A Phase 3 interventional study of LY2127399 and Placebo in Rheumatoid Arthritis, sponsored by Eli Lilly and Company. Completed at 213 sites in 22 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-04-25.
Sponsored by Eli Lilly and Company · Phase 3, Interventional, and Treatment
The primary purpose of this study is to help answer if LY2127399 is safe and effective in the treatment of rheumatoid arthritis with or without background disease-modifying anti-rheumatic drug (DMARD) therapy.
This study is comprised of 2 periods:
Period 1 - 24-week blinded treatment
Period 2 - 48-week post-treatment follow-up
In consideration of disease severity, all participants were assessed for non-response at Week 16. A total of 66 joints were examined for swelling, and a total of 66 joint were examined for tenderness. For participants who had at least 5 swollen and 5 tender joints at baseline, Week 16 non-responders (NRs) were defined as participants with \<20% improvement from baseline in both tender joint counts and swollen joint counts. For participants who did not have at least 5 swollen and 5 tender joints at baseline, Week 16 NRs were defined as participants who had at least 2 additional tender and 2 additional swollen joints from baseline. All Week 16 NRs and all participants who discontinued study treatment at any time, for any reason, were defined as NRs starting at that timepoint and going forward for all American College of Rheumatology (ACR) imputed analyses, including the Week 24 endpoint.
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Exclusion Criteria:
LY2127399: 120 milligrams (mg), subcutaneous (SC) injection, every 4 weeks for 24 weeks. Participants received a 240-mg (2 SC injections of 120 mg each) loading dose of LY2127399 when initiating treatment. During the Treatment Period, for blinding purposes, participants alternated injections of LY2127399 and injections of Placebo every 2 weeks. After 16 weeks, non-responders received 90 mg of LY2127399 every 2 weeks for the rest of the 24-week Treatment Period.
Drug: LY2127399 · Drug: Placebo
LY2127399: 90 milligrams (mg), subcutaneous (SC) injection, every 2 weeks for 24 weeks. Participants received a 180-mg (2 SC injections of 90 mg each) loading dose of LY2127399 when initiating treatment. After 16 weeks, non-responders continued to receive 90 mg of LY2127399 every 2 weeks for the rest of the 24-week Treatment Period.
Drug: LY2127399
Placebo: subcutaneous (SC) injection, every 2 weeks for 24 weeks. Participants received a loading dose of 2 SC injections of Placebo when initiating treatment. After 16 weeks, non-responders received 90 milligrams (mg) of LY2127399 every 2 weeks for the rest of the 24-week Treatment Period.
Drug: LY2127399 · Drug: Placebo
Also known as: Tabalumab
Percentage of Participants With American College of Rheumatology 20% (ACR20) Response
ACR20 Responder Index: Composite of clinical, laboratory, and functional measures of rheumatoid arthritis. ACR20 Responder: had \>=20% improvement from baseline in both 68 tender and 66 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), joint pain, and C-reactive protein (CRP). Percentage of participants achieving ACR20 response=(number of ACR20 responders/number of participants treated)\*100. All non-responders at Week 16 as well as all participants who discontinued study treatment at any time, for any reason, were defined as non-responders starting at that timepoint and going forward, including Week 24 endpoint.
Time frame: Up to 24 weeks
Percentage of Participants With American College of Rheumatology 50% (ACR50) and 70% (ACR70) Responses
ACR Responder Index: Composite of clinical, laboratory, and functional measures of rheumatoid arthritis. ACR50 Responder: had \>=50% improvement from baseline in both 68 tender joint (TJ) and 66 swollen joint (SJ) counts and \>=50% improvement in at least 3/5 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. Percentage of Pt achieving ACR50 response=(number (No) of ACR50 responders/No of Pts treated)\*100. ACR70 Responder: had \>=70% improvement from baseline in both TJ and SJ counts and \>=70% improvement in at least 3 of same 5 criteria for ACR50. Percentage of Pts achieving ACR70 response=(No of ACR70 responders/No of Pts treated)\*100. All non-responders at Week 16 as well as all Pts who discontinued study treatment at any time, for any reason, were defined as non-responders starting at that timepoint and going forward, including Week 24 endpoint.
Time frame: Up to 24 weeks
Mean Percent Improvement in American College of Rheumatology Percent Improvement (ACR-N)
ACR-N is a continuous measure of clinical, laboratory, and functional outcomes in rheumatoid arthritis that characterizes percentage of improvement in disease activity from baseline based on ACR core set. Percentage of improvement was truncated to range of -100 to 100 to minimize impact of outliers (greater values indicate greater percent improvement). This index was calculated as minimum of a) percentage of improvement in TJ count, b) percentage of improvement in SJ count, or c) third highest percentage of improvement of remaining 5 ACR core criteria: If \>=3 components of the 5 ACR core criteria were missing, then c) was set to missing; if any of 3 components a), b), or c) were missing, then ACR-N was set to missing. Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with treatment, region, tumor necrosis factor-inadequate responder treatment history, and disease-modifying anti-rheumatic drug (DMARD) background as fixed factors and baseline as a covariate.
Time frame: Up to 24 weeks
Change From Baseline to 24 Weeks in Tender Joint Count (68 Joint Count)
Tender joint count is the number of tender and painful joints determined for each participant by examination of 68 joints. Joints were assessed by pressure and joint manipulation on physical examination. Participants were 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. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline to 24 Weeks in Swollen Joint Count (66 Joint Count)
Swollen joint count is the number of swollen joints determined for each participant by examination of 66 joints. Joints were classified as either swollen or not swollen. Swelling was defined as palpable fluctuating synovitis of the joint. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline to 24 Weeks in Participant's Assessment of Pain (Visual Analog Scale)
Participant's assessment of their current arthritis pain using a visual analog scale (VAS) ranged from 0 millimeters (mm) (no pain) to 100 mm (worst possible pain). A decrease in pain score indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline to 24 Weeks in Participant's Global Assessment of Disease Activity (Visual Analog Scale)
Participant's assessment of their current arthritis disease activity using a visual analog scale (VAS) ranged from 0 millimeters (mm) (no arthritis activity) to 100 mm (extremely active arthritis). A decrease in disease activity score indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline to 24 Weeks in Physician's Global Assessment of Disease Activity (Visual Analog Scale)
Physician's assessment of the participant's current arthritis disease activity using a visual analog scale (VAS) ranged from 0 millimeters (mm) (no arthritis activity) to 100 mm (extremely active arthritis). A decrease in disease activity score indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline to 24 Weeks in Disease Activity Score (Based on 28 Joint Count)-C-Reactive Protein (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), C-reactive protein (CRP) (milligrams per liter), and participant global assessment of disease activity using visual analog scale (VAS) (participant global VAS). DAS28-CRP was calculated using following formula: 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 1.0-9.4, where lower scores indicated less disease activity and remission is DAS28-CRP \<2.6. A decrease in DAS28-CRP indicated an improvement in participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline to 24 Weeks in Health Assessment Questionnaire-Disability Index (HAQ-DI)
The HAQ-DI questionnaire assesses the participant's self-perception on the 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, reaching, gripping, and performing other daily activities. Scores for each functional area, which ranged from 0 (no disability) to 3 (severe disability), were averaged to calculate HAQ-DI. A decrease in HAQ-DI score indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Time to American College of Rheumatology 20% (ACR20) Response
ACR20 Responder Index: Composite of clinical, laboratory, and functional measures of rheumatoid arthritis. ACR20 Responder: had \>= 20% improvement from baseline in both 68 tender and 66 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), joint pain, and C-reactive protein (CRP). The Kaplan-Meier estimator was used to summarize time to ACR20 response over the Treatment Period (24 weeks). The time to American College of Rheumatology 20% (ACR20) response (in weeks) is calculated as: (Date of the first postbaseline visit during the Treatment Period meeting ACR20 response criteria - Date of first injection of study treatment + 1) / 7.
Time frame: Baseline through 24 weeks
Probability of an ACR20 Response by 24 Weeks
ACR20 Responder Index: Composite of clinical, laboratory, and functional measures of rheumatoid arthritis. ACR20 Responder: had \>= 20% improvement from baseline in both 68 tender and 66 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), joint pain, and C-reactive protein (CRP). The Kaplan-Meier estimator was used to summarize time to ACR20 response over the Treatment Period (24 weeks). The time to American College of Rheumatology 20% (ACR20) response (in weeks) is calculated as: (Date of the first postbaseline visit during the Treatment Period meeting ACR20 response criteria - Date of first injection of study treatment + 1) / 7.
Time frame: Baseline through 24 weeks
Percentage of Participants With DAS28-Based European League Against Rheumatism (EULAR) Response
EULAR Responder index based on 28 joint count categorizes clinical response based on improvement since baseline in DAS28-CRP. Participants are categorized as EULAR responders or non-responders based on improvement of DAS28-CRP scores from baseline. EULAR28 responder is defined as either DAS28-CRP \<=5.1 and DAS28-CRP change \<-0.6; or DAS28-CRP \>5.1 and DAS28-CRP change \<-1.2. EULAR28 responder index is defined as good response: DAS28-CRP \<=3.2 and DAS28-CRP change \<-1.2; moderate response: DAS28-CRP change \<-1.2 except cases defined in good response; or DAS28-CRP \<=5.1 and DAS28-CRP change \<-0.6 and \>-1.2. EULAR Remission is defined as a DAS28-CRP score of \<2.6.
Time frame: Up to 24 weeks
Change From Baseline to 24 Weeks in Medical Outcomes Study 36-Item Short Form (SF-36) Health Status Survey Domain and Summary Scores
The SF-36 is a health-related survey that assesses participant's quality of life and consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems and emotional problems, general health, mental health, social functioning, vitality, and 2 component scores (mental \[MCS\] and physical health \[PCS\]). Domain scores calculated by summing each item for each domain and transforming scores into 0-100 scale; higher scores indicated better health status. MCS score consisted of social functioning, vitality, mental health, and role-emotional scales. PCS score consisted of physical functioning, bodily pain, role-physical, and general health scales. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline in C-reactive Protein (CRP) up to Week 24 Endpoint
CRP is an indicator of inflammation. A negative change indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline to 24 Weeks in Absolute CD3-CD20+ B-cell Counts
Cell-surface marker cluster designation (CD) 3 negative, CD20 positive (CD3-CD20+) defines total mature B cells. B-lymphocyte antigen CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all mature B cells. Baseline B-cell count is determined by calculating the average of the 2 pretreatment B-cell counts obtained once during Days -28 through -7 and on Day 0. A positive or negative change indicated an increase or decrease, respectively in B-cell count. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Change From Baseline to 24 Weeks in Serum Immunoglobulin (Ig) Levels
Immunoglobulins, 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. Change from baseline serum immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) levels are reported. A negative change indicated a decrease in immunoglobulin levels. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
Time frame: Baseline, up to 24 weeks
Population Pharmacokinetics (PK)
Population estimate of constant clearance as determined by population pharmacokinetics (PK) analysis. A 2-compartment model was used in PK modeling.
Time frame: Baseline through 24 weeks
Percentage of Participants Developing Anti-LY2127399 Antibodies
LY2127399 anti-drug antibodies (ADA) were assessed at baseline, 1, 4, 16, and 24 weeks. Percentage of participants (Pts) with ADA=(number of Pts with treatment-emergent ADA/number of Pts assessed)\*100. Pts with treatment-emergent ADA were Pts who had any sample from baseline up to and through Week 24 that was a 4-fold increase (2-dilution increase) in immunogenicity titer over baseline titer, or Pts who tested negative at baseline and positive post-baseline (at titer of ≥1:20).
Time frame: Baseline through 24 weeks
| Milestone | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Started | 379 | 374 | 251 |
| Received at least one dose of study drug | 379 | 371 | 250 |
| Completed | 332 | 322 | 216 |
| Not completed | 47 | 52 | 35 |
| Withdrew: Entry criteria not met | 0 | 3 | 1 |
| Withdrew: Adverse event | 11 | 9 | 10 |
| Withdrew: Death | 2 | 1 | 0 |
| Withdrew: Lack of efficacy | 6 | 8 | 7 |
| Withdrew: Lost to follow-up | 0 | 2 | 1 |
| Withdrew: Parent / caregiver decision | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 17 | 18 | 14 |
| Withdrew: Physician decision | 0 | 1 | 0 |
| Withdrew: Protocol violation | 7 | 5 | 2 |
| Withdrew: Sponsor decision | 4 | 4 | 0 |
ACR20 Responder Index: Composite of clinical, laboratory, and functional measures of rheumatoid arthritis. ACR20 Responder: had \>=20% improvement from baseline in both 68 tender and 66 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), joint pain, and C-reactive protein (CRP). Percentage of participants achieving ACR20 response=(number of ACR20 responders/number of participants treated)\*100. All non-responders at Week 16 as well as all participants who discontinued study treatment at any time, for any reason, were defined as non-responders starting at that timepoint and going forward, including Week 24 endpoint.
| percentage of participants | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Percentage of Participants With American College of Rheumatology 20% (ACR20) Response | 34.4 | 33.5 | 31.5 |
ACR Responder Index: Composite of clinical, laboratory, and functional measures of rheumatoid arthritis. ACR50 Responder: had \>=50% improvement from baseline in both 68 tender joint (TJ) and 66 swollen joint (SJ) counts and \>=50% improvement in at least 3/5 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. Percentage of Pt achieving ACR50 response=(number (No) of ACR50 responders/No of Pts treated)\*100. ACR70 Responder: had \>=70% improvement from baseline in both TJ and SJ counts and \>=70% improvement in at least 3 of same 5 criteria for ACR50. Percentage of Pts achieving ACR70 response=(No of ACR70 responders/No of Pts treated)\*100. All non-responders at Week 16 as well as all Pts who discontinued study treatment at any time, for any reason, were defined as non-responders starting at that timepoint and going forward, including Week 24 endpoint.
| percentage of participants | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| ACR50 | 11.6 | 11.7 | 12.7 |
| ACR70 | 4.7 | 6.3 | 4.7 |
ACR-N is a continuous measure of clinical, laboratory, and functional outcomes in rheumatoid arthritis that characterizes percentage of improvement in disease activity from baseline based on ACR core set. Percentage of improvement was truncated to range of -100 to 100 to minimize impact of outliers (greater values indicate greater percent improvement). This index was calculated as minimum of a) percentage of improvement in TJ count, b) percentage of improvement in SJ count, or c) third highest percentage of improvement of remaining 5 ACR core criteria: If \>=3 components of the 5 ACR core criteria were missing, then c) was set to missing; if any of 3 components a), b), or c) were missing, then ACR-N was set to missing. Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with treatment, region, tumor necrosis factor-inadequate responder treatment history, and disease-modifying anti-rheumatic drug (DMARD) background as fixed factors and baseline as a covariate.
| units on a scale | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Mean Percent Improvement in American College of Rheumatology Percent Improvement (ACR-N) | -11.5 ± 4.6 | -9.5 ± 4.6 | -11.5 ± 5.0 |
Tender joint count is the number of tender and painful joints determined for each participant by examination of 68 joints. Joints were assessed by pressure and joint manipulation on physical examination. Participants were 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. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| joint count | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline to 24 Weeks in Tender Joint Count (68 Joint Count) | -1.61 ± 1.30 | -1.63 ± 1.31 | -2.11 ± 1.40 |
Swollen joint count is the number of swollen joints determined for each participant by examination of 66 joints. Joints were classified as either swollen or not swollen. Swelling was defined as palpable fluctuating synovitis of the joint. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| joint count | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline to 24 Weeks in Swollen Joint Count (66 Joint Count) | -2.59 ± 0.97 | -3.18 ± 0.99 | -3.59 ± 1.05 |
Participant's assessment of their current arthritis pain using a visual analog scale (VAS) ranged from 0 millimeters (mm) (no pain) to 100 mm (worst possible pain). A decrease in pain score indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| millimeters | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline to 24 Weeks in Participant's Assessment of Pain (Visual Analog Scale) | -9.0 ± 2.3 | -9.6 ± 2.4 | -6.9 ± 2.5 |
Participant's assessment of their current arthritis disease activity using a visual analog scale (VAS) ranged from 0 millimeters (mm) (no arthritis activity) to 100 mm (extremely active arthritis). A decrease in disease activity score indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| millimeters | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline to 24 Weeks in Participant's Global Assessment of Disease Activity (Visual Analog Scale) | -10.2 ± 2.3 | -10.2 ± 2.4 | -6.9 ± 2.5 |
Physician's assessment of the participant's current arthritis disease activity using a visual analog scale (VAS) ranged from 0 millimeters (mm) (no arthritis activity) to 100 mm (extremely active arthritis). A decrease in disease activity score indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| millimeters | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline to 24 Weeks in Physician's Global Assessment of Disease Activity (Visual Analog Scale) | -10.0 ± 2.3 | -12.4 ± 2.4 | -9.7 ± 2.5 |
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), C-reactive protein (CRP) (milligrams per liter), and participant global assessment of disease activity using visual analog scale (VAS) (participant global VAS). DAS28-CRP was calculated using following formula: 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 1.0-9.4, where lower scores indicated less disease activity and remission is DAS28-CRP \<2.6. A decrease in DAS28-CRP indicated an improvement in participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| units on a scale | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline to 24 Weeks in Disease Activity Score (Based on 28 Joint Count)-C-Reactive Protein (DAS28-CRP) | -0.42 ± 0.12 | -0.49 ± 0.12 | -0.41 ± 0.13 |
The HAQ-DI questionnaire assesses the participant's self-perception on the 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, reaching, gripping, and performing other daily activities. Scores for each functional area, which ranged from 0 (no disability) to 3 (severe disability), were averaged to calculate HAQ-DI. A decrease in HAQ-DI score indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| units on a scale | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline to 24 Weeks in Health Assessment Questionnaire-Disability Index (HAQ-DI) | -0.21 ± 0.05 | -0.18 ± 0.05 | -0.15 ± 0.05 |
ACR20 Responder Index: Composite of clinical, laboratory, and functional measures of rheumatoid arthritis. ACR20 Responder: had \>= 20% improvement from baseline in both 68 tender and 66 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), joint pain, and C-reactive protein (CRP). The Kaplan-Meier estimator was used to summarize time to ACR20 response over the Treatment Period (24 weeks). The time to American College of Rheumatology 20% (ACR20) response (in weeks) is calculated as: (Date of the first postbaseline visit during the Treatment Period meeting ACR20 response criteria - Date of first injection of study treatment + 1) / 7.
| weeks | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Time to American College of Rheumatology 20% (ACR20) Response | 16.7 (16.1 to 20.1) | 16.1 (12.1 to 20.1) | 16.4 (15.9 to 23.6) |
ACR20 Responder Index: Composite of clinical, laboratory, and functional measures of rheumatoid arthritis. ACR20 Responder: had \>= 20% improvement from baseline in both 68 tender and 66 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), joint pain, and C-reactive protein (CRP). The Kaplan-Meier estimator was used to summarize time to ACR20 response over the Treatment Period (24 weeks). The time to American College of Rheumatology 20% (ACR20) response (in weeks) is calculated as: (Date of the first postbaseline visit during the Treatment Period meeting ACR20 response criteria - Date of first injection of study treatment + 1) / 7.
| probability of response | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Probability of an ACR20 Response by 24 Weeks | 0.612 | 0.611 | 0.608 |
EULAR Responder index based on 28 joint count categorizes clinical response based on improvement since baseline in DAS28-CRP. Participants are categorized as EULAR responders or non-responders based on improvement of DAS28-CRP scores from baseline. EULAR28 responder is defined as either DAS28-CRP \<=5.1 and DAS28-CRP change \<-0.6; or DAS28-CRP \>5.1 and DAS28-CRP change \<-1.2. EULAR28 responder index is defined as good response: DAS28-CRP \<=3.2 and DAS28-CRP change \<-1.2; moderate response: DAS28-CRP change \<-1.2 except cases defined in good response; or DAS28-CRP \<=5.1 and DAS28-CRP change \<-0.6 and \>-1.2. EULAR Remission is defined as a DAS28-CRP score of \<2.6.
| percentage of participants | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Percentage of Participants With DAS28-Based European League Against Rheumatism (EULAR) Response | 50.3 | 49.7 | 46.4 |
The SF-36 is a health-related survey that assesses participant's quality of life and consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems and emotional problems, general health, mental health, social functioning, vitality, and 2 component scores (mental \[MCS\] and physical health \[PCS\]). Domain scores calculated by summing each item for each domain and transforming scores into 0-100 scale; higher scores indicated better health status. MCS score consisted of social functioning, vitality, mental health, and role-emotional scales. PCS score consisted of physical functioning, bodily pain, role-physical, and general health scales. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| units on a scale | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Physical functioning domain | 2.07 ± 0.84 | 3.14 ± 0.85 | 1.48 ± 0.91 |
| Bodily pain domain | 1.62 ± 0.82 | 2.08 ± 0.83 | 1.34 ± 0.89 |
| Role limitations due to physical problems domain | 1.60 ± 0.83 | 2.40 ± 0.84 | 1.65 ± 0.91 |
| Role limitations due to emotional problems domain | 3.30 ± 1.01 | 3.23 ± 1.02 | 3.11 ± 1.09 |
| General health perception domain | 1.93 ± 0.76 | 1.99 ± 0.77 | 1.81 ± 0.82 |
| Mental health domain | 3.09 ± 0.89 | 3.00 ± 0.90 | 2.31 ± 0.97 |
| Social function domain | 1.17 ± 1.00 | 1.24 ± 1.01 | 0.33 ± 1.08 |
| Vitality domain | 2.85 ± 0.87 | 2.58 ± 0.88 | 2.22 ± 0.94 |
| Physical component summary score | 1.19 ± 0.79 | 2.10 ± 0.79 | 1.14 ± 0.85 |
| Mental component summary score | 3.18 ± 0.95 | 2.68 ± 0.96 | 2.54 ± 1.03 |
CRP is an indicator of inflammation. A negative change indicated an improvement in the participant's condition. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| milligrams per liter (mg/L) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline in C-reactive Protein (CRP) up to Week 24 Endpoint | 2.69 ± 1.42 | 1.92 ± 1.44 | 1.76 ± 1.54 |
Cell-surface marker cluster designation (CD) 3 negative, CD20 positive (CD3-CD20+) defines total mature B cells. B-lymphocyte antigen CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all mature B cells. Baseline B-cell count is determined by calculating the average of the 2 pretreatment B-cell counts obtained once during Days -28 through -7 and on Day 0. A positive or negative change indicated an increase or decrease, respectively in B-cell count. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| cells per microliter | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Change From Baseline to 24 Weeks in Absolute CD3-CD20+ B-cell Counts | -50.5 ± 19.4 | -74.4 ± 19.3 | -0.7 ± 20.9 |
Immunoglobulins, 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. Change from baseline serum immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) levels are reported. A negative change indicated a decrease in immunoglobulin levels. LS means were calculated using ANCOVA with treatment, region, tumor necrosis factor-inadequate responder treatment history, and DMARD background as fixed factors and baseline as a covariate.
| grams per liter (g/L) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Immunoglobulin G | -0.813 ± 0.165 | -0.758 ± 0.165 | 0.117 ± 0.178 |
| Immunoglobulin A | -0.209 ± 0.044 | -0.224 ± 0.044 | 0.139 ± 0.047 |
| Immunoglobulin M | -0.267 ± 0.026 | -0.275 ± 0.025 | -0.049 ± 0.028 |
Population estimate of constant clearance as determined by population pharmacokinetics (PK) analysis. A 2-compartment model was used in PK modeling.
| milliliter per hour (mL/h) | LY2127399 |
|---|---|
| Population Pharmacokinetics (PK) | 3.60 ± 2.54 |
LY2127399 anti-drug antibodies (ADA) were assessed at baseline, 1, 4, 16, and 24 weeks. Percentage of participants (Pts) with ADA=(number of Pts with treatment-emergent ADA/number of Pts assessed)\*100. Pts with treatment-emergent ADA were Pts who had any sample from baseline up to and through Week 24 that was a 4-fold increase (2-dilution increase) in immunogenicity titer over baseline titer, or Pts who tested negative at baseline and positive post-baseline (at titer of ≥1:20).
| percentage of participants | 120 mg LY2127399 | 90 mg LY2127399 | Placebo |
|---|---|---|---|
| Percentage of Participants Developing Anti-LY2127399 Antibodies | 2.4 | 1.9 | 2.8 |
Non-serious events are listed at a 2% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 120 mg LY2127399, Randomized Treatment Period | — | 14/379 (3.7%) | 174/379 (45.9%) |
| 90 mg LY2127399, Randomized Treatment Period | — | 8/371 (2.2%) | 154/371 (41.5%) |
| Placebo, Randomized Treatment Period | — | 7/250 (2.8%) | 98/250 (39.2%) |
| 120 mg LY2127399, Rescue Period | — | 5/81 (6.2%) | 23/81 (28.4%) |
| 90 mg LY2127399, Rescue Period | — | 0/72 (0%) | 16/72 (22.2%) |
| Placebo, Rescue Period | — | 0/56 (0%) | 9/56 (16.1%) |
| 120 mg LY2127399, Follow-up Period | — | 0/40 (0%) | 12/40 (30%) |
| 90 mg LY2127399, Follow-up Period | — | 4/45 (8.9%) | 17/45 (37.8%) |
| Placebo, Follow-up Period | — | 3/37 (8.1%) | 13/37 (35.1%) |
| 120 mg LY2127399 to 90 mg LY212739 (Week 16), Follow-up Period | — | 1/7 (14.3%) | 5/7 (71.4%) |
| Placebo to 90 mg LY2127399 (Week 16), Follow-up Period | — | 2/12 (16.7%) | 2/12 (16.7%) |
| Event | 120 mg LY2127399, Randomized Treatment Period | 90 mg LY2127399, Randomized Treatment Period | Placebo, Randomized Treatment Period | 120 mg LY2127399, Rescue Period | 90 mg LY2127399, Rescue Period | Placebo, Rescue Period | 120 mg LY2127399, Follow-up Period | 90 mg LY2127399, Follow-up Period | Placebo, Follow-up Period | 120 mg LY2127399 to 90 mg LY212739 (Week 16), Follow-up Period | Placebo to 90 mg LY2127399 (Week 16), Follow-up Period |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Gastric ulcer haemorrhageGastrointestinal disorders | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 1/7 | 0/12 |
| Joint dislocation postoperativeInjury, poisoning and procedural complications | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 0/7 | 1/12 |
| Juvenile arthritisMusculoskeletal and connective tissue disorders | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 0/7 | 1/12 |
| Spinal osteoarthritisMusculoskeletal and connective tissue disorders | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 0/7 | 1/12 |
| Spindle cell sarcomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 0/7 | 1/12 |
| Uterine cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/293 | 0/292 | 0/208 | 0/61 | 0/60 | 0/42 | 0/31 | 0/35 | 1/27 | 0/7 | 0/12 |
| Anaphylactic reactionImmune system disorders | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 1/37 | 0/7 | 0/12 |
| Rheumatoid arthritisMusculoskeletal and connective tissue disorders | 2/379 | 0/371 | 3/250 | 1/81 | 0/72 | 0/56 | 0/40 | 0/45 | 1/37 | 0/7 | 0/12 |
| Gastrooesophageal reflux diseaseGastrointestinal disorders | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 1/45 | 0/37 | 0/7 | 0/12 |
| Upper gastrointestinal haemorrhageGastrointestinal disorders | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 1/45 | 0/37 | 0/7 | 0/12 |
| Event | 120 mg LY2127399, Randomized Treatment Period | 90 mg LY2127399, Randomized Treatment Period | Placebo, Randomized Treatment Period | 120 mg LY2127399, Rescue Period | 90 mg LY2127399, Rescue Period | Placebo, Rescue Period | 120 mg LY2127399, Follow-up Period | 90 mg LY2127399, Follow-up Period | Placebo, Follow-up Period | 120 mg LY2127399 to 90 mg LY212739 (Week 16), Follow-up Period | Placebo to 90 mg LY2127399 (Week 16), Follow-up Period |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Herpes zosterInfections and infestations | 1/379 | 2/371 | 2/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 1/7 | 0/12 |
| SinusitisInfections and infestations | 6/379 | 11/371 | 6/250 | 2/81 | 1/72 | 1/56 | 0/40 | 0/45 | 0/37 | 1/7 | 0/12 |
| Urinary tract infectionInfections and infestations | 7/379 | 4/371 | 6/250 | 2/81 | 2/72 | 2/56 | 0/40 | 1/45 | 1/37 | 1/7 | 0/12 |
| Muscle spasmsMusculoskeletal and connective tissue disorders | 4/379 | 1/371 | 6/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 1/7 | 0/12 |
| Rheumatoid arthritisMusculoskeletal and connective tissue disorders | 17/379 | 10/371 | 13/250 | 1/81 | 0/72 | 0/56 | 0/40 | 0/45 | 2/37 | 1/7 | 1/12 |
| RashSkin and subcutaneous tissue disorders | 2/379 | 4/371 | 6/250 | 2/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 1/7 | 0/12 |
| BalanitisReproductive system and breast disorders | 0/86 | 0/79 | 0/42 | 0/20 | 0/12 | 0/14 | 0/9 | 0/10 | 1/10 | — | — |
| ConjunctivitisEye disorders | 2/379 | 0/371 | 1/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 0/7 | 1/12 |
| CholecystitisHepatobiliary disorders | 0/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 0/7 | 1/12 |
| Procedural painInjury, poisoning and procedural complications | 2/379 | 0/371 | 0/250 | 0/81 | 0/72 | 0/56 | 0/40 | 0/45 | 0/37 | 0/7 | 1/12 |
All randomized participants, including participants who did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol.
| Age, Continuous(years) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo | Total |
|---|---|---|---|---|
| Mean | 52.4 ± 11.2 | 50.6 ± 12.2 | 51.0 ± 12.0 | 51.4 ± 11.8 |
| Sex: Female, Male(Participants) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo | Total |
|---|---|---|---|---|
| Female | 293 | 295 | 209 | 797 |
| Male | 86 | 79 | 42 | 207 |
| Ethnicity (NIH/OMB)(Participants) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo | Total |
|---|---|---|---|---|
| Hispanic or Latino | 38 | 47 | 24 | 109 |
| Not Hispanic or Latino | 193 | 185 | 133 | 511 |
| Unknown or Not Reported | 148 | 142 | 94 | 384 |
| Race (NIH/OMB)(Participants) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 13 | 21 | 9 | 43 |
| Asian | 96 | 93 | 59 | 248 |
| Native Hawaiian or Other Pacific Islander | 1 | 1 | 0 | 2 |
| Black or African American | 12 | 13 | 14 | 39 |
| White | 254 | 235 | 162 | 651 |
| More than one race | 2 | 9 | 6 | 17 |
| Unknown or Not Reported | 1 | 2 | 1 | 4 |
| Region of Enrollment(Participants) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo | Total |
|---|---|---|---|---|
| United States | 126 | 125 | 83 | 334 |
| Argentina | 7 | 6 | 5 | 18 |
| Colombia | 9 | 9 | 5 | 23 |
| Mexico | 20 | 25 | 15 | 60 |
| Bulgaria | 13 | 13 | 12 | 38 |
| Croatia | 2 | 1 | 3 | 6 |
| Hungary | 3 | 12 | 6 | 21 |
| Lithuania | 14 | 10 | 11 | 35 |
| Poland | 27 | 22 | 12 | 61 |
| Romania | 0 | 1 | 3 | 4 |
| Russia | 14 | 13 | 8 | 35 |
| Slovakia | 8 | 3 | 2 | 13 |
| Ukraine | 16 | 15 | 6 | 37 |
| Australia | 2 | 3 | 2 | 7 |
| India | 14 | 9 | 9 | 32 |
| Japan | 44 | 42 | 28 | 114 |
| South Korea | 7 | 6 | 5 | 18 |
| Malaysia | 2 | 4 | 1 | 7 |
| New Zealand | 6 | 2 | 6 | 14 |
| Sri Lanka | 4 | 4 | 2 | 10 |
| South Africa | 32 | 38 | 24 | 94 |
| Taiwan | 9 | 11 | 3 | 23 |
| Tender Joint Count (68 Count)(joint count) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo | Total |
|---|---|---|---|---|
| Mean | 22.8 ± 15.5 | 23.7 ± 17.1 | 22.8 ± 15.2 | 23.2 ± 16.0 |
| Swollen Joint Count (66 Count)(joint count) | 120 mg LY2127399 | 90 mg LY2127399 | Placebo | Total |
|---|---|---|---|---|
| Mean | 14.8 ± 11.6 | 15.3 ± 11.6 | 14.3 ± 10.6 | 14.8 ± 11.4 |
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