Natalizumab in the Treatment of Rheumatoid Arthritis in Subjects Receiving Methotrexate

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability and efficacy of natalizumab in subjects diagnosed with moderate to severe rheumatoid arthritis (RA) receiving concomitant treatment with methotrexate (MTX). It is thought that natalizumab may stop the movement of certain white blood cells, known as lymphocytes, into joint tissue. These cells are thought to cause damage in the joints leading to the symptoms of RA.

Official Title
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A Phase II, Multicenter, Double-blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Intravenous Natalizumab (300 mg) in Subjects With Moderate to Severe Rheumatoid Arthritis (RA) Receiving Concomitant Treatment With Methotrexate (MTX)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: natalizumab
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects will be eligible to begin study participation if they meet all of the following inclusion criteria: Subject is able to read, understand, and voluntarily sign the approved Informed Consent form prior to the performance of any study-specific procedures; Male or female subjects, ≥18 to ≤75 years of age, who has a diagnosis of rheumatoid arthritis Functional Class 1 to 3 by the 1987 Revised American Rheumatism Association Criteria for the Classification of Rheumatoid Arthritis for at least 6 months prior to screening; Subject is on a stable dose of MTX of at least 10 mg/week for ≥3 months prior to randomization (Month 0) without an adequate response; Female subjects of childbearing potential agree to use adequate, contraceptive methods (either intrauterine device [IUD], oral or depot contraceptive, or barrier plus spermicide). Female subjects of childbearing potential use adequate contraception for at least 2 months prior to study entry and continue contraception for at least 3 months after their last infusion of study drug; Subject is willing and able to complete all planned study procedures; Subject has at least 10 painful/tender and 6 swollen joints at the Month 0 (Baseline) visit; Subject has an elevated CRP level (defined as >2.87 mg/L) at Screening. Exclusion Criteria: Subjects will be excluded from the study if they meet any of the following exclusion criteria: Subject is pregnant or lactating; Subject who has experienced an inadequate therapeutic response after at least 3 months of treatment with at least one TNF-alpha inhibitor; Subject who has received treatment with anakinra; Subject who has received prior treatment with natalizumab; Subject does not meet the following criteria regarding concomitant medications for RA: Use of any oral steroid exceeding 10 mg/day of prednisone (or equivalent dose) and not administered at a stable dose for at least 1 month prior to randomization (Month 0); Use of any NSAIDs unless stable for at least 1 month prior to randomization (Month 0); Use of other anti-arthritic treatments, including approved or experimental oral, topical, or injectable biologics or drugs, or devices within 1 month prior to randomization (Month 0); Intra-articular corticosteroid injections within 1 month prior to randomization (Month 0); Treatment with any TNF-alpha inhibitor within 2 months prior to randomization (Month 0); Subject who is expected to be unavailable for the duration of the trial, likely to be noncompliant with the Protocol, or felt to be unsuitable by the Investigator for any other reason; Subject who has a history of a malignancy (other than basal cell carcinoma of the skin); Subject who has a history of clinically significant and/or persistent gastrointestinal, pulmonary, chronic infection, cardiovascular, renal, hepatic, neurological, dermatological, immunological, major psychiatric (including drug or alcohol abusers) or hematological illness, which, in the opinion of the Investigator placed the subject at unacceptable risk for participation in the study; Subject who has any laboratory test at Screening considered significantly abnormal. An alanine transaminase (ALT) or aspartate transaminase (AST) ≥1.5 x upper limits of normal (ULN) and cytopenia (included any of the following: WBC <3.5 x 1000/uL; hemoglobin [Hb] <8 g/dL; platelets <100 x 1000/uL; and/or neutrophils absolute <1.0 x 1000/uL) were considered significantly abnormal; Subject who intends to donate blood or blood products during the period of the study or within 1 month following completion of the study; Subject who has a positive tuberculosis (TB) skin test at Screening or within the 30 days prior to Screening (defined as ≥10 mm induration); Subject who plans or requires any surgical procedure during the study treatment period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Active Comparator: natalizumab<br> | Drug: natalizumab<br> <br> * Other names: TYSABRI;|
| Placebo Comparator: placebo<br> | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| American College of Rheumatology (ACR)20. | ≥20% reduction from baseline in painful/tender joint count and swollen joint count and ≥20% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant) | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| American College of Rheumatology (ACR)50 | ≥50% reduction from baseline in painful/tender joint count and swollen joint count and ≥50% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant) | Month 6 | 
| American College of Rheumatology (ACR)70 | ≥70% reduction from baseline in painful/tender joint count and swollen joint count and ≥70% improvement in at least three of five secondary clinical parameters (e.g., subject global assessment, physician global assessment, pain scale, disability score, and an acute phase reactant) | Month 6 |