Friday, April 27, 2018

Cannabidiol in pediatric and adult patients with treatment-refractory epilepsy

Response to Pharmaceutical Formulation of Purified Cannabidiol (CBD) in Pediatric and Adult Patients with Treatment-Refractory Epilepsy Jerzy Szaflarski, E Bebin, Tyler Gaston, Leslie Perry, Yuliang Liu, Gary Cutter.    American Academy of Neurology (AAN) 2018 Annual Meeting. Abstract PD030. Presented April 22, 2018.


To assess changes in seizure frequency (SF) and severity (Chalfont Seizure Severity Scale; CSSS) and durability of the response to CBD (Epidiolex®) in patients with treatment-refractory epilepsy enrolled in an open-label compassionate use safety study.


Patients with video-EEG confirmed epilepsy who have failed at least 4 different AEDs and were experiencing on average ≥4 countable seizures per month were enrolled.


In 132 patients (70 pediatric) pre-CBD SF and CSSS were averaged over 3 months prior to initiating CBD at 5mg/kg/day; dose increases were made as tolerated q2 weeks by 5mg/kg/day up to a maximum of 50mg/kg/day. SF and CSSS were collected at 12, 24, and 48 weeks after enrollment. Other AEDs were adjusted as needed. Standard statistical measures including censoring for dropouts and early terminations were used for this non-normally distributed cohort. 


At the time of the analyses, of the 132 enrolled patients, 130 had 12 week, 88 had 24 week, and 61 had 48 week data (411 individual encounters). There were no differences between participants who contributed all 4 data points and who contributed less than 4 data points (<4 data points were either due to dropping out or not being in the study for long enough) in basic demographic and seizure variables. For the entire group, bi-weekly SF decreased from mean of 144.4 at entry to 52.2 at 12 weeks (p<0.001), 66.6 at 24 weeks, and 46.7 at 48 weeks (differences between 12, 24, and 48 weeks NS). CSSS numbers were 80.7 (p<0.001), 39.26, 40.72, and 34.6 respectively (differences between 12, 24, and 48 weeks NS). Data split between pediatric and adult groups mimicked the same response pattern. 


This compassionate use open-label study indicates significant improvements in SF and CSSS at 12 weeks with response maintained over the 48-week duration of the study.  

Study supported by: State of Alabama 

"Pharmaceutical-grade cannabidiol improves seizure frequency in children and adults, and also decreases their severity," Jerzy P Szaflarski, MD, PhD, professor and director of the UAB Epilepsy Center in Birmingham, Alabama, told Medscape Medical News. 

"There was a dramatic seizure decrease in children, driven mainly by the patients with very high seizure frequencies," he added...

Pediatric patients tended to experience generalized seizures, whereas adults reported mainly partial or focal-onset seizures, "which may explain some of the differences we see." The accuracy of seizure counts in diaries prepared by patients and families was another potential limitation... 

Going forward, Szaflarski would like to determine whether cannabidiol, in combination with other cannabinoids such as tetrahydrocannabinol, is more efficacious than cannabidiol alone. He also would like to assess other cannabinoids that might have efficacy in seizure control. "We need to determine the effects of cannabidiol on the central nervous system, neuroimaging, cognition [and more]," he added. 

Commenting on the findings for Medscape Medical News, Gregory D Cascino, MD, Whitney MacMillion Jr professor of neuroscience at the Mayo Clinic College of Medicine, enterprise director of epilepsy for the Mayo Clinic (both in Rochester, Minnesota), and a fellow of the AAN, said it is "an important study." 

"They looked at a composition of patients like those that we see in the real clinical practice setting — adults and pediatric patients. They also had patients who were refractory to four or more antiepileptic drugs, so [the patients] clearly had drug-resistant epilepsy," he said

"This is a well-done, open-label study," Cascino added. "What I found was helpful is there was benefit at 12 weeks, a sustained benefit as they followed patients out several months." 

"As with many of the drug investigation studies, there was a moderate reduction in seizure tendency. It certainly compares very favorably to patients who are enrolled in adjunctive antiepileptic drug trials."

1 comment:

  1. Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, Herkes GK, Farrell M, Degenhardt L. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018 Mar 6. pii: jnnp-2017-317168. doi: 10.1136/jnnp-2017-317168. [Epub ahead of print]


    Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy. Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL). Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5-55 years). Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17). CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs. Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed.

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