{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:08:21Z","timestamp":1779890901528,"version":"3.53.1"},"reference-count":15,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"unspecified","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013365","name":"West China Hospital, Sichuan University","doi-asserted-by":"publisher","award":["ZYGD23004"],"award-info":[{"award-number":["ZYGD23004"]}],"id":[{"id":"10.13039\/501100013365","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014219","name":"National Science Fund for Distinguished Young Scholars","doi-asserted-by":"publisher","award":["1.3"],"award-info":[{"award-number":["1.3"]}],"id":[{"id":"10.13039\/501100014219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014219","name":"National Science Fund for Distinguished Young Scholars","doi-asserted-by":"publisher","award":["82225049"],"award-info":[{"award-number":["82225049"]}],"id":[{"id":"10.13039\/501100014219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,4,30]]},"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, may benefit from immunomodulatory drugs. Nevertheless, numerous clinical trials of these drugs have failed to demonstrate efficacy, partly due to substantial heterogeneous treatment responses. Subgroup analyses from these trials are frequently employed to investigate different treatment effects across subgroups. However, which drugs might have different effects across subgroups and how credible these findings are have not been well summarised and evaluated. Additionally, the differences in the characteristics and results of subgroup analyses based on whether the primary trial\u2019s main effect is statistically significant remain unclear. We will conduct a systematic review to comprehensively address these questions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      We will include randomised controlled trials (RCTs) evaluating immunomodulatory drugs for adult sepsis and exclude quasi-randomised trials, single-arm studies, animal research, conference abstracts, study protocols and non-English publications. To comprehensively search for subgroup analyses, we will search both RCTs and their published secondary analyses across PubMed, Embase, Web of Science, ClinicalTrials.gov and the Cochrane Library from their inception. Four reviewers will independently screen eligible studies and only one subgroup analysis will be selected for data extraction using standardised forms. The credibility of subgroup effects will be assessed using the Instrument for assessing the Credibility of Effect Modification Analyses. We will analyse the proportion and characteristics of subgroup analyses reported in trials. We will qualitatively summarise the results of subgroup analyses, focusing on findings with a subgroup-specific p value&lt;0.05\u2009or an interaction p value&lt;0.05. If two or more studies examined the same drug within a subgroup, we will perform data synthesis using a random-effects model to estimate pooled subgroup effects. We will compare the differences based on whether the primary trial\u2019s main effect was statistically significant using t-tests, Mann-Whitney U tests, \u03c7\n                      <jats:sup>2<\/jats:sup>\n                      test or Fisher\u2019s exact test, as appropriate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>No ethical approval is required because the data we will use do not include individual patient data. Findings will be disseminated through publication in a peer-reviewed journal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>CRD420251089737.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-108626","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:00:19Z","timestamp":1779883219000},"page":"e108626","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Differential treatment effects across subgroups in immunomodulatory drugs for sepsis: protocol for a systematic review"],"prefix":"10.1136","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0276-4282","authenticated-orcid":false,"given":"Ling","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China"},{"name":"Cochrane China and MAGIC China Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China"},{"name":"NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu, Sichuan, China"},{"name":"Sichuan Center of Technology Innovation for Real World Data, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyang","family":"Bai","sequence":"additional","affiliation":[{"name":"School of Nursing, Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linge","family":"Jian","sequence":"additional","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Fudan University Eye Ear Nose and Throat Hospital Department of ENT and Otorhinolaryngology, Shanghai, Shanghai, 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Sichuan University, Chengdu, Sichuan, China"},{"name":"Cochrane China and MAGIC China Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China"},{"name":"NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu, Sichuan, China"},{"name":"Sichuan Center of Technology Innovation for Real World Data, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China"},{"name":"Cochrane China and MAGIC China Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China"},{"name":"NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu, Sichuan, China"},{"name":"Sichuan Center of Technology Innovation for Real World Data, Chengdu, Sichuan, 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