ARTICLE IN BRIEF
The first randomized, placebo-controlled study of cannabidiol oil for Lennox-Gastaut syndrome found the drug to be safe and effective for reducing drop seizures, but it also had adverse effects.
Cannabidiol (CBD) oil significantly reduced drop seizures in Lennox-Gastaut syndrome, according to the first placebo-controlled randomized study to test its benefits published in the January 25 online edition of The Lancet.
Epidiolex, the marijuana plant-based drug, is CBD purified from the cannabis plant and does not contain the psychoactive component of cannabis, tetrahydrocannabinol.
“Epidiolex is efficacious and well-tolerated,” said the study's principal investigator Elizabeth A. Thiele, MD, PhD, director of the pediatric epilepsy program and the Carol and James Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital, and professor of neurology at Harvard Medical School.
“The findings are encouraging,” said Dr. Thiele. “Lennox-Gastaut Syndrome is a tough seizure disorder to treat. The mean age of the patients in the study was 15 years old, and many had tried and stopped an average of six antiepileptic drugs,” she said. During the study, many were taking three different medicines to control their seizures, she added.
The results show that CBD oil works to reduce seizures, but it doesn't work for everyone and it is not without its side effects, Dr. Thiele said. If it is approved for the treatment of Lennox-Gastaut, it would be the first cannabinoid drug for the treatment of epilepsy. It is also being tested in patients with Dravet syndrome.
GW Pharmaceuticals, the company developing the marijuana plant-based drug Epidiolex, has submitted the data from this study and another one to the Food and Drug Administration.
STUDY METHODS, FINDINGS
The study enrolled 171 patients from 24 clinical centers throughout the United States, the Netherlands, and Poland. Patients between ages 2 and 55 who failed at least two antiepileptic drugs were eligible for the study. They were all taking other antiepileptic medicines during the CBD trial, which was designed to test the added benefit of CBD versus a placebo dose.
Patients enrolled in the study had to have a history of slow (<3 Hz) spike and wave patterns on an electroencephalogram, more than one type of seizure for a duration of at least six months, and at least two drop seizures a week (many had dozens, even hundreds) during the month-long baseline period.
They were randomized to receive 20 mg/kg purified CBD oil daily (divided twice daily) or a matched placebo for 14 weeks. Patients and/or their families recorded the number of drop seizures and adverse events every day. Patients were assessed in the clinic four times throughout the study and another two times by phone.
The study investigators compared the percentage change in drop seizures during the treatment period in everyone who received at least one dose of the purified drug (86 patients) or placebo (85 patients). Fourteen patients in the CBD group and one in the placebo group dropped out of the study.
Among findings, the median percent reduction in monthly drop seizures from baseline to the end of the study was 43.9 percent in the CBD group compared to 21.8 percent in the placebo group.
In addition to this primary outcome measure, there were several secondary endpoints, including the proportion of patients who achieved a reduction of 50 percent or more in the frequency of drop seizures, percentage change in total seizure frequency, and a change in patient and/or caregiver global impression of change from baseline to the end of the study. Three patients from the CBD group were free of drop seizures throughout the 14-week study. No one in the placebo group had a drop seizure free period.
Adverse events were common in both groups: 86 percent of the patients on the active medicine reported some new symptoms, including diarrhea, tiredness, fever, decreased appetite or vomiting, compared to 69 percent of those on placebo. Most were mild to moderate in severity, but 23 percent of the 86 patients taking the CBD oil had serious adverse events compared to 5 percent of those on a placebo.
One patient in the CBD group died of acute respiratory distress during the study, which the drug monitoring committee believes was unrelated to treatment.
There were also important drug-drug interactions: Patients in the CBD arm taking clobazam had an increase in the drug's active metabolite, and more reports of sedation. Also, sixteen of 36 patients taking valproate had increases in liver enzymes that did not cause clinical problems and resolved once CBD oil was stopped.
An open-label extension study has been underway since the randomized study ended in October 2015.
This study only used one dose of cannabidiol. There is another randomized controlled study in Lennox-Gastaut syndrome, also sponsored by GW Pharmaceuticals, that is testing two doses against a placebo.
“This is scientific evidence that we can take back to our patients,” said Jacqueline A. French, MD, FAAN, professor of neurology and director of translational research and clinical trials in epilepsy at the New York University Comprehensive Epilepsy Center and an investigator in the trial. “The study shows that there are benefits and risks. This is not a miracle drug but one that could benefit some of our patients with epilepsy. Its use needs to be guided by a physician.”
“Lennox-Gastaut is one of the most difficult epilepsy conditions to treat,” said Elaine C. Wirrell, MD, FAAN, director of pediatric epilepsy at Mayo Clinic in Rochester, MN, who was not involved with this study. Dr. Wirrell, who is an investigator on another Epidiolex study for Lennox-Gastaut syndrome, said: “Having another treatment that holds promise to significantly reduce drop seizures is important.”
Dr. Wirrell knows that many of her patients are taking non-pharmaceutical grade CBD preparations. “We don't know what's in it or whether last week's batch will be the same as next week's. We would all feel more comfortable knowing that the drug is from a reliable and consistent source.”
“Folks are desperate to find something to reduce their drop seizures,” said Shlomo Shinnar, MD, PhD, FAAN, professor of neurology, pediatrics and epidemiology and population health, the Hyman Climenko professor of neuroscience research at Albert Einstein College of Medicine, and director of the Comprehensive Epilepsy Management Center at Montefiore Medical Center. Montefiore was one of the study sites for the CBD oil study in Lennox-Gastaut.
“This offers a valuable addition,” he said. “The drug is clearly superior to placebo, but rarely makes people seizure-free and has a lot of side effects.”
Anup D. Patel, MD, FAAN, section chief of neurology at Nationwide Children's Hospital, and associate professor of neurology and pediatrics at The Ohio State University College of Medicine, became interested in CBD oil four years ago when a patient's family was thinking about moving to Colorado to get access to CBD for the treatment of their child's seizures. He begged the family not to do it and made a deal: He offered to approach GW and ask about enrolling the patient into one of its open-access studies. “I told them that if I am not successful they could move.”
The company said yes, for that one child. The child did well on the drug, and Dr. Patel asked the company for even more access. He ended up enrolling 20 of his young patients into the randomized controlled study testing two doses to placebo. (Results from this second study have also been submitted to the FDA as part of GW Pharmaceutical's bid for approval.) Dr. Patel has 26 others in GW's expanded access program.
Dr. Patel added: “I wanted the question to be answered scientifically: Does a purified CBD oil work or not?”
He said that the investigators have also seen a high placebo response. “GW planned the trial and knew that we had to account for parent's belief in the power of the oil.” Dr. Patel receives research funding from GW and has been a consultant to the company. He has not received funds tied to the Lennox-Gastaut study.