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

  • STATUS
    Recruiting
  • End date
    Jun 1, 2026
  • participants needed
    500
  • sponsor
    Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Updated on 10 August 2022
diabetes
cardiovascular disease
insulin
electrocardiogram
body mass index
fasting
oral glucose tolerance test
insulin resistance
fatty acids
a 12
sugars

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.

...

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 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). From among up to 500 individuals screened, we will conduct a randomized, double-blinded, 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.

Details
Condition Obesity, Insulin Resistance, Inflammation
Treatment Placebo, colchicine
Clinical Study IdentifierNCT05017571
SponsorEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Last Modified on10 August 2022

Eligibility

Yes No Not Sure

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
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 be still eligible
Age >= 18y for adults; age 12y to <18y for adolescents
Obesity BMI >= 30 kg/m2 (adults) or BMI >= 95th percentile for age and sex per Centers for Disease Control Standards (adolescents)
Weight <= 450 lbs (204.5 kg)
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
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
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
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
Good general health. In general subjects should take no medications. The use of
Age >= 18y
over-the-counter and prescription medications will be reviewed on a case-by-case
BMI >= 18 kg/m2
basis; depending on the medication, subjects who have continued to take prescription
Weight <= 450 lbs (204.5 kg)
medication or have stopped taking an exclusionary medication for at least 3 months
prior to study entry may still be eligible
Willing and able to provide consent for Evaluation-Only study
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

Exclusion Criteria

Exclusion Criteria for subject randomized to colchicine or placebo
HbA1c > 7.0%
Type 2 diabetes mellitus, as determined by either having
All individuals meeting any of the exclusion criteria at screening or baseline will be
two of the following three
excluded from study participation
ii. Hemoglobin A1c >= 6.5%
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
c. one of the above three criteria (bi.-biii.) meeting the T2DM cutoff on two
discretion of the investigators
different days
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
i. fasting plasma glucose >= 126 mg/dL
iii. An oral glucose tolerance test glucose concentration of >= 200 mg/dL at 2 hours
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 glucose is in the non-diabetes range, and the HbA1c is < 7.0%, we will
consider them not to have diabetes
Recent or regular use of colchicine, anorexiant, or diabetic medications in the last 3
months, or plan to start in the following 3 months
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
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. 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
Known allergy to colchicine
Previous history of agranulocytosis, gout, or significant myositis
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
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
Current users of tobacco or nicotine (e.g. nicotine patch, e-cigarettes) products
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)
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