Rheumatoid Arthritis
Conditions
Keywords
Moderate Rheumatoid Arthritis
Brief summary
To assess comparative radiographic efficacy, clinical efficacy and safety of etanercept (ETN) + methotrexate (MTX) with usual disease-modifying anti-rheumatic drug (DMARD) treatment in subjects with moderate RA who were treated with MTX monotherapy, but continue to have moderate disease activity.
Interventions
DRUGetanercept (EnbrelTM)
DRUGmethotrexate
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meet the 1987 ACR Revised Criteria for Rheumatoid Arthritis. * Documented evidence, confirmed by a blinded 3rd party assessor, of at least one erosion observed by X-ray at randomization based on X-ray taken at the screening visit. * Have received MTX as stable dose for 28 days prior to the screening visit.
Exclusion criteria
* Previous treatment with ETN, infliximab, adalimumab, other Tumor necrosis factor (TNF) -a inhibitors, anakinra or other biological agents. * Receipt of any DMARD, other than MTX, within 28 days before screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Total Sharp Score (TSS) at Week 52 | Baseline, Week 52 | Modified TSS is a measure of change in joint health. TSS is defined as joint space narrowing score (range 0 \[no narrowing\] to 168 \[high narrowing\]) plus (+) erosion score (range is from 0 \[no erosion\] to 280 \[high erosion\]). The modified TSS range is from 0 (no damage) to 448 (bad joint status). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Joint Space Narrowing at Week 52 | Baseline, Week 52 | Joint space narrowing score (a component of the modified TSS) is a measure of change in joint health. Joint space narrowing score range is 0 (no narrowing) to 168 (high narrowing). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. |
| Percentage of Participants Showing no Radiographic Progression (TSS Change <0.5) at Week 52 | Baseline, Week 52, Last observation carried forward (LOCF) | Radiographic non-progression determined based on TSS change \<0.5 using the dichotomous response Yes / No. The modified TSS range is from 0 (no damage) to 448 (bad joint status). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. |
| Percentage of Participants Achieving a Patient Acceptable Symptom State (PASS) | Week 4, Week 12, Week 24, Week 40, Week 52 | Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of pain they had during the last 48 hours. |
| Percentage of Participants Achieving >1.2 Improvement in Disease Activity Score Based on a 28-joint Count (DAS28) | Baseline, Week 12, Week 24, and Week 52 | Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and general health (GH) using Visual Analog Scale (VAS); range 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 square root (√) (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score \>5.1=higher disease activity; \<3.2=low disease activity; \<2.6=clinical remission. Achievement of \>1.2 improvement defined as decrease in DAS28 \>1.2 (change in DAS28 \< -1.2). |
| Percentage of Participants Achieving Remission (DAS28 <2.60) | Week 12, Week 24, and Week 52 | Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score \>5.10=higher disease activity; \<3.20=low disease activity; \<2.60=clinical remission. |
| Percentage of Participants Achieving Low Disease Activity (DAS28 ≤3.20) | Week 12, Week 24, and Week 52 | Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score \>5.10=higher disease activity; \<3.20=low disease activity; \<2.60=clinical remission. |
| Percentage of Participants Achieving a >0.6 Disease Activity Score (DAS)28 Response | Week 12, Week 24, and Week 52 | Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and participant's assessment of general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score \>5.10=higher disease activity; \<3.20=low disease activity; \<2.60=clinical remission. DAS28 response of \>0.6 defined as decrease in DAS28 \>0.6 (change in DAS28 \< -0.6). |
| Health Related Quality of Life: EuroQol-5D Health Index | Baseline, Week 12, Week 24, and Week 52 | EQ-5D is a self-administered questionnaire to assess health-related quality of life in 5 domains (mobility, self care, usual activities, pain or discomfort, and anxiety or depression). Scores from the 5 domains are used to calculate the Health State Profile Score as a single index value; range: 0.0 (death) to 1.0 (perfect health); higher scores indicate a better health state. |
| Change From Baseline in Erosions at Week 52 | Baseline, Week 52 | Erosion score (a component of the modified TSS) is a measure of change in joint health. Erosion score range is from 0 (no erosion) to 280 (high erosion). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. |
| Percentage of Participants With American College of Rheumatology 20% (ACR20) Response | Week 12, Week 24, Week 52 | American College of Rheumatology 20% (ACR20) response: responder = ≥ 20% improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders. |
| Percentage of Participants With American College of Rheumatology 50% (ACR50) Response | Week 12, Week 24, Week 52 | American College of Rheumatology 50% (ACR50) response: responder = ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders. |
| Percentage of Participants With American College of Rheumatology 70% (ACR70) Response | Week 12, Week 24, Week 52 | American College of Rheumatology 70% (ACR70) response: responder = ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and erythrocyte sedimentation rate (ESR) . Subjects withdrawing early were non-responders. |
| Percentage of Participants With American College of Rheumatology 90% (ACR90) Response | Week 12, Week 24, Week 52 | American College of Rheumatology 90% (ACR 90) response: responder = ≥ 90% improvement in tender joint count; ≥ 90% improvement in swollen joint count; and ≥ 90% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders. |
| Change From Baseline in Mean Daily Dose of Corticosteroids to Manage Flare-ups Across the 52-week Treatment Period | Week 4, Week 12, Week 24, Week 40, Week 52 | Mean daily dose of corticosteroids to manage flare-ups (temporary increases in corticosteroid dose or use of intra-articular steroids) during treatment period. Daily dose of equivalent prednisone derived in mg/day: oral corticosteroids: 5 mg of prednisone = 5 mg of prednisolone = 25 mg of cortisone = 20 mg of hydrocortisone = 4 mg of methylprednisolone = 4 mg of triamcinolone = 2mg of paramethasone = 0.75 mg of betamethasone = 0.75 of dexamethasone = 0.3 of cortivazol. |
| Percentage of Participants Achieving a Minimal Clinically Important Improvement (MCII) | Week 12, Week 52 | Participants were asked how their pain had been during the last 48 hours compared to baseline. Participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse-more pain. |
| Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) | Baseline, Week 12, Week 24, and Week 52 | EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. |
| Percentage of Participants Achieving Moderate or Good Response on European League Against Rheumatism (EULAR) Response Criteria | Week 12, Week 24, Week 52 | Response to treatment assessed by EULAR response criteria. Participants were characterized as good, moderate, or non-responders based on both Disease Activity Score (DAS) level attained and change in DAS. Good response defined as \>1.2 improvement in DAS from Baseline and DAS attained during follow-up of ≤2.4. Non-responders = participants with improvement of ≤0.6 or participants with improvement of \>0.6 but ≤1.2 and DAS attained during follow-up of \>5.1. Remaining participants were classified as moderate. Scores of good and moderate were considered to have therapeutic response. |
Countries
Czechia, France, Germany, Hungary, Italy, Poland, Spain, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
141 participants were randomized, 1 participant performed all the planned visits, and 140 participants were discontinued before completion of the study; 115 participants prematurely withdrew due to discontinuation of the study by the sponsor.
Participants by arm
| Arm | Count |
|---|---|
| Usual Care Utilized Disease-Modifying Antirheumatic Drugs (DMARDs) from a list of the 6 most commonly prescribed in the participating countries (Methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, cyclosporine A and gold). | 63 |
| ETN + MTX Etanercept (ETN) 50 milligrams (mg) sub-cutaneous (SC) injection once weekly (pre-filled syringe) plus continuation of current dose of Methotrexate (MTX) either oral (PO), SC, or intramuscular (IM). | 71 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Discontinuation of study by sponsor | 52 | 63 |
| Overall Study | Lack of Efficacy | 3 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Protocol Violation | 3 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 1 |
Baseline characteristics
| Characteristic | Usual Care | ETN + MTX | Total |
|---|---|---|---|
| Age Continuous | 57.3 years STANDARD_DEVIATION 12.1 | 53.8 years STANDARD_DEVIATION 13.1 | 55.5 years STANDARD_DEVIATION 12.7 |
| Sex: Female, Male Female | 50 Participants | 56 Participants | 106 Participants |
| Sex: Female, Male Male | 13 Participants | 15 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 63 | 37 / 71 |
| serious Total, serious adverse events | 4 / 63 | 5 / 71 |
Outcome results
Primary
Change From Baseline in Modified Total Sharp Score (TSS) at Week 52
Modified TSS is a measure of change in joint health. TSS is defined as joint space narrowing score (range 0 \[no narrowing\] to 168 \[high narrowing\]) plus (+) erosion score (range is from 0 \[no erosion\] to 280 \[high erosion\]). The modified TSS range is from 0 (no damage) to 448 (bad joint status). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement.
Time frame: Baseline, Week 52
Population: Modified intent-to-treat (mITT) population including all participants with an erosion at randomization confirmed by the blinded expert assessor, received at least 1 dose of subject treatment, and had data for randomization and 1 post randomization X-ray. Efficacy data not analyzed due to early termination of the study.
Secondary
Change From Baseline in Erosions at Week 52
Erosion score (a component of the modified TSS) is a measure of change in joint health. Erosion score range is from 0 (no erosion) to 280 (high erosion). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement.
Time frame: Baseline, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Change From Baseline in Joint Space Narrowing at Week 52
Joint space narrowing score (a component of the modified TSS) is a measure of change in joint health. Joint space narrowing score range is 0 (no narrowing) to 168 (high narrowing). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement.
Time frame: Baseline, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Change From Baseline in Mean Daily Dose of Corticosteroids to Manage Flare-ups Across the 52-week Treatment Period
Mean daily dose of corticosteroids to manage flare-ups (temporary increases in corticosteroid dose or use of intra-articular steroids) during treatment period. Daily dose of equivalent prednisone derived in mg/day: oral corticosteroids: 5 mg of prednisone = 5 mg of prednisolone = 25 mg of cortisone = 20 mg of hydrocortisone = 4 mg of methylprednisolone = 4 mg of triamcinolone = 2mg of paramethasone = 0.75 mg of betamethasone = 0.75 of dexamethasone = 0.3 of cortivazol.
Time frame: Week 4, Week 12, Week 24, Week 40, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Health Related Quality of Life: EuroQol-5D Health Index
EQ-5D is a self-administered questionnaire to assess health-related quality of life in 5 domains (mobility, self care, usual activities, pain or discomfort, and anxiety or depression). Scores from the 5 domains are used to calculate the Health State Profile Score as a single index value; range: 0.0 (death) to 1.0 (perfect health); higher scores indicate a better health state.
Time frame: Baseline, Week 12, Week 24, and Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS)
EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.
Time frame: Baseline, Week 12, Week 24, and Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants Achieving >1.2 Improvement in Disease Activity Score Based on a 28-joint Count (DAS28)
Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and general health (GH) using Visual Analog Scale (VAS); range 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 square root (√) (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score \>5.1=higher disease activity; \<3.2=low disease activity; \<2.6=clinical remission. Achievement of \>1.2 improvement defined as decrease in DAS28 \>1.2 (change in DAS28 \< -1.2).
Time frame: Baseline, Week 12, Week 24, and Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants Achieving a >0.6 Disease Activity Score (DAS)28 Response
Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and participant's assessment of general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score \>5.10=higher disease activity; \<3.20=low disease activity; \<2.60=clinical remission. DAS28 response of \>0.6 defined as decrease in DAS28 \>0.6 (change in DAS28 \< -0.6).
Time frame: Week 12, Week 24, and Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants Achieving a Minimal Clinically Important Improvement (MCII)
Participants were asked how their pain had been during the last 48 hours compared to baseline. Participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse-more pain.
Time frame: Week 12, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants Achieving a Patient Acceptable Symptom State (PASS)
Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of pain they had during the last 48 hours.
Time frame: Week 4, Week 12, Week 24, Week 40, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants Achieving Low Disease Activity (DAS28 ≤3.20)
Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score \>5.10=higher disease activity; \<3.20=low disease activity; \<2.60=clinical remission.
Time frame: Week 12, Week 24, and Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants Achieving Moderate or Good Response on European League Against Rheumatism (EULAR) Response Criteria
Response to treatment assessed by EULAR response criteria. Participants were characterized as good, moderate, or non-responders based on both Disease Activity Score (DAS) level attained and change in DAS. Good response defined as \>1.2 improvement in DAS from Baseline and DAS attained during follow-up of ≤2.4. Non-responders = participants with improvement of ≤0.6 or participants with improvement of \>0.6 but ≤1.2 and DAS attained during follow-up of \>5.1. Remaining participants were classified as moderate. Scores of good and moderate were considered to have therapeutic response.
Time frame: Week 12, Week 24, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants Achieving Remission (DAS28 <2.60)
Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score \>5.10=higher disease activity; \<3.20=low disease activity; \<2.60=clinical remission.
Time frame: Week 12, Week 24, and Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants Showing no Radiographic Progression (TSS Change <0.5) at Week 52
Radiographic non-progression determined based on TSS change \<0.5 using the dichotomous response Yes / No. The modified TSS range is from 0 (no damage) to 448 (bad joint status). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement.
Time frame: Baseline, Week 52, Last observation carried forward (LOCF)
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants With American College of Rheumatology 20% (ACR20) Response
American College of Rheumatology 20% (ACR20) response: responder = ≥ 20% improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders.
Time frame: Week 12, Week 24, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants With American College of Rheumatology 50% (ACR50) Response
American College of Rheumatology 50% (ACR50) response: responder = ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders.
Time frame: Week 12, Week 24, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants With American College of Rheumatology 70% (ACR70) Response
American College of Rheumatology 70% (ACR70) response: responder = ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and erythrocyte sedimentation rate (ESR) . Subjects withdrawing early were non-responders.
Time frame: Week 12, Week 24, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.
Secondary
Percentage of Participants With American College of Rheumatology 90% (ACR90) Response
American College of Rheumatology 90% (ACR 90) response: responder = ≥ 90% improvement in tender joint count; ≥ 90% improvement in swollen joint count; and ≥ 90% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders.
Time frame: Week 12, Week 24, Week 52
Population: mITT; efficacy data not analyzed due to early termination of the study.