Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial

GWPCARE4 Study Group

doi:10.1016/S0140-6736(18)30136-3

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial

GWPCARE4 Study Group

Pediatrics

Research output: Contribution to journal › Article › peer-review

632 Scopus citations

Abstract

Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2–55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR −69·6 to −1·9) in the cannibidiol group and 21·8% (IQR −45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was −17·21 (95% CI −30·32 to −4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. Funding: GW Pharmaceuticals.

Original language	English (US)
Pages (from-to)	1085-1096
Number of pages	12
Journal	The Lancet
Volume	391
Issue number	10125
DOIs	https://doi.org/10.1016/S0140-6736(18)30136-3
State	Published - Jan 1 2018

Funding

EAT received grants from GW Research Pharmaceuticals; was the principal investigator on clinical trials for GW Pharmaceuticals and Zogenix, outside the submitted work; and serves as a consultant for Eisai Medical Research, Greenwich Biosciences, Ovid Therapeutics, UCB, Aquestive, and Zogenix. EDM received grants from GW Pharmaceuticals during the conduct of the trial; received a grant from GW Pharmaceuticals outside the submitted work; received personal fees from Stanley Brothers Social Enterprises, Eisai Pharma, and Cydan Co; and is the principal investigator for studies sponsored by Neuren Pharma and Zogenix Pharma. JAF receives New York University salary support from the Epilepsy Foundation and for consulting work on behalf of the Epilepsy Study Consortium for Acadia Acorda, Adamas, Alexza, Anavex, Axcella Health, Biogen, BioPharm Solutions, Cavion, Cerecor, Concert Pharmaceuticals, Covance, CuroNZ, Eisai, Empatica, Engage, Georgia Regents University, GlaxoSmithKline, GW Pharmaceuticals, Johnson & Johnson Pharmaceuticals, Marinus, MonosolRx, Monteris, Nestle-Health Science, Neurelis, Novartis, Otsuka, Ovid, Pfizer, Pfizer-Neusentis, Sage Therapeutics, Shire, SK Life Sciences, Sunovion, Takeda, UCB, Upsher Smith, Ultragenyx, Xenon Pharmaceuticals, Xeris, Zogenix, and Zynerba; has received research grants from Acorda, Alexza, Eisai Medical Research, LCGH, Lundbeck, Pfizer, SK Life Sciences, Sunovion, Takeda, and UCB; has grants from the Epilepsy Research Foundation, Epilepsy Study Consortium, Epilepsy Therapy Project, and National Institute of Neurological Disorders and Stroke; is on the Scientific Advisory Board of Ovid, Sage Therapeutics, and Blackfynn; is on the editorial board of Lancet Neurology, Neurology Today, and Epileptic Disorders; is scientific officer for the Epilepsy Foundation for which New York University receives salary support; and has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Biogen, Eisai, Engage, GW Pharmaceuticals, GlaxoSmithKline, Novartis, Otsuka, Ovid, Pfizer, Sage, Sunovion, SK Life Sciences, Takeda, UCB, Ultragenyx, Upsher-Smith, Zogenix, and Zynerba. SRB received grants from GW Pharmaceuticals during the conduct of this study; and serves as a speaker or consultant for Eisai Medical Research, Livanova, Lundbeck, Neuropace, Sunovion, and UCB. CJ has a patent pending for the use of cannabidiol in febrile infection-related epilepsy syndrome. AT and CR are employed by GW Research and own shares or stock options in GW Pharmaceuticals. KS is full-time employee of Greenwich Biosciences and owns stock options in GW Pharmaceuticals. MM-B and PDL have nothing to disclose.

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/S0140-6736(18)30136-3

Cite this

@article{1b288f19fdac4cf481aadf58bf322234,

title = "Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial",

abstract = "Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2–55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR −69·6 to −1·9) in the cannibidiol group and 21·8% (IQR −45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was −17·21 (95% CI −30·32 to −4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. Funding: GW Pharmaceuticals.",

author = "{GWPCARE4 Study Group} and Thiele, {Elizabeth A.} and Marsh, {Eric D.} and French, {Jacqueline A.} and Mazurkiewicz, {Maria B.} and Benbadis, {Selim R.} and Charuta Joshi and Lyons, {Paul D.} and Adam Taylor and Claire Roberts and Kenneth Sommerville and Boudewjin Gunning and Jacek Gawlowicz and Pawel Lisewski and {Mitosek Szewczyk}, Krystyna and Barbara Steinborn and Marta Zolnowska and Elaine Hughes and Ailsa McLellan and Selim Benbadis and Michael Ciliberto and Gary Clark and Dennis Dlugos and Francis Filloux and Robert Flamini and Jacqueline French and Michael Frost and Sheryl Haut and Charuta Joshi and Siddarth Kapoor and Sudha Kessler and Linda Laux and Paul Lyons and Eric Marsh and David Moore and Richard Morse and Venkatesh Nagaraddi and William Rosenfeld and Laurie Seltzer and Ren{\'e}e Shellhaas and Elizabeth Thiele and Thio, {Liu Lin} and David Wang and Angus Wilfong",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

month = jan,

day = "1",

doi = "10.1016/S0140-6736(18)30136-3",

language = "English (US)",

volume = "391",

pages = "1085--1096",

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TY - JOUR

T1 - Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4)

T2 - a randomised, double-blind, placebo-controlled phase 3 trial

AU - GWPCARE4 Study Group

AU - Thiele, Elizabeth A.

AU - Marsh, Eric D.

AU - French, Jacqueline A.

AU - Mazurkiewicz, Maria B.

AU - Benbadis, Selim R.

AU - Joshi, Charuta

AU - Lyons, Paul D.

AU - Taylor, Adam

AU - Roberts, Claire

AU - Sommerville, Kenneth

AU - Gunning, Boudewjin

AU - Gawlowicz, Jacek

AU - Lisewski, Pawel

AU - Mitosek Szewczyk, Krystyna

AU - Steinborn, Barbara

AU - Zolnowska, Marta

AU - Hughes, Elaine

AU - McLellan, Ailsa

AU - Benbadis, Selim

AU - Ciliberto, Michael

AU - Clark, Gary

AU - Dlugos, Dennis

AU - Filloux, Francis

AU - Flamini, Robert

AU - French, Jacqueline

AU - Frost, Michael

AU - Haut, Sheryl

AU - Joshi, Charuta

AU - Kapoor, Siddarth

AU - Kessler, Sudha

AU - Laux, Linda

AU - Lyons, Paul

AU - Marsh, Eric

AU - Moore, David

AU - Morse, Richard

AU - Nagaraddi, Venkatesh

AU - Rosenfeld, William

AU - Seltzer, Laurie

AU - Shellhaas, Renée

AU - Thiele, Elizabeth

AU - Thio, Liu Lin

AU - Wang, David

AU - Wilfong, Angus

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2–55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR −69·6 to −1·9) in the cannibidiol group and 21·8% (IQR −45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was −17·21 (95% CI −30·32 to −4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. Funding: GW Pharmaceuticals.

AB - Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2–55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR −69·6 to −1·9) in the cannibidiol group and 21·8% (IQR −45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was −17·21 (95% CI −30·32 to −4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. Funding: GW Pharmaceuticals.

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UR - http://www.scopus.com/inward/citedby.url?scp=85041583750&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(18)30136-3

DO - 10.1016/S0140-6736(18)30136-3

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JO - The Lancet

JF - The Lancet

IS - 10125

ER -

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial

Abstract

Funding

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UN SDGs

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