Active Rheumatoid Arthritis, Arthritis, Rheumatoid, Rheumatoid Arthritis
Conditions
Brief summary
Study to evaluate whether there is sustained remission and productivity in subjects with early rheumatoid arthritis started on etanercept plus methotrexate treatment.
Interventions
DRUGetanercept
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of early rheumatoid arthritis. * Methotrexate (MTX) naive. * Active early rheumatoid arthritis at the time of enrollment.
Exclusion criteria
* Previous or current treatment with etanercept, other tumor necrosis factor-alpha (TNF) inhibitors, or other biologic agents. * Concurrent treatment with any disease-modifying anti-rheumatoid drugs (DMARD), within 4 weeks before baseline. * Concurrent treatment with more than 1 non-steroidal anti-inflammatory drug (NSAID) at baseline.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Met Sustained Remission at Week 76 and Week 91 Based on DAS28 Score | 76 and 91 weeks | Sustained remission was defined as a DAS28 \<2.6 at the Week 76 and Week 91 visits without requiring a corticosteroid boost between the Week 52 and Week 64 visits, where the requirement for a corticosteroid boost was defined as a value of DAS28 \>3.2 at either the Week 56 or Week 64 visit. DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity. The participants who met sustained remission in both Week 76 and 91 are presented here. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 and Final on Therapy | 52 week and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. |
| Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem | 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem | 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem | 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem | 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. |
| Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | ACR50 response: greater than or equal to (≥) 50 percent (%) improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. |
| Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | ACR70 response: greater than or equal to (≥) 70 percent (%) improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. |
| Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | ACR90 response: greater than or equal to (≥) 90 percent (%) improvement in tender or swollen joint counts and 90% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. |
| Change From Baseline in Physician's Global Assessment of Disease Activity | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | Physician Global Assessment of Disease Activity was measured on a 0 to 100 Visual Analog Scale (VAS), with 0 = no disease activity and 100 = extreme disease activity. |
| Change From Baseline in Participant's Global Assessment of Disease Activity | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm Visual Analog Scale (VAS), with 0 mm = no disease activity and 100 = extreme disease activity |
| Change From Baseline in DAS44 Score at All Visits | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity. |
| Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity. |
| Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity. |
| Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at) | The PASS is defined as a symptom state that the participants consider acceptable. |
| Number of Participants With an American College of Rheumatology 20% (ACR20) Response | 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and C-Reactive Protein (CRP). |
| Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | ACR50 response: greater than or equal to (≥) 50 percent (%) improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. |
| Number of Participants Achieving Complete Response (Using Disease Activity Score Based on 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire) | End of Phase 1 | The composite measure of complete response over the last 3 months of Phase 1 was defined as: 1. DAS28 \<2.6 at the week 39 and 52 visits and, 2. No radiographic progression during Phase 1, defined as mean change in modified total Sharp score (mTSS) ≤0.5 and, 3. Health Assessment Questionnaire (HAQ) ≤ 0.5 at the week 39 and week 52 visits |
| Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | 52, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | ACR90 response: greater than or equal to (≥) 90 percent (%) improvement in tender or swollen joint counts and 90% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. |
| Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity. |
| Number of Participants Achieving Complete Response (Using Disease Activity Score Based on a 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire) | 52 and 91 weeks | The composite measure of complete response over the last 3 months of Phase 2 was defined as: 1. DAS28 \<2.6 at the Week 76 and Week 91 visits and 2. No radiographic progression during Phase 2, defined as mean change from Week 52 in mTSS of ≤0.5. 3. Participant must achieve HAQ score ≤0.5 at Week 76 and 91 visits. HAQ is self-reported, valid assessment of functional disability in rheumatoid arthritis. Assessed based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. HAQ score range: 0-3: without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. HAQ total scores expressed as overall mean score with range 0-3: 0-0.25=normal functioning; 0.25-0.5=mild functional limitation; 0.5-1=moderate functional limitation; more than 1=significant functional limitation.A subject had to satisfy all 3 criteria at thevisits to be defined as a responder |
| Physician's Global Assessment of Disease Activity | 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | Physician Global Assessment of Disease Activity was measured on a 0 to 100 Visual Analog Scale (VAS), with 0 = no disease activity and 100 = extreme disease activity. |
| Participant's Global Assessment of Disease Activity | 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm Visual Analog Scale (VAS), with 0 mm = no disease activity and 100 = extreme disease activity |
| Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | 100-mm line (Visual Analog Scale) marked by the participant to measure their degree of pain over past 2-3 weeks. Range: 0 = no pain to 100 = pain as bad as it could be. |
| Number of Participants Achieving Patient Acceptable Symptom State (PASS) | 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | The PASS is defined as a symptom state that the subjects consider acceptable. |
| Modified Total Sharp Score (mTSS) at Week 52 | 52 weeks | mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. |
| Change From Baseline mTSS at Week 91 and Final on Therapy | 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. |
| Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | 52 weeks | WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at) | WPAI is a 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | 52 Weeks | WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at) | WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | 52 weeks | WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at) | WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | 52 weeks | WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at) | WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named Percent impairment While Working) and as such range from 0 to 100. |
| Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at) | ACR70 response: greater than or equal to (≥) 70 percent (%) improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. |
Countries
France, Germany, Ireland, Italy, Monaco, Netherlands, Poland, Qatar, Romania, Russia, Spain, Switzerland, United Kingdom
Participant flow
Recruitment details
This report presents the results of open-label 52-week treatment period (Phase 1), 39 week, double blind randomized (Phase 2) and 26 week observational period (Phase 3) part of a 121 week Phase 4 study program. Responders in Phase 1 were randomized to 3 arms (1:1:1 ratio) in Phase 2. Responders in Phase 2, continued to Phase 3 observational period
Pre-assignment details
Phase 1 responders, defined as subjects with Disease Activity Score based on 28-joints count (DAS28) ≤ 3.2 at Week 39 and DAS28 \<2.6 at Week 52, were randomized to Phase 2. The responders of Phase 2 were observed for 26-weeks in Phase 3 study that include 2 to 4 week period of double blind treatment taper of MTX followed by observational period
Participants by arm
| Arm | Count |
|---|---|
| ETN 50 QW + MTX (Phase 1) Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count \[DAS28\] ≤3.2 at Week 39 and DAS28 \<2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study. | 306 |
| Total | 306 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Phase 1 | Adverse Event | 20 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 | Lost to Follow-up | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 | Non-Responder | 54 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 | Protocol Violation | 10 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 | Sponsor | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 | Subject Request | 17 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 | Unsatisfactory Response per Investigator | 7 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 2 | Adverse Event | 0 | 3 | 0 | 1 | 0 | 0 | 0 |
| Phase 2 | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Phase 2 | Non-Responder | 0 | 5 | 7 | 12 | 0 | 0 | 0 |
| Phase 2 | Protocol Violation | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Phase 2 | Subject Request | 0 | 0 | 1 | 2 | 0 | 0 | 0 |
| Phase 2 | Unsatisfactory Response per Investigator | 0 | 0 | 11 | 17 | 0 | 0 | 0 |
| Phase 3 | Adverse Event | 0 | 0 | 0 | 0 | 5 | 4 | 1 |
| Phase 3 | Lost to Follow-up | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
| Phase 3 | Non-Responder | 0 | 0 | 0 | 0 | 0 | 1 | 3 |
| Phase 3 | Unsatisfactory Response per Investigator | 0 | 0 | 0 | 0 | 14 | 11 | 4 |
| Phase 3 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | ETN 50 QW + MTX (Phase 1) |
|---|---|
| Age, Continuous | 49.94 Years STANDARD_DEVIATION 13.7 |
| Sex: Female, Male Female | 213 Participants |
| Sex: Female, Male Male | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 130 / 306 | 10 / 63 | 8 / 65 | 11 / 65 | 13 / 53 | 8 / 46 | 4 / 32 |
| serious Total, serious adverse events | 28 / 306 | 3 / 63 | 2 / 65 | 2 / 65 | 0 / 53 | 0 / 46 | 2 / 32 |
Outcome results
Primary
Number of Participants That Met Sustained Remission at Week 76 and Week 91 Based on DAS28 Score
Sustained remission was defined as a DAS28 \<2.6 at the Week 76 and Week 91 visits without requiring a corticosteroid boost between the Week 52 and Week 64 visits, where the requirement for a corticosteroid boost was defined as a value of DAS28 \>3.2 at either the Week 56 or Week 64 visit. DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity. The participants who met sustained remission in both Week 76 and 91 are presented here.
Time frame: 76 and 91 weeks
Population: Modified intent-to-treat (mITT) population, which included all participants who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants That Met Sustained Remission at Week 76 and Week 91 Based on DAS28 Score | 40 Participants |
| MTX + PBO (Phase 2) | Number of Participants That Met Sustained Remission at Week 76 and Week 91 Based on DAS28 Score | 26 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants That Met Sustained Remission at Week 76 and Week 91 Based on DAS28 Score | 15 Participants |
Comparison: The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: <0.000195% CI: [2.7, 12.5]Regression, Logistic
Comparison: The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.008595% CI: [1.3, 5.3]Regression, Logistic
Comparison: The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.039795% CI: [1, 4.8]Regression, Linear
Secondary
Change From Baseline in DAS44 Score at All Visits
DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in DAS44 Score at All Visits | Week 26 (N = 276) | -2.9 units on a scale | Standard Deviation 1.2 |
| E25 + MTX (Phase 2) | Change From Baseline in DAS44 Score at All Visits | Week 2 (N = 297) | -1.3 units on a scale | Standard Deviation 0.9 |
| E25 + MTX (Phase 2) | Change From Baseline in DAS44 Score at All Visits | Week 4 (N = 293) | -1.9 units on a scale | Standard Deviation 1.1 |
| E25 + MTX (Phase 2) | Change From Baseline in DAS44 Score at All Visits | Week 8 (N = 293) | -2.3 units on a scale | Standard Deviation 1.1 |
| E25 + MTX (Phase 2) | Change From Baseline in DAS44 Score at All Visits | Week 13 (N = 282) | -2.5 units on a scale | Standard Deviation 1.2 |
| E25 + MTX (Phase 2) | Change From Baseline in DAS44 Score at All Visits | Week 39 (N = 259) | -3.2 units on a scale | Standard Deviation 1.2 |
| E25 + MTX (Phase 2) | Change From Baseline in DAS44 Score at All Visits | Week 52 (N = 221) | -3.4 units on a scale | Standard Deviation 1.2 |
| E25 + MTX (Phase 2) | Change From Baseline in DAS44 Score at All Visits | Final on Therapy (N = 305) | -3.0 units on a scale | Standard Deviation 1.3 |
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 2, 4, 8, 13, 26, 39, 52 and final on therapyp-value: <0.0001Paired t-test
Secondary
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 and Final on Therapy
mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.
Time frame: 52 week and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 and Final on Therapy | Week 52 (N = 200) | 0.3 Units on a scale | Standard Deviation 3 |
| E25 + MTX (Phase 2) | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 and Final on Therapy | Final on Therapy (N = 269) | 0.4 Units on a scale | Standard Deviation 2.8 |
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 52p-value: 0.1183Paired t-test
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Final on therapyp-value: 0.0286Paired t-test
Secondary
Change From Baseline in Participant's Global Assessment of Disease Activity
Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm Visual Analog Scale (VAS), with 0 mm = no disease activity and 100 = extreme disease activity
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in Participant's Global Assessment of Disease Activity | Week 2 (N = 301) | -23.4 units on a scale | Standard Deviation 24.4 |
| E25 + MTX (Phase 2) | Change From Baseline in Participant's Global Assessment of Disease Activity | Week 4 (N = 299) | -27.4 units on a scale | Standard Deviation 26.2 |
| E25 + MTX (Phase 2) | Change From Baseline in Participant's Global Assessment of Disease Activity | Week 8 (N = 294) | -31.8 units on a scale | Standard Deviation 26 |
| E25 + MTX (Phase 2) | Change From Baseline in Participant's Global Assessment of Disease Activity | Week 13 (N = 285) | -34.6 units on a scale | Standard Deviation 26.8 |
| E25 + MTX (Phase 2) | Change From Baseline in Participant's Global Assessment of Disease Activity | Week 26 (N = 277) | -40.1 units on a scale | Standard Deviation 28.1 |
| E25 + MTX (Phase 2) | Change From Baseline in Participant's Global Assessment of Disease Activity | Week 39 (N = 260) | -44.8 units on a scale | Standard Deviation 26.6 |
| E25 + MTX (Phase 2) | Change From Baseline in Participant's Global Assessment of Disease Activity | Week 52 (N = 233) | -48.6 units on a scale | Standard Deviation 26.2 |
| E25 + MTX (Phase 2) | Change From Baseline in Participant's Global Assessment of Disease Activity | Final on Therapy (N = 305) | -42.8 units on a scale | Standard Deviation 28.4 |
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 2, 4, 8, 13, 26, 39, 52 and final on therapyp-value: <0.0001Paired t-test
Secondary
Change From Baseline in Physician's Global Assessment of Disease Activity
Physician Global Assessment of Disease Activity was measured on a 0 to 100 Visual Analog Scale (VAS), with 0 = no disease activity and 100 = extreme disease activity.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in Physician's Global Assessment of Disease Activity | Week 2 (N = 300) | -21.1 Units on a scale | Standard Deviation 18.2 |
| E25 + MTX (Phase 2) | Change From Baseline in Physician's Global Assessment of Disease Activity | Week 4 (N = 299) | -29.9 Units on a scale | Standard Deviation 19.7 |
| E25 + MTX (Phase 2) | Change From Baseline in Physician's Global Assessment of Disease Activity | Week 8 (N = 294) | -34.8 Units on a scale | Standard Deviation 19.9 |
| E25 + MTX (Phase 2) | Change From Baseline in Physician's Global Assessment of Disease Activity | Week 13 (N = 284) | -38.7 Units on a scale | Standard Deviation 20 |
| E25 + MTX (Phase 2) | Change From Baseline in Physician's Global Assessment of Disease Activity | Week 26 (N = 277) | -42.4 Units on a scale | Standard Deviation 18.9 |
| E25 + MTX (Phase 2) | Change From Baseline in Physician's Global Assessment of Disease Activity | Week 39 (N = 260) | -46.5 Units on a scale | Standard Deviation 18.5 |
| E25 + MTX (Phase 2) | Change From Baseline in Physician's Global Assessment of Disease Activity | Week 52 (N = 223) | -49.2 Units on a scale | Standard Deviation 17.2 |
| E25 + MTX (Phase 2) | Change From Baseline in Physician's Global Assessment of Disease Activity | Final on Therapy (N = 305) | -45.0 Units on a scale | Standard Deviation 19.8 |
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 2, 4, 8, 13, 26, 39, 52 week and final on therapyp-value: <0.0001Paired t-test
Secondary
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem
WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem | Week 13 (N = 244) | -30.3 units on a scale | Standard Deviation 26 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem | Week 26 (N = 241) | -34.7 units on a scale | Standard Deviation 27.5 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem | Week 39 (N = 224) | -39.9 units on a scale | Standard Deviation 27 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem | Week 52 (N = 194) | -41.3 units on a scale | Standard Deviation 28.6 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem | Final on Therapy (N = 270) | -36.4 units on a scale | Standard Deviation 29.4 |
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 13, 26, 39, 52 and final on therapyp-value: <0.0001Paired t-test
Secondary
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem
WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem | Final on Therapy (N = 169) | -33.7 units on a scale | Standard Deviation 30.3 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem | Week 13 (N = 140) | -27.1 units on a scale | Standard Deviation 27.8 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem | Week 26 (N = 138) | -31.5 units on a scale | Standard Deviation 28 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem | Week 39 (N = 129) | -35.3 units on a scale | Standard Deviation 27.3 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem | Week 52 (N = 116) | -36.6 units on a scale | Standard Deviation 31.5 |
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 13, 26, 39, 52 and final on therapyp-value: <0.0001Paired t-test
Secondary
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem
WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem | Week 39 (N = 97) | -35.9 units on a scale | Standard Deviation 27 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem | Week 13 (N = 100) | -27.6 units on a scale | Standard Deviation 27.4 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem | Week 26 (N = 94) | -32.2 units on a scale | Standard Deviation 28 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem | Week 52 (N = 81) | -37.3 units on a scale | Standard Deviation 30.7 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem | Final on Therapy (N = 124) | -35.5 units on a scale | Standard Deviation 31.3 |
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 13, 26, 39, 52 and final on therapyp-value: <0.0001Paired t-test
Secondary
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem
WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem | Week 13 (N = 116) | -8.9 units on a scale | Standard Deviation 34.5 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem | Week 26 (N = 110) | -8.8 units on a scale | Standard Deviation 32.5 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem | Week 39 (N = 110) | -9.0 units on a scale | Standard Deviation 30.7 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem | Week 52 (N = 93) | -12.9 units on a scale | Standard Deviation 32.4 |
| E25 + MTX (Phase 2) | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem | Final on Therapy (N = 138) | -10.7 units on a scale | Standard Deviation 35.3 |
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 13p-value: 0.0063Paired t-test
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 26p-value: 0.0053Paired t-test
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 39p-value: 0.0027Paired t-test
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Week 52p-value: 0.0002Paired t-test
Comparison: Significance tests were based on paired t-tests using a 2-sided α=0.05.~Final on therapyp-value: 0.0005Paired t-test
Secondary
Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem
WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 64 (N = 56, 60, 57) | -0.5 Units on a scale | Standard Error 3.21 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 76 (N = 57, 55, 41) | 2.9 Units on a scale | Standard Error 2.94 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 91 (N = 53, 49, 37) | -1.8 Units on a scale | Standard Error 2.83 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Final on Therapy (N = 60, 64, 64) | -0.9 Units on a scale | Standard Error 3.24 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Final on Therapy (N = 60, 64, 64) | 12.2 Units on a scale | Standard Error 3.13 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 64 (N = 56, 60, 57) | 9.9 Units on a scale | Standard Error 3.1 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 91 (N = 53, 49, 37) | 7.3 Units on a scale | Standard Error 2.87 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 76 (N = 57, 55, 41) | 7.1 Units on a scale | Standard Error 2.96 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Final on Therapy (N = 60, 64, 64) | 24.2 Units on a scale | Standard Error 3.16 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 76 (N = 57, 55, 41) | 13.9 Units on a scale | Standard Error 3.35 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 91 (N = 53, 49, 37) | 17.9 Units on a scale | Standard Error 3.2 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | Week 64 (N = 56, 60, 57) | 19.1 Units on a scale | Standard Error 3.18 |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.025695% CI: [-17.1, -1.1]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: <0.000195% CI: [-28.1, -11.1]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.016195% CI: [-19, -2]Longitudinal statistical model
Secondary
Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem
WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 91 (N = 37, 35, 18) | 1.8 Units on a scale | Standard Error 3.16 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 64 (N = 37, 49, 31) | -2.5 Units on a scale | Standard Error 3.57 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Final on Therapy (N = 45, 50, 40) | 1.1 Units on a scale | Standard Error 3.51 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 76 (N = 38, 38, 23) | -0.6 Units on a scale | Standard Error 2.16 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 91 (N = 37, 35, 18) | 8.6 Units on a scale | Standard Error 3.06 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 76 (N = 38, 38, 23) | 2.3 Units on a scale | Standard Error 2.01 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 64 (N = 37, 49, 31) | 9.6 Units on a scale | Standard Error 3.16 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Final on Therapy (N = 45, 50, 40) | 11.1 Units on a scale | Standard Error 3.1 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Final on Therapy (N = 45, 50, 40) | 19.9 Units on a scale | Standard Error 3.76 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 64 (N = 37, 49, 31) | 18.2 Units on a scale | Standard Error 3.96 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 76 (N = 38, 38, 23) | 12.2 Units on a scale | Standard Error 2.54 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | Week 91 (N = 37, 35, 18) | 18.4 Units on a scale | Standard Error 4.23 |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.130395% CI: [-15.5, 2]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.002495% CI: [-27.1, -6]Longitudinal statisitical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.062195% CI: [-20.2, 0.5]Longitudinal statistical model
Secondary
Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem
WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 91 (N = 28, 30, 13) | 5.4 Units on a scale | Standard Error 3.98 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Final on Therapy (N = 34, 48, 28) | 4.4 Units on a scale | Standard Error 4.32 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 76 (N = 27, 30, 18) | -0.9 Units on a scale | Standard Error 2.4 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 64 (N = 29, 43, 25) | 0.1 Units on a scale | Standard Error 4.49 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 91 (N = 28, 30, 13) | 9.5 Units on a scale | Standard Error 3.74 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 76 (N = 27, 30, 18) | 2.6 Units on a scale | Standard Error 2.18 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Final on Therapy (N = 34, 48, 28) | 13.3 Units on a scale | Standard Error 3.6 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 64 (N = 29, 43, 25) | 11.5 Units on a scale | Standard Error 3.75 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Final on Therapy (N = 34, 48, 28) | 25.1 Units on a scale | Standard Error 4.84 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 64 (N = 29, 43, 25) | 22.4 Units on a scale | Standard Error 2.01 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 76 (N = 27, 30, 18) | 16.6 Units on a scale | Standard Error 2.95 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | Week 91 (N = 28, 30, 13) | 22.0 Units on a scale | Standard Error 5.75 |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.466495% CI: [-15, 6.9]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.02195% CI: [-30.6, -2.6]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.071395% CI: [-26.2, 1.1]Longitudinal statistical model
Secondary
Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem
WPAI is a 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 64 (N = 30, 44, 26) | 1.9 Units on a scale | Standard Error 2.78 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 76 (N = 28, 33, 18) | -0.1 Units on a scale | Standard Error 2.38 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 91 (N = 29, 32, 14) | 4.4 Units on a scale | Standard Error 3.78 |
| E25 + MTX (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Final on Therapy (N = 34, 48, 29) | 3.6 Units on a scale | Standard Error 3.65 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Final on Therapy (N = 34, 48, 29) | 5.3 Units on a scale | Standard Error 3.07 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 64 (N = 30, 44, 26) | 2.6 Units on a scale | Standard Error 2.29 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 91 (N = 29, 32, 14) | 4.0 Units on a scale | Standard Error 3.63 |
| MTX + PBO (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 76 (N = 28, 33, 18) | 2.9 Units on a scale | Standard Error 2.19 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Final on Therapy (N = 34, 48, 29) | 10.2 Units on a scale | Standard Error 4.06 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 76 (N = 28, 33, 18) | 2.6 Units on a scale | Standard Error 3.09 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 91 (N = 29, 32, 14) | 7.0 Units on a scale | Standard Error 5.79 |
| Placebo (PBO) (Phase 2) | Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | Week 64 (N = 30, 44, 26) | 6.1 Units on a scale | Standard Error 3.04 |
Comparison: Change from Week 52 to Week 91. The hyothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.933895% CI: [-10, 10.9]ANCOVA
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.71395% CI: [-16.4, 11.2]ANCOVA
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.662895% CI: [-16.6, 10.6]ANCOVA
Secondary
Change From Baseline mTSS at Week 91 and Final on Therapy
mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.
Time frame: 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Change From Baseline mTSS at Week 91 and Final on Therapy | Week 91 (N = 51, 45, 30) | 0.0 Units on a scale | Standard Error 0.16 |
| E25 + MTX (Phase 2) | Change From Baseline mTSS at Week 91 and Final on Therapy | Final on Therapy (N = 58, 56, 49) | 0.1 Units on a scale | Standard Error 0.14 |
| MTX + PBO (Phase 2) | Change From Baseline mTSS at Week 91 and Final on Therapy | Week 91 (N = 51, 45, 30) | 0.0 Units on a scale | Standard Error 0.17 |
| MTX + PBO (Phase 2) | Change From Baseline mTSS at Week 91 and Final on Therapy | Final on Therapy (N = 58, 56, 49) | -0.0 Units on a scale | Standard Error 0.15 |
| Placebo (PBO) (Phase 2) | Change From Baseline mTSS at Week 91 and Final on Therapy | Week 91 (N = 51, 45, 30) | 0.5 Units on a scale | Standard Error 0.21 |
| Placebo (PBO) (Phase 2) | Change From Baseline mTSS at Week 91 and Final on Therapy | Final on Therapy (N = 58, 56, 49) | 0.4 Units on a scale | Standard Error 0.16 |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.965295% CI: [-0.5, 0.4]ANCOVA
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.216895% CI: [-1, 0]ANCOVA
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.213195% CI: [-1, 0]ANCOVA
Secondary
Modified Total Sharp Score (mTSS) at Week 52
mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.
Time frame: 52 weeks
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| E25 + MTX (Phase 2) | Modified Total Sharp Score (mTSS) at Week 52 | 8.4 Units on a scale | Standard Deviation 13.5 |
| MTX + PBO (Phase 2) | Modified Total Sharp Score (mTSS) at Week 52 | 8.4 Units on a scale | Standard Deviation 15.1 |
| Placebo (PBO) (Phase 2) | Modified Total Sharp Score (mTSS) at Week 52 | 8.6 Units on a scale | Standard Deviation 12.8 |
Secondary
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response
ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | Week 2 (N = 297) | 139 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | Week 4 (N = 295) | 195 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | Week 8 (N = 290) | 225 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | Week 13 (N = 280) | 232 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | Week 26 (N = 272) | 232 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | Week 39 (N = 256) | 235 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | Week 52 (N = 221) | 212 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response | Final on Therapy (N = 301) | 258 Participants |
Comparison: Binomial test-value tests the null hypothesis that the proportion is significantly different from 0.~Week 2, 4, 8, 13, 26, 39, 52 and final on therapyp-value: <0.0001Binomial test
Secondary
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response
ACR50 response: greater than or equal to (≥) 50 percent (%) improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | Week 2 (N = 297) | 52 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | Week 4 (N = 295) | 114 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | Week 8 (N = 290) | 144 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | Week 13 (N = 280) | 169 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | Week 26 (N = 272) | 190 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | Week 39 (N = 256) | 218 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | Week 52 (N = 221) | 202 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response | Final on Therapy (N = 301) | 229 Participants |
Comparison: Binomial test-value tests the null hypothesis that the proportion is significantly different from 0.~Week 2, 4, 8, 13, 26, 39, 52 week and final on therapyp-value: <0.0001Binomial test
Secondary
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response
ACR70 response: greater than or equal to (≥) 70 percent (%) improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | Week 2 (N = 297) | 17 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | Week 4 (N = 295) | 49 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | Week 8 (N = 290) | 80 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | Week 13 (N = 280) | 115 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | Week 26 (N = 272) | 146 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | Week 39 (N = 256) | 178 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | Week 52 (N = 221) | 176 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response | Final on Therapy (N = 301) | 198 Participants |
Comparison: Binomial test-value tests the null hypothesis that the proportion is significantly different from 0.~Week 2, 4, 8, 13, 26, 39, 52 and final on therapyp-value: <0.0001Binomial test
Secondary
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response
ACR90 response: greater than or equal to (≥) 90 percent (%) improvement in tender or swollen joint counts and 90% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | Week 2 (N = 297) | 2 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | Week 4 (N = 295) | 11 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | Week 8 (N = 290) | 22 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | Week 13 (N = 280) | 34 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | Week 26 (N = 272) | 70 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | Week 39 (N = 256) | 85 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | Week 52 (N = 221) | 97 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response | Final on Therapy (N = 301) | 105 Participants |
Comparison: Binomial test-value tests the null hypothesis that the proportion is significantly different from 0.~Week 2, 4, 8, 13, 26, 39, 52 and final on therapyp-value: <0.0001Binomial test
Secondary
Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response
ACR50 response: greater than or equal to (≥) 50 percent (%) improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 52 (N = 63, 63, 65) | 58 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 56 (N = 63, 63, 63) | 55 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 64 (N = 62, 61, 62) | 59 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 76 (N = 60, 55, 46) | 54 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 91 (N = 57, 50, 38) | 48 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Final on Therapy (N = 63, 63, 65) | 50 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Final on Therapy (N = 63, 63, 65) | 47 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 52 (N = 63, 63, 65) | 61 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 76 (N = 60, 55, 46) | 48 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 91 (N = 57, 50, 38) | 45 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 56 (N = 63, 63, 63) | 58 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 64 (N = 62, 61, 62) | 47 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 56 (N = 63, 63, 63) | 48 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 64 (N = 62, 61, 62) | 33 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Final on Therapy (N = 63, 63, 65) | 32 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 76 (N = 60, 55, 46) | 33 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 52 (N = 63, 63, 65) | 62 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response | Week 91 (N = 57, 50, 38) | 29 participants |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.595195% CI: [0.3, 2]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.093495% CI: [0.9, 5.5]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.031495% CI: [1.1, 7.4]Longitudinal statistical model
Secondary
Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response
ACR70 response: greater than or equal to (≥) 70 percent (%) improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 52 (N = 63, 63, 65) | 52 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 56 (N = 63, 63, 63) | 46 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 64 (N = 62, 61, 62) | 49 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 76 (N = 60, 55, 46) | 47 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 91 (N = 57, 50, 38) | 44 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Final on Therapy (N = 63, 63, 65) | 46 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Final on Therapy (N = 63, 63, 65) | 39 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 52 (N = 63, 63, 65) | 56 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 76 (N = 60, 55, 46) | 41 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 91 (N = 57, 50, 38) | 39 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 56 (N = 63, 63, 63) | 51 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 64 (N = 62, 61, 62) | 42 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 56 (N = 63, 63, 63) | 37 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 64 (N = 62, 61, 62) | 24 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Final on Therapy (N = 63, 63, 65) | 26 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 76 (N = 60, 55, 46) | 25 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 52 (N = 63, 63, 65) | 52 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response | Week 91 (N = 57, 50, 38) | 25 participants |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.615295% CI: [0.5, 2.8]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.043295% CI: [1, 5.4]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.118995% CI: [0.8, 4.3]Longitudinal statistical model
Secondary
Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response
ACR90 response: greater than or equal to (≥) 90 percent (%) improvement in tender or swollen joint counts and 90% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time frame: 52, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Final on Therapy (N = 63, 63, 65) | 31 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 64 (N = 62, 61, 62) | 29 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 91 (N = 57, 50, 38) | 30 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 52 (N = 63, 63, 65) | 32 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 76 (N = 60, 55, 46) | 25 participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 56 (N = 63, 63, 63) | 32 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 76 (N = 60, 55, 46) | 18 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 91 (N = 57, 50, 38) | 19 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 56 (N = 63, 63, 63) | 31 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Final on Therapy (N = 63, 63, 65) | 19 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 52 (N = 63, 63, 65) | 31 participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 64 (N = 62, 61, 62) | 22 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 64 (N = 62, 61, 62) | 11 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 52 (N = 63, 63, 65) | 25 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 56 (N = 63, 63, 63) | 20 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Final on Therapy (N = 63, 63, 65) | 12 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 76 (N = 60, 55, 46) | 13 participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response | Week 91 (N = 57, 50, 38) | 12 participants |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.053595% CI: [1, 4.7]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.006495% CI: [1.4, 7.5]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.369695% CI: [0.6, 3.6]Longitudinal statistical model
Secondary
Number of Participants Achieving Complete Response (Using Disease Activity Score Based on 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire)
The composite measure of complete response over the last 3 months of Phase 1 was defined as: 1. DAS28 \<2.6 at the week 39 and 52 visits and, 2. No radiographic progression during Phase 1, defined as mean change in modified total Sharp score (mTSS) ≤0.5 and, 3. Health Assessment Questionnaire (HAQ) ≤ 0.5 at the week 39 and week 52 visits
Time frame: End of Phase 1
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving Complete Response (Using Disease Activity Score Based on 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire) | 89 Participants |
Comparison: Binomial test-value tests the null hypothesis that the proportion is significantly different from 0.~End of Phase 1p-value: <0.0001Binomial test
Secondary
Number of Participants Achieving Complete Response (Using Disease Activity Score Based on a 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire)
The composite measure of complete response over the last 3 months of Phase 2 was defined as: 1. DAS28 \<2.6 at the Week 76 and Week 91 visits and 2. No radiographic progression during Phase 2, defined as mean change from Week 52 in mTSS of ≤0.5. 3. Participant must achieve HAQ score ≤0.5 at Week 76 and 91 visits. HAQ is self-reported, valid assessment of functional disability in rheumatoid arthritis. Assessed based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. HAQ score range: 0-3: without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. HAQ total scores expressed as overall mean score with range 0-3: 0-0.25=normal functioning; 0.25-0.5=mild functional limitation; 0.5-1=moderate functional limitation; more than 1=significant functional limitation.A subject had to satisfy all 3 criteria at thevisits to be defined as a responder
Time frame: 52 and 91 weeks
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving Complete Response (Using Disease Activity Score Based on a 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire) | 36 Participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving Complete Response (Using Disease Activity Score Based on a 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire) | 19 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving Complete Response (Using Disease Activity Score Based on a 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire) | 7 Participants |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.001795% CI: [1.6, 6.7]Regression, Logistic
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: <0.000195% CI: [4.4, 28]Regression, Logistic
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.011195% CI: [1.3, 8.8]Regression, Logistic
Secondary
Number of Participants Achieving Patient Acceptable Symptom State (PASS)
The PASS is defined as a symptom state that the subjects consider acceptable.
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 52 (N = 61, 65, 64) | 57 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 56 (N = 63, 63, 64) | 57 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 64 (N = 61, 60, 60) | 58 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 76 (N = 60, 56, 45) | 57 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 91 (N = 57, 52, 38) | 52 Participants |
| E25 + MTX (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Final on Therapy (N = 63, 65, 65) | 56 Participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Final on Therapy (N = 63, 65, 65) | 50 Participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 52 (N = 61, 65, 64) | 64 Participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 76 (N = 60, 56, 45) | 48 Participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 91 (N = 57, 52, 38) | 46 Participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 56 (N = 63, 63, 64) | 58 Participants |
| MTX + PBO (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 64 (N = 61, 60, 60) | 51 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 56 (N = 63, 63, 64) | 53 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 64 (N = 61, 60, 60) | 42 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Final on Therapy (N = 63, 65, 65) | 38 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 76 (N = 60, 56, 45) | 38 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 52 (N = 61, 65, 64) | 61 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants Achieving Patient Acceptable Symptom State (PASS) | Week 91 (N = 57, 52, 38) | 33 Participants |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.471795% CI: [0.5, 4.6]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.055195% CI: [1, 7.8]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.214195% CI: [0.7, 4.8]Longitudinal statistical model
Secondary
Number of Participants With an American College of Rheumatology 20% (ACR20) Response
ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and C-Reactive Protein (CRP).
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 52 (N = 63, 63, 65) | 61 participants |
| E25 + MTX (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 56 (N = 63, 63, 63) | 59 participants |
| E25 + MTX (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 64 (N = 62, 61, 62) | 61 participants |
| E25 + MTX (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 76 (N = 60, 55, 46) | 57 participants |
| E25 + MTX (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 91 (N = 57, 50, 38) | 55 participants |
| E25 + MTX (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Final on Therapy (N = 63, 63, 65) | 58 participants |
| MTX + PBO (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Final on Therapy (N = 63, 63, 65) | 52 participants |
| MTX + PBO (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 52 (N = 63, 63, 65) | 63 participants |
| MTX + PBO (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 76 (N = 60, 55, 46) | 51 participants |
| MTX + PBO (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 91 (N = 57, 50, 38) | 48 participants |
| MTX + PBO (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 56 (N = 63, 63, 63) | 59 participants |
| MTX + PBO (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 64 (N = 62, 61, 62) | 51 participants |
| Placebo (PBO) (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 56 (N = 63, 63, 63) | 56 participants |
| Placebo (PBO) (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 64 (N = 62, 61, 62) | 44 participants |
| Placebo (PBO) (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Final on Therapy (N = 63, 63, 65) | 37 participants |
| Placebo (PBO) (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 76 (N = 60, 55, 46) | 40 participants |
| Placebo (PBO) (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 52 (N = 63, 63, 65) | 64 participants |
| Placebo (PBO) (Phase 2) | Number of Participants With an American College of Rheumatology 20% (ACR20) Response | Week 91 (N = 57, 50, 38) | 31 participants |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.407595% CI: [0.4, 7.6]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.001195% CI: [2.4, 33.1]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.003195% CI: [1.7, 13.9]Longitudinal statistical model
Secondary
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity
DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participant who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 2 (N = 297) | 67 participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 4 (N = 293) | 122 participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 8 (N = 293) | 157 participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 13 (N = 282) | 194 participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 26 (N = 276) | 210 participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 39 (N = 259) | 236 participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 52 (N = 221) | 214 participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Final on Therapy (N = 305) | 249 participants |
Comparison: Binomial test-value tests the null hypothesis that the proportion is significantly different from 0.~Week 2, 4, 8, 13, 26, 39, 52 week and final on therapyp-value: <0.0001Binomial test
Secondary
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity
DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 52 (N = 63, 65, 65) | 63 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 56 (N = 63, 65, 63) | 62 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 64 (N = 62, 63, 60) | 61 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 76 (N = 60, 57, 46) | 57 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 91 (N = 57, 52, 38) | 56 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Final on Therapy (N = 63, 65, 65) | 60 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Final on Therapy (N = 63, 65, 65) | 50 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 52 (N = 63, 65, 65) | 65 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 76 (N = 60, 57, 46) | 54 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 91 (N = 57, 52, 38) | 47 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 56 (N = 63, 65, 63) | 60 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 64 (N = 62, 63, 60) | 52 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 56 (N = 63, 65, 63) | 54 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 64 (N = 62, 63, 60) | 38 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Final on Therapy (N = 63, 65, 65) | 35 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 76 (N = 60, 57, 46) | 37 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 52 (N = 63, 65, 65) | 65 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity | Week 91 (N = 57, 52, 38) | 33 Participants |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.054895% CI: [1, 59.5]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.016695% CI: [1.6, 94.2]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.361995% CI: [0.6, 4.5]Longitudinal statistical model
Secondary
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission
DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 52 (N = 63, 65, 65) | 60 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 56 (N = 63, 65, 63) | 52 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 64 (N = 62, 63, 60) | 54 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 76 (N = 60, 57, 46) | 51 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 91 (N = 57, 52, 38) | 48 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Final on Therapy (N = 63, 65, 65) | 51 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Final on Therapy (N = 63, 65, 65) | 40 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 52 (N = 63, 65, 65) | 62 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 76 (N = 60, 57, 46) | 42 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 91 (N = 57, 52, 38) | 39 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 56 (N = 63, 65, 63) | 52 Participants |
| MTX + PBO (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 64 (N = 62, 63, 60) | 44 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 56 (N = 63, 65, 63) | 47 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 64 (N = 62, 63, 60) | 25 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Final on Therapy (N = 63, 65, 65) | 24 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 76 (N = 60, 57, 46) | 24 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 52 (N = 63, 65, 65) | 60 Participants |
| Placebo (PBO) (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission | Week 91 (N = 57, 52, 38) | 23 Participants |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.078895% CI: [0.9, 5.2]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.000795% CI: [1.9, 11]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.067695% CI: [0.9, 4.7]Longitudinal statistical model
Secondary
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission
DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hour\]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 \<1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | Week 2 (N = 297) | 13 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | Week 4 (N = 293) | 48 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | Week 8 (N = 293) | 81 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | Week 13 (N = 282) | 95 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | Week 26 (N = 276) | 142 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | Week 39 (N = 259) | 174 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | Week 52 (N = 221) | 193 Participants |
| E25 + MTX (Phase 2) | Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission | Final on Therapy (N = 305) | 211 Participants |
Comparison: Binomial test-value tests the null hypothesis that the proportion is significantly different from 0.~Week 2, 4, 8, 13, 26, 39, 52 and final on therapyp-value: <0.0001Binomial test
Secondary
Participant's Global Assessment of Disease Activity
Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm Visual Analog Scale (VAS), with 0 mm = no disease activity and 100 = extreme disease activity
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Participant's Global Assessment of Disease Activity | Week 52 (N = 63, 65, 65) | 5.8 Units on a scale | Standard Deviation 6.3 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Disease Activity | Week 56 (N = 63, 65, 65) | 10.3 Units on a scale | Standard Deviation 14.8 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Disease Activity | Week 64 (N = 62, 63, 62) | 7.6 Units on a scale | Standard Deviation 9.1 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Disease Activity | Week 76 (N = 60, 56, 46) | 8.9 Units on a scale | Standard Deviation 12.1 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Disease Activity | Week 91 (N = 56, 52, 38) | 9.6 Units on a scale | Standard Deviation 14.1 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Disease Activity | Final on Therapy (N = 63, 65, 65) | 11.1 Units on a scale | Standard Deviation 16.2 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Disease Activity | Final on Therapy (N = 63, 65, 65) | 20.7 Units on a scale | Standard Deviation 25.9 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Disease Activity | Week 52 (N = 63, 65, 65) | 5.7 Units on a scale | Standard Deviation 7.7 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Disease Activity | Week 76 (N = 60, 56, 46) | 11.7 Units on a scale | Standard Deviation 17.9 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Disease Activity | Week 91 (N = 56, 52, 38) | 12.3 Units on a scale | Standard Deviation 17.5 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Disease Activity | Week 56 (N = 63, 65, 65) | 9.7 Units on a scale | Standard Deviation 16.3 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Disease Activity | Week 64 (N = 62, 63, 62) | 17.8 Units on a scale | Standard Deviation 25.5 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Disease Activity | Week 56 (N = 63, 65, 65) | 17.3 Units on a scale | Standard Deviation 22.1 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Disease Activity | Week 64 (N = 62, 63, 62) | 31.0 Units on a scale | Standard Deviation 31.4 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Disease Activity | Final on Therapy (N = 63, 65, 65) | 37.1 Units on a scale | Standard Deviation 33.9 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Disease Activity | Week 76 (N = 60, 56, 46) | 18.3 Units on a scale | Standard Deviation 18.7 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Disease Activity | Week 52 (N = 63, 65, 65) | 9.3 Units on a scale | Standard Deviation 14.1 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Disease Activity | Week 91 (N = 56, 52, 38) | 18.8 Units on a scale | Standard Deviation 25.7 |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.247395% CI: [-11.8, 3.1]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.001695% CI: [-21.3, -5.1]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.034895% CI: [-17, -0.6]Longitudinal statistical model
Secondary
Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS)
100-mm line (Visual Analog Scale) marked by the participant to measure their degree of pain over past 2-3 weeks. Range: 0 = no pain to 100 = pain as bad as it could be.
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 52 (N = 63, 65, 65) | 7.3 mm | Standard Deviation 7.7 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 56 (N = 63, 65, 65) | 10.9 mm | Standard Deviation 15 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 64 (N = 62, 63, 62) | 8.0 mm | Standard Deviation 9.8 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 76 (N = 60, 56, 46) | 9.8 mm | Standard Deviation 12.9 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 91 (N = 57, 52, 38) | 9.5 mm | Standard Deviation 12.7 |
| E25 + MTX (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Final on Therapy (N = 63, 65, 65) | 11.4 mm | Standard Deviation 15.4 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Final on Therapy (N = 63, 65, 65) | 21.4 mm | Standard Deviation 24.8 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 52 (N = 63, 65, 65) | 6.9 mm | Standard Deviation 8.6 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 76 (N = 60, 56, 46) | 12.3 mm | Standard Deviation 19.2 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 91 (N = 57, 52, 38) | 13.3 mm | Standard Deviation 16.4 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 56 (N = 63, 65, 65) | 10.2 mm | Standard Deviation 16.9 |
| MTX + PBO (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 64 (N = 62, 63, 62) | 18.0 mm | Standard Deviation 25.1 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 56 (N = 63, 65, 65) | 18.8 mm | Standard Deviation 23.1 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 64 (N = 62, 63, 62) | 31.7 mm | Standard Deviation 31.3 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Final on Therapy (N = 63, 65, 65) | 37.8 mm | Standard Deviation 33.7 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 76 (N = 60, 56, 46) | 17.6 mm | Standard Deviation 18.1 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 52 (N = 63, 65, 65) | 9.9 mm | Standard Deviation 14.8 |
| Placebo (PBO) (Phase 2) | Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) | Week 91 (N = 57, 52, 38) | 19.7 mm | Standard Deviation 26.1 |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.124895% CI: [-12.6, 1.6]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.000495% CI: [-21.8, -6.5]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.030695% CI: [-16.4, -0.8]Longitudinal statistical model
Secondary
Physician's Global Assessment of Disease Activity
Physician Global Assessment of Disease Activity was measured on a 0 to 100 Visual Analog Scale (VAS), with 0 = no disease activity and 100 = extreme disease activity.
Time frame: 52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| E25 + MTX (Phase 2) | Physician's Global Assessment of Disease Activity | Week 52 (N = 63, 65, 65) | 5.0 Units on a scale | Standard Deviation 5.3 |
| E25 + MTX (Phase 2) | Physician's Global Assessment of Disease Activity | Week 56 (N = 63, 65, 65) | 5.5 Units on a scale | Standard Deviation 6.2 |
| E25 + MTX (Phase 2) | Physician's Global Assessment of Disease Activity | Week 64 (N = 62, 63, 62) | 6.0 Units on a scale | Standard Deviation 7.4 |
| E25 + MTX (Phase 2) | Physician's Global Assessment of Disease Activity | Week 76 (N = 60, 57, 46) | 5.5 Units on a scale | Standard Deviation 7.1 |
| E25 + MTX (Phase 2) | Physician's Global Assessment of Disease Activity | Week 91 (N = 57, 52, 38) | 5.8 Units on a scale | Standard Deviation 9.8 |
| E25 + MTX (Phase 2) | Physician's Global Assessment of Disease Activity | Final on Therapy (N = 63, 65, 65) | 6.9 Units on a scale | Standard Deviation 10.8 |
| MTX + PBO (Phase 2) | Physician's Global Assessment of Disease Activity | Final on Therapy (N = 63, 65, 65) | 16.7 Units on a scale | Standard Deviation 21.7 |
| MTX + PBO (Phase 2) | Physician's Global Assessment of Disease Activity | Week 52 (N = 63, 65, 65) | 4.2 Units on a scale | Standard Deviation 4.9 |
| MTX + PBO (Phase 2) | Physician's Global Assessment of Disease Activity | Week 76 (N = 60, 57, 46) | 9.0 Units on a scale | Standard Deviation 13.6 |
| MTX + PBO (Phase 2) | Physician's Global Assessment of Disease Activity | Week 91 (N = 57, 52, 38) | 10.3 Units on a scale | Standard Deviation 16.8 |
| MTX + PBO (Phase 2) | Physician's Global Assessment of Disease Activity | Week 56 (N = 63, 65, 65) | 7.7 Units on a scale | Standard Deviation 12.6 |
| MTX + PBO (Phase 2) | Physician's Global Assessment of Disease Activity | Week 64 (N = 62, 63, 62) | 11.6 Units on a scale | Standard Deviation 16.7 |
| Placebo (PBO) (Phase 2) | Physician's Global Assessment of Disease Activity | Week 56 (N = 63, 65, 65) | 12.2 Units on a scale | Standard Deviation 15.1 |
| Placebo (PBO) (Phase 2) | Physician's Global Assessment of Disease Activity | Week 64 (N = 62, 63, 62) | 23.6 Units on a scale | Standard Deviation 26 |
| Placebo (PBO) (Phase 2) | Physician's Global Assessment of Disease Activity | Final on Therapy (N = 63, 65, 65) | 30.7 Units on a scale | Standard Deviation 28.4 |
| Placebo (PBO) (Phase 2) | Physician's Global Assessment of Disease Activity | Week 76 (N = 60, 57, 46) | 14.6 Units on a scale | Standard Deviation 18.1 |
| Placebo (PBO) (Phase 2) | Physician's Global Assessment of Disease Activity | Week 52 (N = 63, 65, 65) | 6.3 Units on a scale | Standard Deviation 8 |
| Placebo (PBO) (Phase 2) | Physician's Global Assessment of Disease Activity | Week 91 (N = 57, 52, 38) | 15.9 Units on a scale | Standard Deviation 21.7 |
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.032895% CI: [-16.6, -0.7]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: <0.000195% CI: [-30.1, -13.2]Longitudinal statistical model
Comparison: Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.p-value: 0.003595% CI: [-21.5, -4.5]Longitudinal statistical model
Secondary
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit
The PASS is defined as a symptom state that the participants consider acceptable.
Time frame: 2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)
Population: Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E25 + MTX (Phase 2) | Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | Week 52 (N = 220) | 206 Participants |
| E25 + MTX (Phase 2) | Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | Final on Therapy (N = 305) | 250 Participants |
| E25 + MTX (Phase 2) | Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | Week 2 (N = 297) | 151 Participants |
| E25 + MTX (Phase 2) | Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | Week 4 (N = 292) | 180 Participants |
| E25 + MTX (Phase 2) | Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | Week 8 (N = 288) | 189 Participants |
| E25 + MTX (Phase 2) | Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | Week 13 (N = 279) | 197 Participants |
| E25 + MTX (Phase 2) | Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | Week 26 (N = 268) | 213 Participants |
| E25 + MTX (Phase 2) | Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit | Week 39 (N = 257) | 219 Participants |
Comparison: P-value is from McNemar's test for no change from baseline in response rate.~Week 2, 4, 8, 13, 26, 39, 52 week and final on therapyp-value: <0.0001McNemar
Secondary
Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem
WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 52 weeks
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| E25 + MTX (Phase 2) | Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | 0.2 units on a scale | Standard Deviation 1.2 |
| MTX + PBO (Phase 2) | Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | 0.1 units on a scale | Standard Deviation 0.6 |
| Placebo (PBO) (Phase 2) | Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem | 0.0 units on a scale | Standard Deviation 0 |
Secondary
WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem
WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 52 weeks
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| E25 + MTX (Phase 2) | WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | 8.6 Units on a scale | Standard Deviation 11 |
| MTX + PBO (Phase 2) | WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | 10.0 Units on a scale | Standard Deviation 15.9 |
| Placebo (PBO) (Phase 2) | WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem | 16.8 Units on a scale | Standard Deviation 20 |
Secondary
WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem
WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 52 Weeks
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| E25 + MTX (Phase 2) | WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | 6.2 units on a scale | Standard Deviation 9.2 |
| MTX + PBO (Phase 2) | WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | 8.9 units on a scale | Standard Deviation 15.5 |
| Placebo (PBO) (Phase 2) | WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem | 14.2 units on a scale | Standard Deviation 17.9 |
Secondary
WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem
WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named Percent impairment While Working) and as such range from 0 to 100.
Time frame: 52 weeks
Population: Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| E25 + MTX (Phase 2) | WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | 5.3 units on a scale | Standard Deviation 9.8 |
| MTX + PBO (Phase 2) | WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | 6.7 units on a scale | Standard Deviation 15 |
| Placebo (PBO) (Phase 2) | WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem | 9.2 units on a scale | Standard Deviation 12.8 |