A Dose Range Finding Study of JNJ-38518168 in Patients With Active Rheumatoid Arthritis in Spite of Treatment With Methotrexate

Study Overview
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Brief Summary
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The purpose of this dose range finding study is to assess the effectiveness, safety and tolerability of JNJ-38518168 at doses of 3, 10, and 30 mg/d compared with placebo in patients with active rheumatoid arthritis (RA) despite concomitant methotrexate (MTX) therapy.

Detailed Description
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This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor patient knows the treatment that the patient receives), multicenter, placebo-controlled (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial), parallel-group (each group of patients will be treated at the same time), dose range finding study of JNJ-38518168 in patients with active RA despite concomitant MTX therapy. The study will consist a screening period, a 24-week placebo-controlled period and a 4-week follow-up period between the last dose and the last visit. The duration of participation in the study for an individual patient will be up to 34 weeks (including screening). The patients will be assigned to 1 of 4 treatment groups in a 1:1:1:1 ratio to placebo and JNJ-38518168 (3 mg or 10 mg or 30 mg). Safety assessments and evaluations to determine the efficacy of JNJ-38518168 to reduce the signs and symptoms of RA will be performed at study visits. Safety will be monitored throughout the study.

Official Title
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A Phase 2b Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel Group, Dose Range Finding Study of JNJ-38518168 in Subjects With Active Rheumatoid Arthritis Despite Concomitant Methotrexate Therapy

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Placebo
* Drug: JNJ-38518168 (3 mg)
* Drug: JNJ-38518168 (10 mg)
* Drug: JNJ-38518168 (30 mg)
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has had rheumatoid arthritis for at least 6 months prior to the date of signing the informed consent at screening Must be positive for either anti-cyclic citrullinated peptide antibody or rheumatoid factor in serum at screening Must have active rheumatoid arthritis (at least 6 swollen and 6 tender joints using a 66/68 joint count at the time of screening and at baseline and Serum C reactive protein greater than or equal to 0.80 mg/dL at the time of screening Has been treated with and tolerated methotrexate treatment at dosages from 10 to 25 mg/week inclusive, for a minimum of 6 months with stable dose for at least 8 weeks prior to the date of signing the informed consent at screening Exclusion Criteria: Has inflammatory diseases other than rheumatoid arthritis, including but not limited to adult onset Still's disease, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, and Lyme disease that might confound the evaluation of the benefit of study agent therapy Has current signs or symptoms of liver or renal insufficiency or cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, psychiatric, or metabolic disturbances that are severe, progressive or uncontrolled Has ever received any approved or investigational biologic agent for a rheumatoid indication Has been treated with any nonbiologic disease modifying antirheumatic drugs within 4 weeks prior to the first administration of study agent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Form=tablet, route=oral. Placebo will be administered once daily from week 0 to week 24.<br>Drug: Methotrexate<br>* Participants must have been treated with and tolerated Methotrexate (MTX) treatment at dosages from 10 to 25 milligram per week (mg/week) inclusive, for a minimum of 6 months prior to the date of signing the informed consent at screening and must have a stable MTX dose for a minimum of 8 weeks prior to the date of signing the informed consent at screening and continue to receive the same MTX dose at Week 0 through Week 24.<br>|
| Experimental: JNJ-38518168 (3 mg/d)<br> | Drug: JNJ-38518168 (3 mg)<br>* Type=exact number, unit=mg, number=3, form=tablet, route=oral. JNJ-38518168 will be administered once daily up to 24 weeks.<br>Drug: Methotrexate<br>* Participants must have been treated with and tolerated Methotrexate (MTX) treatment at dosages from 10 to 25 milligram per week (mg/week) inclusive, for a minimum of 6 months prior to the date of signing the informed consent at screening and must have a stable MTX dose for a minimum of 8 weeks prior to the date of signing the informed consent at screening and continue to receive the same MTX dose at Week 0 through Week 24.<br>|
| Experimental: JNJ-38518168 (10 mg/d)<br> | Drug: JNJ-38518168 (10 mg)<br>* Type=exact number, unit=mg, number=10, form=tablet, route=oral. JNJ-38518168 will be administered once daily up to 24 weeks.<br>Drug: Methotrexate<br>* Participants must have been treated with and tolerated Methotrexate (MTX) treatment at dosages from 10 to 25 milligram per week (mg/week) inclusive, for a minimum of 6 months prior to the date of signing the informed consent at screening and must have a stable MTX dose for a minimum of 8 weeks prior to the date of signing the informed consent at screening and continue to receive the same MTX dose at Week 0 through Week 24.<br>|
| Experimental: JNJ-38518168 (30 mg/d)<br> | Drug: JNJ-38518168 (30 mg)<br>* Type=exact number, unit=mg, number=30, form=tablet, route=oral. JNJ-38518168 will be administered once daily up to 24 weeks.<br>Drug: Methotrexate<br>* Participants must have been treated with and tolerated Methotrexate (MTX) treatment at dosages from 10 to 25 milligram per week (mg/week) inclusive, for a minimum of 6 months prior to the date of signing the informed consent at screening and must have a stable MTX dose for a minimum of 8 weeks prior to the date of signing the informed consent at screening and continue to receive the same MTX dose at Week 0 through Week 24.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Activity Score 28 (DAS28) (C-reactive protein [CRP]) at Week 12 | The DAS28 using CRP is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP, and Patient's Global Assessment of Disease Activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in DAS28 (CRP) at Week 24 |  | Baseline and Week 24 | 
| Change from baseline in DAS28 (erythrocyte sedimentation rate [ESR]) at Week 12 and Week 24 |  | Baseline, Week 12 and Week 24 | 
| DAS28 (CRP) response rates at Week 12 and Week 24 |  | Week 12 and Week 24 | 
| DAS28 (ESR) response rates at Week 12 and Week 24 |  | Week 12 and Week 24 | 
| DAS28 (CRP) remission rates at Week 12 and Week 24 |  | Week 12 and Week 24 | 
| DAS28 (ESR) remission rates at Week 12 and Week 24 |  | Week 12 and Week 24 | 
| American College of Rheumatology (ACR) 20/50/70 response rates at Week 12 and Week 24 | An ACR 20/50/70 response is defined as a greater than or equal to 20/50/70 percentage improvement from baseline in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) 2. greater than or equal to 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain (VAS) (0-10 cm) b.Patient's Global Assessment of Disease activity (VAS) (0-10 cm) c. Physician's Global Assessment of Disease Activity (VAS) (0-10 cm) d. Patient's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C reactive protein (CRP). | Week 12 and Week 24 | 
| Hybrid ACR response at Week 12 and Week 24 | The hybrid ACR response is a continuous variable that is limited to an overall score of -100 (maximal worsening) to +100 (maximal improvement). | Week 12 and Week 24 | 
| ACR/European League Against Rheumatism (EULAR) remission rates at Week 12 and Week 24 | According to the ACR/EULAR provisional definition, a patients RA can be defined as being in remission based on either of 2 definitions: when scores on the tender joint count, swollen joint count, CRP (in mg/dL), and patient global assessment (0-10 scale) are all less than or equal to 1 OR when the score on the simplified disease activity index (SDAI) is less than or equal to 3.3 Analyses based on each definition will be performed. | Week 12 and Week 24 | 
| Change from baseline in Simplified Disease Activity Index (SDAI) at Week 12 and Week 24 | The SDAI is the numerical sum of 5 outcome parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint assessment, patient global assessment of disease activity (PGA VAS in cm), physician global assessment of disease activity (MDGA VAS in cm) and C-reactive protein (CRP in mg/dL). | Baseline, Week 12 and Week 24 | 
| Change from baseline in Clinical Disease Activity Index (CDAI) at Week 12 and Week 24 | The CDAI is the numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA, and MDGA. | Baseline, Week 12 and Week 24 | 
| Health Assessment Questionnaire - Disability Index (HAQ-DI) response at Week 12 and Week 24 | The HAQ-DI is a 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0 (no difficulty), to 3 (inability to perform a task in that area). | Week 12 and Week 24 | 
| Change from baseline in HAQ-DI score at Week 12 and Week 24 |  | Baseline, Week 12 and Week 24 | 
| Percent change from baseline in ESR levels at Week 12 and Week 24 |  | Baseline, Week 12 and Week 24 | 
| Percent change from baseline in ACR components at Week 12 and Week 24 |  | Baseline, Week 12 and Week 24 | 
| Number of patients with adverse events |  | Up to Week 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, Swollen and tender joints, Methotrexate, Immunology, Dose range finding study