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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02373813
Recruitment Status : Completed
First Posted : February 27, 2015
Results First Posted : December 19, 2020
Last Update Posted : January 11, 2023
Sponsor:
Information provided by (Responsible Party):
Amgen

Tracking Information
First Submitted Date  ICMJE January 12, 2015
First Posted Date  ICMJE February 27, 2015
Results First Submitted Date  ICMJE November 24, 2020
Results First Posted Date  ICMJE December 19, 2020
Last Update Posted Date January 11, 2023
Actual Study Start Date  ICMJE February 20, 2015
Actual Primary Completion Date December 6, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 24, 2020)
Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission (≤ 3.3) at Week 48: Etanercept Monotherapy vs. Methotrexate Monotherapy [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 23, 2015)
Simplified Disease Activity Index (SDAI) remission (≤ 3.3) at week 48 [ Time Frame: Week 48 Visit ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 24, 2020)
  • Percentage of Participants With SDAI Remission (≤ 3.3) at Week 48: Etanercept and Methotrexate vs. Methotrexate Monotherapy [ Time Frame: 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.
  • SDAI Score at All Measured Timepoints [ Time Frame: 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.
  • Change From Baseline in SDAI Score at All Measured Timepoints [ Time Frame: 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.
  • Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints [ Time Frame: 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.
  • Change From Baseline in DAS28-ESR at All Measured Timepoints [ Time Frame: 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.
  • Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints [ Time Frame: 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.
  • Change From Baseline in DAS28-CRP at All Measured Timepoints [ Time Frame: 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.
  • Clinical Disease Activity Index (CDAI) at All Measured Timepoints [ Time Frame: 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.
  • Change From Baseline in CDAI at All Measured Timepoints [ Time Frame: 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.
  • Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints [ Time Frame: 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.
  • Percentage of Participants With Boolean Remission at All Measured Timepoints [ Time Frame: 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.
  • Percentage of Participants With Disease Worsening [ Time Frame: 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.
  • Time to Disease Worsening [ Time Frame: 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.
  • Time to Recapture SDAI Remission After Starting Rescue Treatment [ Time Frame: 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.
  • Percentage of Participants Receiving Rescue Treatment Who Experienced SDAI Remission at Week 48 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 23, 2015)
  • SDAI score and change from baseline at all measured timepoints [ Time Frame: Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
  • Disease activity score (28 joint) calculated using the erythrocyte sedimentation rate formula (DAS-28-ESR) and change from baseline at all measured timepoints [ Time Frame: Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
  • Disease activity score (28 joint) using the C-reactive protein formula (DAS-28-CRP) and change from baseline at all measured timepoints [ Time Frame: Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
  • Clinical Disease Activity Index (CDAI) and change from baseline at all measured timepoints [ Time Frame: Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
  • Disease worsening defined as an SDAI > 3.3 and ≤ 11 during two consecutive visits at least 2 weeks apart or SDAI > 3.3 and ≤ 11 on three or more separate visits or SDAI > 11 after randomization. [ Time Frame: Visit at 24 weeks prior to Day 1, Visit at 12 weeks prior to Day 1, Visit at 1 week prior to Day1, Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
  • Time to disease worsening defined as an SDAI > 3.3 and ≤ 11 during two consecutive visits at least 2 weeks apart or SDAI > 3.3 and ≤ 11 on three or more separate visits or SDAI > 11 after randomization. [ Time Frame: Visit at 24 weeks prior to Day 1, Visit at 12 weeks prior to Day 1, Visit at 1 week prior to Day1, Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
  • In subjects that receive rescue treatment:Time to recapture SDAI remission after starting rescue treatment and SDAI remission at week 48 [ Time Frame: Timepoints dependent on when rescue is started, but could include Visit at 24 weeks prior to Day 1, Visit at 12 weeks prior to Day 1, Visit at 1 week prior to Day1, Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
  • SDAI remission (≤ 3.3) at all measured timepoints [ Time Frame: Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
  • Boolean remission (at a single time point a subject must satisfy all of the following: tender joint count, swollen joint count, c-reactive protein and patient global assessment must each be less than or equal to 1) at all measured timepoints. [ Time Frame: Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: February 23, 2015)
Safety of etanercept and methotrexate by assessing the adverse events, serious adverse events and lab parameters of participants in the study. [ Time Frame: Visit at 24 weeks prior to Day 1, Visit at 12 weeks prior to Day 1, Visit at 1 week prior to Day1, Day 1, Week 12, Week 24, Week 36 and Week 48 visits ]
 
Descriptive Information
Brief Title  ICMJE Study of Etanercept Monotherapy vs Methotrexate Monotherapy for Maintenance of Rheumatoid Arthritis Remission
Official Title  ICMJE A Randomized Withdrawal Double-blind Study of Etanercept Monotherapy Compared to Methotrexate Monotherapy for Maintenance of Remission in Subjects With Rheumatoid Arthritis
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Rheumatoid Arthritis
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: etanercept pre-filled syringe subcutaneous injection
    • Drug: Oral methotrexate
    • Dietary Supplement: Folic acid (non-investigational product)
  • 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).

    Interventions:
    • Drug: etanercept pre-filled syringe subcutaneous injection
    • Drug: Oral methotrexate
    • Drug: Placebo for etanercept subcutaneous injection
    • Dietary Supplement: Folic acid (non-investigational product)
  • 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).

    Interventions:
    • Drug: etanercept pre-filled syringe subcutaneous injection
    • Drug: Oral methotrexate
    • Drug: Placebo for methotrexate
    • Dietary Supplement: Folic acid (non-investigational product)
  • 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).

    Interventions:
    • Drug: etanercept pre-filled syringe subcutaneous injection
    • Drug: Oral methotrexate
    • Dietary Supplement: Folic acid (non-investigational product)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 9, 2018)
371
Original Estimated Enrollment  ICMJE
 (submitted: February 23, 2015)
720
Actual Study Completion Date  ICMJE December 6, 2019
Actual Primary Completion Date December 6, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Bulgaria,   Canada,   Czechia,   France,   Germany,   Greece,   Hungary,   Italy,   Mexico,   Poland,   Portugal,   South Africa,   Spain,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02373813
Other Study ID Numbers  ICMJE 20110186
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
URL: https://www.amgen.com/datasharing
Current Responsible Party Amgen
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Amgen
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: MD Amgen
PRS Account Amgen
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP