Stopping TNF Alpha Inhibitors in Rheumatoid Arthritis

Remission of rheumatoid arthritis (RA) is an achievable goal with currently available
medications, including the anti-tumor necrosis factor (anti-TNF) agents. However, it is
uncertain if patients with RA in clinical remission while treated with anti-TNF agents and
background disease-modifying antirheumatic drugs (DMARD) would remain in remission if
anti-TNF therapy was stopped. If remission can be sustained off anti-TNF agents, then
patients may be spared the potential toxicity and costs of these medications.

The Stopping Anti-Tumor Necrosis Factor Agents in Rheumatoid Arthritis (STARA) study is a
multicenter, randomized, double-blind, placebo-controlled noninferiority trial that will test
differences in time to relapse between patients with RA in remission who discontinue anti-TNF
agents and patients with RA in remission who continue anti-TNF agents. The secondary
objectives of the study are: 1) to determine if discontinuation of anti-TNF agents results in
a difference in progression of joint damage on radiographs; 2) to determine if
discontinuation of anti-TNF agents results in a difference in physical function, and 3) to
identify predictors of relapse.

Eligible subjects will have RA in remission for at least six months while taking etanercept,
infliximab, or adalimumab. An eight-week run-in period prior to randomization will be used to
confirm remission. Subjects will then be randomized in a 2:1 ratio to receive one of two
blinded treatments: 1) matching placebo or 2) their currently used anti-TNF agent,
respectively. All subjects will maintain their current background DMARD. Clinical assessments
will be performed every 12 weeks. The primary outcome is 48-week relapse-free status.
Secondary outcomes include change from baseline radiographic joint damage score at 48 weeks
and 100 weeks, and change from baseline physical function score at 48 weeks. Subjects who
relapse before week 48 will discontinue study medication and receive treatment through their
rheumatologist. Blinded treated will end at week 48 and subjects will be followed for 52
additional weeks. This study will provide important new information on the best treatment
approach for patients with RA in remission.

- Study personnel will evaluate participant eligibility using a checklist of inclusion
and exclusion criteria as outlined below. Clinical information will be obtained from
subjects by interview and from the medical record.

At the screening visit, potential participants will be included if:

- Age greater than or equal to 18 years

- Have RA, as defined by the 1987 revised American College of Rheumatology criteria

- In sustained clinical remission for the last 6 months while receiving treatment with
either etanercept, infliximab, or adalimumab, and greater than or equal to 1 DMARD
(methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, minocycline,
cyclosporine, azathioprine, gold, penicillamine). DAS28 should be less than 2.6 on
each visit over the preceding 6 months, with at least one visit 2-4 months before
enrollment. If there is no visit 6 months before enrollment, the nearest visit in the
6-12 month period before enrollment should be considered and have a DAS28 less than
2.6.

Potential participants will be excluded if:

- Had dose increase of anti-TNF agent or DMARD in the last 6 months

- Had change of anti-TNF agent or DMARD in the last 6 months

- Treated currently with golimumab or certolizumab

- Treated with greater than 10 mg of prednisone (or equivalent) daily in the last 6
months

- Treated with greater than 5 mg of prednisone (or equivalent) daily in the last 3
months

- Treated with intramuscular or intravenous corticosteroids in the last 6 months for RA
activity

- Treated with anakinra, abatacept, or tocilizumab in the last 6 months

- Treated with rituximab in the last 12 months

- Treated with an investigational RA drug in the last 6 months

- Pregnant (or anticipate pregnancy during the study period) or lactating women

- Absence of documentation in the medical record of clinical remission for the last 6
months

- Unwilling to discontinue anti-TNF agent

- Absence of documentation of negative tuberculin skin test, negative QuantiFERON-TB
Gold test, or treatment for latent tuberculosis prior to starting treatment with the
anti-TNF agent

- Treatment of solid malignancy or non-melanoma skin cancer within the past 5 years, or
any history of melanoma or hematologic or lymphoproliferative malignancy

- Absence of documentation of age-appropriate cancer screening at the time of
randomization

- Absence of documentation of negative hepatitis B serologies, absence of completion of
treatment for chronic hepatitis B, or absence of suppressive antiviral treatment

- Unable to provide informed consent

- Anticipate not being available or able to comply with the schedule of study visits

Study entry is not limited by gender or ethnicity. Children are excluded because
inflammatory polyarthritis developing before age 16 is considered juvenile idiopathic
arthritis and not RA. Patients who developed RA while age 17 would be eligible, but given
the time needed to achieve remission, these patients would in most cases be 18 or older by
the time they would meet other criteria for study entry.

Participants will largely be recruited from the practices of study investigators. To
identify potential subjects, investigators may search rosters of patients in their practice
for patients who meet the inclusion criteria. The number of patients screened and reasons
for exclusion will be tabulated at each site. Subjects may also be recruited by physician
referral. Information about the study will be mailed to local rheumatologists and posted on
the NIAMS website. We do not anticipate self-referral of subjects but eligible
self-referred subjects will not be excluded.

During the course of the study, enrollment of subjects treated with a particular anti-TNF
agent may be suspended or terminated to permit adequate representation of patients treated
with each of the 3 anti-TNF medications, due to problems procuring medication, or due to
other unforeseen issues.