Tuberous Sclerosis Complex, Seizures
Conditions
Brief summary
This trial consists of 2 parts: a double-blinded phase and an open-label extension phase. The blinded phase only will be described in this record. Participants will receive 1 of 2 doses of GWP42003-P or matching placebo. The primary clinical hypothesis is that there will be a difference between GWP42003-P and placebo in their effect on seizure frequency.
Interventions
DRUGGWP42003-P
Yellow oily solution containing cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.
DRUGPlacebo
Yellow oily solution containing the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.
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
1 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participant has a well-documented clinical history of epilepsy. * Participant has a clinical diagnosis of Tuberous Sclerosis Complex (TSC) according to the criteria agreed by the 2012 International TSC Consensus Conference. * All medications or interventions for epilepsy (including ketogenic diet and any neurostimulation devices for epilepsy) must have been stable for 1 month prior to screening and the participant is willing to maintain a stable regimen throughout the trial. Key
Exclusion criteria
* Participant has a history of pseudo-seizures. * Participant has clinically significant unstable medical conditions other than epilepsy. * Participant has an illness in the 4 weeks prior to screening or randomization, other than epilepsy, which in the opinion of the investigator could affect seizure frequency. * Participant has undergone general anesthetic in the 4 weeks prior to screening or randomization. * Participant has undergone surgery for epilepsy in the 6 months prior to screening. * Participant is being considered for epilepsy surgery or any procedure involving general anesthesia. * Participant has been taking felbamate for less than 1 year prior to screening. * Participant is taking an oral mTOR inhibitor. * Participant has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the Investigational Medicinal Product (IMP), such as sesame oil. * Participant has any history of suicidal behavior or any suicidal ideation of type 4 or 5 on the C-SSRS in the last month or at screening. * Participant is currently using or has in the past used recreational or medicinal cannabis, or cannabinoid-based medications, within the 3 months prior to screening and is unwilling to abstain for the duration for the study. * Participant has tumor growth which, in the opinion of the Investigator, could affect the primary endpoint. * Participant has significantly impaired hepatic function at the screening or randomization visit * Participant has received an IMP within the 12 weeks prior to the screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the Treatment Period (Maintenance and Titration) | Baseline; up to Week 16 | TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration) | Baseline; up to Week 16 | Treatment responders are defined as those participants with a ≥ 50% reduction in TSC-associated seizure frequency. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Participants who withdrew from the trial during the treatment period are considered non-responders. |
| Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Baseline; up to Week 16 | The combined caregiver and participant summary uses either the caregiver or participant version if only one version was completed, or the caregiver version if both caregiver and participant versions were completed. The CGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment). The SGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): Since you started treatment, please assess the status of your overall condition (comparing your condition now to your condition before treatment). |
| Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration) | Baseline; up to Week 16 | Total seizures included all seizure types combined. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100. |
| Number of Participants With Any Severe Treatment-emergent Adverse Event (TEAE) | up to approximately Week 22 | A TEAE was defined as an AE with a start date on or after the first dose of IMP during the Blinded Phase up to and including the date of first dose of the Open-label Extension (OLE) Phase (OLE Day 1). |
Countries
Australia, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 255 participants were screened; 31 of whom were screen failures. A total of 224 participants were randomized to double-blind treatment.
Participants by arm
| Arm | Count |
|---|---|
| GWP42003-P 25 mg/kg/Day Participants were randomized to receive GWP42003-P 25 milligrams per kilogram per day (mg/kg/day) (via oral twice daily \[morning and evening\] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks. | 75 |
| GWP42003-P 50 mg/kg/Day Participants were randomized to receive GWP42003-P 50 mg/kg/day (via oral twice daily \[morning and evening\] administration). Participants completed a 4-week dose escalation period, titrating up to their assigned dose, before continuing on a stable dose of blinded GWP42003-P for 12 weeks. | 73 |
| Placebo Participants were randomized to receive placebo matched to GWP42003-P (via oral twice daily \[morning and evening\] administration) for 16 weeks. | 76 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 8 | 0 |
| Overall Study | Difficulties taking IMP | 1 | 0 | 0 |
| Overall Study | Met withdrawal criteria | 0 | 2 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawn by parent/guardian | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | GWP42003-P 25 mg/kg/Day | GWP42003-P 50 mg/kg/Day | Placebo |
|---|---|---|---|---|
| Age, Continuous | 13.659 years STANDARD_DEVIATION 10.0324 | 14.112 years STANDARD_DEVIATION 10.8131 | 12.915 years STANDARD_DEVIATION 8.5324 | 13.918 years STANDARD_DEVIATION 10.6302 |
| Number of Total Seizures | 102.44 seizures STANDARD_DEVIATION 148.495 | 80.87 seizures STANDARD_DEVIATION 84.676 | 108.06 seizures STANDARD_DEVIATION 115.699 | 118.32 seizures STANDARD_DEVIATION 211.868 |
| Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures | 86.66 seizures STANDARD_DEVIATION 91.841 | 77.95 seizures STANDARD_DEVIATION 83.39 | 92.95 seizures STANDARD_DEVIATION 89.782 | 89.22 seizures STANDARD_DEVIATION 101.778 |
| Race/Ethnicity, Customized American Indian/Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Anglo Indian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Arabic | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Biracial Causasian-African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black/African American | 5 Participants | 2 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Black, White, American Indian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian/Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 4 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic And Caucasian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Latin | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White/Caucasian | 199 Participants | 68 Participants | 65 Participants | 66 Participants |
| Sex: Female, Male Female | 93 Participants | 32 Participants | 30 Participants | 31 Participants |
| Sex: Female, Male Male | 129 Participants | 43 Participants | 42 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 73 | 0 / 76 |
| other Total, other adverse events | 66 / 75 | 71 / 73 | 68 / 76 |
| serious Total, serious adverse events | 16 / 75 | 10 / 73 | 2 / 76 |
Outcome results
Primary
Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the Treatment Period (Maintenance and Titration)
TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100.
Time frame: Baseline; up to Week 16
Population: Intent-to-Treat (ITT) Analysis Set: all participants who were randomized and dosed with investigational medicinal product (IMP) in the trial and had post-Baseline efficacy data. Participant data were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GWP42003-P 25 mg/kg/Day | Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the Treatment Period (Maintenance and Titration) | -43.36 percent change |
| GWP42003-P 50 mg/kg/Day | Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the Treatment Period (Maintenance and Titration) | -36.55 percent change |
| Placebo | Percent Change From Baseline in the Number of Tuberous Sclerosis Complex (TSC)-Associated Seizures During the Treatment Period (Maintenance and Titration) | -20.08 percent change |
95% CI: [40.4, 55.8]
95% CI: [39, 54.8]
95% CI: [14.9, 36.5]
p-value: =0.000995% CI: [0.567, 0.861]Mixed Models Analysis
p-value: =0.001895% CI: [0.58, 0.881]Mixed Models Analysis
Secondary
Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit
The combined caregiver and participant summary uses either the caregiver or participant version if only one version was completed, or the caregiver version if both caregiver and participant versions were completed. The CGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): Since your child started treatment, please assess the status of your child's overall condition (comparing their condition now to their condition before treatment). The SGIC comprised the following question, to be rated on a 7-point scale (1, Very Much Improved; 2, Much Improved; 3, Slightly Improved; 4, No Change; 5, Slightly Worse; 6, Much Worse; 7, Very Much Worse): Since you started treatment, please assess the status of your overall condition (comparing your condition now to your condition before treatment).
Time frame: Baseline; up to Week 16
Population: ITT Analysis Set. Only participants with available data were analyzed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GWP42003-P 25 mg/kg/Day | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Participant | 3.3 units on a scale | Standard Deviation 1.51 |
| GWP42003-P 25 mg/kg/Day | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Combined Caregiver and Participant | 3.0 units on a scale | Standard Deviation 1.35 |
| GWP42003-P 25 mg/kg/Day | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Caregiver | 3.0 units on a scale | Standard Deviation 1.34 |
| GWP42003-P 50 mg/kg/Day | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Combined Caregiver and Participant | 3.2 units on a scale | Standard Deviation 1.45 |
| GWP42003-P 50 mg/kg/Day | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Caregiver | 3.1 units on a scale | Standard Deviation 1.4 |
| GWP42003-P 50 mg/kg/Day | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Participant | 4.5 units on a scale | Standard Deviation 1.73 |
| Placebo | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Caregiver | 3.5 units on a scale | Standard Deviation 0.93 |
| Placebo | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Participant | 2.8 units on a scale | Standard Deviation 1.26 |
| Placebo | Change From Baseline in the Caregiver Global Impression of Change (CGIC) or Participant Global Impression of Change (PGIC) Score at the Participant's Last Visit | Combined Caregiver and Participant | 3.5 units on a scale | Standard Deviation 0.96 |
p-value: =0.007495% CI: [1.24, 4.07]nominal
p-value: =0.05895% CI: [0.98, 3.2]nominal
Secondary
Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration)
Treatment responders are defined as those participants with a ≥ 50% reduction in TSC-associated seizure frequency. TSC-associated seizures included: focal motor seizures without impairment of consciousness or awareness (Type 1 focal motor); focal seizures with impairment of consciousness or awareness (Type 2 focal); focal seizures evolving to bilateral generalized convulsive seizures (Type 3 focal); and tonic-clonic, tonic, clonic, or atonic seizures that are countable. Participants who withdrew from the trial during the treatment period are considered non-responders.
Time frame: Baseline; up to Week 16
Population: ITT Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GWP42003-P 25 mg/kg/Day | Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration) | Non-responders | 48 Participants |
| GWP42003-P 25 mg/kg/Day | Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration) | Responders | 27 Participants |
| GWP42003-P 50 mg/kg/Day | Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration) | Non-responders | 44 Participants |
| GWP42003-P 50 mg/kg/Day | Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration) | Responders | 29 Participants |
| Placebo | Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration) | Responders | 17 Participants |
| Placebo | Number of Participants Considered Treatment Responders During the Treatment Period (Maintenance and Titration) | Non-responders | 59 Participants |
p-value: =0.069295% CI: [0.95, 4]Cochran-Mantel-Haenszel
p-value: =0.024595% CI: [1.12, 4.67]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Any Severe Treatment-emergent Adverse Event (TEAE)
A TEAE was defined as an AE with a start date on or after the first dose of IMP during the Blinded Phase up to and including the date of first dose of the Open-label Extension (OLE) Phase (OLE Day 1).
Time frame: up to approximately Week 22
Population: Safety Analysis Set: all participants randomized to treatment who received at least 1 dose of IMP
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GWP42003-P 25 mg/kg/Day | Number of Participants With Any Severe Treatment-emergent Adverse Event (TEAE) | 7 Participants |
| GWP42003-P 50 mg/kg/Day | Number of Participants With Any Severe Treatment-emergent Adverse Event (TEAE) | 9 Participants |
| Placebo | Number of Participants With Any Severe Treatment-emergent Adverse Event (TEAE) | 1 Participants |
Secondary
Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration)
Total seizures included all seizure types combined. Percent change from Baseline was calculated as the (post-Baseline value minus the Baseline value) divided by the Baseline value x 100.
Time frame: Baseline; up to Week 16
Population: ITT Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GWP42003-P 25 mg/kg/Day | Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration) | -34.71 percent change | Standard Deviation 46.15 |
| GWP42003-P 50 mg/kg/Day | Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration) | -35.14 percent change | Standard Deviation 42.53 |
| Placebo | Percent Change From Baseline in Total Seizures During the Treatment Period (Maintenance and Titration) | -19.63 percent change | Standard Deviation 35.137 |
95% CI: [0.447, 0.602]
95% CI: [0.452, 0.607]
95% CI: [0.632, 0.846]
p-value: =0.001395% CI: [0.576, 0.873]Mixed Models Analysis
p-value: =0.001895% CI: [0.582, 0.882]Mixed Models Analysis