E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rett syndrome (RTT) [typical or atypical] |
|
E.1.1.1 | Medical condition in easily understood language |
Rett syndrome (RTT) [typical or atypical] |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10077709 |
E.1.2 | Term | Rett syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of 15 mg/kg/day GWP42003-P, compared with placebo, at the end of 24 weeks’ treatment in reducing symptom severity in patients with RTT using the Rett Syndrome Behaviour Questionnaire (RSBQ). |
|
E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
- To evaluate the efficacy of 15 mg/kg/day GWP42003-P, compared with placebo, at the end of 24 weeks' treatment in reducing symptom severity in patients with RTT using the CGI-I.
- To evaluate the efficacy of 5 mg/kg/day GWP42003-P, compared with placebo in: RSBQ, CGI-I.
- To evaluate the effect of GWP42003-P, compared with placebo, in other measures of disease severity: RSBQ subscales, CGI-S, MBA-9, CSHQ.
- To evaluate the safety of GWP42003-P, compared with placebo, in patients with RTT.
Exploratory Objectives:
- To evaluate the effect of GWP42003-P on caregiver and patient QoL: SF-36 and CHQ-PF50.
- To evaluate the effect of GWP42003-P on HSUQ.
- Caregiver assessment of Rett symptoms (symptom diary).
-To determine the plasma concentrations of CBD and its major metabolites with the aim of evaluating exposure versus efficacy and safety and collecting data for population PK analysis.
-To evaluate the effect of GWP42003-P on exploratory biomarkers. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For inclusion in the trial, patients must fulfil ALL of the following
criteria:
• Patient is female or male aged 2–18 years (inclusive).
• Patient must weigh at least 10 kg.
• 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 a clinical diagnosis of RTT (typical or atypical), defined according to RettSearch Consortium criteria.
• Patient must have a confirmed pathogenic genetic mutation of the MECP2 gene.
• Patient must be post-regression (≥ 6 months since last loss of hand use or verbal language or gross motor regression).
• Patient must have a disease severity of between 10 and 36, defined according to the CSS.
• All medications or interventions (including antiepileptic drugs [AEDs] and non-pharmacological interventions - dietary supplements, probiotics, physical therapy, speech therapy, etc.) for RTT-related symptoms must have been stable for 4 weeks prior to screening and the patient/caregiver should be willing to maintain a stable regimen throughout the trial.
• Patient must have the ability to swallow the IMP provided as a liquid solution, or the ability for IMP to be delivered via gastrostomy (G) or nasogastric (NG) feeding tube (use of G-or NG-tubes is only allowed after discussion with the Medical Monitor to confirm suitability of the tubes being used).
• 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 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 to the investigator. |
|
E.4 | Principal exclusion criteria |
The patient may not enter the trial if ANY of the following apply:
• Patient meets exclusion criteria for RTT diagnosis (traumatic brain injury, neurometabolic disease, or severe infection that causes neurological problems; grossly abnormal psychomotor development in the first 6 months of life).
• Patient has clinically significant abnormal laboratory values, in the investigator’s opinion.
• Patient experiences more than weekly seizures (based on history over the last 2 months prior to screening) i.e., CSS ‘epilepsy/seizure’ score of 4 or 5.
• Patient is taking more than 2 concurrent AEDs.
• Any history of suicidal behavior or any suicidal ideation in the last month or at screening.
• Patient has clinically relevant abnormalities in the ECG measured at screening or randomization (including QT interval, corrected by Bazett's correction formula [QTcB] interval > 450 msec, average of 3 measurements).
• Patient has any concurrent cardiovascular conditions which will, in the investigator’s opinion, interfere with the ability to assess the patient's ECGs or put the patient at risk because of participation in the trial.
• Patient’s first or second degree relative has a history of significant ECG abnormalities, in the opinion of the investigator (e.g. premature cardiac arrest, sudden death).
• Patient has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP (active or 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.
• 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 contraceptives, contraception a 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.
• Female patient is pregnant (positive pregnancy test) or lactating.
• Male patient is fertile (i.e., after puberty unless permanently sterile by bilateral orchiectomy) 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.
• Patient has received an IMP within the 3 months prior to the screening visit.
• Patient has been taking felbamate for less than 1 year prior to screening.
• Patient is 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.
• Patient has a positive Δ9-tetrahydrocannabinol (THC) test at screening.
• 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, other participants, or site staff 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.
• Patient has been previously randomized into this trial.
• Patient has travel outside the country of residence planned during the trial. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
RSBQ (total score) for the 15 mg/kg/day GWP42003-P dose level compared with placebo at the end of 24 weeks. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Visit 2, Visit 5, Visit 6, Visit 7, Visit 8, Visit 9 |
|
E.5.2 | Secondary end point(s) |
CGI-I for the 15 mg/kg/day GWP42003-P dose level compared with placebo at the end of 24 weeks.
Other Secondary Efficacy Endpoints:
• To compare 5 mg/kg/day GWP42003-P with placebo using:
o RSBQ (total score)
o CGI-I
• To compare 15 mg/kg/day GWP42003-P and 5 mg/kg/day GWP42003-P with placebo using:
o RSBQ subscales.
o CGI-S.
o MBA-9.
o CSHQ.
Exploratory endpoints:
• Caregiver QoL questionnaire (SF-36).
• Patient QoL questionnaire (CHQ-PF50)
• Hospital Services Use Questionnaire.
• Caregiver assessment of Rett symptoms (symptom diary).
• Plasma concentrations of CBD and its main metabolites.
• Blood levels of exploratory biomarkers.
Safety:
The safety profile of GWP42003-P compared with placebo will be
assessed by measuring:
• 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 onset of menarche or other
signs of precocious puberty). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to Protocol schedule of events table for detailed information |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
France |
Italy |
Spain |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |