Open access Protocol Stroke Vasc Neurol: first published as 10.1136/svn-2020-000791 on 5 May 2021. Downloaded from Clopidogrel with aspirin in High- risk patients with Acute Non-disabling Cerebrovascular Events II (CHANCE-2): rationale and design of a multicentre randomised trial Yongjun Wang,1,2 Claiborne Johnston ,3 Philip M Bath,4 Xia Meng,1,2 Jing Jing,1,2 Xuewei Xie ,1,2 Anxin Wang ,1,2 Yuesong Pan ,1,2 Anding Xu ,5 Qiang Dong,6 Yilong Wang,1,2 Xingquan Zhao,1,2 Zixiao Li,1,2 Hao Li ,1,2 For the CHANCE-2 Investigators To cite: Wang Y, Johnston C, ABSTRACT High- risk patients with Acute Non- disabling Bath PM, et al. Clopidogrel Background In patients with a minor ischaemic stroke Cerebrovascular Events (CHANCE) trial and with aspirin in High-risk or transient ischaemic attack (TIA), separate trials have patients with Acute Non- the Platelet- Oriented Inhibition in New TIA shown that dual antiplatelet therapy with clopidogrel plus disabling Cerebrovascular and Minor Ischaemic Stroke (POINT) trial, a Events II (CHANCE-2): rationale aspirin (clopidogrel–aspirin) or ticagrelor plus aspirin lower risk of stroke recurrence was observed and design of a multicentre (ticagrelor–aspirin) are more effective than aspirin alone with a combination of clopidogrel and aspirin in stroke secondary prevention. However, these two sets randomised trial. Stroke & (clopidogrel–aspirin) than with aspirin Vascular Neurology 2021;0. of combination have not been directly compared. Since 3 4 doi:10.1136/svn-2020-000791 clopidogrel was less effective in stroke patients who were alone. However, the choice of an optimal CYP2C19 loss- of- function (LOF) allele carriers, whether dual antiplatelet therapy regimen for patients ► Additional online with strokes requires a tailored approach supplemental material is ticagrelor–aspirin is clinically superior to clopidogrel– published online only. To view, aspirin in this subgroup of patients with stroke is unclear. based on the characteristics of the patient. please visit the journal online Aim To describe the rationale and design considerations The genetic substudy of the CHANCE trial (http:// dx. doi. org/ 10. 1136/ svn- of the Clopidogrel in High- risk patients with Acute Non- showed that clopidogrel plus aspirin reduced 2020- 000791). disabling Cerebrovascular Events (CHANCE-2) trial. the risk of stroke recurrence in non- carriers http://svn.bmj.com/ Design CHANCE-2 is a randomised, double- blind, double- Received 9 December 2020 of the cytochrome P450 2C19 (CYP2C19) dummy, placebo- controlled, multicentre trial that compares Revised 15 March 2021 loss-of- function (LOF) alleles compared Accepted 9 April 2021 two dual antiplatelet strategies for minor stroke or TIA with aspirin alone but not in carriers. There- patients who are CYP2C19 LOF allele carriers: ticagrelor fore, clopidogrel may not provide additional (180 mg loading dose on day 1 followed by 90 mg twice benefit in stroke prevention compared with daily on days 2–90) or clopidogrel (300 mg loading dose on 5 day 1 followed by 75 mg daily on days 2–90), plus open- aspirin alone for the carriers. More recently, on September 28, 2021 by guest. Protected copyright. label aspirin with a dose of 75–300 mg on day 1 followed the substudy of POINT failed to reproduce by 75 mg daily on day 2–21. All will be followed for 1 year. the above findings as seen in the CHANCE 6 Study outcomes The primary efficacy outcome is any trial, possibly from a limited statistical power. stroke (ischaemic or haemorrhagic) within 3 months and In addition, a meta- analysis of 15 studies that the primary safety outcome is any severe or moderate included 4762 patients with stroke or TIA bleeding event within 3 months. found that carriers of CYP2C19 LOF alleles Discussion The CHANCE-2 trial will evaluate whether were at higher risk of vascular events than ticagrelor–aspirin is superior to clopidogrel–aspirin for non- carriers when taking clopidogrel.7 minor stroke or TIA patients who are CYP2C19 LOF allele Ticagrelor is a reversible oral antago- carriers. © Author(s) (or their nist directly blocking the P2Y12- adenosine Trial registration number NCT04078737. employer(s)) 2021. Re-use diphosphate receptor that needs no catab- permitted under CC BY-NC. No commercial re- use. See rights olite activation, which in turn yields greater and permissions. Published by INTRODUCTION AND RATIONALE mean levels of platelet inhibition than clopi- BMJ. In patients with acute non-disabling cerebro- dogrel.8 9 From the Acute Stroke or Tran- For numbered affiliations see vascular events, including those with acute sient Ischaemic Attack Treated with Aspirin end of article. minor stroke or transient ischaemic attack or Ticagrelor and Patient Outcomes trial (TIA), the subsequent recurrent stroke and involving participants with acute ischaemic Correspondence to Dr Yongjun Wang; cardiovascular events are more than 6% in stroke or TIA, ticagrelor was not found to 1 2 yongjunwang@ ncrcnd. org. cn the first year. As shown in Clopidogrel in be more effective than aspirin in reducing Wang Y, et al. Stroke & Vascular Neurology 2021;0. doi:10.1136/svn-2020-000791 1 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000791 on 5 May 2021. Downloaded from the risk of 90- day vascular events.5 However, among Genotyping the Asian patients, a tendency towards better efficacy In this study, a novel point- of- care genetic test platform was seen in a subgroup analysis.10 The Platelet Reac- will be used to identify carriers of CYP2C19 LOF alleles tivity in Acute Stroke or Transient Ischaemic Attack including poor metabolisers with at least two *2 or *3 trial showed that participants with ischaemic stroke or alleles (*2/*2, *2/*3, or *3/*3) or intermediate metab- TIA who were treated with ticagrelor plus aspirin (tica- olisers with one *2 or *3 allele (*1/*2 or *1/*3). The grelor–aspirin) had a lower proportion of high platelet CYP2C19 genotyping will be implemented by the GMEX reactivity than those who were treated with clopidogrel– Point- of-Care Genotyping system, including a portable aspirin, particularly in the those who were CYP2C19 LOF DNA analyser, genotyping reagents, and a buccal sample allele carriers.11 The Acute Stroke or Transient Isch- collection kit. The system uses non- invasive sampling aemic Attack Treated with Ticagrelor and Aspirin for by buccal swab and integrates automated steps of DNA Prevention of Stroke and Death trial showed that dual extraction, PCR- based amplification, fluorescent signal antiplatelet therapy (ticagrelor–aspirin) was better than detection and genotype determination. The system inte- mono antiplatelet therapy (aspirin) for secondary stroke grates controls to monitor the performance of a run prevention in people with mild- to-moderate acute isch- and ensure ongoing quality from the GMEX system. aemic stroke or TIA, but the rate of haemorrhage was The analysis includes the single nucleotide polymor- also elevated.12 phisms CYP2C19*2 (681G>A, rs4244285), CYP2C19*3 While separate trials have shown similar treatment (636G>A, rs4986893), and CYP2C19*17 (−806C>T, effects, no direct comparison has been conducted in this rs12248560), which will be genotyped on screening. patient population. In some populations, more than 50% The average result turn- around- time for the method of 13 of them carry CYP2C19 LOF alleles so that the conver- GMEX is 85 min. sion to an active form of clopidogrel is reduced. We hence hypothesised that, compared with clopidogrel– Randomisation aspirin, ticagrelor–aspirin may favourably impact the Participants will be randomised (1:1) to receive either clinical outcomes in high-risk participants with acute non- ticagrelor–aspirin or clopidogrel–aspirin. A randomisa- disabling cerebrovascular events and were carriers of the tion sequence will be generated centrally using random- CYP2C19 LOF allele. Therefore, the CHANCE-2 trial was permuted fixed-size blocks methods from the Statistics designed to test such hypothesis. The intention of this trial and Data Centre at the China National Clinical Research is to evaluate the safety and efficacy of ticagrelor–aspirin Centre for Neurological Diseases. The randomisation versus clopidogrel–aspirin for minor stroke or high- risk computer program makes the treatment assignment TIA patients who were CYP2C19 LOF allele carriers. This based on the current status of treatment group distribu- article describes the design of the CHANCE-2 trial and is tion within each clinical centre as well as overall balance a summary of protocol. of treatment assignment. Following randomised alloca- http://svn.bmj.com/ tion, the study intervention will be administered to the patient as early as possible. METHODS Design and patients population Intervention CHANCE-2 is a randomised, double-blind, double- Eligible participants are randomly assigned to one of two dummy, placebo- controlled multicentre trial. Patients arms: on September 28, 2021 by guest. Protected copyright. with CYP2C19 LOF alleles are randomised with 1:1 to one of the two strategies (ticagrelor–aspirin or clopi- Ticagrelor–aspirin group dogrel–aspirin) within 24 hours of the onset of cere- A 180 mg loading dose of Ticagrelor on day 1, followed brovascular Events. All participants will be followed by 90 mg two times per day on days 2–90 plus a 75–300 for 3 months on study intervention, with another 9 mg loading dose of aspirin, followed by 75 mg daily for months of follow- up on standard of care. The study 21 days; design of the CHANCE-2 is shown in figure 1. The trial will enrol subjects age ≥40 years with acute non- Clopidogrel–aspirin group disabling ischaemic stroke, with a National Institutes A 300 mg loading dose of clopidogrel on day 1, followed of Health Stroke Scale (NIHSS) score ≤3 or high- risk by 75 two times per day on days 2–90 plus a 75–300 mg TIAs (ABCD2 score ≥4).