A Study Investigating the Efficacy and Safety of Upadacitinib (ABT-494) Given With Methotrexate (MTX) in Adults With Rheumatoid Arthritis Who Have Had an Inadequate Response to MTX Alone
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: Placebo; Upadacitinib
Intervention description: Tablets for oral administration; Tablets for oral administration
Intervention MeSH terms: Upadacitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 300.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Musculoskeletal Disease; Arthritis; Joint Diseases; anti-inflammatory agents; antirheumatic agents

Summary:

      The primary objective of the study was to compare the safety and efficacy of multiple doses
      of upadacitinib versus placebo in adults with moderately to severely active rheumatoid
      arthritis (RA) on stable background methotrexate therapy who had not shown an adequate
      response to methotrexate alone.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Diagnosed with RA based on either the 1987-revised American College of Rheumatology
             (ACR) classification criteria or the 2010 ACR/European League against Rheumatism
             (EULAR) criteria for ≥ 3 months.

          2. Have active RA as defined by the following minimum disease activity criteria:

               -  ≥ 6 swollen joints (based on 66 joint counts) at Screening and Baseline Visits.

               -  ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits.

               -  high-sensitivity C-reactive protein (hsCRP) > upper limit of normal (ULN) OR
                  positive for both rheumatoid factor and anti-cyclic citrullinated peptide (CCP)
                  at Screening.

          3. Subjects must have been receiving oral or parenteral methotrexate therapy ≥ 3 months
             and on a stable prescription of 7.5 to 25 mg/week for at least 4 weeks prior to
             Baseline Visit. Subjects should also be on a stable dose of folic acid (or equivalent)
             for at least 4 weeks prior to Baseline Visit. Subjects should continue with their
             stable doses of methotrexate and folic acid throughout the study.

          4. Except for MTX, subjects must have discontinued all oral disease-modifying
             anti-rheumatic drugs (DMARDs) prior to Baseline Visit as specified below or for at
             least five times the mean terminal elimination half-life of a drug, whichever is
             longer:

               -  ≥ 4 weeks prior to Baseline Visit for minocycline, penicillamine, sulfasalazine,
                  hydroxychloroquine, chloroquine, azathioprine, gold formulations,
                  cyclophosphamide

               -  ≥ 8 weeks prior to Baseline Visit for leflunomide if no elimination procedure was
                  followed, or adhere to a washout procedure (i.e., 11 days washout with
                  colestyramine, or 30 days washout with activated charcoal)

          5. Subject has a negative tuberculosis (TB) Screening Assessment. If the subject has
             evidence of a latent TB infection, the subject must initiate and complete a minimum of
             2 weeks (or per local guidelines, whichever is longer) of an ongoing TB prophylaxis or
             have documented completion of a full course of TB prophylaxis, prior to Baseline
             Visit.

          6. Subjects can be taking non-steroidal anti-inflammatory drugs (NSAIDS), acetaminophen,
             oral corticosteroids (equivalent to prednisone ≤ 10 mg), or inhaled corticosteroids at
             a stable dose for at least 4 weeks prior to Baseline Visit for stable medical
             conditions and should be kept at a stable dose throughout the study. NSAIDs,
             acetaminophen, tramadol, codeine, hydrocodone and propoxyphene taken as needed are
             allowed but may not be taken 24 hours prior to any study visit. Oral and inhaled
             corticosteroids taken as needed are allowed but may not be taken 24 hours prior to any
             study visit.

          7. Subjects must have discontinued high potency opiates including (but not limited to):
             oxycodone, oxymorphone, fentanyl, levorphanol, buprenorphine, methadone,
             hydromorphone, and morphine at least 4 weeks prior to Baseline Visit.

        Exclusion Criteria:

          1. Female who is pregnant or breastfeeding.

          2. Prior exposure to Janus activated kinase (JAK) inhibitor (e.g., tofacitinib,
             baricitinib).

          3. Prior exposure to any investigational or approved biologic RA therapy.

          4. Receipt of any investigational drug of chemical or biologic nature within a minimum of
             30 days or 5 half-lives of the drug (whichever is longer) prior to Week 0 Visit.

          5. Current or expected need of other immunosuppressant medications, except methotrexate.
             Use of oral intake of > 10 mg prednisone/day or equivalent corticosteroid therapy (see
             inclusion criterion 7).

          6. Subject has been treated with intra-articular or parenteral administration of
             corticosteroids in the preceding 8 weeks prior to the Week 0 Visit.

          7. Screening laboratory values meeting the following criteria:

               -  Serum aspartate transaminase (AST) or alanine transaminase (ALT) > 1.5 × ULN

               -  Estimated glomerular filtration rate (eGRF) by simplified 4-variable Modification
                  of Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73 m²

               -  Total white blood cell count (WBC) < 3,000/µL

               -  Absolute neutrophil count (ANC) < 1,200/µL

               -  Platelet count < 100,000/µL

               -  Absolute lymphocytes count < 750/ µL

               -  Hemoglobin < 9 gm/dL