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Trial registered on ANZCTR


Registration number
ACTRN12618001706268
Ethics application status
Approved
Date submitted
25/09/2018
Date registered
16/10/2018
Date last updated
3/02/2020
Date data sharing statement initially provided
1/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
EP1 cannabidiol enriched cannabis oil in refractory epilepsy
Scientific title
A Double-blind, Placebo-controlled Study Investigating the Safety, Tolerability, Efficacy and Pharmacokinetics of EP1, an Enriched Cannabidiol Oil, in Children and Adolescents with Medication Resistant, Refractory Epilepsy
Secondary ID [1] 296131 0
None
Universal Trial Number (UTN)
U1111-1220-6763
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paediatric medication-resistant epilepsy 309714 0
Condition category
Condition code
Neurological 308519 308519 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The single intervention in this study is the administration of EP1 to treat epilepsy. EP1 is a drug which contains Cannabidiol (CBD) and Tetrahydrocannabinol (THC) in a ratio of approximately 20:1. It is theorised to reduce and prevent seizures.

EP1 will be dosed using oral syringe (sublingually) twice daily, to provide between 5 and 25 mg/kg/day of CBD, and between 0.25 to 1.25 mg/kg/day of THC. The matching placebo is dosed using oral syringes (sublingually) twice daily.

Participants will be randomised 3:1 to receive EP1 or placebo. They will undergo 1 to 5 weeks (barring any dose suspensions) of dose finding where the dose of EP1 or placebo is increased weekly to determine their own efficacious/tolerated dose. The individually set efficacious/tolerated dose will be administered for a maximum 12 week double-blind treatment period.

Dosing will commence with either EP1 at 5 mg/kg/day or matching placebo solution given in divided doses twice daily. Weekly up-titration with increments of 5 mg/kg/day CBD and 0.25 mg/kg/day THC will be performed based on efficacy and tolerability. Clinical judgment will be used by the Investigator to support dose selection, considering any benefit to the subject and any adverse effects observed. Up-titration may be stopped if an unacceptable AE develops, or if the subject becomes seizure-free. Participants will complete a daily study specific diary where participants/caregivers will record daily dosing details for study medication.

Participant will complete an 8 week screening/baseline period. This consists of a 1 to 4 week screening period, and a 4 week (baseline) open-label placebo run-in period to review subject eligibility. During the (baseline) run-in period, subjects will receive a placebo volume equivalent to a 10 mg/kg/day dose of CBD, given SL BD.
Intervention code [1] 312460 0
Treatment: Drugs
Comparator / control treatment
Placebo. The matching placebo is dosed using an oral syringe (sublingually) twice daily.

Each mL of the placebo will contain, 0 mg CBD, 0 mg THC, 0 mg CBDA, 918 mg of inactive components; organic olive oil, vitamin E, natural flavour masking agent and naturally occurring compounds present in whole plant extracts.
Control group
Placebo

Outcomes
Primary outcome [1] 307492 0
To evaluate the efficacy of EP1 compared to placebo as measured by seizure frequency from baseline to Week 12.

Subjects will complete a placebo run-in baseline period of 4 weeks. Subjects/carers will be asked to record baseline seizure data in a study specific daily seizure diary.
Timepoint [1] 307492 0
Week 12 post-dose-finding period
Primary outcome [2] 307493 0
To evaluate the safety and tolerability of EP1, at individually set efficacious/tolerated doses compared to placebo.

Safety variables for analysis will be the difference in incidence, type and severity of AEs, vital signs, laboratory parameters, and physical examination. Safety assessments will be completed by a medically qualified physician. Laboratory parameters include full blood count, urinalysis (glucose, red blood cell, white blood cell, specific gravity, pH, protein, ketones, urobilinogen, blood, nitrite, microscopic, colour, bilirubin, casts, epithelial cells, leukocyte esterase, and bacteria) and biochemistry: liver function tests (aspartate aminotransaminase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [GGT], alkaline phosphatase [ALP], conjugated bilirubin, total bilirubin), bicarbonate, urea, calcium, chloride, creatinine kinase, lipase, creatinine, magnesium, potassium, sodium, total protein, and glucose.

AEs that may occur as part of this study include; somnolence, fatigue, decreased appetite, gastrointestinal disturbances including diarrhoea and vomiting.
Timepoint [2] 307493 0
Week 12 post-dose-finding period. The incidence, type and severity of AEs and vital signs will be completed in weeks 1, 2, 3, 4, 5, 8, 12. Laboratory parameters and physical examinations will be completed in weeks 4, 8, 12. All assessments/measurements listed here will also be completed 4 weeks post final/last dose.
Secondary outcome [1] 352065 0
Seizure response rate, defined as the percentage of subjects with at least 50% reduction from baseline to Week 12 in seizure frequency compared to placebo.

Subjects will complete a placebo run-in baseline period of 4 weeks. Subjects/carers will be asked to record baseline seizure data in a study specific daily seizure diary. During the study period, seizure frequency is assessed by review of the study specific daily seizure diary.
Timepoint [1] 352065 0
Week 12 post-dose-finding period
Secondary outcome [2] 352066 0
To assess Clinicians Global Impression of Change (CGIC) following treatment with EP1 compared to placebo
Timepoint [2] 352066 0
Week 12 post-dose-finding period
Secondary outcome [3] 352067 0
To assess changes from baseline in the number, duration and intensity of seizures following treatment with EP1 compared to placebo. This is a composite outcome. This is assessed by review of the study specific daily seizure dairy, which includes measures of number, duration and intensity of daily seizures.
Timepoint [3] 352067 0
Week 12 post-dose-finding period
Secondary outcome [4] 352068 0
To characterize the steady state pharmacokinetics (PK) of CBD in subjects aged 12 to 18 years inclusive. Limited sampling will be collected in subjects < 12 years.

This will include a single blood sample collected weekly during dose finding (pre-dose prior to up-titration i.e. trough value of steady state at the previous dose level), and samples collected during the last week of the treatment period, with blood samples collected pre-dose and at 10 min, 20 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post dose. For subjects < 12, limited sampling will be employed, with blood samples collected pre-dose during up-titration and pre-dose for the last blinded dose.

Steady state PK parameters of EP1 including but not limited to Cmax, Tmax, AUClast, will be determined from concentration data of samples collected following the last dose of the blinded treatment period.
Timepoint [4] 352068 0
Week 12 post-dose-finding period
Secondary outcome [5] 352089 0
Open-label extension: To assess the long-term safety and tolerability of EP1.

Safety variables for analysis will be the difference in incidence, type and severity of AEs, vital signs, laboratory parameters, and physical examination. Physical examinations will be performed by a medically qualified physician. Laboratory parameters include full blood count, urinalysis (glucose, red blood cell, white blood cell, specific gravity, pH, protein, ketones, urobilinogen, blood, nitrite, microscopic, colour, bilirubin, casts, epithelial cells, leukocyte esterase, and bacteria) and biochemistry: liver function tests (aspartate aminotransaminase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [GGT], alkaline phosphatase [ALP], conjugated bilirubin, total bilirubin), bicarbonate, urea, calcium, chloride, creatinine kinase, lipase, creatinine, magnesium, potassium, sodium, total protein, and glucose.

AEs that may occur as part of this study include; somnolence, fatigue, decreased appetite, gastrointestinal disturbances including diarrhoea and vomiting.
Timepoint [5] 352089 0
Week 52 from start of dose-finding period. The incidence, type and severity of AEs will be completed in weeks 1, 2, 3, 4, 5, 8, 12, 16, 20, 24, 28, 32, 36 and 40. Vital signs will be completed in weeks 1, 2, 3, 4, 5, 8 and 12. Laboratory parameters and physical examinations will be completed in weeks 4, 8 and 12. All assessments/measurements listed here will also be completed 4 weeks post final/last dose.
Secondary outcome [6] 352090 0
Open-label extension: To assess the long-term efficacy of EP1 and durability of response. This is a composite outcome.

Efficacy assessments include daily seizure rate, determined by a study specific daily seizure diary, CGIC and CaGIC score completed at Weeks 4, 8, 12, 20, 24, 28, 32 36, 40. AEs and study specific seziure diary will also be completed 4 weeks post final/last dose.
Timepoint [6] 352090 0
Week 52 from start of dose-finding period.
Secondary outcome [7] 352629 0
To assess Caregivers Global Impression of Change (CaGIC) following treatment with EP1 compared to placebo
Timepoint [7] 352629 0
Week 12 post-dose-finding period
Secondary outcome [8] 352630 0
To characterize the steady state pharmacokinetics (PK) of THC in subjects aged 12 to 18 years inclusive. Limited sampling will be collected in subjects < 12 years.

This will include a single blood sample collected weekly during dose finding (pre-dose prior to up-titration i.e. trough value of steady state at the previous dose level), and samples collected during the last week of the treatment period, with blood samples collected pre-dose and at 10 min, 20 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post dose. For subjects < 12, limited sampling will be employed, with blood samples collected pre-dose during up-titration and pre-dose for the last blinded dose.

Steady state PK parameters of EP1 including but not limited to Cmax, tmax, AUClast, will be determined from concentration data of samples collected following the last dose of the blinded treatment period.
Timepoint [8] 352630 0
Week 12 post-dose-finding period

Eligibility
Key inclusion criteria
1. Resident in NSW aged 2 to 15 years inclusive at the time Informed Consent is obtained, or resident elsewhere aged 2 to 18 years inclusive at the time Informed Consent is obtained.
2. Weight at screening is less than/or equal to 100 kg.
3. Diagnosed with drug resistant epilepsy, which has not
responded to at least 3 AEDs at therapeutic doses, including one trial of a combination of 2 concomitant drugs. Vagal nerve stimulation, responsive neurostimulation, deep brain stimulation, or the ketogenic diet can each be considered equivalent to an AED.
4. Baseline seizure frequency of at least 2 countable seizures per week (non-countable seizures includes absence and myoclonic seizures). Note: seizures to be classified according to the International League Against Epilepsy (ILAE) 2017 classification.
5. Treatment with between 1-3 baseline anti-seizure medications at stable doses for a minimum of 4 weeks prior to enrolment.
6. If being treated with vagal nerve stimulation, there has been no change of device setting in the 3 months prior to enrolment.
7. If being treated with a ketogenic diet or Aitkin's diet, there has been no change of the diet's parameters in the 3 months prior to enrolment.
8. Prepared to continue treatment with current AED therapy, with no change of dose, throughout the double blind study period. Note: AED use with dose (including changes to dose) will be recorded for the 3 months prior to screening.
9. Clinical laboratory (haematology and biochemistry) values within the normal limits as defined by the local clinical laboratory, unless the investigator decides that out-of-range values are not clinically significant.
10. An Independent Ethics Committee (IEC) approved written informed consent form is signed and dated by either the participant, where appropriate, or the parent or legal representative (guardian or person responsible).
11. Able to fully conform with all study procedures, including visit schedules, seizure reports, PK study and continuation of other AEDs taken during the baseline period.
12. Investigator can confirm consistent seizure count over the past 3 months. The subject will need to provide an updated diary at the time of enrolment.
13. Investigator is able to confirm consistent seizure count over the past 3 months. The subject will need to provide an updated diary at the time of enrolment.
Minimum age
2 Years
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Epilepsies associated with neurodegenerative diseases, such as Rasmussen encephalitis and malignant brain tumours.
2. Epilepsies associated with treatable inborn errors of metabolism.
3. Presence of any medical disorder (including cardiovascular, renal, hepatic or endocrine disorders) considered clinically significant in the opinion of the Investigator.
4. Non-epileptic seizures.
5. Presence of significant medical illness such as heart disease,
compromised renal function, abnormal liver function or an
endocrine disorder requiring medication.
6. Current treatment with clobazam at a dose > 20 mg/day.
7. A significant oral or gastrointestinal condition that, in the
opinion of the investigator, may affect the absorption of
EP1.
8. Allergy or sensitivity to CBD (or any cannabinoids), olive
oil or flavouring agents.
9. Clinically significant current infection.
10. Females of child bearing potential who are currently
pregnant or breastfeeding or planning on becoming pregnant
during the study or within 3 months of study completion.
11. Sexually active males who intend to father children or not
using acceptable forms of contraception during the study and for 3 months thereafter. The acceptable methods of birth control are abstinence or double barrier birth control (i.e., condom plus spermicide or a condom plus diaphragm).
12. Sexually active females of child-bearing potential who are not prepared to take effective contraception. The acceptable methods of birth control are abstinence (from 4 weeks prior to dosing) or double barrier birth control (i.e., condom plus spermicide or a condom plus diaphragm).
13. Currently participating in an investigational drug or device
study.
14. Use of any cannabis related product, (including hemp oil)
based product in the past 12 months as assessed by parental/caregiver questioning; negative screen for CBD and THC levels at Screening.
15. Past treatment with CBD.
16. History of uncontrolled diabetes or hypertension.
17. History of severe personality disorder, suicidal history or
other significant psychiatric disorder/psychosis.
18. History of substance abuse/addiction including within the
last year, or daily consumption of significant alcohol
quantities.
19. In Investigator’s judgement, active medical
condition/treatment that impacts study activities
20. In the opinion of the Investigator, the parent(s)/caregiver(s)
are unable to comply with study requirements, including follow-up visits and tests.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The study is a double-blind study and thus the investigator, site staff (other than pharmacists), sponsor, and participants/caregivers will be blinded to the randomised treatment.

A central randomisation will be used. A computer-generated randomisation schedule will be prepared by an unblinded statistician prior to the start of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A central randomisation will be used. A computer-generated randomisation schedule will be prepared by an unblinded statistician prior to the start of the study. Investigational product will be prepared in accordance with the randomisation list.

Subjects will be randomised on Day 1. At the time of randomisation, the participant will be assigned a unique randomisation number, which will be allocated sequentially based on the predetermined randomisation schedule, and according to their chronological order of inclusion in the study. Confirmation of the treatment number allocated will be documented in the drug accountability records and recorded in the eCRF.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The sample size for this study has been selected without performing a formal sample size calculation to provide descriptive information on the safety, efficacy and tolerability of EP1. The sample size is based on clinical considerations and is considered adequate to provide preliminary efficacy and safety data.

In general, data will be summarised using descriptive statistics.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11945 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 11946 0
The Alfred - Prahran
Recruitment postcode(s) [1] 24091 0
3084 - Heidelberg
Recruitment postcode(s) [2] 24092 0
3004 - Prahran

Funding & Sponsors
Funding source category [1] 300716 0
Commercial sector/Industry
Name [1] 300716 0
Cann Pharmaceutical Australia Limited
Address [1] 300716 0
Level 1, The Realm
18 National Circuit
Barton ACT 2600
Country [1] 300716 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Cann Pharmaceutical Australia Limited
Address
Level 1, The Realm
18 National Circuit
Barton ACT 2600
Country
Australia
Secondary sponsor category [1] 300255 0
None
Name [1] 300255 0
Address [1] 300255 0
Country [1] 300255 0
Other collaborator category [1] 280359 0
Other Collaborative groups
Name [1] 280359 0
CRO: Neuroscience Trials Australia
Address [1] 280359 0
Melbourne Brain Centre
245 Burgundy Street
Heidelberg VIC 3084
Australia
Country [1] 280359 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301500 0
Monash Health - Monash Health Human Research Ethics Committee
Ethics committee address [1] 301500 0
246 Clayton Road
Clayton VIC 3168
Ethics committee country [1] 301500 0
Australia
Date submitted for ethics approval [1] 301500 0
18/09/2018
Approval date [1] 301500 0
11/12/2018
Ethics approval number [1] 301500 0
HREC/46428/MonH-2018-153150(v1)

Summary
Brief summary
This study is a multi-centre, randomised, double-blind, placebo-controlled study evaluating safety, tolerability, efficacy and PK of individually established efficacious/tolerated doses of EP1 compared to placebo. EP1 contains Cannabidiol (CBD) and Tetrahydrocannabinol (THC) in a ratio of approximately 20:1. The study will aim to determine if EP1 is an effective treatment for refractory epilepsy in children, adolescents and young adults by comparing different doses of EP1 against a placebo by measuring seizure frequency and character. Safety will also be measured over a long term open-label extension of the study for a year after the double blind phase.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87206 0
Prof Ingrid Scheffer
Address 87206 0
Austin Health
245 Burgundy Street
Heidelberg VIC 3084
Country 87206 0
Australia
Phone 87206 0
+61 03 9035 7120
Fax 87206 0
Email 87206 0
i.scheffer@unimelb.edu.au
Contact person for public queries
Name 87207 0
Mr Paul Lightfoot
Address 87207 0
Melbourne Brain Centre
245 Burgundy Street
Heidelberg VIC 3084
Country 87207 0
Australia
Phone 87207 0
+61 03 9035 7116
Fax 87207 0
Email 87207 0
paulal@unimelb.edu.au
Contact person for scientific queries
Name 87208 0
Prof Ingrid Scheffer
Address 87208 0
Austin Health
245 Burgundy Street
Heidelberg VIC 3084
Country 87208 0
Australia
Phone 87208 0
+61 03 9035 7120
Fax 87208 0
Email 87208 0
i.scheffer@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The conduct and results of this study will be kept confidential. The results of this study may be published. Upon completion of the Study it is the intention of the parties to prepare a joint publication regarding or describing the Study and all the results there from and both parties shall co-operate in this regard.
What supporting documents are/will be available?
No other documents available
Summary results
No Results