A Dose-range Study of the Safety and Efficacy of Treatment in Adult Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate

A Two-part, Randomized, Double-blind, Multi-center, Placebo-controlled Study of the Dose-range, Safety and Efficacy of 4 and 12 Weeks of Treatment With AP1189 in Adult Rheumatoid Arthritis (RA) Patients With an Inadequate Response to Methotrexate (MTX) Alone - (RESOLVE)

The RESOLVE study is a two-part, randomized, double-blind, multi-center, placebo-controlled study of the safety, dose-range finding confirmation, and efficacy of 4 (Part A) and 12 weeks (Part B) of treatment with AP1189 in adult RA patients with an inadequate response to MTX alone.

In Part A approximately 120 randomized patients will be treated with either 60 mg AP1189, 80 mg AP1189, 100 mg AP1189 or placebo once daily for 4 weeks as add-on treatment to stable MTX treatment. Part A will conclude with an unblinded assessment for risk/benefit and a recommendation for dose selection for Part B.

In Part B patients will be randomized into groups of equal size evaluating 2-3 doses of AP1189 versus placebo. All doses will be administered once daily for 12 weeks as add-on treatment to stable MTX treatment. The proposed sample size per dose group/placebo group is 75 patients, by which the total study population of Part B may be either 225 or 300 patients, depending on the number of dose groups of AP1189 selected for evaluation based on Part A.

Inclusion Criteria:

• Confirmed diagnosis of RA according to the 2010 ACR/EULAR RA classification criteria and are ACR class I-III

• ≥6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts)

• Must meet at least one of the following parameters at Screening:

  1. A positive result for Anti-Cyclic Citrullinated Peptide (anti-CCP) or Rheumatoid Factor (RF),
  2. Serum CRP ≥ 6 mg/L based on central laboratory value

• Ongoing methotrexate therapy ≥12 weeks in a stable dose of 7.5 to 25 mg/week for at least 4 weeks prior to the baseline visit

• Subject has an inadequate clinical response to maximally tolerated methotrexate therapy

• Subjects should be receiving an adequate and prescribed stable dose of folic acid (≥5 mg/week total dose or as per local clinical practice) which should be confirmed or initiated at screening and continued throughout the study

• Negative QuantiFERON-in-Tube test (QFG-IT)

• Females of child-bearing potential must use of highly effective birth control method

• Male participant's partner must use highly effective birth control

Exclusion Criteria:

• Use of all other biologic or nonbiologic DMARDs and immunosuppressive therapy within 4 weeks prior to administration of the first dose of study drug
• Oral steroids at a dose >10 mg/day of prednisone or a prescription for oral steroids which has changed within 4 weeks of baseline
• Receipt of an intra-articular or parenteral corticosteroid injection within 4 weeks prior to baseline
• Major surgery (including joint operation) within 8 weeks prior to screening or planned surgery within the period of the study participation
• Rheumatic autoimmune disease other than RA
• Functional class IV as defined by the ACR Criteria for Classification of Functional Status in RA or wheelchair/bedbound
• Prior history of or current inflammatory joint disease other than RA
• Subjects with fibromyalgia
• Initiation or change in dose for NSAIDs (including low-dose aspirin and Cyclooxygenase (COX-2) inhibitors) within 2 weeks prior to baseline
• Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease
• Serum Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) higher than 1.5 x the upper limit of normal (ULN) and alkaline phosphatase (ALP) and/or bilirubin values above the ULN at the screening visit
• Have prior renal transplant, current renal dialysis, or moderate to severe renal insufficiency
• Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids
• Evidence of active malignant disease (except basal cell carcinoma of the skin that has been excised and cured)
• History of alcohol, drug, or chemical abuse within the 6 months prior to screening
• Neuropathy or other painful, chronic conditions that might interfere with pain evaluation
• Body weight of >150 kg
• HBsAg positive and/or Anti-HBc with sign of current infection.