Title: Sepsis Trials In Critical Care (SepTIC)
Funder: Department of Health and Social Care

Abstract: Sepsis is when the body’s response to severe infection causes vital organs to stop working normally. About one third of patients with sepsis do not survive. For those that do survive, it can be life changing, with long term physical and emotional consequences. We urgently need to know the best treatments for sepsis._x000D_ _x000D_ This research looks to answer three important questions:_x000D_ _x000D_ 1) Is it better for patients if we use rapid microbiology tests (that take only a few hours to work out what the infection is) to allow antibiotics to be changed early? Current tests to find the cause of infection take several days and so doctors have to use very powerful antibiotics (broad spectrum antibiotics) to cover many possible infections for many days, which can lead to antibiotic resistance over time. This means antibiotics become less effective._x000D_ _x000D_ 2) Is it better for patients with sepsis to have less fluid than current standard care? Fluid (through a drip into a vein) is used to help maintain blood flow to the body’s organs but doctors don’t know exactly how much to give. Some studies suggest standard care gives too much fluid and that it might be better, after treating any early lack of fluid, to only give more if there are clear signs that patients need more and other treatment (diuretics) can be given if the patient has too much fluid._x000D_ _x000D_ 3) Does it help to give the sickest patients with sepsis and low white blood cell counts (a sign of a weakened immune system) a drug that stimulates the immune system? In some patients who have sepsis, their immune system stops working properly. White cells are an important part of how the immune system fights infection. These white cells can be stimulated by drugs that may help recovery and prevent new infections._x000D_ _x000D_ By answering three important research questions at the same time we will get answers more quickly and save money. Because these treatments would normally be given together to treat sepsis and they all work in different ways, we can study them at the same time without them affecting each other._x000D_ _x000D_ Our trial will include 3758 patients with sepsis who are admitted to Critical Care over 3 years. Patients will be randomised (allocated to the different treatment groups by chance). For questions 1 and 2, one quarter of patients will get standard care, half of patients will have one of the two interventions and one quarter will have both interventions. Then amongst the most ill patients, half will receive the immune stimulation drug (question 3)._x000D_ _x000D_ We will use information from routine records to see how the patients are at 3, 6 and 12 months after treatment. We will ask patients to complete questionnaires about the quality of their life at 6 months and patients have told us the importance of checking for cognitive impairment (problems with memory and thinking) as this can be a distressing effect after sepsis._x000D_ _x000D_ We have worked with the ICUsteps and UK Sepsis Trust charities to prepare this application. Together we will design ways to give information to help support patients and relatives when deciding if they would like to take part in this trial (‘easy read’ information and a video). Patients and the public will be central in the trial and we will offer training and support for former patients and relatives to be involved in its management. We will work with patient groups and healthcare organisations to make sure the results of this study are used to improve the care of future patients with sepsis.

Lay abstract: Research questions:_x000D_ _x000D_ 1. Do rapid PCR-based microbiological diagnostics combined with procalcitonin improve outcomes and antibiotic stewardship compared to standard care in patients admitted to intensive care (ICU) with sepsis?_x000D_ 2. Does conservative fluid therapy with active removal of accumulated fluid (de-resuscitation) improve outcomes compared to standard care in patients admitted to ICU with sepsis?_x000D_ 3. Does GM-CSF compared to placebo improve outcomes in a high-risk subset of patients admitted to ICU with sepsis?_x000D_ 4. What is the relative cost-effectiveness of each of these interventions compared to current standard of care?_x000D_ _x000D_ Design: A 2x2 factorial pragmatic open-label randomised controlled trial, with an embedded randomised double-blind parallel group trial_x000D_ _x000D_ Setting: 60 general ICUs in the UK_x000D_ _x000D_ Target population: Adult patients who are critically ill due to sepsis_x000D_ _x000D_ Inclusion criteria_x000D_ - Adult patients admitted to ICU due to suspected sepsis and expected to stay for at least 48 hours_x000D_ - Receiving intravenous antibiotics for suspected sepsis_x000D_ - Initial early fluid resuscitation complete_x000D_ - Acute organ dysfunction due to infection_x000D_ _x000D_ Additional criteria for GM-CSF subset_x000D_ - Mechanically ventilated_x000D_ - Receiving vasopressors/inotropes_x000D_ - Absolute lymphocyte count <1.2 x109/L on two consecutive days_x000D_ _x000D_ Exclusion criteria_x000D_ - More than 12hours since ICU admission_x000D_ - Previously admitted to ICU due to sepsis on this hospital admission_x000D_ - Not expected to survive 90 days, due to pre-existing chronic disease_x000D_ - Not expected to survive initial resuscitation (24 hours)_x000D_ - Neutropenia due to chemotherapy/malignancy (but not due to sepsis)_x000D_ - A source of infection that will require a prolonged course of antibiotics, >21 days_x000D_ - Additional exclusion criteria for GM-CSF_x000D_ _x000D_ Health Technologies being assessed_x000D_ 1. Rapid PCR-based microbiological diagnostics combined with procalcitonin compared with standard care_x000D_ 2. Conservative fluid therapy with active removal of accumulated fluid (de-resuscitation) compared to standard care_x000D_ 3. GM-CSF (sargramostim) 6µg/kg/day for 7 days compared to placebo_x000D_ _x000D_ Measurement of costs & outcomes_x000D_ Primary: 90-day all-cause mortality (for all interventions)_x000D_ _x000D_ Secondary:_x000D_ - Duration of mechanical ventilation, shock, renal replacement therapy_x000D_ - Length of stay in ICU and hospital_x000D_ - Antibiotic use (defined daily doses per 1000 occupied bed days)_x000D_ - Infection relapse / recurrence or secondary infection requiring further antibiotic treatment_x000D_ - Adverse events and drug reactions (including antibiotic related adverse events)_x000D_ - Health-related Quality of Life (EQ-5D-5L) and cognitive function (MoCA-Blind) at 6 months_x000D_ - 1-year mortality_x000D_ _x000D_ Sample size: 3758 patients in total, allowing for 10% inflation due to the factorial design and 2% loss to follow-up. 1300 patients are required for the high-risk GM-CSF subset._x000D_ _x000D_ Timeline: After 9 months set-up time, 3 years are required for recruitment, based on 2 patients recruited per ICU per month. Allowing for 1 year follow up and 3 months final analysis and reporting, this totals 60 months for the project._x000D_ _x000D_ Expertise: Our team includes critical care, microbiology and emergency medicine clinicians, trialists, statisticians, health economists, a psychologist and a patient representative. Our team has expertise in sepsis management, antimicrobial resistance, diagnostics, ICU trial design/methodology/analysis, health economics, communication and strong links with patient groups.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM