24-week Study With Open Label Extension of VX-509, an Oral JAK3 Inhibitor, in Subjects Taking Methotrexate

Study Overview
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Brief Summary
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This study is designed to evaluate the safety and efficacy of VX-509, an oral JAK3 inhibitor, for treatment of subjects with active RA who have had an inadequate response to Methotrexate.

Detailed Description
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VX-509 is an oral, selective Janus kinase 3 (JAK3) inhibitor being developed by Vertex. In autoimmune diseases, JAK3 is an essential component of the immune signaling cascade. This cascade ultimately contributes to abnormal immune response that results in chronic inflammation and, in the case of rheumatoid arthritis (RA), irreversible damage to cartilage and bones. Selective inhibition of JAK3 offers a new disease modifying approach to the treatment of RA, and a broad range of other autoimmune diseases.

Official Title
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A 24-week, Double-Blind, Randomized, Parallel Group, Placebo-Controlled, Phase 2 Study of Different Doses of VX-509 in Adult Subjects With Active Rheumatoid Arthritis on Stable Methotrexate Therapy With 104-Week Open Label Extension

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: VX-509
* Drug: VX-509 matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects, between 18 and 80 years of age (inclusive) All subjects must have been diagnosed with RA Must have a swollen joint count of ≥6 out of 66 joints and tender joint count of ≥6 out of 68 joints Baseline CRP level must be above the upper limit of normal All subjects must have been receiving stable MTX coadministered with folic or folinic acid (at least 5 mg/week) Subjects may remain on 1 nonsteroidal anti-inflammatory medication during the study (aspirin ≤ 325 mg/day is allowed). Subjects must not have received prior treatment with a JAK inhibitor Subjects who are on an additional nonbiologic DMARD (e.g., sulfasalazine) must be willing to discontinue that DMARD after signing consent, except for hydroxychloroquine Subjects may have received previous therapy with a single TNF inhibitor (e.g., etanercept, adalimumab, infliximab, golimumab, certolizumab pegol) Females must have a negative pregnancy test prior to study dosing Sexually active subjects and their partners must agree to contraceptive requirements Exclusion Criteria: History or presence of a clinically significant medical disorder other than RA that, in the opinion of the investigator and medical monitor, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. Subjects with inflammatory, rheumatological disorders other than RA Pregnant or nursing female subjects Subjects who have a female partner who is pregnant, nursing, or planning to become pregnant Subjects who have planned major surgery (e.g., joint replacement) or procedures during the study History of drug abuse or positive drug screen History of alcohol abuse or excessive alcohol consumption History of tuberculosis (TB) infection of any kind (pulmonary or extrapulmonary, active or latent), regardless of history of anti-TB treatment.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Arm<br> | Drug: VX-509 matching placebo<br>* 0 mg oral tablet<br>|
| Experimental: VX-509 100 mg qd Arm<br> | Drug: VX-509<br>* 50 mg oral tablet<br>|
| Experimental: VX-509 150 mg qd Arm<br> | Drug: VX-509<br>* 50 mg oral tablet<br>|
| Experimental: VX-509 100 mg bid Arm<br> | Drug: VX-509<br>* 50 mg oral tablet<br>|
| Experimental: VX-509 200 mg qd Arm<br> | Drug: VX-509<br>* 50 mg oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects who achieve a 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C-reactive protein level (ACR20-CRP) response |  | Week 12 | 
| Change from baseline in Disease Activity Score 28 using C-reactive protein (DAS28- CRP) |  | Week 12 | 
| Safety and tolerability | Measured by incidence of treatment-emergent adverse events | Week 12 | 
| Safety and tolerability | Measured by clinical laboratory values (serum chemistry, hematology, coagulation studies, and urinalysis) | Week 12 | 
| Safety and tolerability | Measured by 12-lead ECG outcomes | Week 12 | 
| Safety and tolerability | Measured by vital signs | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects who achieve an ACR20-CRP response |  | Week 24 | 
| Proportion of subjects who achieve ACR50-CRP and ACR70-CRP responses |  | Week 12 and 24 | 
| Proportion of subjects who achieve a moderate or good response according to the European League Against Rheumatism (EULAR) response criteria |  | Week 12 and 24 | 
| Proportion of subjects who achieve remission as defined by DAS28-CRP response |  | Week 12 and 24 | 
| Proportion of subjects who achieve remission as defined by the ACR/EULAR definition of remission |  | Week 12 and 24 | 
| Change from baseline in selected Patient Reported Outcomes (PROs) |  | Week 12 and 24 | 
| Change from baseline in DAS28- CRP |  | Week 24 | 
| Safety and tolerability as indicated by adverse events, hematology, clinical chemistry, coagulation, urinalysis, electrocardiograms (ECGs) and vital signs |  | Week 24 |