E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Dravet Syndrome (DS) or Lennox-Gastaut Syndrome (LGS) |
|
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 | 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 |
|
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 long term safety and tolerability of GWP42003-P, as adjunctive treatment, in children and adults with inadequately controlled Dravet Syndrome or Lennox-Gastaut Syndrome. |
|
E.2.2 | Secondary objectives of the trial |
All Patients:
To evaluate the effect of GWP42003-P, as adjunctive treatment, on:
• Quality of life.
• Adaptive behavior.
• Need for hospitalizations due to epilepsy.
• Usage of rescue medication.
• Maintenance of seizure frequency reduction and freedom from seizures during the open label extension study.
• Frequency of subtypes of seizures.
• Change in duration of subtypes of seizures.
• Number of episodes of status epilepticus.
• Cognitive function.
• Growth and development.
• Menstruation cycles (in females).
• Signals indicating drug abuse liability of GWP42003-P.
DS Patients Only:
• Total convulsive and non-convulsive seizure frequency.
• Number of patients convulsive seizure free.
• Responder rate (defined in terms of percentage reduction in total convulsive seizure frequency).
LGS Patients Only:
• Drop and Non-drop seizure frequency.
• Number of patients drop seizure free.
• Responder rate (defined in terms of percentage reduction in drop seizure frequency). |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patient has completed the treatment phase of their Core Study.
• Patient and/or parent(s)/legal representative must be willing and able to give informed consent/assent 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 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. |
|
E.4 | Principal exclusion criteria |
• Patient is currently using or has in the past used recreational or medicinal cannabis, or synthetic cannabinoid based medications (including Sativex®) within the 3 months prior to study entry, not including IMP received during the Core study.
• 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.
• Any history of suicidal behavior or any suicidal ideation of type 4 or 5 on the C-SSRS at Visit 1.
• Patient has been part of a clinical trial involving an IMP during the inter-study period.
• Patient has previously been enrolled and dosed in this study.
• 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 3 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 3 months thereafter.
• 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.
• 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.
• Patient has significantly impaired hepatic function at the ‘End of Treatment’ visit of their Core Study or at Visit 1 if re-assessed, defined as any of the following:
− ALT or AST >5 × upper limit of normal (ULN).
− ALT or AST >3 × ULN and (TBL >2 × ULN or 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%). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The safety of GWP42003-P will be assessed by the adverse event (AE) profile and by evaluating changes in the following, relative to the pre-randomization baseline of the Core Study:
• Vital signs.
• Physical examination (including height and body weight).
• 12-lead electrocardiogram (ECG).
• Columbia-Suicide Severity Rating Scale (C-SSRS) score.
• Cannabis Withdrawal Scale (CWS) or Pediatric Cannabinoid Withdrawal Scale (PCWS) score, as appropriate.
• Clinical laboratory parameters.
The CWS will be administered to patients aged 18 and older while the PCWS will be administered to patients aged 4–17 (inclusive).
The Children’s C-SSRS will be used for patients aged 6–18 (inclusive) while the C-SSRS will be used for patients aged 19 and older. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Visit 1 to End of Treatment Visit:
Adverse event (AE) profile, Vital signs, Physical examination (including height and body weight), 12-lead electrocardiogram (ECG), laboratory parameters.
-At Visit 1, from Visit 5 to End of Treatment Visit: Columbia-Suicide Severity Rating Scale (C-SSRS) score.
-At End of Taper visit: Cannabis Withdrawal Scale (CWS) and Pediatric Cannabinoid Withdrawal (PCWS) scores. |
|
E.5.2 | Secondary end point(s) |
All Patients:
• Change in quality of life as measured with Quality of Life in Childhood Epilepsy (QOLCE) if 18 years of age or younger, or Quality of Life in Epilepsy (QOLIE) if 19 years of age or older, relative to the pre-randomization baseline of the Core Study, if assessed during the Core Study.
• Change in Subject/Caregiver Global Impression of Change (S/CGIC), relative to the pre-randomization baseline of the Core Study.
• Change in adaptive behavior as measured with the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II), relative to the pre-randomization baseline of the Core Study, if assessed during the Core Study.
• Change in the number of inpatient epilepsy-related hospitalizations (number of hospitalizations due to epilepsy in each 28-day period), relative to the pre-randomization baseline of the Core Study.
• Change in the use of rescue medication (number of days used in each 28-day period), relative to the pre-randomization baseline of the Core Study.
• Maintenance of seizure frequency reduction and freedom from seizures during the OLE study.
• Percentage change in the frequencies of total seizures, relative to the pre-randomization baseline of the Core Study.
• Number of patients considered treatment responders, defined as those with a ≥25%. ≥50%, ≥75%, or 100% reduction in total seizures, relative to the pre-randomization baseline of the Core Study.
• Number of patients experiencing a ≥25% worsening.-25 to +25% no change, 25-50% improvement, 50-75% improvement or >75% improvement in total seizures, relative to the pre-randomization baseline of the Core Study.
• Percentage change in the frequencies of subtypes of seizures, relative to the pre-randomization baseline of the Core Study.
• Changes in duration of seizure subtypes as assessed by the Subject/Caregiver Global Impression of Change in Seizure Duration (S/CGICSD), relative to the pre-randomization baseline of the Core Study.
• Change in the number of episodes of status epilepticus, relative to the pre-randomization baseline of the Core Study.
• Change in cognitive function as measured with a cognitive assessment battery, relative to the pre-randomization baseline of the Core Study, if assessed during the Core Study.
• Change in growth and development for patients less than 18 years of age 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), relative to the pre-randomization baseline of the Core Study.
• Effects on menstruation cycles (in females).
• Drug abuse liability, as measured by AEs of abuse potential, drug accountability and Study Medication Use and Behavior Survey in patients aged 12 and older.
DS Patients Only:
• Percentage change in total convulsive seizure frequency, relative to the pre-randomization baseline of the Core Study.
• Percentage change in total non-convulsive seizure frequency, relative to the pre-randomization baseline of the Core Study.
• Number of patients considered treatment responders, defined as those with a ≥25%, ≥50%, ≥75%, or 100% reduction in convulsive seizures, relative to the pre-randomization baseline of the Core Study.
• Number of patients experiencing a >25% worsening, −25 to +25% no change, 25–50% improvement, 50–75% improvement or >75% improvement in convulsive seizures, relative to the pre-randomization baseline of the Core Study.
LGS Patients Only:
• Percentage change in the number of drop seizures, relative to the pre-randomization baseline of the Core Study.
• Percentage change in the number of non-drop seizures, relative to the pre-randomization baseline of the Core Study.
• Number of patients considered treatment responders, defined as those with a ≥25%, ≥50%, ≥75%, or 100% reduction in drop seizures, relative to the pre-randomization baseline of the Core Study.
• Number of patients experiencing a >25% worsening, −25 to +25% no change, 25–50% improvement, 50–75% improvement or >75% improvement in drop seizures, relative to the pre-randomization baseline of the Core Study. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
All Patients:
-At Visit 1, from Visit 5 to End of Treatment Visit: QOLCE, QOLIE, S/CGIC, S/CGICSD, Vineland-II.
-At Visit 1 and at End of Treatment Visit: Cognitive function.
-From Visit 1 to End of Treatment Visit: Number of epilepsy-related hospitalizations, rescue medication use, maintenance of seizure frequency reduction and seizures freedom, seizures sub-types and number of status epilepticus.
Dravet Syndrome only: Percentage of convulsive and non-convulsive seizure, treatment responders and patients experiencing a worsening, no change or improvement in convulsive seizures.
Lennox-Gastaut Syndrome only: Percentage of drop and non-drop seizures, treatment responders and patients experiencing a worsening, no change or improvement in drop seizures. |
|
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 | No |
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) | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
France |
Israel |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |