Epidiolex for ESES

Overseen By Aaqil Ali

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: Northwell Health

Disqualifiers: Cannabidiol, Pregnancy, Allergic reactions, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 20 weeks

34 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to assess the efficacy of Epidiolex in patients with ESES. ESES is characterized by sleep potentiated spikes with a spike index greater than 85% (conventional definition) and 50% (new definition)1. Several drugs including: steroids, intravenous Gama globulin, Clobazam, other benzodiazepines, Valproic acid, and other anti-epileptic drugs have been tried with mixed benefits2,3. Cannabidiol (CBD) would provide a novel mechanism of action to assess for its efficacy in this population. This will be a double-blind placebo-controlled crossover clinical trial.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that several anti-epileptic drugs have been tried with mixed benefits, so it's best to discuss your current medications with the trial team.

Is Epidiolex (CBD) generally safe for humans?

Epidiolex (CBD) has been studied in various trials and is generally considered safe, though some people may experience side effects like skin rash. It has been used in both children and adults with treatment-resistant epilepsy, and while it can cause some adverse effects, these are usually mild and manageable. ^{1 2 3 4 5}

How is the drug Epidiolex unique for treating ESES?

Epidiolex is unique because it is a plant-derived, highly purified form of cannabidiol (CBD) that is taken as an oral solution, and it has been approved for treating certain types of epilepsy, like Lennox-Gastaut and Dravet syndromes. Its use for ESES is novel, as there are no standard treatments specifically approved for this condition. ^{1 4 6 7 8}

Eligibility Criteria

This trial is for children and teens aged 2-17 with ESES, a type of seizure disorder worsened by sleep. Participants must be in stable health, able to take oral medication, and use effective contraception if applicable. They can't join if they've used CBD recently, are pregnant or breastfeeding, have had a recent feverish illness, taken experimental drugs within the last 6 months, or are allergic to Epidiolex ingredients.

Inclusion Criteria

I am a man who can father children and will use contraception.

I am between 2 and 17 years old.

In good general health as evidenced by medical history or diagnosed with ESES. 'Good health' in relation to this study is understood as stable without current seizures requiring immediate hospitalization

Exclusion Criteria

I have used cannabidiol in the last 4 months.

I have not had a fever or febrile illness in the last month.

You have smoked or used tobacco in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Epidiolex or placebo in a double-blind, placebo-controlled crossover design to assess efficacy in reducing seizure frequency and intensity

20 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Epidiolex

Trial Overview The study tests Epidiolex's effectiveness against ESES compared to a placebo. It's double-blind (neither doctors nor patients know who gets what) and crossover (patients switch from drug to placebo at some point), aiming to see if CBD can help where other treatments have had mixed results.

Participant Groups

Group I: IP Active Control 1 Intervention

Epidiolex (Cannabidiol) is a colorless to yellow solution in a 100mL vial that is to be administered with a 5mL syringe.The starting dosage is 2.5 mg/kg twice daily, or 5 mg/kg/day. After one week, the dosage can be increased to a maintenance dosage of 5mg/kg twice daily, or 10 mg/kg/day. Patients who are tolerating Epidiolex at 10mg/kg per day and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance. Dosage of 10mg/kg twice daily (20mg/kg/day), in weekly increments of 2.5 mg/kg twice daily(5mg/kg/day), as tolerated. For patients in whom a more rapid titration from 10 mg/kg/day to 20 mg/kg/day is warranted, the dosage may be increased to no more frequently than every other day administration of the 20 mg/kg/day. Dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions.

Group II: Placebo Placebo Group 1 Intervention

Placebo is a colorless to yellow solution in a 100mL vial that is to be administered with a 5mL syringe. The starting dosage is 2.5 mg/kg twice daily, or 5 mg/kg/day. After one week, the dosage can be increased to a maintenance dosage of 5mg/kg twice daily, or 10 mg/kg/day. Patients who are tolerating Placebo at 10mg/kg per day and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance. Dosage of 10mg/kg twice daily (20mg/kg/day), in weekly increments of 2.5 mg/kg twice daily(5mg/kg/day), as tolerated. For patients in whom a more rapid titration from 10 mg/kg/day to 20 mg/kg/day is warranted, the dosage may be increased to no more frequently than every other day administration of the 20 mg/kg/day. Dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions.

Epidiolex is already approved in United States, European Union for the following indications:

Approved in United States as Epidiolex for:

• Seizures associated with Lennox-Gastaut syndrome
• Seizures associated with Dravet syndrome
• Seizures associated with tuberous sclerosis complex

Approved in European Union as Epidyolex for:

• Seizures associated with Lennox-Gastaut syndrome
• Seizures associated with Dravet syndrome

Who Is Running the Clinical Trial?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Jazz Pharmaceuticals

Industry Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Greenwich Biosciences

Industry Sponsor

Trials

3

Recruited

150+

Findings from Research

A single oral dose of 750 mg of cannabidiol (CBD) showed significantly increased exposure when taken with a high-fat/calorie meal, with a 3.8-fold increase in overall exposure (AUC0-∞) and a 5.2-fold increase in maximum concentration (Cmax) compared to fasting.

CBD was well-tolerated with no severe adverse events reported, indicating its safety in healthy adults, while its absorption was also enhanced by low-fat meals, whole milk, and alcohol, albeit to a lesser extent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects. Crockett, J., Critchley, D., Tayo, B., et al.[2021]

In a study involving 45 children with treatment-resistant epilepsy, cannabidiol (CBD) significantly reduced major seizure frequency by 54-72% and increased seizure-free days by an average of 7.52 days over 36 months, demonstrating its efficacy as an adjunctive treatment.

CBD was well tolerated at doses up to 50 mg/kg/day, although children who increased their dose beyond 25 mg/kg/day initially reported more adverse events; however, the overall rate of adverse events decreased after transitioning to higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of cannabidiol (CBD) in children with treatment-resistant epilepsy: Results from a state-based expanded access program. Park, YD., Linder, DF., Pope, J., et al.[2021]

In a study of 139 participants with treatment-resistant epilepsy, the use of highly purified cannabidiol (CBD; Epidiolex®) led to significant reductions in adverse events, seizure severity, and seizure frequency over 12 weeks, with improvements sustained for up to 48 weeks.

The study demonstrated that CBD was well-tolerated, with a decrease in adverse events from 40.8 to 33.2 and a reduction in seizure severity scores from 80.7 to 39.2, indicating its efficacy as a treatment option for epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Szaflarski, JP., Bebin, EM., Cutter, G., et al.[2019]

Epidiolex® (cannabidiol) is an FDA-approved medication for treating epilepsy associated with Lennox-Gastaut and Dravet syndromes, showing promise for treatment-resistant epilepsy.

A case study of a 23-year-old female revealed a delayed skin rash related to Epidiolex®, highlighting the need to monitor for potential side effects even when they are rare in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epidiolex-induced skin rash. Singh, J., Antimisiaris, MF.[2021]

Epidiolex, a 99% pure oral CBD extract, has been shown to significantly reduce seizure frequency in patients with medically refractory epilepsy, leading to its FDA approval.

The review highlights the safety profile of Epidiolex, noting that while it is effective, understanding its adverse effects is crucial for patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epidiolex as adjunct therapy for treatment of refractory epilepsy: a comprehensive review with a focus on adverse effects. Sekar, K., Pack, A.[2020]

Epidiolex® (CBD) is effective for treating epilepsy in patients over 2 years old, but it can interact with other medications, as seen in a case where it contributed to lithium toxicity in a patient with Lennox-Gastaut syndrome.

After discontinuing lithium due to toxicity, the patient improved and remained seizure-free on CBD and two other antiseizure medications, highlighting the importance of monitoring drug interactions when adding CBD to treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-Drug Interactions Between Cannabidiol and Lithium. Singh, RK., Dillon, B., Tatum, DA., et al.[2020]

In a study of 108 patients with refractory epilepsy taking Epidiolex®, 75% remained on the treatment at the final evaluation, indicating that it is generally well-tolerated and effective for long-term use.

However, 46.3% of patients experienced treatment-emergent adverse effects, with 14.5% discontinuing due to these effects, highlighting the need for further research on managing side effects and drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world, long-term evaluation of the tolerability and therapy retention of Epidiolex® (cannabidiol) in patients with refractory epilepsy. Georgieva, D., Langley, J., Hartkopf, K., et al.[2023]

Pure, plant-derived cannabidiol (CBD; Epidiolex) has been shown to significantly reduce seizure frequencies in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) by 17% to 23% compared to placebo, making it an effective adjunctive therapy for treatment-resistant epilepsy.

CBD is generally well tolerated, with common side effects including somnolence, diarrhea, and elevated liver enzymes, and it is the first cannabis-derived medication approved by the FDA for these conditions, providing a new treatment option for patients aged 2 years and older.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cannabidiol: A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes. Chen, JW., Borgelt, LM., Blackmer, AB.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of cannabidiol (CBD) in children with treatment-resistant epilepsy: Results from a state-based expanded access program. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Epidiolex-induced skin rash. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Epidiolex as adjunct therapy for treatment of refractory epilepsy: a comprehensive review with a focus on adverse effects. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Drug-Drug Interactions Between Cannabidiol and Lithium. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Real-world, long-term evaluation of the tolerability and therapy retention of Epidiolex® (cannabidiol) in patients with refractory epilepsy. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Cannabidiol: A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes. [2020]