Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis

Rheumatoid arthritis (RA) affects an estimated 1% of the population. RA is a disease where
the immune system attacks the joints, leading to joint inflammation and damage that is felt
by someone with RA as joint pain, stiffness and swelling.

Recent studies have shown that there are markers in the blood called 'autoantibodies' that
precede the onset of joint symptoms of RA. Antibodies are commonly made in the blood to fight
infections. Sometimes, these antibodies attack one's own body. These are called
autoantibodies.

Certain autoantibodies are specific for certain diseases. The autoantibody known as anti-CCP3
is specific for RA and can predict the development of RA in the future, especially if the
level of anti-CCP3 is high. The investigators of this study believe that individuals with
elevations of anti-CCP3 ≥2 times the normal value have approximately a 50% chance of
developing RA within 3 years.

Hydroxychloroquine (HCQ) is already used successfully and safely in the treatment of malaria,
lupus and RA. The objective of this study is to determine whether treatment with HCQ in
individuals with elevations of anti-CCP3 without joint inflammation may help prevent the
future onset of RA. This will involve a 12-month course of HCQ in the prevention of the
development of clinically apparent RA at 36 months in individuals at high-risk for future RA
due to high titer elevations of anti-CCP3. This study will recruit for individuals without a
history or clinical findings of inflammatory arthritis. Eligible subjects will be randomized
in a 1:1 ratio to HCQ versus HCQ placebo.

Inclusion Criteria:

Subjects who meet all of the following criteria are eligible for enrollment into the study:

- Able and willing to give written informed consent and comply with requirements of the
study;

- Age ≥18 years-old at the Screening Visit; and

- Elevation of autoantibody anti-cyclic citrullinated peptide-3 (anti-CCP3) defined by
result of anti-CCP3 ≥40 units, at Screening.

Exclusion Criteria:

Subjects who meet any of the following criteria are ineligible to participate in the study:

- Evidence of significant retinal disease that, in the opinion of the examiner, would
make identification of potential future retinal toxicity from hydroxychloroquine
difficult to evaluate;

- A medical history of inflammatory arthritis (IA) of any type and/or rheumatic disease
and immunologic disease(s) that may be associated with IA . These diseases include but
are not limited to:

- rheumatoid arthritis (RA);

- systemic lupus erythematosus (SLE);

- seronegative spondyloarthropathies;

- inflammatory bowel disease;

- Sjögren's syndrome;

- polymyalgia rheumatic; or

- vasculitis.

Note: Crystalline arthropathies are not exclusionary.

- A medical history of:

- congestive heart failure or functional status of New York Heart Association
(NYHA) Class III or higher at the Screening Visit;

- cardiomyopathy or significant cardiac conduction disorders;

- chronic liver disease;

- psoriasis (due to potential for increased risk for flare of skin disease);

- porphyria;

- and/or serologic evidence during Screening Visit of chronic infections including,
but not limited to, human immunodeficiency virus (HIV), hepatitis B (HBV),
hepatitis C (HCV);

---Exception: hepatitis C antibody positive subjects are eligible with
documentation of:

- receipt of HCV treatment AND

- a negative hepatitis C viral load test post-treatment.

- malignancy within the last 5 years, except for treated basal or squamous cell
carcinoma, treated cervical dysplasia, or treated in situ cervical cancer Grade
I; or

- alcohol or substance abuse within 1 year of treatment randomization.

- Prior or current systemic treatment with disease modifying anti-rheumatic agents,
immunomodulatory agents, or glucocorticoids for IA, other rheumatic diseases, or other
immunologic diseases;

- Tetracycline class antibiotic use for autoimmune conditions, taken within 12 months
prior to Screening;

- Systemic corticosteroid use for non-IA conditions taken 28 days prior to Screening;

- More than 3 local corticosteroid injections, including but not limited to
intra-articular, epidural, and intrabursal injections, during the 3 months prior to
randomization;

- A history of a chronic condition that, in the opinion of the investigator, is highly
likely to require therapy with systemic corticosteroids (oral or intravenous) within
the study period, including but not limited to severe asthma and severe crystalline
arthropathy;

- Women who are pregnant, breastfeeding or desire to become pregnant and/or breast feed
within the duration of the 12-month treatment phase of the study;

- Women of childbearing potential who are not using or who do not agree to use adequate
birth control measures (for example, total abstinence, oral contraceptives,
intrauterine device, barrier method with spermicide, surgical sterilization,
Depo-Provera, or hormonal implants) during the treatment phase of the study;

- An ideal or actual body weight ≤ 24.4 kg (e.g., ≤53 lbs) at Screening Visit;

- Any of the following laboratory abnormalities at the Screening Visit:

- Serum Creatinine Clearance < 50ml/min (as calculated by the Cockcroft-Gault
formula: Creatinine clearance (CrCl)= (140-age) X (Weight in kg) X (0.85 if
female) / (72 X Creatinine));

- Alanine Aminotransferase (ALT) > 2 times the upper limit of normal (ULN);

- Aspartate Aminotransferase (AST) > 2x the upper limit of normal (ULN);

- INR ≥ 1.25 if not currently taking anticoagulation therapy;

- Total white blood count (WBC) < 3.0 x 10^9/L;

- Platelet count ≤ 150 x10^9/L;

- Hemoglobin < 11.5g/dL;

- Absolute Neutrophil Count (ANC) < 2.0 x 10^9/L;

- Evidence of significant retinal disease upon eye examination during the screening
period that in the opinion of the examiner would make identification of potential
future retinal toxicity from HCQ difficult to evaluate:

-- Retinal exam results may be applied to evaluations of subject eligibility for up to
6 months after the initial retinal exam.

- When, in the opinion of the study physician, the subject is not a good study
candidate.