Please select the eligibility criteria that correspond to the clinical trial below.
Title: Optimized Treatment Algorithm in Early Rheumatoid Arthritis: Methotrexate and Intra-articular Glucocorticosteroid Plus Adalimumab or Placebo in the Treatment of Early Rheumatoid Arthritis
Brief Summary: Optimized treatment algorithm in early rheumatoid arthritis:

Methotrexate and intra-articular glucocorticosteroid plus adalimumab or placebo in the treatment of early rheumatoid arthritis.

A Randomised, double-blind and placebo-controlled, two arms, parallel group study of the additive effect of adalimumab concerning inflammatory control and inhibition of erosive development.

Optimized Treatment Algorithms for Patients with Early RA


Options:
A: Other protocol-defined inclusion/exclusion criteria may apply

CORE STUDY

Inclusion Criteria

Core Study Inclusion Criteria At Screening

1. Cooperative male or non-pregnant, non-lactating female patients at least 18 years of age who signed an informed consent before the initiation of any study procedure.
2. Diagnosis of rheumatoid arthritis (RA) classified by American College of Rheumatology (ACR) 1987 revised criteria and with symptoms for at least 3 months before randomization.
3. Functional status class I, II or III classified according to the ACR 1991 revised criteria.
4. Patients treated with methotrexate (MTX) at the maximum tolerated (≤25 mg/week) and stable dose of ≥7.5 mg/week for at least 12 weeks before randomization.
5. Patients who had failed any disease-modifying antirheumatic drugs (DMARDs) (including biologic agents and any DMARD used in combination with MTX) were allowed.
6. For patients with previous treatment of biological therapy, the following wash-out periods were required before randomization:

   * 3 days for Kineret™ (anakinra) - with a terminal half-life of 4 to 6 hours (s.c. route).
   * 4 weeks for Enbrel® (etanercept) - with a terminal half-life of 102 ± 30 hours (s.c.

   route).
   * 8 weeks for Remicade® (infliximab) - with a terminal half-life of 8.0-9. 5 days (intravenous (i.v.) infusion).
   * 12 weeks for Humira® (adalimumab) - with a terminal half-life of 10-20 days (average 2 weeks) (subcutaneous (s.c.) route).
   * 12 weeks for Orencia® (abatacept) - with a terminal half-life of 13.1 (8-25) days (i.v. infusion).
   * 26 weeks for any other biologic - or 10 half-lives, whichever was longer.
7. Patients who took systemic corticosteroids had to be on a stable dose of ≤10 mg/d prednisone or equivalent for at least 4 weeks before randomization.
8. Patients who were regularly taking non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors or paracetamol/ acetaminophen as part of their RA therapy must have been on a stable dose for at least 4 weeks before randomization. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen as needed within 2 weeks before randomization had to stop their medication at least 24 hours before an ACR visit (i.e. Visits 3, 7, 8, 10 and 12 \[End of Study\]). Patients taking folic acid supplementation had to be on stable dose for at least 4 weeks before randomization.
9. Patients with a history of immunization for Influenza (within past 12 months) and Pneumococcal vaccination (within 4 years) were included. If not already immunized, vaccination was completed when medically indicated (only during flu season for influenza) and such patients were included after approximately a 3 week window post-immunization to allow immunity to develop for vaccine.
10. Weight ≥45 kg and body mass index (BMI) \<34.0
11. Women of non-child-bearing potential, defined as all women physiologically not capable of becoming pregnant.

Core Study Inclusion criteria At Baseline (Visit 3)

1. Disease activity criteria of ≥6 out of 28 tender joints and ≥6 out of 28 swollen joints.
2. One of the following also had to be present:

   1. High-sensitive C-Reactive Protein (hsCRP) concentration ≥10 mg/L
   2. Erythrocyte Sedimentation Rate (ESR) ≥28 mm/1st hr
   3. a. + b. based on screening values.

EXCLUSION

1. History of hypersensitivity to study drug or to molecules with similar structures.
2. Any therapy by intra-articular injections (e.g. corticosteroid) required for treatment of acute RA flare within 4 weeks before randomization.
3. Current use of DMARDs other than MTX. DMARDs included but were not limited to: biologic agents, thiolates (D-penicillamine, thiopronine), sulfasalazine, gold compounds, antimalarials, cyclosporine A, azathioprine, leflunomide, and alkylating agents such as cyclophosphamide.
4. If a patient had been discontinued from DMARDs, the patient should have been off the agent for at least 4 weeks, except leflunomide which was 8 weeks.
5. Patients with evidence of active pulmonary disease (e.g. tuberculosis, fungal diseases).
6. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.
7. Who had a live vaccination within 12 weeks before randomization, or were planning to have one during the study and were not willing/able to postpone until study completion.
8. a) With bacterial, fungal or viral infections at the time of enrollment, including patients with evidence of human immunodeficiency virus (HIV) infection, hepatitis B and hepatitis C infection.

   b) History of a positive purified protein derivative (PPD) of tuberculin skin test without a follow-up of a negative chest X-ray.

   c) Patients requiring administration of antibiotics against latent tuberculosis, e.g. isoniazide.
9. Underlying metabolic, hematologic, renal, hepatic, infectious or gastrointestinal conditions which in the opinion of the investigator immunocompromised the patient and/or placed the patient at unacceptable risk for participation in an immunomodulatory therapy. In particular, clinical evidence or history of multiple sclerosis or other demyelinating diseases, or Felty's syndrome.
10. With significant medical problems, including but not limited to the following: uncontrolled hypertension (≥160/95 mmHg), congestive heart failure, type-I-diabetes(well controlled type-II-diabetes was allowed even when requiring insulin), thyroid disease (unless the patient was taking a stable dose of thyroid hormone for at least 12 weeks before randomization).
11. Other rheumatic diseases that could confound the evaluation of efficacy, including but not limited to primary fibromyalgia, ankylosing spondylitis, Lyme disease, adult juvenile RA, systemic lupus erythematosus, gout and pseudo gout, vasculitis, psoriatic arthritis, reactive arthritis, primary Sjoegren's Syndrome, and Behcet's Syndrome.
12. Any medical or psychiatric condition which, in the Investigator's opinion, would preclude the participant from adhering to the protocol or completing the study per protocol.
13. History of malignancy of any organ system, treated or untreated, within the past 5 years (with the exception of adequately treated basal cell carcinoma or squamous-cell carcinoma of the skin, carcinoma in situ of the cervix, colon polyps with non-invasive malignancy that have been removed).
14. Use of any investigational drug other than RA therapy and/or devices at the time of randomization, or within 30 days or 5 half- lives of randomization, whichever was longer.

STUDY EXTENSIONS

Extension Studies Inclusion Criteria:

1. Patients who completed the core CACZ885A2201 study may enter the first extension study upon signing informed consent. A patient is defined as completing the study if he/she completed the core CACZ885A2201 study up to and including Visit 12.
2. Patients who completed the first extension study, may enter the second.

Extension Studies Exclusion Criteria

1. Patients for whom continued treatment in the extension is not considered appropriate by the treating physician.
2. Patients who were non-compliant or who demonstrated a major protocol violation in the core CACZ885A2201 study.
3. Patients who discontinued from the core CACZ885A2201 study before Visit 12.
B: Inclusion Criteria:

1. Patients (more than 18 years) with rheumatoid arthritis according to the ACR classification criteria (1) who have had the diagnose \< 6 months.

2. Moderate to severe rheumatoid arthritis defined as DAS28 (CRP-based) \> 3.2.

3. Negative pregnancy test (serum HCG) for women of childbearing potential prior to trial start. (Non-fertile women are defined as postmenopausal for at least 1 year or surgical sterilisation (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)). Fertile women included in the trial should use contraception during the entire trial period (i.e. one of the following methods: Oral contraception, intrauterine device (IUD), depot injection of progesterone, subdermal implantation, contraceptive vaginal ring, transdermal depot plaster). In addition, contraception should be used for a period of 150 days after any discontinuation of trial medicine.

4. Ability and willingness to inject the sc. injections him/herself or to have an assistant give the injections.

5. Ability and willingness to give written informed consent and to meet the requirements of the trial protocol.

Exclusion Criteria:

1. Persons with latent TB defined with a positive Mantoux test (\>12 mm for vaccinated and 6 mm for non-vaccinated), positive cultivation of mycobacteria in tissue samples, chest X-ray indicating TB,or other risk factors for activation of untreated latent TB, and persons not been given adequate TB prophylaxis according to the instructions of the department.

2. Active or recurrent infections or severe infections requiring hospitalization or treatment with i.v. antibiotics within the last 30 days or oral antibiotics within the last 14 days prior to inclusion

3. Positive serology for Hepatitis B or C indicating active infection.

4. Medical history with a positive HIV status (Check of HIV test upon suspicion).

5. Medical history with histoplasmosis or listeriosis.

6. Previous cancer or lymph proliferative disease except cases teated radically and have been without relapse for a minimum of 5 years.

Patients with previous squamous cell carcinoma, basal cell skin carcinoma or cervical dysplasia, who have been treated successfully and radically can be included.

7. Previous diagnosis or signs of demyelinized disease in the CNS system (e.g. optic neuritis, visual disorder, disturbed gait, facial paralysis, apraxia).

8. Severe renal insufficiency (creatinine clearance \< 35 ml/min - nomogram).

9. Affected liver function: Liver enzymes \> 2 x above normal limit value.

10. Clinical significant drug or alcohol abuse during the past year and/or current daily alcohol consumption.

11. Unstable diabetes, unstable ischemic heart disease, heart insufficiency (NYHA III-IV), active chronic inflammatory intestinal disease, recent cerebral apoplexia (within 3 months), chronic leg ulcer or any other condition (e.g. kateter a demeure)which according to the investigator imposes an increased risk to the subject, if he/she participates in the protocol.

12. Anticoagulant therapy.

13. Pregnancy or breast-feeding.

14. Other inflammatory rheumatic diseases.

15. Aggressive parvovirus B19 infection.

16. Previous treatment with one or more DMARDs.

17. Glucocorticosteroid treatment within the last 4 weeks (except nasal and inhalation steroids).

18. Contraindications for trial medicine.
C: Inclusion Criteria:

* adult patients at least 18 years of age with moderate to severe active RA for at least 6 months;
* inadequate response to current anti-rheumatic therapies, including MTX;
* inadequate response or intolerance to treatment with 1 or more anti-TNF therapies within 1 year of entering study;
* on stable MTX for at least 8 weeks before entering study;
* patients of reproductive potential must be using reliable methods of contraception.

Exclusion Criteria:

* major surgery (including joint surgery) within 8 weeks before screening, or planned major surgery within 6 months after entering study;
* women who are pregnant or breast-feeding.
D: Inclusion Criteria:

* Patients have a diagnosis of rheumatoid arthritis (RA) (according to the revised 1987 criteria of the ACR) for at least 3 months prior to screening
* Have active RA as defined by persistent disease activity with at least 4 swollen and 4 tender joints, at the time of screening and baseline
* Must have been previously treated with at least one dose of etanercept, adalimumab, or infliximab
* If currently using methotrexate, sulfasalazine and/or hydroxychloroquine must have tolerated these agents for at least 12 weeks and be on a stable dose for at least 4 weeks prior to the first administration of study agent
* If using NSAIDs or other analgesics must be on a stable dose for at least 2 weeks prior to the first administration of study agent
* If using oral corticosteroids must be on a stable dose equivalent to \<= 10 mg of prednisone/day for at least 2 weeks prior to first administration of study agent
* Are considered eligible according to specified tuberculosis (TB) screening criteria.

Exclusion Criteria:

* Patients cannot have other inflammatory diseases other than RA that might interfere with the evaluation of the benefit of golimumab therapy
* No history of treatment with natalizumab, rituximab or cytotoxic agents
* No history of demyelinating diseases such as multiple sclerosis or optic neuritis or of concurrent congestive heart failure (CHF), lymphoproliferative disease, known malignancy or history of malignancy within the previous 5 years (with the exception of a nonmelanoma skin cancer that has been treated with no evidence of recurrence)
* No history of, or ongoing, chronic or recurrent infectious disease
* No serious infection within 2 months prior to first administration of study agent.

Answer: B