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Downloaded from Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting: a study protocol for a pilot and definitive randomised double-blind placebo-controlled trial (CannabisCINV) For peer review only Journal: BMJ Open Manuscript ID bmjopen-2017-020745 Article Type: Protocol Date Submitted by the Author: 31-Dec-2017 Complete List of Authors: Mersiades, Antony; University of Sydney, NHMRC Clinical Trials Centre Tognela, Annette; South Western Sydney Local Health District, Macarthur Cancer Therapy Centre, Campbelltown Hospital Haber, Paul; University of Sydney - Camperdown and Darlington Campus, Discipline of Addiction medicine; Sydney Local Health District, Drug Health Services Stockler, Martin; University of Sydney , NHMRC Clinical Trials Centre; Sydney Local Health District, Dept of Medical Oncology, Concord Cancer Care Centre Lintzeris, Nicholas; South East Sydney Local Health District, The Langton Centre; University of Sydney - Camperdown and Darlington Campus, Discipline of Addiction Medicine http://bmjopen.bmj.com/ Simes, John; University of Sydney, NHMRC Clinical Trials Centre; Chris O'Brien Lifehoue, Dept of Medical Oncology McGregor, Iain; University of Sydney, Lambert Initiative for Cannabinoid Therapeutics Olver, Ian; University of South Australia, Sansom Institute for Health Research Allsop, David; University of Sydney, Lambert Initiative for Cannabinoid Therapeutics Gedye, Craig; Calvary Mater Newcastle, Dept of Medical Oncology on September 28, 2021 by guest. 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Kirby, Adrienne; University of Sydney, NHMRC Clinical Trials Centre Morton, Rachael; The University of Sydney, NHMRC Clinical Trials Centre Fox, Peter; Orange Health Service, Central West Cancer Care Centre Clarke, Stephen; North Sydney Local Health District, Dept of Medical Oncology, Royal North Shore Hospital; Kolling Institute of Medical Research Briscoe, Karen; Mid North Coast Local Health District, Mid North Coast Cancer Institute Aghmesheh, Morteza; Illawarra Shoalhaven Local Health District, Illawarra Shoalhaven Cancer and Haematology Network, Wollongong Hospital Wong, Nicole; University of Sydney, NHMRC Clinical Trials Centre Walsh, Anna; University of Sydney, NHMRC Clinical Trials Centre Hahn, Carmel; Chris O'Brien Lifehouse Grimison, Peter; University of Sydney, NHMRC Clinical Trials Centre; Chris O'Brien Lifehouse, Dept of Medical Oncology Cannabis, Cannabidiol, Chemotherapy-induced nausea and vomiting, Keywords: Randomized trial, Antiemetic, Marijuana For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 12 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020745 on 12 September 2018. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 12 BMJ Open: first published as 10.1136/bmjopen-2017-020745 on 12 September 2018. Downloaded from 1 2 3 Oral cannabinoid-rich THC/CBD cannabis extract for secondary 4 5 prevention of chemotherapy-induced nausea and vomiting: a 6 7 study protocol for a pilot and definitive randomised double- 8 blind placebo-controlled trial (CannabisCINV) 9 10 Antony Mersiades 1, Annette Tognela 2, Paul S Haber 3 4, Martin Stockler 1 5 6, Nicholas Lintzeris 3 7, 11 John Simes 1 5, Iain McGregor 8, Ian Olver 9, David J Allsop 8, Craig Gedye 10, Adrienne Kirby 1, 12 Rachael L Morton 1, Peter Fox 11, Stephen Clarke 12 13, Karen Briscoe 14, Morteza Aghmesheh 15, 13 Nicole Wong 1, Anna Walsh 1, Carmel Hahn 5, Peter Grimison 1 5 14 15 16 Author Dr Antony ForJ Mersiades peer review only 17 Co-authors Dr Annette Tognela, Prof Paul S Haber, Prof Martin Stockler, Prof Nicholas Lintzeris, Prof John Simes, Prof Iain McGregor, Prof Ian Olver, Dr David J Allsop, Prof Craig Gedye, Ms Adrienne Kirby, Dr 18 Rachael L Morton, Dr Peter Fox, Prof Stephen Clarke, Dr Karen Briscoe, Dr Morteza Aghmesheh, Ms Nicole 19 Wong, Mrs Anna Walsh, Carmel Hahn, A/Prof Peter Grimison 20 21 Corresponding author 22 Dr Antony J Mersiades 23 NHMRC Clinical Trials Centre, University of Sydney 24 Lifehouse, Level 6, 119-143 Missenden Road, Camperdown, NSW, Australia, 2050 25 Email [email protected] 26 Phone +612 9562 5000 27 Author affiliations 28 1NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia 29 2Macarthur Cancer Therapy Centre, Campbelltown Hospital, NSW, Australia 30 3Discipline of Addiction Medicine, University of Sydney, NSW, Australia 31 4Drug Health Services, Sydney Local Health District, NSW, Australia 32 5Dept of Medical Oncology, Chris O’Brien Lifehouse, NSW, Australia 6Dept of Medical Oncology, Concord Cancer Care Centre, Concord Hospital, NSW, Australia 33 http://bmjopen.bmj.com/ 7 34 Drug and Alcohol Services, South East Sydney Local Health District, NSW, Australia 8Lambert Initiative for Cannabinoid Therapeutics, University of Sydney, NSW, Australia 35 9 36 Sansom Institute for Health Research, University of South Australia, Australia 10Dept of Medical Oncology, Calvary Mater Newcastle, NSW, Australia 37 11Central West Cancer Care Centre, Orange Health Service, NSW, Australia 38 12Dept of Medical Oncology, Royal North Shore Hospital, NSW, Australia 39 13Kolling Institute of Medical Research, NSW, Australia 40 14Mid North Coast Cancer Institute, Coffs Harbour Hospital, NSW, Australia 15 41 Illawarra Shoalhaven Cancer and Haematology Network, Wollongong Hospital, NSW, Australia on September 28, 2021 by guest. Protected copyright. 42 43 Keywords 44 Cannabis, cannabidiol, chemotherapy-induced nausea and vomiting, randomized trial, antiemetic 45 46 Word count - 3672 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 12 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020745 on 12 September 2018. Downloaded from 1 2 3 ABSTRACT 4 Introduction Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients 5 receiving chemotherapy despite guideline consistent antiemetic therapy. Trials using delta-9- 6 Tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events, 7 and flawed study design. Trials using cannabinoid-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids 8 for this indication, nor has the potential economic impact of incorporating such regimens into the Australian 9 healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of 10 adding TN-TC11M, an oral cannabidiol-rich THC/CBD extract to guideline-consistent anti-emetics in the 11 secondary prevention of CINV. 12 Methods and analysis The current multi-centre, 1:1 randomised cross-over, placebo-controlled pilot study will 13 recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic 14 chemotherapy despite guideline consistent antiemetics. Patients receive oral TN-TC11M (2.5/2.5mg) capsules 15 or placebo capsules TDS on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug 16 regimen during Cycle B of chemotherapy, and the preferred drug regimen during cycle C. The primary end- point is the proportionFor of subjects peer attaining a completereview response to CINV. only Secondary and tertiary endpoints 17 include regimen tolerability, impact on quality of life and health system resource use. The primary assessment 18 tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled 19 parallel phase III trial will recruit a further 250 patients. 20 Ethics and dissemination The protocol was approved by ethics review committees for all participating sites. 21 Results will be disseminated in peer-reviewed journals and at scientific conferences. 22 Trial registration number Pre-results, ACTRN number 12616001036404) 23 24 Strengths and limitations of the study 25 ♦ 26 Largest and most definitive