Clinical trial NCT05900284: Safety and Feasibility of Metformin for Sepsis Induced AKI
Official title: A Randomized Clinical Trial of the Safety and Feasibility of Metformin as a Treatment for Sepsis Induced AKI.
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: Sepsis
Septic Shock
Acute Kidney Injury
Metformin
Keywords: Sepsis
Septic Shock
Acute Kidney Injury
Metformin
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2023-06-12
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age \> 18 years
2. Admitted to the ICU with sepsis per sepsis 3 criteria (defined as suspected infection or initiation of anti-biotics plus an increase in SOFA ≥ 2 points)
3. Available enteral access

Exclusion Criteria:

1. Estimated glomerular filtration rate (eGFR) \< 30 ml/min/1.73m2 prior to study drug administration
2. Not expected to survive more than 24 hours
3. Advanced directive to withhold life-sustaining treatment
4. Metformin use in the last 30 days from admission (assessed by medical or refill prescription history, and by medication reconciliation)
5. The treating clinician believes that participation in the trial would not be in the best interests of the patient
6. Known or suspected pregnancy
7. On mechanical circulatory support of any kind
8. History of allergy to metformin
9. Having severe metabolic acidosis defined by a venous or arterial pH \< 7.2, with PaCO2 \< 45 or PvCO2 \< 50 mmHg at the time of enrolment.

   * Patients co-enrolled in observational studies will be eligible for enrollment in LiMiT AKI. However, patients enrolled in interventional studies will need to be assessed on an individual basis to define whether the patient will be eligible.
   * Children will be excluded from recruitment for this study. Etiologic causes of sepsis, acute kidney injury, and prognostic factors for children differ from those for adults; and for these reasons the proposed study focuses only on the adult population (age 18 years or older).

Primary outcomes:
measure: The development of metformin associated serious adverse events (mSAE) which will include hyperlactatemia, hypoglycemia, metabolic acidosis and/or gastrointestinal intolerance during the treatment period
timeFrame: Hospital discharge or 30 days, whatever occurs first
measure: Feasibility: Recruitment, retention and adherence
timeFrame: Hospital discharge or 30 days, whatever occurs first
measure: Feasibility: Investigating the reasons for denial of enrollment by patients, surrogates or clinicians
timeFrame: Hospital discharge or 30 days, whatever occurs first
measure: Feasibility: Data accrual and loss to follow-up
timeFrame: Hospital discharge or 30 days, whatever occurs first
Secondary outcomes:
measure: Area under the curve of the concentration of the renal biomarker TIMP2 (Time Point 2)/ Insulin-like growth factor-binding protein (IGFBP7) in time
timeFrame: Baseline, Day 1, 3, 5 to define the area under the concentration curve
measure: Pharmacokinetic Accumulation Profile
timeFrame: Day 5
measure: Pharmacokinetic Absorption Profile
timeFrame: Day 2
measure: Change in Platelet Mitochondrial Respiration
timeFrame: Change from baseline, Day 1, 3, 5
measure: Change in Platelet Mitochondrial Electron Transport Chain Complex Expression
timeFrame: Change from baseline, Day 1, 3, 5
measure: Acute Kidney Injury at day 7
timeFrame: At day 7
measure: Acute Kidney Injury at day 30 or discharge
timeFrame: Hospital discharge or day 30, whichever comes first.
measure: Number of patients requiring Renal Replacement Therapy within the hospitalization
timeFrame: Hospital discharge or 30 days, whichever comes first.
measure: In-hospital Mortality
timeFrame: Hospital discharge or Day 30
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Hernando Gomez, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Saraiva IE, Hamahata N, Huang DT, Kane-Gill SL, Rivosecchi RM, Shiva S, Nolin TD, Chen X, Minturn J, Chang CH, Li X, Kellum J, Gomez H. Metformin for sepsis-associated AKI: a protocol for the Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI). BMJ Open. 2024 Apr 30;14(4):e081120. doi: 10.1136/bmjopen-2023-081120.