A Multi-Site Study to Evaluate the Safety and Effect of Study Drug on Participants With Rheumatoid Arthritis

Study Overview
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Brief Summary
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This study is a multicenter, double-blind, study to evaluate the safety and effectiveness of treatment with LY2127399 (in addition to the standard of care treatment, methotrexate) for participants with Rheumatoid Arthritis. Participants will receive three intravenous doses of LY2127399 or placebo. Participants will participate in 10 or more visits to the study site, over 6 months. Evaluation of safety and efficacy will be conducted throughout the study.

Official Title
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Phase II Study of Safety and Efficacy of Intravenous LY2127399 in Patients With Rheumatoid Arthritis Treated With Methotrexate

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: LY2127399
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between the ages of 18 and 75 years Have given written informed consent approval Women must not be at risk to become pregnant during study participation Diagnosis of Rheumatoid Arthritis according to the 1987 revised American Rheumatism Association (ARA) criteria for the classification of RA Serum C-reactive protein (CRP) measurement greater than the upper limit of normal (ULN, 0.574 mg/dL), or erythrocyte sedimentation rate (ESR) ≥28 mm/hr Current, regular use of Methotrexate, at a stable dose Biologic DMARD naïve, and have had an insufficient response (in the opinion of the investigator) to an adequate therapeutic dose of at least 1 oral DMARD Exclusion Criteria: Use of excluded medications (reviewed by study doctor) Surgical treatment of a joint with 2 months of study enrollment that is to be assessed in the study Are unable to ambulate; that is, confined to bed or wheelchair bound Have medical findings which, in the opinion of the study doctor, put participant at an unacceptable risk for participation in the study Have had recent or ongoing infection which, in the opinion of the study doctor put participant at an unacceptable risk for participation.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: LY2127399<br>* 30 mg, 60 mg or 160 mg, IV (in the vein) in weeks 0, 3 and 6. Treatment duration: 6 weeks.<br>|
| Placebo Comparator: B<br> | Drug: Placebo<br>* IV (in vein) in weeks 0, 3 and 6. Treatment duration: 6 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% Response (ACR20) (Effectiveness of LY2127399 in Treating Rheumatoid Arthritis Using the ACR20 Scale) | ACR Responder Index is a Composite of clinical, laboratory, and functional measures of rheumatoid arthritis (RA). ACR20 Responders: had ≥20% improvement from baseline in both tender and swollen joint counts and ≥20% improvement in at least 3 of 5 criteria: participant's and physician's global assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) (which measured participants' perceived degree of difficulty performing daily activities), visual analog pain scale, and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAE) (Safety of Repeat Doses (3) of LY2127399 Through Evaluation of Laboratory Tests, Vital Signs and Electrocardiograms) | Treatment-emergent adverse events (TEAEs) were defined as those AEs with start date and time equal to or after the start of study medication infusion. In the case of a missing onset time for an AE, an AE with a start date equal to or greater than the dosing date was considered treatment-emergent. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. All participants who received at least one dose of study drug. Due to dosing errors (a participant received 60 mg LY2127399 in the placebo group), the safety population was adjusted to account for actual treatment received. | Baseline through Study Completion (Up to 19 Months) | 
| Evaluation of the Pharmacokinetics of LY2127399: Clearance | Population estimate of constant clearance as determined by population PK analysis. A 2-compartment model was used in PK modeling. Constant clearance is the PK parameter which describes the linear elimination of LY2127399 from serum. | 2 hours pre-dose, pre-dose, 1 hour and 4 hour(s) post dose | 
| Percentage of Participants Achieving ACR 50 and ACR70 | ACR Responder Index: composite of clinical, laboratory, and functional measures of Rheumatoid Arthritis (RA). ACR50 and ACR70 Responder: had either a ≥50% or ≥70% improvement from baseline in both tender and swollen joint counts and either a ≥50% or ≥70% improvement in at least 3 of 5 criteria: participant's (Pt's) and physician's global assessment of disease activity, HAQ-DI (measured Pts' perceived degree of difficulty performing daily activities), joint pain, and CRP (respectively). | Baseline through Week 24 | 
| Change From Baseline in the Disease Activity Score 28 Joint Count (DAS28-CRP) | Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), CRP [milligrams per liter (mg/L)], and participant's global assessment of disease activity using visual analog scale (VAS) (participant global VAS). DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*participant global VAS+0.96. Scores ranged from 1.0-9.4, where lower scores indicated less disease activity and remission is DAS28-CRP <2.6. A negative change indicated an improvement. | Baseline, Week 24 | 
| European League Against Rheumatism (EULAR28) Response: Percentage of Participants With Combined Good and Moderate Responses | EULAR Responder index based on 28 joint counts categorizes clinical response based on improvement since baseline in DAS28-CRP. DAS28-CRP scores range from 1.0-9.4, where lower scores indicated less disease activity. High disease activity: DAS28-CRP >5.1, low disease activity: DAS28-CRP <3.2, and remission: DAS28-CRP <2.6. Participants are categorized as EULAR responders or non-responders (NR) based on improvement of DAS28-CRP scores from baseline. EULAR DAS28-CRP responder index defines a good (absolute: <3.2 or >1.2 improvement from baseline), moderate (absolute: 3.2-5.1 or 0.6-1.2 improvement from baseline), or no response (absolute: >5.1 or <0.6 improvement from baseline). Percentage of participants with DAS28-CRP based EULAR response =(number of participants with specific response) / (number of participants analyzed in the group) * 100. | Baseline, Week 24 | 
| Change From Baseline (CFB) in Serum Immunoglobulins IgG, IgA and IgM | Immunoglobulins (Ig), or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. A negative change indicates a decrease in Ig levels. | Baseline, Week 24 | 
| Change From Baseline in CD20+ B Cell Number Count | CD20+ B-cells are a disease-related peripheral blood biomarker used to assess disease progression of Rheumatoid Arthritis (RA). A reduction in CD20+ B-cell values may indicate an improvement in RA symptoms. | Baseline, Week 24 |