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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: AP1189, 60 mg
* Drug: AP1189, 80 mg
* Drug: AP1189, 100 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: A positive result for Anti-Cyclic Citrullinated Peptide (anti-CCP) or Rheumatoid Factor (RF), 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-center, two-part, randomized, double-blind, placebo-controlled study 4 and 12 weeks study with repeated doses of AP1189
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AP1189, 60 mg<br>Part A: (AP1189, 60 mg); Part B: (TBD) | Drug: AP1189, 60 mg<br>* AP1189 tablets for oral use<br>|
| Experimental: AP1189, 80 mg<br>Part A: (AP1189, 80 mg); Part B: (TBD) | Drug: AP1189, 80 mg<br>* AP1189 tablets for oral use<br>|
| Experimental: AP1189, 100 mg<br>Part A: (AP1189, 100 mg); Part B: (TBD) | Drug: AP1189, 100 mg<br>* AP1189 tablets for oral use<br>|
| Placebo Comparator: Placebo<br>Part A: (placebo); Part B: (placebo). | Drug: Placebo<br>* Matching placebo tablets for oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Change in ACR20 | The change in American College of Rheumatology 20% (ACR20) compared to baseline | 4 weeks | 
| Part B: Change in ACR20 | The change in American College of Rheumatology 20% (ACR20) compared to baseline | 12 weeks | 
| Number of reported Adverse Events | Evaluation of the safety and tolerability of AP1189 on the number and severity of reported Adverse Events, compared with placebo | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Change in ACR50 | The change in American College of Rheumatology 50% (ACR50) compared to baseline | 4 weeks | 
| Part B: Change in ACR50 | The change in American College of Rheumatology 50% (ACR50) compared to baseline | 12 weeks | 
| Part A: Change in ACR70 | The change in American College of Rheumatology 70% (ACR70) compared to baseline | 4 weeks | 
| Part B: Change in ACR70 | The change in American College of Rheumatology 70% (ACR70) compared to baseline | 12 weeks | 
| Part A: Change in CDAI | The change Clinical Disease Activity Index (CDAI) compared to baseline | 4 weeks | 
| Part B: Change in CDAI | The change Clinical Disease Activity Index (CDAI) compared to baseline | 12 weeks | 
| Part A: Change in DAS-28 | The change in Disease Activity Score (DAS-28), based on a C-Reactive Protein (CRP) value, compare to baseline | 4 weeks | 
| Part B: Change in DAS-28 | The change in Disease Activity Score (DAS-28), based on a C-Reactive Protein (CRP) value, compare to baseline | 12 weeks |