{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:12:19Z","timestamp":1772169139533,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.18401.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000}}],"reference-count":29,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["203077"],"award-info":[{"award-number":["203077"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>Background Mortality among adults admitted to hospital with community acquired pneumonia in resource-limited settings is high. Recent studies conducted in high-income settings have demonstrated beneficial effects of low-dose corticosteroids in reducing mortality in patients with severe community acquired pneumonia. It is unknown whether these findings apply to low-income settings such as sub-Saharan Africa. This pragmatic randomized-controlled open-label trial will determine the effect of adjunctive low-dose corticosteroids in the management of adults admitted to hospital with community acquired pneumonia on mortality 30-days post-randomization. Methods We will enroll and randomize 2180 patients admitted with a diagnosis of community acquired pneumonia into two arms: the control and intervention arm. Those in the control arm will receive standard care for the treatment of community acquired pneumonia i.e., combination therapy with a beta-lactam and macrolide antibiotic. Those in the intervention arm will receive up to 10-days treatment with low-dose oral corticosteroids in addition to standard care. All participants will be followed up to 30- days post randomization and their final status recorded (alive or dead). Discussion If adjunctive low-dose oral corticosteroids are found to be beneficial, this easily scalable intervention would significantly reduce the currently high mortality associated with community acquired pneumonia. Pan-African Clinical Trials Registry: PACTR202111481740832; ISRCTRN registry: ISRCTN36138594<\/ns3:p>","DOI":"10.12688\/wellcomeopenres.18401.2","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T12:50:09Z","timestamp":1748436609000},"page":"269","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A pragmatic randomized controlled trial of standard care versus corticosteroids plus standard care for treatment of pneumonia in adults admitted to Kenyan hospitals (SONIA)"],"prefix":"10.12688","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6926-8556","authenticated-orcid":false,"given":"Ruth","family":"Lucinde","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7989-2125","authenticated-orcid":false,"given":"Abdirahman","family":"Abdi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedict","family":"Orindi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-0264","authenticated-orcid":false,"given":"Stella","family":"Mwakio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Gathuri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin","family":"Onyango","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salome","family":"Chira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morris","family":"Ogero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynda","family":"Isaaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jimmy","family":"Shangala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene 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Where needed, revisions to the text of the article have been made.&nbsp; Trial registration - Is the trial registered with an international trial registry? Please could the authors provide details. Yes, the trial is registered with the Pan-African Clinical Trials Registry (PACTR202111481740832) and the ISRCTRN registry (ISRCTN36138594). We have included this in the revised article Use of multiple corticosteroids - I appreciate that this a pragmatic study and that the authors have included some mitigation against drug stockouts, but I think that it would be helpful to provide further justification of the decision to permit use of different corticosteroids. Do the published meta-analyses of corticosteroids in the treatment of CAP, suggest any differences in the efficacy or safety of different corticosteroids?  While data on the subgroup effect of different corticosteroids have not been consistent in published meta-analyses of corticosteroids in the treatment of CAP (Jheng-Yan et al.,2023 and Pitre et al., 2023) our decision to allow multiple corticosteroids was largely informed by the variable availability of low-dose oral corticosteroids at the study sites. &nbsp;  Maintaining a pragmatic approach allows for our trial to generate real-world evidence on the effect of corticosteroids. Our trial is not powered to detect differences in effect by corticosteroid but may provide insights that may inform future studies evaluating these differences. Discussion about potential impact of TB - Observational studies of CAP from Kenya (Scott et al., Lancet 20001) and other settings in sub-Saharan Africa (Aston et al. AJRCCM 20192) suggest that in contrast to the high-income settings where previous clinical trials of corticosteroids in CAP have largely been conducted, a significant proportion of patients recruited to this trial will have tuberculosis - either as a primary reason of presentation or as a co-pathogen. The authors hint at this with reference to a previous trial in South Africa (ref 14), but do not discuss further the potential implications and\/or proposed mitigations. Whilst not mandated by protocol, do they expect to have fairly complete testing for TB by Xpert or otherwise to permit subgroup analysis?&nbsp; Testing for pulmonary tuberculosis is largely available in Kenya but underutilized (Oliwa et al., 2018, https:\/\/doi.org\/10.1186\/s12879-018-3237-z ). Given the pragmatic nature of the trial, we will rely on clinician-initiated tests for pulmonary tuberculosis to define the proportion of participants with co-infection at enrollment. We however don\u2019t expect this pragmatic approach to provide enough numbers for subgroup analyses as it is dependent on access to, availability of and clinician requests for these tests. Discontinuation and modification of intervention - In this pragmatic and open-label study, the authors have allowed for the possibility that clinicians may choose to stop steroids in the intervention group or start them in the control group. To what extent do they anticipate that this may happen and what is the anticipated impact on the power of the trial to detect a mortality difference between arms? With continued engagement and sensitization on trial activities during the conduct of the trial, we hope to limit these instances. Additionally, we will adhere to a strict inclusion and exclusion criteria to limit the possibility of enrolling participants who are likely to then have steroids included or withdrawn from their management. Our sample size calculations allow for 5% drop-off ( ~109 participants) and we anticipate this will cover any instances of clinician-initiated protocol deviations that lead to withdrawals. Capture of adverse events - The authors highlight that steroids are commonly used drugs with well characterised safety profiles and mention in the introduction the harmful effects of long-term use. There are well recognised harms associated with short term use of steroids (e.g. hyperglycaemia, gastrointestinal bleed, delirium). Could the authors describe how confident they are that the proposed methods for recording adverse events will capture these potential effects of steroids and, in particular, do so without bias given the open-label nature of the study?&nbsp; By recording vital signs, measuring and recording random blood sugars for all participants and soliciting for all common side effects of corticosteroids, we believe we\u2019ll identify and record most instances of corticosteroid-related adverse events while our patients are in-patient. Our calls to participants at 14- and 30- days post-enrolment are also intended to solicit for adverse events in addition to recording of vital status. We however recognize that some adverse events may be unreported and thus don\u2019t expect our summary of safety data to be used in place of hypothesis testing Non-mortality endpoints - Given the pragmatic, open-label nature of the trial, the authors have opted for a primary endpoint of mortality. Previous clinical trials of steroids in CAP have used alternative endpoints including clinical\/treatment failure, ICU admission\/mechanical ventilation, length of stay, readmission to hospital. Will the trial capture data to be able to report these endpoints in exploratory analyses? Yes, the trial will record data on length of stay and report the effect of steroids on this in exploratory analyses. On the other hand, ICU admission and mechanical ventilation are largely inaccessible to many in Kenya and tracking readmission to hospital may be difficult if these readmissions are to non-trial sites. We therefore may not have enough data for exploratory analyses of these alternative endpoints. Impact of HIV - Based on previous observational data, what proportion of recruits do the authors anticipate will be HIV-infected? Whilst not mandated by protocol, do the authors anticipate that HIV testing will be fairly comprehensive, such that they will be able to do appropriate sub-group\/multivariable\/interaction analyses? As with testing for pulmonary tuberculosis, testing for HIV is largely available but depended on clinician requests and patient consent (https:\/\/nacc.or.ke\/wp-content\/uploads\/2018\/11\/HIV-estimates-report-Kenya-20182.pdf ). The prevalence of HIV among patients presenting to these trial sites is expected to be ~ 5% as we report elsewhere (Lucinde et al., 2024, https:\/\/doi.org\/10.1186\/s12879-024-10140-6 ). However, we do not expect the proportion of patients having these test done during their admission to be enough to conduct subgroup analyses. Severity of illness - In the statistical methods section, the authors indicate that adjusted Cox model could be developed that takes into account severity of illness. Could they elaborate on how severity of illness will be characterised? For example, in peripheral sites, will physiological observations including saturations be reliably captured? We will use oxygen saturation at enrollment as a surrogate measure of disease severity for subgroup analyses. The trial team will ensure oxygen saturation is measured for all participants at enrolment and during the duration of their hospital stay. The final analyses for the trial will be outlined in the trial\u2019s statistical analysis plan (SAP) and will reflect whether the trial will deem this approach to quantifying disease severity as adequate or not. Discussions with the trial\u2019s steering committee (TSC) and data safety and monitoring board (DSMB) will guide the development of the final SAP. There are a couple of additional important references in this area that I would suggest should be included: Thank you for these suggestions. These references have been included in the revised article","URL":"https:\/\/wellcomeopenresearch.org\/articles\/7-269\/v2#referee-comment-6096","order":1,"name":"referee-comment-6096","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.26398.r124505, Matthias Briel, Christof Sch\u00f6nenberger, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, 18 Jun 2025, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/7-269\/v2#referee-response-124505","order":2,"name":"referee-response-124505","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The trial funded by the KEMRI-Wellcome Trust Research Programme\u2019s core funding (203077\/B\/16\/Z). Funding has been assured for the duration of the study.\r\nKEMRI CGMR-Coast will provide indemnity for study staff. \r\nThe University of Oxford, the study\u2019s sponsor, has a specialist insurance policy in place - Newline Underwriting Management Ltd, at Lloyd\u2019s of London \u2013 which would operate in the event of any participant suffering harm as a result of their involvement in the research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}