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    Summary
    EudraCT Number:2014-002941-23
    Sponsor's Protocol Code Number:GWEP1423
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-03-31
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2014-002941-23
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of cannabidiol (GWP42003-P; CBD) as adjunctive treatment for seizures associated with Lennox- Gastaut syndrome in children and adults
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures associated with Lennox-Gastaut Syndrome in children and adults
    A.4.1Sponsor's protocol code numberGWEP1423
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02224690
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGW Research Ltd.
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGW Research Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGW Research Ltd
    B.5.2Functional name of contact pointGW Research Ltd. Switchboard
    B.5.3 Address:
    B.5.3.1Street AddressSovereign House, Vision Park, Chivers Way
    B.5.3.2Town/ cityHiston, Cambridge
    B.5.3.3Post codeCB24 9BZ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441223266800
    B.5.5Fax number+441223235667
    B.5.6E-mailinfo@gwpharm.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCannabidiol (CBD)
    D.3.2Product code GWP42003-P
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number 13956-29-1
    D.3.9.2Current sponsor codeGWP42003-P
    D.3.9.3Other descriptive nameCANNABIDIOL
    D.3.9.4EV Substance CodeSUB26600
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product Yes
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product Yes
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Lennox-Gastaut syndrome
    E.1.1.1Medical condition in easily understood language
    Epilepsy
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10048816
    E.1.2Term Lennox-Gastaut syndrome
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of GWP42003-P as adjunctive treatment in reducing the number of drop seizures when compared with placebo, in patients with LGS.
    Drop seizure is defined as an attack or spell (atonic, tonic or tonic-clonic,) involving the entire body, trunk or head that led or could have led to a fall, injury, slumping in a chair or hitting the patient’s head on a surface.
    E.2.2Secondary objectives of the trial
    To assess the following in LGS patients taking GWP42003-P as adjunctive treatment, when compared with placebo:
    Key:
    • Number of patients drop seizure-free.
    • Responder rate, in terms of reduction in drop seizures.
    • Reduction in the number of non-drop seizures.
    • Frequency of subtypes of seizures.
    • Safety and tolerability of GWP42003-P through monitoring of:
    − AEs, Suicidal ideation, Abuse liability, Cannabis withdrawal effects, Clinical laboratory tests, Vital signs.
    − Menstruation cycles (in females).
    Other:
    • Number of episodes of status epilepticus.
    • Need for hospitalization due to epilepsy.
    • Change in duration of subtypes of seizures.
    • Sleep disruption and daytime sleepiness.
    • Quality of life, Adaptive behavior, Cognitive function, Growth and development.
    • To determine the PKs of CBD and its major metabolites following single and multiple doses of GWP42003-P.
    • To determine effects of GWP42003-P on plasma concentrations of concomitant AEDs, where available.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 55 years (inclusive).
    • Patient must have a clinical diagnosis of LGS. This includes written documentation of having met electroencephalogram (EEG) diagnostic criteria during the patient’s history and evidence of more than one type of generalized seizure, including drop seizures (atonic, tonic or tonic-clonic), for at least six months. Care should be taken not to include benign myoclonic epilepsy of infancy, atypical benign partial epilepsy (pseudo-Lennox syndrome), or continuous spike-waves of slow sleep.
    • Patients who have a history of slow (<3.0 Hz) spike-and-wave pattern in an EEG prior to the enrollment into the baseline period.
    • Patients must have at least two drop seizures each week during the first 28 days of the baseline period.
    • Patients should be refractory; that is having documented failures on more than one AED.
    • Patient must be taking one or more AEDs at a dose which has been stable for at least four weeks prior to screening.
    • 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 is 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.
    E.4Principal exclusion criteria
    • Etiology of patient's seizures is a progressive neurologic disease. Patients with tuberous sclerosis will not be excluded from study participation, unless there is a progressive tumor.
    • Patient has had an anoxic episode requiring resuscitation within six months of screening.
    • 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 investigators 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 any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP, such as 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 a highly effective method of 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 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 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.
    • 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 × 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.
    • 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.
    • 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 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.
    • Patient is taking more than four concurrent AEDs.
    • Patient has taken corticotropins in the six months prior to screening.
    • Patient is currently taking long-term systemic steroids (excluding inhaled medication for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception will be made for prophylactic medication, for example, for idiopathic nephrotic syndrome or asthma.
    • Patient is taking felbamate, and they have been taking it for less than one year prior to screening.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the mean percentage change from baseline in number of drop seizures (average per 28 days) during the treatment period (Day 1 to the end of the evaluable period) in patients taking GWP42003-P compared with placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The baseline period is Screening (V1)- Randomisation (V2). Mean percentage change from baseline in number of drop seizures (average per 28 days) during the treatment period (Day 1 to the end of the evaluable period) in patients taking GWP42003-P compared with placebo.
    E.5.2Secondary end point(s)
    The following endpoints will be compared between treatment groups over the 14-week, double-blind treatment period, unless specified otherwise:
    • Percentage change from baseline in number of drop seizures (average per 28 days) during the Weeks 1–4, 5–8 and 9–12 of the maintenance period.
    • Number of patients considered treatment responders, defined as those with a ≥25%, ≥50%, ≥75%, or 100% reduction in drop seizures from baseline (overall and four-weekly).
    • Number of patients experiencing a >25% worsening, −25 to +25% no change, 25–50% improvement, 50–75% improvement or >75% improvement in drop seizures from baseline.
    • Percentage change from baseline in number of non-drop seizures (average per 28 days).
    • Percentage change from baseline in the frequencies of subtypes of seizures (average per 28 days).
    • Changes from baseline in duration of seizure subtypes as assessed by the Subject/Caregiver Global Impression of Change in Seizure Duration (S/CGICSD).
    • Changes from baseline in number of episodes of status epilepticus.
    • Changes from baseline in number of inpatient hospitalizations due to epilepsy.
    • Changes from baseline in quality of life as assessed by the Quality of Life in Childhood Epilepsy (QOLCE), for patients aged between two and 18 years of age, or Quality of Life in Epilepsy, version 2, (QOLIE-31-P) for patients aged 19 years and older.
    • Changes from baseline in the Subject/Caregiver Global Impression of Change (S/CGIC) score.
    • Change from baseline in adaptive behavior as measured with the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) score.
    • Change from baseline in cognitive function as measured with the Cognitive Assessment Battery.
    • 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.
    • Change from baseline 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 years [inclusive], or earlier if clinically indicated by onset of menarche or other signs of precocious puberty).
    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 plasma concentration (tmax)
    − Area under the plasma concentration-time 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 assessed by measuring:
    • AEs.
    • Clinical laboratory parameters.
    • Columbia-Suicide Severity Rating Scale (C-SSRS) score.
    • Vital signs.
    • Physical examination parameters.
    • 12-lead electrocardiogram (ECG).
    • Cannabis Withdrawal Scale (CWS) or Pediatric Cannabinoid Withdrawal Scale (PCWS) score, as appropriate.
    • Abuse liability.
    • Effects on menstruation cycles (in females).
    E.5.2.1Timepoint(s) of evaluation of this end point
    The baseline period is Screening (V1) - Randomisation (V2). Mean percentage change from baseline will be measured over the 14-week, double-blind treatment period, unless specified otherwise, in patients taking GWP42003-P compared with placebo.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Netherlands
    Poland
    United States
    E.8.7Trial 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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months11
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 67
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 33
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 34
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 33
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Some LGS Subjects will have some level of cognitive impairment
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 47
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following study completion, all patients will be invited to continue to receive GWP42003-P in an open label extension (OLE) study (under a separate protocol).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-30
    P. End of Trial
    P.End of Trial StatusCompleted
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