Using colchicine to reduce inflammation and improve insulin resistance in people with obesity

COLSIO Trial: Phase II Randomized, Controlled Trial of Colchicine to Suppress Inflammation and Improve Insulin Resistance in Adults and Adolescents With Obesity

This study is testing if colchicine can help reduce inflammation and improve insulin sensitivity in adults and teens with obesity.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 500 (estimated)
• Ages: 12 Years to 100 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: prednisone, HOMAB
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT05017571 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the effectiveness of colchicine, an anti-inflammatory medication, in improving metabolic health in adults and adolescents with obesity and insulin resistance. Participants aged 12 and older will be screened for eligibility based on their medical history, physical exams, and various tests, including blood and urine tests. The study will compare the effects of colchicine versus a placebo on inflammation levels and insulin sensitivity over a series of visits. The goal is to determine if colchicine can help prevent the onset of diabetes and cardiovascular diseases associated with obesity.

Who should consider this trial

Good fit: Ideal candidates include adults and adolescents aged 12 and older with obesity and signs of insulin resistance.

Not a fit: Patients who are not overweight or do not exhibit signs of insulin resistance may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for managing obesity-related metabolic issues and reducing the risk of diabetes.

How similar studies have performed: Other studies have shown promise in using anti-inflammatory treatments for metabolic conditions, but this specific approach with colchicine is relatively novel.

Eligibility 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 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 heart failure, or CKD Stage 3b or worse (eGFR \< 60 mL/min/1.73 m2), or American Society of Anesthesiologists Physical Status Class 3 or above) or other serious disorders at the discretion of the investigators.
2. HbA1c \> 7.0%
3. Type 2 diabetes mellitus, as determined by either having:

   1. clear clinical diagnosis of diabetes, such as a patient in a hyperglycemic crisis or classic symptoms of hyperglycemia and a random plasma glucose \>= 200 mg/dL
   2. 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 2 hours.

   c. one of the above three criteria (bi.-biii.) meeting the T2DM cutoff on two different days.

   If only one of the above three criteria (bi.-biii.) meet the T2DM threshold during the Screening Visit, that test will be repeated on another day to determine if the subject has T2DM or not. As per ADA guidelines, The diagnosis \[of T2DM\] is made on the basis of the confirmed test.

   Moreover, because HbA1c has been shown to be higher in African Americans (AA) as compared to other races for the same glycemia, AA who do not have diabetes may be unfairly excluded by their HbA1c alone 96-98. Therefore, for AA subjects, if their fasting and 2h glucose is in the non-diabetes range, and the HbA1c is \< 7.0%, we will consider them not to have diabetes.
4. Recent or regular use of colchicine, anorexiant, or diabetic medications in the last 3 months, or plan to start in the following 3 months.
5. Recent or regular use of anti-inflammatory medications (e.g. prednisone, NSAIDs) in the last 7 days, or plan to start in the following 3 months.
6. Current use of a strong or moderate CYP3A4 inhibitor or P-glycoprotein (P-gp), as this may cause a significant increase in colchicine plasma concentrations and risk for side effects. Oral contraceptive use will be permitted, provided the contraceptive has been used for at least two months before starting study medication. Note: HMA-CoA reductase inhibitors ( statins ) in adults only will also be

   explicitly allowed because of the recent clinical trial data finding it is safe to administer low-dose colchicine even with high-dose statin therapy. 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 be eligible.
7. Known allergy to colchicine.
8. Previous history of agranulocytosis, gout, or significant myositis.
9. 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 45 days in premenopausal women.
10. Individuals who have current substance abuse or a DSM 5 Axis I psychiatric disorder or DSM Axis II Mental Retardation diagnosis that in the opinion of the investigators would impede competence, compliance, or participation in the study.
11. Current users of tobacco or nicotine (e.g., nicotine patch, e-cigarettes) products.
12. Participation in a formal weight loss program (e.g., Weight Watchers) or recent weight 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).

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Jack A Yanovski, M.D. — Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Study coordinator: Sheila M Brady, C.R.N.P.

Conditions Obesity; Insulin Resistance; Inflammation; Diabetes; Overweight; comorbidities; Microbiome; C-Reactive Protein