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 | 20.0 |
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 assess the efficacy of GWP42003-P as an adjunctive antiepileptic treatment compared with placebo, with respect to the percentage change from baseline during the treatment period of the study in convulsive seizure frequency. The dose response effect between two GWP42003-P Dose Levels (10 mg/kg/day and 20 mg/kg/day) and placebo will also be explored. Convulsive seizures are defined as tonic-clonic, tonic, clonic or atonic and non-convulsive seizures as myoclonic, partial or absence. |
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E.2.2 | Secondary objectives of the trial |
• To assess changes from baseline in non-convulsive seizure frequency, duration, usage of rescue medication, number of
inpatient hospitalizations due to epilepsy, sleep disruption, daytime sleepiness, quality of life, growth and development, and conduct behavioral and cognitive assessments in patients taking GWP42003-P as an adjunctive treatment, when compared with placebo.
• To determine the pharmacokinetics (PKs) of cannabidiol (CBD) and its major metabolites following single and multiple doses of GWP42003-P.
• To determine effects of GWP42003-P on plasma concentrations of concomitant antiepileptic drugs (AEDs), where available.
• To assess the safety of both GWP42003-P doses when compared with placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patient and/or parent(s)/legal representative must be willing and able to give informed assent/consent for participation in the study.
• Patient and their caregiver must be willing and able (in the investigator’s opinion) to comply with all study requirements.
• Patient must be male or female aged between two and 18 years (inclusive).
• Patient must have a documented history of DS which is not completely controlled by current AEDs.
• Patient must be experiencing four or more convulsive seizures (i.e., tonic-clonic, tonic, clonic, atonic seizures) during the first 28 days of the baseline period.
• Patient must be taking one or more AEDs at a dose which has/have been stable for at least four weeks.
• All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation [VNS]) must have been stable for four weeks prior to screening and patient and caregiver are willing to maintain a stable regimen throughout the study. The ketogenic diet and VNS treatments are not counted as an AED.
• Patient and/or parent(s)/legal representative is willing to allow his or her primary care practitioner and consultant to be notified of participation in the study.
• Patient has completed their Interactive Voice Response System (IVRS) telephone diary on at least 25 days of the baseline period; patients who are non-compliant will be deemed ineligible to continue. |
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E.4 | Principal exclusion criteria |
• Patient has clinically significant unstable medical conditions other than epilepsy.
• Patient has had clinically relevant symptoms or a clinically significant illness in the four weeks prior to screening or randomization, other than epilepsy.
• Patient has clinically significant abnormal laboratory values, in the investigator’s opinion, at screening or randomization.
• Patient has clinically relevant abnormalities in the ECG measured at screening or randomization.
• Patient has any concurrent cardiovascular conditions which will, in the investigator’s opinion, interfere with the ability to assess their ECGs.
• Patient has a history or presence of alcohol or substance abuse within the last two years prior to the study or daily consumption of five or more alcohol-containing beverages.
• 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 is unwilling to abstain from using recreational or medicinal cannabis, or synthetic cannabinoid based medications (including Sativex®) during the study.
• 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.
• Patient has ingested alcohol in the 24-hour period prior to the first study visit and/or is unwilling to abstain from drinking alcohol throughout the treatment period.
• Patient has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMPs (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.
• Patient has been part of a clinical trial involving another IMP in the previous six months.
• 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 affect the patient’s ability to participate in the study.
• Patient has significantly impaired hepatic function at screening (Visit 1) or randomization (Visit 2), defined as any of the
following:
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper limit of normal (ULN).
- ALT or AST >3 x ULN and (total bilirubin [TBL] >2 x 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%).
• 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 study.
• Patient is unwilling to abstain from donation of blood during the study.
• There are plans for the patient to travel outside their country of residence during the study.
• Patient has previously been randomized into this study.
• Any history of suicidal behavior or any suicidal ideation of type four or five on the C-SSRS at screening. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the mean percentage change from baseline in total convulsive seizure frequency during the treatment period (Day 1 to the end of the evaluable period) in patients taking GWP42003-P compared with placebo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessed from Visit 2 to Visit 8 (Day 1 to Day 99). |
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E.5.2 | Secondary end point(s) |
The following endpoints will be compared between treatment groups over the 14-week, double-blind treatment period:
• Number of patients experiencing a >25% worsening, −25 to +25% no change, 25–50% improvement, 50–75% improvement or >75% improvement in convulsive seizures from baseline.
• Number of patients considered treatment responders, defined as those with a ≥25%, ≥50% or ≥75% reduction in convulsive seizures from baseline (overall and four-weekly).
• Number of patients who are convulsive seizure free.
• Percentage changes from baseline in total non-convulsive seizure frequency.
• Change in types of seizures.
• Changes from baseline in number of episodes of status epilepticus.
• Changes from baseline in duration of seizure subtypes as assessed by the Caregiver Global Impression of Change in Seizure Duration (CGICSD).
• Changes from baseline in usage of rescue medication.
• Changes from baseline in number of inpatient hospitalizations due to epilepsy.
• Changes from baseline in Sleep Disruption 0–10 Numerical Rating Scale (0–10 NRS) score.
• Changes from baseline in Epworth Daytime Sleepiness Scale (EDSS) score.
• Changes from baseline in the Quality of Life in Childhood Epilepsy (QOLCE) score.
• Changes from baseline in the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) score.
• Change from baseline in cognitive function as measured with a cognitive assessment battery.
• Change from baseline in growth and development by measurement of height, weight, insulin-like growth factor-1 (IGF-1) levels and Tanner Staging (for patients aged 10–17 [inclusive], or earlier if clinically indicated by onset of menarche or other signs of precocious puberty).
• Changes from baseline in the Caregiver Global Impression of Change (CGIC) score.
PK:
• The plasma concentration/time curve of CBD and its major metabolites will be described following single and multiple doses of GWP42003-P, with the aim being to define:
- Peak plasma concentration (Cmax).
- Time to peak concentration (tmax).
- Area under the plasma concentration curve from time zero to infinity (AUC(0–∞)) or to the last measurable concentration (AUC(0–tz)).
- Terminal half-life (t½).
• Plasma concentrations of concomitant AEDs before and after treatment with GWP42003-P, where available.
The safety profile of GWP42003-P compared with placebo will also be the assessed at each Dose Level by measuring:
• Adverse events (AEs).
• Vital signs.
• Physical examination parameters.
• 12-lead Electrocardiogram (ECG).
• Clinical laboratory parameters.
• Columbia-Suicide Severity Rating Scale (C-SSRS) score.
• Cannabis Withdrawal Scale (CWS) or Pediatric Cannabinoid Withdrawal Scale (PCWS) score, as appropriate.
• Abuse liability.
• Effects on menstruation cycles (in females). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessed from Visit 2 to Visit 8 (Day 1 to Day 99). |
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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 | 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) | No |
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 | 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 | 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 |
Israel |
Netherlands |
Poland |
Spain |
United States |
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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
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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 | |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |