A Study for Patients With Rheumatoid Arthritis on Methotrexate (MTX) With an Inadequate Response to TNFα Inhibitor Therapy

Study Overview
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Brief Summary
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The purpose of this study is to explore whether LY2127399 is effective in relieving signs and symptoms of rheumatoid arthritis (RA) in patients with a history of inadequate response or intolerance to at least 1 Tumor Necrosis Factor-Alpha (TNFα) inhibitor therapy. Examples of these TNFα inhibitor therapies that are currently on the market include Enbrel® (etanercept), Remicade® (infliximab), and Humira® (adalimumab).

Official Title
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A Phase 2 Study of Multiple Intravenous Doses of LY2127399 in Patients With Rheumatoid Arthritis on Concomitant Methotrexate and an Inadequate Response to TNFα Inhibitor Therapy

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Biological: LY2127399
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have given written informed consent approval Women must not be at risk to become pregnant during study participation Diagnosis of Rheumatoid Arthritis Active Rheumatoid Arthritis Current, regular use of Methotrexate, at a stable dose Have been on at least 1 biologic tumor necrosis factor-alpha (TNFα) inhibitor therapy and either failed or were intolerant to treatment Other criteria to be reviewed by study doctor Exclusion Criteria: Use of excluded medications (reviewed by study doctor) Have medical findings which, in the opinion of the study doctor, put patient at an unacceptable risk for participation in the study Have had recent or ongoing infection which, in the opinion of the study doctor put patient at an unacceptable risk for participation Evidence of tuberculosis Have systemic inflammatory condition other than rheumatoid arthritis (RA), such as juvenile RA, seronegative spondyloarthropathy, Crohn's disease, ulcerative colitis, or psoriatic arthritis. Other criteria to be reviewed by study doctor

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: 30 milligram (mg) LY2127399<br>Double-blind Treatment: 30 mg LY2127399 administered as a single intravenous (IV) infusion over 30 minutes at 0, 3, and 6 weeks. Rescue: At Week 16 primary endpoint, participants without at least 20% improvement in either tender or swollen joint counts based on 28 joints, could receive an additional (unblinded) 30 minute infusion of LY2127399 80 mg or remain on initial randomized treatment up to Week 24. Follow-up: Optional visits beyond Week 24, if needed, to assess safety including B cell count recovery. | Biological: LY2127399<br>* LY2127399 will be administered as a single IV infusion over 30 minutes.<br>|
| Experimental: 80 mg LY2127399<br>Double-blind Treatment: 80 mg LY2127399 administered as a single IV infusion over 30 minutes at 0, 3, and 6 weeks. Rescue: At Week 16 primary endpoint, participants without at least 20% improvement in either tender or swollen joint counts based on 28 joints, could receive an additional (unblinded) 30 minute infusion of LY2127399 80 mg or remain on initial randomized treatment up to Week 24. Follow-up: Optional visits beyond Week 24, if needed, to assess safety including B cell count recovery. | Biological: LY2127399<br>* LY2127399 will be administered as a single IV infusion over 30 minutes.<br>|
| Placebo Comparator: Placebo<br>Double-blind Treatment: Placebo comparator administered as a single IV infusion over 30 minutes at 0, 3, and 6 weeks. Rescue: At Week 16 primary endpoint, participants without at least 20% improvement in either tender or swollen joint counts based on 28 joints could receive an additional (unblinded) 30 minute infusion of LY2127399 80 mg or remain on same initial randomized treatment up to Week 24. Follow-Up: Optional visits beyond Week 24, if needed, to assess safety including B cell count recovery. | Drug: Placebo<br>* Placebo will be administered as a single IV infusion over 30 minutes.<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 (ACR)50 Response at Week 16 | ACR50 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. ACR50 Responder is defined as a participant with greater than 50% improvement from baseline in both tender and swollen joint counts and in at least 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure (Health Assessment Questionnaire-Disability Index which measures participants' perceived degree of difficulty when performing various daily activities), visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing An Adverse Event | Serious adverse events and other non-serious adverse events are located in the Reported Adverse Event section. | Baseline up to 68 weeks | 
| Change From Baseline in Medical Outcome Study 36-Item Short Form Health Survey (SF-36) at Week 16 | Self-reported questionnaire of 36 questions in 8 domains (physical functioning, social functioning, bodily pain, vitality, mental health, role-physical, role-emotional, general health). Each domain is scored by summing individual items and transforming scores into a 0-100 scale (higher scores=better health status/function). The mental and physical component summaries are based on the 8 domains. Component scores are transformed scores representing a mean (50) and standard deviation (10) in the general United States (US) population. Scores > or <50 are above or below the average US population. | Baseline, 16 weeks | 
| Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Response at Week 16 | ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An ACR20 Responder is defined as a participant with at least 20% improvement from baseline in both tender and swollen joint counts and in at least 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure (Health Assessment Questionnaire-Disability Index which measures participants' perceived degree of difficulty when performing various daily activities), visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. | 16 weeks | 
| Percentage of Participants Achieving American College of Rheumatology (ACR)70 Response at Week 16 | ACR70 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An ACR70 Responder is defined as a participant with at least 70% improvement from baseline in both tender and swollen joint counts and in at least 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure (Health Assessment Questionnaire-Disability Index which measures participants' perceived degree of difficulty when performing various daily activities), visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. | 16 weeks | 
| Change From Baseline in Tender Joint Count at Week 16 | The number of tender and painful joints is determined by examination of 28 joints (14 on each side) which include: the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 2 knees. The joints are assessed and classified as tender or not tender. | Baseline, 16 weeks | 
| Change From Baseline in Swollen Joint Count at Week 16 | The number of swollen joints is determined by examination of 28 joints (14 on each side) which include: the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 2 knees. The joints are assessed and classified as swollen or not swollen. | Baseline, 16 weeks | 
| Change From Baseline in Participant's Assessment of Joint Pain at Week 16 | Participant's assessment of joint pain using a visual analog scale (VAS), which ranged from 0 to 100 millimeters, where 0 indicated no pain and 100 indicated worst possible pain. | Baseline, 16 weeks | 
| Change From Baseline in Participant's Assessment of Disease Activity at Week 16 | Participant's assessment of their current arthritis disease activity using a visual analog scale (VAS), which ranged from 0 to 100 millimeters, where 0 indicated no arthritis activity and 100 indicated extremely active arthritis. | Baseline, 16 weeks | 
| Change From Baseline in Physician's Global Assessment of Disease Activity at Week 16 | Physician's global assessment of arthritis disease activity using a visual analog scale (VAS) which ranged from 0 to 100 millimeters, where 0 indicates no arthritis activity and 100 indicates extremely active arthritis. | Baseline, 16 weeks | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 16 | The HAQ-DI questionnaire scores the participant's self-perception on the degree of difficulty when dressing and grooming, arising, eating, walking, hygiene, reach, grip, and performing other daily activities (0=without any difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do). The scores for each of the functional areas, which have a range from 0 to 3, are averaged to calculate the functional disability index. Higher scores are associated with greater disability. | Baseline, 16 weeks | 
| Percent Change From Baseline in C-reactive Protein (CRP) at Week 16 |  | Baseline, 16 weeks | 
| Change From Baseline in Disease Activity Score (DAS28) at Week 16 | Disease Activity Score (modified to include the 28 joint count [DAS28]) consists of a composite score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP), and participant global assessment of their disease activity (patient global VAS). It is calculated by using the following formula:DAS28-CRP=0.56 times the square root of(28TJC)+0.28 times the square root of(28SJC)+0.36*natural log (ln)(CRP+1)+0.014*patient global VAS+0.96. Scores ranged from 1.0-9.4, where lower scores indicated less disease activity, and remission was DAS28-CRP <2.6. A decrease in DAS28-CRP indicated an improvement in participant's condition. | Baseline, 16 weeks | 
| Number of Participants With Response (Response Rate) Based Upon European League Against Rheumatism Responder Index, 28 Joint Count (EULAR28) at Week 16 | EULAR28 categorizes clinical response based upon improvement since baseline in Disease Activity Score modified to include the 28 joint count (DAS28) and post-baseline DAS28. DAS28 consists of a composite score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP), and participant global assessment of their disease activity (patient global VAS). EULAR28 categories include: No Response (improvement in DAS28 of less than or equal to 0.6 units or post-baseline DAS28 score greater than 5.1 with improvement by less than or equal to 1.2 units), Moderate Response (post-baseline DAS28 score less than or equal to 5.1 with improvement by more than 0.6 units but no greater than 1.2 units or post-baseline DAS28 score greater than 3.2 with improvement by more than 1.2 units), and Good Response (post-baseline DAS28 score less than or equal to 3.2 with improvement by more than 1.2 units). | 16 weeks | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 16 | The FACIT Fatigue Score is a brief patient-reported measure of fatigue and consists of 13 items. Scores range from 0 to 52, with higher scores indicating less fatigue. | Baseline, 16 weeks | 
| Pharmacodynamics: Change From Baseline in Absolute CD20 + B Cell Count at Week 16 | B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all mature B-cells. For this endpoint, total B cell counts (CD20+CD3- cells) are represented by number of cells per microliter. The reference range for the absolute counts is 43-602 cells per microliter. | Baseline, 16 weeks | 
| Pharmacodynamics: Change From Baseline in Total B Cells (CD20 + CD3-) as a Percentage of Total Lymphocytes | B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all mature B-cells. For this outcome, total B cells (CD20+CD3- cells) are expressed as the relative percent of lymphocytes. There is no reference range provided for this parameter by the performing laboratory. | Baseline, 16 weeks | 
| Pharmacodynamics: Change From Baseline in Serum Immunoglobulins at Week 16 | Serum immunoglobulin measured by Immunoglobulin A (IgA), Immunoglobulin G (IgG), and Immunoglobulin M (IgM) levels. | Baseline, 16 weeks | 
| Pharmacokinetics: Predicted Population Mean Parameter: C-trough Steady-state | C-trough is defined as the concentration of LY at the end of the dosing interval at steady state. Mean C-trough value was obtained by conducting a simulation consisting of 1000 participants. The simulated data were then used to determine the noncompartmental PK parameters for each regimen. Mean and standard deviation of the Ctrough values were calculated for each dose group based on simulated data. | Pre-dose, Day 1 through Week 24 | 
| Pharmacokinetics: Predicted Population Mean Parameter: T-half Life (t1/2, Tau) | T-half life (t1/2, tau) is defined as the apparent steady state elimination within the dosing interval. T-half life was obtained by conducting a simulation consisting of 1000 participants using the study drug regimens (30 and 80 mg, intravenous infusion over 30 minutes, once every 3 weeks). The simulated data were then used to determine the noncompartmental PK parameters for each regimen. Mean and standard deviation of the t-half life values were calculated for each dose group based on simulated data. | Pre-dose, Day 1 through Week 24 |