Conditions: Rett Syndrome RTT
Keywords: Cannabidiol CBD Epidiolex GWP42003-P
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
This study will be conducted to evaluate the long-term safety of cannabidiol oral solution (GWP42003-P, CBD-OS) in participants with Rett syndrome.

Detailed description:

Arms:
arm 1: 100 milligrams per milliliter (mg/mL) GWP42003-P oral solution, taken twice daily (morning and evening).

Interventions: intervention 1: GWP42003-P
Intervention descriptions: intervention 1: GWP42003-P presented as an oral solution containing cannabidiol in the excipients sesame oil with anhydrous ethanol, sweetener (sucralose), and strawberry flavoring

Protocol document:
Prot_000.pdf: 
Study GWND19002 
 
Final Synoptic CSR (V1.0), 08-Nov-2021 
Product: GWP42003-P 
GWND19002 
Confidential
Appendix 1.1 
Protocol and Protocol Amendments 
GWND19002 Protocol V1 date 09-Aug-2019 
GWND19002 Protocol V2 date 18-Dec-2019 
GWND19002 Protocol Annex 1 V1 date 28-May-2020 
GWND19002 Protocol Annex 1 V2 date 11-Nov-2020 
GWND19002 Protocol Annex 1 Amendment 1 V2 date 11-Nov-2020 
Page 1 of 265


SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 1 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
AN OPEN-LABEL EXTENSION TRIAL TO INVESTIGATE THE 
LONG-TERM SAFETY OF CANNABIDIOL ORAL SOLUTION 
(GWP42003-P, CBD-OS) IN PATIENTS WITH RETT SYNDROME 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
CLINICAL PROTOCOL 
GW Research 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 Research Ltd (GW) that must 
not be disclosed to anyone other than the recipient study 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. 
 
Page 2 of 265


Study Code: GWNDI9002 
EudraCT Number: 2019-001605-24 
Clinical Protocol VI 09Augl9 
Investigator Agreement 
SPONSOR: GW RESEARCH LIMITED 
I have read the attached clinical protocol entitled' An open-label extension trial to 
investigate the long-term safety of cannabidiol oral solution (GWP42003-P, CBD-OS) in 
patients with Rett syndrome', dated 09 August 20 19, and agree to abide by all provisions 
set forth therein. 
The sponsor and I agree to comply with applicable regulatory requirement(s); the United 
States (US) Food and Drug Administration (FDA) regulations relating to Good Clinical 
Practice (GCP) and clinical trials, the European Union (EU) Clinical Trials Directive 
(2001 /20/EC), the EU GCP Directive (2005/28/EC) and subsequent applicable 
regulatory/statutory instruments, or the International Council for Harmonisation (ICH) 
Harmonised Guideline: Integrated Addendum to ICH E6(Rl): 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 participants 
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 ofGW. 
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 ofGW. 
Center No.: 
Print name: 
Principal investigator 
Signature: 
GW Authorization 
Confidential 
Clinical Protocol Template (Phase 2-4) 
Page 2 of 125 
Date: 
(DD-MMM-YY) 
Date: fk ... ~ 
11 
(DD-MM - Y) 
VI, 24Sepl5 
Page 3 of 265
PI


SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 3 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
1 
PROTOCOL SYNOPSIS 
Trial Title 
An Open-label Extension Trial to Investigate the Long-term Safety 
of Cannabidiol Oral Solution (GWP42003-P, CBD-OS) in Patients 
with Rett Syndrome 
Clinical Trial Type 
Phase 3 
Indication 
Rett syndrome (RTT) [typical or atypical] 
Primary Objective 
To evaluate the long-term safety of GWP42003-P in patients with 
RTT 
Secondary 
Objective(s) 
Secondary objectives: 
• To evaluate the effect of GWP42003-P in measures of disease 
severity 
o Rett Syndrome Behaviour Questionnaire (RSBQ) 
o Clinical Global Impressions - Improvement (CGI-I) 
o Clinical Global Impressions - Severity (CGI-S) 
o 9-items Motor Behavioral Assessment (MBA-9) 
o Children’s Sleep Habits Questionnaire (CSHQ) 
Exploratory objectives: 
• To evaluate the effect of GWP42003-P on caregiver and 
patient quality of life (QoL) 
o 36-item Short Form [SF-36] and Child Health 
Questionnaire Parent Form 50 [CHQ-PF50], 
respectively 
• To evaluate the effect of GWP42003-P on health utilization 
o Hospital Services Use Questionnaire 
o Caregiver Assessment of Rett Symptoms 
Trial Design 
This is a 28-week, multicenter, open-label extension (OLE) trial 
for patients with RTT who have completed the randomized, 
double-blind, placebo-controlled trial (GWND18064).   
Entry to this OLE trial is recommended to be on the same day as 
Visit 9 of the randomized controlled trial (RCT); however, patients 
may enter the OLE trial up to the point of the RCT follow-up visit 
(Visit 11).   
All patients entering this OLE trial will begin dosing with 
5 mg/kg/day GWP42003-P (2.5 mg/kg twice daily [b.i.d.]) on 
Day 1.  Patients will be observed, and after 1 week, the dose may 
be escalated further, at the investigator’s discretion, up to 
15 mg/kg/day GWP42003-P (7.5 mg/kg b.i.d.), in weekly 
Page 4 of 265


SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 4 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
increments of 5 mg/kg/day (2.5 mg/kg b.i.d.).   
Patients should then remain on a stable dose of GWP42003-P for 
the duration of the maintenance period of the trial (up to 
28 weeks), with the option for doses to be decreased or increased 
to a maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.) based on 
clinical response and tolerability as deemed necessary by the 
investigator, until the optimal dose is found.  Patients whose dose 
has been decreased can have their dose increased again if 
tolerability improves.  
At the end of treatment (Visit 8 [Day 197]), the dose of 
GWP42003-P will be reduced over a 10-day taper period, and 
patients will enter the 4-week follow-up period.  
If a patient permanently discontinues treatment at any point during 
the trial, GWP42003-P should be gradually reduced over 10 days 
(unless inadvisable due to an adverse event [AE]).  
The patient should attend a withdrawal visit (Visit 8) as soon as 
possible after the decision is made to permanently discontinue 
GWP42003-P. Unless inadvisable due to an AE, the patient will 
taper GWP42003-P and attend the End of Taper visit and then 
complete the 4-week follow-up period.   
Primary Endpoint 
Safety: 
The long-term safety profile of GWP42003-P will be assessed by 
evaluating changes in the following, relative to the 
prerandomization baseline of the RCT: 
• AEs 
• Clinical laboratory parameters 
• Vital signs 
• Physical examination procedures 
• 12-lead electrocardiogram (ECG) 
• Effects on menstruation cycles 
• Suicidality 
• Change in growth and development by measurement of 
height, weight, serum insulin-like growth factor-1 (IGF-1) 
levels, and Tanner Staging (for patients aged ≥ 7 years or 
earlier, if clinically indicated by the onset of menarche or 
other signs of precocious puberty) 
Secondary 
Endpoint(s) 
Secondary endpoints: 
The following will be assessed by evaluating changes relative to 
the prerandomization baseline of the RCT: 
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SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 5 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
• RSBQ 
• CGI-I 
• CGI-S 
• MBA-9 
• CSHQ 
Exploratory endpoints: 
The following will be assessed by evaluating changes relative to 
the prerandomization baseline of the RCT: 
• SF-36 
• CHQ-PF50 
• Hospital Services Use Questionnaire 
• Caregiver Assessment of Rett Symptoms 
Sample Size 
All patients with RTT who completed the randomized, 
double-blind, placebo-controlled trial (GWND18064) who wish to 
take GWP42003-P and meet the eligibility criteria can be included 
in this trial.  Approximately 252 patients will be enrolled.  
Summary of Patient 
Eligibility Criteria 
Inclusion criteria 
For inclusion in the trial, patients must fulfil all of the following 
criteria: 
• Patient has completed all scheduled visits of the treatment 
phase of the RCT, GWND18064, and has transitioned to 
OLE by the point of RCT follow-up (Visit 11). 
• Patient (if possessing adequate understanding, in the 
investigator’s opinion) and/or her parent(s)/legal 
representative is willing and able to give informed 
consent/assent for participation in the trial. 
• Patient and her caregiver are willing and able (in the 
investigator’s opinion) to comply with all trial requirements 
(including the completion of all caregiver assessments by 
the same caregiver throughout the trial). 
• Patient must have the ability to swallow the investigational 
medicinal product (IMP) provided as a liquid solution or 
the ability for the IMP to be delivered via gastrostomy (G) 
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SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 2 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
or nasogastric (NG) feeding tube (only G- or NG-tubes 
made from polyurethane or silicon are allowed). 
• Patient and/or parent(s)/legal representative is willing to 
allow the responsible authorities to be notified of 
participation in the trial, if mandated by local law. 
• Patient and/or parent(s)/legal representative is willing to 
allow the patient’s primary care practitioner (if she has one) 
and consultant (if she has one) to be notified of 
participation in the trial if the primary care 
practitioner/consultant is different from the investigator. 
Exclusion criteria  
If the RCT ‘End of Treatment’/‘End of Taper Period’ visit 
assessments or Visit 1 reassessments (as applicable) raise any 
safety concerns, the investigator should consider whether it will be 
appropriate for the patient to continue to participate in the OLE 
trial or if the patient should be withdrawn. 
The patient may not enter the trial if ANY of the following apply: 
• Patient meets the withdrawal criteria (including clinically 
significant abnormal laboratory values), in the 
investigator’s opinion.  
• Patient met during the RCT the criteria for permanent IMP 
discontinuation (unless in case of an AE, if AE was not 
considered related with the IMP; patients that met alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) 
elevations discontinuation criteria must be excluded). 
• Patient is of childbearing potential, unless willing to ensure 
that they or their partner use a highly effective method of 
birth control (e.g., combined [estrogen and progestogen 
containing] hormonal contraceptiona associated with 
inhibition of ovulation [oral, intravaginal or transdermal], 
progestogen-only hormonal contraceptiona associated with 
inhibition of ovulation [oral, injectable or implantableb] 
intrauterine devices/hormone-releasing systemsc, bilateral 
                                                 
a The effect of GWP42003-P on oral contraceptives has not been investigated.  GWP42003-P is 
not an inducer of CYP3A4 and therefore is not expected to alter the PK of hormonal 
contraceptives. 
b Contraception methods that are considered to have low user dependency. 
c Contraception methods that are considered to have low user dependency. 
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SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 3 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
tubal occlusiona, vasectomized partnera,a, sexual 
abstinenceb during the trial and for 3 months thereafter. 
• Patient has been previously enrolled and dosed in this trial. 
• Patient is unwilling to abstain from donation of blood 
during the trial. 
Criteria for 
Withdrawal 
Patient must be withdrawn from the trial if any of the following 
apply: 
• Administrative decision by the investigator, GW Research 
Ltd (GW), or a regulatory authority 
• Pregnancy 
• Protocol deviation that is considered to potentially 
compromise the safety of the patient 
• Withdrawal of patient assent 
• Withdrawal of parent(s)/legal representative consent 
• ALT or AST > 3 × upper limit of normal (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 (total bilirubin [TBL] 
> 2 × ULN or international normalized ratio [INR] > 1.5) 
Note: Prior to withdrawal for the transaminase elevations noted 
above, the investigator may choose to confirm the transaminase 
elevations by repeating the following laboratory tests within 24 
to 48 hours: ALT, AST, TBL, INR, % eosinophils, gamma-
glutamyl transferase,  alkaline phosphatase, and eosinophils.  
Should the above transaminase elevation criteria be 
confirmed, the patient must be withdrawn from the trial.  
In cases where the transaminase elevation withdrawal 
criteria are not met or confirmed, the dose of IMP or a 
concomitant medication with known hepatotoxicity may be 
                                                 
a Provided that partner is the sole sexual partner of the trial patient of childbearing potential and 
that the vasectomized partner has received medical assessment of the surgical success. 
b Only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the trial treatments.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Page 8 of 265


SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 4 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
reduced.  Dose adjustments should be discussed with the 
GW medical monitor.  The final decision regarding dose 
adjustments should be taken by the investigator. 
• Lost to follow-up. 
The patient may also be withdrawn from the trial for any of the 
following: 
• Patient or caregiver noncompliance 
• AE (including clinically significant laboratory results) that, 
in the opinion of the investigator, would compromise the 
continued safe participation of the patient in the trial 
• Failure to meet the eligibility criteria 
• Any evidence of use of drugs of abuse or drug diversion 
• Suicidal ideation or behavior during the treatment period 
Investigational 
Medicinal Product: 
Formulation, Mode 
of Administration, 
Dose, and Regimen 
GWP42003-P oral solution is formulated as follows: (100 mg/mL 
cannabidiol [CBD] in sesame oil with anhydrous ethanol, 
sweetener [sucralose], and strawberry flavoring).  
GWP42003-P is to be taken orally (swallowed) b.i.d. (morning and 
evening) using the syringe(s) provided.  GWP42003-P should be 
taken at the same time each day consistently with food, i.e., within 
30 minutes after the end of a meal and in line with the patients’ 
normal feeding schedule and dietary habits.  The time of 
GWP42003-P administration in relation to food should be kept 
consistent throughout the trial.  In patients with G- or NG-tubes but 
where oral dosing of GWP42003-P is possible, oral dosing is 
preferable.  Only in patients where oral dosing is not possible 
should GWP42003-P be administered via G- or NG-tubes made 
from polyurethane or silicon only  The investigator should contact 
the medical monitor to review IMP administration guidelines if 
administration via G-or NG-tubes is planned.  The volume of 
GWP42003-P will be determined by patient’s weight.   
All patients will begin dosing with 5 mg/kg/day GWP42003-P 
(2.5 mg/kg b.i.d.) for 1 week.  After 1 week’s treatment, depending 
on clinical response and tolerability, the patients’ dose can be 
further increased in weekly increments of 5 mg/kg/day (2.5 mg/kg 
b.i.d.) up to 15 mg/kg/day GWP42003-P (7.5 mg/kg b.i.d.).   
Patients should then remain on a stable dose of GWP42003-P for 
the duration of the maintenance period of the trial (up to 
28 weeks), with the option for doses to be decreased or increased 
to a maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.) based on 
clinical response and tolerability, as deemed necessary by the 
investigator. 
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SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 5 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Patients discontinuing GWP42003-P treatment at the end of the 
trial or at any other time if they discontinue treatment early should 
undergo a 10-day taper period (unless continued dosing is 
inadvisable, e.g., due to an AE). 
Control Group 
Not applicable. 
Procedures 
Before the patient undergoes any assessments or observations, the 
patient’s parent(s)/legal representative is required to give written 
informed consent.  The nominated caregiver will be asked to 
consent to complete the QoL questionnaires.  In cases where the 
patient possesses adequate understanding, her assent will be taken, 
along with parent(s)/legal representative consent.  Due to the 
degree of cognitive impairment in patients with RTT, patients 18 
years of age or older will not be required to provide consent and 
will only be required to provide assent in cases where the patient 
possesses adequate understanding, along with parent(s)/legal 
representative consent.  Visits 2, 3, and 10 (safety visits) are to be 
conducted by telephone.   
OLE Visit 1 (Day 1): Every effort should be made for this visit to 
take place on the same day as the RCT ‘End of Treatment’ visit.  
However, patients can still enter the OLE trial up to the point of 
the RCT follow-up visit (Visit 11).   
OLE Visit 1 assessments required for all patients: 
• 
Informed consent and assent  
• 
Eligibility check 
• 
New medical history 
• 
AE review 
• 
GWP42003-P dispensing 
OLE Visit 1 assessments required if OLE Visit 1 occurs on a 
different date than RCT Visit 9: 
• 
Vital signs 
• 
Suicidality assessment 
• 
Hospital Services Use Questionnaire  
OLE Visit 1 assessments required if OLE Visit 1 occurs 
> 28 days after RCT Visit 9: 
• 
Physical examination (including weight) 
• 
ECG 
• 
Clinical laboratory blood sampling (hematology and 
biochemistry) 
• 
Dipstick urinalysis (where possible) 
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SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 6 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
OLE assessments on Visit 2 to Visit 10: 
• Concomitant medications review (Visits 2 to 10). 
• AE review (Visits 1–10) 
• Menstruation cycle review (Visit 8) 
• Physical examination (including weight) (Visits 1, 4, 6, and 8) 
• Height (Visit 8) 
• ECG (Visits 1, 4, 6, and 8) 
• Vital signs (Visits 1, 4, 5, 6, 7, 8, and 9) 
• Safety laboratory assessments (hematology and biochemistry) 
(Visits 1, 4, 5, 6, and 8, plus Visit 7 for patients taking 
concomitant valproic acid as well as for patients whose dose 
exceeds 15 mg/kg/day) 
Note: Hepatic function monitoring should be carried out within 
1 month following increases in GWP42003-P dose or 
introduction of medications that are known to impact liver 
function.  If the concerned change does not occur within 
1 month of a scheduled biochemistry assessment, the 
investigator should perform an additional hepatic monitoring 
within 1 month of the change.   
• Dipstick urinalysis (Visits 1 and 8) 
• Serum IGF-1 levels (Visits 8) 
• Serum pregnancy test (if appropriate) (Visit 8) 
• Questionnaires: 
o RSBQ (Visits 4, 5, 6, 7, and 8) 
o CSHQ (Visits 6 and 8) 
o SF-36 and CHQ-PF50 (Visit 8) 
o Hospital Services Use Questionnaire (Visits 1, 4, 5, 6, 
7, and 8)  
o Tanner Staging (for patients aged ≥ 7 years or earlier, if 
clinically indicated by onset of menarche or other signs 
of precocious puberty) (Visit 8) 
o Caregiver Assessment of Rett Symptoms, to be 
completed by the caregiver (Visits 4, 5, 6, 7, and 8) 
• MBA-9 (Visits 6 and 8) 
• CGI-S and GCI-I (Visits 4, 5, 6, 7, and 8). 
• Suicidality assessment (Visits 1, 4, 5, 6, 7, 8, and 9). 
• GWP42003-P dispensing (Visits 1, 4, 5, 6, 7, and 8) (All 
caregivers will be provided with a dosing schedule.) 
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SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
• GWP42003-P collection and compliance review (Visits 4, 5, 6, 
7, 8, and 9) 
• Caregivers are asked to confirm dosing in the dosing schedule 
daily throughout the trial; the dosing schedule will be reviewed 
at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
Statistical 
Considerations 
All data that will be collected during this trial will be summarized 
across time, using appropriate descriptive statistics.  Where 
baseline data are available from the RCT, changes from baseline 
will also be presented, where appropriate.  There will be no formal 
hypothesis testing.  A detailed statistical analysis plan will be 
written. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
 
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SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
Confidential 
Page 8 of 121 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Figure 1-1 
Trial Design and Treatment Schematic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Day 1  
Visit 3 
Day 15 ± 3 
(Telephone) 
Visit 8 
Day 197 ± 7 
Visit 7 
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Visit 6 
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Visit 5 
Day 57 ± 7 
Visit 2 
Day 8 ± 3 
(Telephone) 
Visit 4 
Day 29 ± 7  
Visit 9 
Day 207 + 7 
Visit 10 
Day 235 + 7
(Telephone)
__ 
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SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V1 09Aug19 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Table of Contents 
1 
PROTOCOL SYNOPSIS .................................................................... 3 
Table of Contents ........................................................................................... 9 
List of Appendices ....................................................................................... 14 
List of In-text Tables ................................................................................... 15 
List of In-text Figures .................................................................................. 16 
List of Abbreviations ................................................................................... 17 
Definition of Terms...................................................................................... 20 
2 
OBJECTIVES ..................................................................................... 21 
2.1 
Primary .............................................................................................................. 21 
2.2 
Secondary .......................................................................................................... 21 
3 
BACKGROUND AND RATIONALE .............................................. 22 
3.1 
Disease .............................................................................................................. 22 
3.2 
Investigational Medicinal Product Background................................................ 23 
3.2.1 
Nonclinical Studies ........................................................................................ 24 
3.2.1.1 
Efficacy Pharmacology ............................................................................... 24 
3.2.1.2 
Safety Pharmacology .................................................................................. 26 
3.2.1.3 
Mechanism of Action ................................................................................. 26 
3.2.2 
Clinical Studies .............................................................................................. 26 
3.3 
Rationale ........................................................................................................... 27 
3.3.1 
Choice of Endpoints ....................................................................................... 27 
3.3.1.1 
Choice of Primary Endpoints...................................................................... 27 
3.3.1.2 
Choice of Secondary Endpoints ................................................................. 27 
3.3.1.3 
Choice of Exploratory Endpoints ............................................................... 28 
3.3.2 
Choice of Dosing Regimen ............................................................................ 28 
3.4 
Clinical Hypothesis ........................................................................................... 29 
4 
EXPERIMENTAL PLAN ................................................................. 30 
4.1 
Trial Design ...................................................................................................... 30 
4.1.1 
Primary Endpoint ........................................................................................... 31 
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4.1.2 
Secondary Endpoints ...................................................................................... 31 
4.1.2.1 
Secondary endpoints: .................................................................................. 31 
4.1.2.2 
Exploratory endpoints:................................................................................ 31 
4.2 
Number of Trial Centers ................................................................................... 32 
4.3 
Number of Patients ........................................................................................... 32 
5 
INVESTIGATIONAL MEDICINAL PRODUCT .......................... 33 
5.1 
GWP42003-P Oral Solution ............................................................................. 33 
5.2 
Packaging, Storage, and Drug Accountability .................................................. 33 
5.2.1 
Packaging and Labeling ................................................................................. 33 
5.2.2 
Storage ............................................................................................................ 34 
5.2.3 
Supply and Return of Investigational Medicinal Product .............................. 34 
5.2.4 
Investigational Medicinal Product Accountability ......................................... 35 
5.2.5 
Post-trial Provision ......................................................................................... 36 
6 
PATIENT ELIGIBILITY .................................................................. 37 
6.1 
Inclusion Criteria .............................................................................................. 37 
6.2 
Exclusion Criteria ............................................................................................. 37 
7 
PATIENT ENROLLMENT .............................................................. 39 
7.1 
Treatment Assignment ...................................................................................... 39 
7.2 
Randomization .................................................................................................. 39 
8 
TREATMENT PROCEDURES........................................................ 40 
8.1 
Investigational Medicinal Product Dosage, Administration, and Schedule ..... 40 
8.1.1 
Dose Administration ...................................................................................... 40 
8.1.2 
Dose Escalation and Dose Adjustments ......................................................... 40 
8.2 
Concomitant Therapy........................................................................................ 42 
8.3 
Prohibited Therapy During the Trial Period ..................................................... 42 
8.4 
Compliance in Investigational Medicinal Product Administration .................. 43 
8.5 
Access to Blinded Treatment Assignment ........................................................ 43 
9 
TRIAL PROCEDURES ..................................................................... 44 
9.1 
Trial Procedures by Visit .................................................................................. 44 
9.1.1 
Clinic Visits .................................................................................................... 45 
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9.1.1.1 
Visit 1 (Day 1 [+ 3]) ................................................................................... 45 
9.1.1.2 
Visit 4 (Day 29 [± 7]) ................................................................................. 46 
9.1.1.3 
Visit 5 (Day 57 [± 7]) ................................................................................. 46 
9.1.1.4 
Visit 6 (Day 85 [± 7]) ................................................................................. 47 
9.1.1.5 
Visit 7 (Day 141 [± 7]) ............................................................................... 48 
9.1.1.6 
Visit 8 (Day 197 [± 7], End of Treatment/Withdrawal Visit) .................... 48 
9.1.1.7 
Visit 9 (Day 207 [+ 7], End of Taper) ........................................................ 49 
9.1.2 
Telephone Visits ............................................................................................. 50 
9.1.2.1 
Visits 2 (Day 8 [± 3]) and 3 (Day 15 [± 3]) ................................................ 50 
9.1.2.2 
Visit 10 (Day 235+7, End of Trial) ............................................................ 50 
9.1.3 
Unscheduled Visits ......................................................................................... 50 
9.2 
Trial Procedure Listing ..................................................................................... 51 
9.2.1 
Informed Consent/Assent ............................................................................... 51 
9.2.2 
Contraception Requirements .......................................................................... 52 
9.2.3 
Concomitant Medication ................................................................................ 53 
9.2.4 
New Medical History ..................................................................................... 53 
9.2.5 
Menstruation ................................................................................................... 53 
9.2.6 
Physical Examination ..................................................................................... 54 
9.2.7 
12-Lead Electrocardiogram ............................................................................ 54 
9.2.8 
Vital Signs ...................................................................................................... 54 
9.2.9 
Clinical Laboratory Sampling ........................................................................ 54 
9.2.10 
Randomization and Trial Supply Management System ................................. 57 
9.2.11 
Dosing Schedule/Compliance Review ........................................................... 57 
9.2.12 
Questionnaires and Assessments Completed at Scheduled Visits ................. 57 
9.2.12.1 
Rett Syndrome Behaviour Questionnaire ................................................... 57 
9.2.12.2 
Children’s Sleep Habit Questionnaire ........................................................ 58 
9.2.12.3 
36-Item Short Form .................................................................................... 58 
9.2.12.4 
Child Health Questionnaire Parent Form 50 .............................................. 58 
9.2.12.5 
Hospital Services Use Questionnaire.......................................................... 59 
9.2.12.6 
Caregiver Assessment of Rett Symptoms .................................................. 59 
9.2.12.7 
Rett Syndrome Motor-Behavioral Assessment Scale ................................. 59 
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9.2.12.8 
Clinical Global Impressions Questionnaire ................................................ 59 
9.2.12.9 
Suicidality Assessment ............................................................................... 60 
9.2.13 
Tanner Staging ............................................................................................... 60 
9.2.14 
Investigational Medicinal Product Accountability ......................................... 60 
9.2.15 
Adverse Events ............................................................................................... 61 
10 
IMP DISCONTINUATION AND WITHDRAWAL ...................... 62 
11 
URGENT SAFETY MEASURES ..................................................... 64 
12 
ADVERSE EVENT REPORTING ................................................... 65 
12.1 
Definitions......................................................................................................... 65 
12.1.1 
Adverse Event ................................................................................................ 65 
12.1.2 
Investigator ..................................................................................................... 65 
12.2 
Serious Adverse Events .................................................................................... 65 
12.3 
Reporting Procedures for Serious Adverse Events ........................................... 66 
12.4 
Pregnancy .......................................................................................................... 67 
12.5 
Causality Assessment........................................................................................ 67 
12.6 
Reporting Procedures for All Adverse Events .................................................. 68 
12.7 
Follow-up Procedures for Adverse Events ....................................................... 70 
12.8 
Potential Cases of Drug-induced Liver Injury .................................................. 70 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities, and IRBs/IECs .............................................................................. 71 
13 
STATISTICAL CONSIDERATIONS ............................................. 74 
13.1 
Sample Size, Power, and Significance Levels .................................................. 74 
13.2 
Interim Analysis ................................................................................................ 74 
13.3 
Analysis Sets ..................................................................................................... 74 
13.3.1 
Protocol Deviations ........................................................................................ 74 
13.4 
General Considerations ..................................................................................... 74 
13.5 
Accountability and Background Characteristics ............................................... 75 
13.5.1 
Enrollment and Disposition ............................................................................ 75 
13.5.2 
Baseline and Demographic Characteristics .................................................... 75 
13.5.3 
Concomitant Medication ................................................................................ 75 
13.6 
Endpoints and Statistical Methods .................................................................... 75 
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13.6.1 
Evaluable Period ............................................................................................ 75 
13.6.2 
Primary Safety Endpoints ............................................................................... 75 
13.6.2.1 
Treatment Compliance and Extent of Treatment Exposure ....................... 76 
13.6.2.2 
Adverse Events ........................................................................................... 76 
13.6.2.3 
Vital Signs, 12-Lead Electrocardiogram, Physical Examination, and 
Other Safety Data ....................................................................................... 76 
13.6.2.4 
Clinical Laboratory Data ............................................................................ 77 
13.6.2.5 
Menstruation ............................................................................................... 77 
13.6.2.5.1 
Suicidality ............................................................................................... 77 
13.6.3 
Secondary Endpoint(s) ................................................................................... 77 
13.6.4 
Exploratory Endpoint(s) ................................................................................. 78 
13.6.5 
Handling of Missing Data .............................................................................. 78 
14 
SAFETY MONITORING COMMITTEE ....................................... 79 
15 
REGULATORY AND ETHICAL OBLIGATIONS ...................... 80 
15.1 
Declaration of Helsinki ..................................................................................... 80 
15.2 
Informed Consent/Assent.................................................................................. 80 
15.3 
Institutional Review Board/Independent Ethics Committee............................. 81 
15.4 
Pretrial Documentation Requirements .............................................................. 81 
15.5 
Patient Confidentiality ...................................................................................... 82 
16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................... 84 
16.1 
Protocol Amendments and End of Trial or Termination .................................. 84 
16.2 
Trial Documentation and Storage ..................................................................... 84 
16.3 
Trial Monitoring and Data Collection............................................................... 85 
16.4 
Quality Assurance ............................................................................................. 86 
16.5 
Compensation ................................................................................................... 86 
16.6 
Publication Policy ............................................................................................. 87 
16.7 
Intellectual Property Rights .............................................................................. 87 
16.8 
Confidential Information .................................................................................. 88 
17 
REFERENCES ................................................................................... 89 
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List of Appendices 
Appendix 1 
Schedule of Assessments ................................................... 95 
Appendix 2 
Trial Personnel ................................................................... 98 
Appendix 2.1 
Investigator Details ................................................................................. 98 
Appendix 2.2 
Sponsor Contact Details .......................................................................... 98 
Appendix 3 
Questionnaires/Assessments ............................................. 99 
Appendix 3.1 
9-Item Motor-Behavioral Assessment Scale ........................................... 99 
Appendix 3.2 
Clinician Global Impressions - Severity Scale ..................................... 101 
Appendix 3.3 
Clinician Global Impressions - Improvement Scale ............................. 102 
Appendix 3.4 
Rett Syndrome Behaviour Questionnaire ............................................. 103 
Appendix 3.5 
36-Item Short Form ............................................................................... 105 
Appendix 3.6 
Tanner Staging ...................................................................................... 111 
Appendix 3.7 
Hospital Services Use Questionnaire .................................................... 112 
Appendix 3.8 
Suicidality Assessment ......................................................................... 115 
Appendix 3.9 
Children’s Sleep Habits Questionnaire ................................................. 116 
Appendix 3.10 
Caregiver Assessment of Rett Symptoms ......................................... 119 
 
 
 
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List of In-text Tables 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution ................................. 33 
Table 9.2.9-1 
Biochemistry, Hematology, and Urinalysis................................... 55 
 
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List of In-text Figures 
Figure 1-1 
Trial Design and Treatment Schematic ........................................... 8 
 
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List of Abbreviations 
Abbreviation or 
special term 
Definition or Explanation 
AE 
Adverse event 
AED 
Antiepileptic drug 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BAC 
Blood alcohol content 
BDNF 
Brain-derived neurotrophic factor 
BDS 
Botanical drug substance 
b.i.d. 
Twice daily 
CB 
Cannabinoid 
CB1 
Cannabinoid receptor type 1 
CB2 
Cannabinoid receptor type 2 
CBD 
Cannabidiol 
CBD-OS 
Cannabidiol oral solution 
CGI 
Clinical global impressions 
CGI-I 
Clinical Global Impressions - Improvement 
CGI-S 
Clinical Global Impressions - Severity 
CHQ-PF50 
Child Health Questionnaire Parent Form 50 
CIOMS 
Council for International Organizations of Medical Sciences 
CRO 
Contract research organization 
CSHQ 
Children’s Sleep Habits Questionnaire 
CYP 
Cytochrome P450 
DS 
Dissociative seizures 
ECG 
12-lead electrocardiogram 
eCRF 
Electronic case report form 
EU 
European Union 
FDA 
Food and Drug Administration 
G 
Gastrostomy  
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Abbreviation or 
special term 
Definition or Explanation 
GABA 
γ-aminobutryic acid 
GPR55 
G-protein-coupled receptor 55 
GCP 
Good Clinical Practice 
GW 
GW Research Ltd 
i.p. 
Intraperitoneal 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like growth factor-1 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
i.v. 
Intravenous 
KO 
Knock out 
LGS 
Lennox-Gastaut Syndrome 
MBA-9 
9-items Motor Behavioral Assessment 
MCS 
mental health composite score 
MeCP2 
Methyl-CpG-binding protein 2 
NCU 
Intensive Care Unit 
NG 
Nasogastric  
NOEL 
No observed effect level 
OLE 
Open-label extension 
PCP 
Phencyclidine 
PCS 
physical health composite score 
PhS 
Standardized Physical Summary 
PI 
Principal investigator 
PRN 
Packaging reference number 
PsS 
Standardized Psychosocial Summary 
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Abbreviation or 
special term 
Definition or Explanation 
PVD 
Pharmacovigilance Department 
QoL 
Quality of life 
RCT 
Randomized controlled trial 
RSBQ 
Rett Syndrome Behaviour Questionnaire  
RTSM 
Randomization and Trial Supply Management 
RTT 
Rett syndrome 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-36 
36-item Short Form 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
THC 
Δ9-tetrahydrocannabinol 
UGT 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
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Definition of Terms 
Term 
Definition 
Caregiver 
An assigned patient’s parent or designated care 
provider. 
Day 1 
The day a patient first receives the investigational 
medicinal product in this trial. 
End of treatment 
Completion of the treatment period (Visit 8 [Day 197]) 
or withdrawal. 
End of trial 
Last patient’s last visit/telephone call. 
Enrolled patient 
Any patient whose parent(s)/legal representative has 
provided written informed consent for the patient to 
take part in the trial and, if possessing adequate 
understanding to do so, who has provided informed 
assent.  
International normalized ratio 
A calculation made to standardize prothrombin time. 
Investigational medicinal 
product 
The term used to describe both investigational active 
product and reference therapy (placebo). 
Investigator 
Trial principal investigator or a formally delegated 
study physician. 
Methyl-CpG-binding protein 2 
Methyl-CpG-binding protein 2 is denoted differently in 
this document: the italicized abbreviation MECP2 
denotes the human gene, the italicized Mecp2 denotes 
the mouse gene, and the nonitalicized abbreviation 
MeCP2 denotes the protein. 
Postregression 
≥ 6 months since the last loss of hand use or verbal 
language or gross motor regression. 
 
 
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2 
OBJECTIVES 
2.1 
Primary 
Key objective: 
• To evaluate the long-term safety of GWP42003-P in patients with Rett syndrome 
(RTT) 
2.2 
Secondary 
Secondary objectives: 
• To evaluate the effect of GWP42003-P in measures of disease severity 
• Rett Syndrome Behaviour Questionnaire (RSBQ)  
• Clinical Global Impressions - Improvement (CGI-I)  
• Clinical Global Impressions - Severity (CGI-S) 
• 9-items Motor Behavioral Assessment (MBA-9) 
• Children’s Sleep Habits Questionnaire (CSHQ) 
Exploratory objectives: 
• To evaluate the effect of GWP42003-P on caregiver and patient quality of life 
(QoL) 
• 36-item Short Form [SF-36] and Child Health Questionnaire Parent Form 
50 [CHQ-PF50], respectively 
• To evaluate the effect of GWP42003-P on health utilization 
• Hospital Services Use Questionnaire 
• Caregiver Assessment of Rett Symptoms 
 
 
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3 
BACKGROUND AND RATIONALE 
3.1 
Disease 
Rett syndrome is a rare, noninherited, X-linked neurodevelopmental disorder affecting 
approximately 1 in 10,000 live female births, resulting in abnormal neuronal 
development and function.1,2  Rett syndrome is one of the leading causes of intellectual 
disability in young girls and is only rarely seen in males.  Development of RTT is 
progressive, with early onset at 6 to 18 months characterized by a subtle slowing or 
regression of development.  Infants/young children aged 1 to 4 years progress to a rapid 
destructive phase characterized by loss of purposeful hand skills with stereotypic hand 
movements, loss of spoken language, breathing irregularities such as apnea and 
hyperventilation, cardiac irregularities, microcephaly, and autistic-like behaviors such as 
social withdrawal.  After a period of regression, the disorder enters a plateau phase 
associated with apraxia, motor problems, and seizures.  Over time, motor function 
continues to deteriorate, resulting in reduced mobility, scoliosis, rigidity, muscular 
weakness, and spasticity.3,4,5  
Rett syndrome is most commonly caused by heterozygous de novo mutations in the gene 
encoding methyl-CpG-binding protein 2 (MeCP2).6  Methyl-CpG-binding protein 2 is 
widely expressed in many tissues, with the highest expression in the brain7; MeCP2 is 
essential for nerve cell function, acting as a complex transcriptional modulator of genes 
involved in neuronal development, synaptic transmission, and plasticity, including brain-
derived neurotrophic factor (BDNF).8  However, mutations in MECP2 are not 
synonymous with RTT.  Between 3% and 5% of individuals who strictly meet clinical 
criteria for RTT do not have an identified mutation in MECP2, and only 50% to 70% of 
patients with atypical RTT have an identified mutation in MECP2.9  Moreover, 
cyclin-dependent kinase-like (CDKL5) and Forkhead box protein G1 (FOXG1) gene 
mutations are associated with 2 other variant forms of RTT.  Given that MECP2 
mutations are neither necessary nor sufficient to make the diagnosis of RTT, diagnostic 
criteria are often utilized9 at initial diagnosis. 
A number of genetic mouse models of RTT are available, where the deficiency of 
MeCP2, globally or specifically in developing neurons, produces similar clinical features 
to those in humans, including tremors, motor impairments, and stereotypical 
motions.10,11,12  Genetic and pharmacological intervention can ameliorate or reverse 
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behavioral deficits in Mecp2 knockout (KO) mice, suggesting that there is significant 
potential for pharmacological interventions to treat RTT.13 
Aberrant synaptic plasticity and an imbalance of excitatory and inhibitory neuronal 
networks is thought to underlie the neurological phenotype in RTT.14  Besides these 
neuronal deficits in RTT, there is evidence that neuroinflammation and glial cells may 
play a role.  Selective restoration of MeCP2 in astrocytes significantly improved 
locomotion and anxiety levels, restored respiratory functions, and greatly prolonged 
lifespan in mice, with modified astrocytes compared with control Mecp2 KO mice.  
Restoration of MeCP2 in astrocytes also returned dendritic morphology to normal.15  
Microglia from Mecp2 KO mice demonstrate enhanced release of glutamate, which is 
associated with neuronal toxicity, and also show impaired phagocytosis.16  There is also 
increasing evidence that the immune system and inflammation may be involved in 
several neurodevelopmental disorders, including RTT.17  In addition, symptoms such as 
hyperventilation and apnea can be indicative of mitochondrial dysfunction, and before the 
advent of genetic testing, RTT was proposed to be a metabolic disorder.  Changes in the 
morphology of mitochondria and genes associated with these structures as well as redox 
balance have been demonstrated in patients with RTT, but it is not clear whether some of 
these changes are a primary cause or secondary to these mechanisms.18  Finally, mouse 
models have highlighted a potential role of the growth factors, BDNF and insulin-like 
growth factor 1 (IGF-1) in the pathology of RTT19 an involvement that is corroborated by 
efficacy in clinical trials targeting these agents.20 
There is currently no curative therapy for RTT, and therefore, there is a critical need for 
treatments.21  Medical management of RTT is essentially symptomatic and supportive.  
Current options for patients focus on managing the associated conditions and include the 
use of medications to control breathing problems, heart rhythm abnormalities, seizures, 
constipation, gastroesophageal reflux disease, and sleep disturbances.22  Other therapy 
options include physiotherapy, occupational therapy, speech therapy, and feeding 
assistance (feeding tubes or other feeding aids).21 
3.2 
Investigational Medicinal Product Background 
The investigational medicinal product (IMP), GWP42003-P, is formulated from extracts 
prepared from Cannabis sativa L. plants that have a defined chemical profile and contain 
consistent levels of cannabidiol (CBD) as the principal phytocannabinoid.  Extracts from 
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these plants are processed to yield purified (≥ 98%) CBD that typically contains 
< 0.1% (weight by weight) Δ9-tetrahydrocannabinol (THC) (for oral formulations).  The 
purified CBD is subsequently dissolved in excipients with added sweetener and flavoring. 
Cannabidiol possesses very low affinity and lacks appreciable functional activity at 
cannabinoid (CB) receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor 
type 2 (CB2).23  In addition, CBD does not significantly interact with enzymes 
responsible for the synthesis and degradation of endocannabinoids at clinically relevant 
concentrations.24,25,26,27  Furthermore, considerable data describing the 
polypharmacology of CBD and its modulation of nonendocannabinoid system targets 
exist.  Indeed, CBD has the ability to interact with multiple 7-transmembrane receptor 
systems, ion channels, transporters, and enzymes.28,29 
At least 2 mechanisms of anticonvulsant action are proposed for CBD.  The first is 
modulation of intracellular Ca2+ mobilization via antagonism of the G protein-coupled 
receptor 55 (GPR55) and/or activation (and subsequent desensitization) of transient 
receptor potential (TRP) channels, particularly transient receptor potential cation channel 
subfamily V member 1 (TRPV1).30,31,32  The second is inhibition of adenosine 
reuptake.33,34,35 
Based on the lack of pharmacological engagement by CBD at therapeutically relevant 
concentrations, modulation of the following targets is considered not relevant to the 
anticonvulsant mechanism of action: CB1 and CB2 receptors, fatty acid amide hydrolase, 
voltage-gated sodium channels, benzodiazepine, and γ-aminobutryic acid (GABA) 
binding sites of the GABAA receptor. 
Importantly, CBD does not produce THC-like euphoric effects.  Furthermore, CBD 
demonstrates anticonvulsant, antipsychotic, anxiolytic, neuroprotective, antioxidant, and 
anti-inflammatory activity in a range of nonclinical models and has received Food and 
Drug Administration (FDA) approval for the treatment of seizures associated with the 
Lennox-Gastaut syndrome or the Dravet syndrome in patients 2 years of age and older.36   
3.2.1 
Nonclinical Studies 
3.2.1.1 
Efficacy Pharmacology 
In a subchronic phencyclidine (PCP) model in rats where there is disruption of cognition 
and deficits in social behavior, CBD reversed the PCP-induced recognition memory 
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deficit at doses of 2, 20, and 100 mg/kg intraperitoneal (i.p.)37 and significantly reduced 
the subchronic PCP-induced increase in avoidance behavior at 2, 10, 20, and 100 mg/kg 
i.p.38  In addition, CBD improved cognitive deficits in other nonclinical models, 
including Fmr1 KO mice, a model of Fragile X syndrome, at 100 and 200 mg/kg i.p. and 
improved bicuculline-induced memory impairments in neonatal rats at 100 mg/kg i.p.39  
Cannabidiol also improved hypoxic ischemia in rats (1 mg/kg subcutaneous)40 and 
piglets (1 mg/kg i.v.)41 when CBD was given post hypoxia-ischemia injury.   
Cellular mechanisms that are thought to be involved in the neurobehavioral deficits 
present in RTT include aberrant synaptic plasticity14, neuroinflammation15,16 and 
immune17 and metabolic malfunction.18,42  A number of studies demonstrate that CBD 
may have the potential to modulate each of these basic pathophysiological mechanisms43 
albeit not in RTT models.  For example, CBD has the potential to modulate 
excitatory/inhibitory imbalance, as demonstrated by its anticonvulsant 
activity.44,45,46,47,48  Cannabidiol also shows anti-inflammatory and antioxidant actions in 
a number of accepted animal models of inflammation, notably of the gut and the joints, 
where it inhibits the tissue production of chemical mediators of inflammation, such as 
tumor necrosis factor alpha and interleukin-2.49  Cannabidiol (1 mg/kg i.v.) also reverses 
hypoxic ischemia-induced neuroinflammation, reactive oxygen species production, and 
excitatory and metabolic derangement in rats40 and piglets41 after a hypoxic ischemic 
insult.   
Loss of language and ability to communicate is also a feature of RTT.4  In a songbird 
model of vocal learning, damage to a cortical-like premotor region of the zebra finch 
brain results in a temporary disruption of vocal patterns that recovers over about 7 days 
and is dependent on the ability of birds to hear as part of sensorimotor learning.  
Cannabidiol 10 and 100 mg/kg (intramuscular) improved the phonology and syntax of the 
zebra finch song over the first 6 to 9 days post lesion.50 
Finally, there is evidence that cannabidivarin, a cannabinoid structurally similar to CBD 
that shares molecular and behavioral pharmacology, rescued behavioral and brain 
alterations in MeCP2-308 male mice51 a validated RTT model, including improvement of 
general health status, sociability, and brain weight, with partial restoration of motor 
coordination.  
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3.2.1.2 
Safety Pharmacology 
In a rat primary observation Irwin test of central nervous system function, no behavioral, 
physiological, or body temperature changes were observed following administration of 
CBD botanical drug substance (BDS) at 10 to 100 mg/kg.52 
In the cardiovascular system, CBD as CBD BDS inhibited human ether-à-go-go-related 
gene tail current in a concentration-dependent manner52 (no-observed-effect level 
[NOEL], 43 ng/mL) and had no effect on Purkinje fiber action potentials or QT interval 
changes52 (NOEL, 22 ng/ml).  Changes in cardiovascular parameters (heart rate, blood 
pressure, and electrocardiogram [ECG]) in the conscious dog were not considered to be 
adverse.52 
In the respiratory system, CBD as CBD BDS had no biologically significant effect on 
respiratory parameters in conscious rats.52 
3.2.1.3 
Mechanism of Action 
Cannabidiol has micromolar affinity/potency at several molecular targets, whose 
relevance to RTT is unclear.  How CBD interacts with signaling pathways and cellular 
processes modulated by MeCP2 that are important in RTT is a matter of active 
investigation and is yet to be fully elucidated.   
3.2.2 
Clinical Studies 
Human efficacy data from 3 positive Phase 3 trials in patients (predominantly pediatric 
patients) with treatment-resistant epilepsies support a role for GWP42003-P as a 
treatment for central nervous system disorders.  Overall, GWP42003-P was generally 
well tolerated at doses up to 20 mg/kg/day; adverse events (AEs) were usually mild to 
moderate in severity and transient.  Elevated liver enzymes (particularly transaminases 
alanine aminotransferase [ALT] and aspartate aminotransferase [AST], and less 
commonly reported terms of abnormal liver function tests and hepatotoxicity) have been 
reported in some patients receiving GWP42003-P for severe, refractory epilepsies, 
notably in patients taking concomitant valproic acid.  None of the cases fulfilled the Hy’s 
Law criteria for potential severe liver injury.  There were no cases with a concomitant 
increase in bilirubin > 2 × upper limit of normal (ULN).  Monitoring of the blood levels 
of enzymes that are markers of liver function is advised, particularly at the start of 
treatment and with dose increases of GWP42003-P, as well as at the time of initiation or 
dose increase of concomitant medication. 
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3.3 
Rationale 
A number of studies across a range of nonclinical behavioral paradigms, as discussed 
above, suggest that CBD has the potential to treat some of the core symptoms of RTT, 
such as cognition, language, social behavior, and motor function (see Section 3.2.1.1).  
Indeed, there are suggestions from clinical studies that, in addition to treating seizures, 
CBD may have beneficial effects on cognition and behavior as well as on patient 
QOL.53,54   
This open-label extension (OLE) trial will evaluate the long-term safety of GWP42003-P 
in patients with RTT who carry a MECP2 gene mutation. 
3.3.1 
Choice of Endpoints 
Overall, the range of assessments cover the key symptom domains: behavior and 
emotion, motor function, breathing abnormalities, and sleep.   
3.3.1.1 
Choice of Primary Endpoints 
Safety, selected as the primary endpoint, will be assessed by evaluating changes in AEs, 
clinical laboratory parameters, vital signs, physical examination procedures, 12-lead 
ECGs, effects on menstruation cycles, and suicidality.  Change in growth and 
development will also be measured by height, weight, serum IGF-1 levels, and Tanner 
Staging (for patients aged ≥ 7 years or earlier, if clinically indicated by the onset of 
menarche or other signs of precocious puberty).   
3.3.1.2 
Choice of Secondary Endpoints 
Secondary endpoints, scales, and assessments were selected to evaluate a wide range of 
symptoms observed in patients with RTT: 
• RSBQ.  This caregiver-completed assessment has been specifically developed for 
use in patients with RTT.55  The RSBQ total score is used as a global measure to 
assess the patient’s overall condition, whereas subscales of the RSBQ allow 
evaluation of more-specific domains (behavior and emotion, motor function, and 
breathing abnormalities).   
• CGI-I and CGI-S.  CGI-I was selected as a clinician-rated assessment that has 
been used extensively in neuropsychiatric disorders in both clinical practice and 
clinical trial settings56,57,58 and reported to have successfully been implemented in 
the RTT patient population.59  CGI-I is a global measure used to assess the 
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patient’s overall condition.  CGI-I assesses change in symptoms relative to the 
baseline CGI-S. 
• MBA-9.  This scale was selected as it provides a clinician assessment of a set of 
motor and behavior items of the original MBA60,61 that are deemed amenable to 
change. 
• CSHQ.  This questionnaire was selected as sleep problems are reported for the 
majority of patients with RTT.  CSHQ has been used to characterize sleep in other 
developmental disability populations (e.g., autism spectrum disorder62) and in a 
sample of patients with RTT.63  
3.3.1.3 
Choice of Exploratory Endpoints 
The required constant care and supervision of patients with RTT places a significant 
burden on the parent(s)/caregiver; as such, effects on caregiver QoL will be assessed as 
an exploratory endpoint using the SF-36 questionnaire.  In addition, caregiver-reported 
patient QoL will be assessed using CHQ-PF50.  Information on health utilization will be 
assessed using the Hospital Services Use Questionnaire, which aims to analyze the 
frequency of patient hospitalizations and hospital visits.   
The Caregiver Assessment of Rett Symptoms has been specifically developed for the 
proposed clinical trial with the intent of obtaining data on the patient’s condition and 
aims to provide additional information on selected key areas of interest: breathing, hand 
stereotypies, interactions, problem behaviors, sleep, constipation, seizures, and global 
function.   
3.3.2 
Choice of Dosing Regimen 
Given that the objective of the trial is to monitor long-term safety, a flexible dose 
escalation based on efficacy and tolerability, as judged by the investigator, will be used.  
The maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.) is set in accordance with the 
maximum dose per the United States (US) prescribing information for CBD.64  
The GWP42003-P solution contains 7.9% w/v anhydrous ethanol, which is required as 
sucralose is not soluble in sesame oil.  A dose of 15 mg/kg/day (administered as 
7.5 mg/kg twice daily [b.i.d.]) in a 10 kg child will result in a blood alcohol content 
(BAC) of 0.0098 g/L, which equates to an ethanol ingestion of 5.93 mg/kg.  Both these 
amounts are well under the threshold for a BAC of 0.125 g/L and an ethanol ingestion of 
75 mg/kg for patients 6 years and older and also under the maximum BAC level of 
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0.01 g/L and ethanol ingestion of 6 mg/kg for children less than <6 years old.65  At the 
highest recommended therapeutic dose of 20 mg/kg/day (administered as 10 mg/kg 
b.i.d.), a single dose of 10 mg/kg cannabidiol oral solution (CBD-OS) in a 10 kg child 
theoretically results in a BAC of 0.013 g/L and an ethanol ingestion of 7.9 mg/kg, slightly 
above the recommended threshold for BAC of 0.01 g/L for children less than 6 years old.  
In light of the wide safety margins observed in toxicology studies and taking the severity 
of the condition into account, this theoretical risk is judged to be acceptable.  
Please refer to the investigator’s brochure (IB) and Development Core Safety Information 
for the most current safety data. 
3.3.3 
Benefit-risk Analysis  
There are no approved medications for RTT, neither disease modifying nor for 
symptomatic therapy.  Nonclinical and clinical data indicate that CBD-OS may benefit 
patients with RTT (see Section 3.2.1.1, Section 3.2.2, and Section 3.3). 
The key risks identified from the CBD-OS clinical development program for 
Lennox-Gestaut Syndrome (LGS) and dissosicated seziures (DS) (described in 
Section 3.2.2) are broadly expected to be the same for the RTT population - as the patient 
demographics and comorbidities have a significant amount of overlap.  Importantly, the 
risk of raised transaminases is reduced in the context of this RTT trial where lower doses 
of CBD-OS are planned and valproic acid use is expected to be lower in this population.   
In the context of the anticipated benefit of CBD-OS in RTT patients, the key risks 
identified from the CBD OS clinical development program in LGS and DS are acceptable 
given the proposed dose level (maximum dose of 20 mg/kg/day)  and the age range of 2–
18 years.  Thus, the overall benefit-risk for the development of CBD-OS in the RTT 
population is favorable. 
3.4 
Clinical Hypothesis 
There will be no formal hypothesis testing in this trial. 
 
 
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4 
EXPERIMENTAL PLAN 
4.1 
Trial Design 
This is a 28-week, multicenter, OLE trial for patients with RTT who have completed the 
randomized, double blind, placebo-controlled trial (GWND18064). 
Entry to this OLE trial is recommended to be on the same day as Visit 9 of the 
randomized controlled trial (RCT); however, patients may enter the OLE up to the RCT 
follow-up visit (Visit 11). 
All patients entering this OLE trial will begin dosing with 5 mg/kg/day GWP42003-P 
(2.5 mg/kg b.i.d.) on Day 1.  Patients will be observed, and after 1 week, the dose may 
further be escalated, at the investigator’s discretion, up to 15 mg/kg/day GWP42003-P 
(7.5 mg/kg b.i.d.) in weekly increments of 5 mg/kg/day (2.5 mg/kg b.i.d.).   
Patients should then remain on a stable dose of GWP42003-P for the duration of the 
maintenance period of the trial (up to 28 weeks), with the option for doses to be 
decreased or increased to a maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.) based on 
clinical response and tolerability, as deemed necessary by the investigator, until the 
optimal dose is found.  Patients whose dose has been decreased can have their dose 
increased again if tolerability improves.   
At the end of treatment (Visit 8 [Day 197]), the dose of GWP42003-P will be reduced 
over a 10-day taper period, and patients will enter the 4-week follow-up period.   
If a patient permanently discontinues treatment at any point during the trial, 
GWP42003-P should be gradually reduced over 10 days (unless inadvisable due to an 
AE).  The patient should attend a withdrawal visit (Visit 8) as soon as possible after the 
decision is made to permanently discontinue GWP42003-P.  If applicable, the patient will 
taper GWP42003-P, attend the End of Taper visit, and then complete the 4-week 
follow-up period.   
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. 
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4.1.1 
Primary Endpoint 
Safety: 
The long-term safety profile of GWP42003-P will be assessed by evaluating changes in 
the following, relative to the prerandomization baseline of the RCT: 
• AEs 
• Clinical laboratory parameters 
• Vital signs 
• Physical examination procedures 
• 12-lead ECG 
• Effects on menstruation cycles 
• Suicidality 
• Change in growth and development by measurement of height, weight, IGF-1 
levels, and Tanner Staging (for patients aged ≥ 7 years or earlier, if clinically 
indicated by the onset of menarche or other signs of precocious puberty) 
4.1.2 
Secondary Endpoints 
4.1.2.1 
Secondary endpoints: 
The following will be assessed by evaluating changes relative to the prerandomization 
baseline of the RCT: 
• RSBQ 
• CGI-I 
• CGI-S 
• MBA-9 
• CSHQ 
4.1.2.2 
Exploratory endpoints: 
The following will be assessed by evaluating changes relative to the prerandomization 
baseline of the RCT: 
• SF-36 
• CHQ-PF50 
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• Hospital Services Use Questionnaire 
• Caregiver Assessment of Rett Symptoms 
4.2 
Number of Trial Centers 
Approximately 25 trial centers are expected to participate in this trial.  The number of 
centers may be reduced or increased depending on recruitment performance. 
4.3 
Number of Patients 
All patients with RTT who complete the randomized, double-blind, placebo-controlled 
trial (GWND18064) who wish to take GWP42003-P and meet the eligibility criteria will 
transition to 5 mg/kg/day GWP42003-P (2.5 mg/kg b.i.d.) on Day 1 of the OLE.  
Approximately 252 patients will be enrolled.  
 
 
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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
Please refer to the separate pharmacy manual for more detailed information on 
GWP42003-P. 
5.1 
GWP42003-P Oral Solution 
The GWP42003-P oral solution is presented as a solution containing 100 mg/mL CBD 
dissolved in the excipients sesame oil and anhydrous ethanol (10% v/v), sweetener 
(sucralose), and strawberry flavoring (Table 5.1-1). 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution 
Ingredients 
Quantity 
CBD 
100 mg/mL 
Anhydrous ethanol 
79 mg/mL 
Sucralose 
0.5 mg/mL 
Strawberry flavor 
0.2 mg/mL 
Refined sesame oil 
Makes up to 1 mL 
5.2 
Packaging, Storage, and Drug Accountability 
5.2.1 
Packaging and Labeling  
GWP42003-P will be manufactured, packaged, labeled, and/or distributed by GW or 
delegated contractors.  GWP42003-P will be presented in 100 mL amber glass bottles 
with child-resistant screw caps and packed in cartons.  GWP42003-P will be dispensed at 
each relevant visit.  A unique identification number will be used to identify each carton 
and the GWP42003-P it contains.  The unique identification number together with the 
packaging reference number (PRN) will permit full traceability of manufacture, pack, and 
label activities conducted at or on behalf of GW and the IMP information held on the 
Randomization and Trial Supply Management (RTSM) system.  GW will ensure that all 
GWP42003-P 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., “GWP42003-P”) 
• Dose and/or potency (e.g., “100 mg/mL GWP42003-P”) 
• Trial code number 
• Expiry date 
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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 caregiver.  Caregivers will be instructed to retain and carry this 
information with the patient at all times. 
5.2.2 
Storage 
GWP42003-P must be stored upright at room temperature (< 30°C) and must not be 
refrigerated or frozen.  It must also be kept away from heat and direct sunlight. 
GWP42003-P must be stored in compliance with the local regulations for a controlled 
drug (if applicable to country).  The sponsor must approve the storage location and 
facilities.  Temperature records of the clinical center storage location must be maintained 
(recording a minimum of Monday to Friday, excluding public holidays) from the date of 
receipt of the first shipment until the end-of-trial dispensing period at each center.  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 the transit of GWP42003-P to the center 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 GWP42003-P remains suitable for 
use.  GWP42003-P must be placed under quarantine until written confirmation is 
received that GWP42003-P is suitable for use. 
Caregivers will be provided with instructions regarding home storage requirements for 
GWP42003-P. 
5.2.3 
Supply and Return of Investigational Medicinal Product 
At trial initiation and as needed thereafter, GWP42003-P will be shipped to the identified 
responsible person, such as the pharmacist, at the investigator’s center, who will check 
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the amount received against the shipment request and the condition of the drug 
(i.e., integrity, physical appearance, and temperature during transit).  Details of 
GWP42003-P received will be recorded in the GWP42003-P accountability record (see 
Section 5.2.4).  The center will acknowledge the GWP42003-P receipt and will complete 
any receipt forms required.  GWP42003-P will be dispensed and returned as detailed in 
Section 8.4.  As directed, all supplies, including unused, partially used, or empty 
containers, will be returned to the GW/depot or destroyed at a GW-approved center if 
agreed in writing by the trial monitor. 
5.2.4 
Investigational Medicinal Product Accountability 
The investigator has overall responsibility for the accountability of all used and unused 
GWP42003-P.  A drug accountability record for GWP42003-P must be kept current and 
should contain the following: 
• Trial code 
• PRN, treatment number, date of receipt, and quantity of GWP42003-P received 
• Patient’s trial identification and/or treatment number 
• Date and quantity of GWP42003-P dispensed 
• The initials of the dispensing/dosing party 
• Date and quantity of GWP42003-P returned to the investigator 
• GWP42003-P expiry dates 
GWP42003-P will be dispensed at Visits 1, 4, 5, 6, 7, and 8 (at Visit 8 for patients 
entering the 10-day taper period).  Caregivers will be asked to return all GWP42003-P 
(used and unused) at each relevant visit (Visits 4, 5, 6, 7, 8, and 9).  The center will check 
the returned GWP42003-P against the expected usage.  Any discrepancies will be 
discussed with the caregiver at the time of the visit and documented accordingly within 
the patient’s source documents.   
The investigator must inform GW promptly of all missing or unaccountable 
GWP42003-P. 
A record of returned GWP42003-P must be completed and included in the shipment of 
used and unused GWP42003-P to the relevant drug distribution depot.  At the end of the 
trial, a record/statement of reconciliation must be completed and provided to GW. 
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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 
GWP42003-P. 
5.2.5 
Post-trial Provision 
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 European Union (EU) law. 
 
 
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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, 
and sex, as allowed per local regulations) and outcome of screening. 
6.1 
Inclusion Criteria 
For inclusion in the trial patients must fulfil all of the following criteria: 
6.1.1 Patient has completed all scheduled visits of the treatment phase of the RCT, 
GWND18064, and has transitioned to OLE by the point of RCT follow-up 
(Visit 11). 
6.1.2 Patient (if possessing adequate understanding, in the investigator’s opinion) 
and/or her parent(s)/legal representative is willing and able to give informed 
consent/assent for participation in the trial. 
6.1.3 Patient and her caregiver are willing and able (in the investigator’s opinion) to 
comply with all trial requirements (including the completion of all caregiver 
assessments by the same caregiver throughout the trial). 
6.1.4 Patient must have the ability to swallow the IMP provided as a liquid solution 
or the ability for the IMP to be delivered via gastrostomy (G) or nasogastric 
(NG) feeding tube (only G- or NG-tubes made from polyurethane or silicon 
are allowed). 
6.1.5 Patient and/or parent(s)/legal representative is willing to allow the responsible 
authorities to be notified of participation in the trial, if mandated by local law. 
6.1.6 Patient and/or parent(s)/legal representative is willing to allow the patient’s 
primary care practitioner (if she has one) and consultant (if she has one) to be 
notified of participation in the trial if the primary care practitioner/consultant 
is different from the investigator. 
6.2 
Exclusion Criteria  
If the RCT ‘End of Treatment’/‘End of Taper Period’ visit assessments or Visit 1 
reassessments (as applicable) raise any safety concerns, the investigator should consider 
whether it will be appropriate for the patient to continue to participate in the OLE trial or 
if the patient should be withdrawn.  The patient may not enter the trial if ANY of the 
following apply: 
6.2.1 Patient meets the withdrawal criteria (including clinically significant abnormal 
laboratory values) in the investigator’s opinion (refer to Section 10).   
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6.2.2 Patient met during the RCT the criteria for permanent IMP discontinuation 
(unless in case of an AE, if AE was not considered related with the IMP; 
patients that met ALT/AST elevations discontinuation criteria must be 
excluded). 
6.2.3 Patient is of childbearing potential, unless willing to ensure that they or their 
partner use a highly effective method of birth control (e.g., combined 
[estrogen and progestogen containing] hormonal contraceptiona associated 
with inhibition of ovulation [oral, intravaginal or transdermal], 
progestogen-only hormonal contraceptiona associated with inhibition of 
ovulation [oral, injectable or implantableb] intrauterine devices/hormone-
releasing systemsb, bilateral tubal occlusionb, vasectomized partnerb,c, , sexual 
abstinenced during the trial and for 3 months thereafter. 
6.2.4 Patient has been previously enrolled and dosed in this trial. 
6.2.5 Patient is unwilling to abstain from donation of blood during the trial. 
 
 
                                                 
a The effect of GWP42003-P on oral contraceptives has not been investigated.  GWP42003-P is 
not an inducer of CYP3A4 and therefore is not expected to alter the PK of hormonal 
contraceptives. 
b Contraception methods that are considered to have low user dependency 
c Provided that partner is the sole sexual partner of the trial patient of childbearing potential and 
that the vasectomized partner has received medical assessment of the surgical success. 
d Only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the trial treatments.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. 
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7 
PATIENT ENROLLMENT 
Before patients may be entered into the trial, GW requires a copy of the relevant center’s 
institutional review board (IRB) or independent ethics committee (IEC) written approval 
of the protocol, informed consent/assent forms, and other patient information material.  
Patients will be considered enrolled in the trial from the time of providing written 
informed consent/assent.  All parent(s)/legal representatives must personally sign and 
date the consent forms prior to any procedures being performed (refer to Section 9.2.1 
and Section 15.2).  The nominated caregiver will be asked to consent to complete the 
QoL questionnaires.  If the patient possesses adequate understanding, assent will also be 
taken along with parent(s)/legal representative consent (refer to Section 9.2.1 and 
Section 15.2).  Due to the degree of cognitive impairment in patients with RTT, patients 
18 years of age or older will not be required to provide consent and will only be required 
to provide assent in cases where the patient possesses adequate understanding, along with 
parent(s)/legal representative consent. 
7.1 
Treatment Assignment 
As this is a single-group OLE trial, all patients will receive GWP42003-P.  Patients will 
not be informed of their allocated treatment group in the RCT.  Patients will retain the 
patient number allocated to them during the RCT. 
7.2 
Randomization 
This is an OLE of the GWND18064 trial.  Randomization will not occur.  At the start of 
the GWND18064 trial, enrolled patients were allocated a unique patient number.  Patients 
will retain this number during the OLE trial.  
 
 
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8 
TREATMENT PROCEDURES 
8.1 
Investigational Medicinal Product Dosage, Administration, and 
Schedule 
GWP42003-P will be presented as an oral solution containing 100 mg/mL CBD.  For 
details regarding IMP formulations, see Section 5.  
Before the patient undergoes any assessments or observations, the patient’s 
parent(s)/legal representative is required to give written informed consent or assent (see 
Section 9.2.1 and Section 15.2).  The nominated caregiver will be asked to consent to 
complete the QoL questionnaires.   
8.1.1 
Dose Administration 
GWP42003-P will be administered orally (swallowed) b.i.d. (morning and evening) using 
the syringe(s) provided.  GWP42003-P may be taken with other concomitant 
medications, as directed by the investigator.  In patients with G- or NG-tubes but where 
oral dosing of GWP42003-P is possible, oral dosing is preferable.  Only in patients where 
oral dosing is not possible should GWP42003-P be administered via G- or NG-tubes 
made from polyurethane or silicon only.  GWP42003-P should be preferentially taken 
with food, i.e., within 30 minutes after the end of a meal and in line with the patients’ 
normal feeding schedule and dietary habits.  The time of GWP42003-P administration in 
relation to food should be kept consistent throughout the trial The investigator should 
contact the medical monitor to review IMP administration guidelines if administration via 
G-or NG-tubes is planned. 
8.1.2 
Dose Escalation and Dose Adjustments 
The daily volumes of the GWP42003-P solution to be taken will be calculated based on 
the patients’ weight, and the dosing schedule will be provided to the caregiver.  Further 
information on dispensing procedures will be provided in a separate Pharmacy Manual. 
Caregivers will be trained on dose administration during the GWND18064 trial.   
All patients entering this OLE trial will begin dosing with 5 mg/kg/day GWP42003-P 
(2.5 mg/kg b.i.d.) on Day 1.  Patients will be observed, and after 1 week the dose may 
escalate further, at the investigator’s discretion, up to 15 mg/kg/day GWP42003-P 
(7.5 mg/kg b.i.d.) in weekly increments of 5 mg/kg/day (2.5 mg/kg b.i.d.).   
Patients should then remain on a stable dose of GWP42003-P for the duration of the 
maintenance period of the trial (up to 28 weeks), with the option for doses to be 
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decreased or increased if deemed necessary by the investigator, to a maximum dose of 
20 mg/kg/day (10 mg/kg b.i.d.).   
If an unacceptable AE develops at any time during the dose escalation period(s), dosing 
should initially be suspended or amended, at the investigator’s discretion, until the event 
has resolved.  Patients who have escalated above 5 mg/kg/day should return to the 
previous dose level tolerated in steps of 5 mg/kg/day each week, unless a quicker 
reduction is judged to be required for safety reasons.  If a patient cannot tolerate 
5 mg/kg/day, doses should be reduced to 2.5 mg/kg/day.  If necessary, dosing may be 
temporarily suspended. 
Patients whose dose has been decreased can have their dose increased again if tolerability 
improves.  Patients unable to tolerate the target dose may stay at a lower dose.  However, 
if a patient cannot tolerate a dose of 2.5 mg/kg/day, the patient should be withdrawn from 
treatment, unless a lower dose level is agreed in discussion with the medical monitor and 
can be accurately measured (minimum single-dose volume of 0.1 mL).  Dose adjustments 
should be discussed with the GW medical monitor.  The final decision regarding dose 
adjustments should be taken by the investigator. 
Hepatic function monitoring should be carried out within 1 month following increases in 
GWP42003-P dose or introduction or dose increases of medications that are known to 
impact liver function.  If the concerned change does not occur within 1 month of a 
scheduled biochemistry assessment, the investigator should perform an additional hepatic 
monitoring within 1 month of the change.  
Transaminase elevations should be medically managed by the investigator either by 
reducing the GWP42003-P dose as described above or by reducing concomitant 
medications judged to be causing the elevation (per Section 8.2).  Dose adjustments 
should be discussed with the GW medical monitor.  For potential cases of drug-induced 
liver injury, see Section 12.8. 
At the end of treatment (Visit 8 [Day 197]), the dose of GWP42003-P will be reduced 
over a 10-day taper period, and patients will enter the 4-week follow-up period.  
Patients discontinuing GWP42003-P treatment at any other time should undergo a 10-day 
taper period (unless continued dosing is inadvisable, e.g., due to an AE).  The decision on 
whether to taper GWP42003-P or not will be left to the investigator’s clinical judgment. 
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8.2 
Concomitant Therapy 
It is theoretically possible that GWP42003-P may modify the metabolism of other drugs 
(including antiepileptic drugs [AEDs]) administered concurrently, and there remains the 
possibility of pharmacological interactions between GWP42003-P and other concurrently 
administered drugs.  If there are side-effects suspected of being related to an elevation in 
the concomitant concentration, the investigator should contact the GW medical monitor 
to discuss best management.  Decisions should be based on clinical symptoms and not 
plasma levels of concomitant medications.  The final decision regarding dose adjustments 
should be taken by the investigator.  Cannabidiol has the potential to induce the 
expression of hepatic CYP enzymes (CYP1A2, 2B6 and 3A4) at clinically relevant 
concentrations.  Careful titration of CBD in patients taking concomitant medications 
metabolized by CYP3A4, CYP2C19, or CYP2B6 is advised, with plasma monitoring of 
such medications or their metabolites to be undertaken at the investigator’s discretion.  
Further information on drug interactions can be found in the IB 52.  Any concerns 
regarding potential interactions with concomitant medications can be discussed with the 
trial medical monitor(s). 
Changes in concomitant medications are allowed, but increases in dose of medications 
that affect liver function should be discussed with the medical monitor.  Introduction of 
new medications is allowed, but introduction of new psychotropic and/or central acting 
agents intended as long-term treatment requires prior discussion with the medical 
monitor.  
The use of rescue medication is allowed, when necessary (i.e., AED for transient 
exacerbation of seizures).  Any medication, other than GWP42003-P, taken during the 
trial must be recorded on the electronic case report form (eCRF). 
8.3 
Prohibited Therapy During the Trial Period 
The following medications are prohibited for the duration of the trial.  However, any 
patients taking these medications after screening should not be discontinued from 
treatment, unless there are safety concerns.  
• St John’s wort 
• Recreational or medicinal cannabis or cannabinoid-based medications (including 
Sativex or CBD oral solutions) 
• Any other IMP 
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• Felbamate that has been taken for less than 1 year 
Care should be taken with drugs, or their metabolites, that are CYP2C19 substrates, such 
as N-desmethylclobazam.  Care should also be taken with drugs, or their metabolites, that 
are solely or primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase 
(UGT)1A9 and UGT2B7. 
8.4 
Compliance in Investigational Medicinal Product Administration 
GWP42003-P is dispensed to the patient at Visits 1, 4, 5, 6, 7, and 8 (at Visit 8 for 
patients entering the 10-day taper period).  Further guidance on GWP42003-P dispensing 
will be provided in a separate pharmacy manual.   
Caregivers will be asked to confirm dosing in the dosing schedule daily.  Caregivers 
should return all GWP42003-P (used and unused) at each of Visits 4, 5, 6, 7, 8, and 9.  
The returned medication will be checked against the expected usage, and any 
discrepancies will be discussed with the caregiver at the time of the visit and documented 
accordingly within the patient’s source documents.  Caregivers will also be asked about 
the time of GWP42003-P administration in relation to meals. 
The investigator must inform GW promptly of all missing or unaccountable 
GWP42003-P.   
Records of GWP42003-P accountability will be maintained according to Section 5.2.4. 
8.5 
Access to Blinded Treatment Assignment 
This is not applicable. 
 
 
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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. 
The location of the source data for the following procedures will be documented, per 
center, in a signed source data verification plan; for further details, see Section 16.2. 
9.1 
Trial Procedures by Visit 
Patients and their parent(s)/legal representative will be invited to take part in the trial and 
will be issued with the patient information and informed assent (if applicable) and the 
parent(s)/legal representative information and informed consent.  Due to the degree of 
cognitive impairment in patients with RTT, patients 18 years of age or older will not be 
required to provide consent and will only be required to provide assent in cases where the 
patient possesses adequate understanding, along with parent(s)/legal representative 
consent.  Following ample time to discuss the trial with the investigator, nurse, relatives, 
or caregiver, as wished, patients for whom the parent(s)/legal representatives provide 
written informed consent, and in cases where the patient possesses adequate 
understanding, patients who give their assent will be screened for entry into the trial.  The 
nominated caregiver will be asked to consent to complete the QoL questionnaires. 
Each visit should be scheduled to take place at approximately the same time of day 
(i.e., morning or afternoon), whenever possible.  Visits 2, 3, and 10 are to be conducted 
by telephone.   
The investigator should use his/her judgment and knowledge of the patient to determine 
when to best collect the blood and urine samples in order to mitigate the risk that invasive 
procedures may cause the patient to become stressed, thereby affecting the results of 
other patient assessments. 
All assessments should reflect the patient’s regular state, therefore it should be ensured 
the patient had adequate time to settle prior to each assessment.  The CGI-S and CGI-I 
assessments should be based on the entirety of the visit. 
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9.1.1 
Clinic Visits 
9.1.1.1 
Visit 1 (Day 1) 
Every effort should be made for this visit to take place on the same day as the RCT ‘End 
of Treatment’ visit.  However, patients can still enter the OLE trial up to the point of the 
RCT follow-up (Visit 11).   
OLE Visit 1 Assessments required for all patients: 
• Informed consent and assent 
• Eligibility check 
• New medical history 
• AE review 
• GWP42003-P dispensing 
OLE Visit 1 assessments required if OLE Visit 1 occurs on a different date than 
RCT Visit 9: 
• Vital signs 
• Hospital Services Use Questionnaire  
• Suicidality assessment 
OLE Visit 1 assessments required if OLE Visit 1 occurs > 28 days after RCT Visit 9: 
• Physical examination (including weight) 
• ECG 
• Clinical laboratory blood sampling (hematology and biochemistry) 
• Dipstick urinalysis (where possible) 
Patients who satisfy all of the inclusion criteria and none of the exclusion criteria 
specified in Section 6 will begin the treatment period. 
Patients will be dispensed sufficient GWP42003-P and a dosing schedule for the 
following 3 weeks.  Caregivers will be instructed on how to use the dosing schedule and 
how to measure and administer the medication.  At the next visit, all GWP42003-P (used 
and unused) will be collected, and a check of the returned GWP42003-P against usage 
should be made.   
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Based on Section 9.1.3, assessments may be performed at unscheduled visits in the event 
of a safety concern, as deemed necessary by the investigator. 
The investigator should review the laboratory results as soon as these become available.  
If the results show a patient is ineligible, the patient will fail screening. 
9.1.1.2 
Visit 4 (Day 29 [± 7]) 
This visit will occur 28 days after Visit 1.  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. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
The investigator must assess adherence to the dosing schedule.   
Physical examination (including body weight) and ECG assessments will be performed.  
Vital sign assessments will be performed.  
Clinical laboratory samples (urine [where possible] and blood) will be taken for 
hematology and biochemistry.   
The caregiver will complete the RSBQ and Caregiver Assessment of Rett Symptoms.   
The Hospital Services Use Questionnaire will be completed via interview. 
The investigator will complete the CGI-S, CGI-I, and suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 4 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.3 
Visit 5 (Day 57 [± 7]) 
This visit will occur 28 days after Visit 4.  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. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
The investigator must assess adherence to the dosing schedule.   
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Clinical laboratory samples (urine [where possible] and blood) will be taken for 
hematology and biochemistry.   
The caregiver will complete the RSBQ and Caregiver Assessment of Rett Symptoms.   
The Hospital Services Use Questionnaire will be conducted via interview. 
The investigator will complete CGI-S, CGI-I, and suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 4 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.4 
Visit 6 (Day 85 [± 7]) 
This visit will occur 28 days after Visit 5.  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. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
The investigator must assess adherence to the dosing schedule.   
Physical examination (including body weight) and ECG assessments will be performed.  
Vital sign assessments will be performed.  
Clinical laboratory samples (urine [where possible] and blood) will be taken for 
hematology and biochemistry.   
The caregiver will complete the RSBQ, CSHQ and Caregiver Assessment of Rett 
Symptoms.   
The Hospital Services Use Questionnaire will be completed via interview. 
The investigator will complete MBA-9, CGI-S, CGI-I, and suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 8 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
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9.1.1.5 
Visit 7 (Day 141 [± 7]) 
This visit will occur 56 days after Visit 6.  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. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
The investigator must assess adherence to the dosing schedule.   
Clinical laboratory samples (urine [where possible] and blood) will be taken for 
hematology and biochemistry for patients taking concomitant valproic acid, as well as for 
patients whose dose exceeds 15 mg/kg/day.   
The caregiver will complete the RSBQ and Caregiver Assessment of Rett Symptoms.   
The Hospital Services Use Questionnaire will be completed via interview. 
The investigator will complete CGI-S, CGI-I, and suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 8 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.6 
Visit 8 (Day 197 [± 7], End of Treatment/Withdrawal Visit) 
This visit will occur 56 days after Visit 7 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. 
The patient should attend a withdrawal visit (Visit 8) as soon as possible after the 
decision is made to permanently discontinue GWP42003-P.   
Information regarding changes to concomitant medications, AEs, and menstruation cycle 
(where applicable) will be reviewed.  Physical examination (including body weight), 
height, and ECG assessments will be performed.  Vital sign assessments will be 
performed.   
Clinical laboratory samples (urine [where possible] and blood) will be taken for the 
following: 
• Hematology 
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• Biochemistry 
• Dipstick urinalysis (provided urine can be obtained) 
• Pregnancy test using a serum sample (as appropriate [Section 9.2.2])   
• Determination of serum IGF-1 levels (Section 9.2.9) 
The caregiver will complete the RSBQ, CSHQ, SF-36, CHQ-PF50, and Caregiver 
Assessment of Rett Symptoms. 
The Hospital Services Use Questionnaire will be completed via interview. 
The Tanner Stage will be recorded (where appropriate).   
The investigator will complete MBA-9, CGI-S, CGI-I, and suicidality assessment. 
The investigator must assess adherence to the dosing schedule.   
Patients will receive sufficient GWP42003-P for the 10-day taper period, as applicable.  
Dosing schedules will be provided accordingly.  For patients who discontinue 
GWP42003-P early, the taper period should start at the time the decision is made to 
discontinue, unless tapering the dose of GWP42003-P is inadvisable (e.g., continued 
dosing is not possible due to an AE).  For patients who discontinue GWP42003-P early, 
the decision on whether or not to taper GWP42003-P will be left to the investigator’s 
clinical judgment.   
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.7 
Visit 9 (Day 207 [+ 7], End of Taper) 
This visit will occur 10 days after the end of treatment (Visit 8).  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.  This visit marks the end of the 
taper period. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
Vital sign assessments will be performed.  The investigator must assess adherence to the 
dosing schedule.   
The investigator will complete the suicidality assessment. 
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All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.   
9.1.2 
Telephone Visits  
9.1.2.1 
Visits 2 (Day 8 [± 3]) and 3 (Day 15 [± 3]) 
Visits 2 and 3 will occur 7 and 14 days after randomization (Visit 1), respectively. 
A visit window of ± 3 days from the scheduled visit date is permitted, but it is preferred 
that the visit is performed on the scheduled visit day, where possible.  
Telephone visits will be conducted by a center nurse (the center investigator only needs 
to be involved if necessary, e.g., if any concerns are raised during the call).  Information 
regarding changes to concomitant medications and AEs will be reviewed.  The center (the 
nurse and, if necessary, the investigator) must assess adherence to the dosing schedule. 
9.1.2.2 
Visit 10 (Day 235+7, End of Trial) 
This visit will occur 28 days after Visit 9 (or Visit 8 if the patient did not taper).  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.  This visit marks the end of 
the trial. 
Visit 10 constitutes the last scheduled safety follow-up.  The purpose of the visit is to 
ascertain the status of AEs continuing after the cessation of GWP42003-P or any new 
AEs commencing after discontinuation.  All causally related AEs that result in a patient’s 
early termination from the trial or are present at the end of the trial should be followed up 
until a satisfactory resolution occurs, i.e., until the AE resolves or is considered clinically 
insignificant, or until the investigator is satisfied that the AE is not related to 
GWP42003-P and needs no further investigation.  Information regarding changes to 
concomitant medications will be reviewed.   
9.1.3 
Unscheduled Visits 
Unscheduled visits and assessments may be performed in the event of a safety concern, 
as deemed necessary by the investigator.  Data from any unscheduled visits should be 
reported on the unscheduled visits eCRF.  
9.1.4 
End of Trial 
The end of trial is defined as last patient last visit/telephone call. 
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9.2 
Trial Procedure Listing 
9.2.1 
Informed Consent/Assent 
The parent(s)/legal representative of all patients in the trial must personally sign and date 
the IRB/IEC-approved informed consent form (ICF) before any trial-specific procedures 
are performed or any patient-related data are recorded for the trial.  The nominated 
caregiver will be asked to consent to complete the QoL questionnaires. 
In cases where the patient possesses adequate understanding in the opinion of the 
investigator, assent will be taken along with parent(s)/legal representative consent, using 
IRB/IEC-approved assent forms.  If appropriate, prior to signing, the assent form will be 
read to the patient, and the patient will be given the opportunity to ask questions and 
discuss with their parent(s)/legal representative.  If appropriate, the patient must 
personally sign and date the assent form.  Patients who cannot write can give 
consent/assent by “making their mark” on the assent form (e.g., writing an “X”).  If the 
patient possesses adequate understanding but is not physically able to sign, an impartial 
witness should be present during the entire assent discussion and should sign and 
personally date the assent form.  By signing, the witness attests that the information in the 
assent form and any other written information were accurately explained to and 
apparently understood by the patient and that assent was freely given by the patient.  
Assent is defined as the minor’s permission or affirmative agreement to participate in the 
trial.  If a minor who is capable of forming an opinion and assessing the information 
provided makes an explicit wish to refuse participation in or to be withdrawn from the 
clinical trial at any time, this wish must be considered by the investigator.  Given the 
severity of the condition, it is expected that the majority of patients will have an 
insufficient level of understanding of what is proposed, in which case solely 
parent(s)/legal representative consent will be sought.  All decisions made by the 
investigator relating to a patient’s level of understanding and ability to provide assent 
must be documented in the patient’s medical records. 
GW Research Ltd requires a physician to be present for consent and assent and to also 
sign the consent and assent forms.  The original signed informed consent/assent forms 
should be retained, and a copy should be provided to the patient and/or parent(s)/legal 
representative.  Patients’ parent(s)/legal representatives 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, see Section 15.2. 
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9.2.2 
Contraception Requirements 
Contraception requirements must be assessed by the investigator on a case by case basis.  
Where applicable, the patient or their partner must use highly effective contraception for 
the duration of the study and for three months thereafter.  Contraception requirements 
must be assessed by the investigator on a case-by-case basis.  Where applicable, patients 
of childbearing potential (i.e., fertile, following menarche and until becoming 
postmenopausal for ≥ 12 consecutive months, unless permanently sterile by 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy per the definition of 
woman of childbearing potential) must use highly effective birth control method 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.66  Such methods 
include:  
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with the inhibition of ovulationa: 
• Oral. 
• Intravaginal. 
• Transdermal. 
• Progestogen-only hormonal contraception associated with inhibition of 
ovulationa: 
• Oral. 
• Injectable. 
• Implantableb. 
• Intrauterine devicesb 
• Intrauterine hormone-releasing systemsb. 
• Bilateral tubal occlusionb. 
 
 
                                                 
a The effect of GWP42003-P on oral contraceptives has not been investigated.  GWP42003-P is not an 
inducer of CYP3A4 and therefore is not expected to alter the PK of hormonal contraceptives. 
b Contraception methods that are considered to have low user dependency. 
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• Vasectomized partnera,b provided that partner is the sole sexual partner of the 
patient of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success. 
• 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 (e.g., calendar, ovulation, symptothermal, and postovulation methods) 
and withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method are not acceptable methods of contraception.67  
Serum pregnancy tests will be performed for any patients of childbearing potential at 
RCT Visit 9 and OLE Visit 8; patients must test negative for pregnancy to be eligible for 
the trial.  Additional pregnancy tests must be performed during the treatment period if 
considered clinically indicated by the investigator. 
9.2.3 
Concomitant Medication 
Details of all current medications will be recorded during the RCT.  Any changes in 
concomitant medication during the trial must be recorded on the eCRF at trial visits.  
Changes in concomitant medications are allowed, but increases in the dose of 
medications that affect liver function should be discussed with the medical monitor.  
Introduction of new medications is allowed, but introduction of new psychotropic and/or 
central acting agents intended as long-term treatment requires prior discussion with the 
medical monitor.  
9.2.4 
New Medical History 
Any changes to medical history since the RCT will be recorded. 
9.2.5 
Menstruation 
Any changes in menstrual cycles since the RCT will be captured at the end-of-treatment 
visit. 
                                                 
a Contraception methods that are considered to have low user dependency. 
b Provided that partner is the sole sexual partner of the trial patient of childbearing potential and 
that the vasectomized partner has received medical assessment of the surgical success. 
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9.2.6 
Physical Examination 
Physical examinations will include body weight measurements.  At Visit 8, height will be 
collected.  If an accurate measurement of height is not possible, an estimate should be 
provided. 
9.2.7 
12-Lead Electrocardiogram  
Triplicate ECGs will be performed after 5 minutes rest.  Triplicate ECGs should be taken 
as close together as possible.  An ECG machine will be provided to all centers, and all 
ECGs will be reviewed by a central reader.  The central reader will provide a report 
within 24 hours of collection of the ECG.  Additional alerts will be sent to the center in 
the case of clinically relevant abnormalities.  The central reader will provide 
measurements and an overall assessment to support the investigator in his/her final 
assessment.  If needed, the investigator may update clinical relevance based on patient 
files, medical history, and any clinical symptoms.  The central reader can be supportive 
for any discussions on patient outcomes.  Any abnormal findings considered to indicate 
significant medical history or AEs must be recorded appropriately on the eCRF.  In 
addition to the scheduled assessments, additional ECG measurements can be taken at any 
time during the trial, if clinically indicated.   
9.2.8 
Vital Signs 
Vital sign measurements (blood pressure and pulse rate) will be taken in a sitting position 
at rest for 5 minutes.  Blood pressure should be recorded using the same arm throughout 
the trial, where possible. 
9.2.9 
Clinical Laboratory Sampling 
The investigator should use his/her judgment and knowledge of the patient to determine 
when to best collect the blood and urine samples in order to mitigate the risk that invasive 
procedures may cause the patient to become stressed, thereby affecting the results of 
other patient assessments.   
Laboratory tests will include hematology, biochemistry, and urinalysis (provided urine 
can be obtained), IGF-1 levels, and a serum pregnancy test (if appropriate).  Analysis of 
all clinical blood samples and pregnancy tests will be conducted at a central clinical 
laboratory. 
Urine samples for biochemistry will be analyzed at the trial center by use of a dipstick, 
with any relevant findings being sent for further urinalysis at the central laboratory 
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(urinalysis, microscopy, culture, and sensitivity, as applicable).  In cases where urine 
samples cannot be analyzed at the center due to local regulations, a full set of urine 
samples should be sent to the central laboratory for analysis.  Urine sample volume 
requirements and processing procedures will be detailed in a separate laboratory manual.   
The investigator and trial monitor will be provided with a list of the normal ranges used 
by the testing laboratory for all variables assayed during the trial and a statement of 
accreditation (or similar) for the laboratory.   
The investigator should be aware of blood sampling volume restrictions, particularly for 
patients with low weight, and if additional monitoring is required (maximum total daily 
volume of 0.85mL/kg of body weight68,69 maximum 4-week period volume of 
2.55 mL/kg of body weight, and maximum 8-week period volume of 50 mL).  
Clinical laboratory sample parameters are detailed in Table 9.2.9-1. 
Table 9.2.9-1 
Biochemistry, Hematology, and Urinalysis 
Biochemistry 
(Serum)¹  
Hematology 
(Whole Blood)¹  
Urinalysis 
(Urine)² 
Pregnancy Test 
(Serum)¹ 
Alanine 
aminotransferase3 
Hematocrit 
Blood 
Serum 
Albumin3 
Hemoglobin 
Glucose 
 
Alkaline phosphatase3 
Mean cell volume 
Nitrites 
 
Aspartate 
aminotransferase3 
Mean corpuscular 
hemoglobin 
pH 
 
Calcium 
Platelets 
Protein 
 
Creatine kinase 
Red blood cell count 
White blood cells 
 
Creatinine 
White blood cell count 
with automated 
differential 
Bilirubin 
 
Creatinine clearance 
 
Ketones 
 
Gamma-glutamyl 
transferase3 
 
Specific gravity 
 
Glucose 
 
Urobilinogen 
 
Human chorionic 
gonadotropin 
 
 
 
HDL-cholesterol 
 
 
 
IGF-14 
 
 
 
Potassium 
 
 
 
Prolactin 
 
 
 
Prothrombin time and 
INR (plasma)5 
 
 
 
Sodium 
 
 
 
Total bilirubin3 
 
 
 
Total protein3 
 
 
 
Triglycerides 
 
 
 
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Table 9.2.9-1 
Biochemistry, Hematology, and Urinalysis 
Biochemistry 
(Serum)¹  
Hematology 
(Whole Blood)¹  
Urinalysis 
(Urine)² 
Pregnancy Test 
(Serum)¹ 
Urea (blood urea 
nitrogen) 
 
 
 
¹ Analyzed at a central laboratory. 
² Analyzed at the trial center by use of a dipstick (if allowed per local regulations). 
3 Hepatic function monitoring panel.  
4 Visits 1 and 8 only; IGF-1 laboratory results to remain blinded throughout the trial. 
5 To be requested if ALT or AST > 3 × ULN after Visit 1 (to evaluate IMP discontinuation criteria) 
 
HDL = high-density lipoprotein; INR = international normalized ratio. 
Investigators at trial centers will be notified of laboratory test results.  All laboratory 
results will be reviewed, and the reports will be signed and dated by the investigator.  
Any results considered to be of clinical significance must be addressed and followed up, 
as clinically appropriate.  In cases where after Visit 1, ALT or AST are > 3 × ULN, 
international normalized ratio (INR) testing must be requested.  If only the hepatic 
function monitoring panel was requested and ALT or AST > 3 × ULN, both INR and 
hematology panel (eosinophils) must be requested.  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 the 
investigator is satisfied that the abnormality is not related to GWP42003-P and needs no 
further investigation.   
Additional samples may be collected, as needed, e.g., for monitoring of hepatic function 
(hepatic function monitoring panel) (see Section 8.1.2 and Table 9.2.9-1).  
Blood sample volume requirements and processing procedures will be detailed in a 
separate laboratory manual; the maximum cumulative amount of blood taken in any 
4-week period will be 2.55 mL/kg of body weight and will not exceed a total of 50 mL 
within any 8 week period68,69 taking into account possible repeat tests.  The 
patient/caregiver 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 the patient suffered any blood loss during the 1-month period leading up to 
a planned blood draw. 
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9.2.10 
Randomization and Trial Supply Management System 
The RTSM system will be used to manage the IMP supply.  The RTSM system 
information can be accessed via the eCRF.  
A member of the trial team must register in the eCRF each clinic visit in order to: 
• Obtain dispensing information (Visits 1, 4, 5, 6, 7, and 8). 
• Provide completion/taper/early termination information (Visit 8/the withdrawal 
visit, or Visit 9, as applicable). 
Training will be given to all centers prior to the start of the trial. 
9.2.11 
Dosing Schedule/Compliance Review 
Caregivers will be provided with a dosing schedule.  Caregivers will be asked to confirm 
dosing in the dosing schedule daily from Visit 1 through Visit 9.  Dosing compliance will 
be reviewed at each clinic visit.  Any discrepancies will be discussed with the caregiver 
and documented accordingly within the patient’s source documents.  As part of the 
compliance review, caregivers will be asked at the visits about the time of GWP42003-P 
administration in relation to meals. 
9.2.12 
Questionnaires and Assessments Completed at Scheduled Visits  
Caregiver questionnaires should be completed by the identified caregiver, nominated at 
Visit 1 of the RCT.  The same person should answer/complete the 
questionnaires/assessments in order to maintain consistency.  Questionnaires should be 
completed during the scheduled visits.  The nominated caregiver must have given consent 
to complete the QoL questionnaires prior to the completion of the questionnaires.  
To ensure consistency, investigator-completed questionnaires should be completed for 
each patient by the same investigator throughout the trial.  Investigators must have 
completed the sponsor-specified training for each questionnaire before any questionnaires 
are completed. 
9.2.12.1 
Rett Syndrome Behaviour Questionnaire 
The RSBQ is a caregiver-completed questionnaire that measures the frequency of current 
disease characteristics (45 items) that may or may not apply to the patient 
(see Appendix 3.4).  Each item is rated on a 3-point numerical scale; 0 indicates an item 
that is ‘not true as far as you know,’ 1 indicates an item is ‘somewhat or sometimes true,’ 
and 2 indicates an item that is ‘very true or often true.’  The total maximum score is 90, 
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and higher total scores represent greater severity.  It encompasses 8 subscales: general 
mood, breathing problems, hand behaviors, face movements, body rocking/expressionless 
face, night-time behaviors, anxiety/fear, and walking/standing.55 
9.2.12.2 
Children’s Sleep Habit Questionnaire 
This is a caregiver-completed sleep screening instrument designed for school-aged 
children.70  CSHQ includes 33 items within 8 subscales reflecting the following sleep 
domains: 1) Bedtime Resistance; 2) Sleep Onset Delay; 3) Sleep Duration; 4) Sleep 
Anxiety; 5) Night Wakings; 6) Parasomnias; 7) Sleep-Disordered Breathing; and 
8) Daytime Sleepiness.  Caregivers are to answer based on the last week.  If the last week 
was unusual for a specific reason, the caregiver should choose the most recent typical 
week.  The answers to each question are provided by a choice of 3 markers: “Usually” if 
it occurs 5 or more times in a week; “Sometimes” if it occurs 2 to 4 times in a week; and 
“Rarely” if it occurs never or 1 time in a week.  Some items should be reversed in 
scoring, so a higher score reflects more-disturbed sleep behavior (see Appendix 3.9).  The 
caregiver is also asked to indicate for each item if the sleep item is a problem.   
9.2.12.3 
36-Item Short Form 
Caregivers’ health-related QoL will be assessed using the SF-36 questionnaire 
(see Appendix 3.5).  SF-36 measures 8 domains of health-related QoL within 8 scales: 1) 
limitations in physical activities because of health problems; 2) limitations in social 
activities because of physical or emotional problems; 3) limitations in usual role activities 
because of physical health problems; 4) bodily pain; 5) general mental health 
(psychological distress and well-being); 6) limitations in usual role activities because of 
emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions.  
The domains are used to calculate composite scores – physical health composite score 
(PCS) and mental health composite score (MCS).  The scores for SF-36 are based on a 
0-to-100 scale; 0 represents the lowest possible score, and 100 represents the highest 
possible score, with a higher score indicating a better health state.   
9.2.12.4 
Child Health Questionnaire Parent Form 50 
The CHQ-PF50 is a generic QoL instrument designed and normed for children from 5 to 
18 years of age.  This instrument is a well-validated general QoL measure in pediatric 
populations with chronic illness.  It measures the QoL of the child and the family by 
parent or child report.  The caregiver will be asked to complete the questionnaire on 
behalf of the patient.  The CHQ-PF50 covers mutlidimensional health concepts including 
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Physical Functioning, Role/Social Limitations–Emotional/Behavioral, Role/Social 
Limitations–Physical, Behavior, Mental Health, Self-Esteem, General Health, Bodily 
Pain, Family Activities, Parent Impact–Time, Parent Impact–Emotional, and Family 
Cohesion.  The CHQ-PF50 provides subscale scores as well as a Standardized Physical 
Summary (PhS) score and Standardized Psychosocial Summary (PsS) score.  Scores are 
based on a 0-to-100 scale; a higher score indicates better QoL.   
9.2.12.5 
Hospital Services Use Questionnaire 
This is a health utilization questionnaire designed to analyze the frequency of patient 
hospitalizations and hospital visits (see Appendix 3.7).  Hospitalizations will also be 
recorded in the patient’s CRF and through the serious adverse event (SAE) reporting 
process.  The questionnaire will be completed via caregiver interview.   
9.2.12.6 
Caregiver Assessment of Rett Symptoms  
Caregivers will be asked to rate, on a 0-to-10 numerical rating scale, the patient’s 
condition and performance/severity of symptoms in terms of breathing, hand stereotypies, 
interactions, problem behaviors, constipation, seizures, and sleep (see Appendix 3.10).  
This assessment corresponds to the symptom diary completed weekly in the RCT but will 
be completed at trial visits only in the OLE. 
9.2.12.7 
Rett Syndrome Motor-Behavioral Assessment Scale 
The MBA-9 scale is completed by the investigator and evaluates 9 RTT symptoms.  
MBA-9 was derived from the full MBA scale (37 RTT symptoms) by selecting the items 
that are deemed to be amenable to change and that reflect areas of meaningful clinical 
change.  It includes 5 questions from the original Behavioral/Social Assessment, 
1 question from the Orofacial/Respiratory Assessment, and 3 questions from the Motor 
Assessment/Physical Signs (see Appendix 3.1).  The severity of the current symptoms are 
rated on a 5-point numerical scale: 0 = normal or never; 1 = mild or rare; 2 = moderate or 
occasional; 3 = marked or frequent; or 4 = very severe or constant.  The total maximum 
score is 36, and higher total scores represent greater severity.61  The MBA-9 items 
address the core symptoms of RTT.   
9.2.12.8 
Clinical Global Impressions Questionnaire  
The clinical global impressions (CGI) questionnaire was developed as a clinical trial 
measure to provide a brief, stand-alone assessment of the clinician’s view of the patient’s 
global functioning prior to and after initiating a study medication.56   
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The CGI questionnaire is split into 2 scales: the CGI-S scale and the CGI-I scale 
(see Appendix 3.2 and Appendix 3.3, respectively).  CGI-S is a 7-point scale that requires 
the clinician to rate the severity of the patient’s illness at the time of assessment relative 
to the clinician’s experience with patients who have the same diagnosis.  Considering the 
total clinical experience, a patient will be assessed on the severity of illness at the time of 
rating.  This is rated as follows: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 
4 = moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill.  The second 
scale, CGI-I, is a 7-point scale that requires the clinician to assess how much the patient’s 
illness has improved or worsened relative to a baseline state at the beginning of the 
intervention (RCT Visit 2).  This is rated as follows: 1 = very much improved; 2 = much 
improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much 
worse; or 7 = very much worse.  
To ensure consistency, investigators will be instructed to complete the CGI referring to a 
predefined set of anchors developed specifically for the use of CGI in RTT.59 
The CGI-S and CGI-I assessments should be based on the entirety of the visit. 
9.2.12.9 
Suicidality Assessment 
The profound cognitive impairment of patients with RTT is such that the Children’s 
Columbia-Suicide Severity Rating Scale is not considered appropriate in this trial.  
Instead, suicidality will be assessed by the investigator via a clinical interview with the 
caregiver (see Appendix 3.8).   
9.2.13 
Tanner Staging 
The pubic hair growth and breast development of all adolescent patients (i.e., ≥ 7 years of 
age71 at the time of signing the ICF or earlier, if clinically indicated by the onset of 
menarche or other signs of precocious puberty) will be assessed using Tanner Staging 
(see Appendix 3.6).72  The assessment can either be performed by examination during the 
study visit or the appropriate Tanner Stage can be indicated by the caregiver, with 
reference to the chart provided.’ 
Once a patient reaches a score of V (i.e., 5) the assessment need not be performed again. 
9.2.14 
Investigational Medicinal Product Accountability 
Records of GWP42003-P accountability will be maintained according to Section 5.2.4. 
GWP42003-P will be dispensed at each of the following visits: 
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• Visit 1 (Day 1) 
• Visit 4 (Day 29) 
• Visit 5 (Day 57) 
• Visit 6 (Day 85) 
• Visit 7 (Day 141) 
• Visit 8 (Day 197) 
Caregivers will be asked to return all GWP42003-P (used and unused) at each relevant 
visit (Visits 4, 5, 6, 7, 8, and 9).  The center will check the returned GWP42003-P against 
the expected usage.  Any discrepancies will be discussed with the caregiver at the time of 
the visit and documented accordingly within the patient’s source documents. 
9.2.15 
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 post-trial follow-up visit (Visit 10), whether or 
not attributed to GWP42003-P and observed by the investigator or patient. 
* For the patient’s expected seizure types, these do not routinely require documentation as 
AEs.  However, any worsening, including a change in the pattern or severity of seizures 
should be documented in the eCRF if deemed to meet the definition of an AE, in the 
investigator’s opinion.   
Any AE that meets SAE criteria should still be reported as a SAE. 
Serious adverse events must be reported to GW Pharmacovigilance Department (PVD) 
within 24 hours of discovery or notification of the event via recording in the eCRF.  
Refer to Section 12 for definitions, procedures, and further information on AE reporting. 
 
 
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10 
IMP WITHDRAWAL 
In accordance with the Declaration of Helsinki73 the International Council for 
Harmonisation (ICH) Harmonised Guideline: Integrated Addendum to ICH E6(R1): 
Guideline for Good Clinical Practice (GCP) E6(R2)74 the FDA regulations relating to 
GCP and clinical trials75,76,77 the EU Clinical Trials Directive78 the EU GCP Directive79 
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 her future medical care by the physician or at the institution. 
The patient must be withdrawn permanently discontinued from the trial if any of the 
following apply: 
• Administrative decision by the investigator, GW, or a regulatory authority 
• Pregnancy 
• Protocol deviation that is considered to potentially compromise the safety of the 
patient 
• Withdrawal of patient assent 
• Withdrawal of parent(s)/legal representative consent 
• 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 (total bilirubin [TBL] > 2 × ULN or international 
normalized ratio [INR] > 1.5) 
Note: Prior to withdrawal for the transaminase elevations noted above, the 
investigator may choose to confirm the transaminase elevations by repeating the 
following laboratory tests within 24 to 48 hours: ALT, AST, TBL, INR, % 
eosinophils, gamma-glutamyl transferase, alkaline phosphatase, and 
eosinophils.  Should the above transaminase elevation criteria be confirmed, 
the patient must be withdrawn from the trial.  In cases where the 
transaminase elevation withdrawal criteria are not met or confirmed, the 
dose of IMP or a concomitant medication with known hepatotoxicity may be 
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reduced.  Dose adjustments should be discussed with the GW medical 
monitor.  The final decision regarding dose adjustments should be taken by 
the investigator. 
• Lost to follow-up 
The patient may also be withdrawn permanently from the trial for any of the following: 
• Patient or caregiver 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 
• Failure to meet the eligibility criteria 
• Any evidence of the use of drugs of abuse or drug diversion 
• Suicidal ideation or behavior during the treatment period 
The patient should attend a withdrawal visit (Visit 8) as soon as possible after the 
decision is made to permanently discontinue GWP42003-P.  Patients who discontinue the 
IMP should have their dose of IMP gradually reduced (10% each day) over a period of 
10 days, beginning at the time the decision is made to discontinue (unless inadvisable due 
to an AE).  Patients should continue in the trial and continue to complete trial 
assessments and visits per protocol.  Patients who discontinue the IMP and complete 
tapering of the IMP prior to the completion visit do not need to attend an End of Taper 
visit. 
Should a patient request or decide to withdraw from the trial, all efforts must be made to 
complete and report the observations as thoroughly as possible up to the date of 
withdrawal.  Patients withdrawing due to an AE should be followed up according to 
Section 12.7.  All information should be reported on the applicable eCRF pages.  All 
assessments required at the withdrawal visit should be conducted, if possible.  If the 
tapered dose is administered, patients should return for Visit 9, if possible.  Wherever 
possible, a safety follow-up visit should take place 28 days from the date of last dose of 
IMP.  If the withdrawing patient declines to give a reason for withdrawal of consent, the 
investigator must respect the patient’s wishes. 
 
 
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11 
URGENT SAFETY MEASURES 
The sponsor and investigator may take appropriate urgent safety measures in order to 
protect the patients of a clinical trial against any immediate hazard to their health or 
safety.  If such measures are taken by the investigator, they must notify GW immediately 
or at least within 24 hours of awareness.  GW will report urgent safety measures to 
regulatory authorities by telephone within 24 hours of awareness, wherever possible, and 
will provide a written report to the regulatory authorities and IRB/IEC within 3 days. 
 
 
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12 
ADVERSE EVENT REPORTING 
12.1 
Definitions 
12.1.1 
Adverse Event 
For the purposes of this trial, an AE is defined as follows: 
Any new unfavorable/unintended signs/symptoms (including abnormal laboratory 
findings when relevant) or diagnosis or worsening of a pre-existing condition that occurs 
at any point up to the post-treatment, final safety follow-up visit (Visit 10), which may or 
may not be considered to be related to GWP42003-P.  Any event that is the result of a 
trial procedure must be recorded as an AE. 
Surgical/Investigational procedures are not AEs.  The medical reason for the procedure is 
the AE.  Elective hospitalizations for pretrial existing conditions or elective procedures 
are not AEs.  The exception may be if the patient has an AE during hospitalization that 
prolongs the 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 death 
(e.g., disease or medical condition leading to death). 
12.1.2 
Investigator 
The term “investigator” refers to the trial principal investigator (PI) or a formally 
delegated trial physician. 
12.2 
Serious Adverse Events 
During clinical investigations, AEs may occur, which if suspected to be 
GWP42003-P-related, might be significant enough to lead to important changes in the 
way GWP42003-P is developed (e.g., change in dose, population, monitoring need, 
consent/assent forms).  This is particularly true for events that threaten life or function.  
Such SAEs will be reported promptly to regulatory authorities, applicable IRBs/IECs, 
and investigators (expedited reporting) by GW. 
An AE must only be classed as serious, i.e., an SAE, when the event falls into one of the 
following criteria: 
• Results in death 
• Is life threatening* 
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• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is medically significant** 
* The term “life threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event that, 
hypothetically, might have caused death if it were more severe. 
** Medical and scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations.  Important medical events may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These should also usually be considered serious.  Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or use of drugs of abuse. 
12.3 
Reporting Procedures for Serious Adverse Events 
All SAEs occurring during the trial must be reported to GW with any other supporting 
information and recorded in the AE section of the eCRF.  Any ongoing SAEs should be 
followed up until resolution, wherever possible.  For all deaths, the working diagnosis or 
cause of death as stated on a death certificate, available autopsy reports, and relevant 
medical reports should be sent to GW promptly. 
All SAEs must be recorded in the eCRF within 24 hours of discovery or notification 
of the event.  GW Research Ltd PVD will be automatically notified that an SAE has 
been recorded.  Any additional information required for a case (follow-up or corrections 
to the original case) will be requested by GW PVD through eCRF queries.  
The investigator should continue to document all AEs that occur up to the last formal 
follow-up observational period (Visit 10).  If the investigator subsequently becomes 
aware of any deaths or a new GWP42003-P-related SAE after the last formal follow-up 
period of the trial, these should still be reported to GW PVD. 
Any other problem discovered after Visit 10 that is deemed to be an unexpected safety 
issue and is likely to have an impact on patients who have taken part in the trial must be 
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treated as an SAE and reported to 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 
the final trial data lock.  GW Research Ltd PVD may request safety follow-up 
information after the final trial visit in order to investigate a potential safety issue. 
Contact details for GW PVD are provided at the front of the center files for all trial 
centers. 
12.4 
Pregnancy 
Any patient who has become pregnant while receiving GWP42003-P or within 90 days of 
the last dose of GWP42003-P must be reported to GW PVD.  Where possible, the 
investigator should provide the outcome of the pregnancy. 
All pregnancies must be recorded in the eCRF within 24 hours of awareness.  GW PVD 
will be automatically notified that a pregnancy has been recorded.  Any additional 
information required for a case (follow-up or corrections to the original case) will be 
requested by GW PVD through eCRF queries. 
The investigator is not obliged to actively monitor for any pregnancies that commence 
more than 90 days after the final dose of GWP42003-P.  However, if the investigator 
becomes aware of a new pregnancy outside this time limit, then he/she should report it as 
above.  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 GWP42003-P 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 GWP42003-P: 
“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 the IMP (pretreatment) should be considered as 
not causally related.  Where a pretreatment event worsens in severity following the first 
dose of the IMP, a new event record should be entered into the eCRF. 
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Considering the explanation given above, investigators are strongly encouraged to 
express their opinion on what the cause of an AE might be.  For individual patients, the 
investigator is usually in the best position to assess the underlying suspected cause of an 
AE.  For all AEs, especially SAEs, it is important that the investigator assess not only the 
possible role of GWP42003-P but also other potential contributing factors.  Factors for 
consideration of the underlying cause may include the following: 
• Medical and disease history 
• Lack of efficacy/worsening of treated condition 
• Concomitant or previous treatment 
• IMP discontinuation 
• 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 post-trial follow-up visit (Visit 10), whether or 
not attributed to GWP42003-P and observed by the investigator or patient. 
For the patient’s expected seizure types, these do not routinely require documentation as 
AEs.  However, any worsening, including a change in the pattern or severity of seizures, 
should be documented in the CRF if deemed to meet the definition of an AE, in the 
investigator’s opinion. 
Any AE that meets the SAE criteria should still be reported as an SAE. 
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 
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description.  However, the diagnosis (full or provisional) should be clearly stated, 
e.g., fever and malaise due to respiratory tract infection. 
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, record as much information as possible (i.e., the month and year or, in 
exceptional circumstances, just the year).  When the actual start date becomes known, the 
eCRF must be updated to replace the previously recorded date. 
C) Outcome 
The outcome of the event must be recorded accurately and classified into one of the 
following categories: 
• Recovered 
• Recovered with sequelae 
• Continuing 
• Patient died 
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 the 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. 
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F) Action Taken with IMP 
This question refers to the action taken with GWP42003-P due to an AE.  The action with 
GWP42003-P must be classified as follows: 
• None 
• Dose reduced temporarily 
• Dose reduced 
• IMP interrupted 
• IMP stopped 
12.7 
Follow-up Procedures for Adverse Events 
The investigator may be asked to provide follow-up information to GW PVD for any AEs 
reported or during the investigation of potential safety issues.  Such requests for 
additional safety information may occur post Visit 10, after the trial. 
Adverse events considered related to GWP42003-P 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 removal from treatment.  A patient may also voluntarily 
discontinue from treatment due to what she perceives as an intolerable AE.  Further 
details of discontinuation are presented in Section 10.  If either of these occurs, the 
patient must permanently discontinue from treatment 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 investigational centers are required to submit to GW PVD the laboratory results for 
any patient after randomization who meets the criteria for the selected laboratory 
parameters as follows:  
• 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 
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• 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 GW PVD via e-mail (see Appendix 2.2) within 24 hours of 
becoming aware of the results.  In addition, a copy of the patient’s baseline laboratory 
results with all reports should be sent to GW PVD. 
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 treatment discontinuation 
and important medical events.  The investigator will arrange for the patient to return to 
the investigational center as soon as possible (within 24 to 48 hours of notice of abnormal 
results) for a repeat assessment of ALT, AST, TBL, alkaline phosphatase, 
gamma-glutamyl transferase levels, eosinophils as well as for testing INR (prothrombin 
time), detailed history; and physical examination.  Patients should be followed this way 
until all abnormalities have normalized (in the investigator’s opinion) or returned to the 
baseline state.  However, if the above transaminase elevation criteria are confirmed by 
the first set of follow-up laboratory tests, the patient must be withdrawn from the trial. 
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.  In cases where after Visit 1, ALT or AST are > 3 
× ULN, INR testing must be requested.  If only the hepatic function monitoring panel 
was requested and ALT or AST > 3 × ULN, both INR and hematology panel 
(eosinophils) must be requested.  If the patient cannot return to the investigational center, 
repeat assessments may be done at a local laboratory, and the results should be sent to 
GW PVD. 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities, and IRBs/IECs 
In accordance with the EU Clinical Trials Directive78 relevant parts of the FDA Code of 
Federal Regulations80 and any national regulations, GW will inform the 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). 
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This information will be provided through 2 sources: 
1. IB52: A compilation of the clinical and nonclinical safety data available on the 
IMP that are relevant to the trial.  The IB is updated at least annually or when 
important new safety information becomes available. 
2. 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 investigators should notify their regional 
IRBs/IECs of SAEs or SUSARs occurring at their center 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 guidance75 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, were serious, and would have implications for the conduct of the trial 
(e.g., requiring a significant, and usually safety-related, change in the protocol, such as 
revising inclusion/exclusion criteria or including a new monitoring requirement, informed 
consent/assent, 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 guidance80 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 Research Ltd will inform the 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 the investigators in the trial does not necessarily constitute an unanticipated 
problem unless identified by GW in the submission cover letter. 
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As a minimum, the recipient will be sent all of the above, as well as relevant updates 
between the period from ethical approval and the 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).  Any deviations from the original SAP will be described in the final 
clinical study report. 
13.1 
Sample Size, Power, and Significance Levels 
There is no formal sample size calculation for this trial.  All patients with RTT who 
completed the randomized, double-blind, placebo-controlled trial (GWND18064) who 
wish to take GWP42003-P and who meet eligibility criteria can be included in this trial.   
Approximately 252 patients will be enrolled.  
13.2 
Interim Analysis 
No formal interim analysis will be conducted.  
13.3 
Analysis Sets 
For this trial there will be 1 analysis set: 
Safety Analysis Set 
• All patients who receive at least 1 dose of GWP42003-P in the trial will be 
included.  Only patients for whom it has been confirmed that they did not take any 
GWP42003-P will be excluded from this safety analysis set.  This analysis set will 
be used to report the safety data.  
13.3.1 
Protocol Deviations 
Protocol deviations will be listed and reasons for exclusion from the analysis population 
will be summarized.   
13.4 
General Considerations 
Unless stated otherwise, continuous variables will be summarized showing the number of 
nonmissing values (n), mean, standard deviation, median, minimum, and maximum, and 
categorical variables will be summarized showing the number and percentage of patients 
falling in each category. 
For clinic visit-based endpoints, baseline is defined as the last record or measure 
collected prior to the first dose of IMP in the RCT. 
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13.5 
Accountability and Background Characteristics 
13.5.1 
Enrollment and Disposition 
All patients (screened, randomized, 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 in each specific country), and other 
demographic or baseline characteristics including Clinical Severity Scale score and 
MECP2 mutation (confirmation and definition) will be summarized.  
13.5.3 
Concomitant Medication 
Concomitant medications taken prior to and during the trial will be summarized by 
medication class and active ingredients. 
13.6 
Endpoints and Statistical Methods 
The primary safety endpoint will be analyzed as detailed in Section 13.6.2.  Secondary 
endpoints will be analyzed as detailed in Section 13.6.3.  Exploratory endpoints will be 
analyzed as detailed in Section 13.6.4.  
13.6.1 
Evaluable Period 
The start of the evaluable period of the OLE trial (Day 1) is defined as the date the patient 
took his/her first dose of IMP in the clinic at Visit 1.  All data that will be collected 
during this trial will be summarized over time using appropriate descriptive statistics.  
Changes from baseline of the RCT will also be presented where appropriate.  
13.6.2 
Primary Safety Endpoints 
The safety endpoints are listed below and will be evaluated as detailed in the following 
sections: 
• AEs. 
• Clinical laboratory parameters. 
• Vital signs. 
• Physical examination procedures. 
• 12-lead ECG.  
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• Effects on menstruation cycles. 
• Suicidality. 
• Change in growth and development by measurement of height, weight, serum 
IGF-1 levels, and Tanner Staging (for patients aged ≥ 7 years or earlier, if 
clinically indicated by onset of menarche or other signs of precocious puberty). 
13.6.2.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized. 
13.6.2.2 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 
A treatment-emergent adverse event (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 preferred term and system organ 
class for the safety analysis set.  The number of patients reporting at least 1 TEAE will be 
provided. 
The following summaries will be produced as a minimum: 
• All-causality TEAEs. 
• Treatment-related AEs. 
• 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. 
13.6.2.3 
Vital Signs, 12-Lead Electrocardiogram, Physical Examination, 
and Other Safety Data 
Vital signs, ECG, physical examination, Tanner Staging, and serum IGF-1 levels will be 
summarized at each time point during the treatment period using appropriate summary 
statistics.  Changes in the vital signs and serum IGF-1 levels from baseline of the RCT to 
end of treatment will be summarized.  
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13.6.2.4 
Clinical Laboratory Data 
Clinical laboratory data at the end of treatment in the OLE and the change from baseline 
of the RCT 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.   
13.6.2.5 
Menstruation 
Details of menstruation cycles (where appropriate) will be summarized and listed as 
appropriate. 
13.6.2.5.1 
Suicidality 
Suicidality assessment responses will be summarized and listed as appropriate. 
13.6.3 
Secondary Endpoint(s) 
There are several secondary endpoints.  For each endpoint, the change from baseline of 
the RCT will be derived in patients taking each GWP42003-P dose.  For visit-based 
endpoints, baseline will be taken as the last measurement prior to the first dose of IMP 
(e.g. Visit 1 of the RCT). 
The following secondary endpoints will be assessed by evaluating changes relative to the 
prerandomization baseline of the RCT and will be summarized using appropriate 
descriptive statistics: 
• RSBQ. 
• CGI-I.  
• CGI-S. 
• MBA-9. 
• CSHQ. 
For patients who complete the trial, regardless of whether IMP is discontinued or not, the 
visit effect used in the analysis will correspond to the score at each trial visit 
(see Appendix 1).  However, patients who withdraw from the trial are required to 
complete the procedures at Visit 8 at the time of withdrawal.  For these patients, their 
Visit 8 data will be assigned to the nearest visit (for which the assessment is scheduled to 
be performed), based on the day of the visit.  Further details will be specified in the SAP. 
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13.6.4 
Exploratory Endpoint(s) 
The following exploratory endpoints for the trial will be assessed by evaluating changes 
relative to the prerandomization baseline of the RCT and will be summarized by time 
point: 
• SF-36. 
• CHQ-PF50. 
• Hospital Services Use Questionnaire  
• Caregiver Assessment of Rett Symptoms.  
13.6.5 
Handling of Missing Data 
There will be no imputation of missing data, and all observed data will be summarized. 
 
 
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14 
SAFETY MONITORING COMMITTEE 
No safety monitoring committee will be used 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 Helsinki73 the ICH 
Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP 
E6(R2)74 the EU Clinical Trials Directive78 the EU GCP Directive79 and the clinical trial 
regulations adopting European Commission Directives into national 
legislation.81,82,83,84,85 
15.2 
Informed Consent/Assent 
Initial master informed consent and assent forms will be prepared by GW and provided to 
the investigator, who will tailor these for their center by adding the center’s contact 
details and by using headed paper.  The GW clinical manager will communicate updates 
to the template by letter.  The written informed consent/assent documents 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’s parent(s)/legal representative 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 nominated caregiver will be asked to consent to complete the 
QoL questionnaires.  In cases where the patient possesses adequate understanding, assent 
will be taken (if allowed per local regulations) along with parent(s)/legal representative 
consent.  Assent is defined as the minor’s permission or affirmative agreement to 
participate in the trial.  The patient and/or parent(s)/legal representative must have ample 
time to consider the information provided before giving written consent/assent.  More 
specific definitions of “ample time” may be enforced if required by IRBs/IECs or local 
regulations. 
The acquisition of informed consent/assent must be documented in the patient’s medical 
records and the informed consent/assent forms must be signed and personally dated by 
the patient and/or parent(s)/legal representative/nominated caregiver (as applicable) and 
by the person who conducted the informed consent/assent discussion.  GW Research Ltd 
also requires a physician to be present for consent/assent and to sign the consent/assent 
forms.  The original signed informed consent/assent forms should be retained and a copy 
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provided to the patients’ parent(s)/legal representative/nominated caregiver 
(see Section 9.2.1). 
15.3 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent/assent forms, master informed 
consent/assent forms, 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 informed consent/assent forms 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/assent 
documents.  The investigator must notify the IRB/IEC of deviations from the protocol, 
SAEs occurring at the center, and other AE reports received from GW, in accordance 
with local procedures. 
The investigator will be responsible for obtaining ongoing IRB/IEC approval/renewal 
throughout the duration of the trial.  Copies of the investigator’s reports and the IRB/IEC 
continuance of approval must be sent to GW. 
15.4 
Pretrial Documentation Requirements 
The investigator is responsible for forwarding the following documents to GW or 
designee for review before allowing any patients to consent/assent for entry into the trial: 
• Signed and dated protocol signature page. 
• Copy of IRB/IEC-approved informed consent/assent forms (including version 
number and date) and other patient information material. 
• Copy of the IRB/IEC approval of the protocol, informed consent/assent forms 
(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 sub-investigators. 
• The IRB/IEC composition and/or written statement of the IRB/IEC in compliance 
with the FDA regulations relating to GCP and clinical trials75,76,77,86 the EU 
Clinical Trials Directive78 the EU GCP Directive79 or the ICH Harmonised 
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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. 
• Completed financial disclosure statements for the PI and all sub-investigators, if 
relevant. 
GW will ensure that the center 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 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 informed consent/assent forms, should be kept 
in strict confidence by the investigator. 
In compliance with the FDA regulations relating to GCP and clinical trials75,76,77,86 and 
the EU Clinical Trials Directive78and the ICH Harmonised Guideline: Integrated 
Addendum to ICH E6(R1): Guideline for GCP E6(R2)74 it is required that the 
investigator and institution permit authorized representatives of the company, the 
regulatory authorities, and the IRB/IEC 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 shall remain the sole property of the company.  The 
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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/assent documents.  The IRB/IEC and regulatory authorities must be 
informed of all substantial amendments and give approval.  Amendments for 
administrational 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 center, will be agreed 
with each center prior to patient recruitment.  In the rare situations of data (that would 
normally be recorded elsewhere) 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 ICH 
Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP 
E6[R2], Section 8.274), suitable for inspection at any time by representatives from GW 
and/or applicable regulatory authorities.  Elements should include the following: 
• Patient files containing completed eCRFs, informed consent/assent forms, and 
supporting copies of source documentation. 
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• Trial files containing the protocol with all amendments, IB, copies of pretrial 
documentation (see Section 15.4), and all correspondence to and from the 
IRB/IEC and GW. 
• Enrollment log of all patients who consented to take part in the trial. 
• 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 must be 
maintained and be readily available. 
Following completion or termination of a clinical trial, GW will initiate proper archive of 
clinical trial-related documentation and electronic records generated by the investigator 
and/or GW.  All clinical trial-related documents and electronic records will be retained 
within an archiving system for a period dependent on the 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 requirements79 or if needed by GW. 
GW Research Ltd will inform the investigators for each center 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 the eCRFs, 
questionnaires, and dosing schedule at regular intervals throughout the trial to verify 
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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 access to patient medical records and other trial-related records needed to verify the 
entries on the eCRFs. 
The investigator agrees to cooperate with the trial monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
To ensure the quality of clinical data across all patients and centers, 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 regulations75,76,77,86 ICH Harmonised 
Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP E6(R2)74 and all 
other applicable regulatory requirements.  To resolve any questions arising from the 
clinical data management review process, data queries and/or center notifications will be 
sent to the center for completion and then returned to GW or the CRO, as applicable.  
Investigators and caregivers will be trained on the importance of adhering to the trial 
requirements and assessment completion.  Where issues are identified, additional training 
will be provided. 
16.4 
Quality Assurance 
In accordance with the FDA regulations75,76,77,86 the EU Clinical Trials Directive78, the 
ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP 
E6(R2),74 and the sponsor’s audit plans, representatives from GW’s Clinical Quality 
Assurance Department may select this trial for audit.  Inspection of center 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,78 the ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): 
Guideline for GCP E6(R2),74 and applicable regulatory requirements. 
16.5 
Compensation 
GW will indemnify the investigator and the trial center in the event of any claim in 
respect of personal injury arising due to a patient’s involvement in the trial, provided 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 
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provided for or required by the protocol to which the clinical trial patient would not 
otherwise have been exposed, provided that 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/principal investigators.  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 Law. 
The raw data from this trial may be obtained by the PIs or by their steering committee 
representatives on request.  Should they wish, PIs are allowed to conduct their own 
analyses and are permitted to present such information along with methods and results of 
the clinical trial at symposia or national or regional professional meetings and to publish 
it in theses or dissertations. 
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 for 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. 
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16.8 
Confidential Information 
GW and the PI must ensure that only personnel directly concerned with the trial have 
access to confidential information and that any information coming to either party about 
the other during the course of the trial must be kept strictly confidential and must not be 
disclosed to any third party or made use of without the prior written consent of the other. 
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17 
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16 Maezawa I, Jin LW. Rett syndrome microglia damage dendrites and synapses by the 
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18 Müller M, Can K. Aberrant redox homoeostasis and mitochondrial dysfunction in 
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20 Pozzo-Miller L, Pati S, Percy AK. Rett Syndrome: Reaching for Clinical Trials. 
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21 http://www.nhs.uk/conditions/rett-syndrome/Pages/Introduction.aspx (page accessed 
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22 Chapleau CA, Lane J, Pozzo-Miller L, Percy AK. Evaluation of current 
pharmacological treatment options in the management of Rett syndrome: from the 
present to future therapeutic alternatives. Curr Clin Pharmacol. 2013;8(4):358-69. 
23 GWTX1562 Study Report: In Vitro Pharmacology Study of Several Compounds. 
Dec 2015. 
24 GWOR0873 Study Report. An in vitro evaluation of the effect of phytocannabinoids 
on NAAA. Jan 2013. 
25 GWOR0885 Study Report. An in vitro evaluation of the effect of phytocannabinoids 
on endocannabinoid uptake. Jan 2013. 
26 GWOR0861 Study Report. An in vitro evaluation of the effect of phytocannabinoids 
on FAAH. Jan 2013. 
27 GWOR0849 Study Report. An in vitro evaluation of the effect of phytocannabinoids 
on MAGL & DAGL. Jan 2013. 
28 Turner SE, Williams CM, Iversen L, Whalley BJ. Molecular Pharmacology of 
Phytocannabinoids. Prog Chem Org Nat Prod. 2017;103:61-101. 
29 Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular 
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30 GWOR1209 Study Report. Evaluation of the role of TRP channels in the 
anticonvulsant effects of phytocannabinoids. Jun 2013. 
31 GWOR1141 Study Report. Evaluation of the actions of various phytocannabinoids at 
TRPV2, TRPV3 and TRPV4 channels. Jan 2013. 
32 GWOR1215 Study Report. Evaluation of cannabinoid metabolites at TRP channels 
and in the endocannabinoid system. Jun 2013 
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33 GWPP17018 Study Report. Determination of the ability of pure CBD, CBDV and the 
synthetic metabolites 7-OH-CBD, 7-COOH-CBD, 7-OH-CBDV and 7-COOH-
CBDV and a reference standard to inhibit the uptake of adenosine into rat brain 
synaptosomes. May 2017. 
34 Mijangos-Moreno S, Poot-Aké A, Arankowsky-Sandoval G, Murillo-Rodríguez E. 
Intrahypothalamic injection of cannabidiol increases the extracellular levels of 
adenosine in nucleus accumbens in rats. Neurosci Res. 2014 Jul;84:60-3. 
35 Liou GI, Auchampach JA, Hillard CJ, et al. Mediation of cannabidiol anti-
inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine 
receptor. Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5526-31. 
36 Center for Drug Evaluation and Research, Application Number 210365Orig1s000 
NDA Approval Letter, June 2018. 
[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000Approv
.pdf] 
37 GWCRI1509-B1 Study Report. The ability of cannabidiol in comparison with 
risperidone to improve a cognitive deficit induced by sub-chronic PCP in the novel 
object recognition task. May 2016. 
38 GWCRI1509-B2 Study Report. The ability of cannabidiol in comparison with 
risperidone to improve a deficit induced by sub-chronic PCP in the social interaction 
task. May 2016. 
39 GWCRI1547-C Study Report. The effects of CBD following bicuculline-induced 
seizure in newborn rats and piglets. Jan 2018. 
40 GWCRI09119D Study Report. Evaluation of CBD in a rat model of NHIE. Feb 2015. 
41 GWCRI1547-B Study Report/ The effects of CBD and CBDV following hypoxic-
ischaemic encephalopathy in newborn rats, in the presence or absence of 
hypothermia. Jan 2018. 
42 Pecorelli A, Cervellati C, Hayek J, Valacchi G. OxInflammation in Rett syndrome. 
Int J Biochem Cell Biol. 2016; 81: 246-53.  
43 Sales AJ, Fogaça MV, Sartim AG, et al. Cannabidiol Induces Rapid and Sustained 
Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis 
in the Prefrontal Cortex. Mol Neurobiol. 2019;56(2):1070-81. 
44 Devinsky O, Thiele E, Laux L, et al. Efficacy and safety of Epidiolex (cannabidiol) in 
children and young adults with treatment-resistant epilepsy: Update from the 
Expanded Access Program. American Epilepsy Society Annual Meeting 2015; 
Abstract No 3.397 (www.aesnet.org). 
45 Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-
resistant epilepsy: An open-label interventional trial. Lancet Neurol. 
2015;4422(15):1–9. 
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46 Devinsky O, Cross JH, Wright S. Trial of Cannabidiol for Drug-Resistant Seizures in 
the Dravet Syndrome. N Engl J Med. 2017 Aug 17;377(7):699-700.  
47 Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of 
cannabidiol in Dravet syndrome. Neurology. 2018;90(14):e1204-e1211.  
48 Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on Drop Seizures in the 
Lennox-Gastaut Syndrome. N Engl J Med. 2018 May 17;378(20):1888-97. 
49 GWOR1240 Study Report: An in vitro investigation of cannabinoid 
immunoregulation. May 2013. 
50 GWCRI1581 Study Report. Effects of cannabidiol on recovery from damage to a 
region of vocal-motor cortex in the zebra finch. Oct 2018. 
51 Vigli D, Cosentino L, Raggi C, Laviola G, Woolley-Roberts M, De Filippis B. 
Chronic treatment with the phytocannabinoid Cannabidivarin (CBDV) rescues 
behavioural alterations and brain atrophy in a mouse model of Rett syndrome. 
Neuropharmacology. 2018;140:121-9. 
52 Investigator's Brochure: CBD Medicine. GW Pharma Ltd. Edition 11. Sep 2018. 
53 Rosenberg EC, Louik J, Conway E, Devinsky O, Friedman D. Quality of Life in 
Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical 
study with cannabidiol. Epilepsia. 2017 Aug;58(8):e96-e100. 
54 Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-
resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57(10):1617-24. 
55 Mount RH, Charman T, Hastings RP, Reilly S, Cass H. The Rett Syndrome 
Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett 
syndrome. J Child Psychol Psychiatry. 2002;43(8):1099-110. 
56 Guy, W. Clinical global impressions. In: Guy, W., editor. ECDEU assessment manual 
for psychopharmacology (Revised). National Institute of Mental Health; Rockville, 
Maryland: 1976. p. 217-221. 
57 Busner J, Targum SD. The clinical global impressions scale: applying a research tool 
in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37. 
58 Busner J, Targum SD, Miller DS. The Clinical Global Impressions scale: errors in 
understanding and use. Compr Psychiatry. 2009;50(3):257-62. 
59 Neul JL, Glaze DG, Percy AK, et al. Improving Treatment Trial Outcomes for Rett 
Syndrome: The Development of Rett-specific Anchors for the Clinical Global 
Impression Scale. J Child Neurol. 2015;30(13):1743-8. 
60 Khwaja OS, Ho E, Barnes KV, et al. Safety, pharmacokinetics, and preliminary 
assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment 
of Rett syndrome. Proc Natl Acad Sci U S A. 2014;111(12):4596-601. 
61 FitzGerald PM, Jankovic J, Percy AK. Rett syndrome and associated movement 
disorders. Mov Disord. 1990;5(3):195-202. 
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62 Souders MC, Mason TB, Valladares O, et al. Sleep behaviors and sleep quality in 
children with autism spectrum disorders. Sleep. 2009 Dec;32(12):1566-78. 
63 Merbler AM, Byiers BJ, Garcia JJ, Feyma TJ, Symons FJ. The feasibility of using 
actigraphy to characterize sleep in Rett syndrome. J Neurodev Disord. 2018;10(1):8. 
64 Epidiolex® (cannabidiol) oral solution [package insert]. Carlsbad, CA: Greenwich 
Biosciences, Inc.; 2018. 
65 Questions and Answers on Ethanol in the context of the revision of the guideline on 
‘Excipients in the label and package leaflet of medicinal products for human use’ 
(CPMP/463/00) EMA/CHMP/507988/2013. 
66 ICH Harmonised Tripartate Guideline: Guidance on Nonclinical Safety Studies for 
the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals M3(R2). June 2009. 
67 Clinical Trial Facilitation Group: Recommendations related to contraception and 
pregnancy testing in clinical trials.  September 2014. 
68 Howie SR. Blood sample volumes in child health research: review of safe limits. Bull 
World Health Organ 2011;89(1):46–53. 
69 Directive G for. Ethical considerations for clinical trials on medicinal products with 
the pediatric population. EU Guidel. 2008;1–34. 
70 Owens JA., Spirito A, McGuinn M. The Children’s Sleep Habits Questionnaire 
(CSHQ): psychometric properties of a survey instrument for school-aged children. 
Sleep. 2000, 23(8): 1043–51. 
71 Killian JT, Lane JB, Cutter GR, et al. Pubertal development in Rett syndrome 
deviates from typical females. Pediatr Neurol. 2014;51(6):769-75. 
72 Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis 
Child. 1969;44(235):291-303. 
73 World Medical Association Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. October 2013. 
74 ICH Harmonised Guideline: Integrated addendum to ICH E6(R1) Guideline for Good 
Clinical Practice E6(R2). November 2016. 
75 US Food and Drug Administration Code of Federal Regulations Title 21 (Food and 
Drugs) Part 50-Protection of Human Subjects.  April 2018. 
76 US Food and Drug Administration Code of Federal Regulations Title 21 (Food and 
Drugs) Part 56-Institutional Review Boards.  April 2018. 
77 US Food and Drug Administration Code of Federal Regulations Title 21 (Food and 
Drugs) Part 312-Investigational New Drug Application.  April 2018. 
78 Directive 2001/20/EC of the European Parliament and of the Council of 04 April 
2001 on the approximation of the laws, regulations and administrative provisions of 
the Member States relating to the implementation of good clinical practice in the 
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conduct of clinical trials on medicinal products for human use.  Official Journal of the 
European Communities L 121, 1/5/2001 p.34-44. 
79 Commission Directive 2005/28/EC of 08 April 2005 laying down the principles and 
detailed guidelines for GCP as regards investigational medicinal products for human 
use, as well as the requirements for authorisation of the manufacturing or importation 
of such products.  Official Journal of the European Union L 91, 9/4/2005 p. 13–19. 
80 US Food and Drug Administration Guidance for Clinical Investigators, Sponsors, and 
IRBs.  Adverse Event Reporting to IRBs- Improving Human Subject Protection.  
January 2009. 
81 UK Statutory Instrument 2004 No. 1031: The Medicines for Human Use (Clinical 
Trials) Regulations 2004.  May 2004. 
82 UK Statutory Instrument 2006 No. 1928: The Medicines for Human Use (Clinical 
Trials) Amendment Regulations 2006.  August 2006.  
83 UK Statutory Instrument 2006 No. 2984: The Medicines for Human Use (Clinical 
Trials) Regulations Amendment (No.2) Regulations 2006.  December 2006. 
84 UK Statutory Instrument 2008 No. 941: The Medicines for Human Use (Clinical 
Trials) and Blood Safety and Quality (Amendment) Regulations 2008.  May 2008. 
85 UK Statutory Instrument 2012 No. 1916: The Human Medicines Regulations 2012.  
August 2012. 
86 US Food and Drug Administration Code of Federal Regulations Title 21 (Food and 
Drugs) Part 11-Electronic records; Electronic signatures (Subpart B-Electronic 
Records). April 2018. 
87 Beecham, J. and Knapp, M. Costing psychiatric interventions, in G. Thornicroft (ed.) 
Measuring Mental Health Needs, Gaskell, 2nd edition. 2001;200-224. 
 
 
 
 
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Appendix 1 
Schedule of Assessments 
 
Visit Number 
1 
2a 
3a 
4 
5 
6 
7 
8b,c 
9 
10a 
Day Number 
(Visit Window) 
1 
 
8 
(±3) 
15 
(± 3) 
29 
(± 7) 
57 
(± 7) 
85 
(± 7) 
141 
(± 7) 
197 
(± 7) 
207 
(+ 7) 
235 
(+ 7) 
Informed consent and assentd 
Xe 
 
 
 
 
 
 
 
 
 
Eligibility check 
Xe 
 
 
 
 
 
 
 
 
 
Concomitant medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
New medical history 
Xe 
 
 
 
 
 
 
 
 
 
Adverse events 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Menstruation question (where appropriate) 
 
 
 
 
 
 
 
X 
 
 
Physical examination (including weight) 
Xf 
 
 
X 
 
X 
 
X 
 
 
Height 
 
 
 
 
 
 
 
X 
 
 
ECG 
Xf 
 
 
X 
 
X 
 
X 
 
 
Vital signs 
Xg 
 
 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory blood sampling 
(hematology and biochemistry)h 
Xf 
 
 
X 
X 
X 
 
X 
 
 
Hepatic function monitoring paneli 
 
 
 
 
 
 
Xi 
 
 
 
Dipstick urinalysis (where possible) 
Xf 
 
 
 
 
 
 
X 
 
 
Serum pregnancy test (if appropriate) 
 
 
 
 
 
 
 
X 
 
 
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Visit Number 
1 
2a 
3a 
4 
5 
6 
7 
8b,c 
9 
10a 
Day Number 
(Visit Window) 
1 
 
8 
(±3) 
15 
(± 3) 
29 
(± 7) 
57 
(± 7) 
85 
(± 7) 
141 
(± 7) 
197 
(± 7) 
207 
(+ 7) 
235 
(+ 7) 
Caregiver completed 
questionnaire/assessment 
RSBQ 
 
 
 
X 
X 
X 
X 
X 
 
 
CSHQ 
 
 
 
 
 
X 
 
X 
 
 
Caregiver QoL questionnaire 
(SF-36) 
 
 
 
 
 
 
 
X 
 
 
Patient QoL questionnaire 
(CHQ-PF50) 
 
 
 
 
 
 
 
X 
 
 
Hospital Services Use 
Questionnaire  
Xg 
 
 
X 
X 
X 
X 
X 
 
 
Tanner Staging (where 
appropriate)  
 
 
 
 
 
 
 
X 
 
 
Caregiver Assessment of Rett 
Symptoms 
 
 
 
X 
X 
X 
X 
X 
 
 
MBA-9 
 
 
 
 
 
X 
 
X 
 
 
CGI-S 
 
 
 
X 
X 
X 
X 
X 
 
 
CGI-I 
 
 
 
X 
X 
X 
X 
X 
 
 
Suicidality assessment 
Xg 
 
 
X 
X 
X 
X 
X 
X 
 
GWP42003-P dispensing 
Xe 
 
 
X 
X 
X 
X 
X 
 
 
GWP42003-P collection and compliance 
review 
 
 
 
X 
X 
X 
X 
X 
X 
 
Dosing schedulej 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
a Visit to be conducted by telephone. 
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b To be performed to all patients completing or withdrawing from the trial.  Patients who withdraw early should commence the 10-day GWP42003-P taper 
period, if possible. 
c A safety follow-up Visit 4 weeks after last GWP42003-P dose is required for all patients who withdraw from the trial or complete the trial. 
d Informed consent must be obtained prior to any trial-related procedures.  In cases where the patient possesses adequate understanding, assent will be taken 
along with parent(s)/legal representative consent.  The nominated caregiver will be asked to complete the quality of life questionnaires. 
e Always required. 
f Required only if OLE Visit 1 is > 28 days after RCT Visit 9. 
g Required if OLE Visit 1 does not occur on the same day as RCT Visit 9.  
h Determination of serum IGF-1 levels at Visit 1 and 8 only; IGF-1 laboratory results will remain blinded throughout the trial. 
i Hepatic function monitoring is required following increases in GWP42003-P dose or introduction of medications that are known to impact liver function.  
If the concerned change does not occur within 1 month of a scheduled biochemistry assessment, the investigator should perform an additional hepatic 
monitoring within 1 month of the change.  Hepatic monitoring at Visit 7 is required for patients taking concomitant valproic acid or whose dose exceeds 
15 mg/kg/day. 
j  The dosing schedule is to be completed by the caregiver daily throughout the trial and reviewed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
 
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Appendix 2 
Trial Personnel 
Appendix 2.1 
Investigator Details 
At the time of protocol production, the participating investigators have not been 
confirmed.  A list of all investigators will be maintained within the GW Research Ltd 
(GW) master files (electronically and added to the trial master file at the end of the trial). 
Appendix 2.2 
Sponsor Contact Details 
 
 
Email:
  
Tel: 
 
Fax: 
 
USA Toll-free Fax:  
 
Sponsor: 
GW Research 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 
At the time of protocol production, the contract research organizations (CROs) and the 
clinical 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): 
Trial Conduct 
Premier Research Europe 
1st Floor, Rubra 2 
Mulberry Business Park 
Fishponds Road 
Wokingham, RG41 2GY 
United Kingdom 
Tel: 
 
 
 
 
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PI
PI
PI
PI
PI
PI


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Appendix 3 
Questionnaires/Assessments 
Questionnaires appended exemplify the content of each specific assessment.  All 
questionnaires will be converted to electronic versions and therefore their format will 
differ from what is presented here. 
 
Appendix 3.1 
9-Item Motor-Behavioral Assessment Scale 
An example of the MBA-961 scale is shown below.  
1.   Regression of motor skills 
• 
0   None 
• 
1   Dyspraxia of gait and hand use including bilateral pincer grasps 
• 
2   Able to walk and use one or both hands 
• 
3   Able to walk independently or with support or to use one or both hands 
• 
4   No motor skill 
 
2.   Poor eye/social contact 
• 
0   None 
• 
1   25% of time 
• 
2   50% of time 
• 
3   75% of time 
• 
4   100% of time 
 
3.   Lack of sustained interest 
• 
0   None 
• 
1   25% of time 
• 
2   50% of time 
• 
3   75% of time 
• 
4   100% of time 
 
4.   Does not reach for objects or people 
• 
0   None 
• 
1   25% of time 
• 
2   50% of time 
• 
3   75% of time 
• 
4   100% of time 
 
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5. Chewing difficulties (by history at time of assessment) 
• 
0   None 
• 
1   Coarsely chopped 
• 
2   Finely chopped 
• 
3   Pureed or mashed 
• 
4   Gastrostomy 
 
6. Speech disturbance 
• 
0   Fluent 
• 
1   Phrases/sentences 
• 
2   Words with meaning or intention 
• 
3   Vocalizations, no words 
• 
4   No utterances 
 
7. Hand clumsiness (by history or at time of assessment) 
• 
0   Purposeful hand use 
• 
1   Plays with toys or activates switches purposefully 
• 
2   Uses utensils/cup, may be adaptive 
• 
3   Finger feeds only 
• 
4   No purposeful hand use 
 
8. Dystonia 
• 
0   None 
• 
1   Focal dystonia, one joint 
• 
2   Focal dystonia, more than 1 joint 
• 
3   Generalized dystonia, > 2 extremities 
• 
4   Fixed positional deformity 
 
9. Hypertonia/rigidity 
• 
0   None 
• 
1   Ankle hypertonia/rigidity 
• 
2   Upper or lower limb hypertonia/rigidity 
• 
3   Generalized hypertonia without contractures 
• 
4   Generalized hypertonia with contractures 
 
 
 
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Clinical Protocol Template (Phase 2–4) 
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Appendix 3.2 
Clinician Global Impressions - Severity Scale 
An example of CGI-S is shown below56: 
Considering your total clinical experience with this particular population, how ill 
is the patient at this time? 
1 = Normal, not at all ill 
2 = Borderline ill  
3 = Mildly ill  
4 = Moderately ill  
5 = Markedly ill  
6 = Severely ill 
7 = Extremely ill 
 
Anchors for the CGI-S produced by Neul et al. (2015), should be used by the investigator 
during completion of the CGI-S59. 
 
 
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Appendix 3.3 
Clinician Global Impressions - Improvement Scale 
An example of CGI-I is shown below56: 
Rate total improvement whether, in your judgement, it is due entirely to drug treatment. 
Compared with the patient’s condition at admission to the project, how much has 
the patient changed? 
1 = Very much improved  
2 = Much improved  
3 = Minimally improved  
4 = No change  
5 = Minimally worse  
6 = Much worse  
7 = Very much worse 
 
 
 
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Appendix 3.4 
Rett Syndrome Behaviour Questionnaire 
An example of the RSBQ is shown below55: 
 
II . 
REIT SYNDROME BEBA VI OUR Q.UESTIONNAIRE 
On the following few pages lllere ate items describing various cbanoaeristicslhat she may or may 
not ctllTenlly show. In (act, many of the characteristics may not apply to her. Tbe eharac;tcristies she 
shows now may be dtfferent from those she showed earlier in life. The characteristics may bave changed 
as she has got older. We would like you to think just about the characteristics sho shows JW!· 
For each characteristic, you have to think whether or not it accurately describes her. If the 
characteristic does describe her you are asked to rate it. For these characteristic.• please tick box 2 if the 
item is very tl'ut or often true. Tick box I ifthe item is somewhat or sometimes true. Ifthe 
characteristic does not describe her, please tick box 0 lO lndjcate that the it"em is riOt. true as far as you 
know. If she is unable to 
onn any item lease also tiek box 0. 
~ 
If sbc uses gesturing very frequently to oblain desired objeciS )'OU would tick box 2 to 
indicate that it is very ltUe or often true. 
0 
2 
Uses gesturing to obtain desired objeets. 
l . 
There are times when breatbing is deepnnd fast (hyperventilation). 
2. 
0 
2 
Spells of screaming for no apparent reason during the day. 
3. 
0 
2 
Makes repetitive hand movements with hands apart. 
4. 
0 
2 
Makes repetitive movements involving finger$ around toogue. 
5. 
0 
2 
There are times when breath is held. 
6. 
0 
2 
Air or salivn is expelled from mouth with force. 
7. 
0 
2 
Spells of appa.rcnt anxiety/tear in unfn.milin.r situations. 
8. 
0 
2 
Grinds tCCLh. 
9. 
0 
2 
S«ms frightened when the~ ~~sudden changes in own body position. 
10. 
0 
2 
There are times when pariS of the body an: held rigid. 
II. 
0 
2 
Shill$ sau with a slow horizontal rum of head. 
12. 
0 
2 
Expres.sionless face. 
13. 
0 
2 
Spells of screaming for no apparent reason during the night. 
14. 
0 
2 
Abrupt changes in mood. 
15. 
0 
2 
Titere are cer1aio days/periods where she performs much worse than 
usual. 
16. 
0 
2 
There are tiDl<>S when she appears miserable for oo apparent reason. 
17. 
0 
2 
Seems to look through people into the distance. 
18. 
0 
2 
Does not use hnnds for purposeful graspin&. 
Q Reb<cca ll. Mount, Richard P. Hasting,•, Shccnn Reilly, Hilary Cass, 1998 
II 
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Clinical Protocol Template (Phase 2–4) 
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Appendix 3.5 
36-Item Short Form 
The RAND Corporation SF-36 Survey Instrument was developed at RAND as part of the 
Medical Outcomes Study.  An example is shown below: 
 
Your Health and Well-Being 
T his survey asks for your views abou t your health. This in formation will help 
keep track of how you feel and how well you are able to do your usu al ac.tivities. 
Thnuk you for completiug rids sur.,ey! 
For eac.h of the fo llm~ing questions, please tick the one box that best describes 
your answer. 
1. In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
T 
T 
T 
T 
T 
o , 
o , 
D· 
D· 
D s 
2. Compared to one year ago, h ow would you rate your health in general 
now? 
Much better 
Somewhat 
About the 
Somewhat 
Much worse 
now than one 
better 
same as 
worse 
now than one 
year ago 
now than one 
one year ago 
now than one 
year ago 
year ago 
year ago 
T 
T 
T 
T 
T 
D· 
D· 
D· 
D· 
D· 
SF-36v2* Health Swvey 0 1992. 2002. 2009 ~edical Ourcome.; T:tu;t and Qua!ityMnic IDcwpom!d.. All rights resetwd.. 
S F-3~ 
is a registered trademark of Medical Outcomes llv.st. 
(S F-36\•2~ Hu!lh Stll'\•ey Sta..ll.<brd. Uoited Kingdom (Eogli.;;b)) 
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Clinical Protocol Template (Phase 2–4) 
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3. The following questions are about actiYities you might do during a f)'llical 
day. Does your health now limit you in these actiYities? If so, how much? 
Vigorous activities, such as mnning, lifting 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
heavy objects, participating in strenuous sports ..................... 0 , ............. 0 ' ............ 0 ' 
, Moderate activities, such as moving a table, pushing 
a vacmun cleaner, bowling, or playing golf ........................... 0 , ............. 0 '·· .......... 0 , 
Lifting or carrying gro:eries ................................................... 0 , ............. 0 , ............ 0 , 
, Climbing several flights of stairs ............................................ 0 , ............. 0 , ............ D , 
Climbing one flight of stairs ................................................... 0 ' ............. 0 ' ............ D ' 
r Bending, kneeling, or stooping ............................................... D , ............. D , ............ D , 
• Walking more than a mile ...................................................... 0 ' ............. 0 ' ............ D ' 
, Walking several hundred yards .............................................. D , ............. D ' ............ D ' 
Walking one hundred yards ................................................... 0 ' ............. 0 ' ............ D ' 
; Bathing or dressing yourself ................................................... 0 , ............. 0 , ............ D , 
SF-36v2* Health Swveye 1992.2002. 200~ ~edical Outcome.> Tl'I.H1.md QualityMellk lotwpomed. All rights resm'ed. 
S F-3~ is a registered trademark of Med.i(al Outcomes Tru..1.. 
(S F-36\•l~ Health Sun.'ey Stall.dard. United Kingdom (Eoglhll)) 
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Clinical Protocol Template (Phase 2–4) 
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4. During the past 4 weeks, how muc.h of the time have you had any of the 
following problems with your work or other regular daily activities ~ 
result of vour phvsical health? 
, Cut down on the amollllt of 
time you spent on work or 
All of 
the time 
Most of 
the time 
Some of 
A little of 
None of 
the time 
the time 
the time 
other activities ................................ 0 ............... 0 ' ............. 0 > ••••••••.•.•.• 0 • ............ 0 ' 
• Accomplished less than you 
would like ....................................... 0 ............... 0 , ............. 0 •············· 0 · ............ 0 ' 
, Were limited in the kind of 
work or other activities ................... 0 1. ••••••. •. •. •. 0 ' ............. 0 > ••••••••.•.•.• 0 • ............ 0 ' 
• Had difficultv perfomling the 
work or other activities (for 
example, it took extra effort) .......... 0 ............... 0 ' ............. 0 > .............. 0 • ............ 0 ' 
5. During the past 4 weeks, how muc.h of the time have you had any of the 
following problems with your work or other regular daily activities ~ 
result of any emotional problems (suc.h as feeling depressed or aJL'rious)? 
• Cut down on the. anto\lllt of 
time you spent on work or 
All of 
the time 
Most of 
the time 
Some of 
A little of 
None of 
the time 
the time 
the time 
other activities ................................ 0 ............... 0 ' ............. 0 > .............. 0 • ............ 0 ' 
• Accomplished less than you 
would like ..................... .................. 0 1. ............. 0 ' ............. 0 > .............. 0 • ............ 0 ' 
, Did work or other activities 
less carefully than usual.. ................ 0 ............... 0 ' ............. 0 > .............. 0 • ............ 0 ' 
SF-36v2* Health Swveye 1992. 2002. 200!> Y.edical Ourcomes Ttu;t and Qua!ityMetric 1Dc01J)Cltated.. All rights resm •ed.. 
S F-3~ 
is a registered trademark of Medical Outcomes Trust 
(S F-36\•2~ Hea!lb SUl'\•ey Stall.dard. United Kingdom (Eoglhb)) 
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Clinical Protocol Template (Phase 2–4) 
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6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered \\ith your normal social ac.tivities with 
family, friends, neighbours, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
T 
T 
T 
T 
T 
D· 
7. How much boclilv pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
T 
T 
T 
T 
T 
T 
D o 
D > 
D ) 
D· 
D· 
D· 
8. During the past 4 weeks, how muc.h did pain interfere with your normal 
work (inducting both work outside the home and housework)? 
Not at all 
A linle bit 
Moderately 
T 
T 
D o 
Quite a bit 
T 
D· 
Extremely 
T 
SF-36v2* Health Swveve 1992. 2002. 200!> Y.edical Ourcomes Ttu;t and Oua!itrMetric IDcOJ'l)(ltated.. All rizhts restn'ed.. 
S F-3~ 
is a registered trademMk of Medical Outcomes Trust. 
(S F-36\•l~ Health Sun.'ey Stall.dard. United Kingdom (Eoglhb)) 
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Clinical Protocol Template (Phase 2–4) 
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9. These questions are about h ow you feel and h ow things have been '~ith you 
during the past 4 weeks. For each question, please give the one answer that 
comes closest to th e way you have been feeling. How mu ch of the time 
during the past 4 weeks .. . 
All of 
the time 
Most of 
the time 
Some of 
A little of 
None of 
the time 
the time 
the time 
Did you feel full of life? .......... 0 ........ ... 0 •....... 0 > ••••••••••• 0 '· ...... 0 • 
, Have you been very nervous? ......... 0 ' .............. 0 1. .• .• .• .• .• .• 0 > •••••••••••••• 0 •· ............ 0 • 
, Have you felt so down in the 
dumps that nothing could 
cheer you up? .................................. 0 ............... 0 •............. 0 > •••••••••••••• 0 '· ............ 0 • 
, Have you felt calm and 
peacefut? ................................. 0 , ....... ... 0 ~. ..... .0 '········ .... 0 ........ 0 , 
Did you have a lot of energy? ......... 0 ............... 0 •............. 0 > •••••••••••••• 0 '· ............ 0 • 
r Have you felt downhearted 
and low? ............................ ............. 0 ' .............. 0 1. .• .• .• .• .• .• 0 > •••••••••••••• 0 ·· ............ 0 • 
, Did you feel worn out? ................... 0 , .............. 0 1. .• .• .• .• .• .• 0 > •••••••••••••• 0 ·· ............ 0 • 
, Have you been happy? .................... 0 , .............. 0 1. .• .• .• .• .• .• 0 > •••••••••••••• 0 ·· ............ 0 • 
Did you feel tired? ................. 0 ........ ... 0 > ....... 0 > •••••••••••• 0 '· ...... 0 • 
10. 
During the past 4 weeks, how muc.h of the time has your phvsical health or 
emotional problems in terfered '~ith you r social activities (like visitin g with 
frien ds, relatiws, etc.)? 
All of 
the time 
Most of 
the time 
T 
Some of 
the time 
A little of 
the tin1e 
None of 
the time 
SF-36v2* Health SwveyC> 1992.2002. 200~ ~edical Outcomes Tru;1 and Quali1yMelric Iocwpomed.. All rights resm •ed.. 
S f-j(l• IS a repstefN tr<tel!otark Of M~dJCal CIUlCOIIltS Tl'U.il. 
(SF-36\•l e Huilh Sun.•ey Sta.ll.dMd. United Kingdom (Eoglhb)) 
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Appendix 3.6 
Tanner Staging 
Tanner Staging72 is to be completed by all female adolescent patients (i.e. ≥ 7 years or 
7 to less than 18 years of age71 at the time of signing the informed consent/assent form or 
earlier, if clinically indicated by onset of menarche or other signs of precocious puberty). 
Female Development and Pubic Hair 
Please check the box next to the most appropriate stage; in the event that qualifying 
characteristics are not within the same stage, defer to the lesser stage as the overall 
Tanner Score. 
Tanner Stage 1 (Prepubertal, typically 10 years and younger) 
• No glandular tissue; areola follows the skin contours of the chest. 
• No pubic hair at all. 
Tanner Stage 2 (10 to 11.5 years) 
• Breast bud forms, with small area of surrounding glandular tissue; areola begins 
to widen. 
• Small amount of long, downy hair with slight pigmentation on the labia majora. 
Tanner Stage 3 (11.5 to 13 years) 
• Breast begins to become more elevated and extends beyond the borders of the 
areola, which continues to widen but remains in contour with surrounding breast. 
• Hair becomes more coarse and curly and begins to extend laterally. 
Tanner Stage 4 (13 to 15 years) 
• Increased breast size and elevation; areola and papilla form a secondary mound 
projecting from the contour of the surrounding breast. 
• Adult-like hair quality, extending across pubis but sparing medial thighs. 
Tanner Stage 5 (15+ years) 
• Breast reaches final adult size; areola returns to contour of the surrounding breast, 
with a projecting central papilla. 
• Hair extends to medial surface of the thighs. 
 
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Appendix 3.7 
Hospital Services Use Questionnaire 
An example of the Hospital Services Use questionnaire (based on the Health Service Use 
Questionnaire) is shown below87: 
Baseline 
1. Has your child used any hospital in-patient services in the last 12 months?  (prior to 
starting treatment with the Study Medicine)?  [in-patient services include: Intensive 
Care Unit [ICU] and other hospital department wards]  
Yes/No 
 
2. Has your child used any other specialist medical services in the last 6 months?  
[other hospital services include: Emergency department, other outpatient 
departments (any hospital clinic e.g., neurology, cardiology, gastroenterology, etc.), 
Urgent care.  
Yes/No 
For each in-patient hospital admission in the last 12 months, please record the following: 
Reason for stay 
 
Ward 
Total Number of 
inpatient days 
1. Health issue  
2. Accident related to child’s condition 
(due to motor disability or behaviour)  
3. Accident unrelated to child’s condition 
1. Intensive Care Unit 
(ICU) 
2. Other department / 
ward (non-ICU) 
 
 
Please complete additional in-patient hospital admission forms for each admission that 
occurred in the last 12 months 
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Please record any use of other specialist medical services by your child over the last 6 
months. 
Services used 
Number of 
attendances due 
to health issues 
 
Number of attendances 
due to accidents related 
to child’s condition (due 
to motor disability or 
behaviour) 
Number of 
attendances due to 
accidents unrelated 
to child’s condition 
 
Emergency department 
 
 
 
Other outpatient 
specialist services 
department  
(any hospital clinic e.g., 
neurology, cardiology, 
gastroenterology, etc.)  
 
 
 
Urgent Care 
 
 
 
 
 
 
 
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Appendix 3.8 
Suicidality Assessment 
An example of the suicidality assessment is shown below: 
• Has the child expressed any wish to be dead? 
• Has the child made any suicide attempts? 
• Has the child harmed herself/himself in any way or shown any nonsuicidal 
self-injurious behavior? 
 
 
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Appendix 3.9 
Children’s Sleep Habits Questionnaire 
An example of the CSHQ is shown below.70 
 
Child's Sleep Habits 
(Preschool and School-Aged) 
(Abbreviated Version) 
Coding 
The follow;ng staternents are about your child's sleep habits and possible d rtficulties with sleep. Think about the past week in your 
child's life ·when an swering the questions. If last week was unusual for a specific reason (such as your child had an ear infection 
and did not sleep v.'ell or the TV set was broken), choose the most recent typical v.oeek. Answer USUALLY if something occurs 5 o r 
more times in a week; answer SOMETIMES if it occurs 2-4 times in a week ; answer RARELY if something occurs never or 1 time 
during a week. Also, please indicate whether or not the sleep habit is a problem by circling •v es," "No," or •Not applicable (N/At . 
Bedtime 
Write in child's bedtime: 
3 
2 
Usually 
Sometimes 
Rarely 
Problem? 
15-71 
12-41 
(0-11 
1) Child goes to bed at the same time at night (R) 
D 
D 
D 
Yes 
No 
NJA 
2) 
Ch.ild falls asleep within 20 minutes after going to bed (R) 
D 
D 
D 
Yes 
No 
NJA 
3) 
Ch.ild falls asleep alone in own bed (R) 
D 
D 
D 
Yes 
No 
NJA 
4) 
Ch.ild falls asleep in parent's or sibling's bed 
D 
D 
D 
Yes 
No 
NJA 
5) 
Child needs parent in th.e room to fall asleep 
D 
D 
D 
Yes 
No 
NJA 
6) 
Ch.ild struggles at bedtime 
D 
D 
D 
Yes 
No 
NJA 
(cries, refuses to stay in bed, etc.) 
7) 
Ch.ild is afraid o f sleeping in the dark 
D 
D 
D 
Yes 
No 
NJA 
8) 
Ch.ild is afraid o f sleep ak>ne 
D 
D 
D 
Yes 
No 
NJA 
Sleep Behavior 
Child's usual amount of sleep each day: 
hours and 
minutes 
(combining nighttime sleep and naps) 
3 
2 
Usually 
Sometimes 
Rarely 
Problem? 
15-7! 
12-4! 
!0-1! 
9) 
Child sleeps too litUe 
D 
D 
D 
Yes 
No 
NJA 
10) 
Child sleeps ttle right amount (R) 
D 
D 
D 
Yes 
No 
NJA 
11) 
Child sleeps about th.e same amount each day (R) 
D 
D 
D 
Yes 
No 
NJA 
12) 
Child wets the bed at night 
D 
D 
D 
Yes 
No 
NJA 
13) 
Child talks during sleep 
D 
D 
D 
Yes 
No 
NJA 
14) 
Child is restless and moves a lot during sleep 
D 
D 
D 
Yes 
No 
NJA 
15) 
Child sleepwaJks during the night 
D 
D 
D 
Yes 
No 
NJA 
16) 
Child moves to someone else's bed during th.e night 
D 
D 
D 
Yes 
No 
NJA 
(parent, brother, sister, etc.) 
17) 
Child grinds teeth during sleep (your dentist may h.ave told 
D 
D 
D 
Yes 
No 
NJA 
you this) 
18) 
Child snores loudly 
D 
D 
D 
Yes 
No 
NJA 
CSHQ Abbreviated 
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Clinical Protocol Template (Phase 2–4) 
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Sleep Behavior fcontinuedl 
3 
2 
Usually 
Sometimes 
(5-7) 
(2-4) 
19) 
Child seems to stop breathing during sleep 
D 
D 
20) 
Child snorts and/or gasps during sleep 
D 
D 
21) 
Child llas tr ouble sleeping away from home (visiting 
D 
D 
relatives, vacation) 
22) 
Child awakens during night screaming, sweating, and 
D 
D 
inconsolable 
23) 
Child awakens alarmed by a frightening dream 
D 
D 
Waking During tthe t.Jight 
3 
2 
Usually 
Sometimes 
(5-7) 
(2-4) 
24) 
Child awakes once during the night 
D 
D 
25) 
Child awakes more than once during the night 
D 
D 
Write the number of minutes a night waking usually lasts: 
Morning Wakingl0al1,ime Sleeuiness 
Write in the time of day child usually wakes in the moming: 
3 
2 
Usually 
Sometimes 
(5-7) 
(2-4) 
26) Child wakes. up by him/herself (R) 
D 
D 
27) Child wakes. up in negative mood 
D 
D 
28) AduHs or siblings wake up child 
D 
D 
29) Child has difficulty getting out of bed in the morning 
D 
D 
30) Child takes a long time to become alert in the moming 
D 
D 
31) Child seems tired 
D 
D 
Child has appeared very sleepy or fallen asleep during the fonowing (check all that apply): 
32) Watching TV 
33) 
Riding in ca r 
2 
1 
Not Sleepy 
D 
D 
2 
Very Sleepy 
D 
D 
Coding 
Rarely 
Problem? 
(0-1 ) 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
Rarely 
Problem? 
(0-1 ) 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
Rarely 
Problem? 
(0-1 ) 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
D 
Yes 
No 
N/A 
3 
Falls Aslee;p 
D 
D 
CSHQ Abbreviated 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
 
 
 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Appendix 3.10 
Caregiver Assessment of Rett Symptoms 
An example of the Caregiver Assessment of Rett Symptoms is shown below: 
 
For each question, please choose the number on the scale that best describes your child. 
Please choose your answers based on what you observed over the past 7 days (since the last time 
you completed the diary). 
 
1. Based on what you observed over the past 7 days, how was your child’s condition overall?   
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Poor 
 
 
 
 
 
 
 
 
 
Excellent 
 
 
2. Based on what you observed over the past 7 days, how much of the time was your child’s 
breathing pattern irregular overall? 
Please consider any episodes of irregular breathing, such as your child’s hyperventilation 
and breath holding. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
of the 
Time 
 
 
 
 
 
 
 
 
 
All 
of the 
time 
 
 
3. Based on what you observed over the past 7 days, how constipated was your child overall? 
Please consider how often your child has had bowel movements, how hard it was to push, and 
the size and consistency.  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not at all 
constipated  
 
 
 
 
 
 
 
 
 
Extremely 
constipated 
 
4. Based on what you observed over the past 7 days, how much of the time did your child have 
repetitive hand movements?  
Please consider hand movements such as wringing, tapping, rubbing, washing movements, 
and hand mouthing 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
of the 
time 
 
 
 
 
 
 
 
 
 
All 
of the 
time 
 
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Clinical Protocol Template (Phase 2–4) 
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5. Based on what you observed over the past 7 days, overall, how much of the time did your 
child engage in behavior that led to harm or potential harm to herself or others? 
Please consider any self-injurious behavior and behavior that led to physical harm or 
potential harm to the child herself or others. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
of the 
time 
 
 
 
 
 
 
 
 
 
All 
of the 
time 
 
 
6.  Based on what you observed over the past 7 days, overall, how anxious or sad was your 
child? 
Please consider whether your child showed signs such as fidgeting, crying or screaming. Also 
consider whether she appeared sad, withdrawn, or irritable. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not at all 
anxious/sad 
 
 
 
 
 
 
 
 
 
Extremely 
anxious/sad 
 
 
 
7. Based on what you observed over the past 7 days, how difficult was it for your child to 
communicate her needs?  
Please consider all forms of communication your child may use (including both verbal and 
nonverbal communication, such as gestures, eye pointing, and communication devices). 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
difficult 
at all 
 
 
 
 
 
 
 
 
 
Did not 
communicate 
her needs at 
all 
 
 
 
8. Based on what you observed over the past 7 days, how difficult was it for your child to make 
appropriate eye contact?  
Please consider your child’s eye contact when you speak to her and when she communicates 
with you. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
difficult 
at all 
 
 
 
 
 
 
 
 
 
Extremely 
difficult 
 
 
9. Based on what you observed over the past 7 days, how much of the time was your child 
attentive to her environment and activities?  
Please consider signs of being aware of her surroundings, such as eye movement, turning her 
head, moving her body, and making sounds. 
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Clinical Protocol Template (Phase 2–4) 
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0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
of the 
time 
 
 
 
 
 
 
 
 
 
All 
of the 
time 
 
 
10. Based on what you observed over the past 7 days, how difficult was it for your child to sleep?  
Please consider your child’s night time sleep, if she woke up during the night, how long it 
took her to go back to sleep, and how long she slept overall. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
difficult 
at all 
 
 
 
 
 
 
 
 
 
Extremely 
difficult 
 
 
11. Based on what you observed over the past 7 days, did your child eat by mouth? 
 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
11a.  Based on what you observed over the past 7 days, how difficult was it for your child to eat 
(by mouth)?  Please consider your child’s ability to chew and swallow including any 
choking episodes. Also consider, what she ate, how she ate, and how much time it took to 
complete meals and snacks. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
difficult 
at all 
 
 
 
 
 
 
 
 
 
Extremely 
difficult 
 
 
12. Based on what you observed over the past 7 days, did your child have seizures? 
 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
12a. Based on what you observed over the past 7 days, how much was your child’s condition 
affected by seizures? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not 
affected 
at all 
 
 
 
 
 
 
 
 
 
Extremely 
affected 
 
 
 
 
 
Thank you. You have finished completing the Diary. 
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Clinical Protocol V2 18Dec19 
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Page 1 of 105 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
AN OPEN-LABEL EXTENSION TRIAL TO INVESTIGATE THE 
LONG-TERM SAFETY OF CANNABIDIOL ORAL SOLUTION 
(GWP42003-P, CBD-OS) IN PATIENTS WITH RETT SYNDROME 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
CLINICAL PROTOCOL 
GW Research 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 Research Ltd (GW) that must 
not be disclosed to anyone other than the recipient study 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. 
 
Page 127 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001 605-24 
Clinical Protocol V2 18Dec 19 
Investigator Agreement 
SPONSOR: GW RESEARCH LIMITED 
I have read the attached clinical protocol entitled ' An open-label extension trial to 
investigate the long-term safety of cannabidiol oral solution (GWP42003-P, CBD-OS) in 
patients with Rett syndrome', dated 18 December 2019, and agree to abide by al I 
provisions set forth therein. 
The sponsor and 1 agree to comply with applicable regulatory requirement(s); the United 
States (US) Food and Drug Administration (FDA) regulations relating to Good Clinical 
Practice (GCP) and clinical trials, the European Union (EU) Clinical Trials Directive 
(2001/20/EC), the EU GCP Directive (2005/28/EC) and subsequent applicable 
regulatory/statutory instruments, or the International Council for Harmonisation (ICH) 
Harmonised Guideline: Integrated Addendum to ICH E6(R I): Guideline for GCP E6(R2) 
where the EU Clinical Trials and GCP Directives do not apply, and to complete Form 
FDA 1572, if required. 1 accept responsibility for the overall medical care of participants 
during the trial and for all trial-related medical decisions. 
r 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 ofGW. 
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. 
Center No.: 
Print name: 
Principal investigator 
Signature: 
GW Authorization 
Confidential 
Page 2of 105 
Clinical Protocol Template (Phase 2-4 J 
Date: 
(DD-MMM-YY) 
Date: 
/J ,0 Ee_ 
·2.0 11 
(DD-MMM-YY) 
VI, 24Sepl 5 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
1 
PROTOCOL SYNOPSIS 
Trial Title 
An Open-label Extension Trial to Investigate the Long-term Safety 
of Cannabidiol Oral Solution (GWP42003-P, CBD-OS) in Patients 
with Rett Syndrome 
Clinical Trial Type 
Phase 3 
Indication 
Rett syndrome (RTT) [typical or atypical] 
Primary Objective 
To evaluate the long-term safety of GWP42003-P in patients with 
RTT 
Secondary 
Objective(s) 
Secondary objectives: 
• To evaluate the effect of GWP42003-P in measures of disease 
severity 
o Rett Syndrome Behaviour Questionnaire (RSBQ) 
o Clinical Global Impressions - Improvement (CGI-I) 
o Clinical Global Impressions - Severity (CGI-S) 
o 9-items Motor Behavioral Assessment (MBA-9) 
o Children’s Sleep Habits Questionnaire (CSHQ) 
Exploratory objectives: 
• To evaluate the effect of GWP42003-P on caregiver and 
patient quality of life (QoL) 
o 36-item Short Form [SF-36] and Child Health 
Questionnaire Parent Form 50 [CHQ-PF50], 
respectively 
• To evaluate the effect of GWP42003-P on health utilization 
o Hospital Services Use Questionnaire 
o Caregiver Assessment of Rett Symptoms 
Trial Design 
This is a multicenter, open-label extension (OLE) trial for patients 
with RTT who have completed the randomized, double-blind, 
placebo-controlled trial (GWND18064).   
Entry to this OLE trial is recommended to be on the same day as 
Visit 9 of the randomized controlled trial (RCT), GWND18064; 
however, patients may enter the OLE trial up to the point of the 
RCT follow-up visit (Visit 11).   
All patients entering this OLE trial will begin dosing with 
5 mg/kg/day GWP42003-P (2.5 mg/kg twice daily [b.i.d.]) on 
Day 1.  Patients will be observed, and after 1 week, the dose may 
be escalated further, at the investigator’s discretion, up to 
15 mg/kg/day GWP42003-P (7.5 mg/kg b.i.d.), in weekly 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
increments of 5 mg/kg/day (2.5 mg/kg b.i.d.).   
Patients should then remain on a stable dose of GWP42003-P for 
the duration of the maintenance period of the trial (up to 
104 weeks), with the option for doses to be decreased or increased 
to a maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.) based on 
clinical response and tolerability as deemed necessary by the 
investigator, until the optimal dose is found.  Patients whose dose 
has been decreased can have their dose increased again if 
tolerability improves.  
At the end of treatment (Visit 14 [Day 729]), the dose of 
GWP42003-P will be reduced over a 10-day taper period, and 
patients will enter the 4-week follow-up period.  
If a patient permanently discontinues treatment at any point during 
the trial, GWP42003-P should be gradually reduced over 10 days 
(unless inadvisable due to an adverse event [AE]).  
The patient should attend a withdrawal visit (Visit 14) as soon as 
possible after the decision is made to permanently discontinue 
GWP42003-P. Unless inadvisable due to an AE, the patient will 
taper GWP42003-P and attend the End of Taper visit (Visit 15) 
and then complete the 4-week follow-up period.   
Primary Endpoint 
Safety: 
The long-term safety profile of GWP42003-P will be assessed by 
evaluating changes in the following, relative to the 
prerandomization baseline of the RCT: 
• AEs 
• Clinical laboratory parameters 
• Vital signs 
• Physical examination procedures 
• 12-lead electrocardiogram (ECG) 
• Effects on menstruation cycles 
• Suicidality 
• Change in growth and development by measurement of 
height, weight, serum insulin-like growth factor-1 (IGF-1) 
levels, and Tanner Staging (for patients aged ≥ 7 years or 
earlier, if clinically indicated by the onset of menarche or 
other signs of precocious puberty) 
Secondary 
Endpoint(s) 
Secondary endpoints: 
The following will be assessed by evaluating changes relative to 
the prerandomization baseline of the RCT: 
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Clinical Protocol Template (Phase 2–4) 
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• RSBQ 
• CGI-I 
• CGI-S 
• MBA-9 
• CSHQ 
Exploratory endpoints: 
The following will be assessed by evaluating changes relative to 
the prerandomization baseline of the RCT: 
• SF-36 
• CHQ-PF50 
• Hospital Services Use Questionnaire 
• Caregiver Assessment of Rett Symptoms 
Sample Size 
All patients with RTT who completed the randomized, 
double-blind, placebo-controlled trial (GWND18064) who wish to 
take GWP42003-P and meet the eligibility criteria can be included 
in this trial.  Approximately 252 patients will be enrolled.  
Summary of Patient 
Eligibility Criteria 
Inclusion criteria 
For inclusion in the trial, patients must fulfil all of the following 
criteria: 
• Patient has completed all scheduled visits of the treatment 
phase of the RCT, GWND18064, and has transitioned to 
OLE by the point of RCT follow-up (Visit 11). 
• Patient (if possessing adequate understanding, in the 
investigator’s opinion) and/or the patient’s parent(s)/legal 
representative is willing and able to give informed 
consent/assent for participation in the trial. 
• Patient and the patient’s caregiver are willing and able (in 
the investigator’s opinion) to comply with all trial 
requirements (including the completion of all caregiver 
assessments by the same caregiver throughout the trial). 
• Patient must have the ability to swallow the investigational 
medicinal product (IMP) provided as a liquid solution or 
the ability for the IMP to be delivered via gastrostomy (G) 
or nasogastric (NG) feeding tube (only G- or NG-tubes 
made from polyurethane or silicon are allowed). 
• Patient and/or parent(s)/legal representative is willing to 
allow the responsible authorities to be notified of 
participation in the trial, if mandated by local law. 
• Patient and/or parent(s)/legal representative is willing to 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
allow the patient’s primary care practitioner (if the patient 
has one) and consultant (if the patient has one) to be 
notified of participation in the trial if the primary care 
practitioner/consultant is different from the investigator. 
Exclusion criteria  
If the RCT ‘End of Treatment’/‘End of Taper Period’ visit 
assessments or Visit 1 reassessments (as applicable) raise any 
safety concerns, the investigator should consider whether it will be 
appropriate for the patient to continue to participate in the OLE 
trial or if the patient should be withdrawn. 
The patient may not enter the trial if ANY of the following apply: 
• Patient meets the withdrawal criteria (including clinically 
significant abnormal laboratory values), in the 
investigator’s opinion.  
• Patient met during the RCT the criteria for permanent IMP 
discontinuation (unless in case of an AE, if AE was not 
considered related with the IMP; patients that met alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) 
elevations discontinuation criteria must be excluded). 
• Females of childbearing potential, unless willing to ensure 
that they or their partner use a highly effective method of 
birth control (e.g., combined [estrogen and progestogen 
containing] hormonal contraceptiona associated with 
inhibition of ovulation [oral, intravaginal or transdermal], 
progestogen-only hormonal contraceptiona associated with 
inhibition of ovulation [oral, injectable or implantableb] 
intrauterine devices/hormone-releasing systemsc, bilateral 
tubal occlusiona, vasectomized partnera,d, sexual 
abstinencee during the trial and for 3 months after the last 
 
a The effect of GWP42003-P on oral contraceptives has not been investigated.  GWP42003-P is 
not an inducer of CYP3A4 and therefore is not expected to alter the PK of hormonal 
contraceptives. 
b Contraception methods that are considered to have low user dependency. 
c Contraception methods that are considered to have low user dependency. 
d Provided that partner is the sole sexual partner of the trial patient of childbearing potential and 
that the vasectomized partner has received medical assessment of the surgical success. 
e Only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the trial treatments.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
dose. 
• Patient has been previously enrolled and dosed in this trial. 
• Patient is unwilling to abstain from donation of blood 
during the trial. 
• Male participants who are fertile (i.e., after puberty unless 
permanently sterile by bilateral orchidectomy) and with a 
partner of childbearing potential unless agree to ensure that 
they use male contraception (e.g., condom) or remain 
sexually abstinent during the trial and for 3 months after the 
last dose. 
Criteria for 
Withdrawal 
Patient must be withdrawn from the trial if any of the following 
apply: 
• Administrative decision by the investigator, GW Research 
Ltd (GW), or a regulatory authority 
• Pregnancy 
• Protocol deviation that is considered to potentially 
compromise the safety of the patient 
• Withdrawal of patient assent 
• Withdrawal of parent(s)/legal representative consent 
• ALT or AST > 3 × upper limit of normal (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 (total bilirubin [TBL] 
> 2 × ULN or international normalized ratio [INR] > 1.5) 
Note: Prior to withdrawal for the transaminase elevations noted 
above, the investigator may choose to confirm the transaminase 
elevations by repeating the following laboratory tests within 24 
to 48 hours: ALT, AST, TBL, INR, % eosinophils, gamma-
glutamyl transferase, alkaline phosphatase, and eosinophils.  
Should the above transaminase elevation criteria be 
confirmed, the patient must be withdrawn from the trial.  
In cases where the transaminase elevation withdrawal 
criteria are not met or confirmed, the dose of IMP or a 
concomitant medication with known hepatotoxicity may be 
reduced.  Dose adjustments should be discussed with the 
GW medical monitor.  The final decision regarding dose 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
adjustments should be taken by the investigator. 
• Lost to follow-up. 
The patient may also be withdrawn from the trial for any of the 
following: 
• Patient or caregiver noncompliance 
• AE (including clinically significant laboratory results) that, 
in the opinion of the investigator, would compromise the 
continued safe participation of the patient in the trial 
• Failure to meet the eligibility criteria 
• Any evidence of use of drugs of abuse or drug diversion 
• Suicidal ideation or behavior during the treatment period 
Investigational 
Medicinal Product: 
Formulation, Mode 
of Administration, 
Dose, and Regimen 
GWP42003-P oral solution is formulated as follows: (100 mg/mL 
cannabidiol [CBD] in sesame oil with anhydrous ethanol, 
sweetener [sucralose], and strawberry flavoring).  
GWP42003-P is to be taken orally (swallowed) b.i.d. (morning and 
evening) using the syringe(s) provided.  GWP42003-P should be 
taken at the same time each day consistently with food, i.e., within 
30 minutes after the end of a meal and in line with the patients’ 
normal feeding schedule and dietary habits.  The time of 
GWP42003-P administration in relation to food should be kept 
consistent throughout the trial.  In patients with G- or NG-tubes but 
where oral dosing of GWP42003-P is possible, oral dosing is 
preferable.  Only in patients where oral dosing is not possible 
should GWP42003-P be administered via G- or NG-tubes made 
from polyurethane or silicon only  The investigator should contact 
the medical monitor to review IMP administration guidelines if 
administration via G-or NG-tubes is planned.  The volume of 
GWP42003-P will be determined by patient’s weight.   
All patients will begin dosing with 5 mg/kg/day GWP42003-P 
(2.5 mg/kg b.i.d.) for 1 week.  After 1 week’s treatment, depending 
on clinical response and tolerability, the patients’ dose can be 
further increased in weekly increments of 5 mg/kg/day (2.5 mg/kg 
b.i.d.) up to 15 mg/kg/day GWP42003-P (7.5 mg/kg b.i.d.).   
Patients should then remain on a stable dose of GWP42003-P for 
the duration of the maintenance period of the trial (up to 
104 weeks), with the option for doses to be decreased or increased 
to a maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.) based on 
clinical response and tolerability, as deemed necessary by the 
investigator. 
Patients discontinuing GWP42003-P treatment at the end of the 
trial or at any other time if they discontinue treatment early should 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
undergo a 10-day taper period (unless continued dosing is 
inadvisable, e.g., due to an AE). 
Control Group 
Not applicable. 
Procedures 
Before the patient undergoes any assessments or observations, the 
patient’s parent(s)/legal representative is required to give written 
informed consent.  The nominated caregiver will be asked to 
consent to complete the QoL questionnaires.  In cases where the 
patient possesses adequate understanding, the patient’s assent will 
be taken, along with parent(s)/legal representative consent.  Due to 
the degree of cognitive impairment in patients with RTT, patients 
18 years of age or older will not be required to provide consent and 
will only be required to provide assent in cases where the patient 
possesses adequate understanding, along with parent(s)/legal 
representative consent.  Visits 2, 3, and 16 (safety visits) are to be 
conducted by telephone.   
OLE Visit 1 (Day 1): Every effort should be made for this visit to 
take place on the same day as the RCT ‘End of Treatment’ visit.  
However, patients can still enter the OLE trial up to the point of 
the RCT follow-up visit (Visit 11).   
OLE Visit 1 assessments required for all patients: 
• 
Informed consent and assent  
• 
Eligibility check 
• 
New medical history 
• 
AE review 
• 
GWP42003-P dispensing 
OLE Visit 1 assessments required if OLE Visit 1 occurs on a 
different date than RCT Visit 9: 
• 
Vital signs 
• 
Suicidality assessment 
• 
Hospital Services Use Questionnaire  
OLE Visit 1 assessments required if OLE Visit 1 occurs 
> 28 days after RCT Visit 9: 
• 
Physical examination (including weight) 
• 
ECG 
• 
Clinical laboratory blood sampling (hematology and 
biochemistry) 
• 
Dipstick urinalysis (where possible) 
OLE assessments on Visits 2 to Visit 16 (Follow-up) (see 
Appendix 1 for time points of each assessment): 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
• Concomitant medications review 
• AE review  
• Menstruation cycle review  
• Physical examination (including weight)  
• Height  
• ECG  
• Vital signs  
• Safety laboratory assessments (hematology and biochemistry) 
(Visit 7 only for patients taking concomitant valproic acid as 
well as for patients whose dose exceeds 15 mg/kg/day) 
Note: Hepatic function monitoring should be carried out within 
1 month following increases in GWP42003-P dose or 
introduction of medications that are known to impact liver 
function.  If the concerned change does not occur within 
1 month of a scheduled biochemistry assessment, the 
investigator should perform an additional hepatic monitoring 
within 1 month of the change.   
• Dipstick urinalysis  
• Serum IGF-1 levels  
• Serum pregnancy test (if appropriate)  
• Questionnaires: 
o RSBQ 
o CSHQ 
o SF-36 and CHQ-PF50 
o Hospital Services Use Questionnaire 
o Tanner Staging (for patients aged ≥ 7 years or earlier, if 
clinically indicated by onset of menarche or other signs 
of precocious puberty) 
o Caregiver Assessment of Rett Symptoms  
o MBA-9  
o CGI-S and GCI-I  
o Suicidality assessment  
• GWP42003-P dispensing (All caregivers will be provided with 
a dosing schedule.) 
• GWP42003-P collection and compliance review  
Caregivers are asked to confirm dosing in the dosing schedule 
daily throughout the trial; the dosing schedule will be reviewed  
Statistical 
All data that will be collected during this trial will be summarized 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Considerations 
across time, using appropriate descriptive statistics.  Where 
baseline data are available from the RCT, changes from baseline 
will also be presented, where appropriate.  There will be no formal 
hypothesis testing.  A detailed statistical analysis plan will be 
written. 
Sponsor 
GW Research Ltd 
Sovereign House 
Vision Park 
Chivers Way 
Histon 
Cambridge CB24 9BZ 
United Kingdom 
 
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Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Figure 1-1 
Trial Design and Treatment Schematic  
Visit 9
Day 281 
± 7
Visit 10
Day 365 
± 7
Visit 11
Day 456 
± 7
Visit 12
Day 547 
± 7
Visit 13
Day 638 
± 7
Visit 14
Day 729 
± 7
Visit 15
Day 739
+ 7
Visit 1
Day 1
Visit 2
Day 8 
± 3
Visit 3
Day 15 
± 3
Visit 4
Day 29 
± 7
Visit 5
Day 57 
± 7
Visit 6
Day 85
± 7
Visit 7
Day 141 
± 7
Visit 8
Day 197 
± 7
Visit 16
(28 days 
after last 
dose)
+ 7
Day 1
End of 
Week 104
Taper 
(10 days)
Administration of Open-label GWP42003-P
Telephone 
Visits
Completion of RCT GWND18064
End of 
Treatment
End of 
Taper
Follow-up
(Telephone 
Visit)
Assessment 
Visits
Assessment 
Visit
Resupply 
Visit
Resupply 
Visit
Enrolment 
OLE 
GWND19002
 
OLE = open-label extension; RCT = randomized controlled trial  
 
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Clinical Protocol Template (Phase 2–4) 
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Table of Contents 
1 
PROTOCOL SYNOPSIS .................................................................... 3 
Table of Contents ......................................................................................... 13 
List of Appendices ....................................................................................... 19 
List of In-text Tables ................................................................................... 20 
List of In-text Figures .................................................................................. 21 
List of Abbreviations ................................................................................... 22 
Definition of Terms...................................................................................... 25 
2 
OBJECTIVES ..................................................................................... 26 
2.1 
Primary .............................................................................................................. 26 
2.2 
Secondary .......................................................................................................... 26 
3 
BACKGROUND AND RATIONALE .............................................. 27 
3.1 
Disease .............................................................................................................. 27 
3.2 
Investigational Medicinal Product Background................................................ 28 
3.2.1 
Nonclinical Studies ........................................................................................ 29 
3.2.1.1 
Efficacy Pharmacology ............................................................................... 29 
3.2.1.2 
Safety Pharmacology .................................................................................. 31 
3.2.1.3 
Mechanism of Action ................................................................................. 31 
3.2.2 
Clinical Studies .............................................................................................. 31 
3.3 
Rationale ........................................................................................................... 32 
3.3.1 
Choice of Endpoints ....................................................................................... 32 
3.3.1.1 
Choice of Primary Endpoints...................................................................... 32 
3.3.1.2 
Choice of Secondary Endpoints ................................................................. 32 
3.3.1.3 
Choice of Exploratory Endpoints ............................................................... 33 
3.3.2 
Choice of Dosing Regimen ............................................................................ 33 
3.3.3 
Benefit-risk Analysis ...................................................................................... 34 
3.4 
Clinical Hypothesis ........................................................................................... 34 
4 
EXPERIMENTAL PLAN ................................................................. 35 
4.1 
Trial Design ...................................................................................................... 35 
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4.1.1 
Primary Endpoint ........................................................................................... 36 
4.1.2 
Secondary Endpoints ...................................................................................... 36 
4.1.2.1 
Secondary endpoints: .................................................................................. 36 
4.1.2.2 
Exploratory endpoints:................................................................................ 36 
4.2 
Number of Trial Centers ................................................................................... 37 
4.3 
Number of Patients ........................................................................................... 37 
5 
INVESTIGATIONAL MEDICINAL PRODUCT .......................... 38 
5.1 
GWP42003-P Oral Solution ............................................................................. 38 
5.2 
Packaging, Storage, and Drug Accountability .................................................. 38 
5.2.1 
Packaging and Labeling ................................................................................. 38 
5.2.2 
Storage ............................................................................................................ 39 
5.2.3 
Supply and Return of Investigational Medicinal Product .............................. 39 
5.2.4 
Investigational Medicinal Product Accountability ......................................... 40 
5.2.5 
Post-trial Provision ......................................................................................... 41 
6 
PATIENT ELIGIBILITY .................................................................. 42 
6.1 
Inclusion Criteria .............................................................................................. 42 
6.2 
Exclusion Criteria ............................................................................................. 42 
7 
PATIENT ENROLLMENT .............................................................. 44 
7.1 
Treatment Assignment ...................................................................................... 44 
7.2 
Randomization .................................................................................................. 44 
8 
TREATMENT PROCEDURES........................................................ 45 
8.1 
Investigational Medicinal Product Dosage, Administration, and Schedule ..... 45 
8.1.1 
Dose Administration ...................................................................................... 45 
8.1.2 
Dose Escalation and Dose Adjustments ......................................................... 45 
8.2 
Concomitant Therapy........................................................................................ 47 
8.3 
Prohibited Therapy During the Trial Period ..................................................... 47 
8.4 
Compliance in Investigational Medicinal Product Administration .................. 48 
8.5 
Access to Blinded Treatment Assignment ........................................................ 48 
9 
TRIAL PROCEDURES ..................................................................... 49 
9.1 
Trial Procedures by Visit .................................................................................. 49 
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9.1.1 
Clinic Visits .................................................................................................... 50 
9.1.1.1 
Visit 1 (Day 1) ............................................................................................ 50 
9.1.1.2 
Visit 4 (Day 29 [± 7]) ................................................................................. 51 
9.1.1.3 
Visit 5 (Day 57 [± 7]) ................................................................................. 51 
9.1.1.4 
Visit 6 (Day 85 [± 7]) ................................................................................. 52 
9.1.1.5 
Visit 7 (Day 141 [± 7]) ............................................................................... 52 
9.1.1.6 
Visit 8 (Day 197 [± 7]), Visit 10 (Day 365 [± 7]), and Visit 14 
(Day 729 [± 7], End of Treatment/Withdrawal Visit) ................................ 53 
9.1.1.7 
Visit 9 (Day 281 [± 7]) ............................................................................... 54 
9.1.1.8 
Visit 11 (Day 456 [± 7]) and Visit 13 (Day 638 [± 7]) ............................... 55 
9.1.1.9 
Visit 12 (Day 547 [± 7]) ............................................................................. 55 
9.1.1.10 
Visit 15 (Day 739 [+ 7], End of Taper) ...................................................... 56 
9.1.2 
Telephone Visits ............................................................................................. 56 
9.1.2.1 
Visits 2 (Day 8 [± 3]) and 3 (Day 15 [± 3]) ................................................ 56 
9.1.2.2 
Visit 16 (28 days after last dose IMP [+ 7], Follow-up, End of Trial) ....... 57 
9.1.3 
Unscheduled Visits ......................................................................................... 57 
9.1.4 
End of Trial .................................................................................................... 57 
9.2 
Trial Procedure Listing ..................................................................................... 57 
9.2.1 
Informed Consent/Assent ............................................................................... 57 
9.2.2 
Contraception Requirements .......................................................................... 58 
9.2.3 
Concomitant Medication ................................................................................ 60 
9.2.4 
New Medical History ..................................................................................... 60 
9.2.5 
Menstruation ................................................................................................... 60 
9.2.6 
Physical Examination ..................................................................................... 60 
9.2.7 
12-Lead Electrocardiogram ............................................................................ 60 
9.2.8 
Vital Signs ...................................................................................................... 61 
9.2.9 
Clinical Laboratory Sampling ........................................................................ 61 
9.2.10 
Randomization and Trial Supply Management System ................................. 63 
9.2.11 
Dosing Schedule/Compliance Review ........................................................... 63 
9.2.12 
Questionnaires and Assessments Completed at Scheduled Visits ................. 64 
9.2.12.1 
Rett Syndrome Behaviour Questionnaire ................................................... 64 
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9.2.12.2 
Children’s Sleep Habit Questionnaire ........................................................ 64 
9.2.12.3 
36-Item Short Form .................................................................................... 65 
9.2.12.4 
Child Health Questionnaire Parent Form 50 .............................................. 65 
9.2.12.5 
Hospital Services Use Questionnaire.......................................................... 65 
9.2.12.6 
Caregiver Assessment of Rett Symptoms .................................................. 65 
9.2.12.7 
Rett Syndrome Motor-Behavioral Assessment Scale ................................. 66 
9.2.12.8 
Clinical Global Impressions Questionnaire ................................................ 66 
9.2.12.9 
Suicidality Assessment ............................................................................... 67 
9.2.13 
Tanner Staging ............................................................................................... 67 
9.2.14 
Investigational Medicinal Product Accountability ......................................... 67 
9.2.15 
Adverse Events ............................................................................................... 67 
10 
IMP WITHDRAWAL ........................................................................ 69 
11 
URGENT SAFETY MEASURES ..................................................... 71 
12 
ADVERSE EVENT REPORTING ................................................... 72 
12.1 
Definitions......................................................................................................... 72 
12.1.1 
Adverse Event ................................................................................................ 72 
12.1.2 
Investigator ..................................................................................................... 72 
12.2 
Serious Adverse Events .................................................................................... 72 
12.3 
Reporting Procedures for Serious Adverse Events ........................................... 73 
12.4 
Pregnancy .......................................................................................................... 74 
12.5 
Causality Assessment........................................................................................ 74 
12.6 
Reporting Procedures for All Adverse Events .................................................. 75 
12.7 
Follow-up Procedures for Adverse Events ....................................................... 77 
12.8 
Potential Cases of Drug-induced Liver Injury .................................................. 77 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities, and IRBs/IECs .............................................................................. 78 
13 
STATISTICAL CONSIDERATIONS ............................................. 81 
13.1 
Sample Size, Power, and Significance Levels .................................................. 81 
13.2 
Interim Analysis ................................................................................................ 81 
13.3 
Analysis Sets ..................................................................................................... 81 
13.3.1 
Protocol Deviations ........................................................................................ 81 
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13.4 
General Considerations ..................................................................................... 81 
13.5 
Accountability and Background Characteristics ............................................... 82 
13.5.1 
Enrollment and Disposition ............................................................................ 82 
13.5.2 
Baseline and Demographic Characteristics .................................................... 82 
13.5.3 
Concomitant Medication ................................................................................ 82 
13.6 
Endpoints and Statistical Methods .................................................................... 82 
13.6.1 
Evaluable Period ............................................................................................ 82 
13.6.2 
Primary Safety Endpoints ............................................................................... 82 
13.6.2.1 
Treatment Compliance and Extent of Treatment Exposure ....................... 83 
13.6.2.2 
Adverse Events ........................................................................................... 83 
13.6.2.3 
Vital Signs, 12-Lead Electrocardiogram, Physical Examination, and 
Other Safety Data ....................................................................................... 83 
13.6.2.4 
Clinical Laboratory Data ............................................................................ 84 
13.6.2.5 
Menstruation ............................................................................................... 84 
13.6.2.5.1 
Suicidality ............................................................................................... 84 
13.6.3 
Secondary Endpoint(s) ................................................................................... 84 
13.6.4 
Exploratory Endpoint(s) ................................................................................. 85 
13.6.5 
Handling of Missing Data .............................................................................. 85 
14 
SAFETY MONITORING COMMITTEE ....................................... 86 
15 
REGULATORY AND ETHICAL OBLIGATIONS ...................... 87 
15.1 
Declaration of Helsinki ..................................................................................... 87 
15.2 
Informed Consent/Assent.................................................................................. 87 
15.3 
Institutional Review Board/Independent Ethics Committee............................. 88 
15.4 
Pretrial Documentation Requirements .............................................................. 88 
15.5 
Patient Confidentiality ...................................................................................... 89 
16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................... 91 
16.1 
Protocol Amendments and End of Trial or Termination .................................. 91 
16.2 
Trial Documentation and Storage ..................................................................... 91 
16.3 
Trial Monitoring and Data Collection............................................................... 92 
16.4 
Quality Assurance ............................................................................................. 93 
16.5 
Compensation ................................................................................................... 93 
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16.6 
Publication Policy ............................................................................................. 94 
16.7 
Intellectual Property Rights .............................................................................. 94 
16.8 
Confidential Information .................................................................................. 95 
17 
REFERENCES ................................................................................... 96 
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List of Appendices 
Appendix 1 
Schedule of Assessments ................................................. 102 
Appendix 2 
Trial Personnel ................................................................. 105 
Appendix 2.1 
Investigator Details ............................................................................... 105 
Appendix 2.2 
Sponsor Contact Details ........................................................................ 105 
 
 
 
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Clinical Protocol Template (Phase 2–4) 
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List of In-text Tables 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution ................................. 38 
Table 9.2.9-1 
Biochemistry, Hematology, and Urinalysis................................... 62 
 
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List of In-text Figures 
Figure 1-1 
Trial Design and Treatment Schematic ......................................... 12 
 
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Clinical Protocol Template (Phase 2–4) 
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List of Abbreviations 
Abbreviation or 
special term 
Definition or Explanation 
AE 
Adverse event 
AED 
Antiepileptic drug 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BAC 
Blood alcohol content 
BDNF 
Brain-derived neurotrophic factor 
BDS 
Botanical drug substance 
b.i.d. 
Twice daily 
CB 
Cannabinoid 
CB1 
Cannabinoid receptor type 1 
CB2 
Cannabinoid receptor type 2 
CBD 
Cannabidiol 
CBD-OS 
Cannabidiol oral solution 
CGI 
Clinical global impressions 
CGI-I 
Clinical Global Impressions - Improvement 
CGI-S 
Clinical Global Impressions - Severity 
CHQ-PF50 
Child Health Questionnaire Parent Form 50 
CIOMS 
Council for International Organizations of Medical Sciences 
CRO 
Contract research organization 
CSHQ 
Children’s Sleep Habits Questionnaire 
CYP 
Cytochrome P450 
DS 
Dravet Syndrome 
ECG 
12-lead electrocardiogram 
eCRF 
Electronic case report form 
EU 
European Union 
FDA 
Food and Drug Administration 
G 
Gastrostomy  
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Abbreviation or 
special term 
Definition or Explanation 
GABA 
γ-aminobutryic acid 
GPR55 
G-protein-coupled receptor 55 
GCP 
Good Clinical Practice 
GW 
GW Research Ltd 
i.p. 
Intraperitoneal 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like growth factor-1 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
i.v. 
Intravenous 
KO 
Knock out 
LGS 
Lennox-Gastaut Syndrome 
MBA-9 
9-items Motor Behavioral Assessment 
MCS 
mental health composite score 
MeCP2 
Methyl-CpG-binding protein 2 
NCU 
Intensive Care Unit 
NG 
Nasogastric  
NOEL 
No observed effect level 
OLE 
Open-label extension 
PCP 
Phencyclidine 
PCS 
physical health composite score 
PhS 
Standardized Physical Summary 
PI 
Principal investigator 
PRN 
Packaging reference number 
PsS 
Standardized Psychosocial Summary 
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Abbreviation or 
special term 
Definition or Explanation 
PVD 
Pharmacovigilance Department 
QoL 
Quality of life 
RCT 
Randomized controlled trial 
RSBQ 
Rett Syndrome Behaviour Questionnaire  
RTSM 
Randomization and Trial Supply Management 
RTT 
Rett syndrome 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-36 
36-item Short Form 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
THC 
Δ9-tetrahydrocannabinol 
UGT 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
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Definition of Terms 
Term 
Definition 
Caregiver 
An assigned patient’s parent or designated care 
provider. 
Day 1 
The day a patient first receives the investigational 
medicinal product in this trial. 
End of treatment 
Completion of the treatment period 
(Visit 14 [Day 729]), or withdrawal. 
End of trial 
Last patient’s last visit/telephone call. 
Enrolled patient 
Any patient whose parent(s)/legal representative has 
provided written informed consent for the patient to 
take part in the trial and, if possessing adequate 
understanding to do so, who has provided informed 
assent.  
International normalized ratio 
A calculation made to standardize prothrombin time. 
Investigational medicinal 
product 
The term used to describe both investigational active 
product and reference therapy (placebo). 
Investigator 
Trial principal investigator or a formally delegated 
study physician. 
Methyl-CpG-binding protein 2 
Methyl-CpG-binding protein 2 is denoted differently in 
this document: the italicized abbreviation MECP2 
denotes the human gene, the italicized Mecp2 denotes 
the mouse gene, and the nonitalicized abbreviation 
MeCP2 denotes the protein. 
Postregression 
≥ 6 months since the last loss of hand use or verbal 
language or gross motor regression. 
 
 
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2 
OBJECTIVES 
2.1 
Primary 
Key objective: 
• To evaluate the long-term safety of GWP42003-P in patients with Rett syndrome 
(RTT) 
2.2 
Secondary 
Secondary objectives: 
• To evaluate the effect of GWP42003-P in measures of disease severity 
• Rett Syndrome Behaviour Questionnaire (RSBQ)  
• Clinical Global Impressions - Improvement (CGI-I)  
• Clinical Global Impressions - Severity (CGI-S) 
• 9-items Motor Behavioral Assessment (MBA-9) 
• Children’s Sleep Habits Questionnaire (CSHQ) 
Exploratory objectives: 
• To evaluate the effect of GWP42003-P on caregiver and patient quality of life 
(QoL) 
• 36-item Short Form [SF-36] and Child Health Questionnaire Parent Form 
50 [CHQ-PF50], respectively 
• To evaluate the effect of GWP42003-P on health utilization 
• Hospital Services Use Questionnaire 
• Caregiver Assessment of Rett Symptoms 
 
 
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3 
BACKGROUND AND RATIONALE 
3.1 
Disease 
Rett syndrome is a rare, noninherited, X-linked neurodevelopmental disorder affecting 
approximately 1 in 10,000 live female births, resulting in abnormal neuronal 
development and function.1,2  Rett syndrome is one of the leading causes of intellectual 
disability in young girls and is only rarely seen in males.  Development of RTT is 
progressive, with early onset at 6 to 18 months characterized by a subtle slowing or 
regression of development.  Infants/young children aged 1 to 4 years progress to a rapid 
destructive phase characterized by loss of purposeful hand skills with stereotypic hand 
movements, loss of spoken language, breathing irregularities such as apnea and 
hyperventilation, cardiac irregularities, microcephaly, and autistic-like behaviors such as 
social withdrawal.  After a period of regression, the disorder enters a plateau phase 
associated with apraxia, motor problems, and seizures.  Over time, motor function 
continues to deteriorate, resulting in reduced mobility, scoliosis, rigidity, muscular 
weakness, and spasticity.3,4,5  
Rett syndrome is most commonly caused by heterozygous de novo mutations in the gene 
encoding methyl-CpG-binding protein 2 (MeCP2).6  Methyl-CpG-binding protein 2 is 
widely expressed in many tissues, with the highest expression in the brain7; MeCP2 is 
essential for nerve cell function, acting as a complex transcriptional modulator of genes 
involved in neuronal development, synaptic transmission, and plasticity, including brain-
derived neurotrophic factor (BDNF).8  However, mutations in MECP2 are not 
synonymous with RTT.  Between 3% and 5% of individuals who strictly meet clinical 
criteria for RTT do not have an identified mutation in MECP2, and only 50% to 70% of 
patients with atypical RTT have an identified mutation in MECP2.9  Moreover, 
cyclin-dependent kinase-like (CDKL5) and Forkhead box protein G1 (FOXG1) gene 
mutations are associated with 2 other variant forms of RTT.  Given that MECP2 
mutations are neither necessary nor sufficient to make the diagnosis of RTT, diagnostic 
criteria are often utilized9 at initial diagnosis. 
A number of genetic mouse models of RTT are available, where the deficiency of 
MeCP2, globally or specifically in developing neurons, produces similar clinical features 
to those in humans, including tremors, motor impairments, and stereotypical 
motions.10,11,12  Genetic and pharmacological intervention can ameliorate or reverse 
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behavioral deficits in Mecp2 knockout (KO) mice, suggesting that there is significant 
potential for pharmacological interventions to treat RTT.13 
Aberrant synaptic plasticity and an imbalance of excitatory and inhibitory neuronal 
networks is thought to underlie the neurological phenotype in RTT.14  Besides these 
neuronal deficits in RTT, there is evidence that neuroinflammation and glial cells may 
play a role.  Selective restoration of MeCP2 in astrocytes significantly improved 
locomotion and anxiety levels, restored respiratory functions, and greatly prolonged 
lifespan in mice, with modified astrocytes compared with control Mecp2 KO mice.  
Restoration of MeCP2 in astrocytes also returned dendritic morphology to normal.15  
Microglia from Mecp2 KO mice demonstrate enhanced release of glutamate, which is 
associated with neuronal toxicity, and also show impaired phagocytosis.16  There is also 
increasing evidence that the immune system and inflammation may be involved in 
several neurodevelopmental disorders, including RTT.17  In addition, symptoms such as 
hyperventilation and apnea can be indicative of mitochondrial dysfunction, and before the 
advent of genetic testing, RTT was proposed to be a metabolic disorder.  Changes in the 
morphology of mitochondria and genes associated with these structures as well as redox 
balance have been demonstrated in patients with RTT, but it is not clear whether some of 
these changes are a primary cause or secondary to these mechanisms.18  Finally, mouse 
models have highlighted a potential role of the growth factors, BDNF and insulin-like 
growth factor 1 (IGF-1) in the pathology of RTT19 an involvement that is corroborated by 
efficacy in clinical trials targeting these agents.20 
There is currently no curative therapy for RTT, and therefore, there is a critical need for 
treatments.21  Medical management of RTT is essentially symptomatic and supportive.  
Current options for patients focus on managing the associated conditions and include the 
use of medications to control breathing problems, heart rhythm abnormalities, seizures, 
constipation, gastroesophageal reflux disease, and sleep disturbances.22  Other therapy 
options include physiotherapy, occupational therapy, speech therapy, and feeding 
assistance (feeding tubes or other feeding aids).21 
3.2 
Investigational Medicinal Product Background 
The investigational medicinal product (IMP), GWP42003-P, is formulated from extracts 
prepared from Cannabis sativa L. plants that have a defined chemical profile and contain 
consistent levels of cannabidiol (CBD) as the principal phytocannabinoid.  Extracts from 
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these plants are processed to yield purified (≥ 98%) CBD that typically contains 
< 0.1% (weight by weight) Δ9-tetrahydrocannabinol (THC) (for oral formulations).  The 
purified CBD is subsequently dissolved in excipients with added sweetener and flavoring. 
Cannabidiol possesses very low affinity and lacks appreciable functional activity at 
cannabinoid (CB) receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor 
type 2 (CB2).23  In addition, CBD does not significantly interact with enzymes 
responsible for the synthesis and degradation of endocannabinoids at clinically relevant 
concentrations.24,25,26,27  Furthermore, considerable data describing the 
polypharmacology of CBD and its modulation of nonendocannabinoid system targets 
exist.  Indeed, CBD has the ability to interact with multiple 7-transmembrane receptor 
systems, ion channels, transporters, and enzymes.28,29 
At least 2 mechanisms of anticonvulsant action are proposed for CBD.  The first is 
modulation of intracellular Ca2+ mobilization via antagonism of the G protein-coupled 
receptor 55 (GPR55) and/or activation (and subsequent desensitization) of transient 
receptor potential (TRP) channels, particularly transient receptor potential cation channel 
subfamily V member 1 (TRPV1).30,31,32  The second is inhibition of adenosine 
reuptake.33,34,35 
Based on the lack of pharmacological engagement by CBD at therapeutically relevant 
concentrations, modulation of the following targets is considered not relevant to the 
anticonvulsant mechanism of action: CB1 and CB2 receptors, fatty acid amide hydrolase, 
voltage-gated sodium channels, benzodiazepine, and γ-aminobutryic acid (GABA) 
binding sites of the GABAA receptor. 
Importantly, CBD does not produce THC-like euphoric effects.  Furthermore, CBD 
demonstrates anticonvulsant, antipsychotic, anxiolytic, neuroprotective, antioxidant, and 
anti-inflammatory activity in a range of nonclinical models and has received Food and 
Drug Administration (FDA) approval for the treatment of seizures associated with the 
Lennox-Gastaut syndrome or the Dravet syndrome in patients 2 years of age and older.36   
3.2.1 
Nonclinical Studies 
3.2.1.1 
Efficacy Pharmacology 
In a subchronic phencyclidine (PCP) model in rats where there is disruption of cognition 
and deficits in social behavior, CBD reversed the PCP-induced recognition memory 
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deficit at doses of 2, 20, and 100 mg/kg intraperitoneal (i.p.)37 and significantly reduced 
the subchronic PCP-induced increase in avoidance behavior at 2, 10, 20, and 100 mg/kg 
i.p.38  In addition, CBD improved cognitive deficits in other nonclinical models, 
including Fmr1 KO mice, a model of Fragile X syndrome, at 100 and 200 mg/kg i.p. and 
improved bicuculline-induced memory impairments in neonatal rats at 100 mg/kg i.p.39  
Cannabidiol also improved hypoxic ischemia in rats (1 mg/kg subcutaneous)40 and 
piglets (1 mg/kg i.v.)41 when CBD was given post hypoxia-ischemia injury.   
Cellular mechanisms that are thought to be involved in the neurobehavioral deficits 
present in RTT include aberrant synaptic plasticity14, neuroinflammation15,16 and 
immune17 and metabolic malfunction.18,42  A number of studies demonstrate that CBD 
may have the potential to modulate each of these basic pathophysiological mechanisms43 
albeit not in RTT models.  For example, CBD has the potential to modulate 
excitatory/inhibitory imbalance, as demonstrated by its anticonvulsant 
activity.44,45,46,47,48  Cannabidiol also shows anti-inflammatory and antioxidant actions in 
a number of accepted animal models of inflammation, notably of the gut and the joints, 
where it inhibits the tissue production of chemical mediators of inflammation, such as 
tumor necrosis factor alpha and interleukin-2.49  Cannabidiol (1 mg/kg i.v.) also reverses 
hypoxic ischemia-induced neuroinflammation, reactive oxygen species production, and 
excitatory and metabolic derangement in rats40 and piglets41 after a hypoxic ischemic 
insult.   
Loss of language and ability to communicate is also a feature of RTT.4  In a songbird 
model of vocal learning, damage to a cortical-like premotor region of the zebra finch 
brain results in a temporary disruption of vocal patterns that recovers over about 7 days 
and is dependent on the ability of birds to hear as part of sensorimotor learning.  
Cannabidiol 10 and 100 mg/kg (intramuscular) improved the phonology and syntax of the 
zebra finch song over the first 6 to 9 days post lesion.50 
Finally, there is evidence that cannabidivarin, a cannabinoid structurally similar to CBD 
that shares molecular and behavioral pharmacology, rescued behavioral and brain 
alterations in MeCP2-308 male mice51 a validated RTT model, including improvement of 
general health status, sociability, and brain weight, with partial restoration of motor 
coordination.  
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3.2.1.2 
Safety Pharmacology 
In a rat primary observation Irwin test of central nervous system function, no behavioral, 
physiological, or body temperature changes were observed following administration of 
CBD botanical drug substance (BDS) at 10 to 100 mg/kg.52 
In the cardiovascular system, CBD as CBD BDS inhibited human ether-à-go-go-related 
gene tail current in a concentration-dependent manner52 (no-observed-effect level 
[NOEL], 43 ng/mL) and had no effect on Purkinje fiber action potentials or QT interval 
changes52 (NOEL, 22 ng/ml).  Changes in cardiovascular parameters (heart rate, blood 
pressure, and electrocardiogram [ECG]) in the conscious dog were not considered to be 
adverse.52 
In the respiratory system, CBD as CBD BDS had no biologically significant effect on 
respiratory parameters in conscious rats.52 
3.2.1.3 
Mechanism of Action 
Cannabidiol has micromolar affinity/potency at several molecular targets, whose 
relevance to RTT is unclear.  How CBD interacts with signaling pathways and cellular 
processes modulated by MeCP2 that are important in RTT is a matter of active 
investigation and is yet to be fully elucidated.   
3.2.2 
Clinical Studies 
Human efficacy data from 3 positive Phase 3 trials in patients (predominantly pediatric 
patients) with treatment-resistant epilepsies support a role for GWP42003-P as a 
treatment for central nervous system disorders.  Overall, GWP42003-P was generally 
well tolerated at doses up to 20 mg/kg/day; adverse events (AEs) were usually mild to 
moderate in severity and transient.  Elevated liver enzymes (particularly transaminases 
alanine aminotransferase [ALT] and aspartate aminotransferase [AST], and less 
commonly reported terms of abnormal liver function tests and hepatotoxicity) have been 
reported in some patients receiving GWP42003-P for severe, refractory epilepsies, 
notably in patients taking concomitant valproic acid.  None of the cases fulfilled the Hy’s 
Law criteria for potential severe liver injury.  There were no cases with a concomitant 
increase in bilirubin > 2 × upper limit of normal (ULN).  Monitoring of the blood levels 
of enzymes that are markers of liver function is advised, particularly at the start of 
treatment and with dose increases of GWP42003-P, as well as at the time of initiation or 
dose increase of concomitant medication. 
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3.3 
Rationale 
A number of studies across a range of nonclinical behavioral paradigms, as discussed 
above, suggest that CBD has the potential to treat some of the core symptoms of RTT, 
such as cognition, language, social behavior, and motor function (see Section 3.2.1.1).  
Indeed, there are suggestions from clinical studies that, in addition to treating seizures, 
CBD may have beneficial effects on cognition and behavior as well as on patient 
QOL.53,54   
This open-label extension (OLE) trial will evaluate the long-term safety of GWP42003-P 
in patients with RTT who carry a MECP2 gene mutation. 
3.3.1 
Choice of Endpoints 
Overall, the range of assessments cover the key symptom domains: behavior and 
emotion, motor function, breathing abnormalities, and sleep.   
3.3.1.1 
Choice of Primary Endpoints 
Safety, selected as the primary endpoint, will be assessed by evaluating changes in AEs, 
clinical laboratory parameters, vital signs, physical examination procedures, 12-lead 
ECGs, effects on menstruation cycles, and suicidality.  Change in growth and 
development will also be measured by height, weight, serum IGF-1 levels, and Tanner 
Staging (for patients aged ≥ 7 years or earlier, if clinically indicated by the onset of 
menarche or other signs of precocious puberty).   
3.3.1.2 
Choice of Secondary Endpoints 
Secondary endpoints, scales, and assessments were selected to evaluate a wide range of 
symptoms observed in patients with RTT: 
• RSBQ.  This caregiver-completed assessment has been specifically developed for 
use in patients with RTT.55  The RSBQ total score is used as a global measure to 
assess the patient’s overall condition, whereas subscales of the RSBQ allow 
evaluation of more-specific domains (behavior and emotion, motor function, and 
breathing abnormalities).   
• CGI-I and CGI-S.  CGI-I was selected as a clinician-rated assessment that has 
been used extensively in neuropsychiatric disorders in both clinical practice and 
clinical trial settings56,57,58 and reported to have successfully been implemented in 
the RTT patient population.59  CGI-I is a global measure used to assess the 
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patient’s overall condition.  CGI-I assesses change in symptoms relative to the 
baseline CGI-S. 
• MBA-9.  This scale was selected as it provides a clinician assessment of a set of 
motor and behavior items of the original MBA60,61 that are deemed amenable to 
change. 
• CSHQ.  This questionnaire was selected as sleep problems are reported for the 
majority of patients with RTT.  CSHQ has been used to characterize sleep in other 
developmental disability populations (e.g., autism spectrum disorder62) and in a 
sample of patients with RTT.63  
3.3.1.3 
Choice of Exploratory Endpoints 
The required constant care and supervision of patients with RTT places a significant 
burden on the parent(s)/caregiver; as such, effects on caregiver QoL will be assessed as 
an exploratory endpoint using the SF-36 questionnaire.  In addition, caregiver-reported 
patient QoL will be assessed using CHQ-PF50.  Information on health utilization will be 
assessed using the Hospital Services Use Questionnaire, which aims to analyze the 
frequency of patient hospitalizations and hospital visits.   
The Caregiver Assessment of Rett Symptoms has been specifically developed for the 
proposed clinical trial with the intent of obtaining data on the patient’s condition and 
aims to provide additional information on selected key areas of interest: breathing, hand 
stereotypies, interactions, problem behaviors, sleep, constipation, seizures, and global 
function.   
3.3.2 
Choice of Dosing Regimen 
Given that the objective of the trial is to monitor long-term safety, a flexible dose 
escalation based on efficacy and tolerability, as judged by the investigator, will be used.  
The maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.) is set in accordance with the 
maximum dose per the United States (US) prescribing information for CBD.64  
The GWP42003-P solution contains 7.9% w/v anhydrous ethanol, which is required as 
sucralose is not soluble in sesame oil.  A dose of 15 mg/kg/day (administered as 
7.5 mg/kg twice daily [b.i.d.]) in a 10 kg child will result in a blood alcohol content 
(BAC) of 0.0098 g/L, which equates to an ethanol ingestion of 5.93 mg/kg.  Both these 
amounts are well under the threshold for a BAC of 0.125 g/L and an ethanol ingestion of 
75 mg/kg for patients 6 years and older and also under the maximum BAC level of 
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0.01 g/L and ethanol ingestion of 6 mg/kg for children less than <6 years old.65  At the 
highest recommended therapeutic dose of 20 mg/kg/day (administered as 10 mg/kg 
b.i.d.), a single dose of 10 mg/kg cannabidiol oral solution (CBD-OS) in a 10 kg child 
theoretically results in a BAC of 0.013 g/L and an ethanol ingestion of 7.9 mg/kg, slightly 
above the recommended threshold for BAC of 0.01 g/L for children less than 6 years old.  
In light of the wide safety margins observed in toxicology studies and taking the severity 
of the condition into account, this theoretical risk is judged to be acceptable.  
Please refer to the investigator’s brochure (IB) and Development Core Safety Information 
for the most current safety data. 
3.3.3 
Benefit-risk Analysis  
There are no approved medications for RTT, neither disease modifying nor for 
symptomatic therapy.  Nonclinical and clinical data indicate that CBD-OS may benefit 
patients with RTT (see Section 3.2.1.1, Section 3.2.2, and Section 3.3). 
The key risks identified from the CBD-OS clinical development program for 
Lennox-Gestaut Syndrome (LGS) and Dravet Syndrome (DS) (described in 
Section 3.2.2) are broadly expected to be the same for the RTT population - as the patient 
demographics and comorbidities have a significant amount of overlap.  Importantly, the 
risk of raised transaminases is reduced in the context of this RTT trial where lower doses 
of CBD-OS are planned and valproic acid use is expected to be lower in this population.   
In the context of the anticipated benefit of CBD-OS in RTT patients, the key risks 
identified from the CBD-OS clinical development program in LGS and DS are acceptable 
given the proposed dose level (maximum dose of 20 mg/kg/day)  and the age range of 2–
18 years.  Thus, the overall benefit-risk for the development of CBD-OS in the RTT 
population is favorable. 
3.4 
Clinical Hypothesis 
There will be no formal hypothesis testing in this trial. 
 
 
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4 
EXPERIMENTAL PLAN 
4.1 
Trial Design 
This is a multicenter, OLE trial for patients with RTT who have completed the 
randomized, double blind, placebo-controlled trial (GWND18064). 
Entry to this OLE trial is recommended to be on the same day as Visit 9 of the 
randomized controlled trial (RCT), GWND18064; however, patients may enter the OLE 
up to the RCT follow-up visit (Visit 11). 
All patients entering this OLE trial will begin dosing with 5 mg/kg/day GWP42003-P 
(2.5 mg/kg b.i.d.) on Day 1.  Patients will be observed, and after 1 week, the dose may 
further be escalated, at the investigator’s discretion, up to 15 mg/kg/day GWP42003-P 
(7.5 mg/kg b.i.d.) in weekly increments of 5 mg/kg/day (2.5 mg/kg b.i.d.).   
Patients should then remain on a stable dose of GWP42003-P for the duration of the 
maintenance period of the trial (up to 104 weeks), with the option for doses to be 
decreased or increased to a maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.) based on 
clinical response and tolerability, as deemed necessary by the investigator, until the 
optimal dose is found.  Patients whose dose has been decreased can have their dose 
increased again if tolerability improves.   
At the end of treatment (Visit 14 [Day 729]), the dose of GWP42003-P will be reduced 
over a 10-day taper period, and patients will enter the 4-week follow-up period.   
If a patient permanently discontinues treatment at any point during the trial, 
GWP42003-P should be gradually reduced over 10 days (unless inadvisable due to an 
AE).  The patient should attend a withdrawal visit (Visit 14) as soon as possible after the 
decision is made to permanently discontinue GWP42003-P.  If applicable, the patient will 
taper GWP42003-P, attend the End of Taper visit (Visit 15), and then complete the 
4-week follow-up period.   
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. 
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4.1.1 
Primary Endpoint 
Safety: 
The long-term safety profile of GWP42003-P will be assessed by evaluating changes in 
the following, relative to the prerandomization baseline of the RCT: 
• AEs 
• Clinical laboratory parameters 
• Vital signs 
• Physical examination procedures 
• 12-lead ECG 
• Effects on menstruation cycles 
• Suicidality 
• Change in growth and development by measurement of height, weight, IGF-1 
levels, and Tanner Staging (for patients aged ≥ 7 years or earlier, if clinically 
indicated by the onset of menarche or other signs of precocious puberty) 
4.1.2 
Secondary Endpoints 
4.1.2.1 
Secondary endpoints: 
The following will be assessed by evaluating changes relative to the prerandomization 
baseline of the RCT: 
• RSBQ 
• CGI-I 
• CGI-S 
• MBA-9 
• CSHQ 
4.1.2.2 
Exploratory endpoints: 
The following will be assessed by evaluating changes relative to the prerandomization 
baseline of the RCT: 
• SF-36 
• CHQ-PF50 
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• Hospital Services Use Questionnaire 
• Caregiver Assessment of Rett Symptoms 
4.2 
Number of Trial Centers 
Approximately 25 trial centers are expected to participate in this trial.  The number of 
centers may be reduced or increased depending on recruitment performance. 
4.3 
Number of Patients 
All patients with RTT who complete the randomized, double-blind, placebo-controlled 
trial (GWND18064) who wish to take GWP42003-P and meet the eligibility criteria will 
transition to 5 mg/kg/day GWP42003-P (2.5 mg/kg b.i.d.) on Day 1 of the OLE.  
Approximately 252 patients will be enrolled.  
 
 
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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
Please refer to the separate pharmacy manual for more detailed information on 
GWP42003-P. 
5.1 
GWP42003-P Oral Solution 
The GWP42003-P oral solution is presented as a solution containing 100 mg/mL CBD 
dissolved in the excipients sesame oil and anhydrous ethanol (10% v/v), sweetener 
(sucralose), and strawberry flavoring (Table 5.1-1). 
Table 5.1-1 
Formulation of GWP42003-P Oral Solution 
Ingredients 
Quantity 
CBD 
100 mg/mL 
Anhydrous ethanol 
79 mg/mL 
Sucralose 
0.5 mg/mL 
Strawberry flavor 
0.2 mg/mL 
Refined sesame oil 
Makes up to 1 mL 
5.2 
Packaging, Storage, and Drug Accountability 
5.2.1 
Packaging and Labeling  
GWP42003-P will be manufactured, packaged, labeled, and/or distributed by GW or 
delegated contractors.  GWP42003-P will be presented in 100 mL amber glass bottles 
with child-resistant screw caps and packed in cartons.  GWP42003-P will be dispensed at 
each relevant visit.  A unique identification number will be used to identify each carton 
and the GWP42003-P it contains.  The unique identification number together with the 
packaging reference number (PRN) will permit full traceability of manufacture, pack, and 
label activities conducted at or on behalf of GW and the IMP information held on the 
Randomization and Trial Supply Management (RTSM) system.  GW will ensure that all 
GWP42003-P 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., “GWP42003-P”) 
• Dose and/or potency (e.g., “100 mg/mL GWP42003-P”) 
• Trial code number 
• Expiry date 
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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 caregiver.  Caregivers will be instructed to retain and carry this 
information with the patient at all times. 
5.2.2 
Storage 
GWP42003-P must be stored upright at room temperature (< 30°C) and must not be 
refrigerated or frozen.  It must also be kept away from heat and direct sunlight. 
GWP42003-P must be stored in compliance with the local regulations for a controlled 
drug (if applicable to country).  The sponsor must approve the storage location and 
facilities.  Temperature records of the clinical center storage location must be maintained 
(recording a minimum of Monday to Friday, excluding public holidays) from the date of 
receipt of the first shipment until the end-of-trial dispensing period at each center.  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 the transit of GWP42003-P to the center 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 GWP42003-P remains suitable for 
use.  GWP42003-P must be placed under quarantine until written confirmation is 
received that GWP42003-P is suitable for use. 
Caregivers will be provided with instructions regarding home storage requirements for 
GWP42003-P. 
5.2.3 
Supply and Return of Investigational Medicinal Product 
At trial initiation and as needed thereafter, GWP42003-P will be shipped to the identified 
responsible person, such as the pharmacist, at the investigator’s center, who will check 
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the amount received against the shipment request and the condition of the drug 
(i.e., integrity, physical appearance, and temperature during transit).  Details of 
GWP42003-P received will be recorded in the GWP42003-P accountability record (see 
Section 5.2.4).  The center will acknowledge the GWP42003-P receipt and will complete 
any receipt forms required.  GWP42003-P will be dispensed and returned as detailed in 
Section 8.4.  As directed, all supplies, including unused, partially used, or empty 
containers, will be returned to the GW/depot or destroyed at a GW-approved center if 
agreed in writing by the trial monitor. 
5.2.4 
Investigational Medicinal Product Accountability 
The investigator has overall responsibility for the accountability of all used and unused 
GWP42003-P.  A drug accountability record for GWP42003-P must be kept current and 
should contain the following: 
• Trial code 
• PRN, treatment number, date of receipt, and quantity of GWP42003-P received 
• Patient’s trial identification and/or treatment number 
• Date and quantity of GWP42003-P dispensed 
• The initials of the dispensing/dosing party 
• Date and quantity of GWP42003-P returned to the investigator 
• GWP42003-P expiry dates 
GWP42003-P will be dispensed at visits as per the Schedule of Assessments in 
Appendix 1.  Caregivers will be asked to return all GWP42003-P (used and unused) at 
each relevant visit.  The center will check the returned GWP42003-P against the expected 
usage.  Any discrepancies will be discussed with the caregiver at the time of the visit and 
documented accordingly within the patient’s source documents.   
The investigator must inform GW promptly of all missing or unaccountable 
GWP42003-P. 
A record of returned GWP42003-P must be completed and included in the shipment of 
used and unused GWP42003-P to the relevant drug distribution depot.  At the end of the 
trial, a record/statement of reconciliation must be completed and provided to GW. 
These inventories must be made available for inspection by an authorized GW 
representative and local officials or regulatory agency inspectors. 
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Please refer to the separate pharmacy manual for more detailed information on 
GWP42003-P. 
5.2.5 
Post-trial Provision 
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 European Union (EU) law. 
 
 
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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, 
and sex, as allowed per local regulations) and outcome of screening. 
6.1 
Inclusion Criteria 
For inclusion in the trial patients must fulfil all of the following criteria: 
6.1.1 Patient has completed all scheduled visits of the treatment phase of the RCT, 
GWND18064, and has transitioned to OLE by the point of RCT follow-up 
(Visit 11). 
6.1.2 Patient (if possessing adequate understanding, in the investigator’s opinion) 
and/or the patient’s parent(s)/legal representative is willing and able to give 
informed consent/assent for participation in the trial. 
6.1.3 Patient and/or the patient’s caregiver are willing and able (in the investigator’s 
opinion) to comply with all trial requirements (including the completion of all 
caregiver assessments by the same caregiver throughout the trial). 
6.1.4 Patient must have the ability to swallow the IMP provided as a liquid solution 
or the ability for the IMP to be delivered via gastrostomy (G) or nasogastric 
(NG) feeding tube (only G- or NG-tubes made from polyurethane or silicon 
are allowed). 
6.1.5 Patient and/or parent(s)/legal representative is willing to allow the responsible 
authorities to be notified of participation in the trial, if mandated by local law. 
6.1.6 Patient and/or parent(s)/legal representative is willing to allow the patient’s 
primary care practitioner (if the patient has one) and consultant (if the patient 
has one) to be notified of participation in the trial if the primary care 
practitioner/consultant is different from the investigator. 
6.2 
Exclusion Criteria  
If the RCT ‘End of Treatment’/‘End of Taper Period’ visit assessments or Visit 1 
reassessments (as applicable) raise any safety concerns, the investigator should consider 
whether it will be appropriate for the patient to continue to participate in the OLE trial or 
if the patient should be withdrawn.  The patient may not enter the trial if ANY of the 
following apply: 
6.2.1 Patient meets the withdrawal criteria (including clinically significant abnormal 
laboratory values) in the investigator’s opinion (refer to Section 10).   
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6.2.2 Patient met during the RCT the criteria for permanent IMP discontinuation 
(unless in case of an AE, if AE was not considered related with the IMP; 
patients that met ALT/AST elevations discontinuation criteria must be 
excluded). 
6.2.3 Female patient is of childbearing potential, unless willing to ensure that they 
or their partner use a highly effective method of birth control (e.g., combined 
[estrogen and progestogen containing] hormonal contraceptiona associated 
with inhibition of ovulation [oral, intravaginal or transdermal], 
progestogen-only hormonal contraceptiona associated with inhibition of 
ovulation [oral, injectable or implantableb] intrauterine devices/hormone-
releasing systemsb, bilateral tubal occlusionb, vasectomized partnerb,c, sexual 
abstinenced during the trial and for 3 months after the last dose. 
6.2.4 Patient has been previously enrolled and dosed in this trial. 
6.2.5 Patient is unwilling to abstain from donation of blood during the trial. 
6.2.6 Male participants who are fertile (i.e., after puberty unless permanently sterile 
by bilateral orchidectomy) and with a partner of childbearing potential unless 
agree to ensure that they use male contraception (e.g., condom) or remain 
sexually abstinentd during the trial and for 3 months after the last dose.  
 
 
 
a The effect of GWP42003-P on oral contraceptives has not been investigated.  GWP42003-P is 
not an inducer of CYP3A4 and therefore is not expected to alter the PK of hormonal 
contraceptives. 
b Contraception methods that are considered to have low user dependency 
c Provided that partner is the sole sexual partner of the trial patient of childbearing potential and 
that the vasectomized partner has received medical assessment of the surgical success. 
d Only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the trial treatments.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. 
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7 
PATIENT ENROLLMENT 
Before patients may be entered into the trial, GW requires a copy of the relevant center’s 
institutional review board (IRB) or independent ethics committee (IEC) written approval 
of the protocol, informed consent/assent forms, and other patient information material.  
Patients will be considered enrolled in the trial from the time of providing written 
informed consent/assent.  All parent(s)/legal representatives must personally sign and 
date the consent forms prior to any procedures being performed (refer to Section 9.2.1 
and Section 15.2).  The nominated caregiver will be asked to consent to complete the 
QoL questionnaires.  If the patient possesses adequate understanding, assent will also be 
taken along with parent(s)/legal representative consent (refer to Section 9.2.1 and 
Section 15.2).  Due to the degree of cognitive impairment in patients with RTT, patients 
18 years of age or older will not be required to provide consent and will only be required 
to provide assent in cases where the patient possesses adequate understanding, along with 
parent(s)/legal representative consent. 
7.1 
Treatment Assignment 
As this is a single-group OLE trial, all patients will receive GWP42003-P.  Patients will 
not be informed of their allocated treatment group in the RCT.  Patients will retain the 
patient number allocated to them during the RCT. 
7.2 
Randomization 
This is an OLE of the GWND18064 trial.  Randomization will not occur.  At the start of 
the GWND18064 trial, enrolled patients were allocated a unique patient number.  Patients 
will retain this number during the OLE trial.  
 
 
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8 
TREATMENT PROCEDURES 
8.1 
Investigational Medicinal Product Dosage, Administration, and 
Schedule 
GWP42003-P will be presented as an oral solution containing 100 mg/mL CBD.  For 
details regarding IMP formulations, see Section 5.  
Before the patient undergoes any assessments or observations, the patient’s 
parent(s)/legal representative is required to give written informed consent or assent (see 
Section 9.2.1 and Section 15.2).  The nominated caregiver will be asked to consent to 
complete the QoL questionnaires.   
8.1.1 
Dose Administration 
GWP42003-P will be administered orally (swallowed) b.i.d. (morning and evening) using 
the syringe(s) provided.  GWP42003-P may be taken with other concomitant 
medications, as directed by the investigator.  In patients with G- or NG-tubes but where 
oral dosing of GWP42003-P is possible, oral dosing is preferable.  Only in patients where 
oral dosing is not possible should GWP42003-P be administered via G- or NG-tubes 
made from polyurethane or silicon only.  GWP42003-P should be preferentially taken 
with food, i.e., within 30 minutes after the end of a meal and in line with the patients’ 
normal feeding schedule and dietary habits.  The time of GWP42003-P administration in 
relation to food should be kept consistent throughout the trial The investigator should 
contact the medical monitor to review IMP administration guidelines if administration via 
G-or NG-tubes is planned. 
8.1.2 
Dose Escalation and Dose Adjustments 
The daily volumes of the GWP42003-P solution to be taken will be calculated based on 
the patients’ weight, and the dosing schedule will be provided to the caregiver.  Further 
information on dispensing procedures will be provided in a separate Pharmacy Manual. 
Caregivers will be trained on dose administration during the GWND18064 trial.   
All patients entering this OLE trial will begin dosing with 5 mg/kg/day GWP42003-P 
(2.5 mg/kg b.i.d.) on Day 1.  Patients will be observed, and after 1 week the dose may 
escalate further, at the investigator’s discretion, up to 15 mg/kg/day GWP42003-P 
(7.5 mg/kg b.i.d.) in weekly increments of 5 mg/kg/day (2.5 mg/kg b.i.d.).   
Patients should then remain on a stable dose of GWP42003-P for the duration of the 
maintenance period of the trial (up to 104 weeks), with the option for doses to be 
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decreased or increased if deemed necessary by the investigator, to a maximum dose of 
20 mg/kg/day (10 mg/kg b.i.d.).   
If an unacceptable AE develops at any time during the dose escalation period(s), dosing 
should initially be suspended or amended, at the investigator’s discretion, until the event 
has resolved.  Patients who have escalated above 5 mg/kg/day should return to the 
previous dose level tolerated in steps of 5 mg/kg/day each week, unless a quicker 
reduction is judged to be required for safety reasons.  If a patient cannot tolerate 
5 mg/kg/day, doses should be reduced to 2.5 mg/kg/day.  If necessary, dosing may be 
temporarily suspended. 
Patients whose dose has been decreased can have their dose increased again if tolerability 
improves.  Patients unable to tolerate the target dose may stay at a lower dose.  However, 
if a patient cannot tolerate a dose of 2.5 mg/kg/day, the patient should be withdrawn from 
treatment, unless a lower dose level is agreed in discussion with the medical monitor and 
can be accurately measured (minimum single-dose volume of 0.1 mL).  Dose adjustments 
should be discussed with the GW medical monitor.  The final decision regarding dose 
adjustments should be taken by the investigator. 
Hepatic function monitoring should be carried out within 1 month following increases in 
GWP42003-P dose or introduction or dose increases of medications that are known to 
impact liver function.  If the concerned change does not occur within 1 month of a 
scheduled biochemistry assessment, the investigator should perform an additional hepatic 
monitoring within 1 month of the change.  
Transaminase elevations should be medically managed by the investigator either by 
reducing the GWP42003-P dose as described above or by reducing concomitant 
medications judged to be causing the elevation (per Section 8.2).  Dose adjustments 
should be discussed with the GW medical monitor.  For potential cases of drug-induced 
liver injury, see Section 12.8. 
At the end of treatment (Visit 14 [Day 729]), the dose of GWP42003-P will be reduced 
over a 10-day taper period, and patients will enter the 4-week follow-up period.  
Patients discontinuing GWP42003-P treatment at any other time should undergo a 10-day 
taper period (unless continued dosing is inadvisable, e.g., due to an AE).  The decision on 
whether to taper GWP42003-P or not will be left to the investigator’s clinical judgment. 
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8.2 
Concomitant Therapy 
It is theoretically possible that GWP42003-P may modify the metabolism of other drugs 
(including antiepileptic drugs [AEDs]) administered concurrently, and there remains the 
possibility of pharmacological interactions between GWP42003-P and other concurrently 
administered drugs.  If there are side-effects suspected of being related to an elevation in 
the concomitant concentration, the investigator should contact the GW medical monitor 
to discuss best management.  Decisions should be based on clinical symptoms and not 
plasma levels of concomitant medications.  The final decision regarding dose adjustments 
should be taken by the investigator.  Cannabidiol has the potential to induce the 
expression of hepatic CYP enzymes (CYP1A2, 2B6 and 3A4) at clinically relevant 
concentrations.  Careful titration of CBD in patients taking concomitant medications 
metabolized by CYP3A4, CYP2C19, or CYP2B6 is advised, with plasma monitoring of 
such medications or their metabolites to be undertaken at the investigator’s discretion.  
Further information on drug interactions can be found in the IB 52.  Any concerns 
regarding potential interactions with concomitant medications can be discussed with the 
trial medical monitor(s). 
Changes in concomitant medications are allowed, but increases in dose of medications 
that affect liver function should be discussed with the medical monitor.  Introduction of 
new medications is allowed, but introduction of new psychotropic and/or central acting 
agents intended as long-term treatment requires prior discussion with the medical 
monitor.  
The use of rescue medication is allowed, when necessary (i.e., AED for transient 
exacerbation of seizures).  Any medication, other than GWP42003-P, taken during the 
trial must be recorded on the electronic case report form (eCRF). 
8.3 
Prohibited Therapy During the Trial Period 
The following medications are prohibited for the duration of the trial.  However, any 
patients taking these medications after screening should not be discontinued from 
treatment, unless there are safety concerns.  
• St John’s wort 
• Recreational or medicinal cannabis or cannabinoid-based medications (including 
Sativex or CBD oral solutions) 
• Any other IMP 
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• Felbamate that has been taken for less than 1 year 
Care should be taken with drugs, or their metabolites, that are CYP2C19 substrates, such 
as N-desmethylclobazam.  Care should also be taken with drugs, or their metabolites, that 
are solely or primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase 
(UGT)1A9 and UGT2B7. 
8.4 
Compliance in Investigational Medicinal Product Administration 
GWP42003-P is dispensed to the patient at visits as per the Schedule of Assessments in 
Appendix 1.  Further guidance on GWP42003-P dispensing will be provided in a separate 
pharmacy manual.   
Caregivers will be asked to confirm dosing in the dosing schedule daily.  Caregivers 
should return all GWP42003-P (used and unused) at each of the visits as per the Schedule 
of Assessments in Appendix 1.  The returned medication will be checked against the 
expected usage, and any discrepancies will be discussed with the caregiver at the time of 
the visit and documented accordingly within the patient’s source documents.  Caregivers 
will also be asked about the time of GWP42003-P administration in relation to meals. 
The investigator must inform GW promptly of all missing or unaccountable 
GWP42003-P.   
Records of GWP42003-P accountability will be maintained according to Section 5.2.4. 
8.5 
Access to Blinded Treatment Assignment 
This is not applicable. 
 
 
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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. 
The location of the source data for the following procedures will be documented, per 
center, in a signed source data verification plan; for further details, see Section 16.2. 
9.1 
Trial Procedures by Visit 
Patients and their parent(s)/legal representative will be invited to take part in the trial and 
will be issued with the patient information and informed assent (if applicable) and the 
parent(s)/legal representative information and informed consent.  Due to the degree of 
cognitive impairment in patients with RTT, patients 18 years of age or older will not be 
required to provide consent and will only be required to provide assent in cases where the 
patient possesses adequate understanding, along with parent(s)/legal representative 
consent.  Following ample time to discuss the trial with the investigator, nurse, relatives, 
or caregiver, as wished, patients for whom the parent(s)/legal representatives provide 
written informed consent, and in cases where the patient possesses adequate 
understanding, patients who give their assent will be screened for entry into the trial.  The 
nominated caregiver will be asked to consent to complete the QoL questionnaires. 
Each visit should be scheduled to take place at approximately the same time of day 
(i.e., morning or afternoon), whenever possible.  Visits 2, 3, and 16 (safety follow-up) are 
to be conducted by telephone.   
The investigator should use his/her judgment and knowledge of the patient to determine 
when to best collect the blood and urine samples in order to mitigate the risk that invasive 
procedures may cause the patient to become stressed, thereby affecting the results of 
other patient assessments. 
All assessments should reflect the patient’s regular state, therefore it should be ensured 
the patient had adequate time to settle prior to each assessment.  The CGI-S and CGI-I 
assessments should be based on the entirety of the visit. 
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9.1.1 
Clinic Visits 
9.1.1.1 
Visit 1 (Day 1) 
Every effort should be made for this visit to take place on the same day as the RCT ‘End 
of Treatment’ visit.  However, patients can still enter the OLE trial up to the point of the 
RCT follow-up (Visit 11).   
OLE Visit 1 Assessments required for all patients: 
• Informed consent and assent 
• Eligibility check 
• New medical history 
• AE review 
• GWP42003-P dispensing 
OLE Visit 1 assessments required if OLE Visit 1 occurs on a different date than 
RCT Visit 9: 
• Vital signs 
• Hospital Services Use Questionnaire  
• Suicidality assessment 
OLE Visit 1 assessments required if OLE Visit 1 occurs > 28 days after RCT Visit 9: 
• Physical examination (including weight) 
• ECG 
• Clinical laboratory blood sampling (hematology and biochemistry) 
• Dipstick urinalysis (where possible) 
Patients who satisfy all of the inclusion criteria and none of the exclusion criteria 
specified in Section 6 will begin the treatment period. 
Patients will be dispensed sufficient GWP42003-P and a dosing schedule for the 
following 3 weeks.  Caregivers will be instructed on how to use the dosing schedule and 
how to measure and administer the medication.  At the next visit, all GWP42003-P (used 
and unused) will be collected, and a check of the returned GWP42003-P against usage 
should be made.   
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Based on Section 9.1.3, assessments may be performed at unscheduled visits in the event 
of a safety concern, as deemed necessary by the investigator. 
The investigator should review the laboratory results as soon as these become available.  
If the results show a patient is ineligible, the patient will fail screening. 
9.1.1.2 
Visit 4 (Day 29 [± 7]) 
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. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
The investigator must assess adherence to the dosing schedule.   
Vital sign assessments, physical examination (including body weight) and ECG 
assessments will be performed.   
Clinical laboratory samples (urine [where possible] and blood) will be taken for 
hematology and biochemistry.   
The caregiver will complete the RSBQ and Caregiver Assessment of Rett Symptoms.   
The Hospital Services Use Questionnaire will be completed via interview. 
The investigator will complete the CGI-S, CGI-I, and suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 4 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.3 
Visit 5 (Day 57 [± 7]) 
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. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
The investigator must assess adherence to the dosing schedule.   
Vital sign assessments will be performed. 
Clinical laboratory samples (urine [where possible] and blood) will be taken for 
hematology and biochemistry.   
The caregiver will complete the RSBQ and Caregiver Assessment of Rett Symptoms.   
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The Hospital Services Use Questionnaire will be conducted via interview. 
The investigator will complete CGI-S, CGI-I, and suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 4 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.4 
Visit 6 (Day 85 [± 7]) 
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. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
The investigator must assess adherence to the dosing schedule.   
Vital sign assessments, physical examination (including body weight) and ECG 
assessments will be performed.   
Clinical laboratory samples (urine [where possible] and blood) will be taken for 
hematology and biochemistry.   
The caregiver will complete the RSBQ, CSHQ and Caregiver Assessment of Rett 
Symptoms.   
The Hospital Services Use Questionnaire will be completed via interview. 
The investigator will complete MBA-9, CGI-S, CGI-I, and suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 8 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.5 
Visit 7 (Day 141 [± 7]) 
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. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
The investigator must assess adherence to the dosing schedule.   
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Vital sign assessments will be performed. 
Clinical laboratory samples (urine [where possible] and blood) will be taken for 
hematology and biochemistry for patients taking concomitant valproic acid, as well as for 
patients whose dose exceeds 15 mg/kg/day.   
The caregiver will complete the RSBQ and Caregiver Assessment of Rett Symptoms.   
The Hospital Services Use Questionnaire will be completed via interview. 
The investigator will complete CGI-S, CGI-I, and suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 8 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.6 
Visit 8 (Day 197 [± 7]), Visit 10 (Day 365 [± 7]), and Visit 14 
(Day 729 [± 7], End of Treatment/Withdrawal Visit) 
A visit window of ± 7 days for Visits 8, 10, and 14 from the scheduled visit date is 
permitted, but it is preferred that the visit is performed on the scheduled visit day, where 
possible. 
The patient should attend a withdrawal visit (Visit 14) as soon as possible after the 
decision is made to permanently discontinue GWP42003-P.   
Information regarding changes to concomitant medications, AEs, and menstruation cycle 
(where applicable) will be reviewed. Vital sign assessments, physical examination 
(including body weight), height, and ECG assessments will be performed.     
Clinical laboratory samples (urine [where possible] and blood) will be taken for the 
following: 
• Hematology 
• Biochemistry 
• Dipstick urinalysis (provided urine can be obtained) 
• Pregnancy test using a serum sample (as appropriate [Section 9.2.2])   
• Determination of serum IGF-1 levels (Section 9.2.9) 
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The caregiver will complete the RSBQ, CSHQ, SF-36, CHQ-PF50, and Caregiver 
Assessment of Rett Symptoms. 
The Hospital Services Use Questionnaire will be completed via interview. 
The Tanner Stage will be recorded (where appropriate).   
The investigator will complete MBA-9, CGI-S, CGI-I, and suicidality assessment. 
The investigator must assess adherence to the dosing schedule.  All GWP42003-P (used 
and unused) will be collected, and a check of the returned GWP42003-P against usage 
should be made.  Patients will receive sufficient GWP42003-P and a dosing schedule for 
the period until the next scheduled Visit.  
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
Visit 14 only: Patients will receive sufficient GWP42003-P for the 10-day taper period, 
as applicable.  For patients who discontinue GWP42003-P early, the taper period should 
start at the time the decision is made to discontinue, unless tapering the dose of 
GWP42003-P is inadvisable (e.g., continued dosing is not possible due to an AE).  For 
patients who discontinue GWP42003-P early, the decision on whether or not to taper 
GWP42003-P will be left to the investigator’s clinical judgment.   
9.1.1.7 
Visit 9 (Day 281 [± 7]) 
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.   
Information regarding changes to concomitant medications and AEs will be reviewed.  
Physical examination (including body weight) and vital sign assessments will be 
performed.  Blood samples will be taken for the following: 
• Hematology 
• Biochemistry 
The investigator must assess adherence to the dosing schedule.   
The investigator will complete the suicidality assessment. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 12 weeks. 
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9.1.1.8 
Visit 11 (Day 456 [± 7]) and Visit 13 (Day 638 [± 7]) 
Visits 11 and 13 are resupply visits.  Patient’s taking concomitant valproic acid or whose 
dose exceeds 15 mg/kg/day will need hepatic monitoring.  All other patients do not need 
to attend in person.  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. 
Information regarding changes to concomitant medications and AEs will be reviewed.   
The investigator must assess adherence to the dosing schedule.   
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Sufficient GWP42003-P and a dosing 
schedule will be provided for the following 13 weeks.   
Based on Section 9.1.3, assessments may be performed at an unscheduled visit in the 
event of a safety concern, as deemed necessary by the investigator. 
9.1.1.9 
Visit 12 (Day 547 [± 7]) 
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. 
Information regarding changes to concomitant medications, AEs will be reviewed.  Vital 
sign assessments, physical examination (including body weight), height, and ECG 
assessments will be performed.   
Clinical laboratory samples (urine [where possible] and blood) will be taken for the 
following: 
• Hematology 
• Biochemistry 
• Dipstick urinalysis (provided urine can be obtained) 
• Pregnancy test using a serum sample (as appropriate [Section 9.2.2])   
The investigator will complete suicidality assessment. 
The investigator must assess adherence to the dosing schedule.   
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.  Patients will receive sufficient 
GWP42003-P and a dosing schedule for the following 13 weeks.   
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9.1.1.10 
Visit 15 (Day 739 [+ 7], End of Taper) 
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.  This visit marks 
the end of the taper period. 
Information regarding changes to concomitant medications and AEs will be reviewed.  
Vital sign and suicidality assessments will be performed.   
The investigator must assess adherence to the dosing schedule. 
All GWP42003-P (used and unused) will be collected, and a check of the returned 
GWP42003-P against usage should be made.   
The following assessments are not required but should be performed if clinically 
indicated: 
• Physical examination (including body weight) 
• ECG 
• Clinical laboratory samples (urine [where possible] and blood) will be taken for 
the following: 
• Hematology 
• Biochemistry 
9.1.2 
Dipstick urinalysis (provided urine can be obtained)Telephone 
Visits  
9.1.2.1 
Visits 2 (Day 8 [± 3]) and 3 (Day 15 [± 3]) 
A visit window of ± 3 days from the scheduled visit date is permitted, but it is preferred 
that the visit is performed on the scheduled visit day, where possible.  
Telephone visits will be conducted by a center nurse (the center investigator only needs 
to be involved if necessary, e.g., if any concerns are raised during the call).  Information 
regarding changes to concomitant medications and AEs will be reviewed.  The center (the 
nurse and, if necessary, the investigator) must assess adherence to the dosing schedule. 
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9.1.2.2 
Visit 16 (28 days after last dose IMP [+ 7], Follow-up, End of 
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.  This visit marks 
the end of the trial. 
Visit 16 constitutes the last scheduled safety follow-up.  The purpose of the visit is to 
ascertain the status of AEs continuing after the cessation of GWP42003-P or any new 
AEs commencing after discontinuation.  All causally related AEs that result in a patient’s 
early termination from the trial or are present at the end of the trial should be followed up 
until a satisfactory resolution occurs, i.e., until the AE resolves or is considered clinically 
insignificant, or until the investigator is satisfied that the AE is not related to 
GWP42003-P and needs no further investigation.  Information regarding changes to 
concomitant medications will be reviewed.   
9.1.3 
Unscheduled Visits 
Unscheduled visits and assessments may be performed in the event of a safety concern, 
as deemed necessary by the investigator.  Data from any unscheduled visits should be 
reported on the unscheduled visits eCRF.  
9.1.4 
End of Trial 
The end of trial is defined as last patient last visit/telephone call. 
9.2 
Trial Procedure Listing 
9.2.1 
Informed Consent/Assent 
The parent(s)/legal representative of all patients in the trial must personally sign and date 
the IRB/IEC-approved informed consent form (ICF) before any trial-specific procedures 
are performed or any patient-related data are recorded for the trial.  The nominated 
caregiver will be asked to consent to complete the QoL questionnaires. 
In cases where the patient possesses adequate understanding in the opinion of the 
investigator, assent will be taken along with parent(s)/legal representative consent, using 
IRB/IEC-approved assent forms.  If appropriate, prior to signing, the assent form will be 
read to the patient, and the patient will be given the opportunity to ask questions and 
discuss with their parent(s)/legal representative.  If appropriate, the patient must 
personally sign and date the assent form.  Patients who cannot write can give 
consent/assent by “making their mark” on the assent form (e.g., writing an “X”).  If the 
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patient possesses adequate understanding but is not physically able to sign, an impartial 
witness should be present during the entire assent discussion and should sign and 
personally date the assent form.  By signing, the witness attests that the information in the 
assent form and any other written information were accurately explained to and 
apparently understood by the patient and that assent was freely given by the patient.  
Assent is defined as the minor’s permission or affirmative agreement to participate in the 
trial.  If a minor who is capable of forming an opinion and assessing the information 
provided makes an explicit wish to refuse participation in or to be withdrawn from the 
clinical trial at any time, this wish must be considered by the investigator.  Given the 
severity of the condition, it is expected that the majority of patients will have an 
insufficient level of understanding of what is proposed, in which case solely 
parent(s)/legal representative consent will be sought.  All decisions made by the 
investigator relating to a patient’s level of understanding and ability to provide assent 
must be documented in the patient’s medical records. 
GW Research Ltd requires a physician to be present for consent and assent and to also 
sign the consent and assent forms.  The original signed informed consent/assent forms 
should be retained, and a copy should be provided to the patient and/or parent(s)/legal 
representative.  Patients’ parent(s)/legal representatives 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, see Section 15.2. 
9.2.2 
Contraception Requirements 
Contraception requirements must be assessed by the investigator on a case by case basis.  
Where applicable, the patient or their partner must use highly effective contraception for 
the duration of the study and for three months thereafter.   
To be eligible for the trial, male participants who are fertile (i.e., after puberty unless 
permanently sterile by bilateral orchidectomy) must agree that they are willing to use 
male contraception (e.g.,condom) or remain sexually abstinent during the trial and for 
3 months after the last dose. 
Where applicable, females of childbearing potential (i.e., fertile, following menarche and 
until becoming postmenopausal for ≥ 12 consecutive months, unless permanently sterile 
by hysterectomy, bilateral salpingectomy, or bilateral oophorectomy per the definition of 
woman of childbearing potential) must use highly effective birth control method 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 
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(i.e., less than 1% per year) when used consistently and correctly.66  Such methods 
include:  
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with the inhibition of ovulationa: 
• Oral. 
• Intravaginal. 
• Transdermal. 
• Progestogen-only hormonal contraception associated with inhibition of 
ovulationa: 
• Oral. 
• Injectable. 
• Implantableb. 
• Intrauterine devicesb 
• Intrauterine hormone-releasing systemsb. 
• Bilateral tubal occlusionb. 
• Vasectomized partnerbb, provided that partner is the sole sexual partner of the 
patient of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success. 
• 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 (e.g., calendar, ovulation, symptothermal, and postovulation methods) 
and withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method are not acceptable methods of contraception.67  
Serum pregnancy tests will be performed for any patients of childbearing potential at 
RCT Visit 9 and OLE Visit 8; patients must test negative for pregnancy to be eligible for 
the trial.  Additional pregnancy tests must be performed during the treatment period if 
considered clinically indicated by the investigator. 
 
a The effect of GWP42003-P on oral contraceptives has not been investigated.  GWP42003-P is not an 
inducer of CYP3A4 and therefore is not expected to alter the PK of hormonal contraceptives. 
b Contraception methods that are considered to have low user dependency 
b Provided that partner is the sole sexual partner of the trial patient of childbearing potential and that the 
vasectomized partner has received medical assessment of the surgical success. 
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9.2.3 
Concomitant Medication 
Details of all current medications will be recorded during the RCT.  Any changes in 
concomitant medication during the trial must be recorded on the eCRF at trial visits.  
Changes in concomitant medications are allowed, but increases in the dose of 
medications that affect liver function should be discussed with the medical monitor.  
Introduction of new medications is allowed, but introduction of new psychotropic and/or 
central acting agents intended as long-term treatment requires prior discussion with the 
medical monitor.  
9.2.4 
New Medical History 
Any changes to medical history since the RCT will be recorded. 
9.2.5 
Menstruation 
Any changes in menstrual cycles since the RCT will be captured at the end-of-treatment 
visit. 
9.2.6 
Physical Examination 
Physical examinations will include body weight measurements.  At Visits 8, 10, 12 and 
14 height will be collected.  If an accurate measurement of height is not possible, an 
estimate should be provided. 
9.2.7 
12-Lead Electrocardiogram  
Triplicate ECGs will be performed after 5 minutes of rest.  Triplicate ECGs should be 
taken as close together as possible.  An ECG machine will be provided to all centers, and 
all ECGs will be reviewed by a central reader.  The central reader will provide a report 
within 24 hours of collection of the ECG.  Additional alerts will be sent to the center in 
the case of clinically relevant abnormalities.  The central reader will provide 
measurements and an overall assessment to support the investigator in his/her final 
assessment.  If needed, the investigator may update clinical relevance based on patient 
files, medical history, and any clinical symptoms.  The central reader can be supportive 
for any discussions on patient outcomes.  Any abnormal findings considered to indicate 
significant medical history or AEs must be recorded appropriately on the eCRF.  In 
addition to the scheduled assessments, additional ECG measurements can be taken at any 
time during the trial, if clinically indicated.   
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9.2.8 
Vital Signs 
Vital sign measurements (blood pressure and pulse rate) will be taken in a sitting position 
at rest for 5 minutes.  Blood pressure should be recorded using the same arm throughout 
the trial, where possible. 
9.2.9 
Clinical Laboratory Sampling 
The investigator should use his/her judgment and knowledge of the patient to determine 
when to best collect the blood and urine samples in order to mitigate the risk that invasive 
procedures may cause the patient to become stressed, thereby affecting the results of 
other patient assessments.   
Routine laboratory tests will include hematology, biochemistry, and urinalysis (provided 
urine can be obtained), IGF-1 levels, and a serum pregnancy test (if appropriate).  
Analysis of all clinical blood samples and pregnancy tests will be conducted at a central 
clinical laboratory. 
Urine samples for biochemistry will be analyzed at the trial center 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 urine 
samples cannot be analyzed at the center due to local regulations, a full set of urine 
samples should be sent to the central laboratory for analysis.  Urine sample volume 
requirements and processing procedures will be detailed in a separate laboratory manual.   
The investigator and trial monitor will be provided with a list of the normal ranges used 
by the testing laboratory for all variables assayed during the trial and a statement of 
accreditation (or similar) for the laboratory.   
The investigator should be aware of blood sampling volume restrictions, particularly for 
patients with low weight, and if additional monitoring is required (maximum total daily 
volume of 0.85mL/kg of body weight68,69 maximum 4-week period volume of 
2.55 mL/kg of body weight, and maximum 8-week period volume of 50 mL).  
Clinical laboratory sample parameters are detailed in Table 9.2.9-1. 
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Table 9.2.9-1 
Biochemistry, Hematology, and Urinalysis 
Biochemistry 
(Serum)¹  
Hematology 
(Whole Blood)¹  
Urinalysis 
(Urine)² 
Pregnancy Test 
(Serum)¹ 
Alanine 
aminotransferase3 
Hematocrit 
Blood 
Serum 
Albumin3 
Hemoglobin 
Glucose 
 
Alkaline phosphatase3 
Mean cell volume 
Nitrites 
 
Aspartate 
aminotransferase3 
Mean corpuscular 
hemoglobin 
pH 
 
Calcium 
Platelets 
Protein 
 
Creatine kinase 
Red blood cell count 
White blood cells 
 
Creatinine 
White blood cell count 
with automated 
differential 
Bilirubin 
 
Creatinine clearance 
Prothrombin time and 
INR (plasma)5 
Ketones 
 
Gamma-glutamyl 
transferase3 
 
Specific gravity 
 
Glucose 
 
Urobilinogen 
 
Human chorionic 
gonadotropin 
 
 
 
HDL-cholesterol 
 
 
 
IGF-14 
 
 
 
Potassium 
 
 
 
Prolactin 
 
 
 
Sodium 
 
 
 
Total bilirubin3 
 
 
 
Total protein3 
 
 
 
Triglycerides 
 
 
 
Urea (blood urea 
nitrogen) 
 
 
 
HDL = high-density lipoprotein; INR = international normalized ratio. 
¹ Analyzed at a central laboratory. 
² Analyzed at the trial center by use of a dipstick (if allowed per local regulations). 
3 Hepatic function monitoring panel.  
4 Visits 1, 8, 10 and 14 only; IGF-1 laboratory results to remain blinded throughout the trial. 
5 To be requested if ALT or AST > 3 × ULN after Visit 1 (to evaluate IMP discontinuation criteria) 
Investigators at trial centers will be notified of laboratory test results.  All laboratory 
results will be reviewed, and the reports will be signed and dated by the investigator.  
Any results considered to be of clinical significance must be addressed and followed up, 
as clinically appropriate.  Per protocol requirements, in addition to the pre-scheduled 
biochemistry, further hepatic function monitoring may be needed. In cases where after 
Visit 1, ALT or AST are > 3 × ULN, international normalized ratio (INR) testing must be 
requested.  If only the hepatic function monitoring panel was requested and ALT or AST 
> 3 × ULN, both INR and hematology panel (eosinophils) must be requested.  All 
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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 the 
investigator is satisfied that the abnormality is not related to GWP42003-P and needs no 
further investigation.   
Additional samples may be collected, as needed, e.g., for monitoring of hepatic function 
(hepatic function monitoring panel) (see Section 8.1.2 and Table 9.2.9-1).  
Blood sample volume requirements and processing procedures will be detailed in a 
separate laboratory manual; the maximum cumulative amount of blood taken in any 
4-week period will be 2.55 mL/kg of body weight and will not exceed a total of 50 mL 
within any 8 week period68,69 taking into account possible repeat tests.  The 
patient/caregiver 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 the patient suffered any blood loss during the 1-month period leading up to 
a planned blood draw. 
9.2.10 
Randomization and Trial Supply Management System 
The RTSM system will be used to manage the IMP supply.  The RTSM system 
information can be accessed via the eCRF.  
A member of the trial team must register in the eCRF each clinic visit in order to: 
• Obtain dispensing information (Visits 1, and 4 through 14 [end of 
treatment/withdrawal visit]). 
• Provide completion/taper/early termination information (Visit 14/the end of 
treatment/withdrawal visit, or Visit 15 [end of taper], as applicable). 
Training will be given to all centers prior to the start of the trial. 
9.2.11 
Dosing Schedule/Compliance Review 
Caregivers will be provided with a dosing schedule.  Caregivers will be asked to confirm 
dosing in the dosing schedule daily from Visit 1 through Visit 15 (end of taper).  Dosing 
compliance will be reviewed at each clinic visit.  Any discrepancies will be discussed 
with the caregiver and documented accordingly within the patient’s source documents.  
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As part of the compliance review, caregivers will be asked at the visits about the time of 
GWP42003-P administration in relation to meals. 
9.2.12 
Questionnaires and Assessments Completed at Scheduled Visits  
Caregiver questionnaires should be completed by the identified caregiver, nominated at 
Visit 1 of the RCT.  The same person should answer/complete the 
questionnaires/assessments in order to maintain consistency.  Questionnaires should be 
completed during the scheduled visits.  The nominated caregiver must have given consent 
to complete the QoL questionnaires prior to the completion of the questionnaires.  
To ensure consistency, investigator-completed questionnaires should be completed for 
each patient by the same investigator throughout the trial.  Investigators must have 
completed the sponsor-specified training for each questionnaire before any questionnaires 
are completed. 
9.2.12.1 
Rett Syndrome Behaviour Questionnaire 
The RSBQ is a caregiver-completed questionnaire that measures the frequency of current 
disease characteristics (45 items) that may or may not apply to the patient.  Each item is 
rated on a 3-point numerical scale; 0 indicates an item that is ‘not true as far as you 
know,’ 1 indicates an item is ‘somewhat or sometimes true,’ and 2 indicates an item that 
is ‘very true or often true.’  The total maximum score is 90, and higher total scores 
represent greater severity.  It encompasses 8 subscales: general mood, breathing 
problems, hand behaviors, face movements, body rocking/expressionless face, night-time 
behaviors, anxiety/fear, and walking/standing.55 
9.2.12.2 
Children’s Sleep Habit Questionnaire 
This is a caregiver-completed sleep screening instrument designed for school-aged 
children.70  CSHQ includes 33 items within 8 subscales reflecting the following sleep 
domains: 1) Bedtime Resistance; 2) Sleep Onset Delay; 3) Sleep Duration; 4) Sleep 
Anxiety; 5) Night Wakings; 6) Parasomnias; 7) Sleep-Disordered Breathing; and 
8) Daytime Sleepiness.  Caregivers are to answer based on the last week.  If the last week 
was unusual for a specific reason, the caregiver should choose the most recent typical 
week.  The answers to each question are provided by a choice of 3 markers: “Usually” if 
it occurs 5 or more times in a week; “Sometimes” if it occurs 2 to 4 times in a week; and 
“Rarely” if it occurs never or 1 time in a week.  Some items should be reversed in 
scoring, so a higher score reflects more-disturbed sleep behavior.  The caregiver is also 
asked to indicate for each item if the sleep item is a problem.   
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9.2.12.3 
36-Item Short Form 
Caregivers’ health-related QoL will be assessed using the SF-36 questionnaire.  SF-36 
measures 8 domains of health-related QoL within 8 scales: 1) limitations in physical 
activities because of health problems; 2) limitations in social activities because of 
physical or emotional problems; 3) limitations in usual role activities because of physical 
health problems; 4) bodily pain; 5) general mental health (psychological distress and 
well-being); 6) limitations in usual role activities because of emotional problems; 7) 
vitality (energy and fatigue); and 8) general health perceptions.  The domains are used to 
calculate composite scores – physical health composite score (PCS) and mental health 
composite score (MCS).  The scores for SF-36 are based on a 0-to-100 scale; 0 represents 
the lowest possible score, and 100 represents the highest possible score, with a higher 
score indicating a better health state.   
9.2.12.4 
Child Health Questionnaire Parent Form 50 
The CHQ-PF50 is a generic QoL instrument designed and normed for children from 5 to 
18 years of age.  This instrument is a well-validated general QoL measure in pediatric 
populations with chronic illness.  It measures the QoL of the child and the family by 
parent or child report.  The caregiver will be asked to complete the questionnaire on 
behalf of the patient.  The CHQ-PF50 covers mutlidimensional health concepts including 
Physical Functioning, Role/Social Limitations–Emotional/Behavioral, Role/Social 
Limitations–Physical, Behavior, Mental Health, Self-Esteem, General Health, Bodily 
Pain, Family Activities, Parent Impact–Time, Parent Impact–Emotional, and Family 
Cohesion.  The CHQ-PF50 provides subscale scores as well as a Standardized Physical 
Summary (PhS) score and Standardized Psychosocial Summary (PsS) score.  Scores are 
based on a 0-to-100 scale; a higher score indicates better QoL.   
9.2.12.5 
Hospital Services Use Questionnaire 
This is a health utilization questionnaire designed to analyze the frequency of patient 
hospitalizations and hospital visits.  Hospitalizations will also be recorded in the patient’s 
CRF and through the serious adverse event (SAE) reporting process.  The questionnaire 
will be completed via caregiver interview.   
9.2.12.6 
Caregiver Assessment of Rett Symptoms  
Caregivers will be asked to rate, on a 0-to-10 numerical rating scale, the patient’s 
condition and performance/severity of symptoms in terms of breathing, hand stereotypies, 
interactions, problem behaviors, constipation, seizures, and sleep.  This assessment 
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corresponds to the symptom diary completed weekly in the RCT but will be completed at 
trial visits only in the OLE. 
9.2.12.7 
Rett Syndrome Motor-Behavioral Assessment Scale 
The MBA-9 scale is completed by the investigator and evaluates 9 RTT symptoms.  
MBA-9 was derived from the full MBA scale (37 RTT symptoms) by selecting the items 
that are deemed to be amenable to change and that reflect areas of meaningful clinical 
change.  It includes 5 questions from the original Behavioral/Social Assessment, 
1 question from the Orofacial/Respiratory Assessment, and 3 questions from the Motor 
Assessment/Physical Signs.  The severity of the current symptoms are rated on a 5-point 
numerical scale: 0 = normal or never; 1 = mild or rare; 2 = moderate or occasional; 
3 = marked or frequent; or 4 = very severe or constant.  The total maximum score is 36, 
and higher total scores represent greater severity.61  The MBA-9 items address the core 
symptoms of RTT.   
9.2.12.8 
Clinical Global Impressions Questionnaire  
The clinical global impressions (CGI) questionnaire was developed as a clinical trial 
measure to provide a brief, stand-alone assessment of the clinician’s view of the patient’s 
global functioning prior to and after initiating a study medication.56   
The CGI questionnaire is split into 2 scales: the CGI-S scale and the CGI-I scale.  CGI-S 
is a 7-point scale that requires the clinician to rate the severity of the patient’s illness at 
the time of assessment relative to the clinician’s experience with patients who have the 
same diagnosis.  Considering the total clinical experience, a patient will be assessed on 
the severity of illness at the time of rating.  This is rated as follows: 1 = normal, not at all 
ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 
or 7 = extremely ill.  The second scale, CGI-I, is a 7-point scale that requires the clinician 
to assess how much the patient’s illness has improved or worsened relative to a baseline 
state at the beginning of the intervention (RCT Visit 2).  This is rated as follows: 1 = very 
much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 
5 = minimally worse; 6 = much worse; or 7 = very much worse.  
To ensure consistency, investigators will be instructed to complete the CGI referring to a 
predefined set of anchors developed specifically for the use of CGI in RTT.59 
The CGI-S and CGI-I assessments should be based on the entirety of the visit. 
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9.2.12.9 
Suicidality Assessment 
The profound cognitive impairment of patients with RTT is such that the Children’s 
Columbia-Suicide Severity Rating Scale is not considered appropriate in this trial.  
Instead, suicidality will be assessed by the investigator via a clinical interview with the 
caregiver.   
9.2.13 
Tanner Staging 
The pubic hair growth and breast development of all adolescent patients (i.e., ≥ 7 years of 
age71 at the time of signing the ICF or earlier, if clinically indicated by the onset of 
menarche or other signs of precocious puberty) will be assessed using Tanner Staging.72  
The assessment can either be performed by examination during the study visit or the 
appropriate Tanner Stage can be indicated by the caregiver, with reference to the chart 
provided.’ 
Once a patient reaches a score of V (i.e., 5) the assessment need not be performed again. 
9.2.14 
Investigational Medicinal Product Accountability 
Records of GWP42003-P accountability will be maintained according to Section 5.2.4. 
GWP42003-P will be dispensed at Visit 1 (Day 1) and every scheduled visit thereafter 
(Visit 4 through Visit 14 [end of treatment/withdrawal visit]). 
Caregivers will be asked to return all GWP42003-P (used and unused) at each relevant 
visit (Visits 4 through Visit 15 [end of taper]).  The center will check the returned 
GWP42003-P against the expected usage.  Any discrepancies will be discussed with the 
caregiver at the time of the visit and documented accordingly within the patient’s source 
documents. 
9.2.15 
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 post-trial follow-up visit (Visit 16), whether or 
not attributed to GWP42003-P and observed by the investigator or patient. 
* For the patient’s expected seizure types, these do not routinely require documentation as 
AEs.  However, any worsening, including a change in the pattern or severity of seizures 
should be documented in the eCRF if deemed to meet the definition of an AE, in the 
investigator’s opinion.   
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Any AE that meets SAE criteria should still be reported as a SAE. 
Serious adverse events must be reported to GW Pharmacovigilance Department (PVD) 
within 24 hours of discovery or notification of the event via recording in the eCRF.  
Refer to Section 12 for definitions, procedures, and further information on AE reporting. 
 
 
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10 
IMP WITHDRAWAL 
In accordance with the Declaration of Helsinki73 the International Council for 
Harmonisation (ICH) Harmonised Guideline: Integrated Addendum to ICH E6(R1): 
Guideline for Good Clinical Practice (GCP) E6(R2)74 the FDA regulations relating to 
GCP and clinical trials75,76,77 the EU Clinical Trials Directive78 the EU GCP Directive79 
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/her future medical care by the physician or at the institution. 
The patient must be withdrawn permanently discontinued from the trial if any of the 
following apply: 
• Administrative decision by the investigator, GW, or a regulatory authority 
• Pregnancy 
• Protocol deviation that is considered to potentially compromise the safety of the 
patient 
• Withdrawal of patient assent 
• Withdrawal of parent(s)/legal representative consent 
• 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 (total bilirubin [TBL] > 2 × ULN or international 
normalized ratio [INR] > 1.5) 
Note: Prior to withdrawal for the transaminase elevations noted above, the 
investigator may choose to confirm the transaminase elevations by repeating the 
following laboratory tests within 24 to 48 hours: ALT, AST, TBL, INR, % 
eosinophils, gamma-glutamyl transferase, alkaline phosphatase, and 
eosinophils.  Should the above transaminase elevation criteria be confirmed, 
the patient must be withdrawn from the trial.  In cases where the 
transaminase elevation withdrawal criteria are not met or confirmed, the 
dose of IMP or a concomitant medication with known hepatotoxicity may be 
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reduced.  Dose adjustments should be discussed with the GW medical 
monitor.  The final decision regarding dose adjustments should be taken by 
the investigator. 
• Lost to follow-up 
The patient may also be withdrawn permanently from the trial for any of the following: 
• Patient or caregiver 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 
• Failure to meet the eligibility criteria 
• Any evidence of the use of drugs of abuse or drug diversion 
• Suicidal ideation or behavior during the treatment period 
The patient should attend a withdrawal visit (Visit 14) as soon as possible after the 
decision is made to permanently discontinue GWP42003-P.  Patients who discontinue the 
IMP should have their dose of IMP gradually reduced (10% each day) over a period of 
10 days, beginning at the time the decision is made to discontinue (unless inadvisable due 
to an AE).  Patients who discontinue the IMP and complete tapering of the IMP prior to 
the completion visit do not need to attend an End of Taper visit. 
Should a patient request or decide to withdraw from the trial, all efforts must be made to 
complete and report the observations as thoroughly as possible up to the date of 
withdrawal.  Patients withdrawing due to an AE should be followed up according to 
Section 12.7.  All information should be reported on the applicable eCRF pages.  All 
assessments required at the withdrawal visit should be conducted, if possible.  If the 
tapered dose is administered, patients should return for Visit 15 (End of taper), if 
possible.  Wherever possible, a safety follow-up visit should take place 28 days from the 
date of last dose of IMP.  If the withdrawing patient declines to give a reason for 
withdrawal of consent, the investigator must respect the patient’s wishes. 
 
 
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11 
URGENT SAFETY MEASURES 
The sponsor and investigator may take appropriate urgent safety measures in order to 
protect the patients of a clinical trial against any immediate hazard to their health or 
safety.  If such measures are taken by the investigator, they must notify GW immediately 
or at least within 24 hours of awareness.  GW will report urgent safety measures to 
regulatory authorities by telephone within 24 hours of awareness, wherever possible, and 
will provide a written report to the regulatory authorities and IRB/IEC within 3 days. 
 
 
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12 
ADVERSE EVENT REPORTING 
12.1 
Definitions 
12.1.1 
Adverse Event 
For the purposes of this trial, an AE is defined as follows: 
Any new unfavorable/unintended signs/symptoms (including abnormal laboratory 
findings when relevant) or diagnosis or worsening of a pre-existing condition that occurs 
at any point up to the post-treatment, final safety follow-up visit (Visit 16), which may or 
may not be considered to be related to GWP42003-P.  Any event that is the result of a 
trial procedure must be recorded as an AE. 
Surgical/Investigational procedures are not AEs.  The medical reason for the procedure is 
the AE.  Elective hospitalizations for pretrial existing conditions or elective procedures 
are not AEs.  The exception may be if the patient has an AE during hospitalization that 
prolongs the 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 death 
(e.g., disease or medical condition leading to death). 
12.1.2 
Investigator 
The term “investigator” refers to the trial principal investigator (PI) or a formally 
delegated trial physician. 
12.2 
Serious Adverse Events 
During clinical investigations, AEs may occur, which if suspected to be 
GWP42003-P-related, might be significant enough to lead to important changes in the 
way GWP42003-P is developed (e.g., change in dose, population, monitoring need, 
consent/assent forms).  This is particularly true for events that threaten life or function.  
Such SAEs will be reported promptly to regulatory authorities, applicable IRBs/IECs, 
and investigators (expedited reporting) by GW. 
An AE must only be classed as serious, i.e., an SAE, when the event falls into one of the 
following criteria: 
• Results in death 
• Is life threatening* 
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• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is medically significant** 
* The term “life threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event that, 
hypothetically, might have caused death if it were more severe. 
** Medical and scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations.  Important medical events may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These should also usually be considered serious.  Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or use of drugs of abuse. 
12.3 
Reporting Procedures for Serious Adverse Events 
All SAEs occurring during the trial must be reported to GW with any other supporting 
information and recorded in the AE section of the eCRF.  Any ongoing SAEs should be 
followed up until resolution, wherever possible.  For all deaths, the working diagnosis or 
cause of death as stated on a death certificate, available autopsy reports, and relevant 
medical reports should be sent to GW promptly. 
All SAEs must be recorded in the eCRF within 24 hours of discovery or notification 
of the event.  GW Research Ltd PVD will be automatically notified that an SAE has 
been recorded.  Any additional information required for a case (follow-up or corrections 
to the original case) will be requested by GW PVD through eCRF queries.  
The investigator should continue to document all AEs that occur up to the last formal 
safety follow-up (Visit 16).  If the investigator subsequently becomes aware of any deaths 
or a new GWP42003-P-related SAE after the last formal follow-up period of the trial, 
these should still be reported to GW PVD. 
Any other problem discovered after Visit 10 that is deemed to be an unexpected safety 
issue and is likely to have an impact on patients who have taken part in the trial must be 
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treated as an SAE and reported to 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 
the final trial data lock.  GW Research Ltd PVD may request safety follow-up 
information after the final trial visit in order to investigate a potential safety issue. 
Contact details for GW PVD are provided at the front of the center files for all trial 
centers. 
12.4 
Pregnancy 
Any patient, or patient’s partner, who has become pregnant while receiving 
GWP42003-P or within 90 days of the last dose of GWP42003-P must be reported to GW 
PVD.  Where possible, the investigator should provide the outcome of the pregnancy. 
All pregnancies must be recorded in the eCRF within 24 hours of awareness.  GW PVD 
will be automatically notified that a pregnancy has been recorded.  Any additional 
information required for a case (follow-up or corrections to the original case) will be 
requested by GW PVD through eCRF queries. 
The investigator is not obliged to actively monitor for any pregnancies that commence 
more than 90 days after the final dose of GWP42003-P.  However, if the investigator 
becomes aware of a new pregnancy outside this time limit, then he/she should report it as 
above.  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 GWP42003-P 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 GWP42003-P: 
“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 the IMP (pretreatment) should be considered as 
not causally related.  Where a pretreatment event worsens in severity following the first 
dose of the IMP, a new event record should be entered into the eCRF. 
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Considering the explanation given above, investigators are strongly encouraged to 
express their opinion on what the cause of an AE might be.  For individual patients, the 
investigator is usually in the best position to assess the underlying suspected cause of an 
AE.  For all AEs, especially SAEs, it is important that the investigator assess not only the 
possible role of GWP42003-P but also other potential contributing factors.  Factors for 
consideration of the underlying cause may include the following: 
• Medical and disease history 
• Lack of efficacy/worsening of treated condition 
• Concomitant or previous treatment 
• IMP discontinuation 
• 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 post-trial safety follow-up visit (Visit 16), 
whether or not attributed to GWP42003-P and observed by the investigator or patient. 
For the patient’s expected seizure types, these do not routinely require documentation as 
AEs.  However, any worsening, including a change in the pattern or severity of seizures, 
should be documented in the CRF if deemed to meet the definition of an AE, in the 
investigator’s opinion. 
Any AE that meets the SAE criteria should still be reported as an SAE. 
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 
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description.  However, the diagnosis (full or provisional) should be clearly stated, 
e.g., fever and malaise due to respiratory tract infection. 
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, record as much information as possible (i.e., the month and year or, in 
exceptional circumstances, just the year).  When the actual start date becomes known, the 
eCRF must be updated to replace the previously recorded date. 
C) Outcome 
The outcome of the event must be recorded accurately and classified into one of the 
following categories: 
• Recovered 
• Recovered with sequelae 
• Continuing 
• Patient died 
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 the 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. 
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F) Action Taken with IMP 
This question refers to the action taken with GWP42003-P due to an AE.  The action with 
GWP42003-P must be classified as follows: 
• None 
• Dose reduced temporarily 
• Dose reduced 
• IMP interrupted 
• IMP stopped 
12.7 
Follow-up Procedures for Adverse Events 
The investigator may be asked to provide follow-up information to GW PVD for any AEs 
reported or during the investigation of potential safety issues.  Such requests for 
additional safety information may occur post follow-up Visit 16, after the trial. 
Adverse events considered related to GWP42003-P 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 removal from treatment.  A patient may also voluntarily 
discontinue from treatment due to what he/she perceives as an intolerable AE.  Further 
details of discontinuation are presented in Section 10.  If either of these occurs, the 
patient must permanently discontinue from treatment 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 investigational centers are required to submit to GW PVD the laboratory results for 
any patient after randomization who meets the criteria for the selected laboratory 
parameters as follows:  
• 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 
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• 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 GW PVD via e-mail (see Appendix 2.2) within 24 hours of 
becoming aware of the results.  In addition, a copy of the patient’s baseline laboratory 
results with all reports should be sent to GW PVD. 
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 treatment discontinuation 
and important medical events.  The investigator will arrange for the patient to return to 
the investigational center as soon as possible (within 24 to 48 hours of notice of abnormal 
results) for a repeat assessment of ALT, AST, TBL, alkaline phosphatase, 
gamma-glutamyl transferase levels, eosinophils as well as for testing INR (prothrombin 
time), detailed history; and physical examination.  Patients should be followed this way 
until all abnormalities have normalized (in the investigator’s opinion) or returned to the 
baseline state.  However, if the above transaminase elevation criteria are confirmed by 
the first set of follow-up laboratory tests, the patient must be withdrawn from the trial. 
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.  In cases where after Visit 1, ALT or AST are > 3 
× ULN, INR testing must be requested.  If only the hepatic function monitoring panel 
was requested and ALT or AST > 3 × ULN, both INR and hematology panel 
(eosinophils) must be requested.  If the patient cannot return to the investigational center, 
repeat assessments may be done at a local laboratory, and the results should be sent to 
GW PVD. 
12.9 
Notification of Safety Information to Investigators, Regulatory 
Authorities, and IRBs/IECs 
In accordance with the EU Clinical Trials Directive78 relevant parts of the FDA Code of 
Federal Regulations80 and any national regulations, GW will inform the 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). 
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This information will be provided through 2 sources: 
1. IB52: A compilation of the clinical and nonclinical safety data available on the 
IMP that are relevant to the trial.  The IB is updated at least annually or when 
important new safety information becomes available. 
2. 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 investigators should notify their regional 
IRBs/IECs of SAEs or SUSARs occurring at their center 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 guidance75 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, were serious, and would have implications for the conduct of the trial 
(e.g., requiring a significant, and usually safety-related, change in the protocol, such as 
revising inclusion/exclusion criteria or including a new monitoring requirement, informed 
consent/assent, 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 guidance80 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 Research Ltd will inform the 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 the investigators in the trial does not necessarily constitute an unanticipated 
problem unless identified by GW in the submission cover letter. 
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As a minimum, the recipient will be sent all of the above, as well as relevant updates 
between the period from ethical approval and the 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).  Any deviations from the original SAP will be described in the final 
clinical study report. 
13.1 
Sample Size, Power, and Significance Levels 
There is no formal sample size calculation for this trial.  All patients with RTT who 
completed the randomized, double-blind, placebo-controlled trial (GWND18064) who 
wish to take GWP42003-P and who meet eligibility criteria can be included in this trial.   
Approximately 252 patients will be enrolled.  
13.2 
Interim Analysis 
No formal interim analysis will be conducted.  
13.3 
Analysis Sets 
For this trial there will be 1 analysis set: 
Safety Analysis Set 
• All patients who receive at least 1 dose of GWP42003-P in the trial will be 
included.  Only patients for whom it has been confirmed that they did not take any 
GWP42003-P will be excluded from this safety analysis set.  This analysis set will 
be used to report the safety data.  
13.3.1 
Protocol Deviations 
Protocol deviations will be listed.   
13.4 
General Considerations 
Unless stated otherwise, continuous variables will be summarized showing the number of 
nonmissing values (n), mean, standard deviation, median, minimum, and maximum, and 
categorical variables will be summarized showing the number and percentage of patients 
falling in each category. 
For clinic visit-based endpoints, baseline is defined as the last record or measure 
collected prior to the first dose of IMP in the RCT. 
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13.5 
Accountability and Background Characteristics 
13.5.1 
Enrollment and Disposition 
All patients (screened, randomized, 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 in each specific country), and other 
demographic or baseline characteristics including Clinical Severity Scale score and 
MECP2 mutation (confirmation and definition) will be summarized.  
13.5.3 
Concomitant Medication 
Concomitant medications taken prior to and during the trial will be summarized by 
medication class and active ingredients. 
13.6 
Endpoints and Statistical Methods 
The primary safety endpoint will be analyzed as detailed in Section 13.6.2.  Secondary 
endpoints will be analyzed as detailed in Section 13.6.3.  Exploratory endpoints will be 
analyzed as detailed in Section 13.6.4.  
13.6.1 
Evaluable Period 
The start of the evaluable period of the OLE trial (Day 1) is defined as the date the patient 
took his/her first dose of IMP in the clinic at Visit 1.  All data that will be collected 
during this trial will be summarized over time using appropriate descriptive statistics.  
Changes from baseline of the RCT will also be presented where appropriate.  
13.6.2 
Primary Safety Endpoints 
The safety endpoints are listed below and will be evaluated as detailed in the following 
sections: 
• AEs. 
• Clinical laboratory parameters. 
• Vital signs. 
• Physical examination procedures. 
• 12-lead ECG.  
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• Effects on menstruation cycles. 
• Suicidality. 
• Change in growth and development by measurement of height, weight, serum 
IGF-1 levels, and Tanner Staging (for patients aged ≥ 7 years or earlier, if 
clinically indicated by onset of menarche or other signs of precocious puberty). 
13.6.2.1 
Treatment Compliance and Extent of Treatment Exposure 
Treatment compliance and exposure to treatment will be summarized. 
13.6.2.2 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
dictionary. 
A treatment-emergent adverse event (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 preferred term and system organ 
class.  The number of patients reporting at least 1 TEAE will be provided. 
The following summaries will be produced as a minimum: 
• All-causality TEAEs. 
• Treatment-related AEs. 
• 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. 
13.6.2.3 
Vital Signs, 12-Lead Electrocardiogram, Physical Examination, 
and Other Safety Data 
Vital signs, ECG, physical examination, Tanner Staging, and serum IGF-1 levels will be 
summarized at each time point during the treatment period using appropriate summary 
statistics.  Changes in the vital signs and serum IGF-1 levels from baseline of the RCT to 
end of treatment will be summarized.  
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13.6.2.4 
Clinical Laboratory Data 
Clinical laboratory data at the end of treatment in the OLE and the change from baseline 
of the RCT to end of treatment will be summarized using appropriate summary statistics.  
Categorical shift tables will also be presented, showing the numbers of patients with 
values outside the normal range.   
13.6.2.5 
Menstruation 
Details of menstruation cycles (where appropriate) will be summarized and listed as 
appropriate. 
13.6.2.5.1 
Suicidality 
Suicidality assessment responses will be summarized and listed as appropriate. 
13.6.3 
Secondary Endpoint(s) 
There are several secondary endpoints.  For each endpoint, the change from baseline of 
the RCT will be derived.  For visit-based endpoints, baseline will be taken as the last 
measurement prior to the first dose of IMP (e.g. Visit 1 of the RCT). 
The following secondary endpoints will be assessed by evaluating changes relative to the 
prerandomization baseline of the RCT and will be summarized using appropriate 
descriptive statistics: 
• RSBQ. 
• CGI-I.  
• CGI-S. 
• MBA-9. 
• CSHQ. 
For patients who complete the trial, regardless of whether IMP is discontinued or not, the 
visit effect used in the analysis will correspond to the score at each trial visit 
(see Appendix 1).  However, patients who withdraw from the trial are required to 
complete the procedures at Visit 14 at the time of withdrawal.  For these patients, their 
Visit 14 data will be assigned to the nearest visit (for which the assessment is scheduled 
to be performed), based on the day of the visit.  Further details will be specified in the 
SAP. 
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13.6.4 
Exploratory Endpoint(s) 
The following exploratory endpoints for the trial will be assessed by evaluating changes 
relative to the prerandomization baseline of the RCT and will be summarized by time 
point: 
• SF-36. 
• CHQ-PF50. 
• Hospital Services Use Questionnaire  
• Caregiver Assessment of Rett Symptoms.  
13.6.5 
Handling of Missing Data 
There will be no imputation of missing data, and all observed data will be summarized. 
 
 
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14 
SAFETY MONITORING COMMITTEE 
No safety monitoring committee will be used 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 Helsinki73 the ICH 
Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP 
E6(R2)74 the EU Clinical Trials Directive78 the EU GCP Directive79 and the clinical trial 
regulations adopting European Commission Directives into national 
legislation.81,82,83,84,85 
15.2 
Informed Consent/Assent 
Initial master informed consent and assent forms will be prepared by GW and provided to 
the investigator, who will tailor these for their center by adding the center’s contact 
details and by using headed paper.  The GW clinical manager will communicate updates 
to the template by letter.  The written informed consent/assent documents 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’s parent(s)/legal representative 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 nominated caregiver will be asked to consent to complete the 
QoL questionnaires.  In cases where the patient possesses adequate understanding, assent 
will be taken (if allowed per local regulations) along with parent(s)/legal representative 
consent.  Assent is defined as the minor’s permission or affirmative agreement to 
participate in the trial.  The patient and/or parent(s)/legal representative must have ample 
time to consider the information provided before giving written consent/assent.  More 
specific definitions of “ample time” may be enforced if required by IRBs/IECs or local 
regulations. 
The acquisition of informed consent/assent must be documented in the patient’s medical 
records and the informed consent/assent forms must be signed and personally dated by 
the patient and/or parent(s)/legal representative/nominated caregiver (as applicable) and 
by the person who conducted the informed consent/assent discussion.  GW Research Ltd 
also requires a physician to be present for consent/assent and to sign the consent/assent 
forms.  The original signed informed consent/assent forms should be retained and a copy 
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provided to the patients’ parent(s)/legal representative/nominated caregiver 
(see Section 9.2.1). 
15.3 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent/assent forms, master informed 
consent/assent forms, 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 informed consent/assent forms 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/assent 
documents.  The investigator must notify the IRB/IEC of deviations from the protocol, 
SAEs occurring at the center, and other AE reports received from GW, in accordance 
with local procedures. 
The investigator will be responsible for obtaining ongoing IRB/IEC approval/renewal 
throughout the duration of the trial.  Copies of the investigator’s reports and the IRB/IEC 
continuance of approval must be sent to GW. 
15.4 
Pretrial Documentation Requirements 
The investigator is responsible for forwarding the following documents to GW or 
designee for review before allowing any patients to consent/assent for entry into the trial: 
• Signed and dated protocol signature page. 
• Copy of IRB/IEC-approved informed consent/assent forms (including version 
number and date) and other patient information material. 
• Copy of the IRB/IEC approval of the protocol, informed consent/assent forms 
(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 sub-investigators. 
• The IRB/IEC composition and/or written statement of the IRB/IEC in compliance 
with the FDA regulations relating to GCP and clinical trials75,76,77,86 the EU 
Clinical Trials Directive78 the EU GCP Directive79 or the ICH Harmonised 
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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. 
• Completed financial disclosure statements for the PI and all sub-investigators, if 
relevant. 
GW will ensure that the center 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 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 informed consent/assent forms, should be kept 
in strict confidence by the investigator. 
In compliance with the FDA regulations relating to GCP and clinical trials75,76,77,86 and 
the EU Clinical Trials Directive78and the ICH Harmonised Guideline: Integrated 
Addendum to ICH E6(R1): Guideline for GCP E6(R2)74 it is required that the 
investigator and institution permit authorized representatives of the company, the 
regulatory authorities, and the IRB/IEC 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 shall remain the sole property of the company.  The 
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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/assent documents.  The IRB/IEC and regulatory authorities must be 
informed of all substantial amendments and give approval.  Amendments for 
administrational 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 center, will be agreed 
with each center prior to patient recruitment.  In the rare situations of data (that would 
normally be recorded elsewhere) 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 ICH 
Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP 
E6[R2], Section 8.274), suitable for inspection at any time by representatives from GW 
and/or applicable regulatory authorities.  Elements should include the following: 
• Patient files containing completed eCRFs, informed consent/assent forms, and 
supporting copies of source documentation. 
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• Trial files containing the protocol with all amendments, IB, copies of pretrial 
documentation (see Section 15.4), and all correspondence to and from the 
IRB/IEC and GW. 
• Enrollment log of all patients who consented to take part in the trial. 
• 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 must be 
maintained and be readily available. 
Following completion or termination of a clinical trial, GW will initiate proper archive of 
clinical trial-related documentation and electronic records generated by the investigator 
and/or GW.  All clinical trial-related documents and electronic records will be retained 
within an archiving system for a period dependent on the 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 requirements79 or if needed by GW. 
GW Research Ltd will inform the investigators for each center 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 the eCRFs, 
questionnaires, and dosing schedule at regular intervals throughout the trial to verify 
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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 access to patient medical records and other trial-related records needed to verify the 
entries on the eCRFs. 
The investigator agrees to cooperate with the trial monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
To ensure the quality of clinical data across all patients and centers, 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 regulations75,76,77,86 ICH Harmonised 
Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP E6(R2)74 and all 
other applicable regulatory requirements.  To resolve any questions arising from the 
clinical data management review process, data queries and/or center notifications will be 
sent to the center for completion and then returned to GW or the CRO, as applicable.  
Investigators and caregivers will be trained on the importance of adhering to the trial 
requirements and assessment completion.  Where issues are identified, additional training 
will be provided. 
16.4 
Quality Assurance 
In accordance with the FDA regulations75,76,77,86 the EU Clinical Trials Directive78, the 
ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for GCP 
E6(R2),74 and the sponsor’s audit plans, representatives from GW’s Clinical Quality 
Assurance Department may select this trial for audit.  Inspection of center 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,78 the ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): 
Guideline for GCP E6(R2),74 and applicable regulatory requirements. 
16.5 
Compensation 
GW will indemnify the investigator and the trial center in the event of any claim in 
respect of personal injury arising due to a patient’s involvement in the trial, provided 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 
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provided for or required by the protocol to which the clinical trial patient would not 
otherwise have been exposed, provided that 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/principal investigators.  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 Law. 
The raw data from this trial may be obtained by the PIs or by their steering committee 
representatives on request.  Should they wish, PIs are allowed to conduct their own 
analyses and are permitted to present such information along with methods and results of 
the clinical trial at symposia or national or regional professional meetings and to publish 
it in theses or dissertations. 
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 for 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. 
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16.8 
Confidential Information 
GW and the PI must ensure that only personnel directly concerned with the trial have 
access to confidential information and that any information coming to either party about 
the other during the course of the trial must be kept strictly confidential and must not be 
disclosed to any third party or made use of without the prior written consent of the other. 
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17 
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30 GWOR1209 Study Report. Evaluation of the role of TRP channels in the 
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32 GWOR1215 Study Report. Evaluation of cannabinoid metabolites at TRP channels 
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37 GWCRI1509-B1 Study Report. The ability of cannabidiol in comparison with 
risperidone to improve a cognitive deficit induced by sub-chronic PCP in the novel 
object recognition task. May 2016. 
38 GWCRI1509-B2 Study Report. The ability of cannabidiol in comparison with 
risperidone to improve a deficit induced by sub-chronic PCP in the social interaction 
task. May 2016. 
39 GWCRI1547-C Study Report. The effects of CBD following bicuculline-induced 
seizure in newborn rats and piglets. Jan 2018. 
40 GWCRI09119D Study Report. Evaluation of CBD in a rat model of NHIE. Feb 2015. 
41 GWCRI1547-B Study Report/ The effects of CBD and CBDV following hypoxic-
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44 Devinsky O, Thiele E, Laux L, et al. Efficacy and safety of Epidiolex (cannabidiol) in 
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conduct of clinical trials on medicinal products for human use.  Official Journal of the 
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Appendix 1 
Schedule of Assessments 
 
Visit Number 
1 
2a 
3a 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14b,c 
EoT/ 
Withdrawal 
15  
(end 
of 
taper) 
16a 
(follow-
up) 
Day Number 
(Visit Window) 
1 
 
8 
(±3) 
15 
(± 3) 
29 
(± 7) 
57 
(± 7) 
85 
(± 7) 
141 
(± 7) 
197 
(± 7) 
281 
(± 7) 
365 
(± 7) 
456 
(± 7) 
547 
(± 7) 
638 
(± 7) 
729 
(± 7) 
739 
(+ 7) 
767 
(+ 7) 
Informed consent and assentd 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
New medical history 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Menstruation question (where 
appropriate) 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Physical examination (including 
body weight) 
Xf 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
(X) 
 
Height 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
ECG 
Xf 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
 
Vital signs 
Xg 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Clinical laboratory blood 
sampling (hematology and 
biochemistry)h 
Xf 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
(X) 
 
Hepatic function monitoring 
paneli 
 
 
 
 
 
 
Xi 
 
 
 
Xi 
 
Xi 
 
 
 
Dipstick urinalysis (where 
possible) 
Xf 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
(X) 
 
Page 228 of 265


SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V2 18Dec19 
Confidential 
Page 103 of 105 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
Visit Number 
1 
2a 
3a 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14b,c 
EoT/ 
Withdrawal 
15  
(end 
of 
taper) 
16a 
(follow-
up) 
Day Number 
(Visit Window) 
1 
 
8 
(±3) 
15 
(± 3) 
29 
(± 7) 
57 
(± 7) 
85 
(± 7) 
141 
(± 7) 
197 
(± 7) 
281 
(± 7) 
365 
(± 7) 
456 
(± 7) 
547 
(± 7) 
638 
(± 7) 
729 
(± 7) 
739 
(+ 7) 
767 
(+ 7) 
Serum pregnancy test (if 
appropriate) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Caregiver completed 
questionnaire/assessment
RSBQ 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
CSHQ 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
Caregiver QoL 
questionnaire (SF-36) 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Patient QoL questionnaire 
(CHQ-PF50) 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Hospital Services Use 
Questionnaire  
Xg 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
Tanner Staging (where 
appropriate)  
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Caregiver Assessment of 
Rett Symptoms 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
MBA-9 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
CGI-S 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
CGI-I 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
Suicidality assessment 
Xg 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
GWP42003-P dispensing 
Xe 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
GWP42003-P collection and 
compliance review 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing schedulej 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Page 229 of 265


SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V2 18Dec19 
Confidential 
Page 104 of 105 
Clinical Protocol Template (Phase 2–4) 
V1, 24Sep15 
(X) = if clinically indicated; EoT = end of treatment 
a Visit to be conducted by telephone. 
b To be performed to all patients completing or withdrawing from the trial.  Patients who withdraw early should commence the 10-day GWP42003-P taper 
period, if possible. 
c A safety follow-up Visit 4 weeks after last GWP42003-P dose is required for all patients who withdraw from the trial or complete the trial. 
d Informed consent must be obtained prior to any trial-related procedures.  In cases where the patient possesses adequate understanding, assent will be taken 
along with parent(s)/legal representative consent.  The nominated caregiver will be asked to complete the quality of life questionnaires. 
e Always required. 
f Required only if OLE Visit 1 is > 28 days after RCT Visit 9. 
g Required if OLE Visit 1 does not occur on the same day as RCT Visit 9.  
h Determination of serum IGF-1 levels at Visits 1, 8, 10, and 14 only; IGF-1 laboratory results will remain blinded throughout the trial. 
i Hepatic function monitoring is required following increases in GWP42003-P dose or introduction of medications that are known to impact liver function.  
If the concerned change does not occur within 1 month of a scheduled biochemistry assessment, the investigator should perform an additional hepatic 
monitoring within 1 month of the change.  Hepatic monitoring at Visit 7, 11 and 13 is required for patients taking concomitant valproic acid or whose dose 
exceeds 15 mg/kg/day. 
j  The dosing schedule is to be completed by the caregiver daily throughout the trial and reviewed at Visits 2 through 15. 
 
 
Page 230 of 265


SPONSOR: GW RESEARCH LIMITED 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Clinical Protocol V2 18Dec19 
Confidential 
Page 105 of 105 
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 Research Ltd 
(GW) master files (electronically and added to the trial master file at the end of the trial). 
Appendix 2.2 
Sponsor Contact Details 
 
 
Email: 
  
Tel: 
 
Fax: 
 
USA Toll-free Fax:  
 
Sponsor: 
GW Research 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 
At the time of protocol production, the contract research organizations (CROs) and the 
clinical 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): 
Trial Conduct 
Premier Research Europe 
1st Floor, Rubra 2 
Mulberry Business Park 
Fishponds Road 
Wokingham, RG41 2GY 
United Kingdom 
Tel: 
 
 
 
Page 231 of 265
PI
PI
PI
PI
PI
PI


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 1 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
 
AN OPEN-LABEL EXTENSION TRIAL TO INVESTIGATE THE 
LONG-TERM SAFETY OF CANNABIDIOL ORAL SOLUTION 
(GWP42003-P, CBD-OS) IN PATIENTS WITH RETT SYNDROME 
 
 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
CLINICAL PROTOCOL ANNEX 1 
The purpose of this protocol annex is to detail changes which are applicable only to 
patients who were affected by COVID-19 pandemic containment measures during 
their participation in the parent study GWND18064 
 
GW Research 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 Research Ltd (GW) that 
must not be disclosed to anyone other than the recipient study 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. 
Page 232 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 2 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
Investigator Agreement 
I have read the attached clinical protocol annex 1 entitled An Open-label Extension 
Trial to Investigate the Long-term Safety of Cannabidiol Oral Solution 
(GWP42003-P, CBD-OS) in Patients with Rett Syndrome, dated 28 May 2020 and 
agree to abide by all provisions set forth therein. 
I agree to comply with applicable regulatory requirement(s); the United States (US) 
Food and Drug Administration (FDA) regulations relating to Good Clinical Practice 
(GCP) and clinical trials, the European Union (EU) Clinical Trials Directive 
(2001/20/EC), 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 participants 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. 
Center No: 
 
  
 
 
 
  
 
Print name:  
 Date:  
 
Principal investigator 
 
  
(DD Month YYYY) 
Signature: 
 
  
 
 
GW Authorization  
 Date:  
  
(DD Month YYYY) 
  
 
02 June 2020
Page 233 of 265
PI


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 3 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
Table of Contents 
Title Page ................................................................................................... 1 
Table of Contents ...................................................................................... 3 
List of Abbreviations ................................................................................ 4 
Definition of Terms ................................................................................... 5 
1 
RATIONALE ................................................................................... 6 
2 
SUMMARY OF THE ANNEX ....................................................... 7 
2.1 
Objective ....................................................................................................... 7 
3 
DESIGN AND PROCEDURES...................................................... 8 
3.1 
Patient Eligibility ........................................................................................... 8 
3.2 
Trial Procedures ............................................................................................ 9 
3.2.1 
Visit 1 Procedures ....................................................................................... 9 
4 
DATA ANALYSIS ......................................................................... 10 
5 
IMPLEMENTATION OF THE ANNEX .................................... 11 
6 
REFERENCES .............................................................................. 12 
 
Page 234 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 4 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
List of Abbreviations 
 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CBD 
Cannabidiol 
COVID-19 
Coronavirus disease 2019 
EU 
European Union 
GCP 
Good clinical practice 
GW 
GW Research Ltd 
IMP 
Investigational medicinal product 
OLE 
Open-label extension 
RCT 
Randomized controlled trial 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
Page 235 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 5 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
Definition of Terms 
Term 
Definition 
Caregiver 
An assigned patient’s parent or designated care provider. 
Day 1 
The day a participant first receives investigational medicinal 
product in this trial. 
End of treatment 
Completion of the treatment period (Visit 14 [Day 729]), or 
withdrawal. 
End of trial 
Last participant last visit/telephone call. 
Enrolled participant 
Any patient whose parent(s)/legal representative has 
provided written informed consent for the patient to take part 
in the trial and, if possessing adequate understanding to do 
so, who has provided informed assent. 
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 study 
physician. 
 
Page 236 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 6 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
1 
RATIONALE 
This addendum covers protocol changes which are applicable to patients who were 
affected by COVID-19 pandemic containment measures during their participation in 
the parent study GWND18064:  
• Allowance for patients to enroll into GWND19002 after the point of 
GWND18064 follow-up (Visit 11). 
• Allowance for patients who withdrew from GWND18064 due to COVID-19 
pandemic containment measures to enroll into GWND19002 at a later date, 
when appropriate. 
There are no implications for the conduct of the GWND19002 trial for patients that 
were not affected by the COVID-19 pandemic containment measures, and no changes 
are required to the Clinical Protocol currently approved at each territory.  Please see 
Section 3 for full details of changes. 
 
Page 237 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 7 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
2 
SUMMARY OF THE ANNEX 
2.1 
Objective 
Due to the COVID-19 pandemic situation, patients may have been unable to attend 
the scheduled clinic visits or local safety assessments deemed required for the safe 
continuation of investigational medicinal product (IMP) dosing.  This situation may 
have resulted in the inability to complete GWND18064 or enroll into GWND19002 
within the timeline stipulated in the protocol (up to GWND18064 Visit 11). 
The objective of this annex is to define when patients whose participation in 
Study GWND18064 was disrupted by COVID-19 pandemic containment measures 
are allowed to take part in GWND19002 despite not meeting the criterion ‘Patient has 
completed all scheduled visits of the treatment phase of the randomized controlled 
trial (RCT), GWND18064, and has transitioned to open-label extension (OLE) by the 
point of RCT follow-up (Visit 11)’ defined in the GWND19002 protocol.  The 
measures implemented via this protocol annex do not affect the primary objective of 
GWND19002, which is to evaluate the long-term safety of GWP42003-P in patients 
with Rett Syndrome. 
Page 238 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 8 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
3 
DESIGN AND PROCEDURES 
3.1 
Patient Eligibility 
With the exception of the inclusion criterion that requires patients must have 
completed all scheduled visits of the treatment phase of the RCT, GWND18064, and 
transitioned to OLE by the point of RCT follow-up (Visit 11), all inclusion and 
exclusion criteria defined in the GWND19002 protocol must be met. In addition, the 
following inclusion criteria apply: 
Inclusion criteria 
• Patient has completed all scheduled visits of the treatment phase of the RCT, 
either in clinic or completed as many scheduled assessments as feasible 
remotely, or has withdrawn from GWND18064 after discussion with the 
medical monitor due to inability to adequately monitor safety and benefit risk.  
• Visit 1 is taking place no later than 3 months after screening of new subjects 
for study GWND18064 has reopened at their trial site.  
Exclusion criteria 
• Any history of suicidal behavior or any suicidal ideation in the last month or at 
Visit 1. 
• 
Patient has clinically relevant abnormalities in the electrocardiogram measured at 
Visit 1 (including QT interval, corrected by Bazett's correction formula [QTcB] 
> 450 msec, average of 3 measurements).  
• 
Patient has any known or suspected hypersensitivity to cannabinoids or any of 
the excipients of the IMP (active and placebo), such as sesame oil. 
• 
Patient has moderately impaired hepatic function at screening, defined as serum 
ALT or AST > 3 × ULN or total bilirubin [TBL] > 2 × ULN.  
This criterion can only be confirmed once the Visit 1 laboratory results are 
available.  If Visit 1 laboratory results indicate the patient is not eligible, the 
patient must be withdrawn.  Prior to withdrawal for the transaminase elevations 
noted above, the investigator may choose to confirm the transaminase elevations 
by repeating the following laboratory tests within 24 to 48 hours: ALT, AST, 
TBL, international normalized ratio, % eosinophils, gamma-glutamyl 
transferase, alkaline phosphatase, and eosinophils.  Should the above 
transaminase elevation criteria be confirmed, the patient must be withdrawn 
from the trial. 
• 
Patient has received an IMP (other than GWND18064 IMP) since participation in 
GWND18064.  
• 
Patient has been taking felbamate for less than 1 year prior to Visit 1  
Page 239 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 9 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
• 
Patient is currently using or has used recreational or medicinal cannabis, 
cannabinoid-based medications (including Sativex® [nabiximols]) or cannabidiol 
oral solutions (excluding GWND18064 IMP) within the 3 months prior to Visit 1 
and is unwilling to abstain for the duration of the trial.  
• 
Patient has any other systemic dysfunction (e.g., gastrointestinal, renal, 
respiratory) or significant disease or disorder which, in the opinion of the 
investigator, may either put the patient at risk because of participation in the trial, 
may influence the result of the trial, or the patient’s ability to participate in the 
trial.  
• 
Any abnormalities identified following a physical examination of the patient that, 
in the opinion of the investigator, would jeopardize the safety of the patient if the 
patient took part in the trial.  
• 
Female patient is pregnant (positive pregnancy test) or lactating. 
3.2 
Trial Procedures 
3.2.1 
Visit 1 Procedures 
Visit 1 must include the Visit 1 assessments listed in the GWND19002 protocol as 
required for patients for whom OLE Visit 1 occurs > 28 days after RCT Visit 9. 
In addition the following assessments are required: 
• Concomitant medications review (details of all current and recent medication; 
i.e., those taken within the previous 14 days of Visit 1) 
• Menstruation question (where appropriate) 
• Height 
• Serum pregnancy test (if appropriate) 
• Rett Syndrome Behaviour Questionnaire 
• Children’s Sleep Habits Questionnaire 
• Caregiver QoL questionnaire (SF-36) 
• Patient QoL questionnaire (CHQ-PF50) 
• Tanner Staging (where appropriate) 
• Caregiver Assessment of Rett Symptoms 
• 9-items Motor Behavioral Assessment  
• Clinical Global Impressions - Severity 
• Clinical Global Impressions - Improvement (completed in relation to the 
baseline of the RCT, GWND18064 Visit 2) 
Page 240 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 10 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
4 
DATA ANALYSIS 
All Visit 1 data will be summarized for patients enrolling in the OLE under this 
protocol annex.  Their data will be summarized in the same way as that of patients 
enrolling in the OLE under the GWND19002 protocol.  The summary tables will 
present data from patients enrolling in the OLE under this protocol annex combined 
with that of patients enrolling in the OLE under the GWND19002 protocol.  Their 
data will also be presented separately. 
Page 241 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 11 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
5 
IMPLEMENTATION OF THE ANNEX 
This clinical protocol annex will be issued in conjunction with the current version of 
the main clinical trial protocol to country/sites affected by the COVID-19 pandemic 
containment situation.  It will be kept in the trial master file at GW as well as in each 
investigational centre file and, if applicable, pharmacy site file. 
Page 242 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V1 28May2020 
 
Confidential 
Page 12 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
6 
REFERENCES 
No changes. 
 
Page 243 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
Confidential 
Page 1 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
 
AN OPEN-LABEL EXTENSION TRIAL TO INVESTIGATE THE 
LONG-TERM SAFETY OF CANNABIDIOL ORAL SOLUTION 
(GWP42003-P, CBD-OS) IN PATIENTS WITH RETT SYNDROME 
 
 
Study Code: GWND19002
EudraCT Number: 2019-001605-24 
CLINICAL PROTOCOL ANNEX 1 
The purpose of this protocol annex is to detail changes which are applicable only to 
patients who were affected by COVID-19 pandemic containment measures during 
their participation in the parent study GWND18064 or withdrew from GWND18064 
due to sponsor administrative decision 
 
GW Research 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 Research Ltd (GW) that 
must not be disclosed to anyone other than the recipient study 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. 
Page 244 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
Confidential 
Page 2 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
Investigator Agreement 
I have read the attached clinical protocol annex 1 entitled An Open-label Extension 
Trial to Investigate the Long-term Safety of Cannabidiol Oral Solution
(GWP42003-P, CBD-OS) in Patients with Rett Syndrome, dated 11 Nov 2020 and 
agree to abide by all provisions set forth therein. 
I agree to comply with applicable regulatory requirement(s); the United States (US) 
Food and Drug Administration (FDA) regulations relating to good clinical practice 
(GCP) and clinical trials, the European Union (EU) Clinical Trials Directive 
(2001/20/EC), 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 participants 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. 
Center No: 
 
 
 
 
 
  
 
Print name:  
 Date:  
 
Principal investigator 
 
  
(DD Month YYYY) 
Signature:
 
  
 
GW Authorization 
 
Page 245 of 265
PI
PI


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 3 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
Table of Contents 
Title Page ................................................................................................... 1 
Table of Contents ...................................................................................... 3
List of Abbreviations ................................................................................ 4
Definition of Terms ................................................................................... 5
1 
RATIONALE ................................................................................... 6
2 
SUMMARY OF THE ANNEX....................................................... 7
2.1
Objective ....................................................................................................... 7
3 
DESIGN AND PROCEDURES...................................................... 8
3.1
Patient Eligibility ........................................................................................... 8
3.2
Trial Procedures ............................................................................................ 9
3.2.1
Visit 1 Procedures ....................................................................................... 9
4 
DATA ANALYSIS ......................................................................... 10
5 
IMPLEMENTATION OF THE ANNEX.................................... 11
6 
REFERENCES .............................................................................. 12
 
Page 246 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 4 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
List of Abbreviations 
 
ALT
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CBD 
Cannabidiol 
COVID-19 
Coronavirus disease 2019 
EU 
European Union 
GCP 
Good clinical practice 
GW 
GW Research Ltd 
IMP 
Investigational medicinal product 
OLE 
Open-label extension 
RCT 
Randomized controlled trial 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
Page 247 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 5 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
Definition of Terms 
Term
Definition
Caregiver 
An assigned patient’s parent or designated care provider. 
Day 1 
The day a participant first receives investigational medicinal 
product in this trial. 
End of treatment 
Completion of the treatment period (Visit 14 [Day 729]), or 
withdrawal. 
End of trial 
Last participant last visit/telephone call. 
Enrolled participant 
Any patient whose parent(s)/legal representative has 
provided written informed consent for the patient to take part 
in the trial and, if possessing adequate understanding to do 
so, who has provided informed assent. 
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 study 
physician. 
 
Page 248 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 6 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
1 
RATIONALE 
This annex covers protocol changes which are applicable to patients who were 
affected by COVID-19 pandemic containment measures during their participation in 
the parent study GWND18064 or withdrew from GWND18064 due to sponsor 
administrative decision:  
 Allowance for patients to enroll into GWND19002 after the point of 
GWND18064 follow-up (Visit 11). 
 Allowance for patients who withdrew from GWND18064 due to COVID-19 
pandemic containment measures or withdrew from GWND18064 due to 
sponsor administrative decision to enroll into GWND19002 at a later date, 
when appropriate. 
There are no implications for the conduct of the GWND19002 trial for patients who
were not affected by the COVID-19 pandemic containment measures or 
administrative withdrawal, and no changes are required to the Clinical Protocol 
currently approved at each territory.  Please see Section 3 for full details of changes. 
 
Page 249 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 7 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
2 
SUMMARY OF THE ANNEX 
2.1
Objective 
Due to the COVID-19 pandemic situation, patients may have been unable to attend 
the scheduled clinic visits or local safety assessments deemed required for the safe 
continuation of investigational medicinal product (IMP) dosing.  This situation may 
have resulted in the inability to complete GWND18064 or enroll into GWND19002 
within the timeline stipulated in the protocol (up to GWND18064 Visit 11). 
The objective of this annex is to define when patients whose participation in 
Study GWND18064 was disrupted by COVID-19 pandemic containment measures 
are allowed to take part in GWND19002 despite not meeting the criterion ‘Patient has 
completed all scheduled visits of the treatment phase of the randomized controlled 
trial (RCT), GWND18064, and has transitioned to open-label extension (OLE) by the 
point of RCT follow-up (Visit 11)’ defined in the GWND19002 protocol.  This annex 
also applies to patients who withdrew from GWND18064 due to sponsor 
administrative decision.  The measures implemented via this protocol annex do not 
affect the primary objective of GWND19002, which is to evaluate the long-term 
safety of GWP42003-P in patients with Rett Syndrome. 
Page 250 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 8 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
3 
DESIGN AND PROCEDURES 
3.1
Patient Eligibility 
With the exception of the inclusion criterion that requires patients must have 
completed all scheduled visits of the treatment phase of the RCT, GWND18064, and 
transitioned to OLE by the point of RCT follow-up (Visit 11), all inclusion and 
exclusion criteria defined in the GWND19002 protocol must be met.  
In addition, the following inclusion criteria apply:
Inclusion criteria
 Patient has completed all scheduled visits of the treatment phase of the RCT, 
either in clinic or completed as many scheduled assessments as feasible 
remotely, or has withdrawn from GWND18064 after discussion with the 
medical monitor due to inability to adequately monitor safety and benefit risk, 
or has withdrawn from GWND18064 due to sponsor administrative decision.   
For patients who enroll after the point of RCT follow-up (Visit 11) the following 
additional exclusion criteria must be confirmed:
Exclusion criteria 
 Any history of suicidal behavior or any suicidal ideation in the last month or 
at Visit 1.
 Patient has clinically relevant abnormalities in the electrocardiogram 
measured at Visit 1 (including QT interval, corrected by Bazett's correction 
formula [QTcB] > 450 msec, average of 3 measurements).  
 Patient has any known or suspected hypersensitivity to cannabinoids or any of 
the excipients of the IMP (active and placebo), such as sesame oil. 
 Patient has moderately impaired hepatic function at screening, defined as 
serum ALT or AST > 3 × ULN or total bilirubin [TBL] > 2 × ULN.  
This criterion can only be confirmed once the Visit 1 laboratory results are 
available.  If Visit 1 laboratory results indicate the patient is not eligible, the 
patient must be withdrawn.  Prior to withdrawal for the transaminase 
elevations noted above, the investigator may choose to confirm the 
transaminase elevations by repeating the following laboratory tests within 
24 to 48 hours: ALT, AST, TBL, international normalized ratio, % 
eosinophils, gamma-glutamyl transferase, alkaline phosphatase, and 
eosinophils.  Should the above transaminase elevation criteria be confirmed, 
the patient must be withdrawn from the trial.
 Patient has received an IMP (other than GWND18064 IMP) since 
participation in GWND18064.  
Page 251 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 9 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
 Patient has been taking felbamate for less than 1 year prior to Visit 1  
 Patient is currently using or has used recreational or medicinal cannabis, 
cannabinoid-based medications (including Sativex® [nabiximols]) or 
cannabidiol oral solutions (excluding GWND18064 IMP) within the 3 months 
prior to Visit 1 and is unwilling to abstain for the duration of the trial. 
 Patient has any other systemic dysfunction (e.g., gastrointestinal, renal, 
respiratory) or significant disease or disorder which, in the opinion of the 
investigator, may either put the patient at risk because of participation in the 
trial, may influence the result of the trial, or the patient’s ability to participate 
in the trial.  
 Any abnormalities identified following a physical examination of the patient 
that, in the opinion of the investigator, would jeopardize the safety of the 
patient if the patient took part in the trial.  
 Female patient is pregnant (positive pregnancy test) or lactating.
3.2 
Trial Procedures
3.2.1 
Visit 1 Procedures 
For patients who enroll after the point of RCT Visit 11, GWND19002 Visit 1 must 
include the Visit 1 assessments listed in the GWND19002 protocol as required for 
patients for whom OLE Visit 1 occurs > 28 days after RCT Visit 9 and, in addition,
the following assessments are required: 
 Concomitant medications review (details of all current and recent medication; 
i.e., those taken within the previous 14 days of Visit 1) 
 Menstruation question (where appropriate) 
 Height 
 Serum pregnancy test (if appropriate) 
 Rett Syndrome Behaviour Questionnaire 
Children’s Sleep Habits Questionnaire 
Caregiver QoL questionnaire (SF-36) 
 Patient QoL questionnaire (CHQ-PF50) 
 Tanner Staging (where appropriate) 
 Caregiver Assessment of Rett Symptoms 
 9-items Motor Behavioral Assessment  
 Clinical Global Impressions - Severity 
 Clinical Global Impressions - Improvement (completed in relation to the 
baseline of the RCT, GWND18064 Visit 2) 
Page 252 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 10 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
4 
DATA ANALYSIS 
All Visit 1 data will be summarized for patients enrolling in the OLE under this 
protocol annex.  Their data will be summarized in the same way as that of patients 
enrolling in the OLE under the GWND19002 protocol.  The summary tables will 
present data from patients enrolling in the OLE under this protocol annex combined 
with that of patients enrolling in the OLE under the GWND19002 protocol.  Their 
data will also be presented separately. 
Page 253 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 11 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
5 
IMPLEMENTATION OF THE ANNEX 
This clinical protocol annex will be issued in conjunction with the current version of 
the main clinical trial protocol to applicable country/sites. It will be kept in the trial 
master file at GW as well as in each investigational center file and, if applicable, 
pharmacy site file. 
Page 254 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 V2, Date: 11Nov2020 
 
Confidential 
Page 12 of 12 
Clinical Protocol Annex Template 
V2, 14 Jan 19 
6 
REFERENCES 
No changes. 
 
Page 255 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 1 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
AN OPEN-LABEL EXTENSION TRIAL TO INVESTIGATE THE 
LONG-TERM SAFETY OF CANNABIDIOL ORAL SOLUTION 
(GWP42003-P, CBD-OS) IN PATIENTS WITH RETT SYNDROME 
Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
CLINICAL PROTOCOL ANNEX 1 AMENDMENT 
NUMBER 1 
to be incorporated into the Protocol Annex, creating 
CLINICAL PROTOCOL ANNEX 1 VERSION 2, 
DATE 11 NOVEMBER 2020 
GW Research 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 Research Ltd (GW) that 
must not be disclosed to anyone other than the recipient study 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. 
Page 256 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 2 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
Table of Contents 
Title Page ...................................................................................... 1 
Table of Contents ......................................................................... 2 
1 
RATIONALE ...................................................................... 3 
2 
IMPLEMENTATION OF THE AMENDMENT ............ 4 
3 
PRESENTATION OF AMENDED TEXT ...................... 5 
4 
REFERENCES ................................................................. 10 
 
Page 257 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 3 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
1 
RATIONALE 
This clinical protocol annex amendment 1 (will be incorporated into the Protocol 
Annex creating Clinical Protocol Annex 1 Version 2, Date 11 November 2020) 
addresses the following issue(s): Extension of annex scope to patients who withdraw 
from GWND18064 due to sponsor administrative decision (as a result of 
GWND18064 study termination) 
• Removal of requirement for GWND18064 screening to have reopened at site 
within the last 3 months (given screening for GWND18064 is closed) 
 
 
Page 258 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 4 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
2 
IMPLEMENTATION OF THE AMENDMENT 
The changes detailed in this amendment will be issued as Clinical Protocol Annex 1 
Version 2, Date 11 November 2020.  It will be kept in the trial master file at GW as 
well as in each applicable investigational center file and, if applicable, pharmacy site 
file. 
 
Page 259 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 5 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
3 
PRESENTATION OF AMENDED TEXT 
The text will be amended as follows: 
Revised Protocol 
Annex Section 
Number, Heading 
and Page Number 
Original Wording from Clinical Protocol Annex 1 
Version 1, 
Date 28 May 2020 
(Deleted wording is struck through and in bold) 
Revised Wording from Clinical Protocol Annex 1 
Amendment 1 
(Clinical Protocol Annex 1 Version 2 
Date 11 November 2020) 
(Revised wording is underscored and in bold)  
Rationale for the 
amendment 
Title Page 
p. 1 
The purpose of this protocol annex is to detail changes 
which are applicable only to patients who were affected 
by COVID-19 pandemic containment measures during 
their participation in the parent study GWND18064  
The purpose of this protocol annex is to detail changes 
which are applicable only to patients who were affected 
by COVID-19 pandemic containment measures during 
their participation in the parent study GWND18064 or 
withdrew from GWND18064 due to sponsor 
administrative decision 
See Section 1 
Section 1 
Rationale 
p. 6 
 
 
 
 
 
 
This addendum covers protocol changes which are 
applicable to patients who were affected by COVID-19 
pandemic containment measures during their 
participation in the parent study GWND18064:  
• 
Allowance for patients to enroll into 
GWND19002 after the point of GWND18064 
follow-up (Visit 11). 
• 
Allowance for patients who withdrew from 
GWND18064 due to COVID-19 pandemic 
This addendum covers protocol changes which are 
applicable to patients who were affected by COVID-19 
pandemic containment measures during their 
participation in the parent study GWND18064 or 
withdrew from GWND18064 due to sponsor 
administrative decision:  
• 
Allowance for patients to enroll into 
GWND19002 after the point of GWND18064 
follow-up (Visit 11). 
See Section 1 
Page 260 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 6 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
Revised Protocol 
Annex Section 
Number, Heading 
and Page Number 
Original Wording from Clinical Protocol Annex 1 
Version 1, 
Date 28 May 2020 
(Deleted wording is struck through and in bold) 
Revised Wording from Clinical Protocol Annex 1 
Amendment 1 
(Clinical Protocol Annex 1 Version 2 
Date 11 November 2020) 
(Revised wording is underscored and in bold)  
Rationale for the 
amendment 
Section 1 
Rationale 
p. 6 
(continued) 
containment measures to enroll into 
GWND19002 at a later date, when appropriate. 
There are no implications for the conduct of the 
GWND19002 trial for patients that were not affected by 
the COVID-19 pandemic containment measures, and no 
changes are required to the Clinical Protocol currently 
approved at each territory.  Please see Section 3 for full 
details of changes. 
• 
Allowance for patients who withdrew from 
GWND18064 due to COVID-19 pandemic 
containment measures or withdrew from 
GWND18064 due to sponsor administrative 
decision to enroll into GWND19002 at a later 
date, when appropriate. 
There are no implications for the conduct of the 
GWND19002 trial for patients who were not affected by 
the COVID-19 pandemic containment measures or 
administrative withdrawal, and no changes are 
required to the Clinical Protocol currently approved at 
each territory.  Please see Section 3 for full details of 
changes. 
Page 261 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 7 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
Revised Protocol 
Annex Section 
Number, Heading 
and Page Number 
Original Wording from Clinical Protocol Annex 1 
Version 1, 
Date 28 May 2020 
(Deleted wording is struck through and in bold) 
Revised Wording from Clinical Protocol Annex 1 
Amendment 1 
(Clinical Protocol Annex 1 Version 2 
Date 11 November 2020) 
(Revised wording is underscored and in bold)  
Rationale for the 
amendment 
Section 2.1 
Objective 
p. 7 
(…) 
The objective of this annex is to define when patients 
whose participation in Study GWND18064 was 
disrupted by COVID-19 pandemic containment 
measures are allowed to take part in GWND19002 
despite not meeting the criterion ‘Patient has completed 
all scheduled visits of the treatment phase of the 
randomized controlled trial (RCT), GWND18064, and 
has transitioned to open-label extension (OLE) by the 
point of RCT follow-up (Visit 11)’ defined in the 
GWND19002 protocol.   
(…) 
(…) 
The objective of this annex is to define when patients 
whose participation in Study GWND18064 was 
disrupted by COVID-19 pandemic containment 
measures are allowed to take part in GWND19002 
despite not meeting the criterion ‘Patient has completed 
all scheduled visits of the treatment phase of the 
randomized controlled trial (RCT), GWND18064, and 
has transitioned to open-label extension (OLE) by the 
point of RCT follow-up (Visit 11)’ defined in the 
GWND19002 protocol.  This annex also applies to 
patients who withdrew from GWND18064 due to 
sponsor administrative decision. 
(…) 
See Section 1 
Page 262 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 8 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
Revised Protocol 
Annex Section 
Number, Heading 
and Page Number 
Original Wording from Clinical Protocol Annex 1 
Version 1, 
Date 28 May 2020 
(Deleted wording is struck through and in bold) 
Revised Wording from Clinical Protocol Annex 1 
Amendment 1 
(Clinical Protocol Annex 1 Version 2 
Date 11 November 2020) 
(Revised wording is underscored and in bold)  
Rationale for the 
amendment 
Section 3.1 
Patient Eligibility 
p. 8 
Inclusion criteria 
• 
Patient has completed all scheduled visits of 
the treatment phase of the RCT, either in 
clinic or completed as many scheduled 
assessments as feasible remotely, or has 
withdrawn from GWND18064 after 
discussion with the medical monitor due to 
inability to adequately monitor safety and 
benefit risk. 
• 
Visit 1 is taking place no later than 3 
months after screening of new subjects 
for study GWND18064 has reopened at 
their trial site. 
Exclusion criteria 
(…) 
Inclusion criteria 
• 
Patient has completed all scheduled visits of the 
treatment phase of the RCT, either in clinic or 
completed as many scheduled assessments as 
feasible remotely, or has withdrawn from 
GWND18064 after discussion with the medical 
monitor due to inability to adequately monitor 
safety and benefit risk, or has withdrawn from 
GWND18064 due to sponsor administrative 
decision.  
For patients who enroll after the point of RCT 
follow-up (Visit 11) the following additional exclusion 
criteria must be confirmed: 
Exclusion criteria 
(…) 
See Section 1 
Page 263 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 9 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
Revised Protocol 
Annex Section 
Number, Heading 
and Page Number 
Original Wording from Clinical Protocol Annex 1 
Version 1, 
Date 28 May 2020 
(Deleted wording is struck through and in bold) 
Revised Wording from Clinical Protocol Annex 1 
Amendment 1 
(Clinical Protocol Annex 1 Version 2 
Date 11 November 2020) 
(Revised wording is underscored and in bold)  
Rationale for the 
amendment 
Section 3.2.1  
Visit 1 Procedures 
p. 9 
Visit 1 must include the Visit 1 assessments listed in the 
GWND19002 protocol as required for patients for whom 
OLE Visit 1 occurs > 28 days after RCT Visit 9. 
In addition, the following assessments are required: 
(…) 
For patients who enroll after the point of RCT 
Visit 11, GWND19002 Visit 1 must include the Visit 1 
assessments listed in the GWND19002 protocol as 
required for patients for whom OLE Visit 1 occurs 
> 28 days after RCT Visit 9 and, in addition, the 
following assessments are required: 
(…) 
 
See Section 1 
Section 5 
Implementation of 
the Annex 
p. 11 
This clinical protocol annex will be issued in 
conjunction with the current version of the main clinical 
trial protocol to country/sites affected by the COVID-
19 pandemic containment situation.  It will be kept in 
the trial master file at GW as well as in each 
investigational centre file and, if applicable, pharmacy 
site file. 
This clinical protocol annex will be issued in conjunction 
with the current version of the main clinical trial 
protocol to applicable country/sites.  It will be kept in 
the trial master file at GW as well as in each 
investigational center file and, if applicable, pharmacy 
site file. 
See Section 1 
 
Page 264 of 265


Study Code: GWND19002 
EudraCT Number: 2019-001605-24 
Protocol Annex 1 Amendment 1, Date: 11Nov2020 
 
Confidential 
Page 10 of 10 
Clinical Protocol Amendment Template 
V2, 14 Jan 19 
4 
REFERENCES 
N/A 
Page 265 of 265

SAP_001.pdf: 
Study GWND19002 
 
Final Synoptic CSR (V1.0), 08-Nov-2021 
Product: GWP42003-P 
GWND19002 
Confidential
Appendix 1.9 
Documentation of Statistical Methods 
Statistical Analysis Plan dated 15 June 2021 
Page 1 of 47


 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version Final  | 15-JUN-2021   |    AD-PR-109.02  Effective date: 17-Aug-2020 
         Page 1 of 46 
Statistical Analysis Plan
Sponsor 
GW Research Ltd 
Protocol Title: 
AN OPEN-LABEL EXTENSION TRIAL TO INVESTIGATE 
THE LONG-TERM SAFETY OF CANNABIDIOL ORAL 
SOLUTION (GWP42003-P, CBD-OS) IN PATIENTS WITH 
RETT SYNDROME 
Protocol Number: 
GWND19002 
Premier Research PCN: 
GWRE209830 
EudraCT number: 
2019-001605-24 
ClinicalTrials.gov 
identifier 
NCT04252586 
Document Version: 
FINAL 
Document Date:  
15-JUN-2021 
Approvals 
Role 
Signatures 
Date (dd-Mmm-yyyy) 
 
Biostatistician 
Print Name: 
 
 
Premier 
Research 
 
Sign Name: 
 
 
 
 
 
GW 
Research 
Ltd 
Representative 
Print Name: 
 
 
 
Sign Name: 
 
 
 
 
 

	


Page 2 of 47
PI
PI
PI
PI
PI


 
Statistical Analysis Plan,  
 
GW Research Ltd 
 
Protocol Number GWND19002  
 
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL   |   15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
         Page 2 of 46 
 
 
Table of Contents 
Approvals ........................................................................................................................................ 1 
Table of Contents ............................................................................................................................ 2 
List of Tables .................................................................................................................................. 4 
1. 
Overview ............................................................................................................................. 6 
2. 
Study Objectives and Endpoints ......................................................................................... 6 
2.1 
Study Objectives ........................................................................................................... 6 
2.1.1 Primary Objective ......................................................................................................... 6 
2.1.2 Secondary Objectives.................................................................................................... 6 
2.1.3 Exploratory Objectives ................................................................................................. 7 
2.2 
Study Endpoints ............................................................................................................ 7 
2.2.1 Efficacy Endpoints ........................................................................................................ 7 
2.2.2 Safety Endpoints ........................................................................................................... 7 
3. 
Overall Study Design and Plan ........................................................................................... 8 
3.1 
Overall Design .............................................................................................................. 8 
3.2 
Sample Size and Power ................................................................................................. 8 
3.3 
Study Population ........................................................................................................... 9 
3.4 
Treatments Administered .............................................................................................. 9 
3.5 
Method of Assigning Subjects to Treatment Groups .................................................... 9 
3.6 
Blinding and Unblinding............................................................................................... 9 
3.7 
Schedule of Assessments ............................................................................................ 10 
4. 
Statistical Analysis and Reporting .................................................................................... 14 
4.1 
Introduction ................................................................................................................. 14 
4.2 
Interim Analysis, Data Review ................................................................................... 14 
4.2.1 Interim analysis ........................................................................................................... 14 
4.2.2 Data review ................................................................................................................. 14 
5. 
Analysis Populations ......................................................................................................... 14 
6. 
General Issues for Statistical Analysis .............................................................................. 15 
6.1 
Statistical Definitions and Algorithms ........................................................................ 15 
6.1.1 Conventions for treatment/visit naming...................................................................... 15 
6.1.2 Baseline ....................................................................................................................... 16 
6.1.3 Last Visit ..................................................................................................................... 16 
6.1.4 Day Numbering ........................................................................................................... 16 
6.1.5 Multiple Comparisons ................................................................................................. 17 
6.1.6 Handling of Dropouts or Missing Data ....................................................................... 17 
6.1.7 Pooling of Sites ........................................................................................................... 18 
Page 3 of 47


 
Statistical Analysis Plan,  
 
GW Research Ltd 
 
Protocol Number GWND19002  
 
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL   |   15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
         Page 3 of 46 
 
6.1.8 Derived Variables ....................................................................................................... 18 
6.1.9 Data Adjustments/Handling/Conventions .................................................................. 19 
7. 
Study Patients and Demographics .................................................................................... 19 
7.1 
Disposition of Patients and Withdrawals .................................................................... 19 
7.2 
Protocol Deviations ..................................................................................................... 19 
7.3 
Demographics and Other Baseline Characteristics ..................................................... 20 
7.3.2 Medical and Surgical History and Current Medical Conditions ................................. 20 
7.4 
Exposure and Compliance .......................................................................................... 20 
8. 
Efficacy Analysis .............................................................................................................. 21 
8.1 
Rett Syndrome Behaviour Questionnaire (RSBQ) ..................................................... 21 
8.1.1 RSBQ Subscales ......................................................................................................... 21 
8.2 
Clinical Global Impressions - Improvement (CGI-I).................................................. 21 
8.3 
Caregiver Global Impression of Severity (CGI-S) ..................................................... 22 
8.4 
9-items Motor Behavioral Assessment (MBA-9) ....................................................... 22 
8.4.1 Children’s Sleep Habit Questionnaire (CSHQ) .......................................................... 22 
8.5 
Exploratory Efficacy Endpoints .................................................................................. 23 
8.5.1 Caregiver Quality of Life Questionnaire .................................................................... 23 
8.5.2 Patient Quality of Life Questionnaire ......................................................................... 24 
8.5.3 Hospital Services Use Questionnaire .......................................................................... 25 
8.5.4 Caregiver Assessment of Rett Symptoms ................................................................... 25 
9. 
Safety and Tolerability Analysis ....................................................................................... 25 
9.1 
Adverse Events ........................................................................................................... 25 
9.2 
Clinical Laboratory Evaluation ................................................................................... 27 
9.2.1 Hematology and Biochemistry ................................................................................... 27 
9.2.2 Urinalysis .................................................................................................................... 28 
9.2.3 Pregnancy Test ............................................................................................................ 28 
9.3 
Vital Signs, Other Physical Findings and Other Safety Data ..................................... 28 
9.3.1 Vital Signs ................................................................................................................... 28 
9.3.2 Electrocardiogram ....................................................................................................... 29 
9.3.3 Physical Examination.................................................................................................. 29 
9.3.4 Suicidality Assessment ............................................................................................... 29 
9.3.5 Growth and Development ........................................................................................... 29 
9.3.6 Menstruation ............................................................................................................... 30 
9.4 
Other Measures ........................................................................................................... 30 
9.4.1 Concomitant Medication ............................................................................................. 30 
9.4.2 Procedures and Non-Drug Therapies .......................................................................... 30 
9.4.3 Pregnancy Monitoring Form ....................................................................................... 30 
Page 4 of 47


 
Statistical Analysis Plan,  
 
GW Research Ltd 
 
Protocol Number GWND19002  
 
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL   |   15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
         Page 4 of 46 
 
9.4.4 Patients Impacted by COVID-19 ................................................................................ 31 
9.5 
Changes in the Conduct of the Trial or Planned Analysis .......................................... 31 
10. 
References ......................................................................................................................... 32 
11. 
Tables, Listings, and Figures ............................................................................................ 32 
APPENDIX 1: Abbreviations ....................................................................................................... 33 
APPENDIX 2 
Adverse Events of Special Interest – Abuse Liability based on preferred term 35 
APPENDIX 3 
Ranges for Clinically Significant Changes and Other Defined Flagged Values 
in Vital Signs..................................................................................................................... 36 
APPENDIX 1 
Defined Flagged Values in ECG Parameters .................................................... 37 
APPENDIX 2 
Toxicity Criteria for Laboratory Parameters ..................................................... 38 
APPENDIX 5 
Scoring the CHQ-PF50 ..................................................................................... 40 
 
List of Tables 
Table 1 Schedule of assessments .................................................................................................. 11 
Table 2 
Study treatments.......................................................................................................... 15 
Table 3 
Study Visits ................................................................................................................. 16 
Table 4 
CSHQ Subscales ......................................................................................................... 22 
Table 5 SF-36 Subscales ............................................................................................................... 23 
Table 6 CHQ-PF50 Health Concepts ............................................................................................ 24 
Table 7 
Ranges for Potentially Clinically Significant Changes in Vital Signs ........................ 36 
Table 8 
Other Defined Flagged Values for Vital Signs ........................................................... 36 
Table 9 
Defined Flagged Values for ECG Parameters ............................................................ 37 
Table 10 Toxicity Criteria for Biochemistry Parameters ........................................................... 38 
Table 11 Toxicity Criteria for Hematology Parameters............................................................. 38 
Table 12 Scoring of Global Health Item .................................................................................... 40 
Table 13 Scoring of Item 4.1 for Bodily Pain and Discomfort .................................................. 41 
Table 14 Scoring of Item 4.2 for Bodily Pain and Discomfort .................................................. 41 
Table 15 Scoring of Behavior .................................................................................................... 42 
Table 16 Scoring of Global Behavior Item ................................................................................ 42 
Table 17 Scoring of Mental Health ............................................................................................ 42 
Table 18 Scoring of Self Esteem................................................................................................ 43 
Table 19 Scoring of Global Health Perceptions......................................................................... 43 
Table 20 Scoring of Change in Health Item .............................................................................. 44 
Page 5 of 47


 
Statistical Analysis Plan,  
 
GW Research Ltd 
 
Protocol Number GWND19002  
 
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL   |   15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
         Page 5 of 46 
 
Table 21 Scoring of Emotional Impact on Parent ...................................................................... 44 
Table 22 Scoring of Family Cohesion Item ............................................................................... 45 
 
Page 6 of 47


 
Statistical Analysis Plan,  
 
GW Research Ltd 
 
Protocol Number GWND19002  
 
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL   |   15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
         Page 6 of 46 
 
1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for GW protocol 
number GWND19002 (An open-label extension (OLE) trial to investigate the long-term safety of 
cannabidiol oral solution (GWP42003-P, CBD-OS) in patients with Rett Syndrome, dated 18 
December 2019 version #2.0 and corresponding protocole annex #1, version 2 dated 11 
November 2020. Reference materials for this statistical plan include the protocol and the 
accompanying sample data collection documents. GWND19002 is the extension trial of the 
GWND18064 trial which will be referred to here as lead-in trial. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
The study objectives listed below are according to latest Clinical Study Protocol and Annex. Due 
to potential impact of the COVID-19 pandemic to patients and site personnel the Sponsor made 
the decision to discontinue the randomized trial (GWND18064) as well as the extension trial. 
Specific inclusion of patients in this extension trial is covered by the Annex. As this extension trial 
is stopped prematurely some planned assessments as per protocol will not be performed, see 
Section 9.5 for complete description of the changes. 
The structure and content of this SAP provides sufficient detail to meet the requirements identified 
by the Food and Drug Administration (FDA), European Medicines Agency (EMA), and 
International Conference on Harmonization (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical Trials1.  
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not necessarily 
identified in this SAP may be performed to further examine study data. Any post-hoc or unplanned, 
exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be finalized prior to any 
descriptive analysis of data pertaining to study GWND19002. 
2. 
Study Objectives and Endpoints 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective is to evaluate the long-term safety of GWP42003-P in patients with Rett 
syndrome (RTT). 
2.1.2 
Secondary Objectives 
x To evaluate the effect of GWP42003-P in measures of disease severity: 
o Rett Syndrome Behaviour Questionnaire (RSBQ) 
o Clinical Global Impressions - Improvement (CGI-I) 
o  Clinical Global Impressions - Severity (CGI-S) 
o 9-items Motor Behavioral Assessment (MBA-9) 
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         Page 7 of 46 
 
o Children’s Sleep Habits Questionnaire (CSHQ) 
2.1.3 
Exploratory Objectives 
Exploratory Objectives: 
x To evaluate the effect of GWP42003-P on caregiver and patient quality of life (QoL). 
o 36-item Short Form [SF-36] and Child Health Questionnaire Parent Form 50 [CHQ-
PF50], respectively. 
x To evaluate the effect of GWP42003-P on health utilization. 
o Hospital Services Use Questionnaire. 
x Caregiver assessment of Rett symptoms (symptom diary). 
2.2 
Study Endpoints 
2.2.1 
Efficacy Endpoints 
2.2.1.1 
Primary Efficacy Endpoint 
No primary efficacy endpoint in this open-label extension trial. 
2.2.1.2 
Secondary Efficacy Endpoints 
The following will be assessed by evaluating changes relative to the prerandomization baseline 
of the GWND18064 lead-in trial: 
o RSBQ  
o CGI-I 
o CGI-S. 
o MBA-9. 
o CSHQ. 
Same analyses will be performed compared to OLE baseline. 
2.2.1.3 
Exploratory Efficacy Endpoint(s) 
The following will be assessed by evaluating changes relative to the prerandomization baseline 
of the GWND18064 lead-in trial: 
o Caregiver QoL questionnaire (SF-36). 
o Patient QoL questionnaire (CHQ-PF50). 
o Hospital Services Use Questionnaire. 
o Caregiver assessment of Rett symptoms.  
 
 
The same analyses will be performed compared to OLE baseline. 
2.2.2 
Safety Endpoints 
The long-term safety profile of GWP42003-P will be assessed by evaluating changes in the 
following, relative to the prerandomization baseline of the GWND18064 lead-in trial:  
x Adverse Events (AEs). 
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PCN Number GWRE209830 
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         Page 8 of 46 
 
x Clinical laboratory parameters. 
x Vital signs. 
x Physical examination procedures. 
x 12-lead electrocardiogram (ECG). 
x Effects on menstruation cycles. 
x Suicidality. 
x Change in growth and development by measurement of height, weight, serum insulin-like 
growth factor-1 (IGF-1) levels and Tanner Staging (for patients aged ≥ 7 years, or earlier 
if clinically indicated by onset of menarche or other signs of precocious puberty). 
The same analyses will be performed compared to OLE baseline. 
3. 
Overall Study Design and Plan 
3.1 
Overall Design 
This is a multicenter, OLE trial for patients with RTT who have completed the randomized, 
double blind, placebo-controlled trial (GWND18064). 
Entry to this OLE trial is recommended to be on the same day as Visit 9 of the randomized 
controlled trial (RCT), GWND18064; however, patients may enter the OLE up to the RCT 
follow-up visit (Visit 11). For patients impacted by COVID-19, as per Annex, they are allowed 
to enroll into GWND19002 after the point of GWND18064 follow-up (Visit 11). For the ones 
who withdrew from GWND18064 due to COVID-19 pandemic containment measures or 
withdrew from GWND18064 due to sponsor administrative decision, they are allowed to enroll 
into GWND19002 at a later date, when appropriate.  
All patients entering this OLE trial will begin dosing with 5 mg/kg/day GWP42003-P (2.5 mg/kg 
b.i.d.) on Day 1. Patients will be observed, and after 1 week, the dose may further be escalated, 
at the investigator’s discretion, up to 15 mg/kg/day GWP42003-P (7.5 mg/kg b.i.d.) in weekly 
increments of 5 mg/kg/day (2.5 mg/kg b.i.d.). Patients should then remain on a stable dose of 
GWP42003-P for the duration of the maintenance period of the trial (up to 104 weeks), with the 
option for doses to be decreased or increased to a maximum dose of 20 mg/kg/day (10 mg/kg 
b.i.d.) based on clinical response and tolerability, as deemed necessary by the investigator, until 
the optimal dose is found. Patients whose dose has been decreased can have their dose increased 
again if tolerability improves. At the end of treatment (Visit 14 [Day 729]), the dose of 
GWP42003-P will be reduced over a 10-day taper period, and patients will enter the 4-week 
follow-up period. 
If a patient permanently discontinues treatment at any point during the trial, GWP42003-P 
should be gradually reduced over 10 days (unless inadvisable due to an AE). The patient should 
attend a withdrawal visit (Visit 14) as soon as possible after the decision is made to permanently 
discontinue GWP42003-P. If applicable, the patient will taper GWP42003-P, attend the End of 
Taper visit (Visit 15), and then complete the 4-week follow-up period. 
3.2 
Sample Size and Power 
There is no formal sample size calculation for this trial.  
All patients with RTT who completed the randomized, double-blind, placebo-controlled trial 
(GWND18064) who wish to take GWP42003-P and who meet eligibility criteria or as per annex, 
Page 9 of 47


 
Statistical Analysis Plan,  
 
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Protocol Number GWND19002  
 
PCN Number GWRE209830 
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         Page 9 of 46 
 
all patients who withdrew from GWND18064 due to COVID-19 pandemic containment 
measures or withdrew from GWND18064 due to sponsor administrative decision, are included in 
this trial. 
3.3 
Study Population 
Same study population as the one defined at entry in lead-in trial: 
- 
Female or male patients aged 2–18 years (inclusive), who weight at least 10 kg at entry in 
lead-in trial. 
- 
At entry in lead-in trial, patients must have a clinical diagnosis of RTT (typical or atypical), 
defined according to RettSearch Consortium criteria. Patients must have a confirmed 
pathogenic genetic mutation of the MECP2 gene. 
Patients can be enrolled if they qualify for inclusion criteria and if they do not meet any 
exclusion criteria for GWND19002 protocol and annex. For complete list of 
inclusion/exclusion criteria, please consult clinical study protocol and annex.  
3.4 
Treatments Administered 
The administered treatment is GWP42003-P oral solution. Mode of administration: to be taken 
orally twice daily (morning and evening) using the syringe(s) provided, preferentially with food 
i.e., within 30 minutes after the end of a meal and in line with the patients’ normal feeding schedule 
and dietary habits.  The time of IMP administration in relation to food should be kept consistent 
throughout the trial. Patients will take their first dose of IMP during GWND19002 trial at clinic 
visit Visit 1 and caregivers will be instructed how to measure and administer the IMP to the patient.   
All patients entering this OLE trial will begin dosing with 5 mg/kg/day GWP42003-P (2.5 mg/kg 
b.i.d.) on Day 1. Patients will be observed, and after 1 week the dose may escalate further, at the 
investigator’s discretion, up to 15 mg/kg/day GWP42003-P (7.5 mg/kg b.i.d.) in weekly 
increments of 5 mg/kg/day (2.5 mg/kg b.i.d.). 
Patients should then remain on a stable dose of GWP42003-P for the duration of the maintenance 
period of the trial (up to 104 weeks), with the option for doses to be decreased or increased if 
deemed necessary by the investigator, to a maximum dose of 20 mg/kg/day (10 mg/kg b.i.d.). 
Dose adjustments should be discussed with the GW medical monitor. The final decision 
regarding dose adjustments should be taken by the investigator. 
At the end of treatment (Visit 14 [Day 729]), the dose of GWP42003-P will be reduced over a 
10-day taper period, and patients will enter the 4-week follow-up period. 
Patients discontinuing GWP42003-P treatment at any other time should undergo a 10-day taper 
period (unless continued dosing is inadvisable, e.g., due to an AE). The decision on whether to 
taper GWP42003-P or not will be left to the investigator’s clinical judgment. 
3.5 
Method of Assigning Subjects to Treatment Groups  
As this is an open-label study, with no assignment to treatment group, all patients will receive the 
GWP42003-P treatment. 
3.6 
Blinding and Unblinding  
As this is an open-label study no blinding applicable. 
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3.7 
Schedule of Assessments  
A detailed schedule of events for the study is provided in Table 1 .  
 
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Page 11 of 46 
Table 1 Schedule of assessments 
Visit Number 
1 
2a 
3a 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14b,c 
EoT/ 
Withdrawal 
15  
(end of 
taper) 
16a 
(follow-
up) 
Day Number 
(Visit Window) 
1 
 
8 
(±3) 
15 
(± 3) 
29 
(± 7) 
57 
(± 7) 
85 
(± 7) 
141 
(± 7) 
197 
(± 7) 
281 
(± 7) 
365 
(± 7) 
456 
(± 7) 
547 
(± 7) 
638 
(± 7) 
729 
(± 7) 
739 
(+ 7) 
767 
(+ 7) 
Informed consent and assentd 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
New medical history 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Menstruation question (where 
appropriate) 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Physical examination (including 
body weight) 
Xf 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
(X) 
 
Height 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
ECG 
Xf 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
 
Vital signs 
Xg 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Clinical laboratory blood 
sampling (hematology and 
biochemistry)h 
Xf 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
(X) 
 
Hepatic function monitoring 
paneli 
 
 
 
 
 
 
Xi 
 
 
 
Xi 
 
Xi 
 
 
 
Dipstick urinalysis (where 
possible) 
Xf 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
(X) 
 
Serum pregnancy test (if 
appropriate) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Caregiver 
completed
RSBQ 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
CSHQ 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
Caregiver QoL 
questionnaire (SF-36) 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Page 12 of 47


Statistical Analysis Plan,  
GW Research Ltd 
Protocol Number GWND19002  
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL  | 15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
Page 12 of 46 
Visit Number 
1 
2a 
3a 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14b,c 
EoT/ 
Withdrawal 
15  
(end of 
taper) 
16a 
(follow-
up) 
Day Number 
(Visit Window) 
1 
 
8 
(±3) 
15 
(± 3) 
29 
(± 7) 
57 
(± 7) 
85 
(± 7) 
141 
(± 7) 
197 
(± 7) 
281 
(± 7) 
365 
(± 7) 
456 
(± 7) 
547 
(± 7) 
638 
(± 7) 
729 
(± 7) 
739 
(+ 7) 
767 
(+ 7) 
Patient QoL questionnaire 
(CHQ-PF50) 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Hospital Services Use 
Questionnaire  
Xg 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
Tanner Staging (where 
appropriate)  
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Caregiver Assessment of 
Rett Symptoms 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
MBA-9 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
CGI-S 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
CGI-I 
 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
Suicidality assessment 
Xg 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
GWP42003-P dispensing 
Xe 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
GWP42003-P collection and 
compliance review 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing schedulej 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
(X) = if clinically indicated; EoT = end of treatment 
a Visit to be conducted by telephone. 
b To be performed to all patients completing or withdrawing from the trial.  Patients who withdraw early should commence the 10-day GWP42003-P taper 
period, if possible. 
c A safety follow-up Visit 4 weeks after last GWP42003-P dose is required for all patients who withdraw from the trial or complete the trial. 
d Informed consent must be obtained prior to any trial-related procedures.  In cases where the patient possesses adequate understanding, assent will be taken 
along with parent(s)/legal representative consent.  The nominated caregiver will be asked to complete the quality of life questionnaires. 
e Always required. 
f Required only if OLE Visit 1 is > 28 days after RCT Visit 9 including enrollement after the point of RCT Visit 11 under annex. 
g Required if OLE Visit 1 does not occur on the same day as RCT Visit 9.  
h Determination of serum IGF-1 levels at Visits 1, 8, 10, and 14 only; IGF-1 laboratory results will remain blinded throughout the trial. 
i Hepatic function monitoring is required following increases in GWP42003-P dose or introduction of medications that are known to impact liver function.  
If the concerned change does not occur within 1 month of a scheduled biochemistry assessment, the investigator should perform an additional hepatic 
Page 13 of 47


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monitoring within 1 month of the change.  Hepatic monitoring at Visit 7, 11 and 13 is required for patients taking concomitant valproic acid or whose dose 
exceeds 15 mg/kg/day. 
j  The dosing schedule is to be completed by the caregiver daily throughout the trial and reviewed at Visits 2 through 15. 
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4. 
Statistical Analysis and Reporting 
Statistical analyses will be performed after the database is locked.  
4.1 
Introduction 
Data processing, tabulation of descriptive statistics, and graphical representations will be 
performed primarily using SAS (release 9.4 or higher). If the use of other software is warranted, 
the final statistical methodology report will detail what software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of patients (n) with 
non-missing values, the number of missing values, mean, standard deviation (SD), median, 
minimum, and maximum, unless otherwise specified.  
Categorical (qualitative) variable summaries will include the frequency and percentage of patients 
who are in the particular category for each possible value. In general, the denominator for the 
percentage calculation will be based upon the total number of patients in the study population, 
unless otherwise specified. 
The number of missing values will be calculated as difference between the total number of patients 
in the study population and the number of non-missing values.  
The minimum and maximum will be reported with the same degree of precision (i.e. the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will be 
reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
4.2 
Interim Analysis, Data Review 
4.2.1 
Interim analysis 
No formal interim analysis will be conducted. 
4.2.2 
Data review 
No data review meeting will take place. After database lock, descriptive statistical outputs will 
be created.  
5. 
Analysis Populations 
The following analysis sets will be used for the statistical analysis:  
Enrolled  
• 
All patients from GWND18064 lead-in trial enrolled in GWND19002 trial. 
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Safety Analysis Set  
• 
All patients who receive at least 1 dose of IMP in the GWND19002 trial will be included. 
Only patients for whom it has been confirmed that they did not take any IMP during the 
GWND19002 trial will be excluded from this safety analysis set. This analysis set will be 
used to report all statistical analysis.  
Analysis sets will be identified during the conduct of statistical analysis after database lock. 
6. 
General Issues for Statistical Analysis 
All data collected in the study will be listed, ordered by site, patient number and, where 
applicable, chronological order of the assessment. Visit date is not needed to be included in the 
listings, day numbers will be included where appropriate.  
Other derived variables (e.g. change from baseline values) that are calculated for analysis 
purposes or to aid interpretation of the data will be included in the data listings.  
6.1 
Statistical Definitions and Algorithms 
6.1.1 
Conventions for treatment/visit naming 
In all tables, listings and figures, the treatment arms will be referred to and labelled as per Table 
2. 
Table 2 
Study treatments 
 
Endpoint 
RCT Treatment 
Actual Treatment 
Protocol/Annex 
Treatment Label 
(Table 
column/Figure 
legend) 
Sorting order 
in 
listings, 
column order 
in tables 
All 
Double-Blind 
Treatment 
GWP42003-P 
different dosing 
GWP42003-P, 
at 
different dosing 
Enrolled under 
Protocol 
Double 
Blind 
Treatment: 
GWP42003-P 
Enrolled 
Under 
Protocol 
1 
All 
Double-Blind 
Treatment 
GWP42003-P 
different dosing 
GWP42003-P, 
at 
different dosing 
Enrolled under 
Annex 
Double 
Blind 
Treatment: 
GWP42003-P 
Enrolled 
Under 
Annex 
2 
All 
Double-Blind 
Treatment 
Placebo different 
dosing 
GWP42003-P, 
at 
different dosing 
Enrolled under 
Protocol 
Double 
Blind 
Treatment: 
Placebo 
Enrolled 
Under 
Protocol 
3 
All 
Double-Blind 
Treatment 
Placebo different 
dosing 
GWP42003-P, 
at 
different dosing 
Enrolled under 
Annex 
Double 
Blind 
Treatment: 
Placebo 
Enrolled 
Under 
Annex 
4 
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In all tables, listings and figures, the study visits will be referred to and labelled as per Table 3. 
Table 3 
Study Visits 
Actual Visit 
Visit Label 
Baseline (last record before 1st IMP administration during lead-in trial) 
RCT Baseline 
Baseline (Assessment at extension Visit 1) 
OLE Baseline 
Visit 1: Day 1 
Day 1 
Visit 2: Day 8 Telephone Call 
Day 8 TC 
Visit 3: Day 15 Telephone Call 
Day 15 TC 
Visit 4: Day 29 
Day 29 
Visit 5: Day 57 
Day 57 
Visit 6: Day 85 
Day 85 
Visit 7: Day 141 
Day 141 
Visit 8: Day 197 
Day 197 
Visit 9: Day 281 
Day 281 
Visit 10: Day 365 
Day 365 
Visit 12: Day 547 
Day 547 
Visit 14: Day 729 or withdrawal 
End of Treatment 
Visit 15: Day 739 (end of taper) 
End of Taper 
Visit 16: Day 767 
Follow-up 
No derivation will be used for visits; data will be tabulated and listed according to the visit it was 
recorded under in eCRF. 
6.1.2 
Baseline 
For all endpoints, two baselines will be defined: 
- 
the last non-missing observation recorded prior to the first drug administration during 
GWND18064 lead-in trial will be used as the RCT baseline  
- 
The value reported at Visit 1 during OLE study will be used as the OLE baseline 
6.1.3 
Last Visit 
The last visit for endpoints assessed at clinic visits is defined as the last scheduled visit at which 
a patient’s last evaluation (up to Visit 15/end of treatment visit/any other last visit) is performed.  
6.1.4 
Day Numbering 
The first day of treatment (Day 1) will be the date of Visit 1. 
Any days prior to Day 1 will be numbered relative to this day and calculated as: 
Date − (Date of Day 1) 
to give Day −1, −2, −3 etc. 
Any days post Day 1 will be calculated as:  
1 + Date − (Date of Day 1) 
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6.1.5 
Multiple Comparisons 
No multiple comparisons are planned as no inferential analysis are planned. 
6.1.6 
Handling of Dropouts or Missing Data 
Every effort has been made to minimize missing data for this trial. The patient reported outcomes 
will be completed by the patient’s primary caregiver on electronic devices. These assessments 
have been set up in such a way that the caregiver cannot proceed to the next question if they have 
not entered a response for the current question. In addition, on the off chance that the device does 
not function correctly, paper alternatives of the assessments are available.  
6.1.6.1 
Handling of Missing Data for Efficacy Endpoint (Primary, Secondary and 
Exploratory) 
If a questionnaire has subscales then the missing items in a subscale can be imputed as the mean 
of the non-missing items in that subscale, provided that at least half of the items in the subscale 
were answered. If more than half the items in the subscale are missing then the missing items will 
be imputed as LOCF. 
If a questionnaire does not have subscales (eg MBA-9, CSHQ single item scale) the missing 
items will be imputed using LOCF. 
6.1.6.1.1 SF-36 
The SF-36 assessment will be scored by the QualityMetric Health Outcomes Scoring Software 5.0 
(Maruish, 2011) which assumes that the response to a missing item in a particular scale is the same 
as the mean of the responses to the scale’s answered items. This approach cannot be used to 
estimate item responses on the physical functioning scale due to the hierarchical nature of the items 
included in this scale. If items on the physical functioning scale are missing, the QualityMetric 
Health Outcomes Scoring Software v5.0 estimates the PF score using item response theory. If any 
SF-36 is logged as completed by an alternative caregiver, it will be counted as missing. 
6.1.6.1.2 CHQ-PF50 
Appendix 5 describes the methods of handling missing data for the CHQ-PF50 health scales. 
6.1.6.1.3 Adverse Events 
Missing and/or incomplete dates for AEs will be imputed in a manner resulting in the earliest onset 
or the longest duration during the treatment period, while ensuring that the start date is not after 
the stop date, i.e. missing start dates will be imputed as the first day of the month/first month of 
the year and missing stop dates will be imputed as the last day of the month/last day of the year, 
while ensuring that the start date is not after the stop date. Upper and lower limits of imputation 
will be date of Visit 1 and last visit date as defined in section 6.1.3, and events occurring on date 
of Visit 1 will be assumed post-IMP. Stop dates will not be imputed if the AE is ongoing. 
Imputed dates will be used for calculation of time to first onset and time to AE resolution, they 
will not be presented in AE listings. 
A worst-case approach will be followed in the event of missing severity or causality data.  If the 
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severity is missing, ‘Severe’ will be imputed.  If causality data is missing for a treatment emergent 
AE (TEAE), ‘Yes’ will be imputed for the question ‘Plausible relationship to study medication’. 
6.1.6.1.4 Concomitant Medication 
Missing concomitant medication dates will be handled in a similar fashion as described for AEs 
in Section 6.1.6.1.3. 
6.1.7 
Pooling of Sites 
As there are expected to be relatively few patients per site, the site will not be taken into account 
in the analyses. Therefore the question of pooling of sites does not arise.  
6.1.8 
Derived Variables 
For derivations of the efficacy variables, see Section 8.  The following additional derived and 
computed variables have been initially identified as important for the analyses to be performed for 
this trial.  
In case additional derived variables may be required: the SAP will not be amended for additional 
variables that are not related to the primary or secondary endpoints. Any additional derived or 
computed variables will be identified and documented in the SAS programs that create the analysis 
files. If the SAP is not amended, further derivations related to the primary and secondary endpoints 
will be described in the CSR.  
6.1.8.1 Adverse events 
Any adverse events occuring between last dose of RCT and OLE visit 1 will not be considered 
Treatment Emergent Adverse events (Aes occuring during study break). All other adverse events 
will be considered as treatment-emergent adverse events. 
A TEAE will be considered treatment-related if the plausibility relationship to IMP is recorded on 
the eCRF as ‘yes’.  If the data on plausibility relationship to IMP is missing then the TEAE will 
be considered treatment-related. 
A TEAE will be considered leading to permanent discontinuation of IMP (leading to withdrawal) 
if the action taken with IMP is recorded on the eCRF as ‘trial medication stopped’ or the outcome 
is recorded on the eCRF as ‘patient died’. 
A treatment-related TEAEs leading to withdrawal is a TEAE leading to permanent IMP 
discontinuation and considered treatment-related as per above definition.  
A TEAE will be considered leading to IMP temporary discontinuation if the action taken with IMP 
is recorded on the eCRF as ‘trial medication interrupted’. 
A TEAE will be considered leading to permanent IMP dose reduction excluding permanent 
discontinuation if the action taken with IMP is recorded on the eCRF as ‘dose reduced’. 
A TEAE will be considered fatal if the outcome is recorded on the eCRF as ‘patient died’. 
The time to first onset of AE will be calculated for TEAEs as: 
Start date of AE – Day 1 + 1 
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The time to AE resolution will be calculated for TEAEs as: 
Stop date of AE – Start date of AE + 1 
6.1.8.2 Concomitant medications  
A concomitant medication is defined as any medication that was administered during the treatment 
period (from Visit 1 of OLE trial). This includes medications that started before the treatment 
period and continued while on treatment and medications that started during the treatment period.  
6.1.8.3 Age 
Age will be calculated as: 
(Date of Visit 1 – date of birth) ÷ 365.25. 
6.1.8.4 Exposure 
The total number of dosing days in the treatment period will be calculated as: 
(Date of last IMP dose from Study Outcome eCRF form – Date of Day 1) + 1 
For Day 1 definition see section 6.1.4 
6.1.9 
Data Adjustments/Handling/Conventions  
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings.  
7. 
Study Patients and Demographics 
7.1 
Disposition of Patients and Withdrawals 
Patient disposition, by site, by country and overall, will be summarized overall using standard 
summary statistics. Patients enrolled under Protocol / Annex will also be described. The number 
of patients screened, number of screen failures and number enrolled will be included. 
A screen failure disposition table will be presented, including number of patients screened, number 
failing screening, number enrolled and the reasons for failing screening. 
Patient disposition, including patients treated, patients who completed the treatment period and the 
taper phase, patients discontinued (including reason for discontinuation) from the treatment, and 
taper phases will be summarized by absolute counts (n) and percentages (%). Number and 
percentages of patients completing each study visit will be described. A further table split by site, 
and by country will be produced, showing number of patients enrolled, withdrawn at each site or 
in each country. 
7.2 
Protocol Deviations 
Protocol deviations will be identified and classified. 
Major protocol deviations will be summarized by type of violations for the enrolled population. 
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Protocol deviations will be listed. Protocol deviations due to COVID-19 will be listed separately. 
7.3 
Demographics and Other Baseline Characteristics 
The following demographic data will be summarized overall for the safety analysis sets: 
• 
Age (years); 
• 
Age group (2-5 years, 6-12 years and 13-19 years); 
• 
Sex; 
• 
Race; 
• 
Ethnicity 
• 
Country; 
• 
Region (United States, Rest of the World); 
7.3.1.1 
History of RTT 
The following history of RTT data will be summarized by treatment group and overall for the 
safety analysis set: 
• 
Type of diagnosis (Typical, Atypical). 
• 
Main and supportive criteria for RTT diagnosis. 
• 
Age at diagnosis (months) 
• 
Time since last known loss of hand use or verbal language or gross motor regression 
(months). 
• 
Information about the MECP2 mutation (whether a known mutation is documented and if 
available, the type of mutation). 
• 
Communication methods used by the child. 
• 
Types of seizures that are ongoing. 
• 
Status epilepticus. 
• 
Whether the child lives at home or at a care home/institution. 
• 
Most common feeding method. 
• 
Planned method for IMP administration. 
7.3.2 
Medical and Surgical History and Current Medical Conditions 
All conditions and diagnoses on the ‘medical and surgical history’ eCRF page will be coded using 
Version 21.1 of the Medical Dictionary for Regulatory Activities (MedDRA v21.1) or later 
version. 
Only new medical history not already reported in the lead-in study will be described there. 
The number of patients with relevant or significant new medical or surgical history by system 
organ class, and preferred term, will be summarized by absolute counts (n) and percentages (%).  
Percentages will be calculated based on the number of patients in the analysis population.  
7.4 
Exposure and Compliance 
IMP is to be administered twice daily (morning and evening). The first dose will be taken on Day 
1 (Visit 1).  The date of final dose in the treatment period will be recorded on the eCRF under DS 
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form. The date of final dose, for patients who enter the taper period, will be recorded on the eCRF 
at the end of taper visit under DS2 form. Total number of dosing days will be reported.  
8. 
Efficacy Analysis 
The efficacy analyses will use the safety analysis set. No formal hypothesis testing will be carried 
out for this study. Statistical analysis will be descriptive.  
8.1 
Rett Syndrome Behaviour Questionnaire (RSBQ) 
The RSBQ is a caregiver-completed questionnaire that measures the frequency of current disease 
characteristics (45 items) that may or may not apply to the patient.  Each item is rated on a 3-point 
numerical scale, where all items except for item 31 (“Uses eye gaze to convey feelings, needs and 
wishes”) is scored as follows: 0 indicating an item that is ‘not true as far as you know’, 1 indicating 
an item is ‘somewhat or sometimes true’, and 2 indicating an item that is ‘very true or often true’.   
Item 31 is to be reverse scored, where 0 indicates that this item is ‘very true or often true’, 1 
indicating that this item is ‘somewhat or sometimes true’, and 2 indicating that this item is ‘not 
true as far as you know’. The total maximum score is 90 and higher total scores represent greater 
severity. 
The RSBQ score and its change from baseline (RCT Baseline and OLE Baseline) will be 
summarized on a numerical scale by visit. 
8.1.1 
RSBQ Subscales 
The RSBQ includes 8 subscales: general mood, breathing problems, hand behaviors, face 
movements, body rocking/expressionless face, night-time behaviors, anxiety/fear, and 
walking/standing.  The items included in each subscale are presented in Table 4. 
Table 4 
RSBQ Subscales 
Subscale 
Items Included 
General Mood 
2, 14, 15, 16, 22, 29, 30, 36  
Breathing Problems 
1, 5, 6, 19, 25 
Hand Behaviors 
18, 20, 21, 24, 35, 43 
Face Movements 
4, 28, 32, 34 
Body Rocking/Expressionless Face 
12, 17, 31*, 33, 40, 41 
Night-time Behaviors 
13, 37, 42 
Anxiety/Fear 
7, 9, 10, 38 
Walking/Standing 
23, 39 
* Item 31 is to be reverse scored as described in section 5.5.2. 
The subscale scores are calculated by summing the scores of the items in each subscale. 
Subscale scores and their change from baseline will be summarized by visit for each subscale.  
8.2 
Clinical Global Impressions - Improvement (CGI-I) 
The CGI-I is a 7-point scale that requires the clinician to assess how much the patient’s illness has 
improved or worsened relative to a baseline state at the beginning of the intervention. This is rated 
as: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = 
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Statistical Analysis Plan,  
 
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PCN Number GWRE209830 
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minimally worse; 6 = much worse; or 7 = very much worse. 
The CGI-I score will be summarized on both a categorical scale and a numerical scale by visit. 
8.3 
Caregiver Global Impression of Severity (CGI-S) 
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient's illness at 
the time of assessment, relative to the clinician’s experience with patients who have the same 
diagnosis. Considering total clinical experience, a patient will be assessed on severity of illness at 
the time of rating. This is rated as: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = 
moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill. 
CGI-S scores and their change from baseline (RCT baseline and OLE baseline) will be 
summarized by treatment and visit. Frequency table will be created for CGI-S categories by 
treatment and visit.  
8.4 
9-items Motor Behavioral Assessment (MBA-9) 
The MBA-9 scale is completed by the investigator and addresses core symptoms of RTT. MBA-9 
was derived from the full MBA scale (37 RTT symptoms) by selecting the items that are deemed 
to be amenable to change and that reflect areas of meaningful clinical change. The severity of 
current symptoms is rated on a 5-point numerical scale; 0 = normal or never; 1 = mild or rare; 2 = 
moderate or occasional; 3 = marked or frequent; 4 = very severe or constant. The MBA-9 score is 
calculated by summing the scores of the individual items.  The maximum score is 36 and higher 
scores represent greater severity. 
MBA-9 scores and their change from baseline (RCT baseline and OLE baseline) will be 
summarized by visit.  
8.4.1 
Children’s Sleep Habit Questionnaire (CSHQ) 
The CSHQ includes a total sleep disturbance score and 8 sleep subscales: bedtime resistance, sleep 
onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep disordered breathing 
and daytime sleepiness.  The items included in each subscale are presented in Table 5. 
Table 4 
CSHQ Subscales 
Subscale 
Items Included 
Bedtime resistance 
1*, 3*, 4, 5, 6, 8 
Sleep onset delay 
2* 
Sleep duration 
9, 10*, 11* 
Sleep anxiety 
5, 7, 8, 21  
Night wakings 
16, 24, 25 
Parasomnias 
12, 13, 14, 15, 17, 22, 23 
Sleep disordered breathing 
18, 19, 20 
Daytime sleepiness 
26*, 27, 28, 29, 30, 31, 32, 33 
* These items are to be reverse scored. 
The responses to each item of the CSHQ are to be scored as Usually=3, Sometimes=2, Rarely=1, 
except for the items marked with * in Table 5, which are considered to be “desirable” sleep 
behaviors and are therefore reverse scored.  Items 32 and 33 are scored 1 for “not sleepy”, 2 for 
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PCN Number GWRE209830 
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“very sleepy”, 3 for “falls asleep”.  
CSHQ scores and CSHQ subscale scores along with their change from baseline (RCT baseline and 
OLE baseline) will be summarized by visit.  
8.5 
Exploratory Efficacy Endpoints 
8.5.1 
Caregiver Quality of Life Questionnaire 
The caregiver’s health-related quality of life will be assessed using the 36-item short form (SF-
36). The SF-36 measures 8 domains of health-related quality of life: 1) limitations in physical 
activities because of health problems; 2) limitations in social activities because of physical or 
emotional problems; 3) limitations in usual role activities because of physical health problems; 4) 
bodily pain; 5) general mental health (psychosocial distress and well-being); 6) limitations in usual 
role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health 
perceptions.  These domains are used to calculate 2 composite scores, the physical health 
composite score (PCS) and the mental health composite score (MCS). 
The items included in each subscale are presented in Table 6. 
Table 5 SF-36 Subscales 
Subscale 
Items Included 
Physical functioning 
3 (a to j) 
Role-physical 
4 (a to d) 
Bodily pain 
7 and 8 
General health 
1 and 11 (a to d) 
Vitality 
9 (a, e, g and i) 
Social functioning 
6 and 10 
Role-emotional 
5 (a to c) 
Mental health 
9 (b, c, d, f and h) 
 
The raw SF-36 data will be sent to Optum via Rave Web Services so that the subscales and 
composite scales can be scored by the QualityMetric Health Outcomes™ Scoring Software 5.0.  
The scores will then be uploaded into the electronic database. 
The scoring of the SF-36 questionnaire via the QualityMetric Health Outcomes™ Scoring 
Software 5.0 is based on norm-based scoring which ensures that the scores for the subscales have 
a mean of 50 and a standard deviation of 10, based on the 2009 US general population (Maruish, 
2011). A higher score is indicative of a better health state. 
The steps that the software follows to score the scales and composite scales are summarized below: 
1. Some of the items are recoded to ensure that a higher score corresponds to a better health 
state for all items in the SF-36. 
2. The raw scores for the health domain scales are calculated as the sum of the final response 
values for the items included in each scale. 
3. Transform the score to a 0-100 scale score: 
Transformed scale score = (Actual raw score - Lowest possible raw score)/Possible raw 
score range x 100 
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4. Transform to z-scores ~ Normal(0,1) according to the 2009 US general population norms. 
5. Calculate T scores for each domain = T score = 50 + (domain z-score x 10).  T scores 
calculated to aid interpretation. 
6. Finally calculate MCS and PCS using a 3 step procedure: 
First, the eight health domain scales are standardized using means and standard deviations 
from the 2009 U.S. general population. Second, these standardized scores are aggregated 
using weights (factor score coefficients) from the 1990 U.S. general population. Third, 
aggregate PCS and MCS scores are standardized using a linear Tscore transformation with 
a mean of 50 and a standard deviation of 10. 
SF-36 composite scores and SF-36 subscale scores along with their change from baseline (RCT 
baseline and OLE Baseline) will be summarized by visit.  
8.5.2 
Patient Quality of Life Questionnaire 
This instrument is a well-validated general QoL measure in pediatric populations with chronic 
illness. It measures QoL of the child and the family by parent or child report. The caregiver will 
be asked to complete the questionnaire on behalf of the patient. The CHQ-PF50 covers 
multidimensional health concepts including Physical Functioning, Role/Social Limitations–
Emotional/Behavioral, Role/Social Limitations– Physical, Behavior, Mental Health, Self-Esteem, 
General Health , Bodily Pain, Family Activities, Parent Impact–Time, Parent Impact–Emotional, 
and Family Cohesion. Scores for specific items and subscales, as well as a standardized physical 
summary (PhS) score and a standardized psychosocial summary (PsS) score, can be calculated 
from the CHQ-PF50 questionnaire. Scores are based on a 0 to 100 scale and higher scores indicate 
better quality of life. 
Table 7 presents the items included in each health concept. 
Table 6 CHQ-PF50 Health Concepts 
Health Concept 
Items Included 
Global health item 
1.1 
Physical functioning 
2.1 (a to f) 
Role/social limitations due to emotional/behavioral difficulties 
3.1 (a to c) 
Role/social limitations due to physical health 
3.2 (a to b) 
Bodily pain and discomfort 
4.1 and 4.2 
Behavior  
5.1 (a to e) and 5.2 
Global behavior item 
5.2 
Mental health 
6.1 (a to e) 
Self esteem 
7.1 (a to f) 
General health perceptions 
8.1 (a to e) and 1.1 
Change in health item 
8.2 
Emotional impact on parent 
9.1 (a to c) 
Time impact on parent 
9.2 (a to c) 
Family activities 
9.3 (a to f) 
Family cohesion item 
9.4 
 
Details regarding the scoring of the health concepts of CHQ-PF50 and of the PhS and PsS can be 
found in Appendix 5.  All of the health concepts and scales included in CHQ-PF50, except for the 
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change in health item are continuous. 
CHQ-PF50 standardized scores (as per Appendix 5) CHQ-PF50 subscale scores, PhS and PsS 
scores along with their change from baseline (RCT Baseline and OLE Baseline) will be 
summarized by visit.  
8.5.3 
Hospital Services Use Questionnaire 
The Hospital Services Use Questionnaire captures the frequency of hospital visits and patient 
hospitalizations.  The responses to this questionnaire will be listed only. 
8.5.4 
Caregiver Assessment of Rett Symptoms 
The Caregiver Assessment of Rett Symptoms is a symptom diary, including 12 items, each scored 
between 0 and 10, where a higher score for all items except items 1 and 9 represents a greater 
severity.  Items 1 and 9 will be reverse-scored and a total score will be calculated as the sum of 
items 1 to 10, 11a and 12a. For items 11 and 12, if 11 is ‘No’ then 11a should be scored 10 and if 
12 is ‘No’ then 12a should be scored 0.  A visit score will be derived for each item and for the total 
score as the mean of the scores since the previous visit. 
The total scores and the scores for each item of the Caregiver Assessment of Rett Symptoms along 
with change from baseline (RCT baseline and OLE baseline) will be summarized by visit.  
9. 
Safety and Tolerability Analysis 
9.1 
Adverse Events 
All reported AEs will be classified by system organ class (SOC), and preferred term (PT) and 
lower level term using Version 21.1 of MedDRA or higher.  
The following summaries will be generated (counts are by patient unless specified otherwise): 
Overall summary of TEAEs, including following description: 
• 
Summary of TEAEs. 
• 
Summary of treatment-related TEAEs. 
• 
Summary of TEAEs leading to permanent discontinuation of IMP. 
• 
Summary of serious TEAEs. 
• 
Summary of treatment-related serious TEAEs. 
Following summaries will be presented by SOC and PT: 
• 
Summary of TEAEs 
• 
Summary of treatment-related TEAEs 
• 
Summary of TEAEs by maximal severity. 
• 
Summary of serious TEAEs  
• 
Summary of non-serious TEAEs. 
• 
Summary of treatment-related serious TEAEs. 
• 
Summary of TEAEs leading to permanent discontinuation of IMP. 
• 
Summary of treatment-related TEAEs leading to permanent discontinuation of IMP. 
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• 
Summary of TEAEs leading to IMP dose reduction excluding permanent discontinuation 
(by resolution and overall). 
• 
Summary of treatment-related TEAEs leading to IMP dose reduction excluding permanent 
discontinuation (by resolution and overall). 
• 
Summary of TEAEs leading to IMP interrupted (by resolution and overall). 
• 
Summary of treatment-related TEAEs leading to IMP interrupted (by resolution and 
overall). 
• 
Summary of fatal TEAEs. 
• 
Summary of TEAEs by time of first onset of AE. 
• 
Summary of TEAEs by time to AE resolution. 
• 
Summary of TEAEs reported in ≥ 2% of patients (after rounding)  
• 
List of patients experiencing TEAEs by SOC and preferred term. 
For the summary of TEAEs by maximal severity, for each patient, the worst severity recorded by 
PT, SOC and overall will be used for summary purposes.  If severity is missing, the worst case 
(severe) will be assumed. 
For summaries by resolution, AEs with an outcome of ‘recovered’ or ‘recovered with sequelae’ 
will be summarized as ‘Resolved’ and AEs with an outcome of ‘continuing’, ‘patient died’ or those 
with a missing outcome will be summarized as ‘Not resolved’. 
For the summary of TEAEs by time of first onset of AE, data will be summarized under the 
following categories: 
• 
Month 1 (Day 1–29). 
• 
Month 2 (Day 30–59).  
• 
Month 3 (Day 60–89). 
• 
Month 4-6 (Day 90–179). 
• 
Month 7-9 (Day 180–269). 
• 
Month 10-12 (Day 270–359). 
• 
>1 year (> Day 359). 
If patients have multiple occurrences of an AE then the AE will be counted once for the first 
occurrence only.  Percentages will be based on the number of patients in the safety analysis set 
who have a visit or follow-up call within each time period above. In case there is no planned visits 
in the interval, percentages will be based on the number of patients in the safety analysis set. 
For the summary of TEAEs by time to AE resolution, data will be summarized under the following 
categories: 
• 
1 week (≤7 days). 
• 
2 weeks (8–14 days). 
• 
3 weeks (15–21 days). 
• 
4 weeks (22–28 days). 
• 
>4 weeks (>28 days). 
• 
Ongoing (for AEs not resolved). 
If patients have multiple occurrences of an AE then the AE will be counted once for the occurrence 
with the longest time to AE resolution.  However, if any of the AEs are not resolved then the AE 
will be counted once within the ‘Ongoing’ category. 
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The start and stop day of the AE relative to Day 1 will be calculated as per Section 6.1.4.  
All TEAEs will be listed.  Listings will include the start and stop day of the AE, and limited 
demographic information about the patient (age, sex, race and weight at screening). A separate 
listing will be provided for serious AEs and events of special interest (see APPENDIX ). 
9.2 
Clinical Laboratory Evaluation 
9.2.1 
Hematology and Biochemistry 
Hematology and biochemistry safety parameters are measured at Visit 1, Visit 4, Visit 5, Visit 6, 
Visit 8, Visit 9, Visit 10, Visit 12 and Visit 14 (end of treatment). 
Summaries will be presented for each laboratory parameter at each visit. Change from baseline 
(RCT and OLE baseline) and percent change from baseline to each post-baseline visit will also be 
presented. 
If values for any of the parameters are below or above the limit of quantification of the assay (BLQ 
or ALQ), then they will be included in the summary tables at the BLQ or ALQ thresholds.   
Where laboratory samples are repeated, the baseline value is defined as the final recorded value 
prior to the first dose of IMP during the lead-in trial or prior to Visit 1 in OLE trial. 
Shift tables for hematology and biochemistry parameters will be produced, based upon normal 
ranges and GW toxicity limits (See Appendix 3), to determine the categorical shifts from each 
baseline (RCT and OLE) to each post-baseline visit.  Values will be categorized as ‘Normal’, 
‘Low’ or ‘High’ based on normal ranges and ‘Toxically Low’, ‘Toxically Normal’ or ‘Toxically 
High’ based on GW toxicity limits. 
For eGFR, results will be assigned to the following grades: 
• 
Normal: >60 ml/min/1.73 m2 
• 
Grade 1: 60 ml/min/1.73 m2 
• 
Grade 2: ≥30 and <60 ml/min/1.73 m2 
• 
Grade 3: ≥15 and <30 ml/min/1.73 m2 
• 
Grade 4:  <15 ml/min/1.73 m2 
A separate shift table will be produced for eGFR based upon the above grades to determine the 
categorical shifts from baseline to each post-baseline visit. 
An additional table will be produced, summarizing the number of patients meeting the following 
criteria:  
• 
Alanine aminotransferase (ALT) > 1×ULN at baseline 
• 
Aspartate aminotransferase (AST) > 1×ULN at baseline 
• 
AT > 1×ULN at baseline 
• 
Treatment-emergent ALT > 3×ULN, > 5×ULN and > 8×ULN 
• 
Treatment-emergent AST > 3×ULN, > 5×ULN and > 8×ULN 
• 
Treatment-emergent AT > 3×ULN, > 5×ULN and > 8×ULN 
• 
Treatment-emergent AT > 3×ULN and either bilirubin > 2×ULN or INR > 1.5 
where AT is AST or ALT, and treatment emergent is defined as criteria not met at baseline, but 
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Protocol Number GWND19002  
 
PCN Number GWRE209830 
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met at any time post-baseline.  The above will be summarized overall and for the following 
subgroups:  
• 
Valproic acid use (as a concomitant medication) (Yes, No).  
• 
Clobazam use (as a concomitant medication) (Yes, No).  
• 
Valproic acid use and Clobazam use (as concomitant medications) (Yes/Yes, Yes/No, 
No/Yes, No/No).  
(A medication will be considered concomitant if it has a start date on or after the first dose 
of IMP or if it was started prior to the first dose of IMP and was ongoing.) 
• 
Patients taking 3 or more current AEDs.  
• 
Patients taking 4 or more current AEDs.  
All laboratory data will be listed; listings will include limited demographic information about the 
patient (age, sex, race and weight at baseline).  Abnormal laboratory values will be listed 
separately.  A further listing will be created for the laboratory reference ranges and toxicity limits.  
A listing of liver parameters (ALT, AST, bilirubin and INR) will be produced that includes the 
baseline result, result at the particular visit, change from baseline, upper limit of normal (ULN) 
value, ratio of result to baseline and ratio of result to ULN. 
9.2.2 
Urinalysis 
Urinalysis is assessed using dipsticks at Visit 8, Visit 10, Visit 12, and Visit 14 (end of treatment). 
Urinalysis results will be listed only. 
9.2.3 
Pregnancy Test  
Serum pregnancy test results will be summarized by visit. 
9.3 
Vital Signs, Other Physical Findings and Other Safety Data 
9.3.1 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure and pulse rate) are measured at Visit 
1 , Visit 4, Visit 5, Visit 6, Visit 7, Visit 8, Visit 9 , Visit 10, Visit 12, Visit 14 (end of treatment) 
and Visit 15 (end of taper). 
Summaries will be presented for each vital sign parameter at each visit.  Change from baseline 
RCT and OLE baseline) to each post-baseline visit will also be presented. 
A separate table will be produced, by visit, presenting the incidence of patients with vital signs 
indicative of a medical condition at Visit 1 and indicative of an AE after Visit 1. 
Based on the criteria presented in Appendix 3, potentially clinically significant changes from 
baseline (RCT and OLE baseline) in vital signs measurements and other defined flagged values 
will be identified at each visit. The number of patients with a potentially clinically significant 
change from baseline will be summarized by parameter, and visit.  The number of patients with at 
least one post-baseline flagged vital sign parameter value will be summarized by parameter, and 
flagged criteria. 
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Protocol Number GWND19002  
 
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL  | 15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
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9.3.2 
Electrocardiogram 
An ECG will be performed at Visit 1, Visit 4, Visit 6, Visit 8, Visit 10, Visit 12 and Visit 14 (end 
of treatment). 
Summaries will be presented for mean heart rate, RR interval, PR interval, QRS duration, QT 
interval, QTcB and QTcF, at each visit.  Change from baseline (RCT and OLE baseline) to each 
post-baseline visit will also be presented. 
A separate table will be produced, by visit, presenting the incidence of patients  
Based on the criteria presented in Appendix 3, defined flagged values will be identified at each 
visit.  The number of patients with at least one post-baseline flagged ECG parameter value will be 
summarized by parameter, and flagged criteria. 
9.3.3 
Physical Examination 
A physical examination which includes body weight measurements will be performed at Visit 1, 
Visit 4, Visit 6, Visit 8, Visit 9, Visit 10, Visit 12, and Visit 14 (end of treatment).  Height will be 
collected as part of the physical examination at Visit 8, Visit 10, Visit 12, Visit 14 (end of 
treatment). 
Any relevant findings at screening are included as part of the patient’s medical history. Any 
changes seen after screening that are indicative of an AE are to be recorded as such on the AE 
form and included as part of the AE summaries. 
Weight along with weight change and height data will be summarized by visit where applicable.  
9.3.4 
Suicidality Assessment 
The profound cognitive impairment of RTT patients is such that the Children’s Columbia-Suicide 
Severity Rating Scale is not considered appropriate in this trial. Instead, suicidality will be assessed 
by the investigator via a clinical interview with the caregiver. 
Responses to the suicidality assessment will be summarized by visit. 
9.3.5 
Growth and Development 
IGF-1 levels will be analyzed as part of the clinical laboratory testing.  IGF-1 levels will be 
summarized on a continuous scale, including change from baseline. 
Change from baseline (RCT and OLE baseline) to the end of treatment visit for IGF-1 levels will 
also be plotted against the Tanner Stages, weight, and height recorded at baseline. 
The pubic hair growth (both sexes), genital (males only) and breast (females only) development 
of all adolescent patients (i.e., > 7 years of age at the time of signing the informed consent form, 
or earlier if clinically indicated by onset of menarche or other signs of precocious puberty) will be 
assessed using Tanner Staging.  The assessment can either be performed by examination during 
the study visit or the appropriate Tanner Stage can be indicated by the caregiver, with reference to 
the chart provided. 
Patients will be examined at Visit 8, Visit 10 and Visit 14 (end of treatment).  Once a patient 
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reaches a score of V (i.e., 5) the examination need not be performed again. 
Tanner Stages will be summarized on a categorical scale by Visit. Shift table will be created to 
display shifts from baseline.  
9.3.6 
Menstruation 
Caregivers will be asked if the female patient is menstruating and details will be recorded at 
Visit 1; any changes in normal cycles will be captured at Visit 8, Visit 10, and Visit 14 (end of 
treatment). 
Menstruation details will be summarized as appropriate by visit. 
9.4 
Other Measures 
9.4.1 
Concomitant Medication 
Medications will be coded using the World Health Organization Drug Dictionary WHO-DD 
Enhanced (v.WhoDrugGlobalB3 ̽201903) or later version. 
All medication will be considered concomitant. 
For summaries and listings of medications the following approach will be used to determine the 
Anatomical Therapeutic Chemical (ATC) term to be presented: 
• 
If coded to level 4 then the level 4 coded term will be presented. 
• 
If coding is not performed at level 4 but level 3 coding is present then level 3 coded term 
will be presented. 
• 
If coding is not performed at level 3 but level 2 coding is present then the level 2 coded 
term will be presented. 
• 
If coding is not performed at level 2 but level 1 coding is present then the level 1 coded 
term will be presented. 
Concomitant medications by ATC term and preferred term will be summarized by absolute counts 
(n) and percentages (%). 
The ATC term, preferred term, reported generic name and reported brand name will be listed. 
9.4.2 
Procedures and Non-Drug Therapies 
Procedures and non-drug therapies will be summarized overall. 
9.4.3 
Pregnancy Monitoring Form 
Any patient who has become pregnant whilst receiving IMP, or within 90 days of last dose of IMP, 
must be reported to the GW PVD. Where possible the investigator should provide the outcome of 
the pregnancy and complete the pregnancy monitoring form.  Details of pregnancies will be listed. 
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9.4.4 
Patients Impacted by COVID-19  
A listing of all patients impacted by COVID-19 related study disruption will be provided. The 
listing will include patient ID, site and a description of how the patient’s participation was 
altered.  
Protocol Deviations related to COVID will be provided in a data listing.  
9.5 
Changes in the Conduct of the Trial or Planned Analysis 
After carefully evaluating the study performance and the potential impact of the COVID-19 
pandemic to patients and site personnel the Sponsor made the decision to discontinue the lead-in 
trial. The significant challenges to conducting studies in this vulnerable group of patients were 
magnified by the COVID-19 pandemic leading to the conclusion that it was no longer feasible to 
conduct the studies. All patients enrolled in GWND18064 continued the study as per plan and if 
agreed, entered the OLE extension. When entering the OLE extension, patients will complete this 
trial as per protocol and annex. The annex described conditions for patients entering the extension 
trial if they withdrew from RCT trial due to Covid, due to sponsor administrative decision or 
delayed entry into GWND19002 due to Covid. All OLE trial Visit 1 data will be summarized for 
patients enrolling in the OLE under this protocol annex. Their data will be summarized in the same 
way as that of patients enrolling in the OLE under the GWND19002 protocol. The summary tables 
will present data from patients enrolling in the OLE under the protocol annex combined with that 
of patients enrolling in the OLE under the GWND19002 protocol. Their data will also be presented 
separately.’ 
As a result the analyses described in this SAP differ from those that were initially intended and 
presented in the protocol. Initially only comparison towards RCT baseline was planned, in this 
SAP both comparison with RCT and OLE baseline is planned. 
 
 
 
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10. 
References 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and 
Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
 
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
3. RSS. 
(2014) 
The 
Royal 
Statistical 
Society: 
Code 
of 
Conduct, 
2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
4. HealthActCHQ. (2013). The CHQ Scoring and Interpretation Manual. Boston, MA: 
HealthActCHQ. 
5. Maruish, M. (2011). User's manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated. 
11. 
Tables, Listings, and Figures 
Table, listings and figures shells are provided as a separate document. The final statistical tables 
will be produced in the format of the shells and will additionally include “double” page numbering 
in the format “page xx of yy”. Note that programming notes may be added or modified if 
appropriate after each TLF shell.  
The final statistical output will be provided as fully bookmarked pdf file including a table of 
contents. 
All listings, tables, and graphs will have a header showing the sponsor company name and protocol 
and a footer showing the version of SAS, the file name and path, and the source of the data (eCRF 
page or listing number). 
In general, one listing will be produced per eCRF domain. All listings will be sorted by site, and 
patient number. 
In all listings a blank line will be placed between each patient. Within a data listing, if an item 
appears line after line (eg, repetition of patient number), then only the first occurrence will be 
displayed. 
In data listings, the information for one patient will be kept on one page if at all possible, rather 
than splitting a patient’s information across pages. 
 
 
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APPENDIX 1: Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
CRO 
Contract research organization 
CSR 
Clinical study report 
D 
Day 
eCRF 
Electronical case report form 
ITT 
Intent-to –treat analysis set 
ECG 
Electrocardiogram 
EMA 
European Medicines aAgency 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonisation 
MedDRA 
Medical ictionary for regulatory activities 
OLE 
Open-Label Extension 
PD 
Pharmacodynamics 
PP 
Per-protocol population 
PK 
Pharmacokinetics 
QTc 
QT-interval for ECG corrected for heart rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
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Abbreviation 
Definition 
SAF 
Safety population 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
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APPENDIX 2 Adverse Events of Special Interest – Abuse Liability based on preferred term 
Withdrawal 
Drug withdrawal convulsions 
Drug withdrawal headache 
Drug withdrawal maintenance therapy 
Drug withdrawal syndrome 
Drug withdrawal syndrome neonatal 
Drug rehabilitation 
Rebound effect 
Steroid withdrawal syndrome 
Withdrawal arrhythmia 
Withdrawal syndrome 
Drug abuse and dependence 
Dopamine dysregulation syndrome 
Drug abuse 
Drug abuser 
Drug dependence 
Drug dependence, antepartum 
Drug dependence, postpartum 
Intentional drug misuse 
Intentional overdose 
Maternal use of illicit drugs 
Neonatal complications of substance abuse 
Polysubstance dependence 
Substance abuse 
Substance abuser 
Accidental overdose 
Dependence 
Disturbance in social behaviour 
Drug administered at inappropriate site 
Drug detoxification 
Drug diversion 
Drug level above therapeutic 
Drug level increased 
Drug screen 
Drug screen positive 
Drug tolerance 
Drug tolerance decreased 
Drug tolerance increased 
Medication overuse headache 
Narcotic bowel syndrome 
Needle track marks 
Overdose 
Prescribed overdose 
Prescription form tampering 
Substance use 
Substance-induced mood disorder 
Substance-induced psychotic disorder 
Toxicity to various agents 
 
 
 
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APPENDIX 3 Ranges for Clinically Significant Changes and Other Defined Flagged Values 
in Vital Signs 
The range of values that will be used to identify clinically significant changes in vital signs 
parameters (See Section 9.3.1) are presented in Table 7. 
 
Table 7 
Ranges for Potentially Clinically Significant Changes in Vital Signs 
Vital Sign 
Range 
Sitting Systolic BP (mmHg) 
Change: < -20, > 20 
Sitting Diastolic BP 
(mmHg) 
Change: < -10, > 10 
Pulse Rate (bpm) 
Change: < -10, > 10 
Weight (kg) 
Percent Change: ≤ -7, ≥ 7 
 
Defined flagged values that will be used to identify low or high vital signs parameters (See 
Section 9.3.1) are presented in Table 8. 
 
Table 8 
Other Defined Flagged Values for Vital Signs 
Vital Sign 
Flag 
Sitting Systolic BP (mmHg) 
< 90, > 140, > 160 
Sitting Diastolic BP 
(mmHg) 
< 50, > 90, > 100 
Pulse Rate (bpm) 
< 60, > 100 
Temperature (°C) 
> 38.0, < 36.0 
Respiratory Rate 
(breaths/min) 
< 12, > 20 
 
 
 
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APPENDIX 1 Defined Flagged Values in ECG Parameters 
Defined flagged values that will be used to identify low or high ECG parameters (See Section 
9.3.2) are presented in Table 9. 
 
Table 9 
Defined Flagged Values for ECG Parameters 
ECG Parameter 
Flag 
QTc (ms) 
> 450, > 480, > 500 
 
 
 
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APPENDIX 2 Toxicity Criteria for Laboratory Parameters 
The toxicity criteria that will be used to identify abnormal laboratory parameters are presented in 
Table 10 and Table 11. 
Table 10 
Toxicity Criteria for Biochemistry Parameters 
Parameter 
Toxicity Decrease 
Toxicity Increase 
Chloride 
d0.96xLL 
t1.04xUL 
Calcium 
d0.89xLL 
t1.16xUL 
Sodium 
d0.96xLL 
t1.04xUL 
Potassium 
d0.90xLL 
t1.10xUL 
Glucose (mmol/L) 
d3.2 
t16 
Phosphate 
d0.79xLL 
 
Cholesterol 
d0.85xLL 
t1.6xUL 
AST 
 
t3xUL 
ALT 
 
t3xUL 
Lactate Dehydrogenase 
 
t2.6xUL 
Alkaline phosphatase 
 
t2xUL 
Gamma GT 
 
t2.6xUL 
Bilirubin 
 
>2xUL 
Albumin 
d0.84xLL 
 
Total protein 
d0.84xLL 
t1.16xUL 
Urea 
 
t2.6xUL 
Blood urea nitrogen 
 
t2.6xUL 
Creatinine 
 
t2.6xUL 
Uric acid 
 
t1.16xUL 
UL = upper limit of reference range 
LL = lower limit of reference range 
 
Table 11 
Toxicity Criteria for Hematology Parameters 
Parameter 
Toxicity Decrease 
Toxicity Increase 
Hemoglobin (g/dL) 
d9.4 
 
Hematocrit (%) 
d28 
 
Red cell count 
d0.84xLL 
 
Mean corpuscular volume 
d0.84xLL 
t1.11xUL 
Mean corpuscular hemoglobin 
d0.84xLL 
 
Mean corpuscular hemoglobin concentration 
d0.84xLL 
 
Platelets (x10^9/L) 
d74 
 
Prothrombin time 
 
>1.5xUL 
Prothrombin international normalized ratio 
 
>1.5 
Total white blood cell count (x10^9/L) 
d2.9 
t21 
Total neutrophil count (x10^9/L) 
d1.36 
t14.7 
Segmented neutrophil count (x10^9/L) 
d0.75 
t12.3 
Eosinophils (x10^9/L) 
 
t1.5 
Basophils (x10^9/L) 
 
t0.31 
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Parameter 
Toxicity Decrease 
Toxicity Increase 
Monocytes (x10^9/L) 
 
t2.1 
Lymphocytes (x10^9/L) for patients <18 years 
(auto hematology) 
d1.0 
 
Lymphocytes (x10^9/L) for patients <18 years 
(manual hematology) 
d0.2 
 
Lymphocytes (x10^9/L) for patients ≥18 years 
d0.2 
 
UL = upper limit of reference range 
LL = lower limit of reference range 
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APPENDIX 5 Scoring the CHQ-PF50 
The CHQ-PF50 provides information on various health concepts, as well as the PhS and PsS 
scales.  Details for scoring each of these concepts and scales are based on the CHQ scoring and 
interpretation manual (HealthActCHQ, 2013).  
Global Health Item 
The global health item (item 1.1) of the CHQ-PF50 is calculated using the steps below. 
1. The scores for this item are recoded as presented below, where missing scores remain 
missing. 
Table 12 
Scoring of Global Health Item 
Response 
Precoded Item Values 
Final Item Values 
Excellent 
1 
5 
Very Good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.2 
Poor 
5 
1 
2. The final scores are then transformed so that they range from 0 to 100 in the following 
way: 
(Final item value – 1) / 4 × 100 
Physical Function 
Items 2.1 (a to f) are included in this health concept.  Each item is coded with a value from 1 to 
4, where 1 corresponds to a response “Yes, limited a lot”, 2 “Yes, limited some”, 3 “Yes, limited 
a little“ and d 4 corresponds to the response “No, not limited”. 
The score for the physical function health concept is calculated using the following steps: 
1. The mean of the scores (raw score) for items 2.1 (a to f) is calculated if at least 3 of the 
items have been answered.  If less than 3 items have responses this concept is set to missing. 
2. The standardized score which ranges from 0 to 100 is then calculated as follows: 
(Raw score – 1) / 3 × 100 
Role/Social Limitations Due to Emotional or Behavioral Difficulties 
This health concept is based on items 3.1 (a to c).  Each item is coded with a value from 1 to 4, 
where 1 corresponds to a response “Yes, limited a lot” and 4 corresponds to the response “No, 
not limited”. 
The steps below are followed to score this health concept 
1. If at least 2 of the 3 items have been answered, the mean of the scores (the raw score) for 
items 3.1 (a to c) is calculated, otherwise this concept is set to missing. 
2. The standardized score which ranges from 0 to 100 is then calculated as follows: 
(Raw score – 1) / 3 × 100 
Role/Social Limitations Due to Physical Health 
Items 3.2 (a and b) are included in this health concept.  Each item is coded with a value from 1 to 
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4, where 1 corresponds to a response “Yes, limited a lot” and 4 corresponds to the response “No, 
not limited”. 
The steps below are followed to score this health concept 
1. The raw score is calculated as the mean of the scoresif at least 1 of the items has been 
answered, otherwise this concept is set to missing. 
2. The standardized score which ranges from 0 to 100 is then calculated as follows: 
(Raw score – 1) / 3 × 100 
Bodily Pain and Discomfort 
The Bodily Pain and Discomfort scale includes items 4.1 and 4.2.  The scores for these items are 
to be reversed as presented in Table 13 and Table 14. 
Table 13 
Scoring of Item 4.1 for Bodily Pain and Discomfort 
Item 4.1 Response 
Precoded Item Values 
Final Item Values 
None  
1 
6 
Very mild 
2 
5 
Mild 
3 
4 
Moderate 
4 
3 
Severe 
5 
2 
Very severe 
6 
1 
Table 14 
Scoring of Item 4.2 for Bodily Pain and Discomfort 
Item 4.2 Response 
Precoded Item Values 
Final Item Values 
None of the time 
1 
6 
Once or twice 
2 
5 
A few times 
3 
4 
Fairly often 
4 
3 
Very often 
5 
2 
Every/almost every day 
6 
1 
 
The Bodily Pain and Discomfort scale score is then calculated as follows: 
1. The mean of the two scores (the raw score) is calculated if at least one of the items has 
been answered. 
2. The standardized score which ranges from 0 to 100 is then calculated as follows: 
(Raw score – 1) / 5 × 100 
Behavior 
Items 5.1 (a to e) and 5.2 are included in this health concept.  Items 5.1 (a to e) are coded with a 
value from 1 to 5, where 1 corresponds to a response “Very often”, 2 to “Fairly often”, 3 to 
“Sometimes”, 4 to “Almost never”, and 5 corresponds to the response “Never”.  
Responses to item 5.2 are recoded using the rules in Table 15. 
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Table 15 
Scoring of Behavior 
Response 
Precoded Item Values 
Final Item Values 
Excellent 
1 
5 
Very Good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.2 
Poor 
5 
1 
 
The following steps are then used to calculate the Behavior concept score: 
1. If at least 3 items have been answered the mean is calculated, otherwise this scale is set to 
missing. 
2. The resulting mean, or raw score, is then standardized to range from 0 to 100 as follows: 
(Raw score – 1) / 4 × 100 
Global Behavior Item 
The global behavior item (item 5.2) of the CHQ-PF50 is calculated using the steps below. 
1. The scores for this item are recoded as presented below, where missing scores remain 
missing. 
Table 16 
Scoring of Global Behavior Item 
Response 
Precoded Item Values 
Final Item Values 
Excellent 
1 
5 
Very Good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.2 
Poor 
5 
1 
2. The final score is then transformed to range from 0 to 100 in the following way: 
(Final item value – 1) / 4 × 100 
Mental Health 
Items 6.1 (a to e) are included in this health concept.  Each of the items 6.1 (a to d) is coded with 
a value from 1 to 5, where 1 corresponds to a response of “All of the time” and 5 corresponds to 
the response “None of the time”.  Responses to item 6.1 (e) are reverse scored as indicated in 
Table 17. 
Table 17 
Scoring of Mental Health 
Response 
Precoded Item Values 
Final Item Values 
All of the time 
1 
5 
Most of the time 
2 
4 
Some of the time 
3 
3 
A little of the time 
4 
2 
None of the time 
5 
1 
 
If at least 3 of the items 6.1 (a to e) have been answered the raw score is obtained by calculating 
the mean of the scores.  The raw score is then standardized to range from 0 to 100 as follows: 
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(Raw score – 1) / 4 × 100 
Self Esteem 
The self esteem scale includes Items 7.1 (a to f) which are reverse scored as presented in Table 
18. 
Table 18 
Scoring of Self Esteem 
Response 
Precoded Item Values 
Final Item Values 
Very satisfied 
1 
5 
Somewhat satisfied 
2 
4 
Neither satisfied nor 
dissatisfied 
3 
3 
Somewhat dissatisfied 
4 
2 
Very dissatisfied 
5 
1 
 
If at least 3 of the items 7.1 (a to f) have been answered the mean of the scores is calculated.  The 
mean score is then standardized to range from 0 to 100 as follows: 
(Raw score – 1) / 4 × 100 
General Health Perceptions 
Items 8.1 (a to e) and item 1.1 are included in this scale.  Items 8.1 (a, c, e) are scored from 1 to 5 
where 1 represents the response “Definitely true” and 5 represents “Definitely False”.  Items 8.1 
(b and d) are reverse scored as is seen in Table 19. 
Table 19 
Scoring of Global Health Perceptions 
Response 
Precoded Item Values 
Final Item Values 
Definitely true 
1 
5 
Mostly true 
2 
4 
Don’t know 
3 
3 
Mostly false 
4 
2 
Definitely false 
5 
1 
 
Finally, responses to item 1.1 are recoded as presented in Table 13. 
The general health perceptions scale is then scored using the steps below: 
1. If less than 3 of the items 8.1 (a to e) and 1.1 have been answered, this scale is set to 
missing.  Otherwise calculate the raw score by computing the mean of the responses. 
2. The raw score is then standardized so that it ranges from 0 to 100 as follows: 
(Raw score – 1) / 4 × 100 
 
Change in Health Item 
The change in health item (item 8.2) of the CHQ-PF50 is to be reverse scored as displayed in 
Table 20. 
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Table 20 
Scoring of Change in Health Item 
Response 
Precoded Item Values 
Final Item Values 
Much better now than 1 year ago 
1 
5 
Somewhat better now than 1 year ago 
2 
4 
About the same now than 1 year ago 
3 
3 
Somewhat worse now than 1 year ago 
4 
2 
Much worse now than 1 year ago 
5 
1 
This is a categorical scale and thus no transformation is necessary. 
Emotional Impact on Parent 
This scale includes items 9.1 (a to c) which are to be reverse scored in accordance with Table 21. 
Table 21 
Scoring of Emotional Impact on Parent 
Response 
Precoded Item Values 
Final Item Values 
Not at all 
1 
5 
A little bit 
2 
4 
Some 
3 
3 
Quite a bit 
4 
2 
A lot 
5 
1 
 
The emotional impact on parent scale score is then calculated as follows: 
1. If at least 2 of the items in this scale have been answered, the raw score is obtained by 
computing the mean of the responses, otherwise this scale is set to missing. 
2. The raw score is then standardized so that it ranges from 0 to 100 as follows: 
(Raw score – 1) / 4 × 100 
Time Impact on Parent 
Items 9.2 (a to c) are included in the time impact on parent scale.  The responses range from 1 to 
4 where 1 corresponds to “Yes, limited a lot” and 4 corresponds to a response of “No, not 
limited”.  If at least 2 items in this scale have been answered the raw score is calculated as the 
mean of the items.  If less than 2 items have been answered the scale is set to missing. 
Finally, the standardized score which ranges from 0 to 100 is calculated as  
(Raw score – 1) / 3 × 100 
Family Activities 
The family activities health concept is comprised of items 9.3 (a to f).  The responses range from 
1 to 5 where 1 represents the response “Very often” and 5 the response of “Never”.  If at least 3 
items in this scale the raw score is calculated as the mean of the responses, otherwise the scale is 
sent to missing.   
The raw score is then standardized as: 
(Raw score – 1) / 4 × 100 
 
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Statistical Analysis Plan,  
 
GW Research Ltd 
 
Protocol Number GWND19002  
 
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL  | 15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
Page 45 of 46 
 
Family Cohesion Item 
The family cohesion health concept includes item 9.4 which is recoded using the rules outlined 
inTable 22. 
Table 22 
Scoring of Family Cohesion Item 
Response 
Precoded Item Values 
Final Item Values 
Excellent 
1 
5 
Very good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.2 
Poor 
5 
1 
The score is then transformed so that it ranges from 0 to 100 as follows: 
(Raw score – 1) / 4 × 100 
 
Standardized Physical Summary and Standardized Psychosocial Summary 
The PhS and PsS scales are scored using norm-based methods based on data from from the 
general U.S. population and six clinical samples of children. Table 24 includes the sample means 
and standard deviations, as well as factor score coefficients, used to derive the PhS and PsS scale 
scores. 
 
Table 24 
Information Required for Scoring PhS and PsS Scales 
 
Page 46 of 47


 
Statistical Analysis Plan,  
 
GW Research Ltd 
 
Protocol Number GWND19002  
 
PCN Number GWRE209830 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version FINAL  | 15-JUN-2021    |    AD-PR-109.02  Effective date: 17-Aug-2020 
Page 46 of 46 
 
 
The steps used in calculating PsS and PhS are summarized below: 
1. Calculate each of the CHQ-PF50 scales presented in Table and using the methods outlined 
in this appendix. 
2. Each scale is then standardized using a z-score transformation as follows: 
ݏ݈ܿܽ݁ݏܿ݋ݎ݁െ݉݁ܽ݊݋݂ݏ݈ܿܽ݁
ݏݐ݀݀݁ݒ݅ܽݐ݅݋݊݋݂ݏ݈ܿܽ݁
 
 
where the mean and standard deviation for each scale are obtained from Table 24 
3. Calculate PhS and PsS as a weighted sum of each standardized scale, using the factor score 
coefficients from Table 24 as the weights for each item in each scale. 
4. Transform each scale score to obtain t-score with a mean of 50 and standard deviation of 
10 as follows: 
PhS = PhS weighted sum × 10 + 50 
PhS = PhS weighted sum × 10 + 50. 
 
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