Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6

Abstract

Objective: To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo-controlled, phase 3 trial in patients with drug-resistant epilepsy associated with tuberous sclerosis complex (TSC).

Methods: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4-week titration, 12-week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC-associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.

Results: Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1-56.8) years. Patients had discontinued a median (range) of 4 (0-15) antiseizure medications and were currently taking 3 (0-5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in ≥50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients.

Significance: Onset of treatment effect occurred within 6-10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16-week trial in most patients.

Keywords: antiseizure medication; cannabidiol; epilepsy; focal seizures; medication-resistant seizures; tuberous sclerosis complex.

Conflict of interest statement

J.Y.W. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharmaceuticals and GW Pharmaceuticals and has received research support from both. She has also received support from the National Institutes of Health and TSC Alliance. H.R.C. has received research support as a site investigator from GW Research and from Novartis during the conduct of the study; grant support from the National Institute of Neurological Disorders and Stroke (NINDS); nonfinancial support from the International League Against Epilepsy and European Academy of Neurology; and personal fees for consulting from Bial Pharma and in relation to medicolegal expert witness reports from civil court proceedings in the UK for personal injury cases (via solicitors). O.D. has equity interests in Qstate Biosciences, Tevard Biosciences, Regel Therapeutics, Script Biosciences, Privateer Holdings, Tilray, Receptor Life Sciences, Empatica, Engage, Egg Rock/Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises and receives grant support from NINDS, National Institute of Mental Health, Multidisciplinary University Research Initiative, US Centers for Disease Control and Prevention, and National Science Foundation. He is an investigator for PTC Therapeutics, Stoke Therapeutics, Marinus, Ovid, and GW Pharmaceuticals. C.J. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Zogenix. I.M. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Pharmaceuticals, TS Alliance, DS Foundation, lnsys, Biomarin, Upsher‐Smith, Visualase, Neuroblate, Zogenix, and Ultragenyx. He has received personal compensation in an editorial capacity for Insys Pharmaceuticals, GW Pharmaceuticals, TS Alliance, DS Foundation, Visualase, Neuroblate, Zogenix, and Ultragenyx and has received research support from GW Pharmaceuticals, TS Alliance, DS Foundation, lnsys, Biomarin, Upsher‐Smith, Visualase, Neuroblate, Zogenix, and Ultragenyx. C.M.R. has nothing to disclose. R.S.‐C. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with scientific advisory boards of GW Pharmaceuticals, Zogenix, and Novartis; is a member of the speaker's bureau of GW Pharmaceuticals; and has received research support as a principal investigator for GW Pharmaceuticals‐, Zogenix‐, and Takeda‐initiated trials. D.C. is an employee of GW Research. F.S. is an employee of Greenwich Biosciences. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1

Efficacy outcomes. (A) Cumulative percentage reduction from baseline in the number of tuberous sclerosis complex (TSC)‐associated seizures by day and (B) percentage of patients with ≥50% reduction in TSC‐associated seizures by day. Primary endpoint seizures included all countable focal motor seizures without impairment of awareness, focal seizures with impairment of awareness, focal seizures evolving to bilateral motor seizures, and generalized seizures (tonic–clonic, tonic, clonic, or atonic); they excluded absence, myoclonic, focal sensory, and infantile/epileptic spasms. The dotted line for each dose group represents the data until Day 11, when all patients were receiving the same dose of the trial drug, reflecting small variations in response not attributable to difference in dosage. All CBD, represented by the purple line, shows combined data for both CBD groups up to Day 11, after which patients in the CBD25 dose group remained on 25 mg/kg/day and those in the CBD50 dose group continued titration up to 50 mg/kg/day. CBD, cannabidiol; CBD25, cannabidiol 25 mg/kg/day; CBD50, cannabidiol 50 mg/kg/day; TSC, tuberous sclerosis complex

FIGURE 2

Cumulative percentage reduction from baseline in focal composite seizure score by day. Composite focal seizure score was calculated as the sum of (1 × the number of focal motor seizures without impairment of awareness), (2 × the number of focal seizures with impairment of awareness), and (3 × the number of focal seizures evolving to bilateral convulsive seizures). CBD25, cannabidiol 25 mg/kg/day; CBD50, cannabidiol 50 mg/kg/day

FIGURE 3

Adverse events by time of onset. If a patient had more than one occurrence of an AE, only the first occurrence of that AE was counted. The percentages of patients are based on the number of patients in the safety analysis set who had a visit or follow‐up call within each time period. AE, adverse event; CBD25, cannabidiol 25 mg/kg/day; CBD50, cannabidiol 50 mg/kg/day

FIGURE 4

Time to first occurrence of the three most common adverse events: (A) diarrhea, (B) decreased appetite, and (C) somnolence or sedation. Somnolence and sedation also include the preferred terms fatigue, lethargy, asthenia, and malaise. CBD, cannabidiol; CBD25, cannabidiol 25 mg/kg/day; CBD50, cannabidiol 50 mg/kg/day

FIGURE 5

Occurrence of AEs by time to AE resolution. For patients who had multiple occurrences of an AE, only one occurrence with the longest time to resolution was counted. Any AEs that did not resolve were counted once as ongoing. AE, adverse event; CBD25, cannabidiol 25 mg/kg/day; CBD50, cannabidiol 50 mg/kg/day