| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | Yes |
| 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 stiripentol (STP) or valproate (VPA).
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| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of GWP42003-P in the presence of STP or VPA.
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| 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:
6.1.1 Male or female patients aged 16 to 55 years inclusive.
6.1.2 Patient must be taking STP (for the STP arm) or VPA (for the VPA arm) and no more than two other AEDs during the blinded period of the trial.
- In the VPA arm only, the patient must not be receiving STP (VPA allowed in STP arm).
6.1.3 AED doses, including STP or VPA, must be stable for four weeks prior to screening and regimen must remain stable throughout the duration of the blinded period of the trial.
6.1.4 Patient must have a documented magnetic resonance imaging/computerized tomography of the brain that ruled out a progressive neurologic condition.
6.1.5 Patient must have experienced at least one countable uncontrolled seizures of any type (i.e., tonic-clonic, tonic, clonic, atonic, partial onset or focal: focal seizures with retained consciousness and a motor component, focal seizures with impaired consciousness, focal seizures evolving to bilateral secondary generalization) within two months prior to randomization.
6.1.6 Intervention with vagus nerve stimulation (VNS) and/or ketogenic diet must be stable for four weeks prior to baseline and the patient must be willing to maintain a stable regimen during the blinded period of the trial.
6.1.7 Patients must abstain from alcohol during the blinded period of the trial.
6.1.8 Patient and legal representative (if required) is available to attend all PK visits within the required visit window.
6.1.9 Patient and legal representative (if required) must be willing and able to give informed consent/assent for participation in the trial.
6.1.10 Patient must be willing and able (in the investigator’s opinion) to comply with all trial requirements.
6.1.11 Patient is willing for his or her name to be notified to the responsible authorities for participation in this trial, as applicable.
6.1.12 Patient is willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the trial.
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| E.4 | Principal exclusion criteria |
The patient may not enter the trial if ANY of the following apply:
6.2.1 Patient has clinically significant unstable medical conditions other than epilepsy.
6.2.2 Patient has a history of symptoms (e.g., dizziness, light-headedness, blurred vision, palpitations, weakness, syncope) related to a drop in blood pressure due to postural changes (orthostatic blood pressure changes).
6.2.3 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.
6.2.4 Patient has had clinically relevant symptoms or a clinically significant illness in the four weeks prior to screening or enrollment, other than epilepsy.
6.2.5 Patient is currently using Felbamate and has been taking it for less than 12 months prior to screening.
6.2.6 Patient has consumed alcohol during the seven days prior to enrollment and is unwilling to abstain during the blinded period of the trial.
6.2.7 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 trial entry or is unwilling to abstain for the duration of the trial.
6.2.8 Patient has any known or suspected history of any drug abuse or addiction.
6.2.9 Patient has consumed grapefruit or grapefruit juice seven days prior to enrollment and is unwilling to abstain from drinking or eating grapefruit within seven days of PK visits.
6.2.10 Patient has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP, e.g., sesame oil.
6.2.11 Female patient of child bearing potential, or male patient’s partner is of child bearing potential, unless willing to ensure that they or their partner use a highly effective method of birth control (e.g., hormonal contraceptives, intrauterine devices/hormone-releasing systems, bilateral tubal occlusion, vasectomized partner, sexual abstinence) during the trial and for three months thereafter.
6.2.12 Female patient who is pregnant (positive pregnancy test), lactating or planning pregnancy during the course of the trial and for three months thereafter.
6.2.13 Patient who has received an IMP within the 12 weeks prior to the screening visit.
6.2.14 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 trial, may influence the result of the trial, or the patient’s ability to participate in the trial.
6.2.15 Following a physical examination, the patient has any abnormalities that, in the opinion of the investigator, would prevent the patient from safe participation in the trial.
6.2.16 Patient has significantly impaired hepatic function, as determined 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 x ULN and (total bilirubin [TBL] >2 × ULN or
international normalized ratio [INR] >1.5).
- ALT or AST >3 x 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 trial who are later found to meet this screening criterion must be withdrawn from the trial.
6.2.17 Unwilling to abstain from donation of blood during the trial.
6.2.18 Patient has travel outside the country of residence planned during the trial, unless the patient has confirmation that the IMP is permitted in the destination country/state.
6.2.19 Patients previously enrolled into any GWP42003-P trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints of the trial are to assess the PK parameters (Cmax, tmax, AUC(0-∞), AUC(0–t) and t½) of the following analytes when STP or VPA are taken alone or in combination with GWP42003-P or placebo:
• STP
• VPA
• CBD
• CBD major metabolites
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoints of the trial are the PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t)
and t½) of the following analytes from Visit 1 to the ‘End of Blinded Treatment’:
• STP
• VPA
• CBD
• CBD major metabolites |
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| E.5.2 | Secondary end point(s) |
To assess the safety and tolerability of GWP42003-P compared with placebo when taken in combination with STP or VPA. Safety and tolerability will be assessed using the following parameters:
• AEs
• 12-lead electrocardiogram (ECG)
• Clinical laboratory parameters (biochemistry, hematology and urinalysis)
• Vital signs
• Physical examination
• Columbia-Suicide Severity Rating Scale (C-SSRS)
• Seizure frequency
• Abuse liability
• CYP2C19 and CPY3A4 patient genotype analysis
• 2-propyl-4-pentenoic acid (4-ene-VPA)
PK parameters (Cmax, tmax, AUC(0–∞), AUC(0–t) and t½) of the following analytes will be assessed when STP or VPA were taken alone compared to when they were taken in combination with GWP42003-P or placebo:
• THC
• THC major metabolites
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
To assess the safety and tolerability of GWP42003-P compared with placebo when taken in combination with STP or VPA. Safety and tolerability will be assessed using the following parameters from Visit 1 to End of study:
• AEs
• 12-lead electrocardiogram (ECG)
• Clinical laboratory parameters (biochemistry, hematology and urinalysis)
• Physical examination
• Vital signs
• Columbia-Suicide Severity Rating Scale (C-SSRS)
• Seizure frequency
• Abuse liability
• CYP2C19 and CPY3A4 patient genotype analysis
• 2-propyl-4-pentenoic acid (4-ene-VPA)
PK parameters (Cmax, tmax, AUC(0–∞) AUC(0–t) and t½) of the following analytes from Visit 1 to ‘End of Blinded Treatment’:
• THC
• THC major metabolites
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| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Patients may enter an open label extension period |
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| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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