Efficacy of SGLT2 Inhibitors in Adults With Sepsis

Official title

Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitors in Adults With Sepsis: A Feasibility Study for a Multicenter Double-Blind Randomized Placebo-Controlled Trial

Overview

Goal of this clinical trial is to examine the safety and efficacy of SGLT2 inhibitors on the clinical outcomes in patients with sepsis. Main study outcomes are as follows: (i) Primary objective is to examine the efficacy and safety of SGLT2 inhibitors on clinical outcomes in patients with sepsis. (ii) Secondary objective is to examine the effect of SGLT2 inhibitors on inflammatory markers in patients with sepsis.

Detailed description

Sepsis is a leading epidemic in the world, affecting an estimated 48.9 million individuals annually. Patients who develop consequential organ failure requiring admission to the intensive care unit (ICU) has a mortality of up to 42%. In Hong Kong, sepsis was the second most common cause of ICU admission, accounting for 16.9% of the 14,068 patient admissions in 2018. Sepsis has remained as one of the top 10 leading causes of death in Hong Kong in the past decade.

Recent randomized controlled trials evaluating various therapies in sepsis have not yielded encouraging results. Targeted therapeutic options including adjunctive glucocorticoid therapy, intravenous vitamin C, and sepsis bundles have not been associated with improved clinical outcomes in patients with sepsis. Administration of antibiotics for source control has remained as the only treatment proven effective in sepsis for two decades. There is an urgent unmet need to identify therapies that may modulate the adverse outcomes of sepsis.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of medication that reduces reabsorption of glucose from the kidneys by modulating the sodium-glucose cotransporter in the renal tubules. Although originally developed as a drug for type 2 diabetes, subsequent large randomized clinical trials have firmly established the clinical efficacy of SGLT2 inhibitors in improving cardiovascular and renal outcomes, irrespective of diabetes status. Patients who received SGLT2 inhibitors had a 32% relative risk reduction in all-cause mortality, 40% reduction in adverse renal outcomes, and 30% reduction in hospitalization for heart failure, compared with placebo.

The investigators hypothesize that SGLT2 inhibitors, as compared with placebo, will improve clinical outcomes of patients with sepsis who are receiving standard care.

(i) The primary objective is to examine the efficacy and safety of SGLT2 inhibitors on clinical outcomes in patients with sepsis.

(ii) The secondary objective is to examine the effect of SGLT2 inhibitors on inflammatory markers in patients with sepsis.

(iii) The tertiary objective is to examine the feasibility of conducting a multicenter double-blind randomized placebo-controlled trial in the ICUs of Hong Kong.

Adult patients (age≥18 years) with new onset sepsis and admitted to the ICU will be considered for recruitment based on the study inclusion/exclusion criteria. Eligible subjects will be randomly assigned to the intervention group or the control group in a 1:1 ratio. In the intervention group, the SGLT2 inhibitor empagliflozin 10mg orally daily will be given in addition to standard care until hospital discharge. In the control group, a placebo tablet once orally daily will be given in addition to standard care until hospital discharge. All patients will be followed up daily until hospital discharge or transfer to another facility. Blood samples will be collected and sent for an assay that measures the levels of key inflammatory markers.

Interventions

• Drug Empagliflozin 10 MG
  Empagliflozin 10mg once daily from recruitment to hospital discharge
• Drug Placebo
  Placebo single tablet once daily from recruitment to hospital discharge

Primary outcome measures

• Mortality [Time frame: 28-day mortality]
• Change in Sequential Organ Failure Assessment (SOFA) score [Time frame: Baseline and day 7 score]

Secondary outcome measures (1)

• Interleukin-6, Interleukin-1 beta, TNF-a, IFN-gamma, Procalcitonin, C-reactive protein [Time frame: Baseline and day 7]

Eligibility criteria

Inclusion criteria

• Aged 18 years or above
• New onset of sepsis within 48 hours defined according to the Sepsis-3 criteria. (≥2 SOFA)
• Provision of signed and dated informed consent form from participant or surrogate
• Ability to take and adhere to oral and enteral medication regimen
• Willingness to comply

Exclusion criteria

• Current or recent use of SGLT2 inhibitors (within 12wks prior to randomization)
• Impaired renal function
• Clinically unstable or in refractory hypotension
• History of ketoacidosis
• Gastrointestinal surgery or GI absorption / malabsorption disorder
• Pregnancy
• Known allergic or hypersensitivity reactions to any SGLT2 inhibitors
• Treatment with another investigational drug or other interventions within 30 days prior to trial

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Other

Study locations

Hong Kong · 3 centers

• 4/F Main Clinical Block and Trauma Centre, Prince of Wales Hospital, Shatin, New Territori — Hong Kong
• Adult Intensive Care Unit, Queen Mary Hospital, 102 Pok Fu Lam Road, Hong Kong — Hong Kong
• The University of Hong Kong — Hong Kong

Publications

• Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, Fleischmann-Struzek C, Machado FR, Reinhart KK, Rowan K, Seymour CW, Watson RS, West TE, Marinho F, Hay SI, Lozano R, Lopez AD, Angus DC, Murray CJL, Naghavi M. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lanc PMID 31954465
• Global report on the epidemiology and burden of sepsis: current evidence, identifying gaps and future directions. Geneva: World Health Organization, 2020. (https://apps.who.int/iris/bitstream/handle/10665/334216/9789240010789-eng.pdf).
• Ling L, Ho CM, Ng PY, Chan KCK, Shum HP, Chan CY, Yeung AWT, Wong WT, Au SY, Leung KHA, Chan JKH, Ching CK, Tam OY, Tsang HH, Liong T, Law KI, Dharmangadan M, So D, Chow FL, Chan WM, Lam KN, Chan KM, Mok OF, To MY, Yau SY, Chan C, Lei E, Joynt GM. Characteristics and outcomes of patients admitted to adult intensive care units in Hong Kong: a population retrospective cohort study from 2008 to 2018. PMID 33407925
• Centre for Health Protection DoH, The Government of the Hong Kong Special Administrative Region. Death Rates by Leading Causes of Death, 2001 - 2021. (https://www.chp.gov.hk/en/statistics/data/10/27/117.html).
• Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J; ADRENAL Trial Investigators and the Australian-New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808. doi: PMID 29347874
• Lamontagne F, Masse MH, Menard J, Sprague S, Pinto R, Heyland DK, Cook DJ, Battista MC, Day AG, Guyatt GH, Kanji S, Parke R, McGuinness SP, Tirupakuzhi Vijayaraghavan BK, Annane D, Cohen D, Arabi YM, Bolduc B, Marinoff N, Rochwerg B, Millen T, Meade MO, Hand L, Watpool I, Porteous R, Young PJ, D'Aragon F, Belley-Cote EP, Carbonneau E, Clarke F, Maslove DM, Hunt M, Chasse M, Lebrasseur M, Lauzier F PMID 35704292
• Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/NEJMoa010307. PMID 11794169
• Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022 Nov 19;400(10365):1788-1801. doi: 10.1016/S0140-6736(22)02074-8. Epub 2022 Nov 6. PMID 36351458

Identifiers

NCT: NCT06473844 · UW 23-609

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗