Official Title: “Genotoxic Stress, Atherosclerosis, and Metabolic Syndrome-AIM 2”

Metabolic syndrome consists of a group of co-occuring conditions that increase an individual's risk of developing heart disease, stroke, and diabetes. The purpose of this study is to evaluate the short-term effectiveness of chloroquine, a protein-activation medication, at improving metabolic syndrome.

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind (Subject), Dose Comparison, Crossover Assignment, Efficacy Study

Study Primary Completion Date: November 2008

Metabolic syndrome is one of the most common disorders in industrialized countries. It consists of abnormal serum lipids, glucose intolerance, elevated blood pressure, and central obesity in the setting of insulin resistance. The syndrome substantially increases the risk of developing diabetes and vascular disease, but there is no clear unifying approach to treat this disorder. In animals, activation of the protein ataxia telangiectasia mutated (ATM) using the antimalarial drug chloroquine improves features of metabolic syndrome and decreases atherosclerosis, a build-up of fatty plaque within arteries. The purpose of this study is to evaluate the effectiveness of short-term treatment with low doses of chloroquine as a way of managing metabolic syndrome.

Participants in this study will initially receive placebo for 3 weeks, followed by increasing doses of chloroquine in 3-week intervals. There will be a period of no active treatment for 5 to 7 weeks between each arm. At the end of each 3-week period, participants will be admitted to the research center and will undergo insulin sensitivity testing with the hyperinsulinemic euglycemic clamp procedure. In addition, blood will be collected and blood pressure will be measured.

Intervention(s) in this Clinical Trial

• Drug: Chloroquine
  • 1 chloroquine placebo tablet for 3 weeks; euglycemic clamp procedure; 24 hour Ambulatory Blood Pressure; Oral Glucose tolerance Test; serum collection; 24 hour urine collection; collection of peripheral blood mononuclear cells
• Drug: Chloroquine
  • 80mg tablet once per week for 3 weeks; euglycemic clamp procedure; 24 hour Ambulatory Blood Pressure; Oral Glucose tolerance Test; serum collection; 24 hour urine collection; collection of peripheral blood mononuclear cells
• Drug: Chloroquine
  • 80mg tablet daily for 3 weeks; euglycemic clamp procedure; 24 hour Ambulatory Blood Pressure; Oral Glucose tolerance Test; serum collection; 24 hour urine collection; collection of peripheral blood mononuclear cells
• Drug: Chloroquine
  • 250mg tablet daily for 3 weeks; euglycemic clamp procedure; 24 hour Ambulatory Blood Pressure; Oral Glucose tolerance Test; serum collection; 24 hour urine collection; collection of peripheral blood mononuclear cells

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: 1
• Active Comparator: 2
• Active Comparator: 3
• Active Comparator: 4

Primary Measures

• Insulin sensitivity
  • Time Frame: Measured with a hyperinsulinemic clamp every 8 - 10 weeks
    Safety Issue?: No

Secondary Measures

• Human monocyte activation
  • Time Frame: Measured at the end of each 8-10 week period
    Safety Issue?: No
• Blood pressure
  • Time Frame: measured at end of 8-10 week period
    Safety Issue?: No
• Serum Lipids
  • Time Frame: at the end of every 8-10 week period
    Safety Issue?: No

Inclusion Criteria:

• Diagnosis of metabolic syndrome, as determined by at least three of the following five criteria:
• 1. Elevated fasting triglyceride levels greater than 150 mg/dL
• 2. Low HDL cholesterol levels: less than 50 mg/dL for women and less than 40 mg/dL for men
• 3. Hypertension (>130/85 mm Hg <160/100 mm Hg) untreated; or hypertension controlled (<150/90 mm Hg) on a stable medication regimen for 4 weeks prior to baseline visit.
• 4. Increased waist circumference: greater than 35 inches in women and greater than 40 inches in men
• 5. Elevated fasting glucose levels between 100 mg/dL and 126 mg/dL
• Subjects may be on a stable doses of a statin drug for at least 3 months
• Subjects may be on a stable doses of L-thyroxine for at least 3 months
• Willing to use acceptable form of birth control (e.g., hormonal birth control, double barrier methods)

Exclusion Criteria:

• Prior travel treatment with chloroquine or hydroxychloroquine as follows:
• 1. any exposure in the past 2 years, 2. >30 days of therapy if exposure was between 2 and 5 years ago, 3. >90 days of therapy if exposure was between 5 and 10 years ago, 4. >6 months of therapy if exposure was 10 to 20 years ago, 5. >1 year of therapy if exposure was 20 to 30 years ago, 6. No limit if last exposure was >30 years ago, ex. during the Vietnam conflict.
• Morbid obesity (body mass index [BMI] greater than 45)
• Coronary artery disease or other vascular disease
• History of stroke
• Chronic kidney insufficiency (estimated glomerular filtration rate [eGFR] less than 60 ml/min/1.73m2)
• Diabetes
• Seizure disorder
• History of psoriasis
• Blood disorders, including anemia (i.e., hemoglobin levels less than 13 g/dL in men and less than 12 g/dL in women)
• Current cancer
• Asthma requiring daily beta agonist therapy or intermittent oral steroids is exclusionary. Inhaled steroids are acceptable. Obstructive sleep apnea will be allowed if CPAP or other therapy has been stable for 6 months. Other active respiratory diseases are excluded.
• Liver disease, or liver function test results greater than twice the normal value
• Active infection, including HIV
• Serious illness requiring ongoing medical care or medication
• Treatment with atypical anti-psychotic medication. Treatment with any other medication for psychiatric illness, unless on a stable dose for 6 weeks prior to enrollment. Patients with unstable psychiatric disorders are excluded per the decision of the study MD regardless of medication history.
• Taking any of the following lipid lowering medications: niacin, fibrates, and greater than 1 gm fish oils
• Uncontrolled hypertension (BP >150/90) at baseline visit.
• Need for daily OTC medications, or currently taking cimetidine or >1000 IU vitamin E daily and unwilling to reduce or discontinue the use of vitamin E or discontinue cimetidine for the duration of the study. Patients taking >1000 IU of vitamin E should reduce the dose 30 days prior to randomization.
• Pregnant, breastfeeding, or intending to become pregnant
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Retinal disease (in particular, drusen or pigmentary changes at the macula); any ocular disease that interferes with the eye examination (e.g., cataracts)
• Auditory disease or hearing loss; patients with total, irreversible hearing loss can be enrolled.
• Participation in another clinical trial within past 30 days prior to screening and 60 days prior to randomization. Questionnaire or observational studies are not exclusionary.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 60 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Overall Clinical Trial Officials and Contacts

Clay F. Semenkovich, MD Principal Investigator Washington University in St. Louis  

Overall Contact: Mariko Johnson, MD 314-294-4453 mkjohnson@dom.wustl.edu

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00455325

Study ID Number: 395

ClinicalTrials.gov Identifier: NCT00455325

Health Authority: United States: Federal Government

click here for the ARCH study website

click here for Washington University Volunteer Participant Registry