Atheroma Reduction With Chloroquine in Patients With the Metabolic Syndrome (ARCH-MS)
Condition: Metabolic Syndrome X; Overweight; Hypertension; Dyslipidemias; Prediabetic State
MeSH terms: Overweight; Metabolic Syndrome; Dyslipidemias; Prediabetic State; Syndrome
Study type: Interventional

Summary: 
      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.

      Sub-study: Vascular endothelial growth factor(VEGF)and Cardiometabolic Risk, The purpose is
      to determine if the association of VEGF with atherosclerosis indicates that it should be a
      marker of the disorder.
    

Detailed description: 
      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.

      Sub-Study: VEGF and Cardiometabolic Risk, (This is an observational, case-study of existing
      baseline plasma and carotid intimal-medial thickness measurements) VEGF is also closely
      linked to vascular disease. From cell culture and animal models it is known that VEGF is
      increased in atherosclerotic lesions. It is controversial whether that relationship is
      causative or reparative. Both pro- and anti-VEGF therapies have been proposed for
      atherosclerosis. However, the association of VEGF with atherosclerosis indicates that it
      should be a marker of the disorder, which is the hypothesis we wish to test. No previous
      studies of circulating VEGF have been published.

      Other markers may be related to vascular disease or VEGF in this dataset. Tumor necrosis
      factor (TNF)-alpha results in increased expression of VEGF and may be correlated positively
      with VEGF. By Erenna Technology testing, cardiac troponin I can be measured at levels much
      lower than current clinical assays and is expected to be elevated in ischemia but not
      necessarily in the stable vascular disease anticipated in our subjects. High sensitivity
      C-reactive protein (hsCRP)has been proposed as a marker for vascular disease that merits drug
      treatment in its own right and may also be correlated with VEGF and vascular disease.
      However, currently the relationship between hsCRP and vascular disease is not completely
      clear.

      For this preliminary VEGF study observational data from the baseline only will be studied.
      Baseline testing includes carotid artery intimal-medial thickness, carotid MRI, lipid panel,
      complete blood count, comprehensive metabolic chemistry panel, Thyroid-stimulating hormone
      (TSH) and glucose tolerance test with plasma insulin and glucose responses. Plasma collected
      at baseline (approximately 1 ml) will be transferred to Singulex on dry ice. Samples will be
      coded but will not contain patient identifiers. Erenna Technology assays will be done for
      VEGF-A, cardiac troponin I,TNF-alpha, interleukin-6, interleukin-17A, and other cytokines at
      Singulex. This method utilizes single-photon counting of visible light to improve assay
      sensitivity. Separately, Washington University's Core Lab for Clinical Studies (CLCS) will
      determine hsCRP.
    

Intervention name(s): Chloroquine; Placebo Comparator
Intervention type(s): Drug; Drug
Intervention description(s): 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; Chloroquine Placebo tablet daily for 12 months followed by 12 months off drug with 1 visit at month 24
Other intervention name(s): Arlen; placebo
Intervention MeSH terms: Chloroquine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Metabolic Syndrome; Atherosclerosis