Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome
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.

 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.
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.
-  INCLUSION CRITERIA FOR SUBJECTS RANDOMIZED TO COLCHICINE or PLACEBO::

 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.

 EXCLUSION CRITERIA FOR SUBJECTS RANDOMIZED TO COLCHICINE OR PLACEBO:

 -  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.

 -  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).

 INCLUSION CRITERIA FOR SUBJECTS WHO ARE EVALUATED BUT NOT ELIGIBLE FOR RANDOMIZATION:

 Subjects will qualify for the Evaluation-only arm if they meet the following 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 eligible.

 -  Weight less than 450 lbs in order for subjects to undergo Dual-Energy X-ray
 Absorptiometry (DXA) scanning.

 -  Age 18 years to 100 years.

 EXCLUSION CRITERIA FOR SUBJECTS WHO ARE EVALUATED BUT NOT ELIGIBLE FOR RANDOMIZATION:<TAB>

 -  Type 2 diabetes mellitus that is not well controlled with diet alone: subjects taking
 an antidiabetic medication (e.g. metformin, insulin, sulfonylureas, etc.) or having a
 Hemoglobin A1c > 9.0%

 -  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.

 -  Females who are pregnant, planning to become pregnant, or are currently nursing an
 infant.

 -  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.

 -  History of keloid formation.

 -  Current users of tobacco or nicotine products (e.g. nicotine patch, e-cigarettes).

 INCLUSION CRITERIA FOR SUBJECTS WITH DIET-CONTROLLED T2DM

 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

 -  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.

 EXCLUSION CRITERIA FOR SUBJECTS WITH DIET-CONTROLLED T2DM

 -  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.

 -  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).