Colchicine to Suppress Inflammation and Improve Insulin Resistance in Adults and Adolescents With Obesity

• 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 theexception of oral/implantable contraceptives, antihypertensive medications likediuretics, or for adults HMG-CoA reductase inhibitors (statin cholesterol-reducingmedications). The use of all over-the-counter and prescription medications will bereviewed on a case-by-case basis; depending on the medication, subjects who havecontinued to take prescription medication or have stopped taking an exclusionarymedication 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 perCenters 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 atleast 1 month prior to screening and agreement to use such a method during studyparticipation.

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 insulinresistance.

7. hsCRP >= 2.0 mg/L. We aim to recruit participants with increased baseline level ofinflammation. Individuals with hsCRP above 2.0 mg/L have been shown to have anincreased risk for cardiovascular events.

8. Willing to be randomized (willing and able to give consent/assent as required forrandomized 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 ofover-the-counter and prescription medications will be reviewed on a case-by-casebasis; depending on the medication, subjects who have continued to take prescriptionmedication or have stopped taking an exclusionary medication for at least 3 monthsprior 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 atleast 1 month prior to screening and agreement to use such a method during studyparticipation

6. Willing and able to provide consent for Evaluation-Only study

EXCLUSION CRITERIA:

All individuals meeting any of the exclusion criteria at screening or baseline will be excluded from study participation.

Exclusion Criteria for subject randomized to colchicine or placebo:

1. Individuals with significant medical comorbidities (e.g., NYHA Class III or IV heartfailure, or CKD Stage 3b or worse (eGFR < 60 mL/min/1.73 m2), or American Society ofAnesthesiologists Physical Status Class 3 or above) or other serious disorders atthe discretion of the investigators.

2. HbA1c > 7.0%

3. Type 2 diabetes mellitus, as determined by either having:

4. clear clinical diagnosis of diabetes, such as a patient in a hyperglycemiccrisis or classic symptoms of hyperglycemia and a random plasma glucose >= 200mg/dL

5. two of the following three: i. fasting plasma glucose >= 126 mg/dL ii. Hemoglobin A1c >= 6.5% iii. An oral glucose tolerance test glucose concentration of >= 200 mg/dL at 2hours. c. one of the above three criteria (bi.-biii.) meeting the T2DM cutoff on twodifferent days. If only one of the above three criteria (bi.-biii.) meet the T2DM threshold duringthe Screening Visit, that test will be repeated on another day to determine if thesubject has T2DM or not. As per ADA guidelines, The diagnosis [of T2DM] is made onthe basis of the confirmed test. Moreover, because HbA1c has been shown to be higher in African Americans (AA) ascompared to other races for the same glycemia, AA who do not have diabetes may beunfairly excluded by their HbA1c alone 96-98. Therefore, for AA subjects, if theirfasting and 2h glucose is in the non-diabetes range, and the HbA1c is < 7.0%, wewill consider them not to have diabetes.

6. Recent or regular use of colchicine, anorexiant, or diabetic medications in the last 3 months, or plan to start in the following 3 months.

7. Recent or regular use of anti-inflammatory medications (e.g. prednisone, NSAIDs) inthe last 7 days, or plan to start in the following 3 months.

8. Current use of a strong or moderate CYP3A4 inhibitor or P-glycoprotein (P-gp), asthis may cause a significant increase in colchicine plasma concentrations and riskfor side effects. Oral contraceptive use will be permitted, provided thecontraceptive has been used for at least two months before starting studymedication. Note: HMA-CoA reductase inhibitors ( statins ) in adults only will alsobe explicitly allowed because of the recent clinical trial data finding it is safe toadminister low-dose colchicine even with high-dose statin therapy. The use ofover-the-counter and prescription medications will be reviewed on a case-by-casebasis; depending on the medication, subjects who have continued to take prescriptionmedication or have stopped taking an exclusionary medication for at least 3 monthsprior to study entry may be eligible.

9. Known allergy to colchicine.

10. Previous history of agranulocytosis, gout, or significant myositis.

11. Females who are pregnant, planning to become pregnant, currently nursing an infant,or have irregular menses, defined as cycles less than 21 days or greater than 45days in premenopausal women.

12. Individuals who have current substance abuse or a DSM 5 Axis I psychiatric disorderor DSM Axis II Mental Retardation diagnosis that in the opinion of the investigatorswould impede competence, compliance, or participation in the study.

13. Current users of tobacco or nicotine (e.g., nicotine patch, e-cigarettes) products.

14. Participation in a formal weight loss program (e.g., Weight Watchers) or recentweight change of more than 3% of body weight in the past two months.

Exclusion Criteria for subjects who are evaluated but not eligible for randomization (Evaluation Only Arm):

We will use the same exclusion criteria as employed for randomized participants (see above).