Stopping TNF Alpha Inhibitors in Rheumatoid Arthritis
Stopping TNF Alpha Inhibitors in Rheumatoid Arthritis
Background:

 -  Rheumatoid arthritis (RA) is often treated with drugs known as tumor necrosis factor
 (TNF) inhibitors, that can help decrease joint pain and swelling and can even result in
 RA remission. However, TNF inhibitors may increase risk of serious infections or some
 types of cancer.

 -  It is not clear if people whose RA has been in remission for a long time need to stay on
 the TNF inhibitor to remain in remission. If they can stop taking the TNF inhibitor
 without having their symptoms come back, they will be spared the side effects of these
 medicines. Some studies have shown that people can stay in remission after stopping a
 TNF inhibitor, but other studies have not confirmed it. Researchers want to see if
 people with RA in remission on a TNF inhibitor can stay in remission without this
 medicine. Also there may be a clinical, imaging (MRI, ultrasound), laboratory profile
 that will help to determine which patients remain in remission after stopping these
 drugs.

 Objectives:

 -  To see whether RA remission can continue after discontinuing use of a TNF inhibitor.

 -  To determine if clinical, imaging and immunological measurements can predict which
 participants will flare and which will remain in remission after discontinuing TNF
 inhibitor.

 Eligibility:

 -Individuals at least 18 years of age who have RA that is being controlled with TNF
 inhibitors. We plan to randomize 291 patients.

 Design:

 -  The study has seven visits over about 2 years. Six visits occur in the first year of the
 study, about 12 weeks apart. The final study visit is 1 year after the end of the
 treatment phase.

 -  At the first visit, participants will be screened with a physical exam and medical
 history. They will complete a questionnaire about their RA symptoms. A blood sample will
 be collected. They will continue to take their RA medicines during this time.

 -  The second visit will repeat tests from the first visit. These tests will confirm that
 the RA is in remission. Imaging studies will be performed on the hands, wrists, feet,
 and their connected joints. After this visit, participants will stop taking their TNF
 inhibitors and will start to have injections of a study drug. This drug will be either
 the participant's original TNF inhibitor or a placebo.

 -  There will be follow-up visits at weeks 12, 24, and 36. Participants will have a medical
 history and joint exam. They will also provide blood samples and answer questions about
 their RA symptoms.

 -  At the sixth visit (week 48), participants will repeat the tests and imaging studies
 from the second visit. They will stop taking the study injections.

 -  Continued RA treatment after this visit will be decided by the participant and his or
 her rheumatologist. Participants may take any recommended medicine, including the TNF
 inhibitor they had been taking before the study. They will also receive a questionnaire
 to complete at home and mail back before the final study visit.

 -  At the final visit (week 100), participants will repeat the tests and imaging studies
 from the second and sixth visits.
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.