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

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ClinicalTrials.gov Identifier: NCT02373813
Recruitment Status : Completed
First Posted : February 27, 2015
Results First Posted : December 19, 2020
Last Update Posted : December 19, 2020
Sponsor:
Information provided by (Responsible Party):
Amgen

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
Rheumatoid Arthritis 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

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Study Type : Interventional  (Clinical Trial)
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 : February 20, 2015
Actual Primary Completion Date : December 6, 2019
Actual Study Completion Date : December 6, 2019

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.


  13. 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.


  14. 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.


  15. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02373813


Locations
Show Show 136 study locations
Sponsors and Collaborators
Amgen
Investigators
Layout table for investigator information
Study Director: MD Amgen
  Study Documents (Full-Text)

Documents provided by Amgen:
Study Protocol  [PDF] October 17, 2017
Statistical Analysis Plan  [PDF] January 7, 2020

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT02373813    
Other Study ID Numbers: 20110186
First Posted: February 27, 2015    Key Record Dates
Results First Posted: December 19, 2020
Last Update Posted: December 19, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Folic Acid
Etanercept
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents