A Study in Patients With Rheumatoid Arthritis

Eli Lilly and Company448 enrolled

Overview

The primary purpose of the study is to help answer the following research questions, and not to provide treatment for Rheumatoid Arthritis (RA): * The safety of LY2439821 and any side effects that might be associated with it. * Whether LY2439821 can help participants with active RA. * How much LY2439821 should be given to participants.

Study I1F-MC-RHAK is a multicenter study in participants with active RA on concomitant conventional DMARD therapy. The study is a Phase 2 study with 2 parts. Part A is a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging design and Part B is an optional, open-label extension design. Two participant populations will be evaluated in this study: bDMARD-naive participants and TNFα-IR participants. Participants in Part A receive multiple subcutaneous injections of LY2439821 \[bDMARD-naive participants: 0 (placebo), 3, 10, 30, 80, or 180 mg; TNFα-IR participants: 0 (placebo), 80 or 180 mg\] at Weeks 0, 1, 2, 4, 6, 8, and 10. Participants in Part B receive subcutaneous injections of LY2439821 160 mg at Weeks 16, 18, and 20, and every 4 weeks thereafter through Week 60. Participants who complete both Part A and B have a total study participation of up to approximately 72 to 84 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

448

Conditions

Rheumatoid Arthritis

Interventions

LY2439821BIOLOGICAL

Subcutaneous

PlaceboDRUG

Subcutaneous

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * You must be between the ages of 18 and 75 * You must have active RA Qualifications Specific to the bDMARD-naive Population: You must be regularly using methotrexate (MTX) for at least 12 weeks before your participation in this study Qualifications Specific to the TNFα-IR Population: * You must have been treated with at least 1 biologic TNFα inhibitor therapy and either had an insufficient response to at least 3 months of treatment OR have been intolerant of such treatment * You must be regularly using at least 1 conventional DMARD in a stable treatment regimen Exclusion Criteria: * You are concomitantly using non-steroidal anti-inflammatory drugs (NSAIDS), unless you are on a stable dose within the last 2 weeks * You are a woman who is lactating or breast feeding * You have donated more than 300 milliliters (mL) of blood within the last month * You have received glucocorticoid administered by intra-articular, intramuscular, or intravenous injection or oral corticosteroids at an average daily dose of greater than 10 mg per day of prednisone or its equivalent within the last 4 weeks * You had surgery on a joint that is to be assessed in the study within 2 months of study enrollment, or will require such during the study * You have another serious disorder or illness * You suffered a serious bacterial infection (for example, pneumonia, cellulitis, or bone or joint infections) within the last 3 months * You have a history of uncontrolled high blood pressure * You have clinical laboratory test results at entry that are outside the normal reference range * You are an employee of the clinic or you are an immediate family member of an employee of the clinic. Immediate family member is defined as a spouse, parent, child, or sibling, whether biological or legally adopted * You are currently participating in or were discontinued within the last 30 days from another clinical trial involving an investigational drug * If you are a woman and you could become pregnant during this study, you must talk to the study doctor about the birth control that you will use to avoid getting pregnant during the study. * If you are a post-menopausal woman, you must be at least 45 years of age and have not menstruated for the last 12 months * If you are a post-menopausal woman between 40 and 45 years of age, test negative for pregnancy, and have not menstruated during the last 12 months only, you must have an additional blood test to see if you can participate. * If you are male, you must agree to reduce the risk of your female partner becoming pregnant during the study. Exclusions Specific to the bDMARD-naive Population: * You have received any prior bDMARD therapy such as TNFα, Interleukin (IL)-1, IL-6, T-cell, or B-cell targeted therapies * You have had an inadequate response to a minimum of 3 months of treatment with 5 or more conventional DMARDs \[such as leflunomide, azathioprine, cyclosporine, etcetera (etc.)\] * You have used DMARDs other than MTX, hydroxychloroquine, or sulfasalazine within the last 8 weeks * You have used leflunomide within the last 12 weeks and have not received cholestyramine to speed up the elimination of leflunomide from your body. Exclusions Specific to the TNFα-IR Population: * You are currently using or recently used a bDMARD or a biologic TNFα inhibitor therapy within specified periods * You have had a serious reaction to other biologic DMARDs that, in the study doctor's opinion, puts you at serious risk * You have used cyclosporine or any other immunosuppressive in the 8 weeks before your participation in this study

Locations (75)

Outcomes

Primary Outcomes

Dose-Response Relationship Measured by the Percentage of Participants With American College of Rheumatology (ACR) 20 Response in bDMARD-Naive Population

ACR20 responders are participants with at least 20% improvement from baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: Health Assessment Questionnaire-Disability Index (HAQ-DI) which measured participants perceived degree of difficulty performing daily activities, C-reactive Protein (CRP), Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), Patient's Global Assessment of Disease Activity-VAS(PtGADA-VAS), and Physician's Global Assessment of Disease Activity-VAS (PhGA-VAS). Missing values were imputed using Non-Responder Imputation (NRI). Percentage of participants achieving ACR20 response was calculated as: (number of ACR20 responders / number of participants treated) \* 100.

Time frame: Week 12

Secondary Outcomes

Percentage of Participants With ACR20 Response in Tumor Necrosis Factor Alpha-Inadequate Responder (TNFα-IR) Population

ACR20 responders were participants with at least 20% improvement from baseline for TJC, SJC, and at least 3 of the 5 remaining core set measures: HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, and PhGA-VAS. Missing values were imputed using NRI. Percentage of participants achieving ACR20 response was calculated as: (number of ACR20 responders / number of participants treated) \* 100.

Time frame: Week 12

Smallest Doses That Achieve 10%, 50%, and 90% of the Maximum ACR 20 Response in bDMARD-Naive Population

ACR20 responders are participants with at least 20% improvement from baseline for TJC, SJC, and at least 3 of the 5 remaining core set measures: HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, and PhGA-VAS. The model used in the dose response analysis was used to estimate the doses that achieved 10%, 50%, and 90% of the maximal drug efficacy. Missing values were imputed using NRI. The log transformed dose was evaluated.

Time frame: Week 12

Smallest Doses That Achieved 10%, 50%, and 90% of the Maximum Disease Activity Score (DAS) 28 Response in bDMARD-Naive Population

Data from ClinicalTrials.gov

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For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Peoria, Arizona, United States

La Mesa, California, United States

Palm Desert, California, United States

San Jose, California, United States

Santa Maria, California, United States

Stanford, California, United States

Westlake Village, California, United States

Denver, Colorado, United States

Washington D.C., District of Columbia, United States

Lake Mary, Florida, United States

...and 65 more locations

DAS modified included the 28 diarthrodial joint count (DAS28) that consisted of a composite score of the following variables: TJC out of 28 (TJC28), SJC out of 28 (SJC28), CRP \[milligrams per liter (mg/L)\], and PtGADA on a 0 to 100 millimeter (mm) VAS ranging from 0 mm (no arthritis activity) to 100 mm (extremely active arthritis). DAS28 was calculated as: DAS28 - CRP = 0.56(square root of TJC28) + 0.28(square root of SJC28) + 0.36(ln\[CRP +1\]) + 0.014(VAS) + 0.96.

Smallest Doses That Achieve 10%, 50%, and 90% of the Maximum ACR50 Response in bDMARD-Naive Population

ACR50 responders were participants with at least 50% improvement from baseline for TJC, SJC, and at least 3 of the 5 remaining core set measures: HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, and PhGA-VAS. Missing values were imputed using NRI.

Time frame: Week 12

Change From Baseline in Disease Activity Score (DAS28)-Part A

DAS28 consisted of a composite score of the following variables: TJC28, SJC28, CRP, and PtGADA-VAS. DAS28 was calculated as: DAS28 - CRP =0.56(square root TJC28) + 0.28(square root SJC28) + 0.36(ln\[CRP +1\]) + 0.014(VAS) + 0.96. A negative change indicated an improvement.

Time frame: Baseline, up to Week 12

Change From Baseline in DAS28 - Part B

Time frame: Baseline, Week 64

Percentage of Participants With ACR20/50/70 Response - Part A

ACR20 (or ACR50 or ACR70) responders were participants with at least 20% (or 50% or 70%, respectively) improvement from baseline TJC, SJC, and at least 3 of the 5 remaining core set measures: HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, and PhGA-VAS. Missing values were imputed using NRI. Percentage of participants was calculated as: (number of ACR20 \[or ACR50 or ACR70\] responders per treatment arm) / (total number of participants per treatment arm) \* 100.

Time frame: Week 12

Percentage of Participants With of ACR20/50/70 Response - Part B

ACR20 (or ACR50 or ACR70) responders were participants with at least 20% (or 50% or 70% respectively) improvement from baseline TJC, SJC, and at least 3 of the 5 remaining core set measures: HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, and PhGA-VAS. Missing values were imputed using NRI. Percentage of participants was calculated as: (number of ACR20 \[or ACR50 or ACR70\] responders per treatment arm) / (total number of participants per treatment arm) \* 100\].

Time frame: Week 64

Change From Baseline in Individual Components of the ACR Core Set-TJC - Part A

TJC was determined by examination of 28 joint counts that were assessed for tenderness by pressure and joint manipulation on physical examination. The participant was asked for pain sensations on these manipulations and was watched for spontaneous pain reactions. Any positive response on pressure, movement, or both was translated into a single tender-versus-non-tender dichotomy. Joint assessments for each participant were performed by the same assessor, when possible, throughout the study to minimize variation. Replaced, ankylosed, arthrodesed joints were identified by the investigator and excluded from evaluation during the study. Any joints that required intra-articular injections during the study were excluded from evaluation from the time of the injection to the conclusion of the study. The number of tender joints ranged from 0-28. A negative change indicated fewer tender joints.

Time frame: Baseline, up to Week 12

Change From Baseline in Individual Components of the ACR Core Set-TJC - Part B

Time frame: Baseline, Week 64

Change From Baseline in Individual Components of the ACR Core Set-SJC - Part A

SJC was determined by examination of 28 joint that were classified as either swollen or not swollen. Swelling was defined as palpable fluctuating synovitis of the joint. Swelling secondary to osteoarthrosis was assessed as not swollen, unless there was unmistakable fluctuation. Joint assessments for each participant were performed by the same assessor, when possible, throughout the study to minimize variation. Replaced, ankylosed, or arthrodesed joints were identified by the investigator and were excluded from evaluation during the study. Any joints that required intra-articular injections over the course of the study were excluded from evaluation from the time of the injection to the conclusion of the study. The number of swollen joints count ranged from 0-28. A negative change indicated fewer swollen joints.

Time frame: Baseline, up to Week 12

Change From Baseline in Individual Components of the ACR Core Set-SJC - Part B

SJC was determined by examination of 28 joint that were classified as either swollen or not swollen. Swelling was defined as palpable fluctuating synovitis of the joint. Swelling secondary to osteoarthrosis was assessed as not swollen, unless there was unmistakable fluctuation. Joint assessments for each participant were performed by the same assessor, when possible, throughout the study to minimize variation. Replaced, ankylosed, or arthrodesed joints were identified by the investigator and were excluded from evaluation during the study. Any joints that required intra-articular injections over the course of the study were excluded from evaluation from the time of the injection to the conclusion of the study. The number of swollen joints ranged from 0-28. A negative change indicated fewer swollen joints.

Time frame: Baseline, Week 64

Change From Baseline in Individual Components of the ACR Core Set-PAAP VAS - Part A

Participants were asked to assess his/her current level of arthritis pain by marking a vertical tick on a 100-mm horizontal VAS with the left end (0 mm) marked as "no pain" and the right end (100 mm) marked "worst possible pain." The scale was administered prior to the TJC and SJC count examinations. Results were expressed in mm measured between the left end of the scale and the crossing point of the vertical line of the tick. A negative change indicated a lessening of the participant's arthritis pain.

Time frame: Baseline, up to Week 12

Change From Baseline in Individual Components of the ACR Core Set-PAAP-VAS - Part B

Participants were asked to assess his/her current level of arthritis pain by marking a vertical tick on a 100-mm horizontal VAS with the left end (0 mm) marked as "no pain" and the right end (100 mm) marked "worst possible pain". The scale was administered prior to the TJC and SJC count examinations. Results were expressed in mm measured between the left end of the scale and the crossing point of the vertical line of the tick. A negative change indicated a lessening of the participant's arthritis pain.

Time frame: Baseline, Week 64

Change From Baseline in Individual Components of the ACR Core Set - PtGADA-VAS - Part A

The participant was asked to give an overall assessment of his/her current arthritis disease activity. The participants response was recorded by marking a vertical tick on a 100-mm VAS with the left end (0 mm) marked as "no arthritis activity" to the right end (100 mm) marked "extremely active arthritis." A negative change indicated an improvement in the participant's assessment of disease activity.

Time frame: Baseline, up to Week 12

Change From Baseline in Individual Components of the ACR Core Set - PtGADA-VAS - Part B

Time frame: Baseline, Week 64

Change From Baseline in Individual Components of the ACR Core Set - PhGA-VAS - Part A

The investigator gave an overall assessment of the severity of the participants disease activity. The physician's response was recorded by marking a vertical tick on a 100-mm VAS with the left end (0 mm) marked as "no arthritis activity" and the right end (100 mm) marked as "extremely active arthritis." A negative change indicated a lessening in the severity of the participant's disease activity.

Time frame: Baseline, up to Week 12

Change From Baseline in Individual Components of the ACR Core Set - PhGA-VAS - Part B

The investigator gave an overall assessment of the severity of the participant's disease activity. The physician's response was recorded by marking a vertical tick on a 100-mm VAS with the left end (0 mm) marked as "no arthritis activity" and the right end (100 mm) marked as "extremely active arthritis." A negative change indicated a lessening in the severity of the participant's disease activity.

Time frame: Baseline, Week 64

Change From Baseline in Individual Components of the ACR Core Set - CRP - Part A

CRP is a biological marker of disease activity. A negative change indicated an improvement in participant's disease activity.

Time frame: Baseline, up to Week 12

Change From Baseline in Individual Components of the ACR Core Set - CRP - Part B

CRP is a biological marker of disease activity. A negative change indicated an improvement in participant's disease activity.

Time frame: Baseline, Week 64

Percentage of Participants in European League Against Rheumatism Responder Index (EULAR) 28 - Part A

Assessment of participant's rheumatoid arthritis (RA) by the EULAR that is based on the DAS 28 joint count. Participants were categorized as non-responders or responders (moderate responders + good responders). Percentage of participants was calculated as: (number of responders / number of participants) \* 100.

Time frame: Week 12

Percentage of Participants in EULAR28 - Part B

Assessment of participant's RA by the EULAR that is based on the DAS28 joint count. Participants were categorized as non-responders or responders (moderate responders + good responders). Percentage of participants was calculated as: (number of responders / number of participants) \* 100.

Time frame: Week 64

ACR-N - Part A

ACR-N was a continuous measure of clinical, laboratory and functional outcomes in RA that characterized the percentage of improvement in RA disease activity from baseline. The index was defined as the lowest of either: the percent change in TJC, the percent change in SJC, or the median percent change of the remaining 5 ACR core criteria: HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, and PhGA-VAS. For each criterion, percent change was calculated as: \[(post baseline value - baseline value) / baseline value\] \* 100.

Time frame: Week 12

ACR-N - Part B

Time frame: Week 64

Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale - Part A

The FACIT Fatigue Scale was a brief participant-reported questionnaire measure of fatigue and consisted of 13 items that assessed tiredness, weakness and difficulty conducting usual activities due to fatigue. Each question was scored on a 5-point scale from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue. For missing data, scores were prorated using the average of the other answers in the scales as long as more than 50% of the items were answered. A negative change indicated less fatigue.

Time frame: Baseline, up to Week 12

Change From Baseline in FACIT Fatigue Scale - Part B

The FACIT-Fatigue Scale was a brief participant-reported questionnaire measure of fatigue and consisted of 13 items that assessed tiredness, weakness and difficulty conducting usual activities due to fatigue. Each question was scored on a 5-point scale from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue. For missing data, scores were prorated using the average of the other answers in the scales as long as more than 50% of the items were answered. A negative change indicated less fatigue.

Time frame: Baseline, Week 64

Change From Baseline in Duration of Morning Stiffness (Minutes) - Part A

The investigator queried the participants about the duration of morning stiffness in and around their joints and the results (in minutes) were recorded by the investigator. Duration was the time from when the participants woke up to when normal activities could be resumed. Durations recorded as longer than 12 hours (720 minutes) were summarized as 720 minutes. An increase in duration from baseline indicated a joint worsening and a decrease from baseline indicated joint improvement.

Time frame: Baseline, up to Week 12

Change From Baseline in Duration of Morning Stiffness (Minutes) - Part B

Time frame: Baseline, Week 64

Change From Baseline in HAQ-DI - Part A

HAQ-DI was a participant-reported questionnaire that consisted of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do). The highest score for any question in a category was the score of that category unless special aids or devices or help from another person was required. Answers for at least 6 of the 8 disability domains were required to compute the participant's HAQ-DI score. If the participant had scores for fewer than 6 categories, the HAQ-DI score was considered missing. The HAQ-DI score was calculated as the sum of the category scores divided by the number of categories scored, with a possible scores range of 0 to 3. Negative mean changes from baseline indicated improvement.

Time frame: Baseline, up to Week 12

Change From Baseline in HAQ-DI - Part B

HAQ-DI was a participant-reported questionnaire that consisted of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do). The highest score for any question in a category was the score of that category unless special aids or devices or help from another person was required. Answers for at least 6 of the 8 disability domains were required to compute the participant's HAQ-DI score. If the participant had scores for fewer than 6 categories, the HAQ-DI score was considered missing. The HAQ-DI score was calculated as the sum of the category scores divided by the number of categories scored, with a possible scores range from 0 to 3. Negative mean changes from baseline indicated improvement.

Time frame: Baseline, Week 64

Relationship Between Exposure and Response of Individual Components of the ACR Core Set

Time frame: Through Week 72

Relationship Between Exposure and Response of ACR20/50/70/N

Time frame: Through Week 72

Relationship Between Exposure and Response of DAS28

Time frame: Through Week 72

Relationship Between Exposure and Response of EULAR28

Time frame: Through Week 72

Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2439821 at Steady State

Evaluable PK concentrations from all time points, including data from placebo participants who elected active treatment in Part B, were combined and utilized in a population approach to determine the population median estimates and 90% confidence intervals at steady state. Day 0 and Week 6 postdose samples were collected as late as possible during the dosing visit (in other words, the postdose samples were collected at the end of their respective visits).

Time frame: Predose: Day 0, Day 1 or 2 or 3, Day 7, Weeks 6, 10, 16, 40 and 64 and Postdose: Day 0 and Week 6

Percentage of Participants With Anti-LY2439821 Antibodies

Treatment-emergent anti-LY2439821 antibody positive participants were defined as a titer change from baseline that was at least 2 dilutions (4-fold) increase. Participants must have had an assessment to be classified as treatment emergent antibody positive or negative.

Time frame: Week 16, Week 64