Safety and Feasibility of Metformin for Sepsis Induced AKI

Study Overview
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Brief Summary
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Acute kidney injury (AKI) is an independent risk factor for death that affects 10-15% of hospitalized patients and more than 50% of patients admitted to the intensive care unit. Sepsis is the most frequent cause of AKI, affecting 48 million people worldwide every year, and accounting for approximately 11 million of annual global deaths. Despite these figures, there are no known therapies to prevent or reverse septic AKI; hence this study aims to establish the safety and feasibility of the implementation of metformin in the treatment of AKI in patients with sepsis. This study is the first critical step to inform the design of a future, full-scale efficacy randomized clinical trial.

Detailed Description
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Acute kidney injury (AKI) is an independent risk factor for death, that affects 10-15% of hospitalized patients and more than 50% of patients admitted to the intensive care unit. The most frequent cause of AKI is Sepsis which affects 48 million people worldwide every year. Importantly, the 6-8-fold increase in the risk of death that AKI carries in sepsis, may be reversible because patients with sepsis who recover from AKI have similar 1- and 3-year mortality as those without AKI. These data agree with evidence showing that the development of AKI carries far-reaching consequences like remote organ dysfunction and an increased susceptibility to infection. These data suggest that AKI may be in the causal pathway to death from sepsis and that efforts to reverse AKI may improve the survival in patients with sepsis. However, there are no specific therapies to reverse or prevent the development of AKI during sepsis. Investigators have recently demonstrated that AMP-activated protein kinase (AMPK), a ubiquitous master regulator of cell metabolism and energy balance, is critical to protect the kidney from injury and enhance survival during experimental sepsis. Investigators have shown that pharmacologic activation of AMPK protects from AKI and improves survival, while inhibition increases kidney injury and death. Interestingly, metformin, the recommended first-line agent for the treatment of type 2 diabetes mellitus is a known AMPK activator. Based on this, investigators have demonstrated that treatment with metformin decreases mortality during experimental sepsis. Multiple observational human studies also support this idea. Two recent meta-analyses concluded that exposure to metformin was associated with a decreased risk of mortality. Investigators conducted the largest propensity-score matched retrospective study to date and demonstrated that metformin is associated with a decrease in the odds of moderate-severe AKI and death at 90-days, as well as with an increased odds of recovery from AKI. Despite this evidence, several gaps in knowledge remain. First, it is unclear if the protective effect of metformin is due to confounders. Second, it is unknown if the results of available studies are generalizable to non-diabetic patients. Third, despite a track record of over 60 years of use in diabetic patients, safety has not been established in patients with septic shock. This proposal aims to conduct a randomized, placebo-controlled, feasibility study to establish the safety and feasibility of the use of oral metformin to prevent the development of sepsis-induced acute kidney injury and inform a future full-scale efficacy trial. Our overarching hypothesis is that in treatment of patients with sepsis, metformin is safe and effective in reducing sepsis-induced elevations in AKI biomarkers. Investigators will determine the safety of the use of metformin to treat adult patients with sepsis and will determine the pharmacokinetic profile of oral metformin (Aim 1), the feasibility of implementing this therapy (Aim 2) and estimate the heterogeneity of the effect of metformin on markers of kidney injury/stress and on circulating platelet mitochondrial function (Aim 3). This study is the first critical step to inform the design of a future, full-scale efficacy RCT.

Official Title
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A Randomized Clinical Trial of the Safety and Feasibility of Metformin as a Treatment for Sepsis Induced AKI.

Conditions
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Sepsis, Septic Shock, Acute Kidney Injury, Metformin

Intervention / Treatment
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* Drug: Metformin low dose
* Drug: Metformin high dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients >=18 years of age Admitted to the Intensive Care Unit Septic defined by Sepsis 3 criteria or septic shock defined as patients with sepsis with persistent hypotension requiring vasopressors to maintain a Mean Arterial Pressure >=65 mmHg and having serum lactate >= 2 mmol/L despite adequate volume resuscitation. Able to take oral medication through any enteral access (including but not limited to naso/oro gastric/duodenal tube or gastrostomy tube). Exclusion Criteria: Patients with pre-existing diabetes type 1. Evidence of moderate to severe AKI (KDIGO stage 2 or 3) at admission to the ICU Patients not expected to survive more than 24h after admission to the ICU The decision to withhold life-sustaining treatment, not including those patients committed to full support except cardiopulmonary resuscitation Using metformin at the time of admission or within the last month Physician strongly believes that the study treatment will not be continued according to the study protocol Confirmed pregnancy Patients treated with extracorporeal membrane oxygenation (ECMO) or with ventricular assist devices (VAD) Organ donors with a neurological determination of death Patients with history of allergy to metformin Patients in chronic dialysis use Patients with estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 in prior 30 days Patients with severe metabolic acidosis defined by a potential of hydrogen < 7.2

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: One 500mg or 1,000mg tablet will be administered twice a day for the first (5) days of study treatment. One inactive tablet will be administered twice a day for the first (5) days of study treatment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin 500 mg<br>One 500mg tablet will be administered twice a day for the first (5) days of study treatment. | Drug: Metformin low dose<br>* If randomized to the 500 mg. Metformin arm, a tablet will be administered orally to the study participant twice a day for the initial five days starting on the date of study enrollment. Clinical research coordinators will collect blood and urine samples from study participants in both treatment arms. The blood will be collected at Baseline, Day 1 thru 7, and at hospital discharge or Day 30, whichever occurs first. On Day 2 and Day 5, the blood will be collected at hour-based intervals of 0.5h, 1h, 2h, 4h, 8h, 12h for a pharmacokinetic profile and delivered to the University of Pittsburgh Medical Center Clinical Laboratory for analysis. The remaining blood collection tubes will be delivered to the Clinical Research Biospecimen Core laboratory to be processed, separated into microtubes, and stored at -80°. Urine samples will be collected at Baseline, Day 1, 3, and 5. The urine will be processed, separated into microtubes, and frozen at -80°.<br>* Other names: Glumetza low dose;|
| Placebo Comparator: Placebo<br>One inactive tablet will be administered twice a day for the first (5) days of study treatment. | Drug: Placebo<br>* If randomized to the Placebo arm, a tablet will be administered orally to the study participant twice a day for the initial five days starting on the date of study enrollment. Clinical research coordinators will collect blood and urine samples from study participants in both treatment arms. The blood will be collected at Baseline, Day 1 thru 7, and at hospital discharge or Day 30, whichever occurs first. On Day 2 and Day 5, the blood will be collected at hour-based intervals of 0.5h, 1h, 2h, 4h, 8h, 12h for a pharmacokinetic profile and delivered to the University of Pittsburgh Medical Center Clinical Laboratory for analysis. The remaining blood collection tubes will be delivered to the Clinical Research Biospecimen Core laboratory to be processed, separated into microtubes, and stored at -80°. Urine samples will be collected at Baseline, Day 1, 3, and 5. The urine will be processed, separated into microtubes, and frozen at -80°.<br>* Other names: Placebo dose;|
| Experimental: Metformin 1,000 mg<br>One 1,000mg tablet will be administered twice a day for the first (5) days of study treatment. | Drug: Metformin high dose<br>* If randomized to the 1000 mg. Metformin arm, a tablet will be administered orally to the study participant twice a day for the initial five days starting on the date of study enrollment. Clinical research coordinators will collect blood and urine samples from study participants in both treatment arms. The blood will be collected at Baseline, Day 1 thru 7, and at hospital discharge or Day 30, whichever occurs first. On Day 2 and Day 5, the blood will be collected at hour-based intervals of 0.5h, 1h, 2h, 4h, 8h, 12h for a pharmacokinetic profile and delivered to the University of Pittsburgh Medical Center Clinical Laboratory for analysis. The remaining blood collection tubes will be delivered to the Clinical Research Biospecimen Core laboratory to be processed, separated into microtubes, and stored at -80°. Urine samples will be collected at Baseline, Day 1, 3, and 5. The urine will be processed, separated into microtubes, and frozen at -80°.<br>* Other names: Glutzema high dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The development of metformin associated serious adverse events (mSAE) which will include hyperlactatemia, hypoglycemia, metabolic acidosis and/or gastrointestinal intolerance during the treatment period | Safety will be measured by monitoring the patient for the development of metformin associated serious adverse events (mSAE) which will include hyperlactatemia, hypoglycemia, metabolic acidosis and/or gastrointestinal intolerance during the treatment period. In addition, patients will be monitored for any adverse event or any significant adverse event. | Hospital discharge or 30 days, whatever occurs first | 
| Feasibility: Recruitment, retention and adherence | Investigators will quantify the number of patients screened and consented, the number of patients completing the study treatment, and the number of protocol deviations. | Hospital discharge or 30 days, whatever occurs first | 
| Feasibility: Investigating the reasons for denial of enrollment by patients, surrogates or clinicians | Investigators will identify barriers to implementing the intervention perceived by physicians, patients, or patients' surrogates who decline to participate or who drop out by requesting their feedback. | Hospital discharge or 30 days, whatever occurs first | 
| Feasibility: Data accrual and loss to follow-up | Investigators will estimate the proportion of randomized patients that achieve complete acquisition of outcome and ancillary data and lost to follow-up, and the proportion of missing data per variable. | Hospital discharge or 30 days, whatever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve of the concentration of the renal biomarker TIMP2 (Time Point 2)/ Insulin-like growth factor-binding protein (IGFBP7) in time | Investigators will measure the area under the curve of concentration of the tubular biomarker TIMP2/IGFBP7 vs. time using levels at baseline, day 1, 3 and 5. | Baseline, Day 1, 3, 5 to define the area under the concentration curve | 
| Pharmacokinetic Accumulation Profile | Metformin accumulation levels will be assessed from study blood samples day 5 blood obtained at 0.5h, 1h, 2h, 4h, 8h, 12h, after administration of the last dose of Metformin. | Day 5 | 
| Pharmacokinetic Absorption Profile | Metformin absorption kinetics will be assessed from study blood samples on Day 2, blood will be obtained at 0.5h, 1h, 2h, 4h, 8h, 12h, after first dose administration of Metformin. | Day 2 | 
| Change in Platelet Mitochondrial Respiration | Platelet bioenergetic profile will be assessed by measuring the oxygen consumption rate in the presence of sequential blockade of the different components of the electron transport chain using the SeaHorse analyzer on a subset of participants from each treatment arm. | Change from baseline, Day 1, 3, 5 | 
| Change in Platelet Mitochondrial Electron Transport Chain Complex Expression | Platelet mitochondrial transport chain complex expression will be quantified by western blot using a LI-COR machine normalized to the Integrin alfa-2b protein. | Change from baseline, Day 1, 3, 5 | 
| Acute Kidney Injury at day 7 | AKI will be measured using the worse creatinine and urine output daily for 7 days and at discharge or day 30, whichever comes first. | At day 7 | 
| Acute Kidney Injury at day 30 or discharge | AKI will be measured using the worse creatinine and urine output daily for 7 days and at discharge or day 30, whichever comes first. | Hospital discharge or day 30, whichever comes first. | 
| Number of patients requiring Renal Replacement Therapy within the hospitalization | Participants will be assessed on the need for any form of intermittent or continuous renal replacement therapy. | Hospital discharge or 30 days, whichever comes first. | 
| In-hospital Mortality | The proportion of patients who died while in the hospital | Hospital discharge or Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Septic Shock, Acute Kidney Injury, Metformin