Study of Adalimumab to Lower Cardiovascular Risk in RA Patients With Well Controlled Joint Disease

Excess mortality associated with RA is due largely to CVD that is not explained by
traditional risk factors. Although articular manifestations usually dominate the clinical
picture, RA is a systemic inflammatory disease, and systemic inflammation is the thought to
be the underlying mechanism responsible for the increased CVD risk associated with RA.
Because chronic inflammation can persist in treated RA patients with little or no clinically
detectable joint inflammation, treatment to targets based largely on clinically measured
joint activity may not adequately suppress the systemic inflammation associated with
progression of atherosclerosis. The ACR recommends treatment to a therapeutic target of low
disease activity as determined by standardized clinical assessments. We hypothesize that
treated RA patients who have reached this ACR target of low disease activity nonetheless
have persisting systemic inflammation that contributes to atherogenesis. We further
hypothesize that acceleration of RA-directed therapy with systemic anti-inflammatory
treatments (TNF inhibition) in patients with low disease activity will improve endothelial
function, reduce vascular inflammation and improve the functionality of HDL particles, key
biological features in the progression of atherosclerosis and its clinical manifestations.

Trial design: Prospective, randomized, double-blind crossover trial comparing the addition
of adalimumab to the addition of placebo.

Study population: 60 RA patients on non-biological DMARDs with low disease activity as
determined by a standardized clinical assessment (Disease Activity Score 28 joints [DAS28] <
3.2).

Primary endpoint: Primary endpoint is change in endothelial cell function, as detected by
brachial artery FMD, at 6 months of adalimumab treatment compared to 6 months of placebo. We
postulate that anti-TNF therapy with adalimumab will lead to an absolute increase of 2% in
FMD, which typically translates into a 15% reduction in cardiovascular event rates.

Inclusion Criteria:

- Subject must be able and willing to give written informed consent and comply with the
requirements of the study protocol.

- Diagnosis of Rheumatoid Arthritis by ACR 1987 or ACR/EULAR 2010 criteria.

- Low RA disease activity as defined by DAS28 < 3.2

- No anti-TNF medication or other biologic agent (abatacept, rituximab, or tocilizumab)
within the 12 months prior to enrollment.

- If taking methotrexate, then on a stable dose between 7.5 mg and 25 mg (PO or SQ)
weekly for at least 3 months prior to randomization. If on a DMARD other than
methotrexate, then that DMARD must be at a stable therapeutic dose for at least 3
months prior to randomization.

- If taking prednisone, then a stable dose of less than or equal to 10 mg/daily for at
least 1 month prior to randomization

- If NSAID taken on a regular, daily schedule, then patient must be on a stable dose
for one week prior to FMD studies. PRN use is excluded within 1 week of FMD studies.

- Age > 18

- Subject must be able and willing to self-administer SQ injections or have available
qualified person(s) or caregiver to administer SQ injections

- Negative serum pregnancy test (for women of child bearing age)

- Men and women of reproductive potential must agree to use an acceptable method of
birth control during treatment

- Adequate renal function as indicated by serum creatinine < 2.0.

- No use of phosphodiesterase type 5 inhibitors (PDE5) (i.e. sildenafil, tadalafil, and
vardenafil) 1 week prior to the study and during the course of the study.

Exclusion Criteria:

- Use of an anti-TNF or other biologic medication (Including but not limited to
abatacept, rituximab, or tocilizumab) within the previous 12 months.

- Prior history of MI, CVA, CABG, PTCA, or peripheral vascular disease

- SBP > 140/90 at two months prior to study enrollment

- Diabetes mellitus requiring insulin therapy

- The following laboratory parameters at the Screening visit

- Neutropenia (absolute neutrophil count < 1,500/microliter [ L]);

- Thrombocytopenia (platelets < 100,000/ L);

- Anemia (hemoglobin < 8 g/dL);

- Greater than or equal to 3 times the upper limit of normal (ULN) for either of
the following liver function tests (LFTs): aspartate transaminase (AST) or
alanine transaminase (ALT);

- Renal insufficiency (serum creatinine> 2.0 mg/dL)

- Purified protein derivative (PPD) test of > 5 mm induration regardless of prior
BacilleCalmette Guerin vaccine administration or positive QuantiFERON®-TB Gold
In-Tube Test (QFT-G_IT) without documentation of completed treatment or evidence of
ongoing treatment of latent tuberculosis (TB) for 30 days. Subjects with active TB
infection are excluded.

- History of positive PPD, positive QuantiFERON®-TB Gold In-Tube Test (QFT-G_IT), or
chest x-ray findings indicative of prior TB infection, without documentation of
either treatment for TB infection or chemoprophylaxis for TB exposure

- Prednisone dose > 10 mg/day (or equivalent dose of another corticosteroid) within 1
month of randomization

- Presence of open leg ulcers

- Chronic or persistent infection including but not limited to human immunodeficiency
virus [HIV],hepatitis B, hepatitis C, listeriosis, TB, or other opportunistic
infection)

- Active infection or severe infections requiring hospitalization or treatment with
intravenous(IV) antibiotics, IV antivirals, or IV antifungals within 30 days prior to
randomization, or oral antibiotics, oral antivirals, or oral antifungals within 14
days prior to randomization

- Receipt of a live vaccine within 4 weeks prior to randomization

- History of malignancy within the past 5 years other than treated localized carcinoma
in situ of the cervix or adequately treated non-metastatic squamous or basal cell
skin carcinoma

- Any medical condition, such as uncontrolled diabetes with documented history of
recurrent infections, unstable ischemic heart disease, known coronary artery disease
or known significant cardiac arrhythmias or severe congestive heart failure (New York
Heart Association classes III or IV), recent cerebrovascular accidents, severe,
progressive or uncontrolled neurological disease, and any other condition which, in
the opinion of the investigator, would put the subject at risk by participation in
the protocol

- Women of childbearing potential who are sexually active and who do not agree to
practiceone of the following methods of contraception during the duration of the
study

- condoms, sponge, foams, jellies, diaphragm or intrauterine device;

- oral or parenteral contraceptives for 2 months prior to study product
administration;

- a vasectomized partner;

- abstinence

- Pregnant (all women of childbearing potential must have a negative serum pregnancy
test) or breastfeeding

- Any investigational agent within the earlier of 4 weeks or 5 half-lives prior to
randomization

- History of drug or alcohol abuse within 6 months prior to randomization

- Known allergy or hypersensitivity to any study products

- Any psychiatric disorder that prevents the subject from providing informed consent

- Inability or unwillingness to follow the protocol

- Any condition or treatment, which in the opinion of the investigator, places the
subject at an unacceptable risk as a participant in the trial

- Any individual who plans to start or stop or change the dose of lipid lowering
medication,antihypertensive medication, NSAIDS, Cox-2 inhibitors, aspirin within 1
month of the study or during the study.