PMID- 29540584
OWN - NLM
STAT- MEDLINE
DCOM- 20190808
LR  - 20220520
IS  - 1526-632X (Electronic)
IS  - 0028-3878 (Print)
IS  - 0028-3878 (Linking)
VI  - 90
IP  - 14
DP  - 2018 Apr 3
TI  - Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
PG  - e1204-e1211
LID - 10.1212/WNL.0000000000005254 [doi]
AB  - OBJECTIVE: To evaluate the safety and preliminary pharmacokinetics of a 
      pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet 
      syndrome. METHODS: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 
      20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week 
      baseline, 3-week treatment (including titration), 10-day taper, and 4-week 
      follow-up periods. Completers could continue in an open-label extension. Multiple 
      pharmacokinetic blood samples were taken on the first day of dosing and at end of 
      treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 
      7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite 
      N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and 
      stiripentol). Safety assessments were clinical laboratory tests, physical 
      examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and 
      suicidality. RESULTS: Thirty-four patients were randomized (10, 8, and 9 to the 
      5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed 
      treatment. Exposure to CBD and its metabolites was dose-proportional (AUC(0-t)). 
      CBD did not affect concomitant AED levels, apart from an increase in N-CLB 
      (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, 
      somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal 
      behavior. Six patients taking CBD and valproate developed elevated transaminases; 
      none met criteria for drug-induced liver injury and all recovered. No other 
      clinically relevant safety signals were observed. CONCLUSIONS: Exposure to CBD 
      and its metabolites increased proportionally with dose. An interaction with N-CLB 
      was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. 
      CBD resulted in more AEs than placebo but was generally well-tolerated. 
      CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for 
      children with Dravet syndrome, CBD resulted in more AEs than placebo but was 
      generally well-tolerated.
CI  - Copyright (c) 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on 
      behalf of the American Academy of Neurology.
FAU - Devinsky, Orrin
AU  - Devinsky O
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA. 
      Od4@nyu.edu.
FAU - Patel, Anup D
AU  - Patel AD
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
FAU - Thiele, Elizabeth A
AU  - Thiele EA
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
FAU - Wong, Matthew H
AU  - Wong MH
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
FAU - Appleton, Richard
AU  - Appleton R
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
FAU - Harden, Cynthia L
AU  - Harden CL
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
FAU - Greenwood, Sam
AU  - Greenwood S
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
FAU - Morrison, Gilmour
AU  - Morrison G
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
FAU - Sommerville, Kenneth
AU  - Sommerville K
AD  - From the NYU Comprehensive Epilepsy Center (O.D.), New York, NY;Nationwide 
      Children's Hospital and the Ohio State University College of Medicine (A.D.P.), 
      Columbus; Massachusetts General Hospital (E.A.T.), Boston; Wake Forest School of 
      Medicine (M.H.W.), Winston-Salem, NC; Alder Hey Children's Health Park (R.A.), 
      Liverpool, UK; Mount Sinai Health System (C.L.H.), New York, NY; GW Research Ltd. 
      (S.G., G.M.), Cambridge, UK; and Greenwich Biosciences (K.S.), Carlsbad, CA.
CN  - GWPCARE1 Part A Study Group
LA  - eng
GR  - UL1 TR001420/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20180314
PL  - United States
TA  - Neurology
JT  - Neurology
JID - 0401060
RN  - 0 (Anticonvulsants)
RN  - 12794-10-4 (Benzodiazepines)
RN  - 19GBJ60SN5 (Cannabidiol)
RN  - 2MRO291B4U (Clobazam)
RN  - MZ4L647O2H (N-desmethylclobazam)
MH  - Anticonvulsants/adverse effects/pharmacokinetics/*therapeutic use
MH  - Benzodiazepines/pharmacokinetics/therapeutic use
MH  - Cannabidiol/adverse effects/pharmacokinetics/*therapeutic use
MH  - Child
MH  - Child, Preschool
MH  - Clobazam/pharmacokinetics/therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Therapy, Combination
MH  - Epilepsies, Myoclonic/blood/*drug therapy
MH  - Follow-Up Studies
MH  - Humans
MH  - Treatment Outcome
PMC - PMC5890607
FIR - Wilfong, Angus
IR  - Wilfong A
FIR - Flamini, Robert
IR  - Flamini R
FIR - Laux, Linda
IR  - Laux L
FIR - Miller, Ian
IR  - Miller I
FIR - Cross, Helen
IR  - Cross H
FIR - Joshi, Charuta
IR  - Joshi C
FIR - Chin, Richard
IR  - Chin R
FIR - Zuberi, Sameer
IR  - Zuberi S
EDAT- 2018/03/16 06:00
MHDA- 2019/08/09 06:00
PMCR- 2018/04/03
CRDT- 2018/03/16 06:00
PHST- 2017/05/30 00:00 [received]
PHST- 2018/01/03 00:00 [accepted]
PHST- 2018/03/16 06:00 [pubmed]
PHST- 2019/08/09 06:00 [medline]
PHST- 2018/03/16 06:00 [entrez]
PHST- 2018/04/03 00:00 [pmc-release]
AID - WNL.0000000000005254 [pii]
AID - NEUROLOGY2017824698 [pii]
AID - 10.1212/WNL.0000000000005254 [doi]
PST - ppublish
SO  - Neurology. 2018 Apr 3;90(14):e1204-e1211. doi: 10.1212/WNL.0000000000005254. Epub 
      2018 Mar 14.