Inflammation, Insulin Resistance, Obesity
Conditions
Keywords
Diabetes, Overweight, comorbidities, Microbiome, C-Reactive Protein
Brief summary
Background: About 40 percent of adults and 20 percent of adolescents in the U.S. have a body mass index over 30 kg/m2. Being overweight may lead to a state of low-level inflammation. This may cause health problems. Researchers want to see if an anti-inflammatory medicine can help. Objective: To learn if colchicine can improve metabolism in people who have high body weight, increased inflammation, and high insulin in the blood but who have not yet developed high blood sugar. Eligibility: People aged 12 and older with high body weight who may have increased inflammation and high insulin in the blood. Healthy adult volunteers are also needed. Design: Participants will be screened with the following: Medical history Physical exam Fasting blood tests Urine tests Electrocardiogram Dual energy x-ray absorptiometry (They will lie on a table while a camera passes over their body.) Stool sample and 24-hour food diary (optional) Participants will have 3 study visits and 3 phone check-ins. At visits, they will repeat some screening tests. Healthy volunteers will have the baseline visit only. They will not get the study drug. At the baseline visit, participants will have an Oral Glucose Tolerance Test (OGTT). For this, they will drink a sweet liquid and then give blood samples. They will get a 12-week supply of the study drug or placebo to take daily by mouth. Participants will have study visits 6 weeks and 12 weeks after they started taking the study drug. At the 12-week visit, they will repeat the OGTT. Participation will last for 3 (Omega) to 4 months. ...
Detailed description
Study Description: Obesity affects more than 40% of the adult U.S. population plus approximately 20% of adolescents and is a major risk factor for the development of type 2 diabetes and cardiovascular disease. Mouse models and human data suggest that obesity-induced chronic inflammation is one mechanism promoting obesity-associated comorbid conditions. In obesity, innate immunity is activated when circulating molecules such as fatty acids and cholesterol crystals bind to nucleotide-binding oligomerization (Nod)-like receptor family, pyrin domain containing 3 (NLRP3) receptors. The resultant inflammatory cascade leads to insulin resistance and decreased pancreatic beta-cell reserve. It has been proposed that the suppression of this chronic low-level inflammatory state may impede the onset of diabetes and cardiovascular disease. Recent studies have shown colchicine, a potent microtubule inhibitor that is approved for use in the treatment of gout and some rare inflammatory conditions in adults and children, disrupts intracellular NLRP3 inflammasome assembly. As there are limited medical therapies proven effective to improve obesity-related metabolic dysregulation, we propose to determine the efficacy of oral colchicine 0.6 mg versus placebo once daily in non-diabetic adults and adolescents with obesity, insulin resistance, and inflammation (elevated high-sensitivity C-reactive protein concentrations: hsCRP \>= 2.0). From among up to 500 individuals screened, we will conduct a randomized, double-blind, placebo-controlled trial of colchicine in up to 200 adults. We will also obtain pilot data from 40 adolescents studied in the same (randomized) fashion. This study will determine the effects of colchicine on insulin resistance and beta cell reserve in adults with obesity and allow determination of the sample size needed to conduct an adequately powered study of the effects of colchicine in adolescents. An Evaluation-Only control group of up to 50 adults who do not meet entry criteria for the randomized clinical trial will also be studied with baseline tests only. Objectives: Primary Objective: To compare efficacy of colchicine versus placebo for improving insulin resistance in adults with obesity-related inflammation Secondary Objectives: To compare the effect of colchicine versus placebo on other biomarkers of metabolic health, inflammation, and colchicine action in adults with obesity-related inflammation To determine effect sizes for colchicine versus placebo in adolescents with obesity-related inflammation for insulin resistance as well as other biomarkers of metabolic health, inflammation, and colchicine action Additional Objectives: To compare the effect of colchicine versus placebo on changes in the secretome and stool microbiome in adults with obesity-related inflammation. To examine if there are sex x treatment or race/ethnicity x treatment interactions for the effects of colchicine on change in insulin resistance and other biomarkers in adults with obesity-related inflammation. To compare the effect of colchicine versus placebo on changes in hepatic gluconeogenesis and triglyceride synthesis rate indices in adults with obesity-related inflammation. Endpoints: Primary Endpoint: Change in homeostatic model assessment of insulin resistance (HOMA-IR) from baseline (randomization) to 3 months in adult participants Key Secondary Endpoints: Changes from baseline (randomization) to 3 months in high sensitivity C-reactive protein (hsCRP), Matsuda index, fasting serum glucose and insulin in adult participants. Additional (Exploratory) Study Endpoints: Changes from baseline (randomization) to 3 months in muscle insulin resistance index, adipose insulin resistance index (Adipo-IR), pancreatic beta cell indices (e.g. HOMA-B%, insuligenic index), triglycerides, LDL- and HDL-cholesterol, lipoprotein profile, liver fat content, systolic and diastolic blood pressure, oral glucose tolerance test (OGTT) or oral sugar tolerance test (OSTT) area under the curve (AUC) insulin and glucose, AUC insulin/AUC glucose ratio, hepatic gluconeogenesis and triglyceride synthesis rate indices, other inflammatory and metabolic markers, secretome, and microbiome analyses in adult participants. Post-hoc power calculation of sample size needed, at power \>= 80% and two-sided alpha \<= 0.05 for change in HOMA-IR in adolescent participants. In adolescent participants, changes from baseline (randomization) to 3 months in HOMA-IR, hsCRP, Matsuda index, muscle insulin resistance index, Adipo-IR, OGTT AUC insulin and glucose, AUC insulin/AUC glucose ratio, pancreatic beta cell indices (e.g., HOMAB%, insuligenic index), fasting serum glucose, insulin, triglycerides, LDL- and HDL-cholesterol, lipoprotein profile, systolic and diastolic blood pressure, inflammatory and metabolic markers, secretome, and microbiome analyses.
Interventions
DRUGColchicine
Colchicine 1 capsule (0.6 mg) per day
DRUGPlacebo
Placebo 1 capsule per day
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: All races/ethnicities and people of all genders are eligible to participate. Participants who will be randomized to colchicine or placebo must meet all of the following Inclusion Criteria: 1. Good general health. In general subjects should take no medications with the exception of oral/implantable contraceptives, antihypertensive medications like diuretics, or for adults HMG-CoA reductase inhibitors (statin cholesterol-reducing medications). The use of all over-the-counter and prescription medications will be reviewed on a case-by-case basis; depending on the medication, subjects who have continued to take prescription medication or have stopped taking an exclusionary medication for at least 3 months prior to study entry may be still eligible. 2. Age \>= 18y for adults; age 12y to \<18y for adolescents 3. Obesity BMI \>= 30 kg/m2 (adults) or BMI \>= 95th percentile for age and sex per Centers for Disease Control Standards (adolescents) 4. Weight \<= 450 lbs (204.5 kg) - due to DXA limitations 5. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation. 6. HOMA-IR \>= 2.6 mg/L, calculated as fasting glucose (in mg/dL) x insulin in (microIU/mL/ 405). Our goal is to enroll participants who have pre-existing insulin resistance. 7. hsCRP \>= 2.0 mg/L. We aim to recruit participants with increased baseline level of inflammation. Individuals with hsCRP above 2.0 mg/L have been shown to have an increased risk for cardiovascular events. 8. Willing to be randomized (willing and able to give consent/assent as required for randomized study). Participants who will be evaluated but are not eligible for randomization (Evaluation Only Arm) must meet all of the following Inclusion Criteria: 1. Good general health. In general subjects should take no medications. The use of over-the-counter and prescription medications will be reviewed on a case-by-case basis; depending on the medication, subjects who have continued to take prescription medication or have stopped taking an exclusionary medication for at least 3 months prior to study entry may still be eligible. 2. Age \>= 18y 3. BMI \>= 18 kg/m2 4. Weight \<= 450 lbs (204.5 kg) 5. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation 6. Willing and able to provide consent for Evaluation-Only study
Exclusion criteria
All individuals meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Homeostatic model assessment of insulin resistance (HOMA-IR) | From baseline to 3 months | HOMA-IR is calculated from fasting (f) insulin (I) and glucose (G): Gf (in mg/dL) x If in ( (Micro)IU/mL/ 405). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in fasting serum insulin | From baseline to 3 months | Fasting serum insulin |
| Change in fasting serum glucose | From baseline to 3 months | Fasting serum glucose |
| Change in High-Sensitivity C-Reactive Protein | From baseline to 3 months | High-Sensitivity C-Reactive Protein |
| Change in Matsuda Index | From baseline to 3 months | (10\^4/(\[Gf x 18\] x If x \[mean GOSTTx18\] x mean I-OSTT)0.5), where Gf is fasting glucose, If is fasting insulin, and I-OSTT is mean insulin from oral sugar tolerance test |
Countries
United States
Outcome results
None listed