Tuberous Sclerosis Complex, Seizures
Conditions
Brief summary
This trial consists of 2 parts: a double-blinded phase and an open-label extension phase. The open-label extension phase only will be described in this record. All participants will receive the same dose of GWP42003-P. However, investigators may subsequently decrease or increase the participant's dose until the optimal dose is found.
Interventions
DRUGGWP42003-P
Yellow oily solution containing cannabidiol dissolved in the excipients sesame oil and anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring.
Sponsors
GW Pharmaceuticals Ltd
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Completion of the GWEP1521 Blinded Phase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | OLE Day 1 up to 4 years | An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE that started, or worsened in severity or seriousness, following the first dose of IMP was considered a TEAE. A serious AE was defined as any AE that results in any of the following outcomes: death, life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or cancer, any other experience that suggests a significant hazard, contraindication, side effect or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above, or an event that changes the risk/benefit ratio of the study. |
| Number of Participants With Any TEAE, by Severity | OLE Day 1 up to 4 years | An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE that started, or worsened in severity or seriousness, following the first dose of IMP was considered a TEAE. Grade 1 (Mild) is defined as asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate) is defined as minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living (ADL). Grade 3 (Severe) is defined as medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Number of TSC-associated Seizures During the OLE Treatment Period | OLE Day 1 up to 4 years | TSC-associated seizures include: focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; focal seizures evolving to bilateral generalized convulsive seizures and tonic-clonic, tonic, clonic or atonic seizures. A negative percent change from baseline indicates improvement. |
| Number of Participants Considered Treatment Responders During the OLE Treatment Period | OLE Day 1 up to 4 years | Treatment responders were defined as those participants with a ≥50% reduction from baseline in TSC-associated seizure frequency, during the treatment period, for participants who had not withdrawn from the trial during the treatment period. 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 were countable. Participants who withdrew from the trial during the treatment period were considered non-responders. |
| Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period | OLE Day 1 and up to 4 years | 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). The average CGIC and SGIC scores are being reported, with higher values indicating worse condition. |
| Percent Change From Baseline in Total Seizure Frequency During the OLE Treatment Period | OLE Day 1 up to 4 years | Total seizures included all seizure types, eg. combination of TSC-associated and other seizures. 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 were countable. A negative percent change from baseline indicates improvement in total seizure frequency. |
Countries
United States
Participant flow
Recruitment details
A total of 199 participants with tuberous sclerosis complex (TSC) who met all inclusion criteria and no exclusion criteria and completed the double-blind study GWEP1521 (NCT02544763) were enrolled into this Open-label Extension (OLE) study to receive GWP42003-P.
Pre-assignment details
OLE investigational medicinal product (IMP) was titrated up to 25 mg/kg/day while blinded IMP was simultaneously tapered down to zero to accommodate those participants who had been randomized to placebo during the double-blind phase (DBP) of the study. All participants were to complete the transition and enter the OLE taking 25 mg/kg/day GWP42003-P.
Participants by arm
| Arm | Count |
|---|---|
| GWP42003-P (Double-blind Phase) Participants who had received GWP42003-P during the double-blind phase and then GWP42003-P in the OLE phase. | 124 |
| Placebo (Double-blind Phase) Participants who had received placebo during the double-blind phase and then GWP42003-P in the OLE phase. | 75 |
| Total | 199 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 10 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Met withdrawal criteria | 2 | 2 |
| Overall Study | Other reasons | 69 | 39 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Transition To Commercial Product | 1 | 0 |
| Overall Study | Withdrawal by Parent/Guardian | 8 | 7 |
| Overall Study | Withdrawal by Subject | 10 | 4 |
Baseline characteristics
| Characteristic | GWP42003-P (Double-blind Phase) | Placebo (Double-blind Phase) | Total |
|---|---|---|---|
| Age, Continuous | 12.69 years STANDARD_DEVIATION 9.64 | 13.92 years STANDARD_DEVIATION 10.63 | 13.15 years STANDARD_DEVIATION 10.02 |
| Baseline Total Seizures | 59.95 Seizures | 56.97 Seizures | 58.90 Seizures |
| Baseline Tuberous Sclerosis Complex (TSC)-Associated Seizures | 58.08 Seizures | 55.10 Seizures | 56.90 Seizures |
| Race/Ethnicity, Customized American Indian/Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Black/African American | 4 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 6 Participants | 13 Participants |
| Race/Ethnicity, Customized White/Caucasian | 111 Participants | 66 Participants | 177 Participants |
| Sex: Female, Male Female | 51 Participants | 30 Participants | 81 Participants |
| Sex: Female, Male Male | 73 Participants | 45 Participants | 118 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 124 | 0 / 75 |
| other Total, other adverse events | 117 / 124 | 75 / 75 |
| serious Total, serious adverse events | 38 / 124 | 18 / 75 |
Outcome results
Primary
Number of Participants With Any TEAE, by Severity
An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE that started, or worsened in severity or seriousness, following the first dose of IMP was considered a TEAE. Grade 1 (Mild) is defined as asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate) is defined as minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living (ADL). Grade 3 (Severe) is defined as medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL.
Time frame: OLE Day 1 up to 4 years
Population: Adverse events were assessed in the OLE Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GWP42003-P (Double-blind Phase) | Number of Participants With Any TEAE, by Severity | Mild TEAE | 35 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants With Any TEAE, by Severity | Moderate TEAE | 63 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants With Any TEAE, by Severity | Severe TEAE | 19 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any TEAE, by Severity | Mild TEAE | 16 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any TEAE, by Severity | Moderate TEAE | 48 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any TEAE, by Severity | Severe TEAE | 11 Participants |
Primary
Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE)
An adverse event (AE) was defined as any new unfavorable/unintended signs/symptoms (including abnormal laboratory findings), or diagnosis or worsening of a pre-existing condition, which occurred following screening and at any point up to the post-treatment safety follow-up visit, which may or may not be related to the IMP. An AE that started, or worsened in severity or seriousness, following the first dose of IMP was considered a TEAE. A serious AE was defined as any AE that results in any of the following outcomes: death, life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or cancer, any other experience that suggests a significant hazard, contraindication, side effect or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above, or an event that changes the risk/benefit ratio of the study.
Time frame: OLE Day 1 up to 4 years
Population: Adverse events were assessed in the OLE Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GWP42003-P (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any TEAE | 117 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any treatment-related TEAE | 80 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any treatment-related TEAE leading to permanent discontinuation of IMP | 9 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any serious TEAE | 38 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any treatment-related serious TEAE | 7 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any fatal TEAEs | 1 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any TEAE leading to permanent discontinuation of IMP | 11 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any TEAE | 75 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any treatment-related serious TEAE | 8 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any treatment-related TEAE | 60 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any TEAE leading to permanent discontinuation of IMP | 7 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any treatment-related TEAE leading to permanent discontinuation of IMP | 7 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any fatal TEAEs | 0 Participants |
| Placebo (Double-blind Phase) | Number of Participants With Any Treatment-emergent Adverse Events, Discontinuations Due to AEs, Serious AEs, and Treatment-related AEs (TEAE) | Any serious TEAE | 18 Participants |
Secondary
Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period
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). The average CGIC and SGIC scores are being reported, with higher values indicating worse condition.
Time frame: OLE Day 1 and up to 4 years
Population: Caregiver Global Impression of Change and Subject Global Impression of Change were assessed in the OLE Safety Analysis Set in participants with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GWP42003-P (Double-blind Phase) | Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period | Subjects | 4.0 score on a scale | Standard Deviation 0 |
| GWP42003-P (Double-blind Phase) | Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period | Combined Caregiver and Subjects | 3.2 score on a scale | Standard Deviation 1.56 |
| GWP42003-P (Double-blind Phase) | Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period | Caregiver | 3.2 score on a scale | Standard Deviation 1.58 |
| Placebo (Double-blind Phase) | Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period | Subjects | 2.7 score on a scale | Standard Deviation 1.53 |
| Placebo (Double-blind Phase) | Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period | Combined Caregiver and Subjects | 3.3 score on a scale | Standard Deviation 1.16 |
| Placebo (Double-blind Phase) | Caregiver Global Impression of Change (CGIC) and Subject Global Impression of Change (SGIC) Score During the OLE Treatment Period | Caregiver | 3.4 score on a scale | Standard Deviation 1.12 |
Secondary
Number of Participants Considered Treatment Responders During the OLE Treatment Period
Treatment responders were defined as those participants with a ≥50% reduction from baseline in TSC-associated seizure frequency, during the treatment period, for participants who had not withdrawn from the trial during the treatment period. 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 were countable. Participants who withdrew from the trial during the treatment period were considered non-responders.
Time frame: OLE Day 1 up to 4 years
Population: Treatment responders were assessed in the OLE Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GWP42003-P (Double-blind Phase) | Number of Participants Considered Treatment Responders During the OLE Treatment Period | ≥ 50% reduction: Yes | 70 Participants |
| GWP42003-P (Double-blind Phase) | Number of Participants Considered Treatment Responders During the OLE Treatment Period | ≥ 50% reduction: No | 54 Participants |
| Placebo (Double-blind Phase) | Number of Participants Considered Treatment Responders During the OLE Treatment Period | ≥ 50% reduction: Yes | 36 Participants |
| Placebo (Double-blind Phase) | Number of Participants Considered Treatment Responders During the OLE Treatment Period | ≥ 50% reduction: No | 39 Participants |
Secondary
Percent Change From Baseline in the Number of TSC-associated Seizures During the OLE Treatment Period
TSC-associated seizures include: focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; focal seizures evolving to bilateral generalized convulsive seizures and tonic-clonic, tonic, clonic or atonic seizures. A negative percent change from baseline indicates improvement.
Time frame: OLE Day 1 up to 4 years
Population: TSC-associated seizures were assessed in the OLE Safety Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GWP42003-P (Double-blind Phase) | Percent Change From Baseline in the Number of TSC-associated Seizures During the OLE Treatment Period | -55.66 percent change |
| Placebo (Double-blind Phase) | Percent Change From Baseline in the Number of TSC-associated Seizures During the OLE Treatment Period | -46.76 percent change |
Secondary
Percent Change From Baseline in Total Seizure Frequency During the OLE Treatment Period
Total seizures included all seizure types, eg. combination of TSC-associated and other seizures. 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 were countable. A negative percent change from baseline indicates improvement in total seizure frequency.
Time frame: OLE Day 1 up to 4 years
Population: Total seizure frequency was assessed in the OLE Safety Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GWP42003-P (Double-blind Phase) | Percent Change From Baseline in Total Seizure Frequency During the OLE Treatment Period | -55.18 percent change |
| Placebo (Double-blind Phase) | Percent Change From Baseline in Total Seizure Frequency During the OLE Treatment Period | -46.76 percent change |