Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim2) (MicroB2)

• ClinicalTrials.gov Identifier: NCT02127125
• Recruitment Status: Completed
• First Posted: April 30, 2014
• Results First Posted: September 11, 2020
• Last Update Posted: September 11, 2020
• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborator: American Diabetes Association
• Information provided by (Responsible Party): The University of Texas Health Science Center at San Antonio

Tracking Information

• First Submitted Date: April 24, 2014
• First Posted Date: April 30, 2014
• Results First Submitted Date: August 3, 2020
• Results First Posted Date: September 11, 2020
• Last Update Posted Date: September 11, 2020
• Actual Study Start Date: April 10, 2014
• Actual Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 26, 2020)

Insulin Sensitivity [ Time Frame: Change from baseline insulin sensitivity at 28 days of the intervention. ]

Insulin sensitivity in skeletal muscle (M value) as measured by hyperinsulinemic euglycemic clamp study. The clamp study tests the ability of peripheral tissues such as skeletal muscle to uptake glucose in response to a constant insulin stimulus, which give a measure of sensitivity to insulin action. 60 mU/m2*min insulin was infused into subjects for 180 minutes with concomitant adjustment of glucose infusion rate using D20 glucose to maintain a clamped plasma glucose concentration of 100 mg/dL. When the glucose infusion rate equals the rate of glucose uptake and the targeted glucose concentration is achieved, the clamp is at steady-state equilibrium. Steady-state glucose infusion rate at 150min-180mins was used as the measure to calculate the M value.

• Original Primary Outcome Measures (submitted: April 28, 2014): Insulin Sensitivity [ Time Frame: Change from baseline insulin sensitivity at 28 days of the intervention. ]

Current Secondary Outcome Measures (submitted: August 26, 2020)

• Plasma Endotoxin Level and Its Panel. [ Time Frame: Change from baseline plasma endotoxin level and its panel during 28 days. ]
  Plasma Lipopolysaccharide (LPS) after intervention period
• Gut Permeability [ Time Frame: Change from baseline gut permeability at 24 days of the intervention. ]
  urine lactulose: mannitol ratio.

Original Secondary Outcome Measures (submitted: April 28, 2014)

• Plasma Endotoxin Level and Its Panel. [ Time Frame: Change from baseline plasma endotoxin level and it's panel during 28 days. ]
  Plasma LPS, LBP, soluble CD14, IL-6, and TNF-alpha.
• Gut Permeability [ Time Frame: Change from baseline gut permeability at 24 days of the intervention. ]
  urine for lactulose and mannitol ratio.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim2)
• Official Title: Mechanism of Microbiome-induced Insulin Resistance in Humans (Aim2)
• Brief Summary: The purpose of this study is to determine whether microbiome modulation and an experimental reduction in plasma LPS concentration improve inflammation and insulin action in insulin resistant (obese and T2DM) subjects.
• Detailed Description: In this Aim we will test the hypothesis that lowering lipopolysaccharide (LPS) concentration in the circulation will improve systemic (muscle) inflammation and glucose metabolism in insulin resistant (obese and T2DM) subjects by protecting the intestinal barrier with a synbiotic (Bifidobacterium longum R0175 and oligofructose) or by sequestering LPS in the gastrointestinal lumen with sevelamer.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Insulin Sensitivity

Intervention

• Drug: Maltodextrin
  Maltodextrin treatment as a placebo group. Maltodextrin, 6 gm three times a day for 4 weeks.
• Drug: Synbiotic
  Synbiotic [5 g of oligofructose + 1 g Bifidobacterium longum R0175 (4 billion colony forming unit (CFU)/g) three times a day) for 4 weeks.
• Drug: Sevelamer
  Sevelamer (1.6 g sevelamer + 4.4 g maltodextrin three times a day), for 4 weeks
  Other Name: Renvela

Study Arms

• Placebo Comparator: Type2 Diabetes Mellitus - Placebo
  Type 2 Diabetes Mellitus subjects will receive maltodextrin (placebo)
  Intervention: Drug: Maltodextrin
• Placebo Comparator: Obese with NGT - Placebo
  Obese (BMI = 30-37 kg/m2) normal glucose tolerant (NGT) subjects will receive maltodextrin (placebo)
  Intervention: Drug: Maltodextrin
• Placebo Comparator: Lean with NGT -Placebo
  Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive maltodextrin (placebo)
  Intervention: Drug: Maltodextrin
• Active Comparator: Type2 Diabetes Mellitus - Synbiotic
  Type 2 Diabetic subjects will receive synbiotic
  Intervention: Drug: Synbiotic
• Active Comparator: Type2 Diabetes Mellitus - Sevelamer
  Type 2 Diabetic subjects will receive sevelamer
  Intervention: Drug: Sevelamer
• Active Comparator: Obese with NGT - Synbiotic
  Obese (BMI = 30-37 kg/m2) normal glucose tolerant subjects (NGT) will receive Synbiotic
  Intervention: Drug: Synbiotic
• Active Comparator: Obese with NGT - Sevelamer
  Obese subjects (BMI = 30-37 kg/m2) normal glucose tolerant (NGT) will receive Sevelamer
  Intervention: Drug: Sevelamer
• Active Comparator: Lean with NGT - Synbiotic
  Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive Synbiotic
  Intervention: Drug: Synbiotic
• Active Comparator: Lean with NGT - Sevelamer
  Lean (BMI< 26 kg/m2) normal glucose tolerant (NGT) will receive Sevelamer
  Intervention: Drug: Sevelamer

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 26, 2020): 69
• Original Estimated Enrollment (submitted: April 28, 2014): 108
• Actual Study Completion Date: September 10, 2018
• Actual Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Both genders (50%, male). All races and ethnic groups.
• Premenopausal women in the follicular phase, non-lactating, and with a negative pregnancy test. Postmenopausal women on stable dose of or not exposed to hormone replacement for ≥6 months.
• Hematocrit (HCT)≥ 34%, serum creatinine ≤ 1.4 mg/dl, and normal results of serum electrolytes, urinalysis, and coagulation tests. Liver function tests (LFTs) up to 2 times normal
• Stable body weight (±2%) for ≥ 3 months.
• Two or less sessions of strenuous exercise/wk for last 6 months.

Exclusion Criteria:

• Current treatment with drugs known to affect glucose and lipid homeostasis. If the subject has been on a stable dose for the past 3 months, the following agents will be permitted: calcium channel blockers, β-blockers, ACE inhibitors, angiotensin receptor blockers, and statins
• History of allergy to sevelamer.
• Non-steroidal anti-inflammatory drugs or systemic steroid use for more than a week within 3 months.
• Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be permitted if these can be held for seven days prior to the biopsy in accordance with the primary physician.
• Use of agents that affect gut flora (e.g. antibiotics, colestyramine, lactulose, PEG) within 3 months.
• History of heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the ECG), peripheral vascular disease, pulmonary disease, smokers.
• Poorly controlled blood pressure (systolic BP>170, diastolic BP>95 mmHg).
• Active inflammatory, autoimmune, hepatic, gastrointestinal, malignant, and psychiatric disease.
• History of gastrointestinal surgery or gastrointestinal obstruction within two years.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02127125
• Other Study ID Numbers: HSC20130458H
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: The University of Texas Health Science Center at San Antonio
• Study Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: American Diabetes Association

Investigators

• Principal Investigator: Nicolas Musi, MD.; The University of Texas Health Science Center at San Antonio

• PRS Account: The University of Texas Health Science Center at San Antonio
• Verification Date: August 2020