Long-term cannabidiol treatment in patients with Dravet syndrome

An open-label extension trial

Orrin Devinsky*, Rima Nabbout, Ian Miller, Linda C Laux, Marta Zolnowska, Stephen Wright, Claire Roberts

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Objective: Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. Methods: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d. Results: By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. Significance: This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

Original languageEnglish (US)
Pages (from-to)294-302
Number of pages9
JournalEpilepsia
Volume60
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

Fingerprint

Cannabidiol
Myoclonic Epilepsy
Seizures
Therapeutics
Caregivers
Placebos
Safety
Drug Compounding
Valproic Acid
Appetite
Transaminases
Anticonvulsants
Diarrhea

Keywords

  • cannabinoid
  • epileptic encephalopathy
  • seizures
  • treatment-resistant epilepsy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Devinsky, O., Nabbout, R., Miller, I., Laux, L. C., Zolnowska, M., Wright, S., & Roberts, C. (2019). Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial. Epilepsia, 60(2), 294-302. https://doi.org/10.1111/epi.14628
Devinsky, Orrin ; Nabbout, Rima ; Miller, Ian ; Laux, Linda C ; Zolnowska, Marta ; Wright, Stephen ; Roberts, Claire. / Long-term cannabidiol treatment in patients with Dravet syndrome : An open-label extension trial. In: Epilepsia. 2019 ; Vol. 60, No. 2. pp. 294-302.
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Devinsky, O, Nabbout, R, Miller, I, Laux, LC, Zolnowska, M, Wright, S & Roberts, C 2019, 'Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial', Epilepsia, vol. 60, no. 2, pp. 294-302. https://doi.org/10.1111/epi.14628

Long-term cannabidiol treatment in patients with Dravet syndrome : An open-label extension trial. / Devinsky, Orrin; Nabbout, Rima; Miller, Ian; Laux, Linda C; Zolnowska, Marta; Wright, Stephen; Roberts, Claire.

In: Epilepsia, Vol. 60, No. 2, 01.02.2019, p. 294-302.

Research output: Contribution to journalArticle

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T1 - Long-term cannabidiol treatment in patients with Dravet syndrome

T2 - An open-label extension trial

AU - Devinsky, Orrin

AU - Nabbout, Rima

AU - Miller, Ian

AU - Laux, Linda C

AU - Zolnowska, Marta

AU - Wright, Stephen

AU - Roberts, Claire

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Objective: Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. Methods: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d. Results: By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. Significance: This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

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KW - epileptic encephalopathy

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