a dose-range study of the safety and efficacy of treatment in adult rheumatoid arthritis patients with an inadequate response to methotrexate

Conditions: Rheumatoid Arthritis

Summary: 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.

Eligibility criteria:
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.