A Randomized, Multi-Center Biomarker Trial to Predict Therapeutic Responses of Patients With Rheumatoid Arthritis to a Specific Biologic Mode of Action
Overview
- Phase
- Phase 4
- Intervention
- Remicade
- Conditions
- Rheumatoid Arthritis
- Sponsor
- Medical University of Vienna
- Enrollment
- 115
- Locations
- 9
- Primary Endpoint
- Absolute Change in the Simplified Disease Activity Index (SDAI)
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this study is to find biological response patterns of patients with rheumatoid arthritis to drugs with different biologic modes of action. This study should help to predict therapeutic responses and to find the right therapy for the right patient.
Detailed Description
The investigators propose a randomised, multi-centre strategic biomarker trial of rheumatoid arthritis (RA) patients with failure to methotrexate or leflunomide to one of the four current biological modes of action: targeting TNF (infliximab); co-stimulation (abatacept); IL-6R (tocilizumab); and B cells (rituximab); all agents are licensed for RA and have evidence for efficacy in this indication. Predictors of response to therapy after 24 weeks will be analysed, and include baseline and follow up assessments of clinical, functional, structural, laboratory tests (routine, autoantibodies, cytokines, gene expression, and susceptibility genes). In a second phase, patients not achieving LDA/REM will be randomised to one of the remaining MoA. Two hundred patients, who are started on a new biological therapy will be enrolled over an estimated period of 5 years; 50 patients per group will be included, and studied for a period of 12 months.
Investigators
Daniel Aletaha
Principal Investigator
Medical University of Vienna
Eligibility Criteria
Inclusion Criteria
- •Men and women, ≥18 and ≤75 years of age, capable of understanding and signing an informed consent.
- •Classifiable RA according to the 2010 ACR/EULAR criteria (American College of Rheumatology/European League Against Rheumatism classification criteria) or 1987 ARA criteria (Criteria of American Rheumatology Association) (present or past) (2;3)
- •Duration of RA ≤3 years
- •Ongoing conventional DMARD therapy (Disease Modifying Antirheumatic Drugs) with methotrexate (at least 20mg/week, or lower if not tolerated in higher doses) or leflunomide (≥100mg/week), for ≥6 months or ≥3 months with documented worsening of disease activity.
- •Clinical Disease Activity Index (CDAI)≥15 corresponding to moderate to severe disease activity.
Exclusion Criteria
- •Be incapacitated, largely or wholly bedridden, or confined to a wheelchair, or have little or no ability for self care.
- •Weigh more than 100 kg
- •Use glucocorticoids \>10 mg/day prednisone or equivalent
- •Have previously received other treatments for their rheumatic disease:
- •intra-muscular or intra-articular injection of steroids in the previous month.
- •monoclonal antibodies or antibody fragments, licenced or investigational
- •any investigational drug within 3 months prior to screening or within 5 half-lives of the investigational agent, whichever is longer.
- •Azathioprine or other cytostatic drugs.
- •Have a history of receiving human/murine recombinant products or a known allergy to murine products.
- •Have documentation of seropositivity for human immunodeficiency virus (HIV), or a positive test for hepatitis B surface antigen or hepatitis C ¬antibodies.
Arms & Interventions
Infliximab
Infliximab (Remicade®) will be administered i.v.at a dose of 3 mg/kg at 0 and 2 weeks, and 5 mg/kg at weeks 6, 14, and 22, 30, 38, and 46.
Intervention: Remicade
Abatacept
Abatacept (Orencia®) will be given i.v. at weeks 0, 2, 4, and then every 4 weeks until week 48 at a weight adjusted dose: \<60 kg Body weight (BW): 500 mg; \>60-100 kg BW: 750 mg; alternatively, based on preference and shared decision between patient and physician, patients randomized to the abatacept arm may receive s.c.application at a dose of 125mg weekly.
Intervention: Orencia
Tocilizumab
Tocilizumab (Ro-Actemra®) will be administered every 4 weeks at a dose of 8 mg/kg BW (maximum dose of 800 mg); The employed dosage will be calculated using manufacturer guidelines; alternatively, based on preference and shared decision between patient and physician, patients randomized to the tocilizumab arm may receive s.c. application at a dose of 162mg every week.
Intervention: Ro-Actemra
Rituximab
Rituximab (Mabthera®) will be given as 1000mg at weeks 0 and 2, and then repeated at weeks 24 and 26. Patients will receive 100 mg methylprednisolon i.v. before each infusion, as well as 1000mg paracetamol, as well as 50mg diphenhydramine hydrochloride (Dibondrin©).
Intervention: Mabthera
Outcomes
Primary Outcomes
Absolute Change in the Simplified Disease Activity Index (SDAI)
Time Frame: 24 Weeks
Secondary Outcomes
- Radiographic progression - (Van der Heijde/Sharp Score)(6 months and 12 months)
- Change in sleep (Sleep Score on the Visual Analog Scale)(24 Weeks)
- Proportion achieving a remission state (SDAI ≤3.3)(24 Weeks)
- Absolute and relative change in the Disease Activity Score 28 (DAS28) in percent(24 weeks)
- Achieving an SDAI or CDAI response (50%, 70%, 85%)(24 Weeks)
- Change in quality of life (EuroQoL-5D, SF-36)(24 weeks)
- Change in fatigue (Fatigue Score on the Visual Analog Scale)(24 Weeks)
- Proportion achieving a low disease activity state (SDAI ≤11)(24 Weeks)
- Relative Change in the SDAI in percent(24 Weeks)
- Absolute and relative change in the Clinical Disease Activity Index (CDAI) in percent(24 Weeks)
- Achieving a EULAR response (European League Against Rheumatism)(24 Weeks)
- Change in physical function (HAQ)(24 Weeks)
- Achieving an ACR response (20%, 50%, 70%) (American College of Rheumatology)(24 Weeks)