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ObesityPhase 1/2NCT02153983

Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome

A Phase 1/2 study testing Colchicine 0.6Mg Cap and Colchicine 0.6Mg Tab in people with Obesity and Metabolic Disease, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Background: Being overweight may cause low-level inflammation. This inflammation may cause some of the medical problems of obesity, like high blood sugar (diabetes) and heart disease. Read more about this study

Who is it for?
Ages 18 to 100 yearsHealthy volunteers can take part
Conditions the study is for
Obesity, Metabolic Disease
What is being tested?
Colchicine 0.6Mg Cap and Colchicine 0.6Mg Tab
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
77 participants
Where
1 siteUnited States
Study dates
31 May 2014to 15 Aug 2018
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 100 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Subjects will qualify for the Open Label arm if they meet the following criteria:
  • A diagnosis of T2DM.
  • Not on any diabetic/hypoglycemic agents
  • Not having an alternate cause of hyperglycemia (e.g. T1DM, glucocorticoidinduced, lipodystrophy, acromegaly, etc.)
  • Hemoglobin A1c less than or equal to 9.0%
  • 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 eligible
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  • Age greater than or equal to 18 to 100 years.
  • Obesity, defined as a body mass index (BMI) greater than or equal to 30 kg/m2, but weight less than 450 lbs in order for subjects to undergo Dual-Energy X-ray Absorptiometry (DXA) scanning.
  • Metabolic Syndrome
  • (Any 3 of the following 5):
  • FPG greater than or equal to100 mg/dl or Impaired Glucose Tolerance (Glucose greater than or equal to 140 mg/dl at 2 hours of OGTT)
  • Triglycerides greater than or equal to 150 mg/dl, or on treatment
  • Waist Circumference: Men greater than or equal to 40 in (greater than or equal to 102 cm); Women greater than or equal to 35 in (greater than or equal to 88 cm)
  • Reduced HDL-C: Men < 40 mg/dl; Women < 50 mg/dl, or on treatment
  • Hypertension: greater than or equal to 130 mmHg systolic, or greater than or equal to 85 mmHg diastolic, or on treatment
  • HOMA-IR greater than or equal to 2.6. Our goal is to enroll participants who have pre-existing insulinresistance.
  • hsCRP greater than or equal to 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.

Who cannot join

  • T2DM that is not well controlled with diet alone: subjects will not be eligible if they take an anti-diabetic medication (e.g. metformin, insulin, sulfonylurea, etc.), or have HbA1c >9%.
  • Presence of a significant active or chronic illness likely to limit life span and/or increase risk of intervention, including renal (GFR less than or equal to 30 ml/min/1.73m2), cardiovascular, hepatic (other than obesity-related steatosis), gastrointestinal, immunologic, endocrinologic (e.g. Cushing syndrome), pulmonary (other than either asthma not requiring continuous medication or sleep apnea-related disorders), or other disorders at the discretion of the investigators.
  • Recent use of colchicine or anorexiant medications in the last 3 months.
  • 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.
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  • Individuals who have current substance abuse or a psychiatric disorder or any other condition that in the opinion of the investigators would impede competence, compliance, or participation in the study.
  • Subjects who regularly use prescription medications unrelated to the complications of obesity, especially those known to affect enzymes involved in colchicine metabolism, such as CYP3A4 or P-glycoprotein (P-gp). 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.
  • 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.
  • Use of anti-inflammatory medications (e.g. prednisone, NSAIDs) chronically or in the last 7 days prior to fat biopsy.
  • History of keloid formation.
  • Current users of tobacco or nicotine products (e.g. nicotine patch, e-cigarettes).

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Pilot Study of the Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome

Background:

  • Being overweight may cause low-level inflammation. This inflammation may cause some of the medical problems of obesity, like high blood sugar (diabetes) and heart disease. This study will test whether a medication called colchicine can improve metabolism in adults who are overweight but have not yet developed diabetes.
Read more

Objectives:

  • To learn whether colchicine improves sugar regulation and metabolism.

Eligibility:

  • Healthy overweight adults18 to 100 years old.

Design:

  • Participants must fast before each visit, including the screening visit.
  • Participants will be screened with blood tests,urine tests, medical history, and physical exam. They will have to drink sugar water, and have blood drawn to find out if they are healthy.
  • For visit 1, participants will have a medical history and physical exam and answer questions. They will have blood taken with an intravenous (IV) line, give urine sample, and give 2 stool samples..
  • Also, subjects will get sugar water through one IV. Blood will be drawn from the other. This measures sugar and insulin levels. During this, participants will lie in a bed and can watch TV.
  • Participants will have a full-body X-ray, lying on a table while a camera passes over them. They will also have an abdominal CT scan, lying on a table that moves through a ring that takes pictures.
  • Participants will have a small fat tissue sample taken from their abdomen. It is like getting a mini-liposuction.
  • Participants will be given the study drug or placebo. They will take it twice daily for 3 months.
  • For visit 2, participants will have blood tests, urine tests, medical history, and physical exam.
  • For visit 3, participants will repeat the tests in visit 1.
Read the detailed description

Obesity affects one-third of the adult U.S. population 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 by circulating molecules such as fatty acids and cholesterol crystals bind to nucleotide-binding oligomerization (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) receptors in adipocyte tissue macrophages (ATMs). This binding stimulates NLRP3 oligomerization, inflammasome formation, and proinflammatory cytokine activation. 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 commonly used for the treatment of gout and some rare inflammatory conditions, disrupts intracellular localization of NLRP3, thereby blocking 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 twice daily in non-diabetic obese adults with metabolic syndrome. We will conduct a randomized, double-blinded, placebo-controlled pilot trial of colchicine in forty subjects. We will study changes in insulin resistance, beta-cell reserve, and systemic inflammation. Using adipose tissue obtained from biopsies, we will also study colchicine s local effects on inflammation and insulin resistance. Should results prove promising, this pilot study will allow determination of the sample size needed for an adequately powered study of the effects of colchicine in obese adults with metabolic syndrome.

Seven patients with diet-controlled type 2 diabetes will be given open-label colchicine and followed as described above. We also plan to perform baseline evaluations on 40 subjects who are not eligible for the treatment protocol. This group will consist of non-obese adults, obese adults who are not insulin-resistant, and adults with diet-controlled type 2 diabetes.

Being tested
Colchicine 0.6Mg Cap, Placebo capsules given, Colchicine 0.6Mg Tab
Keywords
Obesity, Colchicine, Inflammation, Metabolic Syndrome, Dyslipidemia
Medical subject headings
Obesity, Metabolic Diseases, Inflammation, Metabolic Syndrome, Dyslipidemias

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Colchicine 0.6Mg CapDrug

    Also called RCT Colchicine

    Colchicine 0.6 mg given twice daily

  • Placebo capsules givenDrug

    Also called RCT Placebo

    Placebo capsules given twice daily

  • Colchicine 0.6Mg TabDrug

    Also called Open-Label Colchicine 0.6 mg given twice daily

    Open-label colchicine

Study groups in NCT02153983
Study groupRoleWhat they receive
Obese Adults with Metabolic Syndrome Randomized to PlaceboExperimentalExperimental treatment with placebo capsules identical in appearance to the experimental colchicine preparation
Receives: Drug: Placebo capsules given
Obese Adults with Metabolic Syndrome Randomized to ColchicineExperimentalExperimental treatment with colchicine capsules identical in appearance to the experimental placebo preparation
Receives: Drug: Colchicine 0.6Mg Cap
Diet-controlled Type 2 Diabetes Adults Assigned to ColchicineExperimentalParticipants with Diet-controlled Type 2 Diabetes who were assigned to Open-label treatment with colchicine. These participants were not randomized and were not part of the randomized controlled trial.
Receives: Drug: Colchicine 0.6Mg Tab
Evaluation Only Non-obese AdultsNo interventionParticipants without obesity seen only for the evaluation component of the study. Such participants are a control group for cross-sectional analyses of baseline data from the experimental cohort.
Evaluation Only Obese Adults Not RandomizedNo interventionParticipants with obesity seen only for the evaluation component of the study. Such participants are a control group for cross-sectional analyses of baseline data from the experimental cohort. These participants were found not eligible for randomization.
Evaluation Only Adults with Type 2 DiabetesNo interventionParticipants with Diet-controlled Type 2 Diabetes seen only for the evaluation component of the study. Such participants are a control group for cross-sectional analyses of baseline data from the experimental cohort.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Insulin Sensitivity From FSIVGTT

    Change (3 month minus minus baseline) in insulin sensitivity value, calculated from frequently-sampled intravenous glucose tolerance tests by Bergman's Minimal Model using intent-to-treat. Higher values represent a better outcome. There are no data from the evaluation-only participants, since they were not followed longitudinally.

    Measured: Baseline to 3 months

Secondary outcomes (2)

  1. Change in HOMA-IR Index

    Change (3 month minus minus baseline) in calculated homeostasis model of insulin sensitivity, calculated from derived from fasting glucose and insulin values = fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5) using intent-to-treat. Higher values represent a worse outcome. There are no data from the evaluation-only participants, since they were not followed longitudinally.

    Measured: Baseline to 3 months

  2. Changes in C-reactive Protein

    Change (3 month minus minus baseline) in High-Sensitivity C-reactive protein concentrations using intent-to-treat. Higher values represent a worse outcome. There are no data from the evaluation-only participants, since they were not followed longitudinally.

    Measured: Baseline to 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jun 2014 (estimated)
  2. Study start31 May 2014
  3. Primary completion15 Aug 2018
  4. Study completion15 Aug 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Note that only 2 of the arms are randomized. Three arms are observational and one is open-label treatment.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
77 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02153983
Sponsor's protocol ID
140119
Other IDs
14-CH-0119, ZIAHD000641-23
Status last verified
Jul 2019
First submitted
31 May 2014
Last updated
13 Aug 2019
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: All individual-level data for the primary and secondary outcomes will be made available upon request. PII will be removed.

Publications

  • Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011 May;12(5):408-15. doi: 10.1038/ni.2022. Epub 2011 Apr 10.

    PubMed 21478880

  • Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011 Feb;17(2):179-88. doi: 10.1038/nm.2279. Epub 2011 Jan 9.

    PubMed 21217695

  • Demidowich AP, Davis AI, Dedhia N, Yanovski JA. Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation. Med Hypotheses. 2016 Jul;92:67-73. doi: 10.1016/j.mehy.2016.04.039. Epub 2016 Apr 25.

    PubMed 27241260

  • Demidowich AP, Levine JA, Onyekaba GI, Khan SM, Chen KY, Brady SM, Broadney MM, Yanovski JA. Effects of colchicine in adults with metabolic syndrome: A pilot randomized controlled trial. Diabetes Obes Metab. 2019 Jul;21(7):1642-1651. doi: 10.1111/dom.13702. Epub 2019 Apr 2.

    PubMed 30869182

  • Levine JA, Han JM, Wolska A, Wilson SR, Patel TP, Remaley AT, Periwal V, Yanovski JA, Demidowich AP. Associations of GlycA and high-sensitivity C-reactive protein with measures of lipolysis in adults with obesity. J Clin Lipidol. 2020 Sep-Oct;14(5):667-674. doi: 10.1016/j.jacl.2020.07.012. Epub 2020 Aug 4.

    PubMed 32863171

  • Demidowich AP, Wolska A, Wilson SR, Levine JA, Sorokin AV, Brady SM, Remaley AT, Yanovski JA. Colchicine's effects on lipoprotein particle concentrations in adults with metabolic syndrome: A secondary analysis of a randomized controlled trial. J Clin Lipidol. 2019 Nov-Dec;13(6):1016-1022.e2. doi: 10.1016/j.jacl.2019.10.011. Epub 2019 Oct 22.

    PubMed 31740368

  • Demidowich AP, Parikh VJ, Dedhia N, Branham RE, Madi SA, Marwitz SE, Roberson RB, Uhlman AJ, Levi NJ, Mi SJ, Jun JY, Broadney MM, Brady SM, Yanovski JA. Associations of the melanocortin 3 receptor C17A + G241A haplotype with body composition and inflammation in African-American adults. Ann Hum Genet. 2019 Sep;83(5):355-360. doi: 10.1111/ahg.12315. Epub 2019 Apr 2.

    PubMed 30937899

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Colchicine 0.6Mg Cap and Colchicine 0.6Mg Tab in people with Obesity and Metabolic Disease, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Insulin Sensitivity From FSIVGTT (time frame: Baseline to 3 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02153983, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2019.

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