Incretin Hormones in Type 1 Diabetes Mellitus;Effect of Metformin Treatment (INCREDIBLE-M)
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|ClinicalTrials.gov Identifier: NCT04177303|
Recruitment Status : Recruiting
First Posted : November 26, 2019
Last Update Posted : February 18, 2020
|Condition or disease||Intervention/treatment||Phase|
|Type 1 Diabetes Mellitus||Drug: Metformin Drug: Placebo||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||44 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Pilot, mechanistic, phase 3, randomized, placebo-controlled, parallel designed, double-blinded clinical trial|
|Masking:||Double (Participant, Investigator)|
|Masking Description:||All pills will be provided as effervescent, pre-scored 1000mg tablets, so that they may easily be dichotomized.Boxes with active drug or placebo will be covered to conceal the identity of the test article. Sponsor will provide covering materials.The unblinded designee will provide the covered boxes to the blinded nurse or blinded investigator who will dispense the pills.Participants will be given study drug diaries, which they will complete during study drug intake.|
|Official Title:||Gut-derived Incretin Hormones in the Pathophysiology of Type 1 Diabetes Mellitus; Effect of Metformin Treatment|
|Actual Study Start Date :||November 29, 2019|
|Estimated Primary Completion Date :||November 29, 2022|
|Estimated Study Completion Date :||November 29, 2022|
Active Comparator: Metformin
Patients will continue with their standard insulin therapy and will additionally receive orally metformin 2gr/day.
Participants will be randomized to metformin 2000 mg
Placebo Comparator: Placebo
Patients will continue with their standard insulin therapy and will additionally receive placebo
Participants will be randomized to placebo
- Change in GLP-1 (glucagon like peptide) and GIP (gastric inhibitory peptide) postprandial secretion [ Time Frame: 4 months ]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.
- Change in glycemic variability pre- and post- treatment [ Time Frame: 4 months ]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.
- Metabolomic profile of each treatment group [ Time Frame: 4 months ]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
- Change in inflammatory state [ Time Frame: 4 months ]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.
- Change in endothelial dysfunction [ Time Frame: 4 months ]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.
- Change in cytokine production [ Time Frame: 4 months ]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.
- Change in matrix metalloproteinase-9 (MMP-9) levels [ Time Frame: 4 months ]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.
- Change in chemokine production [ Time Frame: 4 months ]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.
- Change in gene expression [ Time Frame: 4 months ]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.
- Change in gut microbiome analysis [ Time Frame: 4 months ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04177303
|Contact: Evangelos J Giamarellos-Bourboulis, MD, PhDfirstname.lastname@example.org|
|Contact: Antigoni J Kotsaki, MD,PhDemail@example.com|
|Diabetes Center, 1st Internal Medicine Department, AHEPA University General Hospital of Thessaloniki||Recruiting|
|Thessaloníki, Thessaloniki, Greece, 54636|
|Contact: Kalliopi Kotsa, MD,PhD +306932045201 firstname.lastname@example.org|
|Contact: Antigoni Z Lalia, MD,MSc +306980661463 email@example.com|
|Principal Investigator: Kalliopi Kotsa, MD,PhD|
|Sub-Investigator: Antigoni Lalia, MD,MSc|
|Principal Investigator:||Kotsa Kalliopi, MD,PhD||1st Internal Medicine Department, AHEPA University Hospital|