| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073677 |
| E.1.2 | Term | Severe myoclonic epilepsy of infancy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether GWP42003-P affects the pharmacokinetic (PK) profile of clobazam (CLB) and its primary metabolite N-desmethylclobazam (N-CLB). |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the safety and tolerability of GWP42003-P in the presence of CLB. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female patients aged 18 to 65 years inclusive.
• Patient must have epilepsy as determined by the investigator and be taking CLB.
• Patient must have a documented magnetic resonance imaging/computerized tomography of the brain that ruled out a progressive neurologic condition.
• Patient must have experienced at least one seizure of any type (i.e., convulsive: tonic-clonic, tonic, clonic, atonic; focal: focal seizures with retained consciousness and a motor component, focal seizures with impaired consciousness focal seizures evolving to bilateral secondary generalization) within the two months prior to randomization.
• Patients must be taking CLB and no more than two other anti-epileptic drugs (AEDs) during the course of the study.
• AED(s), including CLB, must be stable for four weeks prior to screening and regimen must remain stable throughout the duration of the blinded phase of the study.
• Intervention with vagus nerve stimulation and/or ketogenic diet must be stable for four weeks prior to baseline and patient/caregiver must be willing to maintain a stable regimen throughout the blinded phase of the study.
• Patients must abstain from alcohol during the blinded phase of the study.
• Patient is available to attend all PK visits within the required visit window.
• Patient and/or legal representative must be willing and able to give informed consent for participation in the study
• Patient and/or legal representative must be willing and able (in the investigator’s opinion) to comply with all study requirements.
• Patient is willing for his or her name to be notified to the responsible authorities for participation in this study, as applicable.
• Patient is willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the study. |
|
| E.4 | Principal exclusion criteria |
• Patient has clinically significant unstable medical conditions other than epilepsy.
• Patients on CLB at doses above 20 mg per day.
• Patients taking CLB intermittently as rescue medication.
• Patient has a history of symptoms (e.g., dizziness, light-headedness, blurred vision, palpitations, weakness, syncope) related to a drop in blood pressure (BP) due to postural changes.
• Any history of suicidal behavior or any suicidal ideation of type four or five on the C-SSRS in the last month or at screening.
• Patient has had clinically relevant symptoms or a clinically significant illness in the four weeks prior to screening or enrollment, other than epilepsy.
• Patient has consumed alcohol during the seven days prior to enrollment and is unwilling to abstain during the blinded phase of the study.
• Patient is currently using or has in the past used recreational or medicinal cannabis, or synthetic cannabinoid based medications (including Sativex®) within the three months prior to study entry.
• Patient has any known or suspected history of any drug abuse or addiction.
• Patient is unwilling to abstain from recreational or medicinal cannabis, or synthetic cannabinoid based medications (including Sativex) for the duration for the study.
• Patient has consumed grapefruit or grapefruit juice seven days prior to enrollment and is unwilling to abstain from drinking grapefruit juice within seven days of PK visits.
• Patient has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP, e.g., sesame oil
• Female patient is of child bearing potential or male patient’s partner is of child bearing potential; unless willing to ensure that they or their partner use highly effective contraception for the duration of the study and for three months thereafter. Highly effective methods of contraception are defined as those, alone or in combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Such methods include hormonal contraceptives, intrauterine devices/ hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence.
• Female patient who is pregnant (positive pregnancy test), lactating or planning pregnancy during the course of the study and for three months thereafter.
• Patients who have received an IMP within the 12 weeks prior to the screening visit.
• Patient is taking felbamate and they have been taking it for less than one year prior to screening.
• Any other significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, may influence the result of the study, or the patient’s ability to participate in the study.
• Following a physical examination, the patient has any abnormalities that, in the opinion of the investigator would prevent the participant from safe participation in the study.
• Patient has significantly impaired hepatic function at screening (Visit 1) or enrollment (Visit 2), defined as any of the following:
- Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) >5 × upper limit of normal (ULN).
- ALT or AST >3 × ULN and total bilirubin (TBL) >2 × ULN or international normalized ratio (INR) >1.5.
- ALT or AST >3 × ULN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
This criterion can only be confirmed once the laboratory results are available; patients randomized into the study who are later found to meet this criterion must be withdrawn from the study.
• Patient has a prolonged QTcB (> 450 msec for males and > 470 msec for females).
• Unwilling to abstain from donation of blood during the study.
• Travel outside the country of residence planned during the study, unless the patient has confirmation that the IMP is permitted in the destination country/state.
• Patients previously enrolled into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints of the study are the PK parameters (Cmax, tmax, AUC(0–∞) AUC(0–t), t½) of the following analytes:
• CLB
• N-desmethylclobazam (N-CLB)
• CBD
• CBD major metabolites |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
From ‘Visit 1’ to the ‘End of Blinded Treatment’
|
|
| E.5.2 | Secondary end point(s) |
To assess the safety and tolerability of GWP42003-P compared with placebo when taken in combination with CLB. Safety and tolerability will be assessed using the following parameters:
• AEs
• 12-lead Electrocardiogram (ECG)
• Clinical laboratory parameters (clinical chemistry, hematology and urinalysis)
• Vital signs
• Columbia-Suicide Severity Rating Scale (C-SSRS)
• Seizure Frequency
• Abuse liability
• CYP2C19 and CPY3A4 patient genotype analysis
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t), t½) of the following analytes:
• THC
• THC major metabolites |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From ‘Visit 1 to End of Study’ |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| 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 | No |
| 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 | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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