Evaluation of Behavioral and Co-occurring Outcomes with Cannabidiol as Adjunctive Therapy in Tuberous Sclerosis Complex-Associated Seizures

Trial ID: 2023-507426-17-00
Protocol: JZP926-402
Sponsor: Jazz Pharmaceuticals Research UK Limited

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Diseases & Conditions

Tuberous sclerosis complex

Objectives

The primary objective of this study is to evaluate the changes in the most problematic behavior as identified by caregivers in participants with **Tuberous Sclerosis Complex** (TSC) who experience seizures. This is clinically relevant as it aims to address the behavioral challenges faced by individuals with TSC, which can significantly impact their quality of life and daily functioning.

Secondary objectives include:

Evaluating changes in TAND (TSC-Associated Neuropsychiatric Disorders) in participants with TSC who experience seizures.
Assessing changes in behaviors and neuropsychiatric symptoms in these participants.
Evaluating changes in other nonseizure outcomes, such as executive function and sleep.
Assessing reported changes in quality of life (QOL) and family functioning.
Evaluating changes in overall symptom severity, treatment retention, seizure response, and seizure-free days.
Assessing changes in behavioral outcomes in participants whose seizures do not respond to CBD-OS treatment.
Evaluating the safety and tolerability of CBD-OS in participants with TSC who experience seizures.

Participants

The clinical trial involves a total of **55 participants** diagnosed with **Tuberous Sclerosis Complex** (TSC), a genetic disorder characterized by the growth of benign tumors in various organs. The study population includes both male and female subjects, ranging in age from 1 to 65 years for participants based in the US, and 2 to 65 years for those outside the US. Participants were selected based on a confirmed clinical diagnosis of TSC with a history of seizures, as per the 2012 International Tuberous Sclerosis Complex Consensus Conference criteria. The trial includes individuals who exhibit moderate to severe behavioral issues, such as aggression, impulsivity, and mood swings, as identified by caregivers. Participants are required to have a dedicated caregiver and must be willing to maintain stable lifestyle factors that could affect seizures, such as alcohol consumption and smoking. The trial population is inclusive of vulnerable groups, ensuring a comprehensive evaluation of the intervention's effectiveness across diverse demographics.

Plans and Procedures

The clinical trial is designed as a **Phase 3b/4**, interventional, multicenter, open-label, single-arm study aimed at assessing behavioral and other co-occurring outcomes following treatment with Epidyolex as an add-on therapy in participants aged 1 to 65 years with seizures associated with **Tuberous Sclerosis Complex** (TSC). The trial will evaluate the primary effectiveness by measuring changes in the most problematic behavior as identified by caregivers. The study will involve the administration of Epidyolex 100 mg/ml oral solution, with a maximum daily dose of 25 mg/kg and a total dose not exceeding 9800 mg over a treatment period of 56 days. The trial is expected to commence recruitment on March 1, 2024, and conclude by January 29, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis of TSC, and behavioral assessments. Follow-up visits will occur at Weeks 4, 13, 26, and 52 to monitor changes from baseline in various behavioral and quality of life measures, including the TAND-SQ, ABC, CBCL/ABCL/ASR, and PROMIS domains. The end-of-study visit will assess the overall impact of the treatment and collect final data on primary and secondary endpoints.

The expected length of participant involvement is approximately 52 weeks, with conditions for early termination including the occurrence of treatment-emergent adverse events (TEAEs) or non-compliance with study requirements. Participants must maintain stable factors affecting seizures, such as medication usage, and adhere to contraceptive guidelines if applicable. The study aims to provide valuable insights into the behavioral outcomes of Epidyolex as an adjunctive treatment for TSC-related seizures.

Treatment

The clinical trial involves the administration of **Epidyolex 100 mg/ml oral solution**, an experimental medication containing the active substance **cannabidiol**. This pharmaceutical product is formulated as an **oral solution** and is manufactured by Jazz Pharmaceuticals Ireland Ltd. The medication is administered via oral, nasogastric tube, or percutaneous endoscopic gastrostomy tube routes. The dosing regimen allows for a maximum daily dose of 25 mg/kg, with a total maximum dose of 9800 mg over a treatment period of up to 56 days. The active substance, cannabidiol, is of chemical origin and is classified under the ATC code N03AX24. The product is designated as an orphan drug, specifically for the treatment of seizures associated with Tuberous Sclerosis Complex (TSC).

In this study, **Epidyolex** is used as an add-on therapy, meaning it is administered in conjunction with other standard-of-care treatments for TSC-related seizures. The trial is designed as an open-label, single-arm study, which implies that all participants receive the experimental treatment without a placebo or comparator group. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial aims to assess behavioral and other co-occurring outcomes following treatment with Epidyolex, focusing on changes in the most problematic behaviors as identified by caregivers of participants aged 1 to 65 years.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint involves evaluating the change from baseline in the most problematic behavior Numeric Rating Scale (NRS) score within the TAND-SQ at Weeks 13, 26, and 52. Secondary endpoints include various measures of behavioral and quality of life changes, such as the change from baseline in TAND-SQ, ABC, CBCL/ABCL/ASR, and PROMIS domains at specified timepoints. Additionally, changes in sleep characteristics using CSHQ/PSQI, executive function using the BRIEF, and quality of life assessments using PedsQL and PedsQL FIM will be evaluated at Week 26.

Further assessments will include caregiver and participant impressions of overall symptom severity using CareGI-S/PGI-S and CGI-S at Weeks 4, 13, 26, and 52. Retention rates, treatment responder numbers, and changes in seizure frequency and seizure-free days will also be monitored. The incidence and severity of **treatment-emergent adverse events (TEAEs)**, changes in clinical laboratory parameters, and ideation scores will be tracked throughout the study. Data collection will occur at multiple timepoints, including Weeks 4, 13, 26, and 52, to ensure comprehensive analysis of the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Is within the required age range at the time of signing (or at the time of the participant’s parent(s)/LAR signing) the informed consent or providing assent (as applicable): • Participants based in the US: 1 to 65 years of age, inclusive. • Participants based outside the US: 2 to 65 years of age, inclusive.
Has a confirmed clinical diagnosis of TSC with a history of seizures in accordance with the 2012 International Tuberous Sclerosis Complex Consensus Conference criteria.
Has behaviors (eg, aggression, impulsivity, temper tantrum, self-injury, hyperactivity, extreme shyness, mood swings, poor eye contact, repetitive behaviors, restlessness, difficulty getting along with peers, rigid/inflexible to procedure and/or change) that are considered moderate or severe per the CareGI-S at Screening. • At Baseline, participants must have a most problematic behavior score of ≥ 6 to remain eligible.
Has behaviors (eg, aggression, impulsivity, temper tantrum, self-injury, hyperactivity, extreme shyness, mood swings, poor eye contact, repetitive behaviors, restlessness, difficulty getting along with peers, rigid/inflexible to procedure and/or change) that are considered moderate or severe per the CareGI-S at Screening. • At Baseline, participants must have a most problematic behavior score of ≥ 6 to remain eligible.
Is naïve to CBD-OS treatment or has been off CBD-OS treatment for at least 3 months prior to Screening.
Is willing to maintain any factors expected to affect seizures stable (eg, alcohol consumption, smoking, concomitant medication usage).
Is male or female a. Male participants: • Male participants are eligible to participate if they agree to the following during the intervention period and for at least 2 weeks, corresponding to the time needed to eliminate the study intervention (eg, 5 terminal half-lives) after the last dose of study intervention: − Refrain from donating fresh unwashed semen. PLUS − Use a male condom in addition to a second method of acceptable contraception used by their female partners when having sexual intercourse with a WOCBP who is not currently pregnant. b. Female participants: • A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies: − Is a woman of nonchildbearing potential. OR − Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency, as described in (Appendix 4 Contraceptive and Barrier Guidance), during the study intervention period and for at least 3 months after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention.
Participant or the participant’s parent(s)/LAR is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. • In cases where the participant’s parent(s)/LAR representative signs the ICF and the participant possesses adequate understanding, assent should also be taken according to local regulations.
Participant and their caregiver are willing and able (in the investigator’s opinion) to comply with all study requirements.
Participant’s parent(s)/ or LAR is willing to allow the responsible authorities to be notified of the participant’s involvement in the study, if mandated by local law.
Participant’s parent(s)/LAR is willing to allow his or her primary care practitioner (if they have one) and consultant (if they have one) to be notified of participation in the study, if the primary care practitioner/consultant is different to the investigator.
Participant (including adults lacking capacity) has a dedicated caregiver to participate in the study.

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Exclusion Criteria

Has a clinically significant unstable medical condition other than epilepsy.
Has an illness during the 4 weeks prior to screening other than epilepsy which, in the investigator’s opinion, could affect study outcomes.
Has TSC-specific tumor growth which, in the investigator’s opinion, could affect the effectiveness endpoints.
Has any other significant disease or disorder which, in the investigator’s opinion, 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.
Has previously undergone significant surgery for epilepsy that, in the investigator’s opinion, may impact the assessment of outcomes.
Has initiated felbamate within the last 12 months prior to Screening.
Is currently using or has in the past used recreational or medicinal cannabis or synthetic cannabinoid-based medications within the 3 months prior to Screening and is not willing to undergo a 1-month washout period before being rescreened.
Has received an investigational medicinal product within the 3 months prior to the Screening Visit.
Has previously been assigned study intervention for this study or is currently enrolled in any other interventional study (including behavioral intervention studies).
Has laboratory values at the Baseline Visit that are abnormal and of clinical significance in the investigator’s opinion.
Participant has significantly impaired hepatic function at the Baseline Visit, defined as any of the following: a. Serum ALT or AST > 5 × ULN b. Serum ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 c. Serum ALT or AST > 3 × ULN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia (> 5%) Note: This criterion can only be confirmed once the laboratory results are available; participants enrolled into the study who are later found to meet this criterion must be withdrawn from the study.
Has any history of suicidal behavior or any suicidal ideation of type 4 or 5 as evaluated with C-SSRS or Children’s C-SSRS at the Screening Visit (for participants ≥ 4 years of age).
Has any known or suspected hypersensitivity to cannabinoids or any of the excipients of CBD-OS.
Has a known or suspected history of alcohol or substance abuse.