Multicentre prospective, randomised open-label, endpoint-blinded study to evaluate the safety and efficacy of propranolol for the prevention of stroke-associated pneumonia in patients with intracerebral haemorrhage (PROCHASE): rationale and design

Design

The ongoing PROCHASE trial is an investigator-initiated, multicentre, prospective, randomised clinical trial with open-label treatment and blinded outcome assessments. The study is designed to recruit 168 patients over 2 years from comprehensive stroke centres across China. A flowchart drafting the study design is presented in figure 1. The study protocol underwent an amendment after the initial recruitment of 8% of patients. Both the original and amended protocols of PROCHASE have been approved by the ethics committees of all participating centres. Changes made to the original and amended protocols are detailed in the supplementary materials, and all enrolled patients met the criteria of the amended protocol.

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Figure 1

PROCHASE study design. PROCHASE, A multicentre prospective, randomised open-label, endpoint-blinded study to evaluate the safety and efficacy of propranolol for the prevention of SAP in patients with ICH.

Patient population

Participants are recruited from stroke centres across China. Patients with persistent neurological deficits who are diagnosed with ICH via head CT are screened in accordance with the study’s inclusion and exclusion criteria (online supplemental material). The inclusion criteria are as follows: patients aged >18 and ≤80, randomisation within 24 hours after ICH onset, no fever or evidence of infection on admission, National Institutes of Health Stroke Scale (NIHSS) score of 11–25, supratentorial parenchymal haematoma of ≥10 mL, Glasgow Coma Scale (GCS) of ≥8 points and patients or family members signed informed consent forms. Exclusion criteria are as follows: infections within the last 4 weeks, use of antibiotics within the last 2 weeks, known pre-ICH dysphagia, planned surgical treatment (including surgical removal of haematoma, decompressive craniectomy, minimally invasive haematoma aspiration and ventricular shunt or lateral ventricular drainage for ICH); primary ventricular haemorrhage or cerebral haemorrhage caused by trauma, vascular malformation, aneurysm, coagulopathy, anticoagulant or antiplatelet drugs, thrombolysis, post-infarction haemorrhagic transformation, haematopathy, moyamoya disease, primary or metastatic tumours, venous sinus thrombosis, vasculitis and other definite causes; history of stroke or pre-onset disability of limb motor function (modified Rankin scale (mRS) of ≥1); pregnancy or within 30 days of delivery; previous (within 1 month) use of beta-blockers or reserpine; bronchial asthma or chronic obstructive pulmonary disease; cardiogenic shock; II-III degree atrioventricular block; severe or acute heart failure; heart rate of <65 beats/min; known to be allergic to propranolol; severe liver or renal insufficiency; history of malignant tumour; currently participating in any other interventional clinical trials; and any treatment with immunosuppressants or immunotherapy.

Randomisation

Following the obtaining of written informed consent, patients will be randomly assigned to the standard medical management group or standard medical management plus intravenous propranolol hydrochloride injection group in a 1:1 ratio. The randomisation process is internet-based and can be accessed via both mobile devices and web platforms. All participating centres will be subject to continuous monitoring to ensure adherence to the study protocol.

Treatment and intervention

Both treatment groups will receive standard medical care, which includes antihypertensive therapy, blood glucose management, intracranial pressure control or a combination of these interventions, in accordance with national and institutional guidelines. Patients are randomised within 24 hours after symptom onset or the timepoint of last seen well.

Intravenous propranolol hydrochloride injection (5 mg daily on day 1–7), provided by Jiangsu Longer Pharmaceutical Co, Ltd is initiated within 2 hour of randomisation if patients are allocated to the propranolol group. Detailed dosing guidelines were established for safety and presented in Supplementary materials.

Study organisation

On-site visits with participants are conducted separately at baseline, 72±12 hours, 7±1 days, 14±2 days or discharge day. Centralised telephone interviews are performed separately at 30±5 days and 90±7 days. NIHSS and GCS scores are recorded at baseline, 72±12 hours and 7±1 days. The mRS scores are recorded at baseline, 30±5 days and 90±7 days. Chest CT should be completed at baseline and conducted at any time within 7±1 days of onset if pneumonia is suspected by clinicians; otherwise, a chest CT will be conducted at 7±1 days. Head CT should be completed at baseline and 7±1 days. Laboratory tests and chest signs should be conducted at baseline, 72±12 hours and 7±1 days.

Primary outcome

SAP is diagnosed according to a defined algorithm within 7±1 days after randomisation. The predefined algorithm is based on the diagnosis of SAP recommendations from pneumonia in stroke consensus group (PISCES)25 and presented in online Supplementary materials.

Secondary outcomes

A favourable outcome is defined as an mRS of 0–3 on 90±7 days.

Safety outcomes

The primary safety outcome is defined as severe or moderate bradycardia within 7±1 days. Bradycardia is diagnosed using ECG monitoring. Severe bradycardia is defined as a heart rate of <40 beats/min. Moderate bradycardia is defined as a heart rate of <55 beats/min. Additional secondary safety outcomes include mortality, adverse events (AEs) and serious AEs, all occurring within 90 days, as reported by the investigators.

Study assessment

All patients undergo evaluation of the NIHSS and GCS at baseline, 72±12 hours and 7±1 days. At baseline, 72±12 hours and 7±1 day post-randomisation, body temperature was measured using an axillary thermometer, and pulmonary auscultation, laboratory tests and chest CT were performed to assess for SAP according to the algorithm defined by the diagnostic criteria from the PISCES group.25 Chest CT was repeated when patients exhibited SAP symptoms or 7 days post-randomisation. The 90 day clinical outcome, as defined by the mRS, was evaluated by independent investigators who were blinded to treatment allocation. All imaging data of the patients will be collected and independently evaluated by neurologists and radiologists, who were also blinded to treatment allocation. Video recordings of patients’ baseline neurological assessments are collected to allow an independent investigator to verify the adequate fulfilment of all the criteria of inclusion and exclusion prior to randomisation. Regular meetings with investigators are held to offer feedback and identify potential areas for improvement.

Sample size calculation

According to published retrospective studies,6 18 19 we predict the occurrence of SAP as follows:

• 30% of patients in the control group.6 26

• 9% of patients in the propranolol group, based on the efficacy data for propranolol in the prevention of SAP.8 19 In addition, the evaluated efficacy of atenolol in primary prevention reveals a relative 70% decrease in SAP risk in ICH patients.18 Based on these assumptions, and considering an alpha threshold of 5%, a power of 90% and an estimated risk of loss to follow-up of 20%, a minimum of 84 evaluable patients per group should be recruited, that is, a total of 168 patients. The sample size was calculated using PASS 21.0.2.

Statistical analyses

The primary outcome measure will be the risk ratio, which compares the proportion of patients who develop SAP within 7±1 days between the two treatment groups. This ratio will be adjusted for key prognostic factors such as age, baseline stroke severity (assessed by NIHSS and GCS), haematoma volume and other relevant variables that could contribute to imbalances between the intervention and control groups. Both intention-to-treat and per-protocol analyses will be conducted. Secondary outcomes will be analysed using log-binomial or linear regression methods, as appropriate, with the same adjustment approach applied as for the primary outcome. Missing baseline data will be reported, and any missing values will be imputed using regression-based methods. Adjusted and unadjusted estimates, along with the corresponding 95% CIs, will be presented. All analyses will be performed using a two-sided significance level of 5%.

Data safety and monitoring board

The data safety and monitoring board (DSMB) is made up of independent academic professionals and statisticians who are not involved in the trial’s implementation. The DSMB’s charter, outlining its membership, duties and responsibilities, will be reviewed and approved by both the board members and the executive committee. The DSMB will conduct continuous monitoring to ensure ethical standards and patient safety, with full access to the final dataset of the trial.

Management and quality control of data

Data will be transferred by an electronic data capture system using electronic case report forms (eCRFs), after being proofread and verified by data managers. All investigators at the participating sites are required to be qualified for good clinical practice (GCP). Clinical monitors will perform regular site visits to ensure full compliance with the study protocol and to verify that the eCRF records match the original data.

Withdrawal criteria for the study

Participants may withdraw from the study at any time, without the need to provide justification. If participants develop conditions that make them unsuitable for continued participation, the investigators will determine whether to withdraw them from the trial.

Management of project

The steering committee is in charge of designing the trial and providing overall strategic guidance. The executive committee oversees the study’s progress, with a particular focus on data collection. The adjudication committee, made up of external experts, will evaluate the study endpoints and AEs, making final decisions. Site investigators will manage patient recruitment, data collection as well as the reporting of clinical events. The National Clinical Research Centre for Neurological Diseases of China will manage the randomisation process, ensure data quality control and perform statistical analyses.