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…
ID
Source
Brief title
Condition
- Seizures (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
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 (t*).
- 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).
Background summary
Given the limitations of current synthetic AEDs, it has been hypothesized that
CBD can be tested for efficacy in children with pharmacoresistant epilepsy. A
recent parent survey has reported that 84% of children with treatment-resistant
epilepsy experienced a reduction in seizures while taking CBD-enriched
cannabis, with over half of those reporting >80% reduction in seizure
frequency. The majority of children had been diagnosed with Dravet Syndrome,
two thirds of which experienced >=50% reduction in seizure frequency with one
patient (8.3%) achieving complete seizure freedom. The CBD-enriched cannabis
was behaviorally well tolerated and children often experienced improved sleep,
increased alertness, and better mood.
Study objective
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 tonicclonic, tonic, clonic or atonic and non-convulsive seizures as
myoclonic, partial or absence.
• 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.
Study design
This study is a 1:1:1 randomized, double-blind, 14-week comparison of two Dose
Levels of GWP42003-P (10 mg/kg/day and 20 mg/kg/day) versus placebo. The
treatment period will consist of a two-week titration period followed by a
12-week maintenance period. The treatment period will be followed by a 10-day
taper period and a fourweek follow-up period. The study will aim to determine
the efficacy, safety and tolerability of two Dose Levels of GWP42003-P compared
with placebo. Patients in the placebo group will be split into two equivalent
cohorts: half receiving 10 mg/kg/day dosing volumes and half receiving 20
mg/kg/day dosing volumes. 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).
Intervention
A total of 150 patients will be randomized to receive one of two Dose Levels
(10 mg/kg/day or 20 mg/kg/day) of active investigational medicinal product
(IMP) or placebo on a 1:1:1 basis (50 patients per treatment group). The
randomization will be stratified by age group (2-5 years, 6-12 years and 13-18
years). Patients in the placebo group will be split into two cohorts (25
receiving 10 mg/kg/day dosing volumes and 25 receiving 20 mg/kg/day dosing
volumes), but it is assumed that these two cohorts can be pooled for the
analyses of efficacy.
Study burden and risks
Like all medicines, the active medication may cause side effects in some
people. The following side effects have been seen in the 107 adult patients who
have previously taken either CBD BDS or pure CBD study medication. It should be
noted that 87 of these patients took a formulation containing small amounts of
other cannabinoids including THC and so may have resulted in a higher incidence
of side effects than with the study medication your child is using. They have
been categorized by the likelihood of them occurring, and listed in the order
they have most commonly been reported. A lot of these effects have also been
seen with the placebo medication. The side effects with a * have been seen in
20 patients who have previously taken the same study medication as the one used
in this study, pure CBD, with all side effects being classed as common, with
the exceptions of headache, feeling irritable and diarrhea which were very
common.
Very common side effects which may affect more than one person in every 10 are:
headache*, feeling sick*, diarrhea*.
Common side effects which may affect more than one person in every 100 are
(excluding the very common side effects above): Mouth problems (including,
pain, discomfort, dry mouth, loss of sense of taste or change in sense of
taste*, reduction in or loss of sensation), feeling tired*, feeling drunk or
abnormal, cold symptoms*, feeling irritable*, feeling depressed or confused,
eating less than usual*, feeling dizzy), body pain* (including back pain and
neck pain), abnormal dreams*, nose bleed, sickness*, bloated* or tummy pain*,
constipation, indigestion*, feeling weak or unwell, flushing, worsening of
multiple sclerosis, muscle spasms.
Uncommon side effects which may affect more than one person in every 1000 are
(excluding the common and very common side effects above): Ear pain*, vertigo*,
belching*, loss of bowel control, difficulty with the capsule size*, tooth
infection*, sore throat*, fall*, joint pain*, tearfulness, urgency to pass
motions*, increased frequency in passing water*, abnormal moods*, trouble
sleeping*, rashes*, itching*, change in liver function blood tests* or
hematology blood tests*. It may also affect some blood tests*.
Sovereign House, Vision Park, Chivers Way
Histon, Cambridge CB24 9BZ
GB
Sovereign House, Vision Park, Chivers Way
Histon, Cambridge CB24 9BZ
GB
Listed location countries
Age
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.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-002939-34-NL |
| ClinicalTrials.gov | NCT02224703 |
| CCMO | NL50788.041.14 |