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Type 1 Diabetes MellitusPhase 3INCREDIBLE-MNCT04177303

Incretin Hormones in Type 1 Diabetes Mellitus;Effect of Metformin Treatment

A Phase 3 study testing Metformin in people with Type 1 Diabetes Mellitus, run by Hellenic Institute for the Study of Sepsis.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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 Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Type 1 Diabetes Mellitus
What is being tested?
Metformin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
0 participants
Where
No sites listed yet
Study dates
29 Nov 2019to 31 Dec 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)

Who cannot join

  • 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
Show all 10Show fewer
  • 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

About this study

Official title: Gut-derived Incretin Hormones in the Pathophysiology of Type 1 Diabetes Mellitus; Effect of Metformin 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

Read the 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.

Being tested
Metformin, Placebo
Keywords
Metformin, Incretin hormones, Inflammation, Microbiome
Medical subject headings
Diabetes Mellitus, Type 1, Inflammation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MetforminDrug

    Participants will be randomized to metformin 2000 mg

  • PlaceboDrug

    Participants will be randomized to placebo

Study groups in NCT04177303
Study groupRoleWhat they receive
MetforminActive comparatorPatients will continue with their standard insulin therapy and will additionally receive orally metformin 2gr/day.
Receives: Drug: Metformin
PlaceboPlacebo comparatorPatients will continue with their standard insulin therapy and will additionally receive placebo
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 4 months

Secondary outcomes (9)

  1. 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.

    Measured: 4 months

  2. 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

    Measured: 4 months

  3. 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.

    Measured: 4 months

  4. 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.

    Measured: 4 months

  5. 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.

    Measured: 4 months

  6. 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.

    Measured: 4 months

  7. 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.

    Measured: 4 months

  8. 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.

    Measured: 4 months

  9. 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.

    Measured: 4 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Nov 2019
  2. Study start29 Nov 2019
  3. Primary completion31 Dec 2024
  4. Study completion31 Dec 2024

Why it stopped: It was not conducted due to the emergency restrictive measures implemented during the COVID-19 pandemic, which made it impossible to carry out the patient visits required by the study protocol.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Pilot, mechanistic, phase 3, randomized, placebo-controlled, parallel designed, double-blinded clinical trial
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04177303
Sponsor's protocol ID
INCREDIBLE-ME
Acronym
INCREDIBLE-M
Status last verified
Feb 2020
First submitted
30 Oct 2019
Last updated
3 Nov 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Metformin in people with Type 1 Diabetes Mellitus, run by Hellenic Institute for the Study of Sepsis.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 3 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in GLP-1 (glucagon like peptide) and GIP (gastric inhibitory peptide) postprandial secretion (time frame: 4 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04177303.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Nov 2026.

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