approach as the 
one used for MS medication presented by predefined categories. 
12.4 Important Protocol Deviations 
All important protocol deviations (IPDs) are defined in a study specific protocol deviation guidance and 
classified as presented in Table 12.4-1. 
The IPDs that are determined to affect the primary efficacy results will be classified as major IPDs as 
reported in Table 12.4-2. 
The occurrence of major IPDs will identify which patients are excluded from PP analysis set. 
Furthermore, IPD linked to COVID-19 will be identified. 
Patients for which at least one IPD has been identified will be listed along with their deviation reason, 
demographics and randomized treatment arm for inclusion in the clinical study report (CSR) based on the 
deviation data entered into an internal system of record named Predictive Study Operations (PSO). 
The study team and the Sponsor will conduct ongoing reviews of the deviation data from PSO in which 
deviation and the resulting set of evaluable patients throughout the study, adjusting the deviation criteria as 
seems appropriate. The PP analysis set must be finalized at the post-freeze data review meeting (or 
earlier), prior to database lock and unblinding. However, if a patient received a treatment kit he/she is not 
allocated to, this will be considered as a major IPD before unblinding but the impact on the PP analysis set 
will only be determined following unblinding. This particular case will clearly be identified prior to database 
lock. 
Based on the FAS, the number and percentage of patients with at least: 
 
one IPD by category,  
 
one IPD linked to COVID-19 by category,  
 
one major IPD by category,  
 
one major IPD linked to COVID-19 by category,  
will be summarized by randomized treatment arm and overall. 
Using the FAS and the SAF (if deemed necessary to account for any patients exposed out of randomization) 
important protocol deviations will be listed by treatment arm and patient identifier and flagged for belonging 
to FAS and SAF. In this listing, major IPDs and IPDs linked to COVID-19 will be identified. 
Furthermore, a COVID-19 deviation listing identifying IPDs COVID-19 related will be issued including date 
of the deviation and duration of the impact. 
 
 
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Table 12.4-1 List of Important Protocol Deviation Category 
Number 
Important protocol deviation category 
01 
Inclusion criteria 
02 
Exclusion criteria 
03 
IMP 
04 
Assessment safety 
05 
Efficacy endpoint data 
06 
Visit window 
07 
Prohibited co-medication 
08  
Overdose/misuse 
09 
Randomization irregularities 
10 
Other 
 
Table 12.4-2 List of Major Important Protocol Deviation Category 
Number 
Major important 
protocol deviation 
category 
Major important protocol deviation criteria (IPD definition) 
01 
Inclusion criteria 
Patient was not diagnosed with any disease subtype of MS, by revised 
2017 McDonald criteria, for at least 12 months prior to Visit 1. 
02 
Inclusion criteria 
Was not treated with at least 1 optimized oral MS antispasticity therapy 
prior to Visit 1 that must include at least oral baclofen or oral tizanidine 
(monotherapy or combination therapy) The dose of the optimized oral MS 
antispasticity therapy should have been stable for at least 30 days before 
Visit 1 and should remain unchanged between Visit 1 and Visit 2. 
03 
Inclusion criteria* 
Did not complete at least 90% of their electronic daily diary reporting 
during the baseline period (at least 26 completed days) 
if < 15 days completed diary data and /or >= 10 consecutive days missing 
diary data 
04 
Inclusion criteria 
Did not have an average daily spasm count of ≥ 4 during the baseline 
period, as recorded by the patient 
06 
Inclusion criteria 
Has more than 35 spasms on any single day of the baseline period, as 
recorded by the patient 
07 
Inclusion criteria 
Patient had > 7 consecutive days without experiencing any spasm during 
the baseline period 
08 
Exclusion criteria 
Previously participated in a clinical trial of nabiximols or has had a poor 
previous response or intolerance to nabiximols or other cannabinoid 
containing products used for therapeutic purposes. 
09 
Exclusion criteria 
Any concomitant disease or disorder that has spasticity like symptoms or 
that may influence the patient’s level of spasticity. 
10 
Exclusion criteria 
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. 
11 
Exclusion criteria 
Has had a relapse of MS within the 60 days prior to Visit 1. 
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Number 
Major important 
protocol deviation 
category 
Major important protocol deviation criteria (IPD definition) 
12 
Exclusion criteria 
Currently using or has used cannabis or a cannabinoid derived product for 
medicinal or recreational use (within 30 days of Visit 1) and is unwilling to 
abstain for the duration of the trial. 
13 
Exclusion criteria 
Did not respond adequately to treatment with nabiximols or another 
cannabis-based medication if exposed at any time before the 30-day 
period prior to Visit 1. 
14* 
Exclusion criteria* 
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. 
For certain disorders, determined with medical monitor 
15 
Study drug 
Patient failing to acknowledge in the mobile health platform (MHP) that 
they have taken at least one spray on 4 or more days out of any 7 
consecutive days within days 57 to 84. 
16 
Study drug 
Patient randomized but not exposed to study drug 
17 
Study drug 
Patients exposed outside of randomization call to IRT. 
18 
Study drug 
Patient receiving a kit number which is not the treatment he/she was 
allocated to by IRT. 
19 
Efficacy endpoint data 
Missing evaluable average daily spasm count pre-dose assessment  
20 
Efficacy endpoint data 
Missing evaluable post baseline average daily spasm count assessment 
21 
Efficacy endpoint data 
Missing evaluable on-treatment Day 85 (between Day 57 and Day 85) 
average daily spasm count assessment  
22 
Prohibited medication 
Patient taking antipsychotic medication at any time during the trial. 
23 
Prohibited medication 
Patient taking benzodiazepine on an as needed (PRN) basis during the 
trial 
24 
Prohibited medication 
Patient taking commercial cannabis or any cannabinoid medication during 
the trial. 
25 
Prohibited medication 
Patient taking botulinum injection during the trial 
26 
Prohibited medication 
Initiation or changes in the dose of MS disease modifying therapy any time 
after randomization at Visit 2 
27 
Prohibited medication 
Initiation of a new course of physiotherapy any time after Visit 1  
28 
Prohibited medication 
Patient taking drugs solely metabolized by UGT1A9 and UGT2B7 during 
the trial 
29 
Prohibited medication 
Patient taking strong CYP3A4 inducer or inhibitor during the trial 
30 
Prohibited medication 
Patient changing dose or introducing antispasticity medication (baclofen, 
tizanidine, dantrolene) 
31 
Prohibited medication 
Patient changing dose or introducing dalfampridine or fampridine 
32 
Randomization 
irregularities 
Deviation description with regards to randomization specification 
33 
Randomization 
irregularities 
Stratification error: region mis-stratification  
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Number 
Major important 
protocol deviation 
category 
Major important protocol deviation criteria (IPD definition) 
34 
Randomization 
irregularities 
Stratification error: prior cannabis use mis-stratification 
PRN = pro re nata meaning as needed; MS = Multiple sclerosis; IPD = important protocol deviation; 
IRT = Interactive response technology 
* Refers to important protocol which may or not be considered as major important deviation 
12.5 Efficacy Analyses 
All efficacy analyses, unless otherwise specified, will be performed on the FAS during the 12-Week 
randomized period (as defined in Section 10.2.2) regardless of treatment compliance and permanent 
treatment discontinuation. 
To assess robustness of the results with regards to intercurrent events some analyses may be repeated, 
for instance: 
 
During the 12-week on-treatment period (as defined in Section 10.2.2), using only on-treatment 
assessments, 
 
During the 12-week randomized period (as defined in Section 10.2.2), using the PP analysis set, 
 
During the 12-week randomized period excluding patients having at least one missing 
assessment due to COVID-19. 
12.5.1 Hypothesis Testing Strategy and Multiplicity 
To control for Type 1 error, the primary endpoint and secondary efficacy endpoint will be tested 
hierarchically, (see Section 12.5.3) starting with the primary endpoint and followed by the key secondary 
endpoint. No additional adjustments for multiplicity will be made for other secondary or the exploratory 
endpoints. 
12.5.2 Primary Endpoint 
The primary endpoint is the change from baseline in the average daily spasm count (Week 9 to 12) 
compared to the average daily spasm count for the baseline period) as described in Section 10.17. 
12.5.2.1 Primary Efficacy Analysis 
The primary analysis on the primary estimand (see Section 9.1) will be analyzed using mixed model 
repeated measures (MMRM) performed with the SAS® MIXED procedure. The comparison between 
nabiximols and placebo will be performed at a type I error level of 0.05 (two-sided). 
This model will include the baseline average daily spasm count and all the available post baseline average 
daily spam counts (as described in Section 9.1) from all patients from the FAS. 
The preferred model will include the fixed categorical effects of treatment arm, timepoint, randomization 
strata of prior cannabis use, randomization strata of region, treatment arm-by-timepoint interaction, as well 
as continuous fixed covariates of baseline average daily spasm count, and baseline-by-timepoint. The 
timepoint effect repeated within each patient will be included as a repeated effect. 
An unstructured matrix will be used to model the within-patient error variance-covariance. The denominator 
degrees of freedom will be calculated according to Kenward-Roger method. 
The timepoint effect will have 3 levels: Week 1 to 4, Week 5 to 8 and Week 9 to 12. 
Stratification classification will be obtained from the ‘Randomization eCRF’ page as this will show the true 
classification in case of mis-stratification. 
This model will provide at each time point (Week 1 to 4, Week 5 to 8, Week 9 to 12), the least squares (LS) 
mean estimates for each treatment arm, along with the standard errors and 95% confidence intervals (CIs) 
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as well as, the LS mean estimates of the treatment difference in change from baseline in average daily 
spasm count along with standard errors of the difference and 95% CIs. T-statistics corresponding to the 
Type III sum of squares for difference in least square means will be used to obtain the p-value for the 
treatment arm comparison at Week 9 to 12 (primary timepoint). 
In case of non-convergence of the preferred model or memory space issue a back-up model will be as 
mentioned in Section 12.0. 
Additionally, LS means change from baseline and 95% CI will be plotted by Week per treatment arm. 
Model assumption assessment 
Distribution of the residuals will be assessed, based on outcome of the primary efficacy endpoint as follow: 
 
The normality of the residuals will be graphically assessed presenting boxplot, histogram, QQ-
plots and scatterplot of residual versus linear predictors, based on studentized residuals obtained 
from the primary efficacy model. 
 
The distribution of the residuals obtained from the primary efficacy model will also be assessed 
using boxplots with each category of the fixed effect (ie, treatment arm, timepoint, each 
randomization strata)  
Outliers search: Outliers will be identifying based on diagnosis performed from primary outcome measure 
using boxplot, and scatterplot of residual versus linear predictors. If outliers are present, additional 
sensitivity analyses may be conducted with outliers excluded to assess their impact on the results. 
12.5.2.2 Sensitivity Analyses 
Sensitivity analyses will be carried out to assess the robustness of the results of the primary efficacy 
analysis with regard to i) the assumption that missing data are missing at random (MAR) and ii) the 
assumption that the residuals from the fitted model are from a normal distribution. 
12.5.2.2.1 Missing at random assumption for missing data 
To assess the robustness of the treatment effect with regard to missing data, sensitivity analyses based on 
Missing Not at Random (MNAR) multiple imputation (MI) models will be conducted using the FAS. 
The model will be based on a placebo-based multiple imputation approach which is a copy to reference 
model. 
From this framework; missing average daily spasm count will be imputed under MAR assumption if the 
patient withdraws from the study due to a reason related to COVID-19 or if the patient is randomized to 
placebo treatment arm and will otherwise be imputed under the control-based MNAR assumption. For those 
patients having their missing average daily spasm count assumed MNAR, their mean profile will be 
assumed to be the same as those patients in the placebo treatment arm.  
To further test the robustness of the results with regard to these imputed values, a tipping point analysis 
will be conducted.  
These analyses will be conducted on the FAS during the 12-week randomized period as defined in  
Section 10.2.2 on patients with a baseline average daily spasm count. 
12.5.2.2.1.1 Multiple Imputation 
12.5.2.2.1.1.1 Indicator variables 
The following indicator variables will be used to allow inclusion of qualitative variables in the imputation 
models or to determine the imputation strategy with regard to missing data linked to COVID-19. 
 
Treatment arm will be coded as: 
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 
DTRTP=1 for nabiximols treatment arm 
 
DTRTP=0 for placebo treatment arm. 
 
Randomization strata of region will be coded as: 
 
USA=1 for randomization strata of USA 
 
USA=0 for randomization strata of non-USA. 
 
Randomization strata of prior cannabis use will be coded as: 
 
THC=0 for randomization strata of prior cannabis use equal to Yes, 
 
THC=1 for randomization strata of prior cannabis use equal to No. 
 
Withdrawal from study due to COVID-19 will be coded as: 
 
COVID=1 if the patient withdrew from the study due to COVID-19, 
 
COVID=0 if the patient withdrew from the study due to a reason not related to COVID-19. 
12.5.2.2.1.1.2 MI models – General consideration  
Back up models may be implemented if any imputation model has a non-convergence issue due to sparse 
data or a memory space issue, removing randomization strata as described in Section 12.0. 
Each imputation model will use a common random seed value of 20220012 apart for the MCMC stage for 
which the random seed number will be 20220018.  
Linear mixed model applied to each imputed dataset: each imputed dataset will be analyzed using the same 
MMRM as the one used to assess the primary efficacy endpoint (as described in Section 12.5.2.1).  
12.5.2.2.1.1.3 Missing data description  
Description of missing data patterns will present the number and percentage of patients within each missing 
data pattern by treatment arm for the average daily spasm count (as defined in Section 10.17). 
Description of 4-week average daily spasm count monotone missing pattern will be performed by treatment 
arm, presenting the number and percentage of patients within each of the following monotone missing data 
pattern: 
 
Pattern 1: Patient with no baseline average daily spasm count 
 
Pattern 2: Patient with a baseline average daily spasm count but no post-baseline average daily 
spasm count 
 
Pattern 3: Patient with a baseline average daily spasm count and a Week 1 to 4 average daily 
spasm count only 
 
Pattern 4: Patient with a baseline average daily spasm count and average daily spasm count up 
to Week 5 to 8 
 
Pattern 5: Patient with a baseline average daily spasm count and average daily spasm count up 
to Week 9 to 12. 
This summary will also provide Mean (SD) at Baseline, Week 1 to 4, Week 5 to 8 and Week 9 to 12 for 
each monotone missing data pattern. 
Graphical summary of: 
 
Monotone missing data pattern presenting by treatment arm  
 
Average daily spasm count mean (±SD) at baseline, Week 1 to 4, Week 5 to 8 and Week 9 to 12,  
 
Change in average daily spasm count mean (±SD) from baseline to Week 1 to 4, Week 5 to 8 
and Week 9 to 12 
will also be provided. 
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12.5.2.2.1.1.4 Monotone missing data pattern 
Prior to performing any imputation method as described below, since in general the missing data pattern 
will not be monotone, intermittent missing average daily spasm count will be imputed under a MAR model 
using a Markov Chain Monte Carlo (MCMC) method to generate monotone missing data patterns. 
This will be performed using the MCMC method in conjunction with the MONOTONE statement of the SAS® 
MI procedure to partially impute post-baseline average daily spasm counts, separately for each treatment 
arm to create one thousand imputed datasets. 
Therefore, the MCMC model will include factor and covariate in the following order, indicator variables for 
randomization strata of region and prior cannabis use and for treatment arm as well as baseline average 
daily spasm counts and average daily spasm counts for each time period (ie, Week 1 to 4, Week 5 to 8 and 
Week 9 to 2). 
Details regarding indicator variables and back-up models are described respectively in Section 12.5.2.2.1.1 
and in Section 12.0. 
12.5.2.2.1.1.5 Pattern Mixture Model (PMM) Placebo-based Multiple Imputation method 
The pattern mixture placebo-based multiple imputation method which is a “copy to reference method” will 
be implemented using baseline average daily spasm count to predict Week 1 to 4, Week 5 to 8 and Week 
9 to 12 average daily spasm counts in a MNAR model. 
For each of the 1,000 monotone datasets generated as described in Section 12.5.2.2.1.1.4, the remaining 
missing data will be imputed separately for each treatment arm using the REGRESSION method in 
conjunction with the MONOTONE statement and either MNAR statements (for nabiximols treatment arm 
following first model imputation strategy described in Section 12.5.2.2) or MAR statement (for either placebo 
treatment arm or nabiximols treatment arm following first model imputation strategy described in Section 
12.5.2.2) of the SAS® MI procedure. 
 
Step 1, the imputation model will create 1,000 monotone datasets, as described in Section 
12.5.2.2.1.1.4. 
 
Step 2, 
 
For patients on the nabiximols treatment arm who withdraw from the study due to a reason 
not related to COVID-19 with non-missing baseline average daily spasm count but non-
intermittent missing post baseline average daily spasm count at Week t (eg, Week 1 to 4,  
Week 5 to 8, Week 9 to 12), the active arm baseline will be used to predict each missing 
Week t average daily spasm count using non missing baseline and Week t average daily 
spasm count from patients on placebo treatment arm. The indicator representing 
randomization strata will be included in modelling the MNAR process in the same order in 
step 1 (as described in Section 12.5.2.2.1.1.4). Therefore, the model used to generate 
nabiximols  
Week t average daily spasm count will include, in the following order, indicator variables 
representing randomization strata of region and prior cannabis use, and baseline average 
daily spasm count. 
 
While for patients on the nabiximols treatment arm who withdraw from the study due 
COVID-19 with non-missing baseline average daily spasm count but non-intermittent 
missing post baseline average daily spasm count at month t (eg, Week 1 to 4, Week 5 to 
8, Week 9 to 12), missing average daily spasm will be imputed sequentially at each 
assessment using a MAR imputation based on all non-missing average daily spasm count 
from that Week and data from prior Week (after imputation). The indicator variables for 
randomization strata of region and prior cannabis use will be included in the modelling of 
the MAR process in the same order as in Step 1 (as described in Section 12.5.2.2.1.1.4). 
Therefore, the model used to generate Week 9 to 12 average daily spasm count will 
include, in the following order, randomization strata of region and prior cannabis use as 
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well as baseline average daily spasm count and all average daily spasm count values 
(Week 1 to 4 and Week 5 to 8). 
 
And for patients on the placebo treatment arm with non-missing baseline average daily 
spasm count but non-intermittent missing post baseline average daily spasm count at 
Week t (eg, Week 1 to 4, Week 5 to 8, Week 9 to 12), missing average daily spasm count 
will be imputed sequentially at each assessment using a MAR imputation based on all non-
missing average daily spasm count from that Week and data from prior Week (after 
imputation). The indicator variables for randomization strata of region and prior cannabis 
use will be included in modelling of the MAR process in the same order as in Step 1 (as 
described in Section 12.5.2.2.1.1.4). Therefore, the model used to generate Week 9 to 12 
average daily spasm count will include, in the following order, randomization strata of 
region and prior cannabis use as well as baseline average daily spasm count and all 
average daily spasm count values (Week 1 to 4 and Week 5 to 8). 
 
Step 3, Each of the 1000 values generated from the fit of one thousand placebo-based imputation 
models for each missing average daily spasm count generated in Step 2 will correspond to a 
unique imputation number, and combination of imputed and non-missing average daily spasm 
count for each result in 1,000 complete datasets. 
 
Step 4: Imputed values from each of the 1,000 imputation datasets selected from Step 3 and non-
missing average daily spasm count will be analyzed by MMRM as described in Section 12.5.2.1. 
In case of non-convergence the model will be modify/simplified as described in Section 12.0. 
 
Step 5: Result from each MMRM model will be combined as described in Section 12.5.2.2.1.1.6. 
12.5.2.2.1.1.6 Combining multiple imputation results 
The analysis models will be evaluated in each imputed dataset and, the point estimates and SEs will be 
combined using Rubin’s rules to produce valid global estimates with corresponding CIs and p-values. SAS® 
MIANALYZE procedure will be used for this purpose. 
12.5.2.2.1.2 Tipping point analyses 
Using monotone datasets generated as described in Section 12.5.2.2.1.1.4, the remaining missing data will 
be imputed using a REGRESSION method in conjunction with the MONOTONE statement and either the 
MNAR statement (for nabiximols treatment arm following imputation strategy described in Section 12.5.2.2) 
or MAR statement (for either placebo treatment arm or nabiximols treatment arm following imputation 
strategy described in Section 12.5.2.2) of the SAS® MI procedure. 
 
Step1, the imputation model will create 1,000 monotone datasets, as described in Section 
12.5.2.2.1.1.4. 
 
Step 2, for patients with non-missing baseline average daily spasm count, missing Week t (eg, 
Week 1 to 4, Week 5 to 8, Week 9 to 12), post baseline average daily spasm count will firstly be 
imputed using the same placebo-based MNAR MI method as the one described in Section 
12.5.2.2.1.1.5, Step 2. This MI-MNAR model will correspond to the first imputation model fit in the 
tipping-point analysis (i.e, delta=0). In subsequent models, a common (non-zero) delta value 
(where delta value represents average daily spasm count) will be added following MNAR 
imputation to each imputed average count in nabiximols treatment arm for patients with missing 
average daily spasm count not related to COVID-19 (eg, MNAR mechanism), while imputed value 
for placebo treatment arm and for patients from nabiximols treatment arm due to COVID-19 
remains as MAR (no delta addition). MNAR imputations followed by delta additions will be 
performed at each Week t (eg Week 1 to 4, Week 5 to 8, Week 9 to 12) post-treatment assessment 
and models will include in the following order, indicator variables representing randomization 
strata of region and prior cannabis use, as well as baseline average daily spasm count. 
 
For the first imputation model (delta=0) one thousand (1000) imputed datasets will be 
generated at Step 2. For the subsequent models (Delta >0), the same monotone datasets as 
those used for first imputation model (delta=0) will be retrieved. 
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 
Step 3, the thousand (1000) imputation datasets generated from each delta values will be 
analyzed by a MMRM as described in Section 12.5.2.1. 
 
Step 4, for each value of delta, results from each MMRM as described in Section 12.5.2.1 will be 
combined is described in Section 12.5.2.2.1.1.6. 
 
Step 5, the tipping point will correspond to the first instance where the primary inference changes 
(i.e, p>0.05 for between treatment arm difference in LS means). Consequently, the testing (Step 
2 to Step 4) will be repeated for a plausible ẟ_nabiximols values using a grid search method. For 
example, from larger changes in delta values initially followed by smaller changes as the tipping 
point is reached. Therefore, the values of delta will be indexed and the tipping point will be given 
with a two decimal place precision. 
 
Step 6, results corresponding to each delta values will be presented within a summary table 
including combined LS mean estimate and corresponding SE and 95% CI for each treatment arm 
along with the combined LS mean estimate of the difference versus placebo along with its 
corresponding SE and confidence interval. The tipping point will be identified. 
12.5.2.2.2 Distribution assumption 
To assess the robustness of the treatment effect with regard to the assumption of normality two analyses 
will be carried out: 
12.5.2.2.2.1 Log-transformation 
The primary model as described in Section 12.5.2.1 will be repeated on the change from baseline based 
on natural log-transformations of the data (average daily spasm count).  Should any patient have an 
average spasm of zero in any of the time periods, 1 spasm will be added to averages for all patients and 
periods (including baseline) prior to log-transformation.  The natural log-transformation of the baseline will 
be used in place of the baseline average daily spasm count.  
The estimated visit/baseline ratio will be presented by treatment arm for each time point (Week 1 to 4, Week 
5 to 8, Week 9 to 12) along with their 95% CIs, using the exponential of the LS mean estimates from the 
model. The treatment ratio, at the corresponding timepoints, along with their 95% CIs will also be presented, 
based on the exponential of the difference in LS mean estimates. T-statistics corresponding to the Type III 
sum of squares for difference in LS means will be used to obtain the p-value for the treatment arm 
comparison at Week 9 to 12 (primary timepoint). 
12.5.2.3 Supplemental Analyses on Primary endpoint 
12.5.2.3.1 Subgroup Analysis  
The treatment effect across the different subgroups indicated in Table 9.3-2 will be explored on the primary 
efficacy endpoint: change from baseline at Week 9 to 12 in average daily spasm count.  
If the value of a group variable cannot be determined, the patient will be excluded from the corresponding 
subgroup analysis. 
The treatment arm-by-subgroup interaction will be assessed for the primary efficacy endpoint using the 
MMRM as described in Section 12.5.2.1 with subgroup and the subgroup-by-treatment arm interaction, 
subgroup-by-timepoint interaction and subgroup-by-timepoint-by-treatment arm interaction as 4 additional 
fixed effects.  
The subgroups mentioned in Table 9.3-2 will be used to assess subgroup–by-treatment-arm-interaction. 
The treatment estimates and difference between nabiximols and placebo, SEs and 95% CIs will be 
presented for each level of the subgroup effect by week. In addition, the p-value of the effect by treatment 
arm interaction at Week 9 to 12, testing the hypothesis that the effect level treatment differences are 
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homogeneous at the primary timepoint, will be presented.  The analysis will not be carried out for a sub-
group if one of the levels contains less than 5 patients.  
A forest plot will be used to evaluate interactions for each subgroup analysis and will display number of 
patients, estimate of treatment difference, SEs and interaction nominal p-values. 
As the study is not stratified by site it is not planned to explore the impact of site on the treatment effect.  
12.5.2.3.2 Response analysis 
The reduction from baseline to Week 9 to 12 of respectively >=20%, >=30%, >=40%, >=50% (as described 
in Section 10.17) will be analyzed using a logistic regression performed with the SAS® LOGISTIC 
procedure. The preferred model will include the randomization strata of region and prior cannabis use as 
well as the treatment arm and will be adjusted on the baseline average daily spasm count. This model will 
provide, for each response analysis, at Week 9 to 12; the estimate of the adjusted proportion of the 
responders along with corresponding CIs as well as, adjusted odds ratios (OR) representing the odds in 
nabiximols treatment arm versus placebo treatment arm and corresponding 95% Wald CI and nominal p-
values. These parameters will be summarized by treatment arm along with the number of responders and 
associated crude response rates (as percentage). 
In case of non-convergence of the preferred model because of sparse data or memory space issue back 
up models will be used firstly removing the randomization strata in the order in Section 12.0 then removing 
the baseline assessment. 
If less than 5 patients in either treatment arm are considered as responders, the unadjusted proportions 
along with the unadjusted difference of proportions and corresponding 95% CI using Chan-Zhang method 
and p-value from the Fisher’s exact test will be provided. 
12.5.2.3.3 Follow-up Analysis after End of IMP 
The change from baseline for the follow-up average daily spasm count will be analyzed during the follow-
up period using the FUAS by the mean of an analysis of covariance (ANCOVA) using the same approach 
as the one presented in Section 12.5.4.4. 
Descriptive statistics on the baseline for the follow-up analysis, follow-up, change and relative change from 
baseline will be provided using the FUAS. 
12.5.2.3.4 Impact of Intercurrent event 
12.5.2.3.4.1 Impact of -treatment discontinuation 
The robustness of the treatment effect with regards to off-treatment data (IMP discontinuation) will be 
assessed as follows: 
 
The change from baseline to Week 9 to 12 will be analyzed on the FAS using the same MMRM 
model (see Section 12.5.2.1) as the one used to analyze the primary estimand but during the 12-
week on-treatment period (as defined in Section 10.2.2) using on-treatment average daily spasm 
count (as defined in Section 10.17). 
12.5.2.3.4.2 Impact on major important protocol deviation 
If more than 10% of patients from FAS are excluded in the PP Analysis Set; the robustness of the  
28-day average daily spasm count results with regard to major IPDs will be assessed as follow. The change 
from baseline to Week 9 to 12 will be analyzed during the 12-week randomized period (as defined in Section 
10.2.2), using the same MMRM model (see Section 12.5.2.1) as the one used to analyze the primary 
estimand but using the PP analysis set. 
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12.5.2.3.4.3 Impact of COVID-19 
As average daily spasm count is an eDiary endpoint, impact on COVID-19 will be assessed based on 
whether there was an important protocol deviation relating to missing primary endpoint data (ie major IPD 
20 or 21 in Table 12.4-2) indicated as being related to COVID-19 (see Section 12.4). 
The change from baseline to Week 9 to 12 will be analyzed on the FAS during the 12-week randomized 
period (as defined in Section 10.2.2), using the same MMRM model (see Section 12.5.2.1) as the one used 
to analyze the primary estimand but removing that patients that had missing spasm count data related to 
COVID-19. This analysis will only be carried out if at least 5 patients are indicated as having missing data 
spasm count data related to COVID-19. 
12.5.2.4 Summary descriptions and listings 
The 28-day average daily spasm count, change from baseline and relative change from baseline will be 
summarized by treatment arm for each 28-day period. 
The above summary will be repeated for the subgroups presented in Table 9.3-2. 
Boxplot of 28-day average daily spasm count and change from baseline in 28-day average daily spasm 
count will be plotted by treatment arm. 
A cumulative distribution function (CDF) plot, based on the three 28-day periods, on respectively observed, 
change from baseline and relative change from baseline in daily spasm count will be provided. 
A patient listing for 28-day average daily spasm count on observed, change from baseline and relative 
change from baseline along with responder status (as defined in Section 10.17) will be presented. 
12.5.3 Secondary Efficacy Endpoint 
The family-wise Type 1 error related to the primary endpoint and the secondary efficacy endpoint will be 
controlled at 2-sided 0.05 level by a hierarchical testing procedure. 
For comparison of nabiximols treatment arm versus placebo treatment arm, if the primary endpoint is 
significant, the statistical test will be performed. The Type I error rate for comparing nabiximols treatment 
arm to placebo treatment arm for the secondary endpoint will be controlled at the nominal 0.05 level (2-
sided). The statistical test between nabiximols treatment arm and placebo treatment arm will be performed 
and inference will be provided. Otherwise, if primary endpoint does not reach the statistical significance at 
the nominal Type I error rate, p-value will be calculated but no claim could be made based on that p-value 
as per testing strategy described above. 
12.5.3.1 Primary Analyses 
The MSSS-88 is a patient self-report measure of the impact of spasticity (muscle stiffness and spasms) in 
MS. It is composed of 88 items ranging from 1 (not at all bothered) to 4 (extremely bothered). 
The secondary efficacy endpoint, change from baseline to Week 12 in of the MSSS-88 total score (as 
defined in Section 10.18) will be analyzed on patients belonging to the FAS, during the 12-week randomized 
period (see Section 10.2.2) using the same MMRM approach as the one applied to the primary efficacy 
estimand (as described in Section 12.5.2.1). However, the timepoint effect will have 2 levels: Week 8 and 
Week 12. 
The comparison between nabiximols treatment arm and placebo treatment arm will be performed following 
the testing procedure outlined above and assesses the secondary estimand (as defined in Section 9.1). 
Additionally, LS means change from baseline and 95% CI at Week 8 and Week 12 per treatment arm will 
be plotted.  
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12.5.3.2 Sensitivity Analyses 
Sensitivity analyses will be carried out to assess the robustness of the results of the primary efficacy 
analysis for the secondary estimand with regard to i) the assumption that missing data are MAR and ii) the 
assumption that the residuals from the fitted model are from a normal distribution. 
12.5.3.2.1 Missing at random assumption 
To assess the robustness of the treatment effect with regard to missing data, sensitivity analyses based on 
a MNAR MI model using a placebo-based multiple imputation approach (as described for primary endpoint 
in Section 12.5.2.2) will be conducted using FAS during the 12-week randomized period (as defined in 
Section 10.2.2. 
12.5.3.2.1.1 MI models - General consideration  
The same indicator variables as presented for the primary endpoint will be used (see Section 12.5.2.2.1.1)  
Back up models may be implemented if any imputation model has a non-convergence issue due to sparse 
data or a memory space issue, removing randomization strata as described in Section 12.0. 
Each imputation model will use a common random seed value of 20220312 apart for the MCMC stage for 
which the random seed number will be 20220318. Furthermore, any imputed value below -351 will be set 
to -351 and any imputes value above 353 will be set 353 to account for the range of change in score. 
Each imputed dataset will be analyzed using the same MMRM as the one used to assess the primary 
analysis (as described in Section 12.5.3.1). 
12.5.3.2.1.2 Missing data description  
Description of missing data patterns will present the number and percentage of patients within each missing 
data pattern by treatment arm for the MSSS-88 total score (as defined in Section 10.18). 
Description of MSSS-88 total score monotone missing pattern will be performed by treatment arm, 
presenting the number and percentage of patients within each of the following monotone missing data 
pattern: 
 
Pattern 1: Patient with no baseline score 
 
Pattern 2: Patient with a baseline score but no post-baseline scores 
 
Pattern 3: Patient with a baseline score and a Week 8 score only 
 
Pattern 4: Patient with a baseline score and score up to Week 12 
This summary will also provide Mean (SD) at Baseline, Week 8 and Week 12 for each monotone missing 
data pattern. 
Graphical summary of missing data pattern presenting by treatment arm  
 
MSSS-88 total score mean (±SD) at baseline, Week 8 and Week 12  
 
Change in MSSS-88 total score mean (±SD) from baseline to Week 8 and Week 12 
will also be provided. 
12.5.3.2.1.3 Monotone missing data pattern 
1,000 monotone datasets will be obtained using the same approach as the one used to analyze average 
daily spasm count (as described in Section 12.5.2.2.1.1.4). However, the MCMC model used to analyze 
the MSSS-88 total score will include factor and covariate in the following order, indicator variables for 
randomization strata of region and prior cannabis use and for treatment arm as well as baseline MSSS-88 
total score and MSSS-88 total score for each Week (i.e. Week 8, Week 12). 
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12.5.3.2.1.4 Pattern Mixture Model Placebo-based Multiple Imputation method 
Using the same approach as the one used for primary endpoint (as described in Section 12.5.2.2.1.1.5), a 
pattern mixture placebo-based multiple imputation method will be implemented using baseline MSSS-88 
total score to predict Week 8 and Week 12 MSSS-88 total score in a MNAR model. 
However, at Step 2 
 
For patients from nabiximols treatment arm who withdraw from the study due to a reason not 
related to COVID-19 with non-missing MSSS-88 total score but non-intermittent missing Week t 
(eg Week 8, Week 12) MSSS-88 total score, the active arm baseline will be used to predict each 
missing Week t MSSS-88 total score using non missing baseline and Week t MSSS-88 total score 
from patients on placebo treatment arm. The indicator representing randomization strata will be 
included in modelling the MNAR process in the same order as presented in Section 12.5.3.2.1.3. 
Therefore, the model used to generate nabiximols Week t MSSS-88 total score will include, in the 
following order, indicator variables representing randomization strata of region and prior cannabis 
use, and baseline MSSS-88 total score. 
 
While for patients on the nabiximols treatment arm who withdraw from the study due to a reason 
related to COVID-19 or for patients on the placebo arm with non-missing baseline MSSS-88 total 
score, but non-intermittent missing post baseline MSSS-88 total score at Week t (eg, Week 8, 
Week 12), and separately for each treatment arm, missing MSSS-88 total score will be imputed 
sequentially at each assessment using a MAR imputation based on all non-missing MSSS-88 
total score from that Week and data from prior Week (after imputation). The indicator variables 
for randomization strata of region and prior cannabis use will be included in modelling of the MAR 
process in the same order as presented in Section 12.5.3.2.1.3. Therefore, the model used to 
generate Week 12 MSSS-88 total score will include, in the following order, randomization strata 
of region and prior cannabis use as well as baseline MSSS-88 total score as well as Week 8 
MSSS-88 total score. 
12.5.3.3 Supplemental Analyses  
12.5.3.3.1 Impact of intercurrent events 
12.5.3.3.1.1 Impact on treatment discontinuation 
The robustness of the treatment effect with regards to off-treatment data (IMP discontinuation) will be 
assessed as follows: 
 
The change from baseline to Week 12 will be analyzed on the FAS using the same MMRM model 
as the one used to analyze the secondary estimand (see Section 12.5.3.1) but during the 12-
week on-treatment period (as defined in Section 10.2.2) using on-treatment MSSS-88 total score 
assessments. 
12.5.3.3.1.2 Impact on major important protocol deviation 
If more than 10% of patients from FAS are excluded in the PP Analysis Set; the robustness of the  
MSSS-88 total score with regard to major IPDs will be assessed as follow. The change from baseline to 
Week 12 will be analyzed during the 12-week randomized period (as defined in Section 10.2.2), using the 
same MMRM model as the one used to analyzed the secondary estimand (see Section 12.5.3.1) but using 
the PP analysis set. 
12.5.3.3.1.3 Impact on COVID-19 
If at least 5 patients have at least one MSSS-88 assessment impacted by COVID-19, as assessed by the 
investigator, the impact of COVID-19 on the treatment effect will be assessed on MSSS-88 total score by 
analyzing the change from baseline to Week 12 on FAS during the 12-week randomized period (as defined 
in Section 10.2.2), using the same MMRM model as the one used to analyze the secondary estimand (see 
Section 12.5.3.1) but removing that patients having at least one visit impacted by COVID-19. 
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12.5.3.4 Summary description and Listings 
The MSSS-88 total score along with the 8 subscale scores (as described in Section 10.18) will be 
summarized by treatment arm using classical descriptive statistics (as defined in Section 12.0) but also 
presenting the floor and the ceiling effect defined by the number (percentage) of patients scoring the worst 
possible (floor effect) and the best possible (ceiling effect).  
Additionally, using the ALPHA option along with the NOMISS option of the SAS® CORR procedure, the 
internal consistency of each score will be assessed using the Cronbach’s alpha coefficient. 
Boxplot of total score and change from baseline in total score by treatment arm will be presented by Week. 
CDF plot of change from baseline to Week 12 value will be plotted by treatment arm. 
A by-patient listing presenting the MSSS-88 total score along with the 8 subscale scores (as described in 
Section 12.5.4.1) and their corresponding change from baseline value will be provided. 
12.5.4 Exploratory Efficacy Analyses 
12.5.4.1 The MS Spasticity Scale 
The 88 items of the MSSS-88 scale (as presented in Section 12.5.3.1) are grouped to derive 8 subscales 
(as defined in Section 10.18) within 3 different categories which are composed of: 3 spasticity symptoms 
(i.e., muscle stiffness, pain and discomfort, muscles spams), 3 areas of physical functioning (i.e., effects on 
daily activities, ability to walk, body movement) and 2 areas of psychosocial impact (i.e., emotional health 
and social functioning). 
The same approach as the one used to analyze the MSSS-88 will be applied as primary analyses of each 
of the 8 sub-scores (as described respectively in Section 12.5.3.1).  
12.5.4.2 NRS for spasm severity  
The NRS spasm scale is ranging from 0 (no spasms) to 10 (Worst possible spasm) to assess the overall 
severity of spasm in patients with MS during the last 24 hours. 
The exploratory efficacy endpoint, change from baseline to Week 9 to 12 in 28-day average NRS spasm 
severity score (as defined in Section 10.19) will be analyzed on patients belonging to the FAS, during the 
12-week randomized period (see Section 10.2.2) using the same MMRM approach as the one applied to 
the primary efficacy estimand (as described in Section 12.5.2.1). 
The average NRS spasm severity score and change from baseline score, will be summarized by treatment 
arm for each 4-weekperiod. 
A by-patient listing presenting the average NRS spasm severity scores for the 12-week randomized period 
and the follow-up period will be provided. 
12.5.4.3 NRS for spasticity  
The NRS spasticity scale is ranging from 0 (no spasticity) to 10 (worst possible spasticity) to assess the 
overall spasticity in patients with MS during the last 24 hours. 
The exploratory efficacy endpoint, change from baseline in 7-day average daily NRS spasticity score (as 
defined in Section 10.4.1) compared to the 7-day daily NRS spasticity score from Day 78 to Day 84 (as 
described in Section 10.20). 
This exploratory endpoint will be analyzed on patients belonging to the FAS, during the 12-week 
randomized period (see Section 10.2.2) using the same MMRM approach as the one applied to the primary 
efficacy estimand (as described in Section 12.5.2.1). However, the timepoint effect will have 12 levels: 
Week 1 through to Week 12 (as defined in Section 10.20). 
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The average NRS for spasticity score and change from baseline score, will be summarized by treatment 
arm for each 1-week period 1 (as defined in Section 10.20)  
A by-patient listing presenting the average NRS spasm spasticity scores for the 12-week randomized period 
and the follow-up period will be provided. 
12.5.4.4  Timed 25-foot Walk 
A decrease in average time to complete the two trials will show an improvement. 
The change from baseline to Week 12 in average timed 25-foot walk (as described in Section 10.5 ) will be 
analyzed during the 12-week randomized period using ANCOVA performed with the SAS® MIXED 
procedure. 
This model will include all patients belonging to the FAS with a baseline average T25FW (as defined in 
Section 10.4.1) and at least one post-baseline average T25FW value (as described in Section 10.21). In 
case of premature study discontinuation before Week 12, averageT25FW values will be imputed using a 
last observation carried forwards (LOCF) methodology. 
The preferred model will include the fixed categorical effects of treatment arm, randomization strata of prior 
cannabis use and randomization strata of region as well as, the baseline average T25FW as covariate. 
The treatment arm will have 2 levels: nabiximols and placebo. 
The randomization strata of prior cannabis use will have 2 levels: Yes and No. 
The randomization strata of region will have 2 levels: USA and non-USA. 
Stratification classification will be obtained from the ‘Randomization eCRF’ page as this will show the true 
classification in case of mis-stratification. 
This model will provide the LS mean estimates for each treatment arm, along with the standard errors and 
95% confidence intervals (CIs) as well as, the least squares mean estimates of the mean treatment 
difference in change from baseline in average T25FW with the standard error of the difference and 95% CI. 
T-statistics corresponding to the Type III sum of squares for difference in LS means will be used to obtained 
nominal p-value for treatment arm comparison at Week 12. 
In case of non-convergence of the preferred model or memory space issue a back-up model will be used 
removing some of the randomization strata as mentioned in Section 12.0. 
Additionally, a plot of LS mean change from baseline and corresponding 95% CI at Week 12 per treatment 
arm.  
Descriptive statistics for the average T25FW values and change from baseline by treatment arm will be 
provided. A by-patient listing presenting observed and derived variables will be presented.  
A patient listing presenting observed and derived variables will be presented. 
12.5.4.5 Modified Ashworth Transformed Score 
Modified Ashworth Scale (MAS) Transformed Score was planned to be conducted and scored on 10 lower 
limb muscle groups (hip flexors and adductors, knee flexors and extensors, and plantar flexors) on the left 
and the right side of the body at Baseline (Day 1) and Week 12 (or early withdrawal) for all patients having 
given their informed consent before Protocol Version 5 was approved. This assessment was removed in 
Protocol Version 5. 
Consequently, no statistical analysis, description or listing will be performed on MAS scores thus no 
dedicated ADaM will be programmed. However, corresponding SDTM will be created. 
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12.6 Quality of life 
12.6.1 36-items Short Form Survey (SF-36) 
The SF-36 version 2 is a health-related quality of life (HRQOL) questionnaire. It is composed of 36 items 
used to derive 8 domain scale scores (concepts) ranging for 0 to 100% and two component summary 
measures (as described in Section 10.22). For each domain score/component summary higher 
score/measure is representing better health.  
All the analyses and summaries will be performed using the FAS during the 12-week randomized period. 
The change from baseline to Week 12 (LOCF) of each of the 8 domain scale scores and the 2 component 
summary measures (as described in Section 10.5) will be analyzed during the 12-week randomized period 
by an ANCOVA model performed with the SAS® MIXED procedure using the same approach as the one 
described in Section 12.5.4.4.  
The profile of scores will be illustrated by a plot presenting LS mean (± 95% CI) change from baseline to 
Week 12 by treatment arm of each of the 10 domain scale/component summary scores.   
The 8 domain scale scores and the 2 component summary measures will also be summarized by treatment 
arm at baseline, Week 12 (LOCF) and on change from baseline to Week 12 (LOCF) using classical 
descriptive statistics as described in (Section 12.0). 
The floor and the ceiling effect defined by the number (percentage) of patients scoring the worst possible 
(floor effect: 0) and the best possible (ceiling effect: 100%) will be also provided for the 8 domain scale 
score. 
Additionally, the internal consistency of each domain scale score (derived from more than 2 items) will be 
assessed using the Cronbach’s alpha coefficient (as described in Section 12.5.3.4). 
Furthermore, the Self-Evaluated Transition domain score will be also evaluated using a shift table from 
baseline to Week 12 (LOCF). 
A patient listing presenting observed and derived variables will be presented. 
12.7 PK Analyses  
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 Day 1 and Day 15, Day 29 or Day 75 pre-dose and at 3 different post dose timepoints as 
described in Table 10.2-2 for those patients following a semi-intensive PK draw assessment  
 
at Day 1 pre-dose and at any time during Day 15, Day 29, Day 57 and Day 85 as described in 
Table 10.2-3 for those patients undergoing a sparse PK draw assessment 
Concentration data will be summarized separately for sparse and semi-intensive regimen by analysis visit 
and predefined timepoint (semi intensive regimen only) as described respectively in Table 10.2-3 and Table 
10.2-2. 
Concentrations that are below the limit of quantification (BLQ) will be excluded from the computation of 
descriptive statistics but the number of patients presenting a concentration below the limit of quantification 
will be presented at each time point. The number of observations, mean, standard deviation, geometric 
mean, geometric standard deviation, coefficient of variation (%), median, minimum, maximum values will 
be displayed. 
Individual data will be presented in listing. 
If concentration data show that sufficient systemic exposure for THC or one or more of the metabolites is 
available, relevant PK parameters may be calculated using a population PK model. In that case, PK 
modeling will be presented a stand-alone report. 
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12.8 Safety Analyses 
The safety analyses will be conducted during the 12-week on-treatment period (as defined in Section 
10.2.2). All safety analysis will be performed by actual treatment arm (as defined in Section 9.4.1) using the 
SAF. 
Some analyses of adverse events and laboratory parameters will assess the potential impact of IMP among 
the subgroups presented in Table 9.3-3. 
12.8.1 Adverse Events 
Adverse events will be coded using MedDRA 23.0 or higher according to the version in use at time of 
database lock. All safety analyses will be performed by actual treatment arm and reported using the SAF. 
A TEAE is one that started, or worsened in severity or seriousness, following the first dose of IMP. Any 
adverse event that worsens or becomes serious after the first IMP dose are recorded as a separate AE, 
therefore for programming purposes an AE will be classified as a TEAE if it first occurs on or after the IMP 
Start Date and before the IMP End Date + 30 days.  
All AEs will be classified during the pre-treatment period, the 24-week on-treatment period or during the 
follow-up period as follows:  
 
Events that occurred before IMP Start Date are classified as pre-treatment AEs 
 
Events that occurred between IMP Start Date and 30 days after IMP End Date are considered 
on-treatment and classified as treatment-emergent AEs (TEAEs) 
 
Events occurring more than 30 days after IMP End Date are classified as follow-up AEs.  
The following counting rules will be applied: 
 
For incidence reporting, if a patient reported more than one AE that was coded to the same 
preferred term/system organ class within a given treatment arm, the patient will be counted only 
once for that specific preferred term/system organ class by treatment arm and the rules defined 
below will be applied.  
 
For TEAEs presented by action taken on IMP, the worst action taken among the events with same 
SOC/PT will be selected for each patient. If action taken is missing for a TEAE, the action taken 
“drug withdrawn” will be assigned considering the AE leads to permanent IMP discontinuation. 
The imputed values for action taken will be used for incidence summaries, while the actual values 
will be used in data listings. 
 
For TEAEs presented by severity, the worst severity among the events with same SOC/PT will 
be selected for each patient. If the severity is missing for a TEAE, then a severity of “Severe” will 
be assigned. The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings. 
 
For TEAEs presented by relationship to IMP, the relationship to IMP, as assigned by the 
investigator, for each event during the clinical trial will be presented for each patient. If the 
relationship to investigational product is missing for a TEAE, a causality of “Related” will be 
assigned. The imputed values for relationship assessment will be used for incidence summaries, 
while the actual values will be presented in data listings. 
 
For TEAEs presented by categories for time of first onset of AE, if the AE start date is missing, it 
will be imputed as specified in Table 10.23-1 for AE summary but actual values will be presented 
in data listing.  
For the purpose of inclusion in TEAE tables, incomplete AE onset dates will be imputed as specified in 
Table 10.23-1. No duration will be calculated for adverse events with incomplete start or stop dates, or for 
ongoing adverse events. 
The following denominators will be used for percentages: 
 
For summary by SOC and PT the denominator to derive the percentage will be the number of 
patients in the treatment arm. 
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 
For subgroup analysis by SOC and PT the denominator to calculate the percentage will be the 
number of patients in the treatment arm and in the category of the analyzed subgroup.  
 
For summary by SOC and PT and category of time to first onset of AE the denominator to derive 
the percentage will be the number of patients at risk in the treatment arm for in each time interval 
category. 
 
For summary by SOC and PT and category of duration of AE the denominator to derive the 
percentage will be the number of patients in the treatment arm in each time interval category. 
All summary by SOC and PT will be sorted by internationally agreed SOC order then, PT will be presented 
by alphabetical order. 
12.8.1.1 Listing of Adverse Events 
All AEs, SAEs, AEs leading to IMP discontinuation and AE with outcome of death will be listed. 
The listings will include subject identifier, actual IMP received, SOC, preferred term, investigator term, start 
and stop date of the AE, whether or not the AE was treatment emergent, duration, frequency, severity, 
relatedness, action taken, outcome, and seriousness of the AE. Imputed start or stop dates will not be 
displayed in listings of AEs. These listings will be sorted by actual treatment arm, subject identifier and 
onset of adverse events. 
12.8.1.2 Overall Adverse Event Summary 
An overall adverse event summary will provide, by treatment arm, the number of adverse events as well as 
the number and percentage of patients with at least AE in the following categories: 
 
TEAE 
 
TEAE related to IMP 
 
Confirmed or suspected COVID-19 TEAE, (as described in Section 10.23.2) 
 
TEAE leading to permanent IMP discontinuation 
 
TEAE related to IMP leading to permanent IMP discontinuation 
 
Serious TEAE 
 
Serious TEAE related to IMP 
 
AE with outcome of death 
 
AE with outcome of death related to IMP. 
12.8.1.3 All-causality Treatment-emergent Adverse Event Summaries 
Descriptive presentations of TEAEs will be given by PT and SOC for the SAF. The number and percentage 
of patients reporting at least 1 will be provided by treatment arm. As appropriate, the number of adverse 
events by SOC and PT will also be added. 
 
All TEAEs by SOC and PT 
 
All TEAEs by SOC, PT and subgroups (as described in Table 9.3-3) 
 
*Most common TEAEs (incidence ≥ 2 % in either treatment arm) by SOC and PT 
 
*Most common TEAEs (incidence ≥ 2 % in either treatment arm) by SOC, and PT and subgroups 
(as described in Table 9.3-3) 
 
All TEAEs by SOC, PT and maximum severity 
 
All TEAEs by SOC, PT and worst action taken on IMP 
 
All TEAEs by SOC, PT and time of first onset of AE categorized as: 
 
1-7 day, 8 to 14 days, 15 to 28 days, 29 to 42 days, 43 to 84 and > 84 days (as described in 
Section 10.23.3) 
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 
All TEAEs by SOC, PT and AE duration, categorized as: 
 
1-7 day, 8 to 14 days, 15 to 28 days, 29 to 42 days ,43 to 84 days ,> 84 days, ongoing, 
indeterminate (as described in Section 10.23.4) 
 
All TEAEs by SOC, PT and relationship to IMP 
 
All treatment-related TEAEs by SOC and PT and maximum severity 
 
All treatment-related TEAEs by SOC and PT and subgroups (as described in Table 9.3-3) 
 
All treatment-related TEAEs leading to permanent IMP discontinuation by SOC and PT 
 
All TEAEs leading to permanent IMP discontinuation by SOC and PT 
 
All TEAEs leading to permanent IMP discontinuation by SOC and PT and subgroups (as 
described in Table 9.3-3) 
 
All treatment-related TEAEs leading to permanent IMP discontinuation by SOC and PT and 
maximum severity 
 
All non-serious TEAEs by SOC and PT 
* These tables will not present the number of AEs by SOC/PT per treatment arm 
12.8.2 Death, Serious Adverse Events and Other Significant Adverse Events 
12.8.2.1 Death 
All deaths recorded in the EDC as adverse events, as the result of an adverse event or as fatal outcome of 
an adverse event will be listed and summarized as described in Section 12.8.1 and described in depth as 
narrative. 
Descriptive presentations of fatal TEAEs will be given by PT and SOC for the SAF. The number and 
percentage of patients reporting at least one fatal TEAE as well as the number of events within a given 
treatment arm will be provided as described below:  
 
All TEAEs leading to death by SOC and PT (if at least 2 patients experienced a fatal issue TEAE) 
 
 All treatment-related TEAEs leading to death by SOC and PT (if at least 2 patients experienced 
a fatal issue TEAE related to IMP). 
12.8.2.2 Serious Adverse Events 
Descriptive presentations of serious TEAEs will be given by PT and SOC for the SAF. The number and 
percentage of patients reporting at least one serious TEAE, as well as the number of events, within a given 
treatment arm will be provided as described below: 
 
All serious TEAEs by SOC and PT, 
 
All serious TEAEs by SOC, PT and subgroups (as described in Table 9.3-3), 
 
All serious TEAEs leading to permanent IMP discontinuation by SOC and PT, 
 
All serious treatment-related TEAEs by SOC and PT, 
 
All serious treatment-related TEAEs by SOC and PT leading to permanent IMP discontinuation 
by SOC and PT. 
12.8.3 Laboratory Data 
The clinical safety laboratory data (hematology and biochemistry) are planned to be collected at Screening, 
Visit 2, Visit 4 and Visit 6.  
For the purposes of summarization in both the tables and listings, all laboratory values will be converted 
(as needed) to SI units. The investigator and trial monitor will be provided with a list of the normal ranges 
used by the central clinical laboratory for all variables assessed during the trial and a statement of 
accreditation (or similar) for the laboratory. 
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Only scheduled laboratory parameters defined in Table 9.3-3 coming from central laboratory and those 
derived from them as eGFR (as defined in Section 10.14) will be included in summary tables. However 
unscheduled laboratory values (coming from central or local laboratories) will be used in abnormality 
summary tables and will be presented in listings (using categories as defined in Appendix 2). 
Baseline, Visit 4, Visit 6, minimal, maximal and last on-treatment values along with the change from baseline 
to Visit 4, Visit 6, minimal, maximal and last on-treatment assessment will be summarized using the SAF, 
by treatment arm, separately for red blood cells parameters and white blood cells parameters, hepatobiliary 
parameters, renal parameters, coagulation parameters and electrolytes and proteins (as described 
Appendix 1). Furthermore AST, ALT, GGT, ALP and total bilirubin will also be summarized as a multiple of 
the upper limit of normal (ULN). The definitions for minimal and maximal values are given in Section 10.24.2 
and the definition for last on-treatment value is given in Section 10.2.4. 
Laboratory, hematology and biochemistry (as described in Appendix 1) abnormalities will be evaluated, on 
patients from the SAF using shift tables from baseline to the last on-treatment value and on the most 
extreme on-treatment value (as defined in Section 10.24.2) during the 12-week on-treatment period 
according to baseline status with categories based on: 
 
Reference ranges as either normal, below the lower limit of normal (LLN) as “Low” or above the 
ULN as “High”  
 
CTCAE toxicity grade using version 5.0 or higher (as defined in Appendix 3 for hematology 
parameters and in Appendix 4 for biochemistry and urinalysis parameters), 
Additionally, shift tables by treatment arm on patients from the SAF will be used to present change in status 
category (as defined in Section 10.14) for eGFR from baseline to last on-treatment value and to the lowest 
value during the 12-week on-treatment period. 
Furthermore, a summary of patients with laboratory values outside the reference ranges at baseline and 
during the 12-week on-treatment period (as defined in Section 10.2.2) will be presented for scheduled 
parameter including either scheduled visit only or scheduled and unscheduled visits, by treatment arm. 
Regarding AST, ALT, GGT, ALP and total bilirubin these parameters will be summarized by treatment arm 
within the SAF for the 12-week on-treatment period using SI units and as a proportion of the population 
with no missing assessment if abnormal values with reference to ULN are presented using the categories 
as described in Table 12.8-1. 
Table 12.8-1 Hepatic Abnormality Criteria 
Hepatic laboratory Parameters 
Abnormality criteria 
ALT  
> 3 x ULN 
 
>5 x ULN  
 
> 8 x ULN 
 
> 10 x ULN 
 
> 20 x ULN 
AST  
> 3 x ULN 
 
>5 x ULN  
 
> 8 x ULN 
 
> 10 x ULN 
 
> 20 x ULN 
ALP 
> 1.5 x ULN 
 
> 2 x ULN 
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> 3 x ULN 
Total bilirubin 
> 1.5 x ULN 
 
> 2 x ULN 
 
> 3 x ULN 
 
> 5 x ULN 
GGT 
> 1 x ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase; 
GGT= gamma-glutamyl transferase. 
All laboratory values will be listed and all test values outside the normal range will be flagged. 
 
Urinalysis results, planned to be collected at Screening and Day 85 (end of treatment) will be 
summarized and listed 
12.8.3.1 Potential Drug-induced Liver Injury (DILI) 
Liver function test data will also be provided in separate listings for: 
 
Patients who possibly met Hy’s Law criteria (ie, had any elevated ALT or AST of >3 x ULN, and 
increase in total bilirubin >=2 x ULN, and ALP <2 x ULN at the same visit) 
 
Patients who met any one or more of the following criteria at any post-baseline visit (list laboratory 
parameters ALT, AST, ALP and total bilirubin only) 
 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
 
ALT or AST > 8 x ULN 
 
ALT or AST > 5 x ULN for more than 2 weeks 
 
ALT or AST > 3 x ULN and (TBL > 2 x ULN or INR > 1.5). 
A summary table will also be provided by treatment arm for number of patients who met any of the criteria 
specified above at any post-baseline visit during the 12-week on-treatment period. 
All post-baseline potential drug-induced liver injury laboratory data will be listed. 
12.8.4 Vital Signs 
Vital signs will include sitting systolic and diastolic blood pressure (BP) and pulse rate (PR) which are 
planned to be measured at Screening, Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7 (FU) and for last on-
treatment assessment (as defined in Section 10.2.4). 
Observed and change from baseline value in vital signs measures at each scheduled timepoint (Visit 3, 
Visit 4, Visit 5, Visit 6), at last on-treatment assessment and at Visit 7 (FU) will be summarized by treatment 
arm. 
The number and percentage of patients with any clinically significant change in vital signs (as defined in 
Table 12.8-2) during the 12-week on-treatment period will be summarized by treatment arm. Any 
measurement (scheduled or unscheduled), not taken in standing position, will be used to determine if any 
abnormality criteria is met. 
 
 
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Table 12.8-2 Blood Pressures and Pulse Rate Abnormality Criteria 
Blood 
pressures 
and 
pulse rate criteria 
Abnormality criterion value 
Abnormality criterion on change 
from baseline 
SBP 
> 180 mmHg 
≥ 20 mmHg increase from baseline 
 
< 90 mmHg 
≥ 20 mmHg decrease from baseline 
DBP 
> 105 mmHg 
≥ 15 mmHg increase from baseline 
 
< 50 mmHg 
≥ 15 mmHg decrease from baseline 
Pulse rate 
> 120 bpm 
≥ 10 bpm increase from baseline 
 
< 50 bpm 
≥ 10 bpm decrease from baseline 
SBP = Systolic blood pressure; DBP = diastolic blood pressure; bpm=beats per minutes 
to be classified as potentially clinically significant, the measurement must satisfy both criteria: the 
criterion for the value and the criterion for the change relative to baseline. 
All vital signs will be listed. 
12.8.5 Physical Examinations, ECGs, and other Observations Related to Safety 
12.8.5.1 Physical examination: Weight and BMI 
Weight is planned to be measured at Screening, Visit 2, Visit 4 and Visit 6 (early withdrawal). 
Based on the SAF weight and BMI (as defined in Section 10.12) observed and change from baseline values 
(Visit 4, Visit 6 and last on-treatment assessment (as defined in Section 10.2.4)) will be summarized by 
treatment arm during the 12-week on-treatment period. 
The number and percentage of patients meeting a clinically significant change in weight (as defined in  
Table 12.8-3) at any time during the 12-week on-treatment period will be summarized by treatment arm. All 
measurements (scheduled or unscheduled) will be used to determine if any abnormality criteria is met. 
Table 12.8-3 Weight Abnormality Criteria 
Weight criteria 
Abnormality criteria 
Weight (kg) 
≥ 7% increase from baseline 
 
≥ 7% decrease from baseline 
Weight and BMI will be listed. 
12.8.5.2 Electrocardiograms 
Based on the SAF, 12-lead ECG parameters (Heart rate (beats/min), PR interval (msec), QRS duration 
(msec), QTc B interval (Bazett’s formula) (msec), QTcF (Fridericia’s formula) and QT interval (msec) will 
be summarized by treatment arm. 
ECG results will be summarized for continuous variables and will be presented for the absolute result and 
change from baseline values (Visit 4, Visit 6 and last on-treatment value (as defined in Section 10.2.4)) by 
treatment arm for the safety population. 
The number and percentage of patient with any abnormal QTcF values or any other clinically significant 
ECG abnormality (as defined in Table 12.8-4) at baseline and within each subsequent measures performed 
during the 12-week on-treatment period will be summarized by treatment arm within the SAF. 
Interpretation of All ECG results will be listed. Furthermore, any patients fulfilling at least one ECG 
abnormality criteria (as described in Table 12.8-4) or having at least one abnormal ECG assessed as 
significant by the investigator will be listed presenting all their ECG information. 
 
 
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Table 12.8-4 ECG Abnormality Criteria 
ECG criteria 
Abnormality criteria 
QTcF interval prolongation* 
> 450 msec 
 
> 480 msec 
 
> 500 msec  
Change from baseline in QTcF interval*  
> 30 msec increase from baseline 
 
> 60 msec increase from baseline 
PR interval 
< 120 msec 
 
> 200 msec 
QRS complex 
< 80 msec 
 
> 120 msec 
HR 
< 60 bpm  
 
> 100 bpm 
*Abnormal QTcF interval categories as defined in ICH Guidelines E14  
12.8.5.3 Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a patient questionnaire that evaluates suicidal 
ideation and behaviors. In this study, the C-SSRS is assessed at Screening using the “Baseline” version 
and at subsequent timepoints using the “Since Last Visit” version.  
The C-SSRS questionnaire is planned to be administered by the investigator (or designee) at Screening, 
Visit 2, Visit 3, Visit 4, Visit 5 and Visit 6. 
Derived parameters are presented in Section 10.25. 
On-treatment assessment 
The number and percentage of patients who have answer “Yes” to each of the 5 suicidal ideation subtypes 
and each of the 5 suicidal behavior subtypes along with the number and percentage of patients presenting: 
 
A suicidal ideation  
 
A suicidal behavior 
 
A suicidal ideation or behavior 
 
A self-injurious behavior without suicidal intent. 
will be summarized at baseline, for each scheduled on-treatment timepoint, for the 12-week on-treatment 
period and for last on-treatment assessment by treatment arm. 
Shift table from baseline to maximal suicidal ideation score as well as a shift table for change in category 
(no suicidal ideation or behavior, suicidal ideation [without suicidal behavior], suicidal behavior) will also be 
summarized by treatment arm for patients having a baseline and at least 1 post baseline on-treatment 
assessment. 
The number and percentage of patients presenting a suicide-related treatment-emergent events: 
 
A treatment emergent suicidal ideation (without suicidal behavior) compared to recent history 
 
A treatment emergent serious suicidal ideation compared to recent history 
 
An emergence of serious suicidal ideation compared to recent history 
 
An emergence of suicidal behavior compared to all prior history 
will be summarized by treatment arm for the 12-week on-treatment period. 
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Observed and change from baseline in suicidal ideation score and in suicidal intensity rating score will be 
summarized at baseline and for each scheduled on-treatment timepoint, for the last on-treatment 
assessment (as defined in Section 10.2.4) and for the worst on-treatment score by treatment arm using n, 
mean, median, SD, Q1, Q3, min and max. 
Cumulative distribution function on change from baseline to last on-treatment value and to worst on-
treatment value will be plotted by treatment arm for each score. This will be displayed as increasing CDFs. 
For patients with any post-baseline suicidal ideation or suicidal behavior, listings will be prepared including 
all C-SSRS scores for these patients. 
12.8.5.4  Drug of abuse 
Drug of abuse screen (including THC) is planned to be collected at Screening and Visit 2 whereas blood 
THC test is planned to be performed at Screening. 
A by-patient listing presenting all THC measures along with urinary drug screen results will also be provided. 
12.8.5.5 Pregnancies 
Any reported positive pregnancy results or reported pregnancies will be listed. 
12.8.5.6 Examination of oral mucosa 
Based on the SAF, results of oral mucosa examination (normal, abnormal NCS and abnormal CS) will be 
described by treatment arm according to baseline status.  
Each patient presenting at least one abnormal assessment will be listed. 
12.8.5.7 Covid-19 Impact 
The impact of COVID-19 on each visit will be summarized by treatment arm and a by-patient listing 
presenting patients impacted by COVID-19 during the conduct of the trial will be provided. 
12.8.6 Monitoring of Drug Abuse Liability 
Using the Potential Misuse, abuse and diversion drug event reporting System (MADDERS) “Site 
classification form” as reported in EDC, a summary of patients triggered for potential abuse-related adverse 
events will be provided by Visit (Visit 3 (titration phase), Visit 4, Visit 5 and Visit 6), for the maintenance 
phase (Visit 4, Visit 5 and Visit 6) and for the 12-Week on-treatment period using the SAF during the 12-
week on-treatment period.  
The summary will present 
 
The number of adjudicated events 
 
The number and percentage of patients with at least one adjudicated event 
 
The number of adjudicated events related to IMP 
 
The number and percentage of patients with at least one trigger event related to IMP 
 
The number and percentage of patients by category of type of event: 
 
Tampering 
 
Withdrawal 
 
Addiction related indication 
 
Diversion 
 
Overdose 
As reported by site personnel.  
This summary will be repeated based on the final adjudication assessment.  
 
 
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Furthermore, the number and percentage of patients with at least  
 
one supplemental drug accountability form (MADDERS) completed 
 
one supplemental adverse event form (MADDERS) completed  
will also be summarized by treatment arm. 
The MADDERS medication use survey is a 6-item questionnaire, the 1st item includes 3 additional sub-
items and the 4th item has 2 parts.  Each item/sub-item is being scored as “Never”, “Seldom”, “Sometimes” 
and “Often”. The questionnaire is taken at end of treatment visit. Each item will be summarized by treatment 
arm. 
Patient wise listings of the events with respect to site/investigator classification and adjudication 
classification will be presented. 
 References 
SAS Institute Inc. 2015. Base SAS 9.4 Procedures Guide. 5th ed. Cary, NC: SAS Institute Inc.  
Rubin, D. (1976). Inference and Missing Data. Biometrika, 63(3), 581-592.  
Mary E. Nilsson, Shailaja Suryawanshi. Cristiana Gassmann-Mayer, Sarah Dubrava, Paul McSorley, and 
Kaihong Jiang Columbia-Suicide Severity Rating Scale Scoring and Analysis guide -  Version 2.0 FEB 2013 
Jill S. Fischer, Amy J. Jak, Judith E. Kniker, Richard A, Rudick, Gary Cutter, Multiple sclerosis functional 
composite (MSFC) administration – administration and scoring manual. Revised, October 2001. 2011.. 
Maruish, M. E. (Ed.). User’s manual for SF-36v2 Health Survey (3rd. ED) Lincoln, RI: QualityMetric 
Incorporated,  
Bangs ME, Tauscher-Wisniewski S, Polzer J et al. Meta-analysis of suicide-related behavior events in 
patients treated with atomoxetine. J Am Acad Child Adolesc Psychiatry. 2008;47(2):209–18 
 
 
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 Glossary of Abbreviations 
Glossary of Abbreviations: 
11-COOH-THC 
11-nor-9-carboxy-Δ9-tetrahydrocannabinol 
11-OH-THC 
11-hydroxy-Δ9-tetrahydrocannabinol 
7-COOH-CBD 
7-carboxy-cannabidiol 
7-OH-CBD 
7-hydroxy-cannabidiol 
ADaM 
Analysis dataset model 
ADL 
Activity of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ATC 
Anatomic therapeutic class 
AR(1) 
First order autoregressive 
AST 
Aspartate aminotransferase 
BDZ 
Benzodiazepine 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BP 
Bodily pain 
bpm 
Beats per minutes 
CBD 
Cannabidiol 
CDF 
Cumulative distribution function 
CFB 
Change from baseline 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019  
CRF 
Case report form 
CS 
Compound symmetric 
CS 
Clinically significant 
CSR 
Clinical study report 
C-SSRS 
Columbia-suicide severity rating scale 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
CYP 
Cytochrome 450 
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Glossary of Abbreviations: 
D 
Day 
DBP 
Diastolic blood pressure 
DILI 
Drug-induced liver injury 
DMD 
Disease modifying drug 
ECG 
12-lead electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eDiary 
Electronic diary 
EDSS 
Expanded disability status scale 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
FAS 
Full analysis set 
FU 
Follow-up 
FUAS 
Follow-up analysis set 
GGT 
Gamma-glutamyl transferase 
GH 
General health 
GW 
GW Pharma Ltd / GW Pharma Limited 
H 
Hour 
HR 
Heart rate 
HRQOL 
health-related quality of life 
hrs 
hours 
HT 
Health transition 
ICH 
International Council for Harmonization 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IPD 
Important protocol deviation 
IRT 
Interactive response technology 
KR 
Kenward-Roger 
LLN 
Lower Limit of Normal 
LOCF 
Last observation carried forward 
LS mean 
Least square mean 
M 
Month 
MADDERS 
Misuse, abuse and diversion drug event reporting system 
MAR 
Missing at random 
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Glossary of Abbreviations: 
MAS 
Modified Ashworth scale  
Max 
Maximum 
MCMC 
Markov chain Monte Carlo 
MCS 
Mental component summary 
ME 
Most extreme 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Mental health 
MHP 
Mobile health platform 
MI 
Multiple imputation 
Min 
Minimum 
MMRM 
Mixed model repeated measures 
MNAR 
Missing not at random 
MS 
Multiple sclerosis 
MSS 
Multiple sclerosis spasticity 
MSSS-88 
Multiple Sclerosis Spasticity Scale 
MUS 
Medication Use Survey 
NA 
Not applicable 
NCS 
Not clinically significant 
NRS 
Numerical rating scale 
OR 
Odds ratio 
PCS 
Physical component summary 
PF 
Physical functioning 
PK 
Pharmacokinetics 
PMM 
Pattern mixture model 
PP 
Per protocol 
PR 
Pulse rate 
PRN 
pro re nata (As-needed) 
PRO 
Patient reported outcome 
PSO 
Predictive study operations 
PT 
Preferred term 
PUC 
Prior use of cannabis 
Q1 
First Quartile / Quartile 1 
Q3 
Third Quartile / Quartile 3 
QoL 
Quality of life 
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Glossary of Abbreviations: 
QTc B 
QT corrected Bazett’s formula 
QTc F 
QT corrected Fridericia’s formula 
RE 
Role-emotional 
RP 
Role-physical 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAT 
Satterthwaite 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SE 
Standard error 
sec 
second 
SF 
Social functioning 
SF-36 
36-Item short form health survey 
SI 
Standard international 
SOC 
System organ class 
T25FW 
Timed 25-Foot Walk 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
THC 
Δ9-tetrahydrocannabinol 
TOEP 
Toeplitz 
UGT 
Glucuronosyltransferase 
ULN 
Upper limit of normal 
UN 
Unstructured 
US 
United States 
USA 
United States of America 
VT 
Vitality 
WHO-DD 
World Health Organization-Drug Dictionary 
Y 
Year 
 
 
 
 
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Scheduled Clinical Laboratory Parameters 
 
Biochemistry (Serum¹) 
Hematology (Whole Blood¹) 
Urinalysis 
(Urine²) 
Category 
Parameters 
Category 
Parameters 
Parameters 
Hepatobiliary  
Alanine 
aminotransferase 
Red blood cells  
Hematocrit 
Blood 
Hepatobiliary  
Albumin 
Red blood cells 
Hemoglobin 
Glucose 
Hepatobiliary  
Alkaline phosphatase 
Red blood cells 
Mean cell volume 
Nitrites 
Hepatobiliary  
Aspartate 
aminotransferase 
Red blood cells 
Mean corpuscular 
hemoglobin 
pH 
Electrolytes 
and proteins 
Calcium 
Coagulation parameter 
Platelets 
Protein 
Renal  
Creatinine 
Red blood cells 
Red blood cell count 
White blood cells 
Hepatobiliary  
Gamma-glutamyl 
transferase 
White blood cells 
parameters 
White blood cell count 
with automated 
differential 
Specific gravity 
Electrolytes 
and proteins 
Potassium 
 
 
Ketones 
Electrolytes 
and proteins 
Sodium 
 
 
Urobilinogen 
Hepatobiliary  
Total bilirubin 
 
 
Bilirubin 
Electrolytes 
and proteins 
Total protein 
 
 
 
Renal  
Urea (blood urea 
nitrogen) 
 
 
 
Coagulation 
parameters 
Prothrombin time 
(plasma4) 
 
 
 
¹Analyzed at a central laboratory. 
²Analyzed at the trial site by use of a dipstick (if allowed per local regulations). 
4Analyzed at Screening (Visit 1) only. 
 
 
 
 
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Unscheduled Clinical Laboratory Parameters  
 
Biochemistry (Serum) 
Hematology (Whole Blood) 
Urinalysis 
(Urine) 
Category 
Parameters 
Category 
Parameters 
Parameters 
Hepatobiliary  
Alanine 
aminotransferase 
Red blood cells  
Hematocrit 
Blood 
Hepatobiliary  
Albumin 
Red blood cells 
Hemoglobin 
Glucose 
Hepatobiliary  
Alkaline phosphatase 
Red blood cells 
Mean cell volume 
Nitrites 
Hepatobiliary  
Aspartate 
aminotransferase 
Red blood cells 
Mean corpuscular 
hemoglobin 
pH 
Electrolytes, 
proteins and 
creatinine 
kinase 
Calcium 
Coagulation parameter 
Platelet count 
Protein 
Renal  
Creatinine 
Red blood cells 
Red blood cell count 
White blood cells 
Hepatobiliary  
Gamma-glutamyl 
transferase 
White blood cells 
parameters 
White blood cell count  
Specific gravity 
Electrolytes, 
proteins and 
creatinine 
kinase 
Potassium 
White blood cells 
parameters 
Total neutrophil count 
Ketones 
Electrolytes, 
proteins and 
creatinine 
kinase 
Sodium 
White blood cells 
parameters 
Monocyte count 
Urobilinogen 
Hepatobiliary  
Total bilirubin 
White blood cells 
parameters 
Lymphocyte count 
Bilirubin 
Electrolytes, 
proteins and 
creatinine 
kinase 
Total protein 
White blood cells 
parameters 
Basophil count 
Squamous 
epithelial cells 
Renal  
Urea (blood urea 
nitrogen) 
White blood cells 
parameters 
Eosinophil count 
Mucus 
Coagulation 
parameters 
Prothrombin time 
(plasma4) 
 
 
Microscopy  
Hepatobiliary 
Amylase 
 
 
Leucocyte esterase 
Electrolytes, 
proteins and 
creatinine 
kinase 
chloride 
 
 
Color 
Electrolytes, 
proteins and 
creatinine 
kinase 
Bicarbonate 
 
 
Appearance 
Lipids 
HDL-Cholesterol 
 
 
Bacteria 
Lipids 
LDL-Cholesterol 
 
 
 
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Biochemistry (Serum) 
Hematology (Whole Blood) 
Urinalysis 
(Urine) 
Lipids 
Total Cholesterol 
 
 
 
Lipids 
Triglycerides 
 
 
 
Hepatobiliary 
Lipase 
 
 
 
Electrolytes 
and proteins 
Magnesium 
 
 
 
Electrolytes, 
proteins and 
creatinine 
kinase  
Phosphorus 
 
 
 
Renal 
Creatinine clearance 
 
 
 
Endocrinology Insulin-like growth 
factor-1 
 
 
 
Endocrinology Prolactin 
 
 
 
Renal 
Estimate glomerular 
filtration rate 
 
 
 
Coagulation 
INR 
 
 
 
Endocrinology Glucose 
 
 
 
Electrolytes, 
proteins and 
creatinine 
kinase 
Creatinine Kinase  
 
 
 
Immunology 
HBaAg 
 
 
 
Immunology 
HCV 
 
 
 
Immunology 
HIV 
 
 
 
 
 
 
 
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Toxicity Criteria for Laboratory Hematology and 
Coagulation Parameters based on CTCAE version 5.0  
 
Laboratory 
Toxicity  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Hematology  
Anemia  
(Hemoglobin 
Decreased)  
<LLN – 6.2 mmol/L  
<LLN - 100 g/L  
<LLN – 10.0 g/L 
<6.2 – 4.9 mmol/L 
<100 - 80 g/L 
<10.0 to 80.0 g/dL  
<4.9 mmol/L  
<80 g/L 
<8.0 g/dL 
  
Hemoglobin 
increased  
Increase in >0 - 2 
g/dL  
Increase in >2 - 4 g/dL 
Increase in >4 g/dL  
 
White Blood Cells 
Decreased  
<LLN – 3000/mm3  
<LLN – 3.0 x 109/L  
<3000 - 2000/mm3  
<3.0 – 2.0 x 109/L  
<2000 - 1000/mm3  
<2.0 – 1.0 x 109/L  
<1000/mm3  
<1.0 x 109/L  
Neutrophils 
count 
Decreased  
<LLN – 1500/mm3  
<LLN – 1.5 x 109/L  
<1500 - 1000/mm3  
<1.5 – 1.0 x 109/L  
<1000 - 500/mm3  
<1.0 – 0.5 x 109/L  
<500/mm3  
<0.5 x 109/L  
Lymphocytes count  
Decreased  
<LLN – 800/mm3  
<LLN – 0.8 x 109/L  
<800 – 500/mm3  
<0.8 – 0.5 x 109/L  
<500 - 200/mm3  
<0.5 – 0.2 x 109/L  
<200/mm3  
< 0.2 x 109/L  
Lymphocyte 
count 
increased  
 
>4000/mm3-20,000/mm3 
 >4 - 20 x 109/L 
>20,000/mm3  
> 20 x 109/L 
 
Platelets 
count 
Decreased  
<LLN – 75,000/mm3  
<LLN – 75.0 x 109/L  
<75,000 – 50,000/mm3  
<75.0 – 50.0 x 109/L  
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109/L  
<25,000/mm3  
<25.0 x 109/L  
Activated 
partial 
thromboplastin time 
prolonged (aPTT) 
>ULN – 1.5 x ULN 
>1.5 – 2.5 x ULN 
>2.5 ULN  
 
 
 
 
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Toxicity Criteria for Laboratory Biochemistry and 
Urinalysis Parameters based on CTCAE version 5.0  
Laboratory 
Toxicity  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Chemistry  
Sodium Increased 
(Hypernatremia) 
>ULN - 150 mmol/L  
>150 - 155 mmol/L  
>155 - 160 mmol/L  
>160 mmol/L  
Sodium Decreased  
(Hyponatremia) 
<LLN - 130 mmol/L  
 
<130 - 120 mmol/L  
<120 mmol/L  
Potassium Increased  
(Hyperkaliemia) 
>ULN - 5.5 mmol/L  
>5.5 - 6.0 mmol/L  
>6.0 - 7.0 mmol/L  
>7.0 mmol/L;  
Potassium 
Decreased 
(Hypokaliemia)  
<LLN - 3.0 mmol/L  
<LLN - 3.0 mmol/L  
<3.0 - 2.5 mmol/L  
<2.5 mmol/L  
Calcium Increased  
(Hypercalcemia) 
>ULN - 11.5 mg/dL; 
 >ULN - 2.9 mmol/L  
Ionized calcium 
>ULN - 1.5 mmol/L 
>11.5 - 12.5 mg/dL;  
>2.9 - 3.1 mmol/L  
Ionized calcium 
>1.5 - 1.6 mmol/L 
>12.5 - 13.5 mg/dL; 
>3.1 - 3.4 mmol/L;  
Ionized calcium >1.6 - 
1.8 mmol/L 
>13.5 mg/dL; 
 >3.4 mmol/L;  
Ionized calcium 
>1.8 mmol/L 
Calcium Decreased   
(Hypocalcemia) 
<LLN - 8.0 mg/dL; 
 <LLN - 2.0 mmol/L;  
Ionized calcium  
<ULN – 1.0 mmol/L 
<8.0 - 7.0 mg/dL; 
 <2.0 - 1.75 mmol/L  
Ionized calcium  
<1.0 - 0.9 mmol/L 
<7.0 - 6.0 mg/dL; 
<1.75 - 1.5 mmol/L;  
Ionized calcium  
<0.9-0.8 mmol/L 
<6.0 mg/dL; 
 <1.5 mmol/L;  
Ionized calcium  
<0.8 mmol/L 
Albumin Decreased  
(hypoalbuminemia) 
<LLN - 3 g/dL;  
<LLN - 30 g/L  
<3 - 2 g/dL;  
<30 - 20 g/L  
<2 g/dL; <20 g/L  
 
Alkaline 
Phosphatase 
increased  
>ULN - 2.5 x ULN if 
baseline normal 
2.0 - 2.50 x baseline 
if baseline abnormal 
>2.5 - 5.0 x ULN if 
baseline normal 
>2.5 – 5.0 x 
baseline if baseline 
abnormal 
>5.0 - 20.0 x ULN if 
baseline normal 
>5.0 – 20.0 x baseline 
if baseline abnormal 
>20.0 x ULN if 
baseline normal 
20.0 x baseline if 
baseline abnormal   
Alanine amino 
transferase 
increased  
>ULN - 3.0 x ULN if 
baseline normal 
1.5 - 3.0 x baseline if 
baseline abnormal 
> 3.0 - 5.0 ULN if 
baseline normal 
>3.0 - 5.0 x 
baseline if baseline 
abnormal  
>5.0 – 20.0 x ULN if 
baseline normal 
>5.0 - 20.0 x baseline 
if baseline abnormal 
>20.0 x ULN if 
baseline normal 
> 20.0 x baseline if 
baseline abnormal 
Aspartate amino 
transferase 
increased  
>ULN - 3.0 x ULN if 
baseline normal 
1.5 - 3.0 x baseline if 
baseline abnormal 
> 3.0 - 5.0 ULN if 
baseline normal 
>3.0 - 5.0 x 
baseline if baseline 
abnormal  
>5.0 – 20.0 x ULN if 
baseline normal 
>5.0 - 20.0 x baseline 
if baseline abnormal 
>20.0 x ULN if 
baseline normal 
> 20.0 x baseline if 
baseline abnormal 
Blood Bilirubin 
Increased  
>ULN – 1.5 x ULN if 
baseline normal 
>1.0-1.50 x baseline 
if baseline abnormal 
>1.5 – 3.0 x ULN if 
baseline normal 
>1.5-3.0 x baseline 
if baseline 
abnormal 
>3.0 – 10.0 x ULN if 
baseline normal 
>3.0- 10.0 x baseline if 
baseline abnormal 
>10.0 x ULN if 
baseline normal 
> 10.0 x baseline if 
baseline abnormal 
Gamma Glutamyl 
Transferase 
Increased  
>ULN - 2.5 x ULN if 
baseline normal 
>2.5 - 5.0 x ULN if 
baseline normal 
>5.0 - 20.0 x ULN if 
baseline normal 
>20.0 x ULN if 
baseline normal 
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Laboratory 
Toxicity  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
2.0 - 2.5 x baseline if 
baseline abnormal 
>2.5 - 5.0 x  
baseline if baseline 
abnormal 
>5.0 - 20.0 x  baseline 
if baseline abnormal 
>20.0 x ULN if 
baseline abnormal 
 
Creatinine Increased   >ULN – 1.5 x ULN  
>1.5 - 3.0 x 
baseline; 
 >1.5 – 3.0 x ULN  
>3.0 baseline;  
>3.0 – 6.0 x ULN  
>6.0 x ULN  
Chronic Kidney 
Disease  
eGFR (estimated 
Glomerular Filtration 
Rate) or CrCl 
(creatinine 
clearance) 
 <LLN - 60 
ml/min/1.73 m2 or 
proteinuria 2+ 
present; urine 
protein/creatinine 
>0.5  
eGFR or CrCl 59 - 
30 ml/min/1.73 m2  
eGFR or CrCl 29 - 15 
ml/min/1.73 m2  
eGFR or CrCl <15 
ml/min/1.73 m2  
Hypoalbuminemia  
<LLN - 3 g/dL;  
<LLN - 30 g/L  
<3 - 2 g/dL;  
<30 - 20 g/L  
<2 g/dL;  
<20 g/L 
 
Proteinuria 
1+ proteinuria 
2+ and 3+ 
proteinuria 
4+ proteinuria 
 
 
 
 
 
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Prohibited Medications Solely Metabolized by 
UGT1A9 and UGT2B7 and Determination Criteria 
Examples of medications that are solely metabolized by UGT1A9 and UGT2B7 and prohibited for the 
duration of the trial are provided in below. 
Medications 
solely 
metabolized by UGT1A9  
Medications solely metabolized by UGT2B7 
Medication 
name 
ATC code 
Medication 
name 
ATC code 
Comments 
Flavopiridol 
 
Benoxaprofen 
M01AE06 
 
Propofol 
N01AX10 
Carbamazepine 
N03AF01 
 
 
 
Codeine 
R05DA12 
R05DA04 
 
N02AJ01 
N02AJ02 
N02AJ03 
N02AJ07 
N02AJ08 
N02AJ09 
N02AA08 
N02AA58 
N02AA59 
N02AA79 
 
 
 
Cyclosporin A 
L04AD01, 
S01XA18 
 
 
 
Epirubicin 
L01DB03 
 
 
 
Indomethacin 
C01EB03 
M01AB01 
M01AB51 
M02AA23 
S01BC01 
S01CC02 
 
 
 
 
 
S01CC02 
also 
contains 
anti-infective 
medications 
 
 
Tacrolimus 
D11AH01 
L04AD02 
 
 
 
Tiaprofenic acid 
M01AE11 
 
 
 
Zaltoprofen 
M01A 
With verbatim (reported) term containing 
“ZALTOPROFEN” 
 
 
Zomepirac 
M01AB04 
 
 
 
Zidovudine 
J05AF01 
J05AR01 
J05AR04 
J05AR05 
 
Combination product 
Combination product 
Combination product 
ATC = Anatomic Therapeutic Class 
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Prohibited Medications Strong CYP3A4 Inducers and 
Determination Criteria 
 
Strong CYP3A4 inducers 
Medication name 
ATC code 
Comments 
Rifampicin 
J04AB02 
J04AB03 
J04AM02 
J04AM05 
J04AM06 
J04AM07 
A07AA13* 
D06AX15* 
S01AA16* 
S02AA12* 
This is a list on rifampicin only but also on products 
which contain rifampicin 
* refers to rifamycin 
carbamazepine 
N03AF01 
 
phenytoin 
N03AB02 
N03AB04 
N03AB05 
N03AB52 
 
phenobarbital, 
N03AA01 
N03AA02 
 
St John’s Wort (hypericum perforatum) 
N06AX25 
 
ATC = Anatomic Therapeutic Class 
 
 
 
 
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Other Prohibited Medications and Determination 
criteria 
 
Other prohibited medication 
Medication name 
ATC code 
Verbatim code 
Comments 
Nabiximols, cannabis 
or cannabinoid-based 
derived product 
N03AX24 
 
 
 
N02BG10 
 
N03AX24: group of other anti-
epileptics and cannabidiol is one of 
them 
 
This 
is 
the 
greater 
group 
of 
analgesics, and N02BG10 is a 
cannabinoid 
Botulinum 
toxin 
injections, 
M03AX01 
Contains: 
‘BO’ and ‘Tox’ 
‘“Dysport 
‘Xeomin 
Muscle relaxant products 
Antipsychotic 
medications, 
N05A  
apart from N05AN (Lithium) 
Including N05AH02 (BDZ) 
 
 
Benzodiazepines 
(if 
not following protocol 
requirements) 
N03AE 
N05BA 
N05CD 
M03BX07 
 
N03AE: clonazepam 
N05BA: broader group of anxiolytics 
contain the main used BDZ 
N05CD broader group of hypnotics 
but also contains melatonin for 
instance. 
M03BX07: tetrazepam 
BDZ=Benzodiazepines 
 
 
 
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Medications used in MS and Determination Criteria 
Any medication used for MS along with its category will be retrieved from the eCRF Concomitant medication 
form. However, the information in the table below will be used to defined subcategory of interest. 
MS 
medications 
type 
WHO-DD 
Therapeutic 
class 
Standardized 
Medication 
name  
ATC code 
Verbatim term 
Comments 
Antispasticity 
medication 
Muscle 
relaxant 
(M03) 
Baclofen 
M03BX01 
Contains:  
 ‘‘BACLOFEN”’ 
 
Tizanidine 
M03BX02 
Contains:  
‘‘TIZANIDINE”’ 
 
Dantrolene 
M03CA 
Contains:  
‘DANTROLENE’ 
 
Tetrazapam 
(BDZ) 
M03BX07 
 
Not considered as a 
BDZ in the coding of 
ATC, 
but 
as 
a 
centrally 
acting 
muscle relaxant. 
Botulinum toxin 
M03AX01 
Contains: 
‘BO’ and ‘Tox’ 
Dysport’ 
‘Xeomin’ 
 
Others 
M03B 
and 
M03C 
apart 
those 
mentioned 
above 
 
Refers to the broader 
group 
of 
muscle 
relaxants 
Antiepileptic (N03) 
Clonazepam  
N03AE 
 
N03AE is a BDZ 
Gabapentin 
N03AX12 
 
 
Pregabaline 
N03AX16 
 
 
Cannabinidiol 
N03AX24 
 
Not 
allowed 
per 
protocol 
Psychoanaleptic 
(N05) 
Clozapine (BDZ) 
N05AH02 
 
 
Benzodiazepines 
N05BA 
N05CD 
 
N05BA and N05CD 
refers to a list of BDZ 
Medication 
to 
treat other MS 
symptoms 
Other 
system 
nervous 
system 
drug (N07) 
Dalfampridine 
N07XX007 
 
 
 
 
Fampridine 
N07XX007 
 
 
MS=Multiple sclerosis; ATC= Anatomic Therapeutic Class; BDZ=Benzodiazepines 
 
 
 
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Addendum to Statistical Analysis Plan (SAP) 
Protocol Title: 
A Double-blind, Randomized, Placebo-controlled, Parallel-group Trial 
of the Efficacy and Safety of Nabiximols Oromucosal Spray as Add-on 
Therapy in Patients with Spasticity Due to Multiple Sclerosis 
Study Code: 
GWSP18023 
Protocol Version No. /Date: 
V5.0 / 01JUN2021 
CRF Version No. / Date: 
V3.0 / 05NOV2021 
SAP Version No. / Date: 
V1.0 / 22MAR2022 
SAP Addendum Version No. / Date 
V1.0 / 17FEB2023 
 
 Approvals 
Author / Title: 
Elizabeth Gardener / Senior Manager, Biostatistics 
Signature / Date: 
NA - approved with eSignature 
 
Reviewer 
Biostatistician / Title: 
 / Associate Director, Biostatistics 
Signature / Date: 
NA - approved with eSignature 
 
Medical Monitor: 
 
Signature / Date: 
NA - approved with eSignature 
 
 
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 Change History 
Version/Date 
Change Log 
1.0 / 17FEB2023 
Created as new 
 
 
 
 
 
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 Table of Contents, List of Tables and Figures  
3.1 Table of Contents 
 Approvals ............................................................................................................................................... 1 
 Change History ....................................................................................................................................... 2 
 Table of Contents, List of Tables and Figures ........................................................................................ 3 
3.1 Table of Contents ................................................................................................................................ 3 
3.2 List of Tables ....................................................................................................................................... 4 
 Purpose 
............................................................................................................................................... 5 
 Scope 
............................................................................................................................................... 5 
 Introduction ............................................................................................................................................. 5 
 Statistical Methods .................................................................................................................................. 5 
 Glossary of Abbreviations ....................................................................................................................... 8 
 
 
 
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3.2 List of Tables 
Table 7-1 Strategy for abbreviated reporting ................................................................................................ 6 
 
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 Purpose 
This addendum to the SAP describes the reporting and analyses of data collected under Protocol 
GWSP18023 V5.0 dated 01JUN2021 following the early termination of the study. 
 Scope 
This addendum supplements the SAP. 
 Introduction 
This SAP addendum should be read in conjunction with the study protocol V5.0 01JUN2021, CRF V3.0 
05NOV2021 and SAP V1.0 22MAR2022.  
Final approval of the SAP addendum will occur prior to study unblinding. 
The decision was made on 9th November 2022 to discontinue the study and halt any further enrollment of 
patients without the planned number of patients being recruited.  As a result of this, an abbreviation of the 
planned analysis and reporting as detailed in the protocol and SAP will be carried out. The possibility of 
early termination was described in Protocol Section 16.1. 
 Statistical Methods 
The abbreviated reporting will follow the strategy as detailed in Table 7-1. Although the study will terminate 
early, the primary hypothesis will still be tested as per the final SAP. 
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Table 7-1 Strategy for abbreviated reporting 
Hierarchy 
Strategy 
Endpoint 
Relevant Sections of SAP V1.0 to be Used 
Primary & 
Secondary Efficacy 
Endpoints 
Conduct primary inferential analysis, 
standard descriptive statistics and 
listing. Sensitivity and supplemental 
(including subgroup analyses) will 
not be conducted. Figures will not 
be produced. 
Daily spasm count 
12.5.2.1 & 12.5.2.4 
MSSS-88 
12.5.3.1 & 12.5.3.4 
 Secondary Safety 
Endpoints (excluding 
PK) 
  
  
  
  
As described in SAP with the 
exception of figures, subgroup 
summaries, repeats on FAS.and 
those specific to an endpoint 
(detailed in final column).  
TEAEs 
12.8.1 & 12.8.2 
Excluding the following summaries: 
 
by time of first onset 
 
by AE duration 
 
of TEAEs related to IMP by maximum severity 
 
of TEAEs related to IMP and leading to IMP 
discontinuation by maximum severity 
 
of serious TEAEs related to IMP 
Clinical laboratory tests 
12.8.3 
Excluding the following summaries: 
 
Values outside of normal ranges 
 
Shift tables based on CTCAE v5.0 grade 
Shift tables based on normal range indicator will be 
presented by visit rather than by most extreme value and last 
on-treatment value. 
Vital signs 
12.8.4 
ECG 
12.8.5.2 
C-SSRS 
12.8.5.3 
 Secondary Safety 
Endpoints (PK) 
No processing, analyses or 
reporting 
PK 
NA 
 
 
 
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Exploratory 
Endpoints 
Listings only, no descriptive or 
inferential statistics or figures. 
MSSS-88 subscales 
12.5.3.4 
NRS spasm severity 
12.5.4.2 
NRS spasticity 
12.5.4.3 
T25FW 
12.5.4.4 
SF-36 
12.6.1 
Other data 
As described in SAP with the 
exception of figures, subgroup 
summaries, repeats on FAS and 
those specific to a section (detailed 
in final column).  
Disposition 
12.1 
Demographics 
12.2.1 
Disease Characteristics 12.2.5 
Medical History 
12.2.4 
Prior and Concomitant 
Medications and 
Therapy 
12.3.2 
Excluding summaries of post-treatment medications 
Treatment Exposure 
12.3.1 
Protocol deviations 
12.4 
Excluding summaries of major IPDs 
Other Safety 
12.8.5.1, 12.8.5.4, 12.8.5.5, 12.8.5.6, 12.8.5.7 
Monitoring of Drug 
Abuse Liability 
12.8.6 
Excluding the summary of triggered events 
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 Glossary of Abbreviations 
Glossary of Abbreviations: 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CRF 
Case report form 
ECG 
Electrocardiograms 
FAS 
Full analysis set 
IPD 
Important protocol deviation 
MSSS-88 
Multiple Sclerosis Spasticity Scale 
NRS 
Numerical rating scale 
PK 
Pharmacokinetic 
SAP 
Statistical analysis plan 
SF-36 
36-Item short form health survey 
T25FW 
Timed 25-foot walk 
TEAE 
Treatment emergent adverse event 
 
DocuSign Envelope ID: CB4870CB-045B-47FC-8A5B-16354CEB59B0
GWSP18023___V1.0_17 Feb 2023_Statistical Analysis Plan_Statistical Analysis Plan Addendum V1.0 | VV-TMF-156296
Approved