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Study of Etanercept Monotherapy vs Methotrexate Monotherapy for Maintenance of Rheumatoid Arthritis Remission

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT02373813
Collaborator
(none)
371
Enrollment
136
Locations
4
Arms
57.5
Actual Duration (Months)
2.7
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of etanercept monotherapy compared to methotrexate monotherapy on maintenance of remission in participants with rheumatoid arthritis (RA) who were on etanercept plus methotrexate therapy.

This is a multicenter, randomized withdrawal, double-blind controlled study in participants with rheumatoid arthritis on etanercept plus methotrexate therapy who are in very good disease control for 6 months prior to study entry. The study will consist of a 30-day screening period, a 24-week open label run-in period, a 48-week double-blind treatment period and a 30-day safety follow-up period.

Condition or Disease Intervention/Treatment Phase
  • Drug: etanercept pre-filled syringe subcutaneous injection
  • Drug: Oral methotrexate
  • Drug: Placebo for etanercept subcutaneous injection
  • Drug: Placebo for methotrexate
  • Dietary Supplement: Folic acid (non-investigational product)
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
371 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized Withdrawal Double-blind Study of Etanercept Monotherapy Compared to Methotrexate Monotherapy for Maintenance of Remission in Subjects With Rheumatoid Arthritis
Actual Study Start Date :
Feb 20, 2015
Actual Primary Completion Date :
Dec 6, 2019
Actual Study Completion Date :
Dec 6, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Open Label Run-In: Etanercept plus Methotrexate

Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 24 weeks. Participants also receive folic acid as standard of care.

Drug: etanercept pre-filled syringe subcutaneous injection
etanercept for injection in pre-filled syringes
Other Names:
  • Enbrel
  • AMG916

    • Drug: Oral methotrexate
    During the open-label run-in period, methotrexate will be provided as 2.5 mg tablets. During the double-blind treatment period, methotrexate will be provided as 2.5 mg capsules.

    Dietary Supplement: Folic acid (non-investigational product)
    Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.
    Experimental: Double-Blind Treatment: Methotrexate Monotherapy

    Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening will initiate rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).

    Drug: etanercept pre-filled syringe subcutaneous injection
    etanercept for injection in pre-filled syringes
    Other Names:
  • Enbrel
  • AMG916

    • Drug: Oral methotrexate
    During the open-label run-in period, methotrexate will be provided as 2.5 mg tablets. During the double-blind treatment period, methotrexate will be provided as 2.5 mg capsules.

    Drug: Placebo for etanercept subcutaneous injection
    etanercept placebo for injection in pre-filled syringes

    Dietary Supplement: Folic acid (non-investigational product)
    Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.
    Experimental: Double-Blind Treatment: Etanercept Monotherapy

    Etanercept 50 mg weekly by subcutaneous injection plus placebo for methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening will initiate rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).

    Drug: etanercept pre-filled syringe subcutaneous injection
    etanercept for injection in pre-filled syringes
    Other Names:
  • Enbrel
  • AMG916

    • Drug: Oral methotrexate
    During the open-label run-in period, methotrexate will be provided as 2.5 mg tablets. During the double-blind treatment period, methotrexate will be provided as 2.5 mg capsules.

    Drug: Placebo for methotrexate
    methotrexate placebo capsules

    Dietary Supplement: Folic acid (non-investigational product)
    Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.
    Experimental: Double-Blind Treatment: Etanercept plus Methotrexate

    Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening will continue on the assigned treatments (as rescue treatment).

    Drug: etanercept pre-filled syringe subcutaneous injection
    etanercept for injection in pre-filled syringes
    Other Names:
  • Enbrel
  • AMG916

    • Drug: Oral methotrexate
    During the open-label run-in period, methotrexate will be provided as 2.5 mg tablets. During the double-blind treatment period, methotrexate will be provided as 2.5 mg capsules.

    Dietary Supplement: Folic acid (non-investigational product)
    Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission (≤ 3.3) at Week 48: Etanercept Monotherapy vs. Methotrexate Monotherapy [Week 48]

      The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

    Secondary Outcome Measures

    1. Percentage of Participants With SDAI Remission (≤ 3.3) at Week 48: Etanercept and Methotrexate vs. Methotrexate Monotherapy [Week 48]

      The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

    2. SDAI Score at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease.

    3. Change From Baseline in SDAI Score at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3. A negative change from baseline indicates improvement.

    4. Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The DAS28-ESR is a modified composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, ESR in mm/hr, and a 100 mm VAS measuring the participant's general health, from 0 (best) to 100 (worst). DAS28-ESR scores range from 0 to 9.4, where higher scores represent higher disease activity.

    5. Change From Baseline in DAS28-ESR at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The DAS28-ESR is a modified composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, ESR in mm/hr, and a 100 mm VAS measuring the participant's general health, from 0 (best) to 100 (worst). DAS28-ESR scores range from 0 to 9.4, where higher scores represent higher disease activity. A negative change from baseline indicates improvement.

    6. Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The DAS28-CRP is a composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, CRP in mg/L, and a 100 mm VAS measuring the participant's general health from 0 (best) to 100 (worst). DAS28-CRP scores range from 0 to 9.4, where higher scores represent higher disease activity.

    7. Change From Baseline in DAS28-CRP at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The DAS28-CRP is a composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, CRP in mg/L, and a 100 mm VAS measuring the participant's general health from 0 (best) to 100 (worst). DAS28-CRP scores range from 0 to 9.4, where higher scores represent higher disease activity. A negative change from baseline indicates improvement.

    8. Clinical Disease Activity Index (CDAI) at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The CDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, and Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable. The CDAI score ranges from 0 to 76, where a higher score represents worse disease.

    9. Change From Baseline in CDAI at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The CDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, and Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable. The CDAI score ranges from 0 to 76, where a higher score represents worse disease. A negative change from baseline indicates improvement.

    10. Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

    11. Percentage of Participants With Boolean Remission at All Measured Timepoints [Baseline, Week 12, Week 24, Week 36 and Week 48]

      A participant achieves Boolean remission (66/68-joint count) if all of the following criteria are met at a single timepoint: 68-joint tender joint count ≤ 1 66-joint swollen joint count ≤ 1 CRP (mg/dL) ≤ 1 Patient's Global Assessment of Disease Activity using a VAS (where 0=no arthritis activity at all and 10=worst arthritis activity imaginable) ≤ 1.

    12. Percentage of Participants With Disease Worsening [Baseline, Week 12, Week 24, Week 36 and Week 48]

      Percentage of participants who fulfilled disease-worsening criteria for the first time is presented. Disease worsening is defined as any of the following: an SDAI > 3.3 and ≤ 11 during 2 consecutive visits at least 2 weeks apart SDAI > 3.3 and ≤ 11 on 3 or more separate visits SDAI > 11 after randomization. The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

    13. Time to Disease Worsening [up to Week 48]

      Disease worsening is defined as any of the following: an SDAI > 3.3 and ≤ 11 during 2 consecutive visits at least 2 weeks apart SDAI > 3.3 and ≤ 11 on 3 or more separate visits SDAI > 11 after randomization. The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

    14. Time to Recapture SDAI Remission After Starting Rescue Treatment [Between rescue and remission or Week 48, whichever comes first.]

      In participants who receive rescue treatment during the double-blind treatment period. The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

    15. Percentage of Participants Receiving Rescue Treatment Who Experienced SDAI Remission at Week 48 [Week 48]

      The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria (Part 1, Run-In Period):

    • Subjects must be adults with a history of moderate to severe rheumatoid arthritis;

    • Subjects must be in very good rheumatoid arthritis disease control for ≥ 6 months and be in remission as defined by a Simplified Disease Activity Index ≤ 3.3 at screening and at the end of the run-in period.

    • Subjects must be on etanercept 50 mg per week plus methotrexate therapy for ≥ 6 months prior to the start of the run-in period. The methotrexate dose must be 10 to 25 mg per week for ≥ 6 months prior to the start of the run-in period and the dose must be stable for ≥ 8 weeks prior to the start of the run-in period.

    • Subject has no known history of active tuberculosis, and has a negative test for tuberculosis during screening.

    Exclusion Criteria (Part 1, Run-In Period):

    • Subject has used biologic disease modifying antirheumatic drug other than etanercept OR has used an oral janus kinase inhibitor ≤ 6 months prior to run-in visit 1

    • Subject has any active infection (including chronic or localized infections) for which anti-infectives were indicated within 4 weeks prior to run-in visit 1.

    • Subject has known alcohol addiction or dependency or uses alcohol daily.

    • Subject has one or more significant concurrent medical conditions per investigator judgment, including the following:

    • poorly controlled diabetes

    • chronic kidney disease stage IIIb, IV, or V

    • symptomatic heart failure (New York Heart Association class II, III, or IV)

    • myocardial infarction or unstable angina pectoris within the past 12 months prior to randomization

    • uncontrolled hypertension

    • severe chronic pulmonary disease (eg, requiring oxygen therapy)

    • multiple sclerosis or any other demyelinating disease

    • major chronic inflammatory disease or connective tissue disease other than rheumatoid arthritis (eg, systemic lupus erythematosus with the exception of secondary Sjögren's syndrome)

    Inclusion Criteria (Part 2, Treatment Period):

    • SDAI ≤ 3.3 at run-in visit 3

    • Subject if female and not at least 2 years postmenopausal or history of hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, has a negative urine pregnancy test at baseline (day 1).

    Exclusion Criteria (Part 2, Treatment Period):

    • Any clinically significant change in the Part 1 eligibility criteria during the run-in period

    • SDAI > 3.3 and ≤ 11 on two consecutive visits at least two weeks apart OR SDAI > 3.3 and ≤ 11 on two or more separate visits OR SDAI > 11 at any time during the run-in period

    • Subject has a clinically significant laboratory abnormality during run-in period which in the opinion of the investigator poses a safety risk, will prevent the subject from completing the study, or will interfere with the interpretation of the study results during the run-in period.

    NOTE: Other inclusion/exclusion criteria may apply per protocol.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Birmingham Alabama United States 35205
    2 Research Site Birmingham Alabama United States 35294
    3 Research Site Huntsville Alabama United States 35801
    4 Research Site Glendale Arizona United States 85306
    5 Research Site Mesa Arizona United States 85202
    6 Research Site Phoenix Arizona United States 85037
    7 Research Site Scottsdale Arizona United States 85258
    8 Research Site Escondido California United States 92025
    9 Research Site Fontana California United States 92335
    10 Research Site Hemet California United States 92543
    11 Research Site Huntington Beach California United States 92646
    12 Research Site La Jolla California United States 92037
    13 Research Site Murrieta California United States 92563
    14 Research Site Orange California United States 92868
    15 Research Site Sacramento California United States 95817
    16 Research Site Santa Maria California United States 93454-6945
    17 Research Site Torrance California United States 90502
    18 Research Site Tustin California United States 92780
    19 Research Site Victorville California United States 92395
    20 Research Site West Hills California United States 91307
    21 Research Site Doral Florida United States 33126
    22 Research Site Fort Lauderdale Florida United States 33309
    23 Research Site Gainesville Florida United States 32607
    24 Research Site Miami Florida United States 33126
    25 Research Site Miami Florida United States 33144
    26 Research Site Orlando Florida United States 32806
    27 Research Site Palm Harbor Florida United States 34684
    28 Research Site Pensacola Florida United States 32514
    29 Research Site Saint Petersburg Florida United States 33705
    30 Research Site Tampa Florida United States 33613
    31 Research Site Lawrenceville Georgia United States 30046
    32 Research Site Boise Idaho United States 83702
    33 Research Site Meridian Idaho United States 83642
    34 Research Site Blue Island Illinois United States 60406
    35 Research Site Skokie Illinois United States 60076
    36 Research Site Springfield Illinois United States 62703
    37 Research Site Granger Indiana United States 46530
    38 Research Site Baton Rouge Louisiana United States 70809
    39 Research Site New Orleans Louisiana United States 70121
    40 Research Site Wheaton Maryland United States 20902
    41 Research Site Ann Arbor Michigan United States 48109
    42 Research Site Detroit Michigan United States 48202
    43 Research Site Grand Rapids Michigan United States 49546
    44 Research Site Kalamazoo Michigan United States 49008
    45 Research Site Lansing Michigan United States 48910
    46 Research Site Lansing Michigan United States 48917
    47 Research Site Saint Louis Missouri United States 63141
    48 Research Site Springfield Missouri United States 65807
    49 Research Site Clifton New Jersey United States 07012
    50 Research Site Freehold New Jersey United States 07728
    51 Research Site Newark New Jersey United States 07103
    52 Research Site Albuquerque New Mexico United States 87102
    53 Research Site Brooklyn New York United States 11201
    54 Research Site Great Neck New York United States 11021
    55 Research Site New York New York United States 10021
    56 Research Site Charlotte North Carolina United States 28204
    57 Research Site Greenville North Carolina United States 27834
    58 Research Site Oklahoma City Oklahoma United States 73103
    59 Research Site Duncansville Pennsylvania United States 16635
    60 Research Site Pittsburgh Pennsylvania United States 15224
    61 Research Site Wynnewood Pennsylvania United States 19096
    62 Research Site Wyomissing Pennsylvania United States 19610
    63 Research Site Charleston South Carolina United States 29406
    64 Research Site Orangeburg South Carolina United States 29118
    65 Research Site Jackson Tennessee United States 38305
    66 Research Site Knoxville Tennessee United States 37909-1900
    67 Research Site Carrollton Texas United States 75007
    68 Research Site Corpus Christi Texas United States 78404
    69 Research Site Cypress Texas United States 77429
    70 Research Site League City Texas United States 77573
    71 Research Site Plano Texas United States 75024
    72 Research Site San Antonio Texas United States 78229
    73 Research Site Webster Texas United States 77598
    74 Research Site Danville Virginia United States 24541
    75 Research Site Buenos Aires Argentina 1425
    76 Research Site Plovdiv Bulgaria 4000
    77 Research Site Plovdiv Bulgaria 4002
    78 Research Site Sofia Bulgaria 1505
    79 Research Site Sofia Bulgaria 1612
    80 Research Site Sofia Bulgaria 1784
    81 Research Site Winnipeg Manitoba Canada R3N 0K6
    82 Research Site Sydney Nova Scotia Canada B1S 3N1
    83 Research Site Hamilton Ontario Canada L8N 1Y2
    84 Research Site Montreal Quebec Canada H2L 1S6
    85 Research Site Rimouski Quebec Canada G5L 8W1
    86 Research Site Trois-Rivieres Quebec Canada G8Z 1Y2
    87 Research Site Quebec Canada G1V 3M7
    88 Research Site Praha 2 Czechia 128 50
    89 Research Site Uherske Hradiste Czechia 686 01
    90 Research Site Bordeaux Cedex France 33076
    91 Research Site Cahors Cedex France 46005
    92 Research Site Montpellier cedex 05 France 34295
    93 Research Site Orleans cedex 2 France 45067
    94 Research Site Paris France 75010
    95 Research Site Berlin Germany 14059
    96 Research Site Frankfurt am Main Germany 60590
    97 Research Site Hildesheim Germany 31134
    98 Research Site Leipzig Germany 04103
    99 Research Site Püttlingen Germany 66346
    100 Research Site Athens Greece 11527
    101 Research Site Athens Greece 12462
    102 Research Site Athens Greece 14561
    103 Research Site Heraklion Greece 71110
    104 Research Site Thessaloniki Greece 54636
    105 Research Site Thessaloniki Greece 56429
    106 Research Site Budapest Hungary 1023
    107 Research Site Budapest Hungary 1036
    108 Research Site Veszprem Hungary 8200
    109 Research Site Bari Italy 70124
    110 Research Site Catania Italy 95124
    111 Research Site Firenze Italy 50139
    112 Research Site Napoli Italy 80131
    113 Research Site Reggio Emilia Italy 42123
    114 Research Site Roma Italy 00128
    115 Research Site Verona Italy 37126
    116 Research Site Mexicali Baja California Norte Mexico 21100
    117 Research Site Guadalajara Jalisco Mexico 44650
    118 Research Site Monterrey Nuevo León Mexico 64020
    119 Research Site Chihuahua Mexico 31000
    120 Research Site Bydgoszcz Poland 85-168
    121 Research Site Karwiany Poland 52-200
    122 Research Site Sopot Poland 81-759
    123 Research Site Stalowa Wola Poland 37-450
    124 Research Site Coimbra Portugal 3000-075
    125 Research Site Lisboa Portugal 1050-034
    126 Research Site Lisboa Portugal 1649-035
    127 Research Site Ponte de Lima Portugal 4990-041
    128 Research Site Panorama Western Cape South Africa 7500
    129 Research Site Sevilla Andalucía Spain 41009
    130 Research Site Salamanca Castilla León Spain 37007
    131 Research Site Barcelona Cataluña Spain 08026
    132 Research Site Valencia Comunidad Valenciana Spain 46017
    133 Research Site A Coruña Galicia Spain 15006
    134 Research Site Majadahonda Madrid Spain 28222
    135 Research Site El Palmar Murcia Spain 30120
    136 Research Site Bilbao País Vasco Spain 48013

    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT02373813
    Other Study ID Numbers:
    • 20110186
    First Posted:
    Feb 27, 2015
    Last Update Posted:
    Dec 19, 2020
    Last Verified:
    Nov 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid
    Folic Acid
    Etanercept
    Methotrexate

    Study Results

    Participant Flow

    Recruitment Details This study was conducted at 97 centers in Canada, United States, Argentina, Bulgaria, Czech Republic, Spain, France, Germany, Greece, Hungary, Italy, Mexico, Poland, Portugal, and South Africa. The first participant enrolled on 20 February 2015; the last participant enrolled on 26 June 2018.
    Pre-assignment Detail After a 24-week open label run-in period, participants were randomly assigned in a 2:2:1 ratio to one of three treatment groups: methotrexate monotherapy, etanercept monotherapy, or etanercept plus methotrexate.
    Arm/Group Title Open Label Run-In: Etanercept Plus Methotrexate Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 24 weeks. Participants also receive folic acid as standard of care. Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Period Title: Run-In Period
    STARTED 371 0 0 0
    Treated 368 0 0 0
    COMPLETED 255 0 0 0
    NOT COMPLETED 116 0 0 0
    Period Title: Run-In Period
    STARTED 0 101 101 51
    Received Investigational Product (IP) 0 101 100 51
    Received Rescue Treatment 0 52 36 15
    COMPLETED 0 88 92 47
    NOT COMPLETED 0 13 9 4

    Baseline Characteristics

    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate Total
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment). Total of all reporting groups
    Overall Participants 101 101 51 253
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    56.2
    (11.4)
    54.8
    (12.8)
    55.9
    (12.6)
    55.6
    (12.2)
    Sex: Female, Male (Count of Participants)
    Female
    76
    75.2%
    77
    76.2%
    40
    78.4%
    193
    76.3%
    Male
    25
    24.8%
    24
    23.8%
    11
    21.6%
    60
    23.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    13
    12.9%
    19
    18.8%
    8
    15.7%
    40
    15.8%
    Not Hispanic or Latino
    88
    87.1%
    82
    81.2%
    43
    84.3%
    213
    84.2%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian or Alaska Native
    4
    4%
    3
    3%
    2
    3.9%
    9
    3.6%
    Asian
    2
    2%
    0
    0%
    1
    2%
    3
    1.2%
    Black
    3
    3%
    7
    6.9%
    5
    9.8%
    15
    5.9%
    White
    92
    91.1%
    86
    85.1%
    42
    82.4%
    220
    87%
    Other, Not Specified
    0
    0%
    5
    5%
    1
    2%
    6
    2.4%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission (≤ 3.3) at Week 48: Etanercept Monotherapy vs. Methotrexate Monotherapy
    Description The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.
    Time Frame Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Nonresponder imputation.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).
    Measure Participants 101 101
    Number [percentage of participants]
    28.7
    28.4%
    49.5
    49%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.004
    Comments The risk difference and its p-value were estimated from the chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 20.8
    Confidence Interval (2-Sided) 95%
    7.6 to 33.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.7
    Estimation Comments
    2. Secondary Outcome
    Title Percentage of Participants With SDAI Remission (≤ 3.3) at Week 48: Etanercept and Methotrexate vs. Methotrexate Monotherapy
    Description The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.
    Time Frame Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Nonresponder imputation.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 51
    Number [percentage of participants]
    28.7
    28.4%
    52.9
    52.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.006
    Comments The risk difference and its p-value were estimated from the chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 24.2
    Confidence Interval (2-Sided) 95%
    7.9 to 40.5
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 8.3
    Estimation Comments
    3. Secondary Outcome
    Title SDAI Score at All Measured Timepoints
    Description The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given timepoints.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Baseline
    1.29
    (0.10)
    1.26
    (0.14)
    1.18
    (0.17)
    Week 12
    7.01
    (1.01)
    4.37
    (0.75)
    4.39
    (1.22)
    Week 24
    5.61
    (0.98)
    4.98
    (0.92)
    3.28
    (0.77)
    Week 36
    4.03
    (0.62)
    2.25
    (0.36)
    2.41
    (0.40)
    Week 48
    3.41
    (0.40)
    2.33
    (0.23)
    2.86
    (0.92)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.58
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.11
    Confidence Interval (2-Sided) 95%
    -0.48 to 0.27
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.19
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.85
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.03
    Confidence Interval (2-Sided) 95%
    -0.37 to 0.31
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.17
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.12
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.61
    Confidence Interval (2-Sided) 95%
    -5.89 to 0.67
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.66
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.037
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.64
    Confidence Interval (2-Sided) 95%
    -5.12 to -0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.26
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.063
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.33
    Confidence Interval (2-Sided) 95%
    -4.80 to 0.13
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.46
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.64
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.63
    Confidence Interval (2-Sided) 95%
    -3.27 to 2.01
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.34
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.031
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.62
    Confidence Interval (2-Sided) 95%
    -3.09 to -0.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.90
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.015
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.77
    Confidence Interval (2-Sided) 95%
    -3.20 to -0.35
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.71
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.58
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.55
    Confidence Interval (2-Sided) 95%
    -2.55 to 1.45
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.87
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.020
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.08
    Confidence Interval (2-Sided) 95%
    -1.99 to -0.17
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.45
    Estimation Comments
    4. Secondary Outcome
    Title Change From Baseline in SDAI Score at All Measured Timepoints
    Description The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3. A negative change from baseline indicates improvement.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Change at Week 12
    5.67
    (1.00)
    3.14
    (0.75)
    3.21
    (1.19)
    Change at Week 24
    4.42
    (0.98)
    3.78
    (0.91)
    2.14
    (0.78)
    Change at Week 36
    2.90
    (0.63)
    1.06
    (0.38)
    1.30
    (0.43)
    Change at Week 48
    2.27
    (0.39)
    1.16
    (0.24)
    1.77
    (0.94)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.13
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.46
    Confidence Interval (2-Sided) 95%
    -5.68 to 0.77
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.63
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.045
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.53
    Confidence Interval (2-Sided) 95%
    -4.99 to -0.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.25
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.071
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.27
    Confidence Interval (2-Sided) 95%
    -4.75 to 0.20
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.45
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.63
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.64
    Confidence Interval (2-Sided) 95%
    -3.28 to 2.00
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.34
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.037
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.61
    Confidence Interval (2-Sided) 95%
    -3.11 to -0.10
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.91
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.013
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.84
    Confidence Interval (2-Sided) 95%
    -3.30 to -0.39
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.73
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.62
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.51
    Confidence Interval (2-Sided) 95%
    -2.54 to 1.53
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.88
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.015
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.12
    Confidence Interval (2-Sided) 95%
    -2.02 to -0.22
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.45
    Estimation Comments
    5. Secondary Outcome
    Title Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints
    Description The DAS28-ESR is a modified composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, ESR in mm/hr, and a 100 mm VAS measuring the participant's general health, from 0 (best) to 100 (worst). DAS28-ESR scores range from 0 to 9.4, where higher scores represent higher disease activity.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Baseline
    1.80
    (0.06)
    1.88
    (0.07)
    1.84
    (0.09)
    Week 12
    2.78
    (0.14)
    2.37
    (0.12)
    2.32
    (0.16)
    Week 24
    2.41
    (0.13)
    2.54
    (0.14)
    2.17
    (0.12)
    Week 36
    2.32
    (0.11)
    2.17
    (0.08)
    2.16
    (0.12)
    Week 48
    2.22
    (0.10)
    2.21
    (0.08)
    2.11
    (0.13)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.75
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.04
    Confidence Interval (2-Sided) 95%
    -0.19 to 0.26
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.11
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.43
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.08
    Confidence Interval (2-Sided) 95%
    -0.11 to 0.27
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.10
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.049
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.46
    Confidence Interval (2-Sided) 95%
    -0.91 to 0.00
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.23
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.032
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.40
    Confidence Interval (2-Sided) 95%
    -0.77 to -0.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.19
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.18
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.24
    Confidence Interval (2-Sided) 95%
    -0.58 to 0.11
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.20
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.48
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.14
    Confidence Interval (2-Sided) 95%
    -0.24 to 0.51
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.19
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.35
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.16
    Confidence Interval (2-Sided) 95%
    -0.51 to 0.18
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.17
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.28
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.15
    Confidence Interval (2-Sided) 95%
    -0.41 to 0.12
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.13
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.48
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.12
    Confidence Interval (2-Sided) 95%
    -0.44 to 0.21
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.92
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.26 to 0.24
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.13
    Estimation Comments
    6. Secondary Outcome
    Title Change From Baseline in DAS28-ESR at All Measured Timepoints
    Description The DAS28-ESR is a modified composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, ESR in mm/hr, and a 100 mm VAS measuring the participant's general health, from 0 (best) to 100 (worst). DAS28-ESR scores range from 0 to 9.4, where higher scores represent higher disease activity. A negative change from baseline indicates improvement.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given time point.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Change at Week 12
    0.96
    (0.13)
    0.50
    (0.10)
    0.48
    (0.18)
    Change at Week 24
    0.65
    (0.12)
    0.69
    (0.13)
    0.34
    (0.11)
    Change at Week 36
    0.53
    (0.10)
    0.31
    (0.08)
    0.35
    (0.12)
    Change at Week 48
    0.43
    (0.09)
    0.34
    (0.07)
    0.32
    (0.14)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.032
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.48
    Confidence Interval (2-Sided) 95%
    -0.91 to -0.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.22
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.005
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.46
    Confidence Interval (2-Sided) 95%
    -0.78 to -0.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.058
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.31
    Confidence Interval (2-Sided) 95%
    -0.63 to 0.01
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.18
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.78
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.05
    Confidence Interval (2-Sided) 95%
    -0.29 to 0.38
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.17
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.27
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.18
    Confidence Interval (2-Sided) 95%
    -0.49 to 0.14
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.078
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.22
    Confidence Interval (2-Sided) 95%
    -0.47 to 0.03
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.12
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.47
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.12
    Confidence Interval (2-Sided) 95%
    -0.43 to 0.20
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.39
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.10
    Confidence Interval (2-Sided) 95%
    -0.33 to 0.13
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.11
    Estimation Comments
    7. Secondary Outcome
    Title Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints
    Description The DAS28-CRP is a composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, CRP in mg/L, and a 100 mm VAS measuring the participant's general health from 0 (best) to 100 (worst). DAS28-CRP scores range from 0 to 9.4, where higher scores represent higher disease activity.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given time point.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Baseline
    1.50
    (0.03)
    1.50
    (0.04)
    1.54
    (0.05)
    Week 12
    2.36
    (0.13)
    1.91
    (0.09)
    1.94
    (0.15)
    Week 24
    2.15
    (0.11)
    2.00
    (0.11)
    1.77
    (0.09)
    Week 36
    1.96
    (0.09)
    1.67
    (0.06)
    1.72
    (0.08)
    Week 48
    1.87
    (0.07)
    1.67
    (0.05)
    1.72
    (0.11)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.60
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.03
    Confidence Interval (2-Sided) 95%
    -0.09 to 0.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.06
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.97
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    -0.10 to 0.10
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.05
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.044
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.41
    Confidence Interval (2-Sided) 95%
    -0.82 to -0.01
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.20
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.004
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.45
    Confidence Interval (2-Sided) 95%
    -0.76 to -0.14
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.009
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.38
    Confidence Interval (2-Sided) 95%
    -0.66 to -0.10
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.17
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.34
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.15
    Confidence Interval (2-Sided) 95%
    -0.46 to 0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.046
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.24
    Confidence Interval (2-Sided) 95%
    -0.47 to 0.00
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.13
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.006
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.29
    Confidence Interval (2-Sided) 95%
    -0.49 to -0.08
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.10
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.25
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.15
    Confidence Interval (2-Sided) 95%
    -0.40 to -0.10
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.13
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.021
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.20
    Confidence Interval (2-Sided) 95%
    -0.37 to -0.03
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.08
    Estimation Comments
    8. Secondary Outcome
    Title Change From Baseline in DAS28-CRP at All Measured Timepoints
    Description The DAS28-CRP is a composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, CRP in mg/L, and a 100 mm VAS measuring the participant's general health from 0 (best) to 100 (worst). DAS28-CRP scores range from 0 to 9.4, where higher scores represent higher disease activity. A negative change from baseline indicates improvement.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Change at Week 12
    0.84
    (0.12)
    0.42
    (0.09)
    0.41
    (0.15)
    Change at Week 24
    0.67
    (0.11)
    0.52
    (0.11)
    0.25
    (0.08)
    Change at Week 36
    0.49
    (0.09)
    0.18
    (0.06)
    0.20
    (0.08)
    Change at Week 48
    0.40
    (0.07)
    0.19
    (0.04)
    0.21
    (0.11)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.030
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.43
    Confidence Interval (2-Sided) 95%
    -0.82 to -0.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.20
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.005
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.42
    Confidence Interval (2-Sided) 95%
    -0.72 to -0.13
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.15
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.42
    Confidence Interval (2-Sided) 95%
    -0.69 to -0.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.34
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.15
    Confidence Interval (2-Sided) 95%
    -0.46 to 0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.014
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.29
    Confidence Interval (2-Sided) 95%
    -0.52 to -0.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.13
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.004
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.30
    Confidence Interval (2-Sided) 95%
    -0.51 to -0.10
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.10
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.12
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.19
    Confidence Interval (2-Sided) 95%
    -0.43 to 0.05
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.12
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.010
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.21
    Confidence Interval (2-Sided) 95%
    -0.37 to -0.05
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.08
    Estimation Comments
    9. Secondary Outcome
    Title Clinical Disease Activity Index (CDAI) at All Measured Timepoints
    Description The CDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, and Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable. The CDAI score ranges from 0 to 76, where a higher score represents worse disease.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Baseline
    1.01
    (0.10)
    0.92
    (0.13)
    0.71
    (0.12)
    Week 12
    6.42
    (0.98)
    4.08
    (0.74)
    3.95
    (1.20)
    Week 24
    5.07
    (0.95)
    4.63
    (0.91)
    2.35
    (0.60)
    Week 36
    3.60
    (0.63)
    1.93
    (0.36)
    2.04
    (0.41)
    Week 48
    3.06
    (0.38)
    2.00
    (0.23)
    2.61
    (0.91)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.067
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.30
    Confidence Interval (2-Sided) 95%
    -0.62 to 0.02
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.59
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.09
    Confidence Interval (2-Sided) 95%
    -0.41 to 0.23
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.13
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.46
    Confidence Interval () 95%
    -5.66 to 0.74
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.62
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.059
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.34
    Confidence Interval (2-Sided) 95%
    -4.76 to 0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.23
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.017
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.72
    Confidence Interval (2-Sided) 95%
    -4.95 to -0.50
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.38
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.74
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.44
    Confidence Interval (2-Sided) 95%
    -3.04 to 2.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.32
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.039
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.56
    Confidence Interval (2-Sided) 95%
    -3.03 to -0.08
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.90
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.66
    Confidence Interval (2-Sided) 95%
    -3.10 to -0.23
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.72
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.65
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.46
    Confidence Interval (2-Sided) 95%
    -2.43 to 1.52
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.85
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.017
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.07
    Confidence Interval (2-Sided) 95%
    -1.94 to -0.19
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.44
    Estimation Comments
    10. Secondary Outcome
    Title Change From Baseline in CDAI at All Measured Timepoints
    Description The CDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, and Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable. The CDAI score ranges from 0 to 76, where a higher score represents worse disease. A negative change from baseline indicates improvement.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Change at Week 12
    5.39
    (0.97)
    3.15
    (0.73)
    3.24
    (1.17)
    Change at Week 24
    4.09
    (0.95)
    3.75
    (0.90)
    1.70
    (0.61)
    Change at Week 36
    2.69
    (0.63)
    1.07
    (0.37)
    1.41
    (0.40)
    Change at Week 48
    2.17
    (0.37)
    1.15
    (0.23)
    2.00
    (0.92)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.18
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.15
    Confidence Interval () 95%
    -5.29 to 1.00
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.59
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.067
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.24
    Confidence Interval (2-Sided) 95%
    -4.63 to 0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.21
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.035
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -2.40
    Confidence Interval (2-Sided) 95%
    -4.62 to -0.17
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.37
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.79
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.34
    Confidence Interval (2-Sided) 95%
    -2.91 to 2.23
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.30
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.090
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.27
    Confidence Interval (2-Sided) 95%
    -2.75 to 0.20
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.91
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.029
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.61
    Confidence Interval (2-Sided) 95%
    -3.06 to -0.17
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.72
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Change at Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.86
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.17
    Confidence Interval (2-Sided) 95%
    -2.15 to 1.81
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.84
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Change at Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.021
    Comments
    Method two sample t-test
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -1.02
    Confidence Interval (2-Sided) 95%
    -1.88 to -0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.43
    Estimation Comments
    11. Secondary Outcome
    Title Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints
    Description The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given time point.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Baseline
    96.0
    95%
    92.1
    91.2%
    96.1
    188.4%
    Week 12
    50.0
    49.5%
    64.0
    63.4%
    74.5
    146.1%
    Week 24
    38.8
    38.4%
    56.6
    56%
    62.0
    121.6%
    Week 36
    36.1
    35.7%
    55.6
    55%
    55.1
    108%
    Week 48
    30.5
    30.2%
    52.1
    51.6%
    56.3
    110.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 1.00
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.1
    Confidence Interval (2-Sided) 95%
    -6.5 to 6.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.4
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.38
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -3.9
    Confidence Interval (2-Sided) 95%
    -10.4 to 2.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 3.3
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.007
    Comments
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 24.5
    Confidence Interval (2-Sided) 95%
    9.0 to 40.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 7.9
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.063
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 14.0
    Confidence Interval (2-Sided) 95%
    0.4 to 27.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.9
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.012
    Comments
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 23.2
    Confidence Interval (2-Sided) 95%
    6.7 to 39.8
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 8.4
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.018
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 17.8
    Confidence Interval (2-Sided) 95%
    4.1 to 31.5
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 7.0
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.044
    Comments
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 19.0
    Confidence Interval (2-Sided) 95%
    2.1 to 35.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 8.6
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.010
    Comments
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 19.5
    Confidence Interval (2-Sided) 95%
    5.8 to 33.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 7.0
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.005
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 25.7
    Confidence Interval (2-Sided) 95%
    8.9 to 42.5
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 8.6
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.004
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 21.6
    Confidence Interval (2-Sided) 95%
    7.9 to 35.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 7.0
    Estimation Comments
    12. Secondary Outcome
    Title Percentage of Participants With Boolean Remission at All Measured Timepoints
    Description A participant achieves Boolean remission (66/68-joint count) if all of the following criteria are met at a single timepoint: 68-joint tender joint count ≤ 1 66-joint swollen joint count ≤ 1 CRP (mg/dL) ≤ 1 Patient's Global Assessment of Disease Activity using a VAS (where 0=no arthritis activity at all and 10=worst arthritis activity imaginable) ≤ 1.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Baseline
    34.0
    33.7%
    34.7
    34.4%
    45.1
    88.4%
    Week 12
    18.0
    17.8%
    23.0
    22.8%
    19.6
    38.4%
    Week 24
    15.2
    15%
    16.7
    16.5%
    26.5
    52%
    Week 36
    14.6
    14.5%
    20.4
    20.2%
    27.1
    53.1%
    Week 48
    20.2
    20%
    13.3
    13.2%
    25.5
    50%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.25
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 11.1
    Confidence Interval (2-Sided) 95%
    -5.4 to 27.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 8.4
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Baseline
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 1.00
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.7
    Confidence Interval (2-Sided) 95%
    -12.5 to 13.8
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.7
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.98
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 1.6
    Confidence Interval (2-Sided) 95%
    -11.6 to 14.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.8
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 12
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.48
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 5.0
    Confidence Interval (2-Sided) 95%
    -6.2 to 16.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.7
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.16
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 11.3
    Confidence Interval (2-Sided) 95%
    -3.1 to 25.7
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 7.3
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.94
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 1.4
    Confidence Interval (2-Sided) 95%
    -9.0 to 11.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.3
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.12
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 12.5
    Confidence Interval (2-Sided) 95%
    -2.1 to 27.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 7.4
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 36
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.40
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 5.8
    Confidence Interval (2-Sided) 95%
    -5.2 to 16.8
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.6
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.63
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 5.3
    Confidence Interval (2-Sided) 95%
    -9.8 to 20.4
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 7.7
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments Week 48
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.31
    Comments The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -6.9
    Confidence Interval (2-Sided) 95%
    -18.0 to 4.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 5.7
    Estimation Comments
    13. Secondary Outcome
    Title Percentage of Participants With Disease Worsening
    Description Percentage of participants who fulfilled disease-worsening criteria for the first time is presented. Disease worsening is defined as any of the following: an SDAI > 3.3 and ≤ 11 during 2 consecutive visits at least 2 weeks apart SDAI > 3.3 and ≤ 11 on 3 or more separate visits SDAI > 11 after randomization. The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.
    Time Frame Baseline, Week 12, Week 24, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 101 101 51
    Baseline
    0.0
    0%
    0.0
    0%
    0.0
    0%
    Week 12
    42.0
    41.6%
    23.0
    22.8%
    17.6
    34.5%
    Week 24
    8.7
    8.6%
    14.6
    14.5%
    6.1
    12%
    Week 36
    10.1
    10%
    3.2
    3.2%
    8.3
    16.3%
    Week 48
    4.8
    4.8%
    0.0
    0%
    4.3
    8.4%
    14. Secondary Outcome
    Title Time to Disease Worsening
    Description Disease worsening is defined as any of the following: an SDAI > 3.3 and ≤ 11 during 2 consecutive visits at least 2 weeks apart SDAI > 3.3 and ≤ 11 on 3 or more separate visits SDAI > 11 after randomization. The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.
    Time Frame up to Week 48

    Outcome Measure Data

    Analysis Population Description
    Primary Analysis Set: all randomized participants. Participants with disease worsening.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 63 40 18
    Median (Full Range) [weeks]
    12.14
    13.21
    18.93
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.001
    Comments P-value was based on the Log-rank test for overall difference on disease-worsening event between two groups.
    Method Log Rank
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.001
    Comments P-value was based on the Log-rank test for overall difference on disease-worsening event between two groups.
    Method Log Rank
    Comments
    15. Secondary Outcome
    Title Time to Recapture SDAI Remission After Starting Rescue Treatment
    Description In participants who receive rescue treatment during the double-blind treatment period. The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.
    Time Frame Between rescue and remission or Week 48, whichever comes first.

    Outcome Measure Data

    Analysis Population Description
    Rescue Analysis Set: randomized participants who met the definition of disease-worsening and received both at least 1 dose of active rescue therapy etanercept and at least 1 dose of active rescue therapy methotrexate. Participants who recaptured SDAI remission. Observed cases.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 37 27 12
    Median (Full Range) [weeks]
    11.00
    12.00
    11.36
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.31
    Comments P-value was based on the Log-rank test for overall difference on disease-worsening event between two groups.
    Method Log Rank
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Monotherapy
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.51
    Comments P-value was based on the Log-rank test for overall difference on disease-worsening event between two groups.
    Method Log Rank
    Comments
    16. Secondary Outcome
    Title Percentage of Participants Receiving Rescue Treatment Who Experienced SDAI Remission at Week 48
    Description The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.
    Time Frame Week 48

    Outcome Measure Data

    Analysis Population Description
    Rescue Analysis Set: randomized participants who met the definition of disease-worsening and received both at least 1 dose of active rescue therapy etanercept and at least 1 dose of active rescue therapy methotrexate. Observed cases.
    Arm/Group Title Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate
    Arm/Group Description Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
    Measure Participants 48 34 15
    Number [percentage of participants]
    54.2
    53.7%
    55.9
    55.3%
    66.7
    130.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment: Methotrexate Monotherapy, Double-Blind Treatment: Etanercept Plus Methotrexate
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.58
    Comments
    Method Chi-squared, Corrected
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 12.5
    Confidence Interval (2-Sided) 95%
    -15.2 to 40.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 14.1
    Estimation Comments

    Adverse Events

    Time Frame Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
    Adverse Event Reporting Description
    Arm/Group Title Open Label Run-In: Etanercept Plus Methotrexate Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate Open Label Rescue: Etanercept Plus Methotrexate
    Arm/Group Description Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 24 weeks. Participants also receive folic acid as standard of care. Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment). After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).
    All Cause Mortality
    Open Label Run-In: Etanercept Plus Methotrexate Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate Open Label Rescue: Etanercept Plus Methotrexate
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Serious Adverse Events
    Open Label Run-In: Etanercept Plus Methotrexate Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate Open Label Rescue: Etanercept Plus Methotrexate
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 14/368 (3.8%) 3/100 (3%) 3/99 (3%) 2/53 (3.8%) 4/103 (3.9%)
    Cardiac disorders
    Atrial fibrillation 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Gastrointestinal disorders
    Gastric ulcer haemorrhage 0/368 (0%) 0/100 (0%) 1/99 (1%) 0/53 (0%) 0/103 (0%)
    Duodenal perforation 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Hepatobiliary disorders
    Cholecystitis 0/368 (0%) 1/100 (1%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Infections and infestations
    Herpes zoster 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Pneumonia 2/368 (0.5%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Respiratory syncytial virus infection 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Abscess intestinal 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Abscess of salivary gland 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Cellulitis 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Injury, poisoning and procedural complications
    Ankle fracture 0/368 (0%) 0/100 (0%) 0/99 (0%) 1/53 (1.9%) 0/103 (0%)
    Aortic pseudoaneurysm 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Concussion 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Spinal fracture 0/368 (0%) 0/100 (0%) 1/99 (1%) 0/53 (0%) 0/103 (0%)
    Foot fracture 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Metabolism and nutrition disorders
    Hyponatraemia 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Musculoskeletal and connective tissue disorders
    Arthritis reactive 0/368 (0%) 1/100 (1%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Osteoarthritis 0/368 (0%) 0/100 (0%) 0/99 (0%) 1/53 (1.9%) 0/103 (0%)
    Rheumatoid arthritis 0/368 (0%) 0/100 (0%) 1/99 (1%) 0/53 (0%) 0/103 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour benign 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Basal cell carcinoma 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Prostate cancer stage III 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Small cell lung cancer 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Nervous system disorders
    Carotid artery stenosis 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Carpal tunnel syndrome 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Cerebrovascular accident 2/368 (0.5%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Psychiatric disorders
    Alcoholism 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Confusional state 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Renal and urinary disorders
    Nephrolithiasis 1/368 (0.3%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Respiratory failure 0/368 (0%) 0/100 (0%) 0/99 (0%) 0/53 (0%) 1/103 (1%)
    Vascular disorders
    Deep vein thrombosis 0/368 (0%) 1/100 (1%) 0/99 (0%) 0/53 (0%) 0/103 (0%)
    Other (Not Including Serious) Adverse Events
    Open Label Run-In: Etanercept Plus Methotrexate Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept Plus Methotrexate Open Label Rescue: Etanercept Plus Methotrexate
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 29/368 (7.9%) 21/100 (21%) 12/99 (12.1%) 8/53 (15.1%) 9/103 (8.7%)
    Infections and infestations
    Bronchitis 6/368 (1.6%) 0/100 (0%) 3/99 (3%) 4/53 (7.5%) 0/103 (0%)
    Upper respiratory tract infection 20/368 (5.4%) 3/100 (3%) 3/99 (3%) 1/53 (1.9%) 7/103 (6.8%)
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis 3/368 (0.8%) 18/100 (18%) 7/99 (7.1%) 3/53 (5.7%) 2/103 (1.9%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen Inc.
    Phone 866-572-6436
    Email medinfo@amgen.com
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT02373813
    Other Study ID Numbers:
    • 20110186
    First Posted:
    Feb 27, 2015
    Last Update Posted:
    Dec 19, 2020
    Last Verified:
    Nov 1, 2020