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Introduction The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.Methods and analysis The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes—time to recovery and mortality. The statistical design uses a Bayesian model with ‘stopping’ and ‘graduation’ criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing.Ethics and dissemination ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals.Trial registration number NCT04488081.

Abstract Background Klebsiella pneumoniae brain abscesses are a rare entity and typically present in immunocompromised patients. We present a case of an overall healthy patient who developed a Klebsiella pneumoniae brain abscess in the absence of liver pathology. Case presentation A 46-year-old Vietnamese man with past medical history significant for hypertension presented to the hospital with acute on chronic worsening of altered mental status, personality changes, and gait dysfunction. Initial vitals revealed temperature of 37.1 °C, heart rate 87 beats/minute, blood pressure 150/87 mmHg, respiratory rate 18/minute, and oxygen saturation 99% on room air. Physical exam was notable for altered mental status, Glasgow Coma Scale (GCS) score of 14, and right lower facial droop. Cardiopulmonary exam was within normal limits. Head computed tomography (CT) showed a left frontotemporal mass, with subsequent brain magnetic resonance imaging (MRI) revealing a ring-enhancing lesion concerning for a brain abscess. The abscess was urgently drained; however, there was intraoperative spillage into the ventricles. Intraoperative cultures grew Klebsiella pneumoniae, and the patient was maintained on appropriate antibiotics. He developed worsening mental status, septic shock, and cerebral edema requiring decompressive left hemicraniectomy. Computed tomography of the abdomen and pelvis revealed no hepatic lesions. The patient did not improve, and the family elected for comfort measures. Conclusion High mortality is associated with Klebsiella pneumoniae (as opposed to Klebsiella oxytoca) brain abscesses, especially in the setting of intraventricular spread. This case illustrates the need for early detection, and an aggressive medical and surgical treatment approach is required for a potential favorable outcome.