Clinical trial NCT04692493: RA-PRO PRAGMATIC TRIAL
Official title: A Real-World Comparative Effectiveness Trial of Treatment Strategies in Patients With Rheumatoid Arthritis: The RA-PRO Pragmatic Trial (RA-PROPR)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
First posted: 2020-12-31
Enrollment: 924
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The 2021 ACR RA treatment guideline, based on widely acknowledged low to moderate quality evidence, recommends switching to a non-tumor necrosis factor (TNFi) biologic (choose among existing medications, currently, rituximab, abatacept, tocilizumab, or sarilumab) or a targeted synthetic DMARD arm (tsDMARD; choose among existing medications, currently, tofacitinib, baricitinib, upadacitinib) in patients with active RA despite the use of a TNFi-biologic. In practice, most patients receive another TNFi-biologic, i.e., a second TNFi-biologic first. This is not based on solid evidence, but on arbitrary algorithms often proposed by health insurance plans, and/or physician experience and habit (TNFis launched 22 yrs ago vs. the first tsDMARD 8 years ago vs. first non-TNF-biologic launched 17 years ago). This study will fill a critical knowledge gap by generating CER data for important PROs between these treatment options, switching to a non-TNFi biologic or a tsDMARD in patients with active RA despite the use of a TNFi-biologic.

Detailed description: Treatment of RA with a non-TNFi biologic (rituximab, abatacept, tocilizumab, or sarilumab) was associated with improved function, quality of life, and productivity. TsDMARDs (tofacitinib, baricitinib, upadacitinib) were similarly effective. No meaningful differences were noted in non-TNFi-biologic vs. tsDMARD, but head-to-head studies of biologics are lacking. HAQ is a sensitive outcome for RA trials. A PCORI systematic review for early RA treatment concluded that "Evidence was insufficient to evaluate any differences between biologics for their impact on either functional capacity or HRQOL", a key knowledge gap our study will fill.

The 2021 ACR RA treatment guideline, based on widely acknowledged low to moderate quality evidence, recommends switching to a non-TNFi biologic or a tsDMARD in patients with active RA despite the use of a TNFi-biologic. In practice, most patients receive another TNFi-biologic first, i.e., a second TNFi. This is not based on solid evidence, but on arbitrary algorithms often proposed by health insurance plans, and physician experience (first TNFi launched 22 yrs ago vs. the first tsDMARD 8 yrs ago vs. first non-TNF-biologic launched 17 years ago). This study will fill a critical knowledge gap by generating CER data for important PROs between these treatment options. This will facilitate informed decision-making, since PROs may be more sensitive to different mechanisms of action, and are highly relevant to patients.

The proposed study will also provide needed evidence for real-world treatment decisions made by public and private payers. This head-to-head pragmatic trial will be the first to provide CER data for improvement in key PROs with recommended strategies in active RA despite the use of a TNFi-biologic and addresses PCORI and IOM priority areas by comparing the two most commonly used RA treatment strategies for people with active RA despite the use of a TNFi-biologic. This research is patient-centered, as study outcomes were identified by patients and payers. Currently, treatment choices are based on physician experience and insurance payer limitations. Investigators will generate evidence to help patients make decisions for themselves based on outcomes they care most about based on the relative efficacy of outcomes.

Investigators will: (1) compare improvements in PROs with RA treatment strategies to each other using a state-of-the-art real-world pragmatic effectiveness study design, which will for the first time include most RA patients with comorbidities;(2) compare their toxicity in a real-world population for TNFi-biologic vs. tsDMARD. To our knowledge, no previous RCT comparing these drugs has examined a PRO as a primary outcome in RA, which our study will pioneer by using HAQ. HAQ is sensitive to change with effective treatments.

Eligibility criteria: Inclusion Criteria:

1. Patients with active, disabling RA (CDAI ≥10 and HAQ ≥0.5) despite the use/experience of a TNFi-biologic OR discontinued the medication(s) due to intolerability or toxicity irrespective of treatment duration prior to the first dose of study drug ;
2. If receiving glucocorticoids (≤10 mg/day of prednisone of equivalent) or NSAIDs, on stable doses for ≥2 weeks prior to randomization; and
3. Insurance plan or patient assistance program allows access to at least 1 drug in each of the two treatment strategies, TNFi-biologic vs. tsDMARD.

Participants will be allowed to continue their conventional synthetic DMARD (csDMARD) therapy if they had been using it for ≥ 3 months and on a stable dose for ≥ 4 weeks prior to the first dose of study drug. The following csDMARDs are allowed: methotrexate (MTX), sulfasalazine, hydroxychloroquine, and leflunomide (TNFi-biologic and tsDMARD) through insurance plan or a patient assistance program/plan.

Exclusion Criteria:

1. Prior treatment with more than three biologics, defined as TNFi-biologic or non-TNFi biologic
2. Prior treatment with targeted synthetic DMARD
3. Concomitant use of leflunomide, sulfasalazine, cyclosporine, or azathioprine within 2-months before randomization;
4. History of sensitivity to all 4 non-TNF-biologic or a targeted synthetic DMARD;
5. Glucocorticoid injection (intravenous, intramuscular, or intraarticular) within 1 month of study entry;
6. Live vaccine within 90 days of study entry;
7. Acute or chronic infections with parenteral antibiotics or hospitalization (including tuberculosis, bacterial sepsis; invasive fungal infections (such as histoplasmosis)) within 1 month or oral antibiotics within 2 weeks of study entry;
8. History of HIV or any opportunistic infection;
9. New York Heart Association Class III or IV heart failure;
10. Latent TB for which anti-tubercular treatment has not been started;
11. Untreated Hepatitis B or C infection;
12. History of deep venous thrombosis or pulmonary embolism; or
13. Pregnant or nursing women; or
14. History of herpes zoster or shingles in the previous 12 months and not subsequently vaccinated with herpes zoster vaccine.

Primary outcomes:
measure: Functional Limitation
timeFrame: Change from baseline to 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Auburn
country: United States
facility: East Alabama Arthritis Center PC
state: Alabama
city: Birmingham
country: United States
facility: Bendcare, LLC
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Peoria
country: United States
facility: SunValley Arthritis Center, Ltd
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Los Angeles
country: United States
facility: Pacific Arthritis Care Center
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Nipomo
country: United States
facility: Arthritis Medical Center
state: California
city: Turlock
country: United States
facility: Turlock Arthritis & Osteoporosis Center,
state: California
city: Woodland Hills
country: United States
facility: Center for Rheumatology Research
state: California
city: Aventura
country: United States
facility: George Munoz MD, PC
state: Florida
city: Clearwater
country: United States
facility: American Arthritis and Rheumatology Associates LLC
state: Florida
city: Coral Springs
country: United States
facility: CZ Rheumatology
state: Florida
city: Fort Lauderdale
country: United States
facility: American Arthritis and Rheumatology Associates LLC
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Jupiter
country: United States
facility: Palm Beach Rheumatology and Wellness
state: Florida
city: Margate
country: United States
facility: Arthritis & Rheumatology Center of South Florida
state: Florida
city: Miami Gardens
country: United States
facility: Life Medical Research Group
state: Florida
city: Riverview
country: United States
facility: Southwest Florida Rheumatology
state: Florida
city: Brunswick
country: United States
facility: Southeast Georgia Physician Associates-Rheumatology
state: Georgia
city: Carmel
country: United States
facility: Indiana University Health
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Tufts University
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Chan Medical School
state: Massachusetts
city: Okemos
country: United States
facility: American Arthritis and Rheumatology Associates -Mi PLLC
state: Michigan
city: Eagan
country: United States
facility: Saint Paul Rheumatology, P.A.
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Clovis
country: United States
facility: Dr. Jayashree Sinha
state: New Mexico
city: Santa Fe
country: United States
facility: Inspire Santa Fe Medical Group
state: New Mexico
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: Cleveland
country: United States
facility: University Hospital Cleveland Medical Ctr
state: Ohio
city: Cleveland
country: United States
facility: The MetroHealth System
state: Ohio
city: Liberty Township
country: United States
facility: Arthritis and Rheumatology of Southwest Ohio
state: Ohio
city: Wheelersburg
country: United States
facility: Southern Ohio Rheumatology
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Exton
country: United States
facility: Rheumatology and Arthritis Care Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny Health Network
state: Pennsylvania
city: Wyomissing
country: United States
facility: PA Regional Center for Arthritis and Osteoporosis Research
state: Pennsylvania
city: Crossville
country: United States
facility: Cumberland Rhematology
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Colleyville
country: United States
facility: Heritage Rheumatology and Arthritis Care
state: Texas
city: Dallas
country: United States
facility: Southwest Medical Center
state: Texas
city: El Paso
country: United States
facility: Texas Arthritis Center, PA
state: Texas
city: Harlingen
country: United States
facility: American Arthritis and Rheumatology Associates-Tx PLLC
state: Texas
city: Houston
country: United States
facility: Baylor University
state: Texas
city: Reston
country: United States
facility: Northern Virginia Center for Arthritis-Reston
state: Virginia
city: Toronto
country: Canada
facility: Mount Sinai Hospital (Canada)
state: Ontario
Study officials:
affiliation: University of Alabama at Birmingham
name: Jasvinder Singh, MD
role: PRINCIPAL_INVESTIGATOR
References: