Fiber and Metformin Combination Therapy in Adolescents With Severe Obesity and Insulin Resistance

Study Overview
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Brief Summary
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This is a 12-month, single center, three-arm parallel design, double-blind, randomized clinical trial, to compare the effects of supplemental dietary fiber and metformin (MET) alone and in combination over 12 months on glucose metabolism (insulin resistance [IR]), inflammation and BMI in adolescents with obesity and IR, and to assess the relationship between therapeutic intervention(s) and changes in gut microbiome composition and function. Since MET and FIBER have been shown to reduce weight and increase insulin sensitivity through distinct but overlapping mechanisms of action, our central hypothesis is that the combination of FIBER + MET will have a synergistic effect and be more effective than FIBER or MET alone in improving metabolic function (IR) and reducing BMI and inflammation in adolescents with obesity, IR and family history (FM) of T2DM. .

Official Title
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Fiber Supplementation and Metformin Combination Therapy in Adolescents With Severe Obesity and Insulin Resistance: Interactions With the Gut Microbiome.

Conditions
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Obesity, Childhood, Insulin Resistance

Intervention / Treatment
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* Drug: Metformin 850 mg oral tablet bid
* Dietary Supplement: Supplemental fiber mixture (35 g total) composed of 6g of Oligofructose + 12g of resistant maltodextrin + 12g of acacia gum + 5g of PGX.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 12-18 years BMI percentile > 95% for age/sex; Total weight fluctuation over past 6 months < 10%; HOMA-IR > 3.16; FH of T2DM (first or second-degree relative). Exclusion Criteria: Current use of insulin or diagnosis of T2DM; Systolic or diastolic blood pressure (BP) > 99th percentile for age and sex; Acute infectious or inflammatory condition over the preceding 1 month; hospitalization > 48 hrs; History of chronic disease such as inflammatory bowel disease, chronic severe liver or kidney disease or neurologic disorders; Active malignancy; Concomitant use of medication/investigational drug known to affect body weight in the past year; Antibiotic use in past 60 days; probiotic and/or prebiotic supplements use in the past 30 days; use of lipid-lowering and anti-inflammatory medication.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MET<br>MET (850 mg po bid - standard of care) + Fiber placebo daily | Drug: Metformin 850 mg oral tablet bid<br>* MET dose: 500 mg daily, increasing to 500 bid if tolerated after 2 weeks, then increasing again 2 weeks later to 850 mg bid (1700 mg daily).<br>|
| Active Comparator: FIBER<br>Fiber supplementation [35g fiber daily] + MET placebo po bid | Dietary Supplement: Supplemental fiber mixture (35 g total) composed of 6g of Oligofructose + 12g of resistant maltodextrin + 12g of acacia gum + 5g of PGX.<br>* The first week of treatment will use 1/3 the daily treatment dose; then 2/3 dose for the second and third weeks; then the full dose thereafter, to allow time for adaptation.<br>|
| Experimental: FIBER + MET<br>Fiber supplementation [35g fiber daily] + MET 850 mg po bid | Drug: Metformin 850 mg oral tablet bid<br>* MET dose: 500 mg daily, increasing to 500 bid if tolerated after 2 weeks, then increasing again 2 weeks later to 850 mg bid (1700 mg daily).<br>Dietary Supplement: Supplemental fiber mixture (35 g total) composed of 6g of Oligofructose + 12g of resistant maltodextrin + 12g of acacia gum + 5g of PGX.<br>* The first week of treatment will use 1/3 the daily treatment dose; then 2/3 dose for the second and third weeks; then the full dose thereafter, to allow time for adaptation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in HOMA-IR | Change in HOMA-IR value | Baseline, 6, and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in body weight | Body weight measured in kg | Baseline, 6, and 12 months | 
| Changes in body mass index (BMI) | BMI percentile and z-score according to age and sex will be estimated | Baseline, 6, and 12 months | 
| Changes in body composition | Body density using air-displacement plethysmography will be assessed to estimate fat mass and fat-free mass. | Baseline, 6, and 12 months | 
| Changes in inflammation | Markers of inflammation that will be measured are: high-sensitivity C-reactive protein, interleukin, tumor necrosis factor-alpha) | Baseline, 6, and 12 months | 
| Changes in metabolic function | The markers of metabolic function that will be measured are: fasting glucose, lipids (total, high and low density lipoprotein cholesterol; triglycerides), and oral glucose tolerance test. | Baseline, 6, and 12 months | 
| Changes in satiety hormones | Markers of satiety that will be measured are: acylated ghrelin, peptide tyrosine tyrosine, GLP-1, leptin, and adiponectin. | Baseline, 6, and 12 months | 
| Changes in quality of life | Quality of life will be measured by the a questionnaire | Baseline, 6, and 12 months | 
| Changes in perceived hunger and satiety | Perceived hunger and satiety will be assessed by a questionnaire | Baseline, 6, and 12 months | 
| Changes in gut microbiota composition | Fecal microbiota composition will be characterized by 16S rRNA gene amplicons sequencing using taxonomic and non-taxonomic based approaches. | Baseline, 6, and 12 months | 
| Changes in gut microbiome functions | Fecal microbiome functions will be assessed through whole metagenomic sequencing, stool SCFAs and bile acids, and plasma metabolomics. | Baseline, 6, and 12 months | 
| Changes in intestinal barrier integrity | Plasma lipopolysaccharide-binding protein and fecal calprotectin will be determined as measures of gut barrier integrity | Baseline, 6, and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dietary fiber, Metformin