A Phase 3 interventional study of GWP42003-P 20 mg/kg/day Dose and Placebo control in Epilepsy and Dravet Syndrome, sponsored by Jazz Pharmaceuticals. Completed at 22 sites in 4 countries. Open to participants aged 2 Years to 18 Years. Per ClinicalTrials.gov, last updated 2022-09-28.
Sponsored by Jazz Pharmaceuticals · Phase 3, Interventional, and Treatment
To investigate the potential antiepileptic effects of cannabidiol (GWP42003-P) in children and young adults with Dravet syndrome.
GWEP1332 Part B recruited an entirely new group of participants than GWEP1332 Part A. Participants who failed the entry criteria for Part A were eligible to take part in Part B.
Part B was a 1:1 randomized, double-blind, placebo-controlled, 14-week comparison of GWP42003-P versus placebo. The aim of Part B was to assess the antiepileptic 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 in children and young adults.
Following the establishment of initial eligibility and baseline measurements, participants entered Part B and began a 28-day baseline observation period.
Eligible participants were then randomized to receive either GWP42003-P or placebo on a 1:1 basis and titrated up to the target dose that was identified in Part A (up to 20 milligrams [mg] per kilogram [kg] per day), which was confirmed following completion of Part A by an independent Data Safety Monitoring Committee who reviewed unblinded safety and pharmacokinetic data from Part A.
Participants received investigational medicinal product for 14 weeks, consisting of a titration period followed by a 12-week maintenance period.
Efficacy and safety were monitored at various clinic visits and via telephone. After 14 weeks of treatment, all participants were offered the option of entering an open label extension (OLE) study. Entry was within seven days of the final treatment visit. Participants who did not immediately enter the OLE study commenced a down-titration taper period lasting up to 10 days. The taper period was interrupted if the participant wished to enter the open label extension study within the seven-day timeframe.
For participants who opted not to enter the OLE study, a follow-up telephone call was made 28 days after the end of dosing and weekly safety telephone calls were made during the 28-day follow-up period.
87 studies on the registry are indexed under Epilepsies, Myoclonic; 23 are open to participants now.
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Key Inclusion Criteria:
Key Exclusion Criteria:
Participants received 20 mg/kg/day of GWP42003-P administered orally, half in the morning and half in the evening. Participants titrated GWP42003-P to 20 mg/kg/day over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day) period.
Drug: GWP42003-P 20 mg/kg/day Dose
Participants received placebo (0 mg/mL CBD), volume-matched to the 20 mg/kg/day dose level, administered orally, half in the morning and half in the evening. To maintain the blinded aspect of the study, participants titrated the placebo dose over 11 days and remained at this dose for the 12-week maintenance period. If the participant did not immediately enter the OLE study, the maintenance period was followed by a 10-day taper (10% per day of the matched dose) period.
Drug: Placebo control
GWP42003-P was an oral solution containing 100 mg/milliliter (mL) cannabidiol (CBD) dissolved in the excipients, sesame oil and anhydrous ethanol (79 mg/mL), with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).
Also known as: Cannabidiol, Epidiolex
Placebo oral solution contained the excipients, sesame oil and anhydrous ethanol (79 mg/mL), with added sweetener (0.5 mg/mL sucralose) and strawberry flavoring (0.2 mg/mL).
Also known as: Placebo
Percentage Change From Baseline In Convulsive Seizure Frequency During The Treatment Period
Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Percentage change from baseline was calculated as: (\[frequency during the treatment period - frequency during baseline\]/frequency during baseline) \* 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) \* 28. Baseline included all available data prior to Day 1 (28-day average). Negative percentages show an improvement from baseline.
Time frame: Baseline to End of Treatment (EOT) (Day 99) or Early Termination (ET)
Number Of Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period
Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.
Time frame: Baseline to EOT (Day 99) or ET
Number of Participants With A ≥25%, ≥75% Or 100% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period
Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.
Time frame: Baseline to EOT (Day 99) or ET
Percentage Change From Baseline In Non-Convulsive Seizure Frequency During The Treatment Period
Non-convulsive seizures (myoclonic, partial, or absence) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure. Only participants with non-convulsive seizures during the baseline period were included. Negative percentages show an improvement from baseline.
Time frame: Baseline to EOT (Day 99) or ET
Caregiver Global Impression Of Change In Seizure Duration (CGICSD)
Seizure duration was assessed qualitatively using the CGICSD. Caregivers were asked "Since the patient started treatment, please assess the average duration of the patient's seizures (comparing their condition now to their condition before treatment)"; responses included decrease, no change, or increase in average duration. For each seizure type, only participants with at least 1 seizure for the corresponding seizure type, reported at any time during the study, were included.
Time frame: Baseline to EOT (Day 99) or ET
Number Of Participants Using Rescue Medication
The use of rescue medication was recorded by the participant or caregiver using a paper diary.
Time frame: Baseline to EOT (Day 99) or ET
Number Of Participants With Inpatient Hospitalizations Due To Epilepsy
Inpatient hospitalizations due to epilepsy were recorded by the participant or caregiver and through the serious adverse events (SAE) reporting process.
Time frame: Baseline to Safety Follow-up (Day 137)
Change From Baseline In Sleep Disruption 0 To 10 Numerical Rating Scale (0 to 10 NRS) Score
The sleep disruption 0 to 10 NRS questionnaire was completed by the participant's caregiver. The caregiver was asked 'On a scale of '0 to 10', please indicate the number that best describes your child's sleep disruption in the last week.' The markers ranged from 0 = 'slept extremely well' to 10 = 'unable to sleep at all'. The change from baseline in the sleep disruption 0 to 10 numerical rating scale score was analyzed using an analysis of covariance (ANCOVA) model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. A negative change from baseline represents an improvement in sleep. Last visit for endpoints assessed at clinic visits was defined as the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed.
Time frame: Baseline to Last Visit (Day 99) or ET
Change From Baseline In Epworth Sleepiness Scale (ESS) Score
The ESS questionnaire was completed by the participant's caregiver. The change from baseline in the ESS score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6- to 2 years and 13 to 18 years) as covariates and treatment group as a fixed factor. The total score was the sum of the 8 item-scores and ranged from 0 to 24. A higher total score represents greater levels of daytime sleepiness.
Time frame: Baseline to Last Visit (Day 99) or ET
Change From Baseline In Quality Of Life In Childhood Epilepsy (QOLCE) Score
The QOLCE questionnaire was completed by the parent or caregiver of participants aged 4 years and above. The change from baseline in the overall quality of life score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. Zero represents the lowest or poorest category and 100 represents the highest level of functioning. The overall quality of life score was calculated by taking the mean of the subscale scores.
Time frame: Baseline to EOT (Day 99) or ET
Change From Baseline In Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Score
The Vineland-II scores (standard scores and adaptive levels for each adaptive behavior domain, the adaptive behavior composite, and the maladaptive behavior index score and level) were assessed by the participant's caregiver. Scores were analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years, and 13 to 18 years) as covariates and treatment group as a fixed factor. Higher scores represent greater levels of functioning except for the maladaptive behavior index, for which a negative change from baseline represents an improvement in condition.
Time frame: Baseline to Last Visit (Day 99) or ET
Caregiver Global Impression Of Change (CGIC)
The CGIC was used to assess the participant's overall condition on a 7-point scale using the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse" (1 = very much improved; 7 = very much worse). On Day 1 (prior to starting IMP), 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.
Time frame: Baseline to Last Visit (Day 99) or ET
| Milestone | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Started | 61 | 59 |
| Safety analysis set | 61 | 59 |
| Intention to treat (itt) analysis set | 61 | 59 |
| Completed | 52 | 56 |
| Not completed | 9 | 3 |
| Withdrew: Adverse event | 8 | 1 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: Withdrawal by subject | 0 | 1 |
| Withdrew: Withdrawn by the investigator | 1 | 0 |
Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an interactive voice response system (IVRS) diary. Percentage change from baseline was calculated as: (\[frequency during the treatment period - frequency during baseline\]/frequency during baseline) \* 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) \* 28. Baseline included all available data prior to Day 1 (28-day average). Negative percentages show an improvement from baseline.
| percent change | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Percentage Change From Baseline In Convulsive Seizure Frequency During The Treatment Period | -38.94 (-69.53 to -4.83) | -13.29 (-52.53 to 20.20) |
Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.
| Participants | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Number Of Participants With A ≥50% Reduction From Baseline In Convulsive Seizure Frequency During The Treatment Period | 26 | 16 |
Convulsive seizures (atonic, clonic, tonic, or tonic-clonic) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure.
| Participants | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| ≥25% Reduction | 38 | 26 |
| ≥75% Reduction | 14 | 7 |
| 100% Reduction | 3 | 0 |
Non-convulsive seizures (myoclonic, partial, or absence) were recorded by the participant or caregiver using an IVRS diary. Percentage change from baseline was calculated as per the primary outcome measure. Only participants with non-convulsive seizures during the baseline period were included. Negative percentages show an improvement from baseline.
| percent change | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Percentage Change From Baseline In Non-Convulsive Seizure Frequency During The Treatment Period | -40.16 (-92.1 to -3.6) | -34.69 (-97.5 to -0.7) |
Seizure duration was assessed qualitatively using the CGICSD. Caregivers were asked "Since the patient started treatment, please assess the average duration of the patient's seizures (comparing their condition now to their condition before treatment)"; responses included decrease, no change, or increase in average duration. For each seizure type, only participants with at least 1 seizure for the corresponding seizure type, reported at any time during the study, were included.
| Participants | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Tonic-Clonic Seizures — Decrease in average duration | 17 | 8 |
| Tonic-Clonic Seizures — No change in average duration | 32 | 31 |
| Tonic-Clonic Seizures — Increase in average duration | 0 | 2 |
| Tonic Seizures — Decrease in average duration | 4 | 2 |
| Tonic Seizures — No change in average duration | 8 | 12 |
| Tonic Seizures — Increase in average duration | 0 | 1 |
| Clonic Seizures — Decrease in average duration | 5 | 3 |
| Clonic Seizures — No change in average duration | 6 | 3 |
| Clonic Seizures — Increase in average duration | 0 | 1 |
| Atonic Seizures — Decrease in average duration | 2 | 2 |
| Atonic Seizures — No change in average duration | 1 | 3 |
| Atonic Seizures — Increase in average duration | 0 | 2 |
| Myoclonic Seizures — Decrease in average duration | 4 | 3 |
| Myoclonic Seizures — No change in average duration | 10 | 12 |
| Myoclonic Seizures — Increase in average duration | 0 | 3 |
| Countable Partial Seizures — Decrease in average duration | 5 | 2 |
| Countable Partial Seizures — No change in average duration | 7 | 9 |
| Countable Partial Seizures — Increase in average duration | 0 | 2 |
| Other Partial Seizures — Decrease in average duration | 0 | 3 |
| Other Partial Seizures — No change in average duration | 3 | 2 |
| Other Partial Seizures — Increase in average duration | 0 | 0 |
| Absence Seizures — Decrease in average duration | 4 | 6 |
| Absence Seizures — No change in average duration | 11 | 12 |
| Absence Seizures — Increase in average duration | 1 | 1 |
The use of rescue medication was recorded by the participant or caregiver using a paper diary.
| Participants | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Number Of Participants Using Rescue Medication | 36 | 41 |
Inpatient hospitalizations due to epilepsy were recorded by the participant or caregiver and through the serious adverse events (SAE) reporting process.
| participants | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Caregiver/participant-reported | 5 | 1 |
| Investigator-reported (serious TEAE) | 2 | 1 |
The sleep disruption 0 to 10 NRS questionnaire was completed by the participant's caregiver. The caregiver was asked 'On a scale of '0 to 10', please indicate the number that best describes your child's sleep disruption in the last week.' The markers ranged from 0 = 'slept extremely well' to 10 = 'unable to sleep at all'. The change from baseline in the sleep disruption 0 to 10 numerical rating scale score was analyzed using an analysis of covariance (ANCOVA) model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. A negative change from baseline represents an improvement in sleep. Last visit for endpoints assessed at clinic visits was defined as the last scheduled visit (not including the end of taper or safety follow-up visits) at which participant's last evaluation was performed.
| units on a scale | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Change From Baseline In Sleep Disruption 0 To 10 Numerical Rating Scale (0 to 10 NRS) Score | -0.7 (-1.5 to 0.1) | -0.3 (-1.1 to 0.5) |
The ESS questionnaire was completed by the participant's caregiver. The change from baseline in the ESS score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6- to 2 years and 13 to 18 years) as covariates and treatment group as a fixed factor. The total score was the sum of the 8 item-scores and ranged from 0 to 24. A higher total score represents greater levels of daytime sleepiness.
| units on a scale | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Change From Baseline In Epworth Sleepiness Scale (ESS) Score | 0.82 (-0.36 to 1.99) | -0.69 (-1.90 to 0.52) |
The QOLCE questionnaire was completed by the parent or caregiver of participants aged 4 years and above. The change from baseline in the overall quality of life score was analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years and 13 to 18 years) as covariates and treatment group as a fixed factor. Zero represents the lowest or poorest category and 100 represents the highest level of functioning. The overall quality of life score was calculated by taking the mean of the subscale scores.
| units on a scale | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Change From Baseline In Quality Of Life In Childhood Epilepsy (QOLCE) Score | 5.6 (1.9 to 9.3) | 4.1 (0.2 to 8.0) |
The Vineland-II scores (standard scores and adaptive levels for each adaptive behavior domain, the adaptive behavior composite, and the maladaptive behavior index score and level) were assessed by the participant's caregiver. Scores were analyzed using an ANCOVA model with baseline and age group (2 to 5 years, 6 to 12 years, and 13 to 18 years) as covariates and treatment group as a fixed factor. Higher scores represent greater levels of functioning except for the maladaptive behavior index, for which a negative change from baseline represents an improvement in condition.
| units on a scale | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Communication Domain Standard Score | -0.8 (-3.2 to 1.5) | 3.0 (0.8 to 5.3) |
| Daily Living Skills Domain Standard Score | -0.8 (-4.0 to 2.4) | -0.8 (-4.1 to 2.6) |
| Socialization Domain Standard Score | -0.6 (-4.6 to 3.5) | -0.6 (-4.0 to 2.7) |
| Motor Skills Domain Standard Score | -2.5 (-5.5 to 0.5) | 1.7 (-1.1 to 4.5) |
| Adaptive Behavior Composite Standard Score | -2.0 (-5.2 to 1.1) | 0.6 (-2.1 to 3.3) |
| Maladaptive Behavior Index v-Scale Score | -0.3 (-0.7 to 0.1) | -0.4 (-0.8 to 0.0) |
The CGIC was used to assess the participant's overall condition on a 7-point scale using the markers "very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse" (1 = very much improved; 7 = very much worse). On Day 1 (prior to starting IMP), 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.
| Participants | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Very Much Improved | 9 | 4 |
| Much Improved | 10 | 4 |
| Slightly Improved | 18 | 12 |
| No Change | 15 | 31 |
| Slightly Worse | 3 | 6 |
| Much Worse | 4 | 1 |
| Very Much Worse | 1 | 0 |
Collected over Day 1 (after dosing) to Day 137. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| GWP42003-P 20 mg/kg/Day Dose | — | 10/61 (16.4%) | 46/61 (75.4%) |
| Placebo | — | 3/59 (5.1%) | 28/59 (47.5%) |
| Event | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| Status epilepticusNervous system disorders | 3/61 | 3/59 |
| SomnolenceNervous system disorders | 3/61 | 0/59 |
| ConvulsionNervous system disorders | 2/61 | 1/59 |
| Respiratory failureRespiratory, thoracic and mediastinal disorders | 1/61 | 1/59 |
| Abdominal distensionGastrointestinal disorders | 1/61 | 0/59 |
| Abdominal painGastrointestinal disorders | 1/61 | 0/59 |
| Gastrointestinal haemorrhageGastrointestinal disorders | 1/61 | 0/59 |
| AstheniaGeneral disorders | 1/61 | 0/59 |
| FatigueGeneral disorders | 1/61 | 0/59 |
| Lower respiratory tract infectionInfections and infestations | 1/61 | 0/59 |
| Event | GWP42003-P 20 mg/kg/Day Dose | Placebo |
|---|---|---|
| DiarrhoeaGastrointestinal disorders | 19/61 | 6/59 |
| SomnolenceNervous system disorders | 19/61 | 6/59 |
| Decreased appetiteMetabolism and nutrition disorders | 16/61 | 3/59 |
| FatigueGeneral disorders | 11/61 | 2/59 |
| VomitingGastrointestinal disorders | 9/61 | 3/59 |
| PyrexiaGeneral disorders | 9/61 | 5/59 |
| Upper respiratory tract infectionInfections and infestations | 7/61 | 5/59 |
| LethargyNervous system disorders | 7/61 | 3/59 |
| ConvulsionNervous system disorders | 5/61 | 2/59 |
| Gamma-glutamyltransferase increasedInvestigations | 4/61 | 0/59 |
Safety Analysis Set: included all participants randomized to treatment who received at least 1 dose of IMP. Participants were analyzed according to the actual treatment they received.
| Age, Continuous(Years) | GWP42003-P 20 mg/kg/Day Dose | Placebo | Total |
|---|---|---|---|
| Mean | 9.736 ± 4.7309 | 9.779 ± 4.8505 | 9.757 ± 4.7699 |
| Sex: Female, Male(Participants) | GWP42003-P 20 mg/kg/Day Dose | Placebo | Total |
|---|---|---|---|
| Female | 26 | 32 | 58 |
| Male | 35 | 27 | 62 |
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