Clinical trial NCT04209075: Prebiotics and Metformin Improve Gut and Hormones in Type 2 Diabetes in Youth (MIGHTY-fiber)
Official title: Prebiotics and Metformin Influences Gut and Hormones in Type 2 Diabetes Youth (MIGHTY)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes
Keywords: Metformin
Type 2 Diabetes
Youth
Microbiome
Gastrointestinal Side Effects
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2019-12-23
Enrollment: 6
Sex: ALL
Minimum age (years): 10
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Background:

Metformin is a pill youth with type 2 diabetes take. It can cause side effects like diarrhea and upset stomach. Researchers want to see if a fiber supplement can help decrease these side effects.

Objective:

To see if a prebiotic fiber supplement helps improve the gastrointestinal side effects of people taking metformin and helps with their blood sugars.

Eligibility:

People ages 10-25 with type 2 diabetes who are taking or will take metformin

Design:

Participants will be screened with:

Physical exam

Medical history

Blood and urine tests

Meeting with a nutritionist

Participants will stop taking all diabetes medication for 1 week. They will then take metformin by mouth for 1 week. They will be randomly assigned to take either a fiber supplement or a placebo by mouth during the same week. They will then stop all study treatments for 2-3 weeks. Then they will restart metformin for 1 week. The groups that received the fiber versus the placebo will be reversed. All participants will then continue taking metformin and take the fiber for 1 month.

Participants will have 6 visits over about 2 months. These will include:

Blood and urine tests

Meal tests: A plastic tube will be inserted in the participant s arm vein for blood draws. They will drink a special meal.

Dual-energy x-ray absorptiometry (DXA) scan: Participants will lie on their back while the scan measures their body fat and muscle.

While they are home, participants will:

Fill out daily surveys online

Wear daily activity and blood sugar monitors

Collect their stool

Eat only certain foods for two 1-week periods...

Detailed description: Metformin is the most widely prescribed anti-diabetes medication in the world and the first-line therapy for treating type 2 diabetes (T2D) in youth and adults. However, metformin s glucose-lowering ability is variable in clinical practice, and efficacy is further limited by poor medication adherence because of metformin-associated adverse effects. Gastrointestinal (GI) symptoms such as bloating, abdominal discomfort, cramping, and diarrhea are the most common side effects associated with metformin use occurring in up to 80% of individuals at drug initiation and up to 30% in individuals on chronic treatment. In youth with type 2 diabetes, the burden of metformin-associated side effects is high because metformin is the only oral FDA-approved for treatment and there are no other oral alternatives. Therefore, identifying ways to mitigate these GI side effects, especially in youth with type 2 diabetes, is of high clinical significance. New data suggest that metformin-induced changes in the gut and/ or the microbiome may be related to both its beneficial (glucose-lowering) and adverse effects. To address this clinical challenge, prebiotic fibers that are non-digestible food ingredients, may help to improve metformin tolerability by increasing beneficial bacteria and stool metabolites, such as short chain fatty acid (SCFA) stool concentrations. This pilot study will test the hypothesis that a prebiotic microbiome modulator (MM) - containing prebiotic fibers and polyphenols - will reduce GI side effects of metformin at time of initiation and change the stool metabolite profile in youth and young adults with T2D treated with metformin, age 10-25 years who are not on insulin therapy. The 9-week study will have 2 phases and 6 outpatient visits at the NIH Clinical Center. Phase 1 is a 5-week randomized double blind cross-over trial with two 1-week intervention periods (metformin + prebiotic and metformin + placebo) during which subjects will eat a standardized diet. Phase 2 will occur immediately following phase 1 in which participants will start an open-label 4-week intervention with metformin and the prebiotic MM.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Age 10-25 years
  2. Pubertal or post-pubertal: Girls - Tanner stage IV-V breast; Boys - Testicular volume \>10cc
  3. Diagnosis of type 2 diabetes by American Diabetes Association (ADA) guidelines \[36\] or with established diagnosis previously treated with metformin.
  4. Negative test for diabetes-related autoantibodies (glutamic acid decarboxylase 65 and tyrosine phosphatase-related islet antigen 2 (IA-2)) documented in NIH CRIS chart or via outside laboratory assessment within the last 10 years.
  5. Hemoglobin A1C \<8% at study initiation

EXCLUSION CRITERIA:

1. Pregnancy or breastfeeding
2. Allergy to study medications
3. Allergy or self-reported intolerance to blueberry, pomegranate, or oats, soy, gluten or dairy products.
4. Chronic insulin therapy or insulin use within the last 3 months
5. Treatment with other medications which are known to affect the parameters under study, including antibiotics within the last month, immunosuppressants, proton-pump inhibitors, supraphysiologic systemic steroids, probiotic or prebiotic supplements
6. Heavy yogurt consumption (2 or more servings of \>=6 oz per day)
7. Chronic GI disease, gastric bypass surgery, cancer diagnosis or autoimmune disease
8. Metabolic derangement such as metabolic acidosis, severe hyperglycemia (fasting blood glucose \>= 200mg/dL), and/or liver enzymes \> three times the upper limit of normal.
9. Any other condition that, in the opinion of the investigators, will increase risk to the subject, or impede the

   accurate collection of study-related data.
10. Body weight \>= 450lbs
11. Body weight \<=58kg
12. Hemoglobin concentration \<10g/dL

Primary outcomes:
measure: Gastrointestinal (GI) Tolerability Score
timeFrame: 1 week (assessed daily for 7 days)
Secondary outcomes:
measure: Stool Short Chain Fatty Acids (SCFA)
timeFrame: 1 week and 4 weeks
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Stephanie T Chung, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burton JH, Johnson M, Johnson J, Hsia DS, Greenway FL, Heiman ML. Addition of a Gastrointestinal Microbiome Modulator to Metformin Improves Metformin Tolerance and Fasting Glucose Levels. J Diabetes Sci Technol. 2015 Jul;9(4):808-14. doi: 10.1177/1932296815577425. Epub 2015 Mar 23.