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NCT07436182

PHASE4

Mitochondrial Redox Modulation in Newly Diagnosed Type 2 Diabetes: A Randomized Controlled Trial Comparing Imeglimin vs. Metformin Monotherapy

Sponsor: Mansoura University

View on ClinicalTrials.gov

Summary

he goal of this clinical trial is to compare the mitochondrial redox effects of imeglimin versus metformin monotherapy in adults with newly diagnosed Type 2 diabetes mellitus who are treatment-naive. The main questions it aims to answer are: Does imeglimin improve the fasting plasma pyruvate/lactate ratio (a validated surrogate of mitochondrial NAD⁺/NADH redox balance) to a greater extent than metformin after 12 weeks of treatment? Does imeglimin produce more favorable changes in secondary mitochondrial and glycemic biomarkers - including fasting plasma lactate, fasting plasma pyruvate, HbA1c, HOMA-IR, and lipid profile - compared to metformin? Researchers will compare imeglimin 1000 mg twice daily to metformin up to 1000 mg twice daily to see if imeglimin produces superior improvement in mitochondrial oxidative capacity and cytoplasmic redox balance, reflected by a greater increase in the fasting plasma pyruvate/lactate ratio, without compromising glycemic efficacy or safety. Participants will: Take either imeglimin 1000 mg twice daily or metformin (titrated up to 1000 mg twice daily) orally for 12 weeks, as assigned by randomization Attend clinic visits at baseline (Week 0) and at Week 12 for fasting blood sample collection, including strict bedside deproteinization of pyruvate samples using ice-cold perchloric acid to ensure analytical accuracy Undergo measurement of fasting plasma pyruvate/lactate ratio, HbA1c, HOMA-IR, fasting glucose, fasting insulin, fasting plasma lactate, fasting plasma pyruvate, and full lipid profile at both visits Be monitored for adverse events and safety parameters, including renal function (eGFR), throughout the study period

Key Details

Gender

All

Age Range

18 Years - Any

Study Type

INTERVENTIONAL

Enrollment

176

Start Date

2026-03-01

Completion Date

2026-06-01

Last Updated

2026-02-27

Healthy Volunteers

Conditions

Mitochondria Metformin

Interventions

DRUG

Imeglimin

Imeglimin 1000 mg tablet orally twice daily with meals for 12 weeks without titration. Imeglimin is a first-in-class triazine antidiabetic agent that enhances mitochondrial Complex I and III activity, reduces mitochondrial ROS, and augments NAD⁺ regeneration, hypothesized to increase the fasting plasma pyruvate/lactate ratio by restoring cytoplasmic NAD⁺/NADH redox balance. Metformin hydrochloride immediate-release tablet initiated at 500 mg twice daily for 2 weeks then increased to 1000 mg twice daily from Week 3 through Week 12, taken with meals. Metformin inhibits mitochondrial Complex I, impairing NADH oxidation and shifting the LDH equilibrium toward lactate production, expected to reduce the fasting plasma pyruvate/lactate ratio. Both agents are compared at equivalent final daily doses of 2000 mg in treatment-naive newly diagnosed Type 2 diabetes patients.

DRUG

Metformin 1000 mg Oral Tablet

meglimin 1000 mg tablet orally twice daily with meals for 12 weeks without titration. Imeglimin is a first-in-class triazine antidiabetic agent that enhances mitochondrial Complex I and III activity, reduces mitochondrial ROS, and augments NAD⁺ regeneration, hypothesized to increase the fasting plasma pyruvate/lactate ratio by restoring cytoplasmic NAD⁺/NADH redox balance. Metformin hydrochloride immediate-release tablet initiated at 500 mg twice daily for 2 weeks then increased to 1000 mg twice daily from Week 3 through Week 12, taken with meals. Metformin inhibits mitochondrial Complex I, impairing NADH oxidation and shifting the LDH equilibrium toward lactate production, expected to reduce the fasting plasma pyruvate/lactate ratio. Both agents are compared at equivalent final daily doses of 2000 mg in treatment-naive newly diagnosed Type 2 diabetes patients.

.1 Inclusion Criteria Participants must meet ALL of the following criteria for enrollment: 1. Age 18 or more inclusive, male or female. 2. Confirmed diagnosis of T2DM within the preceding 12 months prior to screening, established by ADA or WHO criteria: fasting plasma glucose ≥ 126 mg/dL on two separate occasions, and/or 2-hour OGTT plasma glucose ≥ 200 mg/dL, and/or HbA1c ≥ 6.5%, and/or random plasma glucose ≥ 200 mg/dL with classic hyperglycemic symptoms. 3. HbA1c between 6.5% and 7.5 % inclusive at screening. 4. Treatment-naive: no prior antidiabetic pharmacological treatment, or any prior antidiabetic treatment discontinued at least 3 months before screening. 5. Estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m² by CKD-EPI formula at screening. 6. Willing and able to provide written informed consent in Arabic or English. 7. Able to attend all scheduled study visits and comply with study procedures, dietary restrictions, and pre-analytical blood collection requirements. 2 Exclusion Criteria Participants meeting ANY of the following criteria will be excluded: 1. Type 1 diabetes mellitus, Latent Autoimmune Diabetes in Adults (LADA), or other specific types of diabetes (anti-GAD antibody positivity, monogenic diabetes). 2. HbA1c \>7.5 gm% 3. eGFR \< 45 mL/min/1.73m² - increase risk of drug accumulation and lactic acidosis. 4. Hepatic impairment defined as ALT or AST \> 2.5 times the upper limit of normal at screening. Hepatic dysfunction independently elevates plasma lactate by impairing lactate clearance and pyruvate metabolism, confounding the primary endpoint. 5. History of or current congestive heart failure (NYHA Class III-IV) or clinically significant cardiovascular disease with hemodynamic instability major risk factor for lactic acidosis and a confound for tissue lactate metabolism. 6. Active or recent (within 3 months) use of any antidiabetic pharmacological agent. 7. Current use of medications known to significantly affect mitochondrial function or lactate/pyruvate metabolism: valproate, linezolid, nucleoside reverse transcriptase inhibitors (NRTIs), phenformin, zidovudine, or high-dose thiamine-depleting regimens. 8. Pregnancy, planned pregnancy within the trial period, or active breastfeeding. 9. Active malignancy requiring chemotherapy, radiotherapy, or immunosuppression within the preceding 6 months. 10. Significant chronic alcohol use: \> 21 units per week (male) or \> 14 units per week (female). Alcohol is a major independent confound for pyruvate/lactate ratio through its own effects on hepatic NAD+/NADH balance. 11. Acute illness, surgery, trauma, or hospitalization within 4 weeks of screening, acute physiological stress elevates plasma lactate independent of drug effects. 12. Vigorous or unaccustomed physical exercise within 24 hours of any biomarker blood draw, exercise-induced lactate elevation is a major pre-analytical confound. 13. Known hypersensitivity or contraindication to imeglimin or metformin. 14. Participation in another interventional clinical trial within 3 months preceding screening. 15. Any condition that, in the investigator's judgment, would render the patient unable to safely complete the trial or reliably provide valid biomarker samples.

Locations (1)

Mansoura university hospitals

Al Mansurah, Province, Egypt