Epilepsy, Dravet Syndrome
Conditions
Keywords
Cannabidiol, CBD, GWP42003-P, Epidiolex
Brief summary
To investigate the potential antiepileptic effects of cannabidiol (GWP42003-P) in children and young adults with Dravet syndrome.
Detailed description
This study was a 2:2:1:1 randomized, double-blind, 14-week comparison of two dose levels of GWP42003-P (10 milligram/kilogram \[mg/kg\]/day and 20 mg/kg/day) versus placebo (10 mg/kg/day dose-volume equivalent and 20 mg/kg/day dose-volume equivalent; presented as pooled placebo in the study). A 28-day screening period prior to randomization (to establish baseline parameters) preceded the treatment period, which consisted of a 2-week titration period followed by a 12-week maintenance period. The study aimed to determine the efficacy, safety, and tolerability of GWP42003-P compared with placebo. 20 mg/kg/day was recommended by the Data Safety Monitoring Committee (DSMC) after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206). The first participant did not enroll into this study until the DSMC reviewed the safety data from Part A of study GWEP1332 (NCT02091206). Following study completion, all participants were invited to continue to receive GWP42003-P in a separate open-label extension study (GWEP1415; NCT02224573).
Interventions
DRUGGWP42003-P
DRUGPlacebo Control
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participant must have been male or female, aged between 2 and 18 years (inclusive). * Participant must have had a documented history of Dravet syndrome that was not completely controlled by current antiepileptic drugs. * Participant must have been taking 1 or more antiepileptic drugs at a dose that had been stable for at least 4 weeks. * All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation) must have been stable for 4 weeks prior to screening and participant was willing to maintain a stable regimen throughout the study. Key
Exclusion criteria
* Participant had clinically significant unstable medical conditions other than epilepsy. * Participant had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to screening or randomization, other than epilepsy. * Participant was currently using or had in the past used recreational cannabis, medicinal cannabis, or synthetic cannabinoid-based medications (including Sativex®) within the 3 months prior to study entry and was unwilling to abstain for the duration for the study. * Participant had any known or suspected hypersensitivity to cannabinoids or any of the excipients of the investigational medicinal products. * There were plans for the participant to travel outside their country of residence during the study. * Any history of suicidal behavior or any suicidal ideation of type four or five on the Columbia-Suicide Severity Rating Scale (Children's) at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change In Convulsive Seizures During The Treatment Period Compared To Baseline | Baseline to Day 99 or Early Termination (ET) | Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an interactive voice response system (IVRS) diary. The primary endpoint was analyzed using negative binomial regression on the sum of the convulsive seizure counts during the treatment period, based on the ITT analysis set. Baseline included all available data prior to Day 1. Data reported as the ratio of geometric least squares mean in convulsive seizures and expressed as a percentage reduction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change In Total Seizures During The Treatment Period Compared To Baseline | Baseline to Day 99 or ET | Total seizures were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic seizures. Non-convulsive seizures were defined as myoclonic, countable partial, other partial, or absence seizures. Participants or their caregivers recorded the number and type of convulsive seizures and non-convulsive seizures each day from screening until completion of dosing using an IVRS diary. Change compared to baseline was calculated as per the primary outcome measure. Data reported as the ratio of geometric least squares mean in total seizures and expressed as a percentage reduction. |
| Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period | Baseline to Day 99 or ET | Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an IVRS diary. Baseline included all available data prior to Day 1 (28-day average). Percentage change from baseline was calculated as: (\[frequency during the treatment period - frequency during baseline\]/frequency during baseline) x 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) x 28. Baseline included all available data prior to Day 1 (28-day average). |
| Caregiver Global Impression Of Change (CGIC) At The Last Visit | Baseline to Last Visit | On Day 1 (prior to receiving study drug), the caregiver was asked to write a brief description of the participant's overall condition as a memory aid for the CGIC questionnaire at subsequent visits. The CGIC questionnaire comprised the following question, to be rated on a 7-point scale: Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment) using the scale below. The markers were: Very Much Improved; Much Improved; Slightly Improved; No Change; Slightly Worse; Much Worse; Very Much Worse. The CGIC response/score, recorded at each visit, was summarized, on both a categorical and continuous scale, by treatment group. The scores at the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed were analyzed using ordinal logistic regression. |
Countries
Australia, Israel, Netherlands, Poland, Spain, United States
Participant flow
Recruitment details
A total of 43 sites screened participants and 38 sites (23 in the United States, 7 in Spain, 3 in Poland, 2 in Australia, 1 in Israel, and 2 in the Netherlands) randomized participants into the trial. Two sites selected (1 in Israel and 1 in the United States) did not screen any participants.
Pre-assignment details
To assess eligibility, participants, 2-18 years of age with Dravet syndrome had to be taking 1 or more antiepileptic drugs at a dose which had been stable; and medicated for epilepsy for at least 4 weeks were screened. A total of 285 participants were screened, of which 199 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| 10 mg/kg/Day GWP42003-P GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener \[sucralose\] and strawberry flavoring). The 10 mg/kg/day dose was defined as 50% of the 10 mg/kg/day dose. | 64 |
| 20 mg/kg/Day GWP42003-P GWP42003-P oral solution (100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener \[sucralose\] and strawberry flavoring). The 20 mg/kg/day dose was recommended by the DSMC after assessment of safety and pharmacokinetic data from Part A of study GWEP1332 (NCT02091206). | 69 |
| Placebo Control Excipients only. Participants were pooled from 2 placebo cohorts, half receiving 10 mg/kg/day dose-volume equivalent and half receiving 20 mg/kg/day dose-volume equivalent. | 65 |
| Total | 198 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 5 | 0 |
| Overall Study | Advised by medical monitor | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 |
| Overall Study | Withdrawn by investigator | 1 | 0 | 0 |
| Overall Study | Withdrawn by parent/guardian | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo Control | 20 mg/kg/Day GWP42003-P | 10 mg/kg/Day GWP42003-P |
|---|---|---|---|---|
| Age, Continuous | 9.343 Years STANDARD_DEVIATION 4.3626 | 9.617 Years STANDARD_DEVIATION 4.5757 | 9.245 Years STANDARD_DEVIATION 4.3792 | 9.169 Years STANDARD_DEVIATION 4.1744 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 4 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 4 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 11 Participants | 1 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 176 Participants | 55 Participants | 66 Participants | 55 Participants |
| Region of Enrollment Australia | 13 participants | 3 participants | 4 participants | 6 participants |
| Region of Enrollment Israel | 3 participants | 2 participants | 1 participants | 0 participants |
| Region of Enrollment Netherlands | 25 participants | 9 participants | 7 participants | 9 participants |
| Region of Enrollment Poland | 25 participants | 6 participants | 11 participants | 8 participants |
| Region of Enrollment Spain | 39 participants | 13 participants | 14 participants | 12 participants |
| Region of Enrollment United States | 93 participants | 32 participants | 32 participants | 29 participants |
| Sex: Female, Male Female | 104 Participants | 34 Participants | 32 Participants | 38 Participants |
| Sex: Female, Male Male | 94 Participants | 31 Participants | 37 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 69 | 0 / 65 |
| other Total, other adverse events | 56 / 64 | 60 / 69 | 58 / 65 |
| serious Total, serious adverse events | 13 / 64 | 17 / 69 | 10 / 65 |
Outcome results
Primary
Change In Convulsive Seizures During The Treatment Period Compared To Baseline
Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an interactive voice response system (IVRS) diary. The primary endpoint was analyzed using negative binomial regression on the sum of the convulsive seizure counts during the treatment period, based on the ITT analysis set. Baseline included all available data prior to Day 1. Data reported as the ratio of geometric least squares mean in convulsive seizures and expressed as a percentage reduction.
Time frame: Baseline to Day 99 or Early Termination (ET)
Population: Intention-to-treat (ITT) analysis set: All participants who were randomized and dosed in the trial and had post-baseline efficacy data.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| 10 mg/kg/Day GWP42003-P | Change In Convulsive Seizures During The Treatment Period Compared To Baseline | 48.7 percentage reduction |
| 20 mg/kg/Day GWP42003-P | Change In Convulsive Seizures During The Treatment Period Compared To Baseline | 45.7 percentage reduction |
| Placebo Control | Change In Convulsive Seizures During The Treatment Period Compared To Baseline | 26.9 percentage reduction |
Comparison: Model includes total number of seizures as a response variable and age group, time (baseline and treatment period), treatment, and treatment by time interaction as fixed effects, and participant as a random effect. Log-transformed number of days in which seizures were reported by period is included as an offset. Null hypothesis was that the ratio of GWP42003-P to placebo would be 1.p-value: 0.029995% CI: [0.568, 0.971]Negative binomial regression
Comparison: Model includes total number of seizures as a response variable and age group, time (baseline and treatment period), treatment, and treatment by time interaction as fixed effects, and participant as a random effect. Log-transformed number of days in which seizures were reported by period is included as an offset. Null hypothesis was that the ratio of GWP42003-P to placebo would be 1.p-value: 0.009595% CI: [0.538, 0.916]Negative binomial regression
Secondary
Caregiver Global Impression Of Change (CGIC) At The Last Visit
On Day 1 (prior to receiving study drug), the caregiver was asked to write a brief description of the participant's overall condition as a memory aid for the CGIC questionnaire at subsequent visits. The CGIC questionnaire comprised the following question, to be rated on a 7-point scale: Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment) using the scale below. The markers were: Very Much Improved; Much Improved; Slightly Improved; No Change; Slightly Worse; Much Worse; Very Much Worse. The CGIC response/score, recorded at each visit, was summarized, on both a categorical and continuous scale, by treatment group. The scores at the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed were analyzed using ordinal logistic regression.
Time frame: Baseline to Last Visit
Population: Intention-to-treat (ITT) analysis set: All participants who were randomized and dosed in the trial and had post-baseline efficacy data.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 10 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Much Improved | 11 Participants |
| 10 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Slightly Worse | 2 Participants |
| 10 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | No Change | 18 Participants |
| 10 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Very Much Improved | 13 Participants |
| 10 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Very Much Worse | 0 Participants |
| 10 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Much Worse | 1 Participants |
| 10 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Slightly Improved | 21 Participants |
| 20 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | No Change | 17 Participants |
| 20 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Very Much Improved | 11 Participants |
| 20 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Much Improved | 10 Participants |
| 20 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Slightly Improved | 19 Participants |
| 20 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Slightly Worse | 5 Participants |
| 20 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Much Worse | 3 Participants |
| 20 mg/kg/Day GWP42003-P | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Very Much Worse | 1 Participants |
| Placebo Control | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Slightly Worse | 4 Participants |
| Placebo Control | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Much Improved | 8 Participants |
| Placebo Control | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Very Much Worse | 0 Participants |
| Placebo Control | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Much Worse | 2 Participants |
| Placebo Control | Caregiver Global Impression Of Change (CGIC) At The Last Visit | No Change | 32 Participants |
| Placebo Control | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Slightly Improved | 18 Participants |
| Placebo Control | Caregiver Global Impression Of Change (CGIC) At The Last Visit | Very Much Improved | 1 Participants |
p-value: 0.027995% CI: [1.08, 3.78]Regression, Logistic
p-value: 0.000995% CI: [1.56, 5.53]Regression, Logistic
Secondary
Change In Total Seizures During The Treatment Period Compared To Baseline
Total seizures were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic seizures. Non-convulsive seizures were defined as myoclonic, countable partial, other partial, or absence seizures. Participants or their caregivers recorded the number and type of convulsive seizures and non-convulsive seizures each day from screening until completion of dosing using an IVRS diary. Change compared to baseline was calculated as per the primary outcome measure. Data reported as the ratio of geometric least squares mean in total seizures and expressed as a percentage reduction.
Time frame: Baseline to Day 99 or ET
Population: Intention-to-treat (ITT) analysis set: All participants who were randomized and dosed in the trial and had post-baseline efficacy data.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| 10 mg/kg/Day GWP42003-P | Change In Total Seizures During The Treatment Period Compared To Baseline | 56.4 percentage reduction |
| 20 mg/kg/Day GWP42003-P | Change In Total Seizures During The Treatment Period Compared To Baseline | 47.3 percentage reduction |
| Placebo Control | Change In Total Seizures During The Treatment Period Compared To Baseline | 29.7 percentage reduction |
Comparison: Model includes total number of seizures as a response variable and age group, time (baseline and treatment period), treatment, and treatment by time interaction as fixed effects, and participant as a random effect. Log-transformed number of days in which seizures were reported by period is included as an offset.p-value: 0.025595% CI: [0.581, 0.965]Negative binomial regression
Comparison: Model includes total number of seizures as a response variable and age group, time (baseline and treatment period), treatment, and treatment by time interaction as fixed effects, and participant as a random effect. Log-transformed number of days in which seizures were reported by period is included as an offset.p-value: 0.000395% CI: [0.481, 0.799]Negative binomial regression
Secondary
Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period
Convulsive seizures were defined as tonic-clonic, tonic, clonic, or atonic. Participants or their caregivers recorded the number and type of convulsive seizures each day from screening until completion of dosing using an IVRS diary. Baseline included all available data prior to Day 1 (28-day average). Percentage change from baseline was calculated as: (\[frequency during the treatment period - frequency during baseline\]/frequency during baseline) x 100. The frequency during each period was based on 28-day averages and calculated as: (number of seizures in the period/number of reported days in the IVRS period) x 28. Baseline included all available data prior to Day 1 (28-day average).
Time frame: Baseline to Day 99 or ET
Population: Intention-to-treat (ITT) analysis set: All participants who were randomized and dosed in the trial and had post-baseline efficacy data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg/kg/Day GWP42003-P | Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period | 29 Participants |
| 20 mg/kg/Day GWP42003-P | Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period | 33 Participants |
| Placebo Control | Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period | 17 Participants |
p-value: 0.006995% CI: [1.32, 5.7]Cochran-Mantel-Haenszel
p-value: 0.033295% CI: [1.06, 4.62]Cochran-Mantel-Haenszel