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Introduction: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day, is associated with serious adverse drug events (ADE) in 20%-60% of patients. ADEs include hypersensitivity reactions, drug-induced liver injury, cytopenias and renal failure, all of which can be treatment limiting. In a recent meta-analysis of observational studies, reduced dose TMP-SMX for the treatment of PJP was associated with fewer ADEs, without increased mortality., Methods and Analysis: A phase III randomised, placebo-controlled, trial to directly compare the efficacy and safety of low-dose TMP-SMX (10 mg/kg/day of TMP) with the standard of care (15 mg/kg/day of TMP) among patients with PJP, for a composite primary outcome of change of treatment, new mechanical ventilation, or death. The trial will be undertaken at 16 Canadian hospitals. Data will be analysed as intention to treat. Primary and secondary outcomes will be compared using logistic regression adjusting for stratification and presented with 95% CI., Ethics and Dissemination: This study has been conditionally approved by the McGill University Health Centre; Ethics approval will be obtained from all participating centres. Results will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT04851015., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Herpes simplex virus (HSV) encephalitis is a rare severe form of brain inflammation that commonly leaves survivors and their families with devastating long-term consequences. The virus particularly targets the temporal lobe of the brain causing debilitating problems in memory, especially verbal memory. It is postulated that immunomodulation with the corticosteroid, dexamethasone, could improve outcomes by reducing brain swelling. However, there are concerns (so far not observed) that such immunosuppression might facilitate increased viral replication with resultant worsening of disease. A previous trail closed early because of slow recruitment., Method: DexEnceph is a pragmatic multicentre, randomised, controlled, open-label, observer-blind trial to determine whether adults with HSV encephalitis who receive dexamethasone alongside standard antiviral treatment with aciclovir for have improved clinical outcomes compared with those who receive standard treatment alone. Overall, 90 patients with HSV encephalitis are being recruited from a target of 45 recruiting sites; patients are randomised 1:1 to the dexamethasone or control arms of the study. The primary outcome measured is verbal memory as assessed by the Weschler Memory Scale fourth edition Auditory Memory Index at 26 weeks after randomisation. Secondary outcomes are measured up to 72 weeks include additional neuropsychological, clinical and functional outcomes as well as comparison of neuroimaging findings. Patient safety monitoring occurs throughout and includes the detection of HSV DNA in cerebrospinal fluid 2 weeks after randomisation, which is indicative of ongoing viral replication. Innovative methods are being used to ensure recrutiment targets are met for this rare disease., Discussion: DexEnceph aims to be the first completed randomised controlled trial of corticosteroid therapy in HSV encephalitis. The results will provide evidence for future practice in managing adults with the condition and has the potential to improve outcomes ., Ethics and Dissemination: The trial has ethical approval from the UK National Research Ethics Committee (Liverpool Central, REF: 15/NW/0545, 10 August 2015). Protocol V.2.1, July 2019. The results will be published and presented as soon as possible on completion., Trial Registration Numbers: ISRCTN11774734, EUDRACT 2015-001609-16., Competing Interests: Competing interests: TS is supported by the National Institute for Health Research (NIHR) Health Protection Research Unit in Emerging and Zoonotic Infections (Grant No. IS-HPU-1112-10117), NIHR Global Health Research Group on Brain Infections (No. 17/63/110), and the European Union's Horizon 2020 research and innovation program ZikaPLAN (Preparedness Latin America Network), grant agreement No. 734584., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)