Clinical trial NCT03808935: Cannabis Extract in Refractory Epilepsy Study
Official title: A Double-Blind, Placebo-Controlled, Parallel-Group Study of Cannabidiol Plus Tetrahydrocannabinol (CBD+THC) Given as Adjunctive Therapy in Patients With Refractory Seizures
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Drug Resistant Epilepsy
Keywords: epilepsy
drug resistant
refractory
seizures
cannabidiol
cbd
cannabis
Lead sponsor: The Epilepsy Research Program of the Ontario Brain Institute
Sponsor class: OTHER
Collaborators: name: Ontario Brain Institute
name: University of Toronto
name: University Health Network, Toronto
name: London Health Sciences Centre
name: MedReleaf
First posted: 2019-01-18
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to examine whether a low dose of CBD+THC will decrease the frequency of convulsive seizures in adults with drug-resistant epilepsy, when used in addition to standard anti-epileptic drugs (AEDs). This study will also study the genes associated with epilepsy and whether different epileptic syndromes respond to treatment with CBD+THC.

Detailed description: Background: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major compounds found in the cannabis plant. Reports from patients, families, and the scientific community suggest that CBD (when used as an add-on therapy) decreases the number of convulsive seizures in children and adults with Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous sclerosis complex.

Trial design: Phase III, double-blind, randomized, placebo-controlled, parallel-group trial, followed by an open phase where treatment allocation will be revealed and all participants will either continue or begin receiving the active study drug.

Participants: Adults (18 years of age and older) with drug-resistant epilepsy, including patients with Dravet and Lennox Gastaut syndromes, and patients with frequent convulsive seizures (e.g., tonic, tonic-clonic, atonic, drop attacks, and focal motor seizures).

Interventions: Capsules containing a ratio of 16 CBD: 1 THC oil at a maximum total daily dose of approximately 300 mg of CBD per day, divided into equal doses in the morning and evening.

Comparator: Placebo capsules containing high-oleic sunflower oil and no active or medicinal ingredients.

Outcomes: Frequency of seizures; side effects; blood levels of AEDs, CBD, THC, and liver enzymes; impact on cognition and quality of life; genetics.

Sample size: A total of 80 participants (40 assigned to treatment and 40 to control group) recruited from Toronto Western Hospital in Toronto, and University Hospital in London, Ontario.

Time: Each participant will be enrolled for approximately 16 to 18 weeks, while the clinical trial is expected to take place over a period of two years.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of epilepsy according to the ILAE classification.
* At least 4 motor seizures per month at the start of the study, despite treatment with at least two different anti-epileptic drugs (given concurrently or sequentially) for at least one year.
* At least 4 motor seizures per month during the prospective baseline phase (4 weeks) with no 21-day seizure free periods.
* Stable dose(s) of the same AED(s) for one month prior to screening.
* Agrees not to take any cannabinoids during the study or any other investigational compound for one month before the study or outside cannabinoids during the study.
* Is planning to stay in Canada for the duration of the trial.
* Is able to travel to one of the study sites for in-person visits with the study physicians and to a local lab for blood collection.
* Has access to telephone, computer, and internet for regular correspondence and to complete the study questionnaires.

Exclusion Criteria:

* Participation in a study involving administration of an investigational compound within one month of Visit 1.
* Evidence of clinically significant non-epileptic disease (cardiac, respiratory, gastrointestinal, hepatic, hematologic, or renal disease, etc.) that in the opinion of the investigators could affect the patient's safety or trial conduct.
* Progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors.
* Occurrence of psychogenic seizures in the previous year.
* History of drug misuse/abuse (other than cannabinoids). Consideration may be given to allowing inclusion of subjects with remote history of drug abuse (within a defined relevant time period).
* Multiple drug allergies (dermatological, hematological, or organ toxicity) or more than one severe drug reaction(s).
* Pregnancy, breastfeeding.
* Known or suspected hypersensitivity to cannabinoids, or any of the excipients of the investigational medicinal product.
* Patients with a history of major depression, suicidal ideation or attempted suicide, schizophrenia or any other psychotic disorder, patients with a family history of schizophrenia.

Primary outcomes:
measure: Frequency of convulsive seizures
timeFrame: 0 - 10 weeks
Secondary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by the adverse events questionnaire
timeFrame: 0- 10 weeks
measure: Changes in blood levels of CBD and THC from baseline to end of treatment
timeFrame: 0 - 10 weeks
measure: Changes in blood levels of AEDs from baseline to end of treatment
timeFrame: 0 - 10 weeks
measure: Changes in blood levels of liver enzymes AST, ALT, and GGT from baseline to end of treatment
timeFrame: 0 - 10 weeks
measure: Changes in quality of life from baseline to end of treatment as assessed by the Quality of Life in Epilepsy Inventory (QOLIE-31) questionnaire
timeFrame: 0 - 10 weeks
measure: Changes in quality of life from baseline to end of treatment as assessed by the World Health Organization Quality of Life-BREF (WHOQOL-BREF) questionnaire
timeFrame: 0 - 10 weeks
measure: Changes in quality of life from baseline to end of treatment as assessed by the Quality of Life Childhood Epilepsy (QOLCE) questionnaire
timeFrame: 0 - 10 weeks
measure: Changes in symptoms of depression from baseline to end of treatment as assessed by the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E)
timeFrame: 0 - 10 weeks
measure: Changes in symptoms of depression from baseline to end of treatment as assessed by the Quick Inventory of Depressive Symptoms (QIDS)
timeFrame: 0 - 10 weeks
measure: Changes in symptoms of anxiety from baseline to end of treatment as assessed by the Generalized Anxiety Disorder 7-item (GAD-7)
timeFrame: 0 - 10 weeks
measure: Change in overall severity of epilepsy from baseline to end of treatment as assessed by the Global Analysis of Severity of Epilepsy Scale (GASE)
timeFrame: 0 - 10 weeks
measure: Change in quality of sleep from baseline to end of treatment as assessed by the Pittsburgh Sleep Quality Index (PSQI)
timeFrame: 0 - 10 weeks
measure: Change in participant's impression of change from baseline to end of treatment as assessed by the Patients' Global Impression of Change (PGIC) scale
timeFrame: 0 - 10 weeks
measure: Change in caregiver's impression of change from baseline to end of treatment as assessed by the Caregiver's Global Impression of Change (CGIC) scale
timeFrame: 0 - 10 weeks
measure: Changes in psychological symptoms from baseline to end of treatment as assessed by the Brief Symptom Inventory (BSI-53)
timeFrame: 0 - 10 weeks
measure: Changes in functional impairment from baseline to end of treatment as assessed by the Sheehan Disability Scale (SDS)
timeFrame: 0 - 10 weeks
Other outcomes:
Locations:
city: London
country: Canada
facility: University Hospital Campus, London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital
state: Ontario
Study officials:
affiliation: University of Toronto
name: W M Burnham, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Peter Tai, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: London Health Sciences Centre
name: Seyed Mirsattari, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Nancy Mingo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Danielle Andrade, MD
role: PRINCIPAL_INVESTIGATOR
References: