Comparing Semaglutide Versus Placebo on Intestinal Barrier Function in Type 2 Diabetes Mellitus (SIB)

Study Overview
=================
Brief Summary
-----------------
This study plans to learn more about the effect of semaglutide once weekly on intestinal permeability in individuals with type 2 diabetes.

Official Title
-----------------
A Randomized Parallel Comparison of Semaglutide Versus Placebo on Intestinal Barrier Function in Type 2 Diabetes Mellitus (SIB)

Conditions
-----------------
Type 2 Diabetes, Chronic Inflammation, Intestinal Permeability

Intervention / Treatment
-----------------
* Drug: Semaglutide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial, except for protocol described pre-screening activities, which require a separate informed consent. Male or female, age above or equal to 18 years at the time of signing informed consent. Diagnosed with type 2 diabetes mellitus on metformin monotherapy Hemoglobin A1c <8.0% (<64 mmol/mol) on screening day Body mass index (BMI) ≥28 kg/m2 Low-grade inflammation, defined as elevated high sensitivity C-reactive protein (hs- CRP >1.0 and ≤10 mg/L). Impaired intestinal barrier function results in activation of inflammatory pathway; therefore, excluding subjects with no evidence of inflammation (hs-CRP ≤ 1 mg/L) will help to enrich our study population. Similar threshold for hs-CRP as a marker of residual inflammatory risk (29) has been previously used as an independent predictor of future vascular events (26, 30). Exclusion Criteria: Known or suspected hypersensitivity to trial product or related products. Female who is pregnant, breast-feeding or intends to become pregnant or is of child- bearing potential and not using a highly effective contraceptive method. Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening. Any disorder, which in the investigator's opinion might jeopardize patient's safety or compliance with the protocol. Any of the following: myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischemic attack (TIA) within the past 60 days prior to the day of screening. Second anti-diabetic agent use within 3 months of screening. Chronic kidney disease defined as eGFR < 30 mL/min/1.73 m2. C-reactive protein (hs-CRP >10.0 mg/L) to eliminate patients with acute inflammatory process at the time of screening. Any recent infection or antibiotic use within 3 weeks Regular use (more than a week duration) of anti-inflammatory medication (steroid or NSAIDs) within 3 months of screening. Regular use (more than a week duration) of any digestive health supplements, such as probiotics or prebiotics within 3 months screening. Diagnosis of chronic intestinal inflammatory disease such as Crohn's disease, ulcerative colitis or irritable bowel syndrome. Prior bariatric or bowel surgery Heart failure presently classified as being in New York Heart Association (NYHA) Class IV. Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal and squamous cell skin cancer and any carcinoma in-situ is allowed. Personal or family history of multiple endocrine neoplasia type 2 (MEN2) or medullary thyroid carcinoma (MTC). History of chronic pancreatitis or history of acute pancreatitis within 6 months of screening. Chronic consumption of > 2 alcoholic standard drinks per day as defined by: 12 ounces of beer (5% alcohol content). 8 ounces of malt liquor (7% alcohol content). 5 ounces of wine (12% alcohol content). 1.5 ounces or a shot of 80-proof (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, whiskey).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 89 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SC semaglutide<br>Participants receive a once weekly, subcutaneous, Semaglutide injection for 16 weeks in addition to the participants background metformin monotherapy. The participants in this arm will begin at a 0.25 mg dose during the randomization visit, at week 4 this will be escalated to a 0.5 mg dose and at week 8 it will be escalated again to a 1.0 mg dose if tolerable by the participant. If the participant cannot tolerate the 0.25 mg dose at randomization or the 0.5 mg dose at week 4 they will be withdrawn from the study. | Drug: Semaglutide<br>* Semaglutide 1.34 mg/mL solution for injection in 1.5 mL pre-filled PDS290 pen-injector provided by Novo Nordisk.<br>* Other names: PDS290 pen-injector;|
| Placebo Comparator: Placebo<br>Participants in this arm will be given a once weekly, subcutaneous, placebo injection matching the Semaglutide experimental arm in addition to their background metformin monotherapy. | Drug: Placebo<br>* Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector provided by Novo Nordisk.<br>* Other names: PDS290 pen-injector;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in lactulose mannitol ratio (LMR) test as a measure of intestinal permeability between treatment groups | The ratio of lactulose to mannitol will be measured in urine collected within 6 hours after ingestion of dual sugar. This ratio predominantly reflects small intestine permeability. | Week 16 (visit 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences between treatment groups in plasma LBP | Marker of intestinal permeability | Week 8 (visit 4), Week 16 (visit 6) | 
| Differences between treatment groups in Serum zonulin | Marker of intestinal permeability | Week 8 (visit 4), Week 16 (visit 6) | 
| Differences between treatment groups in Fecal Calprotectin | Marker of intestinal inflammation | Week 8 (visit 4), Week 16 (visit 6) | 
| Differences between treatment groups in plasma IL-6 | Marker of chronic inflammation | Week 8 (visit 4), Week 16 (visit 6) | 
| Differences between treatment groups in plasma IL-8 | Marker of chronic inflammation | Week 8 (visit 4), Week 16 (visit 6) | 
| Differences between treatment groups in plasma TNFα | Marker of chronic inflammation | Week 8 (visit 4), Week 16 (visit 6) | 
| Differences between treatment groups in plasma hs-CRP | Marker of chronic inflammation | Week 8 (visit 4), Week 16 (visit 6) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
T2D, Type 2 diabetes, Type 2 diabetes mellitus, obesity, intestinal permeability, chronic inflammation