Efficacy and Safety of Cannabidiol Oral Solution (GWP42003-P, CBD-OS) in Patients With Rett Syndrome

Phase 3

Terminated

Conditions: RTT
Rett Syndrome

Interventions: Drug: GWP42003-P
Drug: Placebo

Registration Number: NCT03848832

Lead Sponsor: Jazz Pharmaceuticals

Brief Summary: To evaluate the efficacy of cannabidiol oral solution (GWP42003-P, CBD-OS) in reducing symptom severity when compared with placebo, in participants with Rett syndrome.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 29

Inclusion Criteria

Participant (if possessing adequate understanding, in the investigator's opinion) and/or their parent(s)/legal representative is willing and able to give informed consent/assent for participation in the trial.
Participant and their 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).
Participant must weigh at least 10 kilograms.
Clinical diagnosis of Rett syndrome (typical or atypical), defined according to RettSearch Consortium criteria
Confirmed pathogenic genetic mutation of the MECP2 gene
Participant must be post-regression (≥ 6 months since last loss of hand use or verbal language or gross motor regression).
Participant must have a disease severity of between 10 and 36, defined according to the Clinical Severity Scale (CSS).
All medications or interventions (including antiepileptic drugs [AEDs] and non-pharmacological interventions - dietary supplements, probiotics, physical therapy, speech therapy, etc.) for Rett syndrome-related symptoms must have been stable for 4 weeks prior to screening and the participant/caregiver must be willing to maintain a stable regimen throughout the trial.
Ability to swallow the investigational medicinal product (IMP) provided as a liquid solution, or the ability for 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 they have one) and consultant (if they have one) to be notified of participation in the trial, if the primary care practitioner/consultant is different than the investigator.

Key

Exclusion Criteria

Participant meets exclusion criteria for Rett syndrome diagnosis (traumatic brain injury, neurometabolic disease, or severe infection that causes neurological problems; grossly abnormal psychomotor development in the first 6 months of life).
Participant has clinically significant abnormal laboratory values, in the investigator's opinion.
Participant is taking more than 2 concurrent AEDs.
Any history of suicidal behavior or any suicidal ideation in the last month or at screening
Clinically relevant abnormalities in the electrocardiogram (ECG) measured at screening or randomization
Concurrent cardiovascular conditions which will, in the investigator's opinion, interfere with the ability to assess their ECGs or put the participant at risk because of participation in the trial
First or second degree relative with a history of significant ECG abnormalities, in the opinion of the investigator (e.g. premature cardiac arrest, sudden death)
Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP (active or placebo), such as sesame oil
Participant has moderately impaired hepatic function at screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) or total bilirubin > 2 × ULN.
Participant 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 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 thereafter.
Pregnant (positive pregnancy test) or lactating
Received an IMP within the 3 months prior to screening
Participant has been taking felbamate for less than 1 year prior to screening.
Currently using or has used recreational or medicinal cannabis, cannabinoid-based medications (including Sativex®), or cannabidiol oral solutions (including CBD-OS [GWP42003-P]) within the 3 months prior to screening and is unwilling to abstain for the duration of the trial
Participant has a positive delta-9-tetrahydrocannabinol (THC) test at screening.
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 participant at risk because of participation in the trial, may influence the result of the trial, or the participant's ability to participate in the trial
Any abnormalities identified following a physical examination of the participant that, in the opinion of the investigator, would jeopardize the safety of the participant if she took part in the trial
Participant has been previously randomized into this trial.
Participant has traveled outside the country of residence planned during the trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
5 milligrams per kilogram per day (mg/kg/day) GWP42003-P	GWP42003-P	100 milligrams per milliliter (mg/mL) GWP42003-P oral solution. Taken twice daily (morning and evening).
15 mg/kg/day GWP42003-P	GWP42003-P	100 mg/mL GWP42003-P oral solution. Taken twice daily (morning and evening).
Placebo	Placebo	Placebo oral solution (0 mg/mL GWP42003-P) volume matched to 5 mg/kg/day or 15 mg/kg/day GWP42003-P. Taken twice daily (morning and evening).

Primary Outcome Measures

Name	Time	Method
Change From Baseline in the Mean Rett Syndrome Behaviour Questionnaire (RSBQ) Total Score at Week 24 for the 15 mg/kg/Day GWP42003-P Dose Level Compared With Placebo	Baseline; Week 24	RSBQ is a caregiver-completed questionnaire that measures the frequency of current disease characteristics (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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in the Mean RSBQ Total Score at Week 24 for the 5 mg/kg/Day GWP42003-P Dose Level Compared With Placebo	Baseline; Week 24	RSBQ is a caregiver-completed questionnaire that measures the frequency of current disease characteristics (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 represent greater severity.
Mean Clinical Global Impressions - Improvement (CGI-I) Score at Week 24	Baseline; Week 24	CGI-I is a 7-point scale that requires the clinician to assess how much a participant'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 = minimally worse; 6 = much worse; or 7 = very much worse.
Change From Baseline in Mean 9-items Motor Behavioral Assessment (MBA-9) Total Score and Subscale Scores at Week 24	Baseline; Week 24	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 (1-Regression of motor skills; 2-Poor eye/social contact; 3-Lack of sustained interest; 4-Does not reach for objects or people; 5-Chewing difficulties; 6-Speech disturbance; 7-Hand clumsiness; 8-Dystonia and 9-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. CFB = Change from Baseline.
Change From Baseline in Mean Clinician Global Impressions - Severity (CGI-S) Score at Week 24	Baseline; Week 24	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 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.
Change From Baseline in Mean RSBQ Subscale Scores at Week 24	Baseline; Week 24	RSBQ is a caregiver-completed questionnaire that measures the frequency of current disease characteristics in individuals with Rett Syndrome. The 45-item RSBQ is comprised of 8 subscales: 1) general mood (score range 0-16), 2) breathing problems (range 0-10), 3) hand behaviors (range 0-12), 4) face movements (range 0-8), 5) body rocking (BR)/expressionless face (range 0-12), 6) night-time behaviors (range 0-6), 7) anxiety/fear (range 0-8), 8) walking/standing (range 0-4). 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"). Higher scores representing greater severity. CFB = Change from Baseline.
Change From Baseline in Mean Children's Sleep Habits Questionnaire (CSHQ) Total Score and Subscale Scores at Week 24	Baseline; Week 24	CSHQ is a caregiver-completed sleep screening instrument designed for school-aged children; which includes 33 items within 8 subscales: 1) bedtime resistance (score range 6-18), 2) sleep onset delay (range 1-3), 3) sleep duration (range 3-9), 4) sleep anxiety (range 4-12), 5) night wakings (range 3-9), 6) parasomnias (range 7-21), 7) sleep-disordered breathing (range 3-9), 8) daytime sleepiness (range 8-24). Item scores 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. In general, a score of 3 indicates greater severity, however, 6 items (1-Goes to bed at same time; 2-Falls asleep in 20 minutes; 3-Falls asleep in own bed; 10-Sleeps the right amount; 11-Sleeps same amount each day; 26-Wakes by himself) are reverse scored. Total summed score ranges from 33 to 99, with higher scores representing more disturbed sleep behavior. CFB = Change from Baseline.