A Study for Patients With Active Rheumatoid Arthritis Despite Ongoing Methotrexate Therapy

Study Overview
=================
Brief Summary
-----------------
To assess the efficacy of LY2127399 versus placebo using American College of Rheumatology (ACR)50 response scale at 24 weeks

Official Title
-----------------
Phase 2, Dose-Ranging Study of Multiple Subcutaneous Doses of LY2127399 in Patients With Active Rheumatoid Arthritis Despite Ongoing Methotrexate Therapy

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Biological: LY2127399
* Drug: Placebo


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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br> | Drug: Placebo<br>* Administered subcutaneously (SC) every 4 weeks over a 24-week period (Weeks 0, 4, 8, 12, 16, and 20).<br>|
| Experimental: 1 mg LY2127399<br> | Biological: LY2127399<br>* Administered SC every 4 weeks over a 24-week period (Weeks 0, 4, 8, 12, 16, and 20).<br>|
| Experimental: 3 mg LY2127399<br> | Biological: LY2127399<br>* Administered SC every 4 weeks over a 24-week period (Weeks 0, 4, 8, 12, 16, and 20).<br>|
| Experimental: 10 mg LY2127399<br> | Biological: LY2127399<br>* Administered SC every 4 weeks over a 24-week period (Weeks 0, 4, 8, 12, 16, and 20).<br>|
| Experimental: 30 mg LY2127399<br> | Biological: LY2127399<br>* Administered SC every 4 weeks over a 24-week period (Weeks 0, 4, 8, 12, 16, and 20).<br>|
| Experimental: 60 mg LY2127399<br> | Biological: LY2127399<br>* Administered SC every 4 weeks over a 24-week period (Weeks 0, 4, 8, 12, 16, and 20).<br>|
| Experimental: 120 mg LY2127399<br> | Biological: LY2127399<br>* Administered SC every 4 weeks over a 24-week period (Weeks 0, 4, 8, 12, 16, and 20).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved American College of Rheumatology (ACR) 50 Response up to 24 Weeks | ACR50 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An ACR50 Responder is defined as a participant with >50% improvement from baseline in both tender and swollen joint counts and in at least 3 of the following 5 criteria: physician global assessment, participant 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. | Up to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving The American College of Rheumatology (ACR)20 Response up to 24 Weeks | ACR20 Responder Index is composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An ACR20 Responder is defined as 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, participant 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. | Up to 24 weeks | 
| Change From Baseline in the Tender Joint Count up to 24 Weeks | Number of tender and painful joints was 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. Joints were assessed by pressure and joint manipulation on physical examination. Participant was asked for pain sensations on these manipulations and watched for spontaneous pain reactions. Any positive response on pressure, movement, or both is translated into a single tender-versus-nontender dichotomy. | Baseline, up to 24 weeks | 
| Change From Baseline in Swollen Joint Count up to 24 Weeks | The number of swollen joints was determined by examination of 28 joints 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. Joints were classified as either swollen or not swollen. Swelling was defined as palpable fluctuating synovitis of the joint. | Baseline, up to 24 weeks | 
| Change From Baseline in the Disease Activity Score (DAS) up to 24 Weeks | DAS (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 his or her disease activity (participant global visual analog scale [pt global VAS]). The DAS28 is calculated by using the following formula: DAS28-CRP = 0.56*sqrt(28TJC) + 0.28*sqrt(28SJC) + 0.36*ln(CRP+1) + 0.014*pt global VAS + 0.96. Scores ranged from 1.0-9.4, where lower scores indicated less disease activity. | Baseline, up to 24 weeks | 
| Percentage of Participants With A European League Against Rheumatism Responder Index Based on the 28 Joint Count (EULAR28) up to 24 Weeks | The EULAR28 categorizes clinical response based upon improvement since baseline in the Disease Activity Score (DAS) modified to include the 28 joint count (DAS28) and post-baseline DAS28 level. 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 (participant global visual analog scale [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). | Up to 24 weeks | 
| Change From Baseline in the Participant's Assessment of Joint Pain up to 24 Weeks | Participant's assessment of joint pain using a visual analog scale (VAS), which ranged from 0 to 100 mm, where 0 indicated no pain and 100 indicated worst possible pain. | Baseline, up to 24 weeks | 
| Change From Baseline in the Participant's Assessment of Disease Activity up to 24 Weeks | Participant's assessment of disease activity using a visual analog scale (VAS), which ranged from 0 to 100 mm, where 0 indicated no arthritis activity and 100 indicated extremely active arthritis. | Baseline, up to 24 weeks | 
| Change From Baseline in the Physician's Assessment of Disease Activity up to 24 Weeks | Physician's assessment of disease activity using a visual analog scale (VAS) that ranged from 0 to 100 mm, where 0 indicated no arthritis activity and 100 indicated extremely active arthritis. | Baseline, up to 24 weeks | 
| Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) up to 24 Weeks | Participant's assessment of physical function. Disability section of questionnaire scores participant's self-perception on degree of difficulty (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do) when dressing and grooming, arising, eating, walking, hygiene, reach, grip, and performing other daily activities. Scores for each of the functional areas were averaged to calculate the functional disability index. The HAQ-DI total score, which is the average of the nonmissing functional scores, ranges from 0 (no disability) to 3 (severe disability). | Baseline, up to 24 weeks | 
| Percent Change From Baseline in C-Reactive Protein (CRP) up to 24 Weeks | Percent change = [(postbaseline CRP - baseline CRP)/baseline CRP]*100. | Baseline, up to 24 weeks | 
| Change From Baseline in the Functional Assessment of Chronic Illness (FACIT) Fatigue Scale up to 24 Weeks | The FACIT Fatigue Scale is a brief participant-reported measure of fatigue and consists of 13 items. Scores range from 0 to 52, with higher scores indicating less fatigue. | Baseline, up to 24 weeks | 
| Change From Baseline in the Short Form Health Survey (SF-36) up to 24 Weeks | A self-reported questionnaire that consists of 36 questions covering 8 health domains (physical functioning, social functioning, bodily pain, vitality, mental health, role-physical, role-emotional, and general health). Each domain is scored by summing the individual items and transforming the scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. The mental component summary (MCS) and the physical component summary (PCS) have been constructed based on the 8 SF-36 domains. MCS and PCS scores = 0 to 100 (higher scores indicate better health status). | Baseline, up to 24 weeks | 
| Pharmacokinetics of LY2127399: C-Trough Steady State Concentration at 24 Weeks | C-trough is defined as the concentration of LY2127399 at the end of the dosing interval after the subcutaneous (sc) injection dosing once every 4 weeks. Mean C-trough value was obtained by conducting a simulation consisting of 1000 participants. The model was then used to predict the concentration-time profile at steady state. The pharmacokinetic (PK) parameters were then estimated from these concentration-time profiles. | 24 weeks | 
| Pharmacokinetics of LY2127399: T-Half Life (t1/2, Tau) at 24 Weeks | T1/2,tau is defined as the apparent steady state elimination within the dosing interval. T1/2,tau was obtained by conducting a simulation consisting of 1000 participants. The model was then used to predict the concentration-time profile at steady state. The pharmacokinetic (PK) parameters were then estimated from these concentration-time profiles. | 24 weeks | 
| Change From Baseline in the Absolute Total B Cell (CD20+CD3- Cells) Count up to 24 Weeks | B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all mature B-cells. Total B cell counts (CD20+CD3-) are represented by the number of cells per microliter (cells/µL). The reference range is 43 - 602 cells/µL. | Baseline, up to 24 weeks | 
| Change From Baseline in Serum Immunoglobulin up to 24 Weeks | Serum immunoglobulin measured by Immunoglobulin G (IgG), Immunoglobulin M (IgM), and Immunoglobulin A (IgA) levels. | Baseline, up to 24 weeks | 
| Number of Participants Experiencing An Adverse Event | Serious adverse events and other nonserious adverse events are located in the Reported Adverse Event section. | Baseline up to 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Arthritis