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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized Withdrawal Double-blind Study of Etanercept Monotherapy Compared to Methotrexate Monotherapy for Maintenance of Remission in Subjects With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label Run-In: Etanercept plus Methotrexate<br>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<br>* etanercept for injection in pre-filled syringes<br>* Other names: AMG916;Drug: Oral methotrexate<br>* 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.<br>Dietary Supplement: Folic acid (non-investigational product)<br>* Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.<br>|
| Experimental: Double-Blind Treatment: Methotrexate Monotherapy<br>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<br>* etanercept for injection in pre-filled syringes<br>* Other names: AMG916;Drug: Oral methotrexate<br>* 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.<br>Drug: Placebo for etanercept subcutaneous injection<br>* etanercept placebo for injection in pre-filled syringes<br>Dietary Supplement: Folic acid (non-investigational product)<br>* Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.<br>|
| Experimental: Double-Blind Treatment: Etanercept Monotherapy<br>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<br>* etanercept for injection in pre-filled syringes<br>* Other names: AMG916;Drug: Oral methotrexate<br>* 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.<br>Drug: Placebo for methotrexate<br>* methotrexate placebo capsules<br>Dietary Supplement: Folic acid (non-investigational product)<br>* Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.<br>|
| Experimental: Double-Blind Treatment: Etanercept plus Methotrexate<br>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<br>* etanercept for injection in pre-filled syringes<br>* Other names: AMG916;Drug: Oral methotrexate<br>* 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.<br>Dietary Supplement: Folic acid (non-investigational product)<br>* Folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission (≤ 3.3) at Week 48: Etanercept Monotherapy vs. Methotrexate Monotherapy | 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. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With SDAI Remission (≤ 3.3) at Week 48: Etanercept and Methotrexate vs. Methotrexate Monotherapy | 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. | Week 48 | 
| SDAI Score at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in SDAI Score at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in DAS28-ESR at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in DAS28-CRP at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Clinical Disease Activity Index (CDAI) at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in CDAI at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Percentage of Participants With Boolean Remission at All Measured Timepoints | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Percentage of Participants With Disease Worsening | 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. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Time to Disease Worsening | 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. | up to Week 48 | 
| Time to Recapture SDAI Remission After Starting Rescue Treatment | 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. | Between rescue and remission or Week 48, whichever comes first. | 
| Percentage of Participants Receiving Rescue Treatment Who Experienced SDAI Remission at 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. | Week 48 |