Primary ObjectiveTo determine whether GWP42003-P affects the pharmacokinetic (PK) profile of stiripentol (STP) or valproate (VPA).Secondary Objective(s)To assess the safety and tolerability of GWP42003-P in the presence of STP or VPA.
ID
Source
Brief title
Condition
- Seizures (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints of the trial are the PK parameters (Cmax, tmax, AUC(0**),
AUC(0*t) and t*) of the following analytes:
* STP
* VPA
* CBD
* CBD major metabolites
Secondary outcome
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)
* 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 t*) of the following analytes:
* THC
* THC major metabolites
Background summary
CYP450 enzymes are a family of heme-containing enzymes responsible for the
metabolism of over half of all prescribed medications, and interactions with
these enzymes are the major source of physiologically-based pharmacokinetic
(PBPK) interactions between drugs. It is anticipated that patients taking
GWP42003-P may also be taking VPA or STP, and as CBD has been shown to both
inhibit CYP450 enzymes in vitro (Ki CYP3A4 = 1.5 *M) and induce CYP450 enzymes
in vitro (EC50 CYP3A4 = 1.2 *g/mL), a possibility of a PK interaction between
GWP42003-P and VPA or STP exists. Given the high likelihood that patients
prescribed GWP42003-P will also be using VPA or STP, it is the aim and purpose
of this trial to determine whether a PK interaction between GWP42003-P, STP and
VPA exists.
CBD can act as both a CYP inhibitor and inducer in human hepatocytes in vitro.
Therefore, the potential for PK interactions with other drugs that are
metabolized by CYP450 enzymes exists. The hypothesis is that the in vivo PK of
STP or VPA may be altered (increased or decreased) by the chronic
administration of GWP42003-P.
Study objective
Primary Objective
To determine whether GWP42003-P affects the pharmacokinetic (PK) profile of
stiripentol (STP) or valproate (VPA).
Secondary Objective(s)
To assess the safety and tolerability of GWP42003-P in the presence of STP or
VPA.
Study design
This is a phase 2, double-blind, randomized, placebo-controlled PK trial in two
parallel groups in 40 patients.
* Patients will enter either the STP or VPA arms and will be randomized in a
4:1 ratio to receive either 20 mg/kg GWP42003-P or placebo from Days 2 to 26.
* At the end of the treatment period, patients will be given the option of
continuing onto an open label extension (OLE) period if the investigator and
patient both agree that it is in their best interests. Doses may be adjusted up
or down, at the investigator*s discretion, to a maximum of 30 mg/kg/day
GWP42003-P. The OLE period will last for a maximum of one year or until
marketing authorization is granted; whichever is earlier.
* Patients that do not continue onto the OLE period will taper off GWP42003-P
over a 10 day period and will have a telephone follow-up visit four weeks after
the end of taper day on Day 64.
* Day 1 (Visit 2): patients will not be dosed with investigational medicinal
product (IMP) (GWP42003-P or placebo) but will continue to take STP or VPA at a
stable dose.
* Day 2 (Visit 2): patients will begin the up-titration with GWP42003-P or
placebo to a maintenance dose or an equivalent maintenance dose of 20 mg/kg/day
over a period of 10 days (Days 2 to 11).
* Day 12 (Visit 3): patients will attend the study site to check safety and
compliance.
* After up-titration with GWP42003-P or placebo, the patients will remain on
the maintenance dose for 14 days (Days 12 to 25) before coming in for the next
PK visit on Day 26.
* On Day 27 (Visit 4), patients will be invited to receive GWP42003-P in the
OLE period. If the patient enters the OLE period of the trial, the patient will
continue to take GWP42003-P as advised by the investigator.
* If the patient does not enter the OLE period of the trial, the patient will
taper off GWP42003-P by reducing the dose by approximately 10% of the
maintenance dose each day until dosing has ceased, with an End of Taper visit
on Day 36 (Visit 5) and a safety follow-up telephone call four weeks after the
end of taper, on Day 64.
PK samples will be taken on the day of enrollment (Visit 2, Days 1 and 2) and
after completing 14 days treatment on GWP42003-P or placebo (Visit 4, Days 26
and 27). The PK assessments will therefore capture the following combinations
of STP, VPA and IMP:
* First PK assessment: STP or VPA alone.
* Second PK assessment: STP or VPA in combination with GWP42003-P/placebo.
Each PK assessment should be performed at time-points in respect to a morning
dose of STP or VPA. The time-points are as follows: Pre-dose, 15 and 30
minutes, then 1, 1.5, 2, 4, 6, 12 and 24 hours post-dose. It is expected that
the patient will continue to take their STP or VPA as advised by their
physician and PK assessments will be scheduled in order to accommodate this
dosing schedule. The GWP42003-P/placebo should be taken twice daily immediately
following the STP or VPA doses.
PK assessments will analyze plasma levels of STP or VPA, cannabidiol (CBD), CBD
major metabolites, *9-tetrahydrocannabinol (THC), THC major metabolites,
Clobazam (CLB), N-desmethylclobazam (N-CLB), Levetiracetam (LEV) and Topiramate
(TPM).
Patients will be required to keep a paper diary to note the time and dose of
IMP and STP or VPA administration each morning and evening, and to record any
adverse events (AEs) that may occur whilst receiving IMP and any other
medications. Patients will also be requested to record the number and type of
seizures experienced each day whilst on the trial.
Intervention
A total of 40 patients will be enrolled in this trial (20 patients in the STP
arm and 20 in the VPA arm). Patients will enter either the STP or VPA arms and
will be randomized in a 4:1 ratio to receive either 20 mg/kg GWP42003-P or
placebo.
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, Histon 0
Cambridge CB24 9BA
GB
Sovereign House, Vision Park, Histon 0
Cambridge CB24 9BA
GB
Listed location countries
Age
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.
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.
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 | EUCTR2015-002939-18-NL |
| ClinicalTrials.gov | NCT02607891/NCT02607904 |
| CCMO | NL55983.041.15 |