Chloroquine to Treat People With Metabolic Syndrome Aim2 (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
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.

Inclusion Criteria:

- Diagnosis of metabolic syndrome, as determined by at least three of the following five
criteria:

1. Elevated fasting triglyceride levels greater than or equal to 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 =<100 mg/dL but =>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 (i.e.,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 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.

- Taking any of the following lipid lowering medications: niacin, fibrates, and greater
than 1 gm fish oils

- Uncontrolled hypertension (BP >150/90) at enrollment.

- Need for daily over the counter 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. Persons 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; persons 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.