Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial

Orrin Devinsky, Eric Marsh, Daniel Friedman, Elizabeth Thiele, Linda Laux, Joseph Sullivan, Ian Miller, Robert Flamini, Angus Wilfong, Francis Filloux, Matthew Wong, Nicole Tilton, Patricia Bruno, Judith Bluvstein, Julie Hedlund, Rebecca Kamens, Jane Maclean, Srishti Nangia, Nilika Shah Singhal, Carey A. Wilson & 2 others Anup Patel, Maria Roberta Cilio

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Abstract

Background Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). Interpretation Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Funding GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

LanguageEnglish (US)
Pages270-278
Number of pages9
JournalThe Lancet Neurology
Volume15
Issue number3
DOIs
StatePublished - Jan 1 2016

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Cannabidiol
Epilepsy
Seizures
Therapeutics
Safety
Young Adult
Myoclonic Epilepsy
Status Epilepticus
Appetite
Cannabis
Patient Safety
Nonparametric Statistics
Sudden Death
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Clinical Neurology

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Devinsky, O., Marsh, E., Friedman, D., Thiele, E., Laux, L., Sullivan, J., ... Cilio, M. R. (2016). Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. The Lancet Neurology, 15(3), 270-278. DOI: 10.1016/S1474-4422(15)00379-8
Devinsky, Orrin ; Marsh, Eric ; Friedman, Daniel ; Thiele, Elizabeth ; Laux, Linda ; Sullivan, Joseph ; Miller, Ian ; Flamini, Robert ; Wilfong, Angus ; Filloux, Francis ; Wong, Matthew ; Tilton, Nicole ; Bruno, Patricia ; Bluvstein, Judith ; Hedlund, Julie ; Kamens, Rebecca ; Maclean, Jane ; Nangia, Srishti ; Singhal, Nilika Shah ; Wilson, Carey A. ; Patel, Anup ; Cilio, Maria Roberta. / Cannabidiol in patients with treatment-resistant epilepsy : an open-label interventional trial. In: The Lancet Neurology. 2016 ; Vol. 15, No. 3. pp. 270-278
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abstract = "Background Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76{\%}) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64{\%}) patients were included in the efficacy analysis. In the safety group, 33 (20{\%}) patients had Dravet syndrome and 31 (19{\%}) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79{\%}) of the 162 patients within the safety group. Adverse events reported in more than 10{\%} of patients were somnolence (n=41 [25{\%}]), decreased appetite (n=31 [19{\%}]), diarrhoea (n=31 [19{\%}]), fatigue (n=21 [13{\%}]), and convulsion (n=18 [11{\%}]). Five (3{\%}) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30{\%}) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12{\%}) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6{\%}]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5{\%} (IQR 0–64·7). Interpretation Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Funding GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.",
author = "Orrin Devinsky and Eric Marsh and Daniel Friedman and Elizabeth Thiele and Linda Laux and Joseph Sullivan and Ian Miller and Robert Flamini and Angus Wilfong and Francis Filloux and Matthew Wong and Nicole Tilton and Patricia Bruno and Judith Bluvstein and Julie Hedlund and Rebecca Kamens and Jane Maclean and Srishti Nangia and Singhal, {Nilika Shah} and Wilson, {Carey A.} and Anup Patel and Cilio, {Maria Roberta}",
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Devinsky, O, Marsh, E, Friedman, D, Thiele, E, Laux, L, Sullivan, J, Miller, I, Flamini, R, Wilfong, A, Filloux, F, Wong, M, Tilton, N, Bruno, P, Bluvstein, J, Hedlund, J, Kamens, R, Maclean, J, Nangia, S, Singhal, NS, Wilson, CA, Patel, A & Cilio, MR 2016, 'Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial' The Lancet Neurology, vol. 15, no. 3, pp. 270-278. DOI: 10.1016/S1474-4422(15)00379-8

Cannabidiol in patients with treatment-resistant epilepsy : an open-label interventional trial. / Devinsky, Orrin; Marsh, Eric; Friedman, Daniel; Thiele, Elizabeth; Laux, Linda; Sullivan, Joseph; Miller, Ian; Flamini, Robert; Wilfong, Angus; Filloux, Francis; Wong, Matthew; Tilton, Nicole; Bruno, Patricia; Bluvstein, Judith; Hedlund, Julie; Kamens, Rebecca; Maclean, Jane; Nangia, Srishti; Singhal, Nilika Shah; Wilson, Carey A.; Patel, Anup; Cilio, Maria Roberta.

In: The Lancet Neurology, Vol. 15, No. 3, 01.01.2016, p. 270-278.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cannabidiol in patients with treatment-resistant epilepsy

T2 - The Lancet Neurology

AU - Devinsky,Orrin

AU - Marsh,Eric

AU - Friedman,Daniel

AU - Thiele,Elizabeth

AU - Laux,Linda

AU - Sullivan,Joseph

AU - Miller,Ian

AU - Flamini,Robert

AU - Wilfong,Angus

AU - Filloux,Francis

AU - Wong,Matthew

AU - Tilton,Nicole

AU - Bruno,Patricia

AU - Bluvstein,Judith

AU - Hedlund,Julie

AU - Kamens,Rebecca

AU - Maclean,Jane

AU - Nangia,Srishti

AU - Singhal,Nilika Shah

AU - Wilson,Carey A.

AU - Patel,Anup

AU - Cilio,Maria Roberta

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Background Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). Interpretation Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Funding GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

AB - Background Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). Interpretation Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Funding GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

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Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. The Lancet Neurology. 2016 Jan 1;15(3):270-278. Available from, DOI: 10.1016/S1474-4422(15)00379-8