Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome
Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Obesity; Metabolic Disease
Intervention: Colchicine 0.6 mg given (Drug); Placebo capsules given (Drug)
Phase: Phase 1/Phase 2
Status: Recruiting
Sponsored by: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Official(s) and/or principal investigator(s): Jack A Yanovski, M.D., Principal Investigator, Affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Overall contact: Andrew P Demidowich, M.D., Phone: (301) 594-1176, Email: demidowicha@mail.nih.gov
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 adults at least 18 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.
Clinical Details
Official title: Pilot Study of the Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Change in insulin sensitivity
Secondary outcome: Change in metabolic parametersChanges in other inflammatory markers
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
- INCLUSION CRITERIA:
Subjects will qualify for inclusion 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 6 months, may be included, at the discretion of
the principal investigator.
- Obesity, defined as a body mass index (BMI) (Bullet) 30 kg/m2, but weight less than
450 lbs in order for subjects to undergo Dual-Energy X-ray Absorptiometry (DXA)
scanning.
- Age greater than or equal to 18 years.
- Metabolic Syndrome, as per NCEP/ATPIII Guidelines
- -(Any 3 of the following 5):
- FPG greater than or equal to 100 mg/dl, or on treatment
- 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.
- 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.
EXCLUSION CRITERIA:
For subjects and controls:
< TAB>
- 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 meeting the T2DM cutoff on two different days. If
only one of the above three criteria 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. 73m(2)), 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.
- 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 exclusionary
medication
- 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 products.
Locations and Contacts
Andrew P Demidowich, M.D., Phone: (301) 594-1176, Email: demidowicha@mail.nih.gov
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL), Phone: 800-411-1222, Ext: TTY8664111010, Email: prpl@mail.cc.nih.gov
Additional Information
NIH Clinical Center Detailed Web Page
Related 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. 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.
Starting date: May 2014
Last updated: May 7, 2015
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