A Phase 3 interventional study of Metformin and Placebo in Type 1 Diabetes Mellitus, sponsored by Hellenic Institute for the Study of Sepsis. Status unknown at 1 site in Greece. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-02-18.
Sponsored by Hellenic Institute for the Study of Sepsis · Phase 3, Interventional, and Treatment
Investigators aim is to conduct an RCT to study the effect of adjunct metformin treatment to insulin monotherapy in patients with type 1 diabetes, targeting the intestinal incretin secretion. The patients will be randomly allocated to metformin or placebo treatment for 4 months
Compared to the large armamentarium of antidiabetic agents for Type 2 Diabetes Mellitus (T2DM), the insulinocentric therapeutic approach in Type 1 Diabetes Mellitus (T1DM) has distracted the scientific perspective from the rise of novel therapies. Insulin monotherapy has long overshadowed the overall hormonal dysregulation that demarcates T1DM . In specific, the significance of the gut-derived incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide), which are implicated with glucose metabolism via the gut-pancreatic axis, has been merely addressed.
Investigators' goal in the current protocol is to delineate the glucoregulatory role of incretin hormones in T1DM and the therapeutic advantages of adjunct metformin treatment over insulin monotherapy. In the absence of such knowledge, the development of effective strategies to improve metabolic homeostasis and ameliorate complications in T1DM patients will remain problematic. The central hypothesis of the study is that metformin, as an incretin-secretagogue, will enhance postprandial incretin secretion in T1DM patients, which will be reflected in reduced glucagon secretion and improvement in glycemic volatility. Mechanistic insight will be provided through changes in specific amino acids and metabolites patterns, chronic inflammation and the microbiome composition.
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This study's planned enrollment of 44 is below the median of 80 across 8,367 interventional studies indexed under Diabetes Mellitus.
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Exclusion Criteria:
Patients will continue with their standard insulin therapy and will additionally receive orally metformin 2gr/day.
Drug: Metformin
Patients will continue with their standard insulin therapy and will additionally receive placebo
Drug: Placebo
Participants will be randomized to metformin 2000 mg
Participants will be randomized to placebo
Change in GLP-1 (glucagon like peptide) and GIP (gastric inhibitory peptide) postprandial secretion
The primary endpoint of the study is the change in postprandial GLP-1(ng/ml) and GIP (ng/ml) secretion with metformin treatment compared to placebo.
Time frame: 4 months
Change in glycemic variability pre- and post- treatment
A continuous glucose-monitoring device will be attached to each participant and record daily glucose measurements (mg/dl) for 6 consecutive days on two separate time points: a) within a week prior to randomization and b) as a follow up, within a week prior to Inpatient Visit 2.
Time frame: 4 months
Metabolomic profile of each treatment group
Untargeted metabolomics analysis and identification of candidate metabolites using mass spectrometry. Quantitative targeted metabolomics will then be applied on candidate metabolites to compare differences pre and post treatment between metformin and placebo treatment arm
Time frame: 4 months
Change in inflammatory state
Corrrelation of CRP levels (mg/dl) and treatment arm, as marker of inflammation. CRP will be measured from plasma blood samples collected during Inpatient Visits 1 and 2.
Time frame: 4 months
Change in endothelial dysfunction
Correlation of Serpin E1/PAI-1 levels (ng/ml), VEGF levels (pg/ml), ICAM1 levels (ng/ml) SYndecan-1 levels (ng/ml) and placebo/metformin administration, as markers of endothelial dysfunction. Concentration of adhesion molecules will be measured and compared from plasma blood samples collected during Inpatient Visits 1 and 2.
Time frame: 4 months
Change in cytokine production
Correlation of TNFα levels (pg/ml) ,IL-6 levels (pg/ml),IL-1β levels (pg/ml),IL-10 levels ,(pg/ml) and placebo/metformin administration, as markers of inflammation. Concentration of cytokines will be measured and compared from plasma blood samples collected during Inpatient Visits 1 and 2.
Time frame: 4 months
Change in matrix metalloproteinase-9 (MMP-9) levels
Correlation of MMP-9 levels (ng/ml) levels and placebo/metformin administration, as markers of inflammation. Concentration of MMP-9 will be measured and compared from plasma blood samples collected during Inpatient Visits 1 and 2.
Time frame: 4 months
Change in chemokine production
Correlation of CCL2 levels (pg/ml) ,CCL3 levels (pg/ml),CCL4 levels (pg/ml) and placebo/metformin administration, as markers of inflammation. Concentration chemokines will be measured and compared from plasma blood samples collected during Inpatient Visits 1 and 2.
Time frame: 4 months
Change in gene expression
RNA from PBMCs collected pre and post intervention will be isolated and Quantitative Real Time PCR will be used to measure the transcription of genes related to inflammation and endothelial function.
Time frame: 4 months
Change in gut microbiome analysis
Stool samples will be collected pre and post the intervention on Inpatient Visits 1 and 2 to identify the changes in the microbiome composition based on phylogenetic analysis of the 16S rRNA gene sequencing classification using quantitative PCR.
Time frame: 4 months
Plan to share: No
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Hellenic Institute for the Study of Sepsis