Remote Ischemic Conditioning for the Prevention of Stroke-Associated Pneumonia (RICA-2): Protocol for A Multicenter, Prospective, Randomized, Double-Blind, Sham-Controlled Phase III Trial

Remote Ischemic Conditioning for the Prevention of Stroke-Associated Pneumonia (RICA-2): Protocol for A Multicenter, Prospective, Randomized, Double-Blind, Sham-Controlled Phase III Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Remote Ischemic Conditioning for the Prevention of Stroke-Associated Pneumonia (RICA-2): Protocol for A Multicenter, Prospective, Randomized, Double-Blind, Sham-Controlled Phase III Trial Lina Jia, Chengbei Hou, Qing Mei, Bowei Zhang, Wenbo Zhao, Heng Zhao, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5497261/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Oct, 2025 Read the published version in Trials → Version 1 posted 6 You are reading this latest preprint version Abstract Background Stroke-associated pneumonia (SAP) is one of the most common complications in acute ischemic stroke (AIS) patients, affecting 8.5% to nearly 30% of cases and significantly impacting both mortality and long-term survival. As its closely related with worse outcome, exploring effective preventive strategies, such as remote ischemic conditioning (RIC), is essential for reducing SAP incidence and improving patient outcomes. This study aims to compare the efficacy and safety of RIC for preventing SAP in patients with ischemic stroke within 24 hours of symptom onset. Methods and design: RICA-2 is a multicenter, randomized, double-blind, parallel-controlled, phase III clinical trial in China. This study will enroll an estimated 1,650 patients aged ≥ 18 years within 24 hours after AIS symptom onset, with National Institutes of Health Stroke Scale ⩾ 4. The patients will be randomly assigned to RIC or sham-RIC(1:1), and will be treated cuff inflation at 200 mmHg, or 60 mmHg, respectively. This procedure will be administered twice daily for seven consecutive days. The primary efficacy endpoint is SAP incidence rate. Safety incidence will be recorded and reported. Discussion RIC has broad clinical application prospects and may play a preventive role in stroke related pneumonia. RICA-2 is designed to verify whether RIC treatment can serve as an adjuvant therapy for preventing stroke associated pneumonia and to identify safety concerns. Trial registration http//www.clinicaltrials.gov, NCT05982015. Remote ischemic conditioning acute ischemic stroke stroke-associated pneumonia clinical trial protocol Figures Figure 1 Introduction and rationale Stroke-associated pneumonia (SAP) is one of the most common complications after stroke [ 1 ] . SAP is strongly associated with increased mortality rates in stroke patients [ 2 ] , significantly increasing the risk of death up to three years poststroke [ 3 ] . During a stroke, local inflammatory activity intensifies while systemic immune function decreases, resulting in immunosuppression, which is a primary independent risk factor for SAP in stroke patients [ 4 ] . Given the substantial impact of infections on functional recovery, numerous trials have explored the efficacy of prophylactic antibiotics in stroke care. However, these studies have shown considerable heterogeneity in design, antibiotic type, and measured outcomes, limiting their generalizability [ 5 ] , as seen in trials such as the Preventive Antibiotics in Stroke Study and STROKE Infection Prevention Study trials [ 6 , 7 ] . Therefore, novel treatments aimed at reducing SAP and improving recovery outcomes in stroke patients are urgently needed [ 8 ] . Remote ischemic conditioning (RIC) has emerged as a promising nonpharmacological intervention to protect distant organs by inducing periodic ischemia and reperfusion in the limbs. Studies suggest that RIC activates endogenous protective mechanisms, protecting remote organs [ 9 , 10 ] . In an experimental ischemia–reperfusion model, RIC has been shown to reduce cerebral ischemia–reperfusion injury, inflammation, brain edema, and neuronal apoptosis [ 11 ] . Whether RIC can be adopted as an effective treatment to decrease SAP occurrence in patients with AIS remains unclear. Therefore, this study aimed to evaluate the efficacy and safety of RIC in preventing SAP in patients with ischemic stroke. This multicenter, double-blind, randomized, sham-controlled phase III trial is designed to provide robust evidence on a novel prevention method for SAP, as well as the potential benefits of RIC. Methods Design This study is a multicenter, randomized, double-blind, sham-controlled phase III clinical trial ( http://www.clinicaltrials.gov . NCT05982015) in China and approved by the Ethics Committee of Xunawu Hospital of Capital Medical University and other cooperative hospitals. The design is shown in Fig. 1 . Patients will be subjected to head computed tomography (CT) or magnetic resonance imaging (MRI) before randomization to identify patients with ischemic stroke. All the subjects received optimal medical therapy on the basis of the 2018 clinical guidelines for AIS [ 12 ] . Before each participant is enrolled, the researcher is responsible for providing a comprehensive overview of the study's purpose, procedures, and potential risks to the patient or their representative. The participants or his or her legally authorized representative signed a written informed consent form and were informed of their right to withdraw from the study at any time. Patient population A total of 1650 patients with acute AIS within 24 hours of onset were recruited from approximately 80 medical centers in China according to the inclusion and exclusion criteria in Table 1. Randomization Randomization will occur after written informed consent is obtained from the patient or their guardian. Following successful screening of participants, patients will be randomly assigned to either the RIC group or the Sham-RIC group at a 1:1 ratio via block randomized blocks (4, 6, and 8) stratified by age (≤ 70 or > 70 years old), stroke severity (NIHSS scores between 4–20 years or higher than 20), and sex (male or female). A central network randomization system will generate random code. Neither patients nor researchers will have information on the group allocation. Both RIC and Sham-RIC will be administered via equipment with the same appearance but with different pressure settings for the two treatment regimens. Additionally, consecutive enrolled subjects will not be placed in the same ward for this study. At the end of this study, the subjects were asked several questions, as shown in Table 2, to investigate unblinding situations. Unblinding will only be allowed if a participant’s health is at risk and the attending physician deems it necessary. Unblinding must be approved by the principal investigator and documented. Baseline measurements In addition to confirming eligibility for AIS, a comprehensive baseline assessment will be conducted prior to randomization. This assessment will encompass several key variables, including demographic characteristics, clinical and medical history, physical examination findings, vital signs, smoking and alcohol consumption status, and medication usage within one week prior to admission. Additionally, laboratory examinations, neuroimaging, and chest imaging, including CT or chest X-ray scans, will also be performed. Furthermore, the assessment will utilize standardized scales such as the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin scale (mRS), the self-rating depression scale (SDS), the generalized anxiety disorder scale (GAD-7), and a swallowing function assessment. Intervention and assessment Eligible patients will be randomly assigned to either the RIC group or the Sham-RIC group. The RIC procedure consisted of 5 cycles of inflation to a pressure of 200 mmHg (RIC group) or 60 mmHg (Sham-RIC group) and deflation for 5 min alternately within 1 hour of enrollment performed on the upper arm by an electric autocontrolled device with cuff (patent number ZL201420846209.5, China), the total process lasted 45 minutes. The Sham-RIC did not result in upper limb ischemia. All patients will receive optimal medical treatment and care from local medical practices throughout the study. The numbers of RIC treatment will be recorded by the study nurse and sighed their names per time. The electronic data collection system will send message to the researcher to remind them to visit patients. The research period spans approximately two years. Research protocol version 3.0, version date July 19, 2023, recruitment date January 22, 2024, recruitment completed on September 12, 2024. The final follow-up period for the subject is expected to be completed on December 12 (± 7 days), 2024. Follow-up visits will be scheduled at each research center on days 1, 3, 7, and 90 after the initiation of treatment, as well as at the conclusion of the study. The details are outlined in Table 3. Outcomes The primary efficacy endpoint is the incidence of SAP within 7 days of intervention after randomization. The details of the SAP diagnostic criteria [ 13 ] are presented in Table 4. The secondary endpoints were as follows: diagnosis of pneumonia by clinical doctors within 7 days; diagnosis of pneumonia by clinical doctors between 8 days and 90 days; mRS score of 0–1 ratio on Day 90; mRS score of 0–2 ratio on Day 90; distribution of mRS scores on Day 90; EuroQoL 5- Dimensions 5-Level questionnaire (EQ-5D-5L) score on Day 90; NIHSS scores at 24 hours after onset; NIHSS scores at Day 7; Incidence of urinary tract infection within 7 days; Incidence of all infections within 7 days; all-cause mortality within 90 days; and total inpatient days. The incidence of adverse events was recorded and reported. Sample size On the basis of previous studies [ 14 ] and a recent survey from Xuanwu Hospital, the estimated incidence of SAP in patients with AIS within 24 hours of onset is 17%. The sample size calculation assumes that RIC will reduce the SAP rate from 17.0–11.9%. With a sample size of 1,486 across both groups, the study will have 80% power to detect a difference in SAP incidence between the Sham-RIC and RIC groups at a two-sided significance level of 0.05. While we anticipate that all (or at least a very high proportion) of the enrolled patients will be evaluable at the end of the study, we intend to recruit 875 patients per treatment group, totaling 1,650 patients for this study. Statistical analysis The analysis of efficacy endpoints will be conducted on an intention-to-treat basis. The primary endpoint was the incidence of SAP within 7 days postrandomization. To assess the difference in SAP incidence between the two groups (RIC group vs. Sham-RIC group), we used a modified Poisson regression model to analyze the primary efficacy endpoint. Adjustments for stratification factors, including age, sex, and NIHSS score, were incorporated into the model to control for potential confounding effects. For secondary endpoints, continuous variables will be analyzed via linear regression models, with the same adjustments applied for stratification factors. Binary variables are analyzed via modified Poisson regression, whereas ordinal variables are analyzed via ordinal regression models. Time-to-event variables will be evaluated via Cox proportional hazards regression, with stratification factors controlled throughout. Adverse events will be documented and reported. Statistical significance will be defined as a P value < 0.05. This study did not set an interim analysis. Study organization An independent data monitoring committee is responsible for regularly monitoring patient safety, treatment efficacy, and overall study progress and for assessing whether early termination or protocol amendments are necessary. Discussion In our previous pilot clinical trial investigating the safety and efficacy of remote ischemic conditioning for SAP, 19 patients with AIS onset within 48 hours were randomly assigned to the RIC group (six consecutive days, twice daily), whereas 22 patients were assigned to the control group. The results of this study showed that RIC was safe among patients with AIS. Although the difference was not statistically significant in either univariate or multivariate analyses, the incidence of SAP was lower in the RIC group (10.5%) than in the control group (27.3%) [ 15 ] . The lack of statistical significance may be attributed to the small sample size, limiting the power to detect differences between groups, and recent evidence suggests that the peak of apoptosis and immune suppression following stroke may occur within the first 24 hours [ 16 ] , indicating that earlier prevention might be more beneficial among these patients. Therefore, we aimed to conduct a fully powered clinical trial with adjusted inclusion and exclusion criteria to investigate the efficacy of RIC in preventing SAP in AIS patients within 24 hours of symptom onset following randomization. We hypothesize that 7 days of RIC will reduce the relative risk of SAP by 30%. We implemented several adjustments to address the limitations identified in the previous study [ 15 ] . The inclusion criteria were refined to ensure that the treatment window was within 24 hours of stroke onset, as this period is critical for effectively reducing apoptosis and modulating immune responses. Since the sample size calculation was based on previous studies [ 14 ] , clinical expertise, and prior surveys on SAP incidence at Xuanwu Hospital of Capital Medical University and our participant selection criteria are relatively broad, we anticipate few practical challenges in recruiting a sufficient number of patients. An important advantage of our approach is that the results of our trial can be generalized to a wider population of stroke patients. Additionally, at the end of the study, we used a method from previous research [ 17 ] and contacted the participants, asking them about their knowledge of group allocation by answering the questions in Table 1. This upcoming trial is anticipated to conclude in the second quarter of 2025. Owing to the low cost and ease of use of RIC devices, this intervention has strong potential for widespread adoption by patients and healthcare providers. If successful, this study could demonstrate that RIC significantly reduces the incidence of SAP, promotes recovery, and ultimately improves the quality of life for a large population of stroke patients. Trial status The participant recruitment for this trial commenced on January 22, 2024, and is anticipated to conclude by the end of June 2025. This protocol is the third version, version date : July 19, 2023. Summary and conclusions RIC is a convenient and noninvasive intervention, and the RICA-2 trial aims to investigate whether RIC treatment can effectively reduce stroke-associated pneumonia while also identifying any potential safety concerns. Declarations Author’s contributions Lina Jia, Chengbei Hou, Qing Mei, Bowei Zhang, Heng Zhao, Suhang Shang, Xiuhai Guo, Wenbo Zhao, Chuanhui Li, Ran Meng, Weihai Xu, Yilong Wang, Gelin Xu, Chuanjie Wu, and Xunming Ji were responsible for the conception and design of the study. Lina Jia drafted the manuscript. All authors participated in interpretation of the findings. Qing Mei, Chengbei Hou, Suhang Shang, Ran Meng, Bowei Zhang, Chuanjie Wu, and Xunming Ji revised and commented the draft, and all authors read and approved the final version of the manuscript. All authors confirm that the content has not been published elsewhere and does not overlap with or duplicate their published work. Declaration of conflicting interests Xunming Ji is the inventor of the remote ischemic preconditioning equipment. The authors declared no potential conflicts of interest for this article's research, authorship, and publication. Funding The study was funded by Beijing Scholars Program (No.060) of Xunming Ji. Acknowledgments We would like to express our sincere gratitude to all the patients and their families who participated in this study, as well as the medical staff and coordinators across all participating centers for their support and dedication. We are also grateful to the members of the independent data monitoring committee for their valuable guidance and oversight throughout the study. Special thanks to Min Wang for facilitating the logistics of this multicenter study. Many thanks to Bo Jiang and Bo Zhang for providing technical assistance. References Westendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, van de Beek D. Post-stroke infection: a systematic review and meta-analysis. BMC Neurol 2011, 11: 110. Kwan J, Horsfield G, Bryant T, Gawne-Cain M, Durward G, Byrne CD, Englyst NA. IL-6 is a predictive biomarker for stroke associated infection and future mortality in the elderly after an ischemic stroke. Exp Gerontol 2013, 48(9): 960-965. Krishnan S, O'Boyle C, Smith CJ, Hulme S, Allan SM, Grainger JR, Lawrence CB. A hyperacute immune map of ischaemic stroke patients reveals alterations to circulating innate and adaptive cells. Clin Exp Immunol 2021, 203(3): 458-471. Meisel C, Meisel A. Suppressing immunosuppression after stroke. N Engl J Med 2011, 365(22): 2134-2136. Westendorp WF, Vermeij JD, Vermeij F, Den Hertog HM, Dippel DW, van de Beek D, Nederkoorn PJ. Antibiotic therapy for preventing infections in patients with acute stroke. Cochrane Database Syst Rev 2012, 1: Cd008530. Westendorp WF, Vermeij JD, Zock E, Hooijenga IJ, Kruyt ND, Bosboom HJ, Kwa VI, Weisfelt M, Remmers MJ, ten Houten R, Schreuder AH, Vermeer SE, van Dijk EJ, Dippel DW, Dijkgraaf MG, Spanjaard L, Vermeulen M, van der Poll T, Prins JM, Vermeij FH, Roos YB, Kleyweg RP, Kerkhoff H, Brouwer MC, Zwinderman AH, van de Beek D, Nederkoorn PJ. The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet 2015, 385(9977): 1519-1526. Kalra L, Irshad S, Hodsoll J, Simpson M, Gulliford M, Smithard D, Patel A, Rebollo-Mesa I. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015, 386(10006): 1835-1844. van Gemmeren T, Schuppner R, Grosse GM, Fering J, Gabriel MM, Huber R, Worthmann H, Lichtinghagen R, Weissenborn K. Early Post-Stroke Infections Are Associated with an Impaired Function of Neutrophil Granulocytes. J Clin Med 2020, 9(3). Mollet I, Marto JP, Mendona M, Baptista MV, Vieira HLA. Remote but not Distant: a Review on Experimental Models and Clinical Trials in Remote Ischemic Conditioning as Potential Therapy in Ischemic Stroke. Molecular Neurobiology 2022, 59(1): 294-325. Xu Y, Wang Y, Ji X. Immune and inflammatory mechanism of remote ischemic conditioning: A narrative review. Brain Circ 2023, 9(2): 77-87. Neuroprotection by Remote Ischemic Conditioning in Rodent Models of Focal Ischemia: a Systematic Review and Meta-Analysis. Translational Stroke Research: 1-13. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019, 50(12): e344-e418. Smith CJ, Kishore AK, Vail A, Chamorro A, Garau J, Hopkins SJ, Di Napoli M, Kalra L, Langhorne P, Montaner J, Roffe C, Rudd AG, Tyrrell PJ, van de Beek D, Woodhead M, Meisel A. Diagnosis of Stroke-Associated Pneumonia: Recommendations From the Pneumonia in Stroke Consensus Group. Stroke 2015, 46(8): 2335-2340. Hannawi Y, Hannawi B, Rao CP, Suarez JI, Bershad EM. Stroke-associated pneumonia: major advances and obstacles. Cerebrovasc Dis 2013, 35(5): 430-443. Zhang B, Zhao W, Ma H, Zhang Y, Che R, Bian T, Yan H, Xu J, Wang L, Yu W, Liu J, Song H, Duan J, Chang H, Ma Q, Zhang Q, Ji X. Remote Ischemic Conditioning in the Prevention for Stroke-Associated Pneumonia: A Pilot Randomized Controlled Trial. Front Neurol 2021, 12: 723342. Todorov V, Dimitrova M. Stroke and the immune system: A review of the new strategies. Folia Medica 2020, 62(3): 431-437. Hou C, Lan J, Lin Y, Song H, Wang Y, Zhao W, Li S, Meng R, Hao J, Ding Y, Chimowitz MI, Fisher M, Hess DC, Liebeskind DS, Hausenloy DJ, Huang J, Li Z, Han X, Yang J, Zhou J, Chen P, Zhu X, Hu P, Pang H, Chen W, Chen H, Li G, Tao D, Yue W, Gao Z, Ji X. Chronic remote ischaemic conditioning in patients with symptomatic intracranial atherosclerotic stenosis (the RICA trial): a multicentre, randomised, double-blind sham-controlled trial in China. Lancet Neurol 2022, 21(12): 1089-1098. Tables Tables are available in the Supplementary Files section. Supplementary Files Tablestrial.pdf Table 1. Patient Selection Criteria Table 2. Blinded Survey Table 3. Schedule of activities and assessments Table 4. Suggested Diagnostic Criteria for Definite and Probable SAP in Non-Ventilated Patients, Based on CDC Guidelines completedSPIRITchecklist1.pdf StructuredStudyProtocol.pdf SPIRIT2013checklist.docx Cite Share Download PDF Status: Published Journal Publication published 16 Oct, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 14 Aug, 2025 Reviewers agreed at journal 13 May, 2025 Reviewers invited by journal 13 May, 2025 Editor invited by journal 28 Apr, 2025 Editor assigned by journal 01 Apr, 2025 First submitted to journal 29 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5497261","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":455893510,"identity":"78b7ecf4-bfd9-4172-a0ca-ea5fde9c1ab7","order_by":0,"name":"Lina Jia","email":"","orcid":"","institution":"Xuanwu Hospital Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lina","middleName":"","lastName":"Jia","suffix":""},{"id":455893511,"identity":"4baaaa19-bcaf-4f0e-81b2-5613f24953cb","order_by":1,"name":"Chengbei Hou","email":"","orcid":"","institution":"Xuanwu Hospital Capital Medical 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16:12:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1281751,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5497261/v1/2db35e49-033b-45d9-8600-8c85e760251d.pdf"},{"id":82888609,"identity":"530d5282-46b6-4017-b69d-ebfee85af5d5","added_by":"auto","created_at":"2025-05-16 12:03:07","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":128682,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1. Patient Selection Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Blinded Survey\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Schedule of activities and assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Suggested Diagnostic Criteria for Definite and Probable SAP in Non-Ventilated Patients, Based on CDC Guidelines\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Tablestrial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5497261/v1/434e95c7e1bd7eabbeed2428.pdf"},{"id":82888604,"identity":"5e63f201-e103-4674-a341-82fb9eb5d78b","added_by":"auto","created_at":"2025-05-16 12:03:07","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":95444,"visible":true,"origin":"","legend":"","description":"","filename":"completedSPIRITchecklist1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5497261/v1/fd0242cc3814c404d1de9325.pdf"},{"id":82891048,"identity":"74b5cefa-d99a-4651-a733-f70607771059","added_by":"auto","created_at":"2025-05-16 12:11:07","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":886300,"visible":true,"origin":"","legend":"","description":"","filename":"StructuredStudyProtocol.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5497261/v1/af2f44c9c094593aa3803b97.pdf"},{"id":82891046,"identity":"d2523bc3-8b7c-46c3-b832-21965a1756e7","added_by":"auto","created_at":"2025-05-16 12:11:07","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":17097,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRIT2013checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-5497261/v1/91076ecb935d0448f4a614ef.docx"}],"financialInterests":"","formattedTitle":"Remote Ischemic Conditioning for the Prevention of Stroke-Associated Pneumonia (RICA-2): Protocol for A Multicenter, Prospective, Randomized, Double-Blind, Sham-Controlled Phase III Trial","fulltext":[{"header":"Introduction and rationale","content":"\u003cp\u003eStroke-associated pneumonia (SAP) is one of the most common complications after stroke \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. SAP is strongly associated with increased mortality rates in stroke patients\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, significantly increasing the risk of death up to three years poststroke\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. During a stroke, local inflammatory activity intensifies while systemic immune function decreases, resulting in immunosuppression, which is a primary independent risk factor for SAP in stroke patients\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Given the substantial impact of infections on functional recovery, numerous trials have explored the efficacy of prophylactic antibiotics in stroke care. However, these studies have shown considerable heterogeneity in design, antibiotic type, and measured outcomes, limiting their generalizability\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, as seen in trials such as the Preventive Antibiotics in Stroke Study and STROKE Infection Prevention Study trials\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Therefore, novel treatments aimed at reducing SAP and improving recovery outcomes in stroke patients are urgently needed\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRemote ischemic conditioning (RIC) has emerged as a promising nonpharmacological intervention to protect distant organs by inducing periodic ischemia and reperfusion in the limbs. Studies suggest that RIC activates endogenous protective mechanisms, protecting remote organs\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. In an experimental ischemia\u0026ndash;reperfusion model, RIC has been shown to reduce cerebral ischemia\u0026ndash;reperfusion injury, inflammation, brain edema, and neuronal apoptosis\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Whether RIC can be adopted as an effective treatment to decrease SAP occurrence in patients with AIS remains unclear.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to evaluate the efficacy and safety of RIC in preventing SAP in patients with ischemic stroke. This multicenter, double-blind, randomized, sham-controlled phase III trial is designed to provide robust evidence on a novel prevention method for SAP, as well as the potential benefits of RIC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign\u003c/h2\u003e \u003cp\u003eThis study is a multicenter, randomized, double-blind, sham-controlled phase III clinical trial (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.clinicaltrials.gov\u003c/span\u003e\u003cspan address=\"http://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. NCT05982015) in China and approved by the Ethics Committee of Xunawu Hospital of Capital Medical University and other cooperative hospitals. The design is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Patients will be subjected to head computed tomography (CT) or magnetic resonance imaging (MRI) before randomization to identify patients with ischemic stroke. All the subjects received optimal medical therapy on the basis of the 2018 clinical guidelines for AIS\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Before each participant is enrolled, the researcher is responsible for providing a comprehensive overview of the study's purpose, procedures, and potential risks to the patient or their representative. The participants or his or her legally authorized representative signed a written informed consent form and were informed of their right to withdraw from the study at any time.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient population\u003c/h3\u003e\n\u003cp\u003eA total of 1650 patients with acute AIS within 24 hours of onset were recruited from approximately 80 medical centers in China according to the inclusion and exclusion criteria in Table\u0026nbsp;1.\u003c/p\u003e\n\u003ch3\u003eRandomization\u003c/h3\u003e\n\u003cp\u003eRandomization will occur after written informed consent is obtained from the patient or their guardian. Following successful screening of participants, patients will be randomly assigned to either the RIC group or the Sham-RIC group at a 1:1 ratio via block randomized blocks (4, 6, and 8) stratified by age (\u0026le;\u0026thinsp;70 or \u0026gt;\u0026thinsp;70 years old), stroke severity (NIHSS scores between 4\u0026ndash;20 years or higher than 20), and sex (male or female). A central network randomization system will generate random code. Neither patients nor researchers will have information on the group allocation. Both RIC and Sham-RIC will be administered via equipment with the same appearance but with different pressure settings for the two treatment regimens. Additionally, consecutive enrolled subjects will not be placed in the same ward for this study.\u003c/p\u003e \u003cp\u003eAt the end of this study, the subjects were asked several questions, as shown in Table\u0026nbsp;2, to investigate unblinding situations. Unblinding will only be allowed if a participant\u0026rsquo;s health is at risk and the attending physician deems it necessary. Unblinding must be approved by the principal investigator and documented.\u003c/p\u003e\n\u003ch3\u003eBaseline measurements\u003c/h3\u003e\n\u003cp\u003eIn addition to confirming eligibility for AIS, a comprehensive baseline assessment will be conducted prior to randomization. This assessment will encompass several key variables, including demographic characteristics, clinical and medical history, physical examination findings, vital signs, smoking and alcohol consumption status, and medication usage within one week prior to admission. Additionally, laboratory examinations, neuroimaging, and chest imaging, including CT or chest X-ray scans, will also be performed. Furthermore, the assessment will utilize standardized scales such as the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin scale (mRS), the self-rating depression scale (SDS), the generalized anxiety disorder scale (GAD-7), and a swallowing function assessment.\u003c/p\u003e\n\u003ch3\u003eIntervention and assessment\u003c/h3\u003e\n\u003cp\u003eEligible patients will be randomly assigned to either the RIC group or the Sham-RIC group. The RIC procedure consisted of 5 cycles of inflation to a pressure of 200 mmHg (RIC group) or 60 mmHg (Sham-RIC group) and deflation for 5 min alternately within 1 hour of enrollment performed on the upper arm by an electric autocontrolled device with cuff (patent number ZL201420846209.5, China), the total process lasted 45 minutes. The Sham-RIC did not result in upper limb ischemia. All patients will receive optimal medical treatment and care from local medical practices throughout the study. The numbers of RIC treatment will be recorded by the study nurse and sighed their names per time. The electronic data collection system will send message to the researcher to remind them to visit patients.\u003c/p\u003e \u003cp\u003eThe research period spans approximately two years. Research protocol version 3.0, version date July 19, 2023, recruitment date January 22, 2024, recruitment completed on September 12, 2024. The final follow-up period for the subject is expected to be completed on December 12 (\u0026plusmn;\u0026thinsp;7 days), 2024. Follow-up visits will be scheduled at each research center on days 1, 3, 7, and 90 after the initiation of treatment, as well as at the conclusion of the study. The details are outlined in Table\u0026nbsp;3.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary efficacy endpoint is the incidence of SAP within 7 days of intervention after randomization. The details of the SAP diagnostic criteria\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e are presented in Table\u0026nbsp;4. The secondary endpoints were as follows: diagnosis of pneumonia by clinical doctors within 7 days; diagnosis of pneumonia by clinical doctors between 8 days and 90 days; mRS score of 0\u0026ndash;1 ratio on Day 90; mRS score of 0\u0026ndash;2 ratio on Day 90; distribution of mRS scores on Day 90; EuroQoL 5- Dimensions 5-Level questionnaire (EQ-5D-5L) score on Day 90; NIHSS scores at 24 hours after onset; NIHSS scores at Day 7; Incidence of urinary tract infection within 7 days; Incidence of all infections within 7 days; all-cause mortality within 90 days; and total inpatient days. The incidence of adverse events was recorded and reported.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSample size\u003c/h3\u003e\n\u003cp\u003eOn the basis of previous studies\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e and a recent survey from Xuanwu Hospital, the estimated incidence of SAP in patients with AIS within 24 hours of onset is 17%. The sample size calculation assumes that RIC will reduce the SAP rate from 17.0\u0026ndash;11.9%. With a sample size of 1,486 across both groups, the study will have 80% power to detect a difference in SAP incidence between the Sham-RIC and RIC groups at a two-sided significance level of 0.05. While we anticipate that all (or at least a very high proportion) of the enrolled patients will be evaluable at the end of the study, we intend to recruit 875 patients per treatment group, totaling 1,650 patients for this study.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe analysis of efficacy endpoints will be conducted on an intention-to-treat basis. The primary endpoint was the incidence of SAP within 7 days postrandomization. To assess the difference in SAP incidence between the two groups (RIC group vs. Sham-RIC group), we used a modified Poisson regression model to analyze the primary efficacy endpoint. Adjustments for stratification factors, including age, sex, and NIHSS score, were incorporated into the model to control for potential confounding effects.\u003c/p\u003e \u003cp\u003eFor secondary endpoints, continuous variables will be analyzed via linear regression models, with the same adjustments applied for stratification factors. Binary variables are analyzed via modified Poisson regression, whereas ordinal variables are analyzed via ordinal regression models. Time-to-event variables will be evaluated via Cox proportional hazards regression, with stratification factors controlled throughout. Adverse events will be documented and reported. Statistical significance will be defined as a \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. This study did not set an interim analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy organization\u003c/h2\u003e \u003cp\u003eAn independent data monitoring committee is responsible for regularly monitoring patient safety, treatment efficacy, and overall study progress and for assessing whether early termination or protocol amendments are necessary.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our previous pilot clinical trial investigating the safety and efficacy of remote ischemic conditioning for SAP, 19 patients with AIS onset within 48 hours were randomly assigned to the RIC group (six consecutive days, twice daily), whereas 22 patients were assigned to the control group. The results of this study showed that RIC was safe among patients with AIS. Although the difference was not statistically significant in either univariate or multivariate analyses, the incidence of SAP was lower in the RIC group (10.5%) than in the control group (27.3%) \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. The lack of statistical significance may be attributed to the small sample size, limiting the power to detect differences between groups, and recent evidence suggests that the peak of apoptosis and immune suppression following stroke may occur within the first 24 hours\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e, indicating that earlier prevention might be more beneficial among these patients. Therefore, we aimed to conduct a fully powered clinical trial with adjusted inclusion and exclusion criteria to investigate the efficacy of RIC in preventing SAP in AIS patients within 24 hours of symptom onset following randomization. We hypothesize that 7 days of RIC will reduce the relative risk of SAP by 30%.\u003c/p\u003e \u003cp\u003eWe implemented several adjustments to address the limitations identified in the previous study\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. The inclusion criteria were refined to ensure that the treatment window was within 24 hours of stroke onset, as this period is critical for effectively reducing apoptosis and modulating immune responses. Since the sample size calculation was based on previous studies\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e, clinical expertise, and prior surveys on SAP incidence at Xuanwu Hospital of Capital Medical University and our participant selection criteria are relatively broad, we anticipate few practical challenges in recruiting a sufficient number of patients. An important advantage of our approach is that the results of our trial can be generalized to a wider population of stroke patients. Additionally, at the end of the study, we used a method from previous research\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e and contacted the participants, asking them about their knowledge of group allocation by answering the questions in Table\u0026nbsp;1. This upcoming trial is anticipated to conclude in the second quarter of 2025.\u003c/p\u003e \u003cp\u003eOwing to the low cost and ease of use of RIC devices, this intervention has strong potential for widespread adoption by patients and healthcare providers. If successful, this study could demonstrate that RIC significantly reduces the incidence of SAP, promotes recovery, and ultimately improves the quality of life for a large population of stroke patients.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003eThe participant recruitment for this trial commenced on January 22, 2024, and is anticipated to conclude by the end of June 2025. This protocol is the third version, version date : July 19, 2023.\u003c/p\u003e \u003c/div\u003e "},{"header":"Summary and conclusions","content":"\u003cp\u003eRIC is a convenient and noninvasive intervention, and the RICA-2 trial aims to investigate whether RIC treatment can effectively reduce stroke-associated pneumonia while also identifying any potential safety concerns.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLina Jia, Chengbei Hou, Qing Mei, Bowei Zhang, Heng Zhao, Suhang Shang, Xiuhai Guo, Wenbo Zhao, Chuanhui Li, Ran Meng, Weihai Xu, Yilong Wang, Gelin Xu, Chuanjie Wu, and Xunming Ji were responsible for the conception and design of the study. Lina Jia drafted the manuscript. All authors participated in interpretation of the findings. Qing Mei, Chengbei Hou, Suhang Shang, Ran Meng, Bowei Zhang, Chuanjie Wu, and Xunming Ji revised and commented the draft, and all authors read and approved the final version of the manuscript. All authors confirm that the content has not been published elsewhere and does not overlap with or duplicate their published work.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDeclaration of conflicting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXunming Ji is the inventor of the remote ischemic preconditioning equipment. The authors declared no potential conflicts of interest for this article\u0026apos;s research, authorship, and publication. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by Beijing Scholars Program (No.060) of Xunming Ji. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our sincere gratitude to all the patients and their families who participated in this study, as well as the medical staff and coordinators across all participating centers for their support and dedication. We are also grateful to the members of the independent data monitoring committee for their valuable guidance and oversight throughout the study. Special thanks to Min Wang for facilitating the logistics of this multicenter study. Many thanks to Bo Jiang and Bo Zhang for providing technical assistance.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWestendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, van de Beek D. Post-stroke infection: a systematic review and meta-analysis. BMC Neurol 2011, 11: 110.\u003c/li\u003e\n\u003cli\u003eKwan J, Horsfield G, Bryant T, Gawne-Cain M, Durward G, Byrne CD, Englyst NA. IL-6 is a predictive biomarker for stroke associated infection and future mortality in the elderly after an ischemic stroke. Exp Gerontol 2013, 48(9): 960-965.\u003c/li\u003e\n\u003cli\u003eKrishnan S, O\u0026apos;Boyle C, Smith CJ, Hulme S, Allan SM, Grainger JR, Lawrence CB. A hyperacute immune map of ischaemic stroke patients reveals alterations to circulating innate and adaptive cells. Clin Exp Immunol 2021, 203(3): 458-471.\u003c/li\u003e\n\u003cli\u003eMeisel C, Meisel A. Suppressing immunosuppression after stroke. N Engl J Med 2011, 365(22): 2134-2136.\u003c/li\u003e\n\u003cli\u003eWestendorp WF, Vermeij JD, Vermeij F, Den Hertog HM, Dippel DW, van de Beek D, Nederkoorn PJ. Antibiotic therapy for preventing infections in patients with acute stroke. Cochrane Database Syst Rev 2012, 1: Cd008530.\u003c/li\u003e\n\u003cli\u003eWestendorp WF, Vermeij JD, Zock E, Hooijenga IJ, Kruyt ND, Bosboom HJ, Kwa VI, Weisfelt M, Remmers MJ, ten Houten R, Schreuder AH, Vermeer SE, van Dijk EJ, Dippel DW, Dijkgraaf MG, Spanjaard L, Vermeulen M, van der Poll T, Prins JM, Vermeij FH, Roos YB, Kleyweg RP, Kerkhoff H, Brouwer MC, Zwinderman AH, van de Beek D, Nederkoorn PJ. The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet 2015, 385(9977): 1519-1526.\u003c/li\u003e\n\u003cli\u003eKalra L, Irshad S, Hodsoll J, Simpson M, Gulliford M, Smithard D, Patel A, Rebollo-Mesa I. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015, 386(10006): 1835-1844.\u003c/li\u003e\n\u003cli\u003evan Gemmeren T, Schuppner R, Grosse GM, Fering J, Gabriel MM, Huber R, Worthmann H, Lichtinghagen R, Weissenborn K. Early Post-Stroke Infections Are Associated with an Impaired Function of Neutrophil Granulocytes. J Clin Med 2020, 9(3).\u003c/li\u003e\n\u003cli\u003eMollet I, Marto JP, Mendona M, Baptista MV, Vieira HLA. Remote but not Distant: a Review on Experimental Models and Clinical Trials in Remote Ischemic Conditioning as Potential Therapy in Ischemic Stroke. Molecular Neurobiology 2022, 59(1): 294-325.\u003c/li\u003e\n\u003cli\u003eXu Y, Wang Y, Ji X. Immune and inflammatory mechanism of remote ischemic conditioning: A narrative review. Brain Circ 2023, 9(2): 77-87.\u003c/li\u003e\n\u003cli\u003eNeuroprotection by Remote Ischemic Conditioning in Rodent Models of Focal Ischemia: a Systematic Review and Meta-Analysis. Translational Stroke Research: 1-13.\u003c/li\u003e\n\u003cli\u003ePowers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019, 50(12): e344-e418.\u003c/li\u003e\n\u003cli\u003eSmith CJ, Kishore AK, Vail A, Chamorro A, Garau J, Hopkins SJ, Di Napoli M, Kalra L, Langhorne P, Montaner J, Roffe C, Rudd AG, Tyrrell PJ, van de Beek D, Woodhead M, Meisel A. Diagnosis of Stroke-Associated Pneumonia: Recommendations From the Pneumonia in Stroke Consensus Group. Stroke 2015, 46(8): 2335-2340.\u003c/li\u003e\n\u003cli\u003eHannawi Y, Hannawi B, Rao CP, Suarez JI, Bershad EM. Stroke-associated pneumonia: major advances and obstacles. Cerebrovasc Dis 2013, 35(5): 430-443.\u003c/li\u003e\n\u003cli\u003eZhang B, Zhao W, Ma H, Zhang Y, Che R, Bian T, Yan H, Xu J, Wang L, Yu W, Liu J, Song H, Duan J, Chang H, Ma Q, Zhang Q, Ji X. Remote Ischemic Conditioning in the Prevention for Stroke-Associated Pneumonia: A Pilot Randomized Controlled Trial. Front Neurol 2021, 12: 723342.\u003c/li\u003e\n\u003cli\u003eTodorov V, Dimitrova M. Stroke and the immune system: A review of the new strategies. Folia Medica 2020, 62(3): 431-437.\u003c/li\u003e\n\u003cli\u003eHou C, Lan J, Lin Y, Song H, Wang Y, Zhao W, Li S, Meng R, Hao J, Ding Y, Chimowitz MI, Fisher M, Hess DC, Liebeskind DS, Hausenloy DJ, Huang J, Li Z, Han X, Yang J, Zhou J, Chen P, Zhu X, Hu P, Pang H, Chen W, Chen H, Li G, Tao D, Yue W, Gao Z, Ji X. Chronic remote ischaemic conditioning in patients with symptomatic intracranial atherosclerotic stenosis (the RICA trial): a multicentre, randomised, double-blind sham-controlled trial in China. Lancet Neurol 2022, 21(12): 1089-1098.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Remote ischemic conditioning, acute ischemic stroke, stroke-associated pneumonia, clinical trial, protocol","lastPublishedDoi":"10.21203/rs.3.rs-5497261/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5497261/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eStroke-associated pneumonia (SAP) is one of the most common complications in acute ischemic stroke (AIS) patients, affecting 8.5% to nearly 30% of cases and significantly impacting both mortality and long-term survival. As its closely related with worse outcome, exploring effective preventive strategies, such as remote ischemic conditioning (RIC), is essential for reducing SAP incidence and improving patient outcomes. This study aims to compare the efficacy and safety of RIC for preventing SAP in patients with ischemic stroke within 24 hours of symptom onset.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods and design:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eRICA-2 is a multicenter, randomized, double-blind, parallel-controlled, phase III clinical trial in China. This study will enroll an estimated 1,650 patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years within 24 hours after AIS symptom onset, with National Institutes of Health Stroke Scale ⩾ 4. The patients will be randomly assigned to RIC or sham-RIC(1:1), and will be treated cuff inflation at 200 mmHg, or 60 mmHg, respectively. This procedure will be administered twice daily for seven consecutive days. The primary efficacy endpoint is SAP incidence rate. Safety incidence will be recorded and reported.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiscussion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eRIC has broad clinical application prospects and may play a preventive role in stroke related pneumonia. RICA-2 is designed to verify whether RIC treatment can serve as an adjuvant therapy for preventing stroke associated pneumonia and to identify safety concerns.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTrial registration\u003c/b\u003e\u003c/p\u003e \u003cp\u003ehttp//www.clinicaltrials.gov, NCT05982015.\u003c/p\u003e","manuscriptTitle":"Remote Ischemic Conditioning for the Prevention of Stroke-Associated Pneumonia (RICA-2): Protocol for A Multicenter, Prospective, Randomized, Double-Blind, Sham-Controlled Phase III Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-16 12:03:02","doi":"10.21203/rs.3.rs-5497261/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-08-14T04:49:26+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-05-13T10:30:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-13T10:29:29+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Trials","date":"2025-04-28T12:03:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-01T07:12:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-03-29T10:28:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"879f9103-4b8d-4884-94d9-3b69bcd703c3","owner":[],"postedDate":"May 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T16:10:09+00:00","versionOfRecord":{"articleIdentity":"rs-5497261","link":"https://doi.org/10.1186/s13063-025-09140-x","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-10-16 15:58:27","publishedOnDateReadable":"October 16th, 2025"},"versionCreatedAt":"2025-05-16 12:03:02","video":"","vorDoi":"10.1186/s13063-025-09140-x","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09140-x","workflowStages":[]},"version":"v1","identity":"rs-5497261","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5497261","identity":"rs-5497261","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}