Trendelenburg position for acute anterior circulation ischaemic stroke with large artery atherosclerosis aetiology (HOPES 3): rationale and design

Design

HOPES 3 is a prospective, randomised, open-label, blinded endpoint and multicentre study in China assessing the benefit of HDP in acute moderate ischaemic stroke patients with LAA. The HOPES 3 trial is registered on www.clinicaltrial.gov (NCT06010641).

Study population

In the HOPES 3 trial, eligible patients are adults with acute anterior circulation moderate ischaemic stroke (initial National Institutes of Health Stroke Scale (NIHSS) 6–16, presenting within 24 hours of onset, or progressing from mild stroke (NIHSS≤5) to moderate stroke (NIHSS 6–16) within 24 hours). Patients who are candidate for reperfusion therapy or planned carotid or intracranial artery revascularisation within 3 months are excluded. Vessel stenosis will be determined by Computed Tomography Angiography(CTA) or Magnetic Resonance Angiography(MRA) before or after randomisation. Moderate stenosis will be estimated as 50% to 69% stenosis and severe stenosis as 70% stenosis or greater according to the Warfarin Aspirin Symptomatic Intracranial Disease(WASID) method of measurement. Patients will be enrolled at approximately 50 sites in China between November 2023 and June 2025. The detailed inclusion and exclusion criteria are shown in box 1.

Randomisation and treatment

As shown in figure 1, patients are randomised 1:1 into the HDP group or control group by using a central and computerised random sequence generation stratified by centre. Consistent with the HOPES 2 trial,25 in the HDP group, patients will be positioned to −20° Trendelenburg position from 8:00 to 22:00 within the first 24 hours after randomisation. During this period, they are instructed to report any discomfort. If this position is not tolerated by the patient, they are slowly repositioned to a horizontal level for 10–30 min, followed by a return to −20°. Repeated position adjustments could be made during HDP intervention. After 24 hours, the patient is positioned at a −20° Trendelenburg for 1–1.5 hours three times a day, 9:00–11:00, 15:00–17:00 and 20:00–22:00, respectively. The treatment will continue for 10 days. During HDP, the patient can be placed in the side-lying position with −20° Trendelenburg if local investigators suspect a high risk of aspiration. In addition, all patients in the intervention arm will receive standard medical care as per national stroke guidelines.7 The control group patients will receive standard medical care in compliance with national guidelines for AIS without any intervention of head position (supine or sitting position to be determined by local investigator).7

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Outcomes

The primary endpoint is favourable functional outcome, defined as modified Rankin Scale (mRS) 0–2 at 90 days.

The secondary endpoints include: excellent functional outcome (mRS score, 0–1) at 90 days; ordinal distribution of mRS at 90 days; early neurological deterioration (END), defined as more than 4-point increase in NIHSS within 48±12 hours, but not due to intracerebral haemorrhage; early neurological improvement (ENI), defined as more than 4-point decrease in NIHSS within 48±12 hours; change in NIHSS Score from baseline at 48±12 hours and 10±2 days; change in infarct volume from baseline at 48±12 hours; new stroke or other vascular event(s) within 90±7 days; all-cause mortality within 90±7 days.

The exploratory endpoints include: change in cortical oxygen saturation determined by near infrared spectroscopy at 24±8 hours and 48±12 hours; change in serum biomarkers at 48±12 hours and 10±2 days compared with baseline.

In agreement with HOPES 2,25 the safety endpoints include any adverse event (AE) or serious AE during HDP, such as patient fear, headache, anxiety, intracranial haemorrhage (European Cooperative Acute Stroke Study [ECASS] definition),26 cardiopulmonary events and pneumonia,27 which were not present at the beginning of the study.

Follow-up procedure

All patients will be visited at 48±12 hours, 10±2 days and 90±7 days after randomisation (table 1). We will record demographic data, laboratory results, neuroimaging data and neurological scoring such as NIHSS and mRS at baseline; repeat non-contrast CT or MRI at 48 hours and NIHSS scoring at 48 hours and 10 days; assess mRS at 90 days. All clinical evaluations, including NIHSS and mRS will be performed by qualified investigators in accordance with standardised protocol brochures in each site. The primary efficacy outcome (90-day mRS) is assessed by trained and certified investigators without knowledge of randomised treatment assignment at each site, either in person or by telephone interview (if in person interview is impossible). The investigators will record concomitant medications and AEs within 90 days after randomisation in detail, which will be judicated by certified assessors. The study period is estimated to be approximately 24 months.

Quality control

The data and safety monitoring committee (DSMC) will conduct data verification for safety every 6 months in this trial. After finishing follow-up of 50% of the participants, an interim analysis will be conducted by an independent statistician of the DSMC who will not be in the management of the trial. The main purpose of the stopping is to protect the patients’ rights and interests and to avoid unwanted financial losses. The DSMC has the right to terminate the study unconditionally, if there is a statistically significant difference in the efficacy and/or safety of one therapy compared with another. Neuroimaging data will be collected centrally and analysed by two independent neuroradiologists.

Data management and monitoring

All patient’s data will be recorded on MedSci (http://HOPES3.medsci.cn), which is able to store the patient case report form. The enrolled participants will be randomised in a 1:1 ratio into either the HDP or control group. Data will be downloaded from MedSci and statistically analysed by dedicated staff. An independent DSMC is set up to assure continuous monitoring of data safety, for example, haemorrhagic events and other AEs. Stopping or sample size modification rule will be prespecified by the DSMC. Based on the results of the analysis, the DSMC will be able to recommend sample size adjustments or early termination of the study to the steering committee of the HOPES 3 trial.

AE monitoring

An AE refers to any adverse medical event that occurs during the trial. All information regarding AEs will be documented on the AE page(s) of the case report, a further determination will be made by the principal investigator as to whether the unexpected AE is related to the HDP treatment.

Sample size estimates

According to our recent HOPES 2 trial,25 the prevalence of favourable functional outcome at 90 days (mRS 0–2) was 50% in the control group and 65.2% in the HDP group, with a 15.2% absolute difference. An absolute 12% increase in primary outcome in the HDP group is conservatively estimated, which translates into primary outcome of 62% in HDP group. A one-sided test with a power of 80% and α set at 0.025 calculated a sample size of 540 patients to test the hypothesis of superiority. The sample size is readjusted to 600 patients given a loss to follow-up rate of 10% and alpha consumption by interim analysis (O’Brien-Fleming method). This study will therefore include 600 patients, 300 in each group.

Statistical analysis

An intention-to-treat analysis is applied to determine the treatment effect between two groups. Normally distributed data will be expressed as mean±SD, and non-normally distributed data will be expressed as median and IQR. For binary outcomes including favourable functional outcome, excellent functional outcome, ENI, END and occurrence of all-cause death in 90 days, treatment effects will be analysed using binary logistic regression. Ordinal logistic regression will be used to analyse mRS distribution at 90 days between treatment groups. A general linear model will be used to analyse change in NIHSS Score or infarct volume between treatment groups, while Cox regression for time to event of stroke recurrence and other vascular events. All data are analysed with SPSS V.23.0 Software. Statistical significance will be achieved if the p value is <0.05.

The primary outcome will further be stratified by age (<60 years vs ≥60 years), sex (female vs male), history of diabetes (yes vs no), history of hypertension (yes vs no), baseline systolic blood pressure (>140 mm Hg vs ≤140 mm Hg), location of index vessel (internal carotid artery vs middle cerebral artery), NIHSS Score at randomisation (6–10 vs 11–16), onset to randomisation time (<12 hours vs ≥12 hours), progression to moderate neurological deficit due to END (yes vs no), degree of responsible vessel stenosis (moderate stenosis vs severe stenosis vs occlusion) and stroke mechanism (artery-to-artery embolism vs perforator infarct vs hypoperfusion). Differences in primary outcome in above-mentioned subgroups will be evaluated by detecting the interaction effect of the prespecified baseline variable on the primary outcome.

Study organisation and funding

The trial steering committee (TSC), made up of external scientific advisors, will regularly oversee the study and data. The TSC will host teleconference or physical meetings every 6 months to provide recommendations on the study. The trial is initiated and supported by the Cerebrovascular Disease Collaboration & Innovation Alliance of Liaoning.

Current status

At the initial submission of this paper, the patients have not yet to be recruited. Enrolment will remain open until the complete sample size is attained, which is anticipated to be in June 2025 at the latest.