Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376: DOI: /NEJMoa

2 Supplementary Appendix: Trial of Cannabidiol for Drug Resistant Seizures in the Dravet Syndrome Table of Contents Supplementary Material S1. The Cannabidiol in Dravet Syndrome Study Group... 2 Supplementary Material S2. Patients entering into the open-label extension study... 3 Supplementary Material S3. The relationship between somnolence and efficacy... 3 Figure S1. Sensitivity analyses for the primary endpoint... 4 Table S1. Palatability Questionnaire... 6 Table S2. Secondary Endpoints... 7 Support Statement

3 Supplementary Material S1. The Cannabidiol in Dravet Syndrome Study Group All the following investigators and collaborators made significant contributions to the planning and execution of the study. Study group members are listed in alphabetical order. France: Claude Cances (Hopital des Enfants, Toulouse, 31059): Anne DeSaint Martin (Hopital de Hautepierre, Strasbourg 67200): Nathalie Villeneuve (Hopital de la Timone, Marseilles 13385) Poland: Maria Mazurkiewicz-Beldzinska (Uniwersyteckie Centrum Kliniczne GUM, Gdansk): Marta Zolnowska (Centrum Medyczne Plejady, Krakow) United Kingdom: Richard Appleton (NHS Foundation Trust, Liverpool L12 2AP): Richard Chin (Muir Maxwell Epilepsy Centre, Edinburgh EH9 1UW): Christin Eltze (Great Ormond Street Hospital, London, UK): Sameer Zuberi (Royal Hospital for Sick Children, Glasgow, G3 8SJ) United States: Todd Barron (Wellspan Pediatric Neurology, York, PA): Judith Bluvstein (NYU Comprehensive Epilepsy Center, New York, NY) Gary D. Clark (Baylor College of Medicine/Texas Children s Hospital, Houston TX): Ronald G. Davis (Epilepsy Center of Central Florida, Orlando FL): Francis M. Filloux (University of Utah School of Medicine, Division of Pediatric Neurology, Salt Lake City, UT): Robert Flamini (Pediatric and Adolescent Neurodevelopmental Associates, Atlanta, GA): Daniel Friedman (NYU Comprehensive Epilepsy Center, New York, NY): Charuta Joshi (Children's Hospital Colorado, Aurora, CO): Anup Patel (Nationwide Children s Hospital, Columbus Ohio): Angus Wilfong (Baylor College of Medicine/Texas Children s Hospital, Houston TX): Elaine C Wirrell (Mayo Clinic, Rochester MN), Matthew Wong (Wake Forest Baptist Medical Center, Winston-Salem, NC) The Epilepsy Consortium: Jacqueline French (NYU Comprehensive Epilepsy Ctr New York NY): Dennis Dlugos, Sudha Kessler (Division of Neurology, Children s Hospital of Philadelphia, PA): Lynette Sadleir (Otago University, Wellington, New Zealand); Joseph Sullivan (UCSF Pediatric Epilepsy Center, San Francisco) GW Pharmaceuticals: Daniel Checketts (Head of Biometrics): Geoffrey Guy (Study Conception and Oversight): Claire Roberts, Kathleen Osborn, Heather Lauder (Clinical Sciences and Operations) 2

4 Supplementary Material S2. Patients entering into the open-label extension study At the end of the double-blind treatment period, 56 patients continued to the open-label extension study (26 cannabidiol and 30 placebo), while 55 patients entered the taper period (29 cannabidiol and 26 placebo). Of the 55 patients who entered the taper period, nine ended the taper early (five cannabidiol and four placebo) to join the open-label extension study, while one (on cannabidiol) withdrew from taper due to an adverse event. At the end of the taper period, 18 of the remaining cannabidiol patients joined the open-label extension study, while all 22 of the placebo patients did so. Supplementary Material S3. The relationship between somnolence and efficacy Because of the relative frequency of somnolence, a post-hoc analysis was carried out to determine whether somnolence was associated with a greater reduction in convulsive seizure frequency. Patients on cannabidiol who reported somnolence (n=22) experienced a median reduction in seizure frequency of 38.41%. Those who did not report somnolence had a median reduction of 38.94%. The estimated difference of 3.63% (95% CI to 22.25) was not significant (p=0.74). The results showed that the reduction in convulsive seizure frequency was very similar regardless of the presence of somnolence as an adverse event. 3

5 Figure S1. Sensitivity analyses for the primary endpoint Endpoint Difference (95% CI) P-value Wilcoxon-Rank Sum Test (Treatment Period) - ITT (-41.06, -5.43) Wilcoxon-Rank Sum Test (Treatment Period) - PP (-44.79, -8.94) Rank ANCOVA (Treatment Period) - ITT (-27.7, -3.5) ANCOVA (Treatment Period) - ITT (-45.20, 1.22) Wilcoxon-Rank Sum Test (After Imputing Unreported Days in IVRS) (Treatment Period) - ITT (-42.20, -4.87) Wilcoxon-Rank Sum Test (Maintenance Period) - ITT (-45.07, -8.24) Wilcoxon-Rank Sum Test (Maintenance Period (Week 1 to 4)) - ITT (-48.75, ) Wilcoxon-Rank Sum Test (Maintenance Period (Week 5 to 8)) - ITT (-44.76, -8.33) Wilcoxon-Rank Sum Test (Maintenance Period (Week 9 to 12)) - ITT (-40.74, 1.25) The Hodges-Lehmann median difference and 95% CI and the P value from the Wilcoxon rank-sum test are presented for the Wilcoxon rank-sum test analyses. The difference in LS means, 95% CI and P value for the difference are presented for the ANCOVA analyses. Note: the log-transformed ANCOVA and multiple imputation to account for MNAR sensitivity analyses are not included. The sensitivity analyses identified in Figure S1 were performed and were pre-specified in the Statistical Analysis Plan prior to unblinding: Difference (20 mg/kg - Placebo) during the treatment period using the PP analysis set. o To assess robustness of the results based on patients who completed the trial and had no major protocol deviations. A rank analysis of covariance (ANCOVA) on percentage change from baseline in convulsive seizure frequency during the treatment period. 4

6 The ranks of the percentage change from baseline and the baseline convulsive seizure frequency were calculated. The rank of the percentage change from baseline was then analyzed using an ANCOVA model with the rank of the baseline convulsive seizure frequency and age group (2-5 years, 6-12 years and years) as covariates and treatment group as a fixed factor. o This analysis applies a transformation to the primary endpoint of percentage change from baseline (i.e. ranks) in order to perform a parametric analysis (ANCOVA). o The purpose is to ensure results are consistent with the non-parametric analysis of the primary endpoint. ANCOVA of log transformed convulsive seizure frequency during the treatment period. The convulsive seizure frequency during the treatment period and the baseline convulsive seizure frequency were log transformed prior to analysis. The log transformed convulsive seizure frequency during the treatment period was then analyzed using an ANCOVA model with the log transformed baseline convulsive seizure frequency and age group as covariates and treatment group as a fixed factor. For any patients with no seizures post-baseline 1 was added to their convulsive seizure frequency prior to log transformation. o The purpose is to ensure results are consistent with the non-parametric analysis of the primary endpoint. ANCOVA on percentage change from baseline in convulsive seizure frequency during the treatment period including baseline and age group as covariates and treatment group as a fixed factor. o As mentioned in the protocol, since the data were not normally distributed and hence the analysis was based on a non-parametric test (Wilcoxon rank-sum test). The proposed analysis if the data were normally distributed is now a sensitivity analysis. during the maintenance period. o This analysis starts counting seizures from Day 15 onwards, i.e. excludes the dose titration period. during each four weeks of the maintenance period (Week 1 to 4, Week 5 to 8 and Week 9 to 12 of the 12-week maintenance period). during the treatment period, using the worst case of last observation carried forward (LOCF), next observation carried backward (NOCB) and the mean from the non-missing data for each patient to 5

7 impute missing data arising from unreported days in the interactive voice-response system (IVRS) during the treatment period only (not the baseline period). Any intermittent missing data for the number of convulsive seizures arising from unreported days in the IVRS was imputed using the worst (highest number of seizures) of the following for each patient: LOCF, NOCB and the mean daily number of seizures during the treatment period based using non-missing data o Proposed to account for missing data arising from unreported days in the IVRS. during the treatment period, using multiple imputation (MI) to impute data under the Missing Not at Random (MNAR) assumption o Proposed to account for missing data from patients who withdraw from the trial and the potential action of MNAR Table S1. Palatability Questionnaire Response: Cannabidiol (n=61) Placebo (n=59) Liked it a lot 6 (10.7%) 6 (10.5%) Liked it 13 (23.2%) 16 (28.1%) Neither liked nor disliked it 20 (35.7%) 26 (45.6%) Did not like it 8 (14.3%) 8 (14.0%) Did not like it at all 9 (16.1%) 1 (1.8%) Caregivers were asked to assess the likeability of the study drug. There were more cases where the patient was assessed to not like it at all on cannabidiol than on placebo, but otherwise the palatability of the two treatments was similar. 6

8 Table S2. Secondary Endpoints Percentage changes from baseline in seizure frequency by individual seizure type: Seizure Type (n vs. n; cannabidiol vs. placebo) Estimated median difference (95% CI) a P value a Tonic-Clonic (55 vs. 52) ( 42.52, 2.11) * Tonic (17 vs. 12) ( 52.63, 48.47) Clonic (14 vs. 11) 2.38 ( 29.48, 40.63) Atonic (5 vs. 11) 1.04( , 96.42) Myoclonic (18 vs. 25) 3.48 ( 34.18, 53.46) Countable partial (15 vs. 14) ( , 5.36) Other partial (3 vs. 4) ( , 47.55) Absence (20 vs. 23) 2.74 ( 19.98, 29.67) Number of patients with emergence of seizure types not experienced during the baseline period: Seizure Type: Cannabidiol n(%) Placebo n(%) Tonic-Clonic 0 1 (1.7) Tonic 1 (1.6) 4 (6.8) Clonic 2 (3.3) 1 (1.7) Atonic 1 (1.6) 0 Myoclonic 3 (4.9) 1 (1.7) Countable partial 2 (3.3) 1 (1.7) Other partial 2 (3.3) 4 (6.8) Absence 2 (3.3) 3 (5.1) Result is numerically in favor of cannabidiol. * Result is statistically significant in favor of cannabidiol. a The Hodges Lehmann median difference and 95% CI, and the p-value from the Wilcoxon rank-sum test are presented. Support Statement This study was funded by GW Pharmaceuticals. Findings reported in this study are specific to the GW Pharmaceuticals formulation of cannabidiol and cannot be extrapolated to other cannabidiol products. 7