Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome

NCT02153983 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 14011914-CH-0119ZIAHD000641-23
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 1

Brief 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. This study will test whether a medication called colchicine can improve metabolism in adults who are overweight but have not yet developed diabetes. 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.

Conditions

Obesity; Metabolic Disease

Keywords

Obesity; Colchicine; Inflammation; Metabolic Syndrome; Dyslipidemia

Outcome Measures

Primary Outcomes (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.

  Baseline to 3 months

Secondary Outcomes (2)

• Change in HOMA-IR Index

  Baseline to 3 months

• Changes in C-reactive Protein

  Baseline to 3 months

Study Arms (6)

Obese Adults with Metabolic Syndrome Randomized to Placebo

EXPERIMENTAL

Experimental treatment with placebo capsules identical in appearance to the experimental colchicine preparation

Drug: Placebo capsules given

Obese Adults with Metabolic Syndrome Randomized to Colchicine

EXPERIMENTAL

Experimental treatment with colchicine capsules identical in appearance to the experimental placebo preparation

Drug: Colchicine 0.6Mg Cap

Diet-controlled Type 2 Diabetes Adults Assigned to Colchicine

EXPERIMENTAL

Participants 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.

Drug: Colchicine 0.6Mg Tab

Evaluation Only Non-obese Adults

NO INTERVENTION

Participants 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 Randomized

NO INTERVENTION

Participants 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 Diabetes

NO INTERVENTION

Participants 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.

Interventions

Colchicine 0.6Mg Cap DRUG

Colchicine 0.6 mg given twice daily

Also known as: RCT Colchicine

Obese Adults with Metabolic Syndrome Randomized to Colchicine

Placebo capsules given DRUG

Placebo capsules given twice daily

Also known as: RCT Placebo

Obese Adults with Metabolic Syndrome Randomized to Placebo

Colchicine 0.6Mg Tab DRUG

Open-label colchicine

Also known as: Open-Label Colchicine 0.6 mg given twice daily

Diet-controlled Type 2 Diabetes Adults Assigned to Colchicine

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects will qualify for randomization to colchicine or placebo if they meet the following criteria:
• Good general health. In general subjects should take no medications. However, individuals taking medications for obesity-related co-morbid conditions, who have not had changes in dosage for more than 3 months, may be included, at the discretion of the principal investigator.
• Obesity, defined as a body mass index (BMI) greater than or equal to 30 kg/m\^2, but weight less than 450 lbs in order for subjects to undergo Dual-Energy X-ray Absorptiometry (DXA) scanning.
• Age 18 to 100 years.
• Metabolic Syndrome defined as any 3 of the following 5:
• FPG greater than or equal to 100 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 insulin resistance.
• high sensitivity C-reactive protein (hs-CRP) 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.

You may not qualify if:

• Type 2 diabetes mellitus, as determined by either having:
• Clear clinical diagnosis of diabetes, such as a patient in a hyperglycemic crisis or classic symptoms of hyperglycemia and a random plasma glucose greater than or equal to 200 mg/dL
• Two of the following three:
• Fasting plasma glucose greater than or equal to 126 mg/dL
• Hemoglobin A1c greater than or equal to 6.5%
• An oral glucose tolerance test glucose concentration of greater than or equal to 200 mg/dL at 2 hours.
• 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, non-diabetic AA may be unfairly excluded by their HbA1c alone. Therefore, for AA subjects, if their 2 hour OGTT and fasting glucoses are in the non-diabetic range, and the HbA1c is \< 7.0%, we will consider them non-diabetic.
• 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 60 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.
• 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.
• 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.

Sponsors & Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (7)

• 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.

  PMID: 21478880 BACKGROUND

• 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.

  PMID: 21217695 BACKGROUND

• 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.

  PMID: 27241260 BACKGROUND

• 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.

  PMID: 30869182 RESULT

• 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.

  PMID: 32863171 DERIVED

• 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.

  PMID: 31740368 DERIVED

• 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.

  PMID: 30937899 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Obesity; Metabolic Diseases; Inflammation; Metabolic Syndrome; Dyslipidemias

Interventions

Colchicine; Capsules

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pathologic Processes; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Alkaloids; Heterocyclic Compounds; Dosage Forms; Pharmaceutical Preparations

Limitations and Caveats

Pilot trial to determine power calculations, so no definitive conclusions should be reached from this trial.

Results Point of Contact

• Title: Dr. Jack Yanovski
• Organization: NICHD, National Institutes of Health

yanovskj@mail.nih.gov

13014960858

Study Officials

• Jack A Yanovski, M.D.

  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: In the randomized portion of the trial, all participants, Study Site staff, and pathology and laboratory personnel are blinded to the individual assignment of the order in which colchicine and placebo are administered.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Section on Growth and Obesity

Model Details: Note that only 2 of the arms are randomized. Three arms are observational and one is open-label treatment.

Study Record Dates

• First Submitted: May 31, 2014
• First Posted: June 3, 2014
• Study Start: May 31, 2014
• Primary Completion: August 15, 2018
• Study Completion: August 15, 2018
• Last Updated: August 13, 2019
• Results First Posted: August 13, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: in July 2021, and then indefinitely
• Access Criteria: Approval of the PI

Locations

US (1)