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Incretin Hormones in Type 1 Diabetes Mellitus;Effect of Metformin Treatment (INCREDIBLE-M)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04177303
Recruitment Status : Recruiting
First Posted : November 26, 2019
Last Update Posted : February 18, 2020
Sponsor:
Information provided by (Responsible Party):
Hellenic Institute for the Study of Sepsis

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Drug: Metformin Drug: Placebo Phase 3

Detailed Description:

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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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Allocation: Randomized
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.
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Metformin
Patients will continue with their standard insulin therapy and will additionally receive orally metformin 2gr/day.
Drug: Metformin
Participants will be randomized to metformin 2000 mg

Placebo Comparator: Placebo
Patients will continue with their standard insulin therapy and will additionally receive placebo
Drug: Placebo
Participants will be randomized to placebo




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 years
  • T1DM (Diagnosis of diabetes before the age of 35 years and insulin use within 1 year of diagnosis)
  • Treatment with multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII)

Exclusion Criteria:

  • Any cardiovascular disease within the last 3 months
  • NYHA stage 3 or 4 heart failure
  • Uncontrolled angina
  • Liver failure [AST>135 IU/L or ALT>129IU/L (3 x the upper normal limit)] • Kidney failure or GFR<60 ml/min/1.73m2
  • Gastrointestinal disease or gastroparesis
  • Prior diagnosis of cancer within 2 years
  • Other medication that affect glucose metabolism within the last 3 months (metformin, SGLT2, GLP-1 analogues, amylin analogues, systemic glucocorticosteroids)
  • Untreated or uncontrolled thyroid disease
  • Pregnancy or breastfeeding
  • Alcohol consumption > 2-drinks per day or other substance abuse

Information from the National Library of Medicine

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


Contacts
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Contact: Evangelos J Giamarellos-Bourboulis, MD, PhD +306945521800 egiamarel@med.uoa.gr
Contact: Antigoni J Kotsaki, MD,PhD +306946637164 antigonebut@yahoo.com

Locations
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Greece
Diabetes Center, 1st Internal Medicine Department, AHEPA University General Hospital of Thessaloniki Recruiting
Thessaloníki, Thessaloniki, Greece, 54636
Contact: Kalliopi Kotsa, MD,PhD    +306932045201    kalli@med.auth.gr   
Contact: Antigoni Z Lalia, MD,MSc    +306980661463    alalia@auth.gr   
Principal Investigator: Kalliopi Kotsa, MD,PhD         
Sub-Investigator: Antigoni Lalia, MD,MSc         
Sponsors and Collaborators
Hellenic Institute for the Study of Sepsis
Investigators
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Principal Investigator: Kotsa Kalliopi, MD,PhD 1st Internal Medicine Department, AHEPA University Hospital

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Responsible Party: Hellenic Institute for the Study of Sepsis
ClinicalTrials.gov Identifier: NCT04177303    
Other Study ID Numbers: INCREDIBLE-ME
First Posted: November 26, 2019    Key Record Dates
Last Update Posted: February 18, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hellenic Institute for the Study of Sepsis:
Metformin
Incretin hormones
Inflammation
Microbiome
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Metformin
Gastric Inhibitory Polypeptide
Hormones
Incretins
Hypoglycemic Agents
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Gastrointestinal Agents