Assessment of Adjunctive Cannabidiol Oral Solution (GWP42003-P) in Children With Tuberous Sclerosis Complex (TSC), Dravet Syndrome (DS), or Lennox-Gastaut Syndrome (LGS) Who Experience Inadequately-controlled Seizures

The study duration will be up to approximately 62 weeks, including a 4-week screening/baseline period, a 52-week dose optimization treatment period (which includes a fixed 2-week titration period followed by flexible dose optimization), a 10-day taper period, and a safety follow-up period (4 weeks after the end-of-taper visit).

• GWP42003-P (Drug), also known as Cannabidiol, Epidiolex, Epidyolex: Oral Solution

Primary outcomes

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [From start of treatment to the post-treatment safety follow-up visit, up to 62 weeks]
• Mean Change From Baseline in Blood Pressure [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in Pulse Rate [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in Respiratory Rate [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in Body Temperature [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in Height [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in Body Weight [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in Heart Rate [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in RR Interval [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in PR Interval [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in QRS Duration [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in QT Interval [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Mean Change From Baseline in QTcB and QTcF [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Number of Participants With a Clinically Significant Change in Laboratory Parameters [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Number of Participants With Emergence of New Types of Seizures [From baseline up to the end of taper follow-up visit (Visit 20), up to 62 weeks]
• Plasma Concentrations of GWP42003-P and Its Major Metabolites [Predose, 3 hours and 6 hours post dose at End of Treatment (Week 52)]
• Number of Participants Based on Percentage Change From Baseline in Indication-Specific Total Countable Seizures as Recorded by Caregivers [Day 1 up to Taper Period, up to Week 52]
• Clinician Global Impression of Severity (CGI/S) Score [At Day 365 (EOT)]: The CGIC/S is a comprehensive neurodevelopmental assessment that covers the following domains: sensory, motor, cognition, emotional/behavioral health, communication, social, and adaptive functioning. This assessment is a 2-question survey per domain to be completed by the clinician. Individual domain scores are reported. The severity of impairment in each domain is rated by the clinician in a scale of 1 through 7 where 1 = Normal, not at all ill; 2 = Borderline ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Among the most extremely ill. Higher scores indicate poor clinical outcome.
• Clinician Global Impression of Change (CGI/C) Score [At Day 365 (EOT)]: The CGI/C is a comprehensive neurodevelopmental assessment that covers the following domains: sensory, motor, cognition, emotional/behavioral health, communication, social, and adaptive functioning. This assessment is a 2-question survey per domain to be completed by the clinician. Individual domain scores are reported. The severity of impairment in each domain is rated by the clinician in a scale of 1 through 7 where 1 = Normal, not at all ill; 2 = Borderline ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Among the most extremely ill. Higher scores indicate poor clinical outcome.

Secondary outcomes

• Number of Treatment Responders [Day 1 up to the taper period, up to Week 52]: Treatment Responders are defined as participants with ≥ 50% reduction from baseline in caregiver-reported total countable seizures
• Number of Participants Who Achieved Seizure-Free Status [Week 12, and every 4 weeks thereafter, up to date of withdrawal or Week 24, whichever occurs first]
• Percentage of Participants Still Receiving GWP42003-P [Week 12, and every 4 weeks thereafter, up to date of withdrawal or Week 24, whichever occurs first]

Other outcomes

• Infant and Toddler Quality of Life Questionnaire Short Form 47 (ITQOL-47) Score [At Day 365 (EOT)]: The Infant and Toddler Quality of Life Questionnaire Short Form 47 (ITQOL-47) was developed for use in infants and toddlers from 12-months-to-5 years of age and assesses levels of health and well-being. The caregiver will complete the assessment on an electronic device. For each concept, item responses are scored, summed, and transformed on a scale from 0 (worst health) to 100 (best health). Higher scores indicate better clinical outcome.
• Percentage Change From Baseline in Indication-Specific Seizure Frequency As Recorded by Caregivers [Day 1 up to Taper Period, up to Week 52]

Sex: All, ages: 1 Month to 23 Months

Key Inclusion Criteria:

* Participants with TSC (1 month to < 2 years of age), or DS (1 year to < 2 years of age), or LGS (1 year to < 2 years of age) within the specified age range at the time of initial informed consent.
* Parent(s)/legal representative is/are willing and able to give informed consent for participation in the study.
* Parent(s)/legal representative is/are willing and able (in the investigator's opinion) to comply with all study requirements (including accurate electronic participant-reported outcome \[ePRO\] diary completion).
* Participants with TSC must have a diagnosis per the 2012 International Tuberous Sclerosis Complex Consensus Conference. Participants with LGS or DS must have a diagnosis that is consistent with International League Against Epilepsy (ILAE) guidelines and confirmed by the Epilepsy Study Consortium (ESCI).
* Participants who have uncontrolled seizures, and who are currently receiving 1 or more antiseizure medication (ASMs).
* A suitable VEEG, as available in the medical record, within 1 year of Visit 1. When a historical VEEG is not available, and if clinically indicated and appropriate (due to uncertainties or new seizures), a VEEG will be completed and read to confirm diagnosis prior to Visit 3. All VEEGs are to be read at baseline by the investigator and by an independent reviewer.
* Has seizures which are not adequately controlled through their current ASMs, defined as ≥ 1 seizure reported on the seizure diary during the screening/baseline period

Key Exclusion Criteria:

* Has tumor growth which, in the opinion of the investigator, could affect participant safety.
* Has clinically significant abnormal laboratory values, in the investigator's opinion, at screening/baseline.
* Has clinically significant abnormalities in the electrocardiogram (ECG) measured at screening/baseline.
* Has any concurrent cardiovascular conditions, that will, in the investigator's opinion, interfere with the ability to assess their ECGs.
* Has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the study intervention such as sesame seed oil.
* Has significantly impaired hepatic function prior to Visit 3, defined as:

  * Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) and (total bilirubin \[TBL\] > 2 × ULN or international normalized ratio \[INR\] > 1.5).
  * Serum ALT or AST > 5 × ULN.
  * Serum ALT or AST > 3 × ULN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
  * Elevated ALT or AST should be discussed with the medical monitor prior to Visit 3; the medical monitor may allow for a confirmatory re-draw prior to Visit 3.
* Has received another study intervention within 4 weeks prior to Visit 1 or plans to take another study intervention during the study.
* Has any other clinically significant disease or disorder which, in the opinion of the investigator, may either put the participant, other participants, or site staff at risk because of participation in the study, may influence the result of the study, or may affect the participant's ability to take part in the study.
* Any clinically significant abnormalities identified following a physical examination of the participant that, in the opinion of the investigator, would jeopardize the safety of the participant if they took part in the study.
* Has previously been enrolled into this study.
* Has plans to travel outside their country of residence during the study, unless the participant has confirmation that the study intervention is permitted in the destination country.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Participant flow

Outcome results

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Primary), Number, participants: Tuberous Sclerosis Complex 2; Dravet Syndrome 1
• Mean Change From Baseline in Blood Pressure (Primary), Mean, mmHg: Tuberous Sclerosis Complex -3.0 +/- 9.90; Dravet Syndrome 11.0 +/- NA
• Mean Change From Baseline in Pulse Rate (Primary), Mean, beats per minute: Tuberous Sclerosis Complex -11.0 +/- 1.41; Dravet Syndrome 11.0 +/- NA
• Mean Change From Baseline in Respiratory Rate (Primary), Mean, breaths/minute: Tuberous Sclerosis Complex -10.0 +/- 16.97; Dravet Syndrome 0 +/- NA
• Mean Change From Baseline in Body Temperature (Primary), Mean, degrees Celsius: Tuberous Sclerosis Complex -0.05 +/- 0.354; Dravet Syndrome -0.10 +/- NA
• Mean Change From Baseline in Height (Primary), Mean, centimeters: Tuberous Sclerosis Complex 1.95 +/- 1.344; Dravet Syndrome 4.20 +/- NA
• Mean Change From Baseline in Body Weight (Primary), Mean, kilogram: Tuberous Sclerosis Complex 0.15 +/- 0.354; Dravet Syndrome 0.60 +/- NA
• Mean Change From Baseline in Heart Rate (Primary), Mean, beats/minute: Tuberous Sclerosis Complex -10.0 +/- NA; Dravet Syndrome 8.0 +/- NA
• Mean Change From Baseline in RR Interval (Primary), Mean, millisecond: Tuberous Sclerosis Complex 48.0 +/- NA; Dravet Syndrome -45.0 +/- NA
• Mean Change From Baseline in PR Interval (Primary), Mean, millisecond: Tuberous Sclerosis Complex 11.0 +/- 12.73; Dravet Syndrome -2.0 +/- NA
• Mean Change From Baseline in QRS Duration (Primary), Mean, millisecond: Tuberous Sclerosis Complex 3.0 +/- 1.41; Dravet Syndrome 6.0 +/- NA
• Mean Change From Baseline in QT Interval (Primary), Mean, millisecond: Tuberous Sclerosis Complex 0 +/- 8.49; Dravet Syndrome 0 +/- NA
• Mean Change From Baseline in QTcB and QTcF (Primary), Mean, millisecond: Tuberous Sclerosis Complex -10.0 +/- NA; Dravet Syndrome 16.0 +/- NA
• Number of Participants With a Clinically Significant Change in Laboratory Parameters (Primary), Number, participants: Tuberous Sclerosis Complex 0; Dravet Syndrome 1
• Number of Participants With Emergence of New Types of Seizures (Primary), Number, participants: Tuberous Sclerosis Complex 1; Dravet Syndrome 0
• Plasma Concentrations of GWP42003-P and Its Major Metabolites (Primary), Mean, ng/mL: Tuberous Sclerosis Complex 55.3 +/- 46.3; Dravet Syndrome 99.8 +/- NA
• Number of Participants Based on Percentage Change From Baseline in Indication-Specific Total Countable Seizures as Recorded by Caregivers (Primary), Number, participants: Tuberous Sclerosis Complex 2; Dravet Syndrome 0
• Clinician Global Impression of Severity (CGI/S) Score (Primary), Mean, score on a scale: Tuberous Sclerosis Complex ; Dravet Syndrome 3.0 +/- NA
• Clinician Global Impression of Change (CGI/C) Score (Primary), Mean, score on a scale: Tuberous Sclerosis Complex ; Dravet Syndrome 3.0 +/- NA
• Infant and Toddler Quality of Life Questionnaire Short Form 47 (ITQOL-47) Score (Other pre specified), Mean, score on a scale: Tuberous Sclerosis Complex 0 +/- NA; Dravet Syndrome 12.50 +/- NA
• 4 more outcome measures not shown.

Adverse events

Time frame: Adverse events were collected from baseline up to 62 weeks.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Three participants were enrolled. There was not enough information to answer the research questions. The limited data collected were not enough to provide meaningful conclusions regarding the efficacy, safety, and PK of CBD-OS in this clinical trial.

• Study Protocol (PDF, 2024-01-24)
• Statistical Analysis Plan (PDF, 2025-03-04)