Atheroma Reduction With Chloroquine in Patients With the Metabolic Syndrome (ARCH-MS)

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.

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 Continuous Positive Airway Pressure (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 over the counter 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.