Official Title: “Genotoxic Stress, Atherosclerosis, and Metabolic Syndrome- Aim 3”

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 long-term effectiveness of chloroquine, a protein-activation medication, at reducing the progression of atherosclerosis in patients with the metabolic syndrome.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2010

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 examine the effect of long-term treatment with low doses of chloroquine on atherosclerosis in people with metabolic syndrome.

At a baseline study visit, participants will undergo an ultrasound of the neck to evaluate carotid artery intima-media thickness (IMT) and MRI to evaluate plaque composition. In addition, blood will be collected for laboratory testing and blood pressure will be measured.

Participants will then be randomly assigned to receive either placebo or chloroquine. Study visits will occur every 3 months for 1 year. At each visit, blood pressure will be measured and blood will be collected. At Months 6 and 12, a repeat ultrasound will be performed. At month 12 a repeat carotid MRI is performed.

Participants will attend one follow-up visit at Month 24 and will undergo a final ultrasound.

Intervention(s) in this Clinical Trial

• Drug: Chloroquine
  • One tablet of 80 mg of chloroquine on a daily basis for 12 months followed by 12 months off drug with 1 visit at month 24
• Drug: Chloroquine Placebo
  • Chloroquine Placebo tablet daily for 12 months followed by 12 months off drug with 1 visit at month 24

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Participants will receive 80 mg of chloroquine on a daily basis.
• Placebo Comparator: 2
  • Participants will receive a placebo tablet on a daily basis.

Primary Measures

• Carotid intima-media thickness
  • Time Frame: Measured at baseline and year 1
    Safety Issue?: No

Secondary Measures

• Blood pressure
  • Time Frame: Measured at 1 year
    Safety Issue?: No
• Glucose levels
  • Time Frame: Measured at 1 year
    Safety Issue?: No
• Change in lipid levels
  • Time Frame: Measured at 1 year
    Safety Issue?: No
• Monocyte activation
  • Time Frame: Measured at 1 year
    Safety Issue?: No

Inclusion Criteria:

• Diagnosis of metabolic syndrome, as determined by at least three of the following five criteria:
• 1. Elevated fasting triglyceride level 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 (greater than or equal to 130/85 mm Hg and less than or equal to 160/100 mm Hg) untreated; or hypertension controlled (less than or equal to 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 level greater than or equal to 100 mg/dL and less than or equal to 126 mg/dL
• Willing to use acceptable form of birth control
• 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

Exclusion Criteria:

• Prior travel treatment with chloroquine or hydroxychloroquine as follows:
• 1. Any exposure in the past 2 years
• 2. More than 30 days of therapy if exposure was between 2 and 5 years ago
• 3. More than 90 days of therapy if exposure was between 5 and 10 years ago
• 4. More than 6 months of therapy if exposure was 10 to 20 years ago
• 5. More than 1 year of therapy if exposure was 20 to 30 years ago
• 6. No limit if last exposure was more than 30 years ago (e.g., during the Vietnam conflict)
• Morbid obesity (body mass index [BMI] greater than 45)
• Coronary artery disease or other vascular disease
• History of stroke
• Significant kidney disease (estimated glomerular filtration rate [eGFR] less than 60 mL/min/1.73 m2)
• 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 malignancy or active treatment for recurrence prevention, example tamoxifen.
• Cancer considered to be cured, either as a result of surgery or other treatment is not exclusionary.
• 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.
• Receiving any of the following lipid lowering medications: niacin, fibrates, or fish oils greater than 1 gram
• Uncontrolled hypertension (blood pressure greater than or equal to 150/90) at baseline visit.
• Need for daily OTC medications, or currently taking cimetidine or greater than 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 greater than 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
• 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: 70 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 School of Medicine  

Overall Contact: Janet B. McGill, MD 314-362-8688 jmcgill@dom.wustl.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00455403

Study ID Number: 482

ClinicalTrials.gov Identifier: NCT00455403

Health Authority: United States: Federal Government

Click here for the ARCH study website

Click here for the Washington University Diabetes Research and Training Center Web site.

click here for Washington University Volunteer Research Participant Registry