Safety and Feasibility of Metformin for Sepsis Induced AKI

NCT ID: NCT05900284

Last Updated: 2025-08-11

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: PHASE2
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-11-08
• Study Completion Date: 2026-03-01

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.

Conditions

Sepsis; Septic Shock; Acute Kidney Injury; Metformin

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Metformin 500 mg

One 500mg tablet will be administered twice a day for the first (5) days of study treatment.

Group Type: EXPERIMENTAL

Metformin low dose

Intervention Type: DRUG

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°.

Placebo

One inactive tablet will be administered twice a day for the first (5) days of study treatment.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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°.

Metformin 1,000 mg

One 1,000mg tablet will be administered twice a day for the first (5) days of study treatment.

Group Type: EXPERIMENTAL

Metformin high dose

Intervention Type: DRUG

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°.

Interventions

Metformin low dose

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°.

Intervention Type: DRUG

Metformin high dose

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°.

Intervention Type: DRUG

Placebo

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°.

Intervention Type: DRUG

Other Intervention Names

Glumetza low dose; Glutzema high dose; Placebo dose

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Hernando Gomez

OTHER

Sponsor Role: lead

Responsible Party

Hernando Gomez

Assistant Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Hernando Gomez, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 38688665 (View on PubMed)

Related Links

https://doi.org/10.1136/bmjopen-2023-081120

BMJ Open Full Published Article

Other Identifiers

1R01DK133142-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY22120032

Identifier Type: -

Identifier Source: org_study_id