Clinical trial NCT02153983: Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome
Official title: Pilot Study of the Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Obesity
Metabolic Disease
Keywords: Obesity
Colchicine
Inflammation
Metabolic Syndrome
Dyslipidemia
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2014-06-03
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Note that only 2 of the arms are randomized. Three arms are observational and one is open-label treatment.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: * 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).

Primary outcomes:
measure: Change in Insulin Sensitivity From FSIVGTT
timeFrame: Baseline to 3 months
Secondary outcomes:
measure: Change in HOMA-IR Index
timeFrame: Baseline to 3 months
measure: Changes in C-reactive Protein
timeFrame: Baseline to 3 months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Jack A Yanovski, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.