Safety and Feasibility of Metformin for Sepsis Induced AKI

NCT05900284 | Enrolling By Invitation Phase 2 DMC FDA Drug

• 2 other identifiers: STUDY221200321R01DK133142-01A1
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

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.

Conditions

Sepsis; Septic Shock; Acute Kidney Injury; Metformin

Keywords

Sepsis; Septic Shock; Acute Kidney Injury; Metformin

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (9)

• Area under the curve of the concentration of the renal biomarker TIMP2 (Time Point 2)/ Insulin-like growth factor-binding protein (IGFBP7) in time

  Baseline, Day 1, 3, 5 to define the area under the concentration curve

• Pharmacokinetic Accumulation Profile

  Day 5

• Pharmacokinetic Absorption Profile

  Day 2

• Change in Platelet Mitochondrial Respiration

  Change from baseline, Day 1, 3, 5

• Change in Platelet Mitochondrial Electron Transport Chain Complex Expression

  Change from baseline, Day 1, 3, 5

Study Arms (3)

Metformin 500 mg

EXPERIMENTAL

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

Drug: Metformin low dose

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Metformin 1,000 mg

EXPERIMENTAL

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

Drug: Metformin high dose

Interventions

Metformin low dose 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°.

Also known as: Glumetza low dose

Metformin 500 mg

Placebo 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°.

Also known as: Placebo dose

Placebo

Metformin high dose 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°.

Also known as: Glutzema high dose

Metformin 1,000 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 18 years
• 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)
• Available enteral access

You may not qualify if:

• Estimated glomerular filtration rate (eGFR) \< 30 ml/min/1.73m2 prior to study drug administration
• Not expected to survive more than 24 hours
• Advanced directive to withhold life-sustaining treatment
• Metformin use in the last 30 days from admission (assessed by medical or refill prescription history, and by medication reconciliation)
• The treating clinician believes that participation in the trial would not be in the best interests of the patient
• Known or suspected pregnancy
• On mechanical circulatory support of any kind
• History of allergy to metformin
• 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).

Sponsors & Collaborators

• Hernando Gomez: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

Related Publications (1)

• 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.

  PMID: 38688665 RESULT

Related Links

• BMJ Open Full Published Article

MeSH Terms

Conditions

Sepsis; Shock, Septic; Acute Kidney Injury

Interventions

Metformin

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Hernando Gomez, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All parties are blinded by participant group.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Model Details: 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

Study Record Dates

• First Submitted: May 22, 2023
• First Posted: June 12, 2023
• Study Start: November 8, 2023
• Primary Completion: April 30, 2026
• Study Completion: April 30, 2026
• Last Updated: February 20, 2026

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: After final enrolled participant is completed. Data will be shared for up to 12 months after the study is closed.
• Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose.

Locations

US (1)