A Long-term Safety Study of Cannabidiol Oral Solution (GWP42003-P, CBD-OS) in Patients With Rett Syndrome

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04252586
• Collaborator: GW Pharmaceuticals (Other)
• Enrollment: 21
• Locations: 31
• Arm: 1
• Actual Duration (Months): 15.3
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Rett Syndrome; RTT	Drug: GWP42003-P	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Feb 28, 2020
• Actual Primary Completion Date: Jun 9, 2021
• Actual Study Completion Date: Jun 9, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GWP42003-P 100 milligrams per milliliter (mg/mL) GWP42003-P oral solution, taken twice daily (morning and evening).	Drug: GWP42003-P; GWP42003-P presented as an oral solution containing cannabidiol in the excipients sesame oil with anhydrous ethanol, sweetener (sucralose), and strawberry flavoring; Other Names: Cannabidiol CBD Epidiolex CBD-OS

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Any Treatment-emergent Adverse Events (TEAEs), Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 16 (Day 767) in the OLE]

   Adverse events (AEs) were defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings when relevant) or diagnosis or worsening of a pre-existing condition that occurs during the study. TEAEs were defined as the AEs that started or worsened in severity or seriousness following the first dose of GWP42003-P. A serious AE was defined as any AE that results in any of the following outcomes: death, life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or cancer, any other experience that suggests a significant hazard, contraindication, side effect or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above, or an event that changes the risk/benefit ratio of the study.

2. Number of Participants With Treatment-emergent Clinical Laboratory Parameters From the Baseline at Any Time Post-dose [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

   Treatment-emergent clinical parameters were defined as the following: Treatment-emergent alanine transferase (ALT) > 3×upper limit of normal (ULN), > 5×ULN and > 8×ULN; Treatment-emergent aspartate aminotransferase (AST) > 3×ULN, > 5×ULN and > 8×ULN; Treatment-emergent ALT or AST > 3×ULN, > 5×ULN and > 8×ULN; Treatment-emergent ALT or AST > 3×ULN and either bilirubin > 2×ULN or international normalized ratio (INR) > 1.5.

3. Number of Participants With Potentially Clinically Significant Changes in Vital Sign Values of Blood Pressure From the Baseline at Any Time Post-dose [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 15 (Day 739) in the OLE]

   Potentially clinically significant vital sign values of blood pressure (BP) were defined as sitting systolic BP (mmHg) change: < -20 or > 20 mmHg and sitting diastolic BP change: < -10 or > 10 mmHg. Vital sign measurements were taken in a sitting position at rest for 5 minutes. Blood pressure readings were recorded using the same arm throughout the trial, when possible.

4. Number of Participants With Clinically Significant Changes in the Vital Sign Values of Pulse Rate From the Baseline at Any Time Post-dose [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 15 (Day 739) in the OLE]

   Potentially clinically significant vital sign values of pulse rate were defined as pulse rate change: < -10 or > 10 beats per minute. Vital sign measurements were taken in a sitting position at rest for 5 minutes.

5. Number of Participants With Clinically Significant Percent Change in Body Weight From the Baseline at Any Time Post-dose [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

   Clinically significant body weight changes were defined as the percent change in body weight (≤7% change or ≥7% change).

6. Number of Participants With At Least One Post Open Label Extension Baseline Flagged ECG Result [Visit 4 (Day 29) up to Visit 15 (Day 739) in the OLE]

   Electrocardiogram assessments were performed for QTcB and QTcF >450 msec, >480 msec, and >500 msec. QTcB = corrected QT interval with Bazette correction. QTcF = QTc corrected by Fridericia.

7. Number of Participants With Any Changes In Menstruation Cycle at Any Time Post-dose [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

   Participants were evaluated for any changes to typical menstrual cycles, duration of menstrual cycles, and typical strength of the menstrual cycles during the study.

8. Number of Participants With Suicidal Ideation or Behavior at the Baseline and at Any Time Post-dose [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

   Suicidal ideation and behavior was assessed by the investigator via a clinical interview with the caregiver. The questionnaire included following questions: Has the child expressed any wish to be dead?, Has the child made any suicide attempts?, Has the child shown any non-suicidal self-injurious behavior? The responses were recorded as Yes/No.

9. Mean Change From Baseline in Insulin-like Growth Factor-1 (IGF-1) Levels at End of Treatment [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

   Blood samples were collected to assess changes in serum IGF-1 levels. A negative mean change from baseline indicates a reduction in IGF-1 levels.

10. Number of Participants With Changes in Tanner Staging at the Baseline and at End of Treatment [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

    Pubic hair growth and breast development of all adolescents were assessed by the investigator or caregiver using Tanner Staging categorization from 1 to 5. Stage 1- No glandular tissue; areola follows skin contours of chest; No pubic hair Stage 2- Breast bud forms; areola begins to widen; a small amount of long, downy hair with slight pigmentation on labia majora Stage 3- Breast begins to become more elevated and extends beyond 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 Stage 4- 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 Stage 5- Breast reaches final adult size; areola returns to the contour of the surrounding breast, with a projecting central papilla; Hair extends to medial surface of the thigh.

Secondary Outcome Measures

1. Mean Change From Baseline in Rett Syndrome Behaviour Questionnaire (RSBQ) Overall Score at End of Treatment [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

   RSBQ is a caregiver-completed questionnaire that assesses the overall condition (45 items) in individuals with Rett Syndrome. Each item is rated on a 3-point scale (0-2); 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 ("Uses eye gaze to convey feelings, needs and wishes") is reverse-scored (0 indicating "very true or often true", 1 indicating "somewhat or sometimes true," and 2 indicating "not true as far as you know"). The total summed score ranges from 0 to 90, with higher scores representing greater severity. A negative mean change from baseline indicates an improvement in overall condition.

2. Mean Clinical Global Impressions-Improvement (CGI-I) Continuous Score at End of Treatment [Visit 14 (Day 729) in the OLE]

   CGI-I is a 7-point scale that requires the clinician to assess whether a patient's condition has improved or worsened relative to a baseline state at the beginning of the intervention. This was rated as: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse. The mean continuous CGI-I score (averaged from each treatment enrolled under protocol and under annex) at Visit 14 (Day 729) is being reported. Higher mean scores indicate worse condition.

3. Mean Clinician Global Impressions - Severity Scale (CGI-S) Continuous Score at End of Treatment [Visit 14 (Day 729) in the OLE]

   CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment relative to the clinician's experience with participants who had the same diagnosis. This was 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. The mean continuous CGI-S score (averaged from each treatment enrolled under protocol and under annex) at Visit 14 (Day 729) is being reported. Higher scores indicate more severe disease.

4. Mean Change From Baseline in Children's Sleep Habits Questionnaire (CSHQ) Total Score at End of Treatment [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

   CSHQ is a caregiver-completed sleep screening instrument designed for school-aged children; which includes 33 items within 8 subscales:bedtime resistance (score range 6-18), sleep onset delay (range 1-3), sleep duration (range 3-9), sleep anxiety (range 4-12), night wakings (range 3-9), parasomnias (range 7-21), sleep-disordered breathing (range 3-9), daytime sleepiness (range 8-24). The 33 items range from 1 to 3, where 3="usually" (≥5 times/week), 2="sometimes" (2-4 times/week), and 1="rarely" (≤1 time/week); for items 31 and 32, 3=fall asleep, 2=very sleepy, 1=not sleepy. A score of 3 indicates greater severity; however, 6 items (1-Goes to bed at same time; 3-Falls asleep in own bed; 26-Wakes by himself; 2-Falls asleep in 20 minutes; 10-Sleeps the right amount; 11-Sleeps same amount each day) are reverse scored. The total summed score ranges from 33 to 99, with higher scores indicating disturbed sleep behavior. A negative mean change from baseline indicates improvement in sleep.

5. Mean Change From Baseline in 9-item Motor Behavioral Assessment (MBA-9) Total Score at End of Treatment [Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE]

   MBA-9 is derived from the full MBA scale (37 Rett syndrome symptoms) by selecting the items deemed amenable to change and which reflected areas of meaningful clinical change. The MBA-9 includes 9 items (Regression of motor skills; Poor eye/social contact; Lack of sustained interest; Does not reach for objects or people; Chewing difficulties; Speech disturbance; Hand clumsiness; Dystonia; and Hypertonia/rigidity). For each item, the severity of current symptoms is rated by the investigator on a 5-point numerical scale ranging from 0 to 4 with higher scores representing greater severity (0 = normal or never; 1 = mild or rare; 2 = moderate or occasional; 3 = marked or frequent; 4 = very severe or constant). Total MBA-9 score was calculated by summing the scores of 9 different subscale items. The total summed score ranges from 0 to 36, with higher scores representing greater severity. A negative mean change from baseline indicates improvement in behavior.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant has completed all scheduled visits of the treatment phase of the randomized controlled trial (RCT), GWND18064 (NCT03848832), and has transitioned to open-label extension (OLE) by the point of RCT follow-up

• Participant (if possessing adequate understanding, in the investigator's opinion) and/or the participant(s)/legal representative is willing and able to give informed consent/assent for participation in the trial.

• Participant and the participant'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).

• 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).

• Participant 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.

• Participant and/or parent(s)/legal representative is willing to allow the participant's primary care practitioner (if the participant has one) and consultant (if the participant has one) to be notified of participation in the trial, if the primary care practitioner/consultant is different from the investigator.

Exclusion Criteria:

• Participant meets the withdrawal criteria (including clinically significant abnormal laboratory values), in the investigator's opinion.

• Participant met during the RCT the criteria for permanent IMP discontinuation (unless in the case of an adverse event [AE], if the AE was not considered related with the IMP; participants 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 contraception associated with inhibition of ovulation [oral, intravaginal, or transdermal], progestogen-only hormonal contraception associated with inhibition of ovulation [oral, injectable, or implantable], intrauterine devices/hormone-releasing systems, bilateral tubal occlusion, vasectomized partner, sexual abstinence during the trial and for 3 months after the last dose

• Participant has been previously enrolled and dosed in this trial.

• Participant 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Trial Site	Birmingham	Alabama	United States	35294-0021
2	Clinical Trial Site	La Jolla	California	United States	92093
3	Clinical Trial Site	Aurora	Colorado	United States	80045
4	Clinical Trial Site	Chicago	Illinois	United States	60612
5	Clinical Trial Site	Baltimore	Maryland	United States	21205
6	Clinical Trial Site	Boston	Massachusetts	United States	02115
7	Clinical Trial Site	Saint Paul	Minnesota	United States	55101
8	Clinical Trial Site	Saint Louis	Missouri	United States	63110-1093
9	Clinical Trial Site	Bronx	New York	United States	10467
10	Clinical Trial Site	Cincinnati	Ohio	United States	45229
11	Clinical Trial Site	Philadelphia	Pennsylvania	United States	19104
12	Clinical Trial Site	Greenwood	South Carolina	United States	29646
13	Clinical Trial Site	Nashville	Tennessee	United States	37232
14	Clinical Trial Site	Houston	Texas	United States	77030
15	Clinical Trial Site	Perth		Australia
16	Clinical Trial Site	South Brisbane		Australia
17	Clinical Trial Site	Toronto		Canada
18	Clinical Trial Site	Vancouver		Canada
19	Clinical Trial Site	Genova		Italy
20	Clinical Trial Site	Messina		Italy
21	Clinical Trial Site	Milano		Italy
22	Clinical Trial Site	Rome		Italy
23	Clinical Trial Site	Siena		Italy
24	Clinical Trial Site #1	Barcelona		Spain
25	Clinical Trial Site #2	Barcelona		Spain
26	Clinical Trial Site #1	Madrid		Spain
27	Clinical Trial Site #2	Madrid		Spain
28	Clinical Trial Site	Valencia		Spain
29	Clinical Trial Site	Edinburgh		United Kingdom
30	Clinical Trial Site	Liverpool		United Kingdom
31	Clinical Trial Site	London		United Kingdom

Sponsors and Collaborators

• Jazz Pharmaceuticals
• GW Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Nov 11, 2020
• Statistical Analysis Plan - Jun 15, 2021

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04252586
• Other Study ID Numbers: GWND19002; 2019-001605-24
• First Posted: Feb 5, 2020
• Last Update Posted: Aug 8, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jazz Pharmaceuticals: Cannabidiol; CBD; Epidiolex; GWP42003-P
• Additional relevant MeSH terms: Rett Syndrome; Syndrome; Cannabidiol

Study Results

Participant Flow

Recruitment Details	A total of 21 participants who had previously participated in the randomized, double-blind, placebo-controlled trial GWND18064 (NCT03848832) entered this open label extension study.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Period Title: Overall Study
STARTED	21
COMPLETED	0
NOT COMPLETED	21

Baseline Characteristics

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Overall Participants	21
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.2 (5.59)
Age, Customized (Count of Participants)
2-5 years	6 28.6%
6-12 years	9 42.9%
13-19 years	6 28.6%
Sex: Female, Male (Count of Participants)
Female	21 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.8%
Not Hispanic or Latino	20 95.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 4.8%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	20 95.2%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Any Treatment-emergent Adverse Events (TEAEs), Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs
Description	Adverse events (AEs) were defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings when relevant) or diagnosis or worsening of a pre-existing condition that occurs during the study. TEAEs were defined as the AEs that started or worsened in severity or seriousness following the first dose of GWP42003-P. A serious AE was defined as any AE that results in any of the following outcomes: death, life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or cancer, any other experience that suggests a significant hazard, contraindication, side effect or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above, or an event that changes the risk/benefit ratio of the study.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 16 (Day 767) in the OLE

Outcome Measure Data

Analysis Population Description

Adverse events were assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Any TEAE	19 90.5%
Treatment-related TEAEs	7 33.3%
TEAEs leading to discontinuation	3 14.3%
Treatment-related TEAE leading to discontinuation	1 4.8%
Serious TEAEs	5 23.8%
Treatment-related serious TEAEs	0 0%

2. Primary Outcome

Title	Number of Participants With Treatment-emergent Clinical Laboratory Parameters From the Baseline at Any Time Post-dose
Description	Treatment-emergent clinical parameters were defined as the following: Treatment-emergent alanine transferase (ALT) > 3×upper limit of normal (ULN), > 5×ULN and > 8×ULN; Treatment-emergent aspartate aminotransferase (AST) > 3×ULN, > 5×ULN and > 8×ULN; Treatment-emergent ALT or AST > 3×ULN, > 5×ULN and > 8×ULN; Treatment-emergent ALT or AST > 3×ULN and either bilirubin > 2×ULN or international normalized ratio (INR) > 1.5.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Clinical laboratory parameters were assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants received GWP42003-P (5 mg/kg/day]) for 1 week. Depending on clinical response and tolerability, the participants' dose was increased in weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participant remained 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 based on clinical response and tolerability, as deemed necessary by the investigator.
Measure Participants	21
Treatment-emergent ALT >3xULN	1 4.8%
Treatment-emergent ALT >5xULN	0 0%
Treatment-emergent ALT >8xULN	0 0%
Treatment-emergent AST >3xULN	0 0%
Treatment-emergent AST >5xULN	0 0%
Treatment-emergent AST >8xULN	0 0%
Treatment-emergent ALT or AST >3xULN	1 4.8%
Treatment-emergent ALT or AST >5xULN	0 0%
Treatment-emergent ALT or AST >8xULN	0 0%
Treatment-emergent ALT or AST > 3×ULN and either bilirubin > 2×ULN or INR > 1.5	0 0%

3. Primary Outcome

Title	Number of Participants With Potentially Clinically Significant Changes in Vital Sign Values of Blood Pressure From the Baseline at Any Time Post-dose
Description	Potentially clinically significant vital sign values of blood pressure (BP) were defined as sitting systolic BP (mmHg) change: < -20 or > 20 mmHg and sitting diastolic BP change: < -10 or > 10 mmHg. Vital sign measurements were taken in a sitting position at rest for 5 minutes. Blood pressure readings were recorded using the same arm throughout the trial, when possible.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 15 (Day 739) in the OLE

Outcome Measure Data

Analysis Population Description

Vital signs were assessed in participants with available data in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Systolic BP Change <-20 mmHg, Baseline	4 19%
Systolic BP Change <-20 mmHg, Day 29	2 9.5%
Systolic BP Change <-20 mmHg, Day 57	1 4.8%
Systolic BP Change <-20 mmHg, Day 85	1 4.8%
Systolic BP Change <-20 mmHg, Day 141	2 9.5%
Systolic BP Change <-20 mmHg, Day 197	2 9.5%
Systolic BP Change <-20 mmHg, Day 281	0 0%
Systolic BP Change <-20 mmHg, Day 365	0 0%
Systolic BP Change <-20 mmHg, End of Treatment (up to Day 729)	1 4.8%
Systolic BP Change <-20 mmHg, Day 739	1 4.8%
Systolic BP Change >20 mmHg, Baseline	1 4.8%
Systolic BP Change >20 mmHg, Day 29	1 4.8%
Systolic BP Change >20 mmHg, Day 57	3 14.3%
Systolic BP Change >20 mmHg, Day 85	2 9.5%
Systolic BP Change >20 mmHg, Day 141	0 0%
Systolic BP Change >20 mmHg, Day 197	0 0%
Systolic BP Change >20 mmHg, Day 281	0 0%
Systolic BP Change >20 mmHg, Day 365	0 0%
Systolic BP Change >20 mmHg, End of Treatment (up to Day 729)	2 9.5%
Systolic BP Change >20 mmHg, Day 739	0 0%
Diastolic BP Change <-10 mmHg, Baseline	7 33.3%
Diastolic BP Change <-10 mmHg, Day 29	4 19%
Diastolic BP Change <-10 mmHg, Day 57	4 19%
Diastolic BP Change <-10 mmHg, Day 85	2 9.5%
Diastolic BP Change <-10 mmHg, Day 141	3 14.3%
Diastolic BP Change <-10 mmHg, Day 197	3 14.3%
Diastolic BP Change <-10 mmHg, Day 281	0 0%
Diastolic BP Change <-10 mmHg, Day 365	0 0%
Diastolic BP Change <-10 mmHg, End of Treatment (up to Day 729)	3 14.3%
Diastolic BP Change <-10 mmHg, Day 739	0 0%
Diastolic BP Change >10 mmHg, Baseline	4 19%
Diastolic BP Change >10 mmHg, Day 29	9 42.9%
Diastolic BP Change >10 mmHg, Day 57	4 19%
Diastolic BP Change >10 mmHg, Day 85	4 19%
Diastolic BP Change >10 mmHg, Day 141	3 14.3%
Diastolic BP Change >10 mmHg, Day 197	1 4.8%
Diastolic BP Change >10 mmHg, Day 281	0 0%
Diastolic BP Change >10 mmHg, Day 365	0 0%
Diastolic BP Change >10 mmHg, End of Treatment (up to Day 729)	5 23.8%
Diastolic BP Change >10 mmHg, Day 739	0 0%

4. Primary Outcome

Title	Number of Participants With Clinically Significant Changes in the Vital Sign Values of Pulse Rate From the Baseline at Any Time Post-dose
Description	Potentially clinically significant vital sign values of pulse rate were defined as pulse rate change: < -10 or > 10 beats per minute. Vital sign measurements were taken in a sitting position at rest for 5 minutes.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 15 (Day 739) in the OLE

Outcome Measure Data

Analysis Population Description

Pulse rate was assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Pulse Rate Change <-10beats/min, Baseline	9 42.9%
Pulse Rate Change <-10beats/min, Day 29	8 38.1%
Pulse Rate Change <-10beats/min, Day 57	7 33.3%
Pulse Rate Change <-10beats/min, Day 85	7 33.3%
Pulse Rate Change <-10beats/min, Day 141	2 9.5%
Pulse Rate Change <-10beats/min, Day 197	5 23.8%
Pulse Rate Change <-10beats/min, Day 281	1 4.8%
Pulse Rate Change <-10beats/min, Day 365	1 4.8%
Pulse Rate Change <-10beats/min, End of Treatment (up to Day 729)	6 28.6%
Pulse Rate Change <-10beats/min, Day 739	0 0%
Pulse Rate Change >10beats/min, Baseline	5 23.8%
Pulse Rate Change >10beats/min, Day 29	2 9.5%
Pulse Rate Change >10beats/min, Day 57	3 14.3%
Pulse Rate Change >10beats/min, Day 85	3 14.3%
Pulse Rate Change >10beats/min, Day 141	3 14.3%
Pulse Rate Change >10beats/min, Day 197	1 4.8%
Pulse Rate Change >10beats/min, Day 281	0 0%
Pulse Rate Change >10beats/min, Day 365	0 0%
Pulse Rate Change >10beats/min, End of Treatment (up to Day 729)	4 19%
Pulse Rate Change >10beats/min, Day 739	2 9.5%

5. Primary Outcome

Title	Number of Participants With Clinically Significant Percent Change in Body Weight From the Baseline at Any Time Post-dose
Description	Clinically significant body weight changes were defined as the percent change in body weight (≤7% change or ≥7% change).
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Body weight was assessed in participants with available data in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Weight Percent Change ≤7%, Baseline	1 4.8%
Weight Percent Change ≤7%, End of Treatment (up to Day 729)	1 4.8%
Weight Percent Change ≥7%, Baseline	8 38.1%
Weight Percent Change ≥7%, End of Treatment (up to Day 729)	10 47.6%

6. Primary Outcome

Title	Number of Participants With At Least One Post Open Label Extension Baseline Flagged ECG Result
Description	Electrocardiogram assessments were performed for QTcB and QTcF >450 msec, >480 msec, and >500 msec. QTcB = corrected QT interval with Bazette correction. QTcF = QTc corrected by Fridericia.
Time Frame	Visit 4 (Day 29) up to Visit 15 (Day 739) in the OLE

Outcome Measure Data

Analysis Population Description

Electrocardiogram assessments were performed in participants with available data in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	20
QTcB Interval, Aggregate > 450 msec, Day 29	4 19%
QTcB Interval, Aggregate > 450 msec, Day 57	0 0%
QTcB Interval, Aggregate > 450 msec, Day 85	4 19%
QTcB Interval, Aggregate > 450 msec, Day 141	0 0%
QTcB Interval, Aggregate > 450 msec, Day 197	0 0%
QTcB Interval, Aggregate > 450 msec, Day 365	0 0%
QTcB Interval, Aggregate > 450 msec, End of Treatment (up to Day 729)	4 19%
QTcB Interval, Aggregate > 450 msec, Day 739	0 0%
QTcB Interval, Aggregate > 480 msec, Day 29	0 0%
QTcB Interval, Aggregate > 480 msec, Day 57	0 0%
QTcB Interval, Aggregate > 480 msec, Day 85	1 4.8%
QTcB Interval, Aggregate > 480 msec, Day 141	0 0%
QTcB Interval, Aggregate > 480 msec, Day 197	0 0%
QTcB Interval, Aggregate > 480 msec, Day 365	0 0%
QTcB Interval, Aggregate > 480 msec, End of Treatment (up to Day 729)	1 4.8%
QTcB Interval, Aggregate > 480 msec, Day 739	0 0%
QTcB Interval, Aggregate > 500 msec, Day 29	0 0%
QTcB Interval, Aggregate > 500 msec, Day 57	0 0%
QTcB Interval, Aggregate > 500 msec, Day 85	0 0%
QTcB Interval, Aggregate > 500 msec, Day 141	0 0%
QTcB Interval, Aggregate > 500 msec, Day 197	0 0%
QTcB Interval, Aggregate > 500 msec, Day 365	0 0%
QTcB Interval, Aggregate > 500 msec, End of Treatment (up to Day 729)	0 0%
QTcB Interval, Aggregate > 500 msec, Day 739	0 0%
QTcF Interval, Aggregate > 450 msec, Day 29	0 0%
QTcF Interval, Aggregate > 450 msec, Day 57	0 0%
QTcF Interval, Aggregate > 450 msec, Day 85	1 4.8%
QTcF Interval, Aggregate > 450 msec, Day 141	0 0%
QTcF Interval, Aggregate > 450 msec, Day 197	0 0%
QTcF Interval, Aggregate > 450 msec, Day 365	0 0%
QTcF Interval, Aggregate > 450 msec, End of Treatment (up to Day 729)	0 0%
QTcF Interval, Aggregate > 450 msec, Day 739	0 0%
QTcF Interval, Aggregate > 480 msec, Day 29	0 0%
QTcF Interval, Aggregate > 480 msec, Day 57	0 0%
QTcF Interval, Aggregate > 480 msec, Day 85	0 0%
QTcF Interval, Aggregate > 480 msec, Day 141	0 0%
QTcF Interval, Aggregate > 480 msec, Day 197	0 0%
QTcF Interval, Aggregate > 480 msec, Day 365	0 0%
QTcF Interval, Aggregate > 480 msec, End of Treatment (up to Day 729)	0 0%
QTcF Interval, Aggregate > 480 msec, Day 739	0 0%
QTcF Interval, Aggregate > 500 msec, Day 29	0 0%
QTcF Interval, Aggregate > 500 msec, Day 57	0 0%
QTcF Interval, Aggregate > 500 msec, Day 85	0 0%
QTcF Interval, Aggregate > 500 msec, Day 141	0 0%
QTcF Interval, Aggregate > 500 msec, Day 197	0 0%
QTcF Interval, Aggregate > 500 msec, Day 365	0 0%
QTcF Interval, Aggregate > 500 msec, End of Treatment (up to Day 729)	0 0%
QTcF Interval, Aggregate > 500 msec, Day 739	0 0%

7. Primary Outcome

Title	Number of Participants With Any Changes In Menstruation Cycle at Any Time Post-dose
Description	Participants were evaluated for any changes to typical menstrual cycles, duration of menstrual cycles, and typical strength of the menstrual cycles during the study.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Changes in menstruation cycle was assessed in participants with available data in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Any change to typical cycle, Yes; Day 1	1 4.8%
Any change to typical cycle, No; Day 1	1 4.8%
Any change to typical cycle; Day 1 Unknown/Missing	19 90.5%
Typical duration of menstruation cycle, <3 days; Day 1	0 0%
Typical duration of menstruation cycle, 3-7 days; Day 1	1 4.8%
Typical duration of menstruation cycle, >7 days; Day 1	0 0%
Typical duration of menstruation cycle; Day 1 Unknown/Missing	20 95.2%
Typical strength of menstruation cycle, Light; Day 1	1 4.8%
Typical strength of menstruation cycle, Moderate; Day 1	0 0%
Typical strength of menstruation cycle, Heavy; Day 1	0 0%
Typical strength of menstruation cycle, Other; Day 1	0 0%
Typical strength of menstruation cycle; Day 1 Unknown/Missing	20 95.2%
Any change to typical cycle, Yes; End of Treatment (up to Day 729)	3 14.3%
Any change to typical cycle, No; End of Treatment (up to Day 729)	3 14.3%
Any change to typical cycle; End of Treatment (up to Day 729) Unknown/Missing	12 57.1%
Typical duration of menstruation cycle, <3 days; End of Treatment (up to Day 729)	0 0%
Typical duration of menstruation cycle, 3-7 days; End of Treatment (up to Day 729)	3 14.3%
Typical duration of menstruation cycle, >7 days; End of Treatment (up to Day 729)	0 0%
Typical duration of menstruation cycle; End of Treatment (up to Day 729) Unknown/Missing	15 71.4%
Typical strength of menstruation cycle, Light; End of Treatment (up to Day 729)	1 4.8%
Typical strength of menstruation cycle, Heavy; End of Treatment (up to Day 729)	2 9.5%
Typical strength of menstruation cycle, Moderate; End of Treatment (up to Day 729)	0 0%
Typical strength of menstruation cycle, Other; End of Treatment (up to Day 729)	0 0%
Typical strength of menstruation cycle; End of Treatment (up to Day 729) Unknown/Missing	15 71.4%

8. Primary Outcome

Title	Number of Participants With Suicidal Ideation or Behavior at the Baseline and at Any Time Post-dose
Description	Suicidal ideation and behavior was assessed by the investigator via a clinical interview with the caregiver. The questionnaire included following questions: Has the child expressed any wish to be dead?, Has the child made any suicide attempts?, Has the child shown any non-suicidal self-injurious behavior? The responses were recorded as Yes/No.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Suicidal ideation or behavior was assessed in participants with available data in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Has the child expressed any wish to be dead? Yes, Baseline	0 0%
Has the child expressed any wish to be dead? No, Baseline	16 76.2%
Has the child expressed any wish to be dead? Unknown/Missing, Baseline	5 23.8%
Has the child expressed any wish to be dead? Yes, End of Treatment (up to Day 729)	0 0%
Has the child expressed any wish to be dead? No, End of Treatment (up to Day 729)	18 85.7%
Has the child made any suicide attempts? Yes, Baseline	0 0%
Has the child made any suicide attempts? No, Baseline	16 76.2%
Has the child made any suicide attempts? Unknown/Missing, Baseline	5 23.8%
Has the child made any suicide attempts? Yes, End of Treatment (up to Day 729)	0 0%
Has the child made any suicide attempts? No, End of Treatment (up to Day 729)	18 85.7%
Has the child shown any non-suicidal self-injurious behavior? Yes, Baseline	0 0%
Has the child shown any non-suicidal self-injurious behavior? Yes, usual behavior, Baseline	3 14.3%
Has the child shown any non-suicidal self-injurious behavior? Yes, worsening behavior, Baseline	0 0%
Has the child shown any non-suicidal self-injurious behavior? No, Baseline	13 61.9%
Has the child shown any non-suicidal self-injurious behavior? Unknown/Missing, Baseline	5 23.8%
Has the child shown any non-suicidal self-injurious behavior? Yes, End of Treatment (up to Day 729)	0 0%
Has child shown any non-suicidal self-injurious behavior? Yes, usual behavior, EOT (up to Day 729)	4 19%
Has child shown any non-suicidal self-injurious behavior? Yes, worse behavior, EOT (up to Day 729)	0 0%
Has child shown any non-suicidal self-injurious behavior? No, End of Treatment (up to Day 729)	14 66.7%

9. Primary Outcome

Title	Mean Change From Baseline in Insulin-like Growth Factor-1 (IGF-1) Levels at End of Treatment
Description	Blood samples were collected to assess changes in serum IGF-1 levels. A negative mean change from baseline indicates a reduction in IGF-1 levels.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

IGF-1 levels were assessed in participants with available data in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	11
Mean (Standard Deviation) [units on a scale]	-41.1 (100.77)

10. Primary Outcome

Title	Number of Participants With Changes in Tanner Staging at the Baseline and at End of Treatment
Description	Pubic hair growth and breast development of all adolescents were assessed by the investigator or caregiver using Tanner Staging categorization from 1 to 5. Stage 1- No glandular tissue; areola follows skin contours of chest; No pubic hair Stage 2- Breast bud forms; areola begins to widen; a small amount of long, downy hair with slight pigmentation on labia majora Stage 3- Breast begins to become more elevated and extends beyond 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 Stage 4- 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 Stage 5- Breast reaches final adult size; areola returns to the contour of the surrounding breast, with a projecting central papilla; Hair extends to medial surface of the thigh.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Changes in Tanner staging was assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Baseline, Tanner Stage 1	6 28.6%
Baseline, Tanner Stage 2	3 14.3%
Baseline, Tanner Stage 3	1 4.8%
Baseline, Tanner Stage 4	2 9.5%
Baseline, Tanner Stage 5	4 19%
Baseline, Tanner Stage Missing	5 23.8%
End of Treatment (up to Day 729), Tanner Stage 1	4 19%
End of Treatment (up to Day 729), Tanner Stage 2	2 9.5%
End of Treatment (up to Day 729), Tanner Stage 3	1 4.8%
End of Treatment (up to Day 729), Tanner Stage 4	3 14.3%
End of Treatment (up to Day 729), Tanner Stage 5	3 14.3%
End of Treatment (up to Day 729), Tanner Stage Missing	5 23.8%

11. Secondary Outcome

Title	Mean Change From Baseline in Rett Syndrome Behaviour Questionnaire (RSBQ) Overall Score at End of Treatment
Description	RSBQ is a caregiver-completed questionnaire that assesses the overall condition (45 items) in individuals with Rett Syndrome. Each item is rated on a 3-point scale (0-2); 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 ("Uses eye gaze to convey feelings, needs and wishes") is reverse-scored (0 indicating "very true or often true", 1 indicating "somewhat or sometimes true," and 2 indicating "not true as far as you know"). The total summed score ranges from 0 to 90, with higher scores representing greater severity. A negative mean change from baseline indicates an improvement in overall condition.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Rett Syndrome Behaviour Questionnaire (RSBQ) was assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants received GWP42003-P (5 mg/kg/day]) for 1 week. Depending on clinical response and tolerability, the participants' dose was increased in weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participant remained 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 based on clinical response and tolerability, as deemed necessary by the investigator.
Measure Participants	21
Mean (Standard Deviation) [units on a scale]	-7.4 (14.93)

12. Secondary Outcome

Title	Mean Clinical Global Impressions-Improvement (CGI-I) Continuous Score at End of Treatment
Description	CGI-I is a 7-point scale that requires the clinician to assess whether a patient's condition has improved or worsened relative to a baseline state at the beginning of the intervention. This was rated as: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse. The mean continuous CGI-I score (averaged from each treatment enrolled under protocol and under annex) at Visit 14 (Day 729) is being reported. Higher mean scores indicate worse condition.
Time Frame	Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Clinical Global Impressions - Improvement was assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Mean (Standard Deviation) [score on a scale]	3.3 (1.15)

13. Secondary Outcome

Title	Mean Clinician Global Impressions - Severity Scale (CGI-S) Continuous Score at End of Treatment
Description	CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment relative to the clinician's experience with participants who had the same diagnosis. This was 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. The mean continuous CGI-S score (averaged from each treatment enrolled under protocol and under annex) at Visit 14 (Day 729) is being reported. Higher scores indicate more severe disease.
Time Frame	Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Clinician Global Impressions - Severity was assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Mean (Standard Deviation) [score on a scale]	4.3 (0.96)

14. Secondary Outcome

Title	Mean Change From Baseline in Children's Sleep Habits Questionnaire (CSHQ) Total Score at End of Treatment
Description	CSHQ is a caregiver-completed sleep screening instrument designed for school-aged children; which includes 33 items within 8 subscales:bedtime resistance (score range 6-18), sleep onset delay (range 1-3), sleep duration (range 3-9), sleep anxiety (range 4-12), night wakings (range 3-9), parasomnias (range 7-21), sleep-disordered breathing (range 3-9), daytime sleepiness (range 8-24). The 33 items range from 1 to 3, where 3="usually" (≥5 times/week), 2="sometimes" (2-4 times/week), and 1="rarely" (≤1 time/week); for items 31 and 32, 3=fall asleep, 2=very sleepy, 1=not sleepy. A score of 3 indicates greater severity; however, 6 items (1-Goes to bed at same time; 3-Falls asleep in own bed; 26-Wakes by himself; 2-Falls asleep in 20 minutes; 10-Sleeps the right amount; 11-Sleeps same amount each day) are reverse scored. The total summed score ranges from 33 to 99, with higher scores indicating disturbed sleep behavior. A negative mean change from baseline indicates improvement in sleep.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Children's Sleep Habits Questionnaire (CSHQ) was assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Mean (Standard Deviation) [units on a scale]	-3.0 (6.87)

15. Secondary Outcome

Title	Mean Change From Baseline in 9-item Motor Behavioral Assessment (MBA-9) Total Score at End of Treatment
Description	MBA-9 is derived from the full MBA scale (37 Rett syndrome symptoms) by selecting the items deemed amenable to change and which reflected areas of meaningful clinical change. The MBA-9 includes 9 items (Regression of motor skills; Poor eye/social contact; Lack of sustained interest; Does not reach for objects or people; Chewing difficulties; Speech disturbance; Hand clumsiness; Dystonia; and Hypertonia/rigidity). For each item, the severity of current symptoms is rated by the investigator on a 5-point numerical scale ranging from 0 to 4 with higher scores representing greater severity (0 = normal or never; 1 = mild or rare; 2 = moderate or occasional; 3 = marked or frequent; 4 = very severe or constant). Total MBA-9 score was calculated by summing the scores of 9 different subscale items. The total summed score ranges from 0 to 36, with higher scores representing greater severity. A negative mean change from baseline indicates improvement in behavior.
Time Frame	Baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 14 (Day 729) in the OLE

Outcome Measure Data

Analysis Population Description

Motor Behavioral Assessment (MBA-9) was assessed in the Safety Analysis Set.

Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
Measure Participants	21
Mean (Standard Deviation) [units on a scale]	0.7 (5.19)

Adverse Events

Time Frame	Adverse event data were collected from baseline of randomized controlled trial (RCT) Visit 1 (Day 1) up to Visit 16 (Day 767) in the OLE.
Adverse Event Reporting Description	A treatment-emergent adverse event (TEAE) are defined as adverse events (AEs) that started or worsened in severity or seriousness following the first dose of GWP42003-P.
Arm/Group Title	GWP42003-P
Arm/Group Description	Participants who received oral GWP42003-P (5 mg/kg/day) on Day 1. After 1 week, depending on clinical response and tolerability, the participants' dose may have been increased at the Investigator's discretion to weekly increments of 5 mg/kg/day up to 15 mg/kg/day GWP42003-P. Participants remained 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 based on clinical response and tolerability, as deemed necessary by the Investigator.
All Cause Mortality
	GWP42003-P
	Affected / at Risk (%)	# Events
Total	2/21 (9.5%)
Serious Adverse Events
	GWP42003-P
	Affected / at Risk (%)	# Events
Total	5/21 (23.8%)
Congenital, familial and genetic disorders
Rett Syndrome	1/21 (4.8%)
Infections and infestations
COVID-19	1/21 (4.8%)
Lower respiratory tract infection	1/21 (4.8%)
Postoperative wound infection	1/21 (4.8%)
Nervous system disorders
Generalised tonic-clonic seizure	1/21 (4.8%)
Status epilepticus	1/21 (4.8%)
Respiratory, thoracic and mediastinal disorders
Respiratory arrest	1/21 (4.8%)
Respiratory failure	2/21 (9.5%)
Other (Not Including Serious) Adverse Events
	GWP42003-P
	Affected / at Risk (%)	# Events
Total	19/21 (90.5%)
Blood and lymphatic system disorders
Neutropenia	2/21 (9.5%)
Congenital, familial and genetic disorders
Rett syndrome	2/21 (9.5%)
Gastrointestinal disorders
Diarrhoea	4/21 (19%)
Vomiting	7/21 (33.3%)
General disorders
Pyrexia	4/21 (19%)
Infections and infestations
Otitis media	2/21 (9.5%)
Upper respiratory tract infection	3/21 (14.3%)
Injury, poisoning and procedural complications
Fall	2/21 (9.5%)
Investigations
Mean cell volume increased	2/21 (9.5%)
Monocyte count decreased	3/21 (14.3%)
Metabolism and nutrition disorders
Decreased appetite	3/21 (14.3%)
Nervous system disorders
Epilepsy	2/21 (9.5%)
Seizure	3/21 (14.3%)
Tremor	2/21 (9.5%)
Psychiatric disorders
Anxiety	2/21 (9.5%)
Bruxism	2/21 (9.5%)
Irritability	3/21 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	2/21 (9.5%)
Respiratory failure	2/21 (9.5%)

Limitations/Caveats

This trial was terminated due to enrollment challenges and the COVID-19 pandemic. Due to early termination and participants withdrawal, the number of participants was small and the length of treatment was reduced.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.