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

Rheumatoid Arthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02373813
• Other study ID #: 20110186
• Status: Completed
• Phase: Phase 3
• Start date: February 20, 2015
• Est. completion date: December 6, 2019

Study information

• Verified date: January 2023
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 371
• Est. completion date: December 6, 2019
• Est. primary completion date: December 6, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

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

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Quebec
Canada	Research Site	Rimouski	Quebec
Canada	Research Site	Sydney	Nova Scotia
Canada	Research Site	Trois-Rivieres	Quebec
Canada	Research Site	Winnipeg	Manitoba
Czechia	Research Site	Praha 2
Czechia	Research Site	Uherske Hradiste
France	Research Site	Bordeaux Cedex
France	Research Site	Cahors Cedex
France	Research Site	Montpellier cedex 05
France	Research Site	Orleans cedex 2
France	Research Site	Paris
Germany	Research Site	Berlin
Germany	Research Site	Frankfurt am Main
Germany	Research Site	Hildesheim
Germany	Research Site	Leipzig
Germany	Research Site	Püttlingen
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Heraklion
Greece	Research Site	Thessaloniki
Greece	Research Site	Thessaloniki
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Veszprem
Italy	Research Site	Bari
Italy	Research Site	Catania
Italy	Research Site	Firenze
Italy	Research Site	Napoli
Italy	Research Site	Reggio Emilia
Italy	Research Site	Roma
Italy	Research Site	Verona
Mexico	Research Site	Chihuahua
Mexico	Research Site	Guadalajara	Jalisco
Mexico	Research Site	Mexicali	Baja California Norte
Mexico	Research Site	Monterrey	Nuevo León
Poland	Research Site	Bydgoszcz
Poland	Research Site	Karwiany
Poland	Research Site	Sopot
Poland	Research Site	Stalowa Wola
Portugal	Research Site	Coimbra
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisboa
Portugal	Research Site	Ponte de Lima
South Africa	Research Site	Panorama	Western Cape
Spain	Research Site	A Coruña	Galicia
Spain	Research Site	Barcelona	Cataluña
Spain	Research Site	Bilbao	País Vasco
Spain	Research Site	El Palmar	Murcia
Spain	Research Site	Majadahonda	Madrid
Spain	Research Site	Salamanca	Castilla León
Spain	Research Site	Sevilla	Andalucía
Spain	Research Site	Valencia	Comunidad Valenciana
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Baton Rouge	Louisiana
United States	Research Site	Birmingham	Alabama
United States	Research Site	Birmingham	Alabama
United States	Research Site	Blue Island	Illinois
United States	Research Site	Boise	Idaho
United States	Research Site	Brooklyn	New York
United States	Research Site	Carrollton	Texas
United States	Research Site	Charleston	South Carolina
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Clifton	New Jersey
United States	Research Site	Corpus Christi	Texas
United States	Research Site	Cypress	Texas
United States	Research Site	Danville	Virginia
United States	Research Site	Detroit	Michigan
United States	Research Site	Doral	Florida
United States	Research Site	Duncansville	Pennsylvania
United States	Research Site	Escondido	California
United States	Research Site	Fontana	California
United States	Research Site	Fort Lauderdale	Florida
United States	Research Site	Freehold	New Jersey
United States	Research Site	Gainesville	Florida
United States	Research Site	Glendale	Arizona
United States	Research Site	Grand Rapids	Michigan
United States	Research Site	Granger	Indiana
United States	Research Site	Great Neck	New York
United States	Research Site	Greenville	North Carolina
United States	Research Site	Hemet	California
United States	Research Site	Huntington Beach	California
United States	Research Site	Huntsville	Alabama
United States	Research Site	Jackson	Tennessee
United States	Research Site	Kalamazoo	Michigan
United States	Research Site	Knoxville	Tennessee
United States	Research Site	La Jolla	California
United States	Research Site	Lansing	Michigan
United States	Research Site	Lansing	Michigan
United States	Research Site	Lawrenceville	Georgia
United States	Research Site	League City	Texas
United States	Research Site	Meridian	Idaho
United States	Research Site	Mesa	Arizona
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Murrieta	California
United States	Research Site	New Orleans	Louisiana
United States	Research Site	New York	New York
United States	Research Site	Newark	New Jersey
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Orange	California
United States	Research Site	Orangeburg	South Carolina
United States	Research Site	Orlando	Florida
United States	Research Site	Palm Harbor	Florida
United States	Research Site	Pensacola	Florida
United States	Research Site	Phoenix	Arizona
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Plano	Texas
United States	Research Site	Sacramento	California
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Saint Petersburg	Florida
United States	Research Site	San Antonio	Texas
United States	Research Site	Santa Maria	California
United States	Research Site	Scottsdale	Arizona
United States	Research Site	Skokie	Illinois
United States	Research Site	Springfield	Illinois
United States	Research Site	Springfield	Missouri
United States	Research Site	Tampa	Florida
United States	Research Site	Torrance	California
United States	Research Site	Tustin	California
United States	Research Site	Victorville	California
United States	Research Site	Webster	Texas
United States	Research Site	West Hills	California
United States	Research Site	Wheaton	Maryland
United States	Research Site	Wynnewood	Pennsylvania
United States	Research Site	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Argentina,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Greece,  Hungary,  Italy,  Mexico,  Poland,  Portugal,  South Africa,  Spain, 

References & Publications (3)

Curtis JR, Emery P, Karis E, Haraoui B, Bykerk V, Yen PK, Kricorian G, Chung JB. Etanercept or Methotrexate Withdrawal in Rheumatoid Arthritis Patients in Sustained Remission. Arthritis Rheumatol. 2021 May;73(5):759-768. doi: 10.1002/art.41589. Epub 2021 Mar 24. — View Citation

Curtis JR, Stolshek B, Emery P, Haraoui B, Karis E, Kricorian G, Collier DH, Yen PK, Bykerk VP. Effects of Disease-Worsening Following Withdrawal of Etanercept or Methotrexate on Patient-Reported Outcomes in Patients With Rheumatoid Arthritis: Results From the SEAM-RA Trial. J Clin Rheumatol. 2023 Jan 1;29(1):16-22. doi: 10.1097/RHU.0000000000001893. Epub 2022 Oct 22. — View Citation

Curtis JR, Trivedi M, Haraoui B, Emery P, Park GS, Collier DH, Aras GA, Chung J. Defining and characterizing sustained remission in patients with rheumatoid arthritis. Clin Rheumatol. 2018 Apr;37(4):885-893. doi: 10.1007/s10067-017-3923-z. Epub 2017 Dec 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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

External Links

•   AmgenTrials clinical trials website