Ultrasound Scores as Imaging Biomarkers of Early Response to Subcutaneous Tocilizumab in Association With Methotrexate in Very Early Rheumatoid Arthritis (TOVERA)
Overview
- Phase
- Phase 3
- Intervention
- Tocilizumab (TCZ)
- Conditions
- Rheumatoid Arthritis
- Sponsor
- Maria Stoenoiu
- Enrollment
- 45
- Locations
- 1
- Primary Endpoint
- Change in global ultrasound scoring system (GLOSS) at MCP (2-5 joints of both hands) and wrist joints
- Last Updated
- 9 years ago
Overview
Brief Summary
This study is aimed at assessing the kinetics of the ultrasound (US) response in DMARD-naive very early rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ) and methotrexate (MTX).
Detailed Description
For most rheumatic autoimmune diseases, treatment has two components: induction of remission and maintenance (to prevent relapse). After screening (week -3 to 0), patients enter into a 3 week run-in period during which no glucocorticoid (GC) treatment is allowed. At week 0, if persistent synovitis is confirmed patients will enter the induction phase. During the induction phase all patients will receive TCZ and MTX from week 0 to week 24. After week 24, all patients will receive MTX. Ultrasound (US) is increasingly used in rheumatic diseases, in particular in rheumatoid arthritis (RA). The great resolution of superficial musculoskeletal structures obtained by using high frequency transducers and the high sensitivity of colour Doppler (CD) and power Doppler (PD) techniques allow to detect synovial vascularisation, synovial hypertrophy (SH) and joint effusion (JE). This is a pilot US trial that allow us to explore the hypothesis that an early US response may be predictive of later clinical response.
Investigators
Maria Stoenoiu
MD, PhD
Université Catholique de Louvain
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of RA fulfilling the 2010 EULAR/ACR (European League Against Rheumatism/ American College of Rheumatology classification criteria)
- •Disease duration no longer than 12 months from the time of first swollen joint and no longer than 12 months from the time of initial diagnosis
- •Age : 18-75 years
- •Disease activity defined by a disease activity score DAS28-CRP \> 3.2 or all must be met: tender joint count (TJC) of ≥4 and swollen joint count (SJC) ≥4
- •US SH or PD synovitis scores \>1 for at least 2 joints (MCP:2-5 or PIP:2-5 or CMC:2-5 or wrist joints or MTP:2-5 or ankle joints) and US SH or PD synovitis scores ≥1 for at least 1 other joint (MCP:2-5 or PIP:2-5 or or CMC:2-5 or wrist joints)
- •Naïve to DMARDs (methotrexate, leflunomide, sulphasalazine) and naïve to any biologics or biosimilars.
Exclusion Criteria
- •History of other concomitant autoimmune disease such as lupus or psoriatic arthritis
- •Meeting diagnostic criteria for any other rheumatic disease than RA (e.g. gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, arthropathy or inflammatory bowel disease)
- •Any previous treatment with :
- •Biologics: Etanercept, infliximab, certolizumab, golimumab, abatacept, adalimumab, anakinra, tocilizumab, tofacitinib, etc.
- •Any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti- CD3, anti-CD19 and anti-CD20
- •Intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
- •Alkylating agents such as chlorambucil, or with total lymphoid irradiation
- •Previous MCP arthroplasty or wrist arthrodesis. Participants who have undergone or are scheduled to undergo joint arthroplasties other than the MCP joints can be recruited in the study provided all other eligibility criteria are met.
- •Current liver disease requiring medication
- •Current symptoms of severe progressive or uncontrolled renal, hematologic, gastro-intestinal, pulmonary, cardiac, neurologic or cerebral disease whether or not related to rheumatoid arthritis, that would jeopardize inclusion in the protocol as judged by the clinician
Arms & Interventions
Tocilizumab (TCZ) + Methotrexate (MTX)
Induction phase: From week 0 to week 24, all subjects will receive TCZ and MTX Maintenance phase: From week 24 to week 54, all subjects will receive MTX
Intervention: Tocilizumab (TCZ)
Tocilizumab (TCZ) + Methotrexate (MTX)
Induction phase: From week 0 to week 24, all subjects will receive TCZ and MTX Maintenance phase: From week 24 to week 54, all subjects will receive MTX
Intervention: Methotrexate (MTX)
Outcomes
Primary Outcomes
Change in global ultrasound scoring system (GLOSS) at MCP (2-5 joints of both hands) and wrist joints
Time Frame: Baseline to weeks 2, 4, 8, 12, 16, 24, 32, 40, 54
MCP=metacarpophalangeal; GLOSS scoring according to OMERACT: Grade 0 or normal=normal joint (no synovial hypertrophy (SH), no Doppler signal); Grade1 or minimal=minimal synovitis (minimal SH, with ≤ grade 1 Doppler signal); Grade 2 or moderate=moderate synovitis (moderate SH, with ≤ grade 2 Doppler signal or minimal SH and grade 2 Doppler signal); Grade 3 or severe=severe synovitis (severe SH with ≤ grade 3 Doppler signal or minimal or moderate SH and grade 3 Doppler signal). Joints are scored 0 to 3, and the sum of individual joints scores represents the total GLOSS for a subject.
The earliest time point at which improvement in GLOSS at MCP (2-5 joints of both hands) and wrists can be detected
Time Frame: Baseline to weeks 2, 4, 8, 12, 16, 24, 32, 40, 54
Secondary Outcomes
- GLOSS measured at 8 and 12 weeks is predictive to later clinical response at 24 and at 48 weeks(weeks 12, 24, 48)
- Change in power Doppler (PD) scores for the whole US joint set(Baseline to weeks 2, 4, 8, 12, 16, 24, 32, 40, 54)
- SDAI during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- CDAI during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- Tender joint count score for disease activity during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- Number of patients fulfilling ACR/EULAR (2011) remission criteria during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- Change in GLOSS for the whole US joint set(Baseline to weeks 2, 4, 8, 12, 16, 24, 32, 40, 54)
- Change in joint effusion (JE) scores for the whole US joint set(Baseline to weeks 2, 4, 8, 12, 16, 24, 32, 40, 54)
- Minimum set of joints to be monitored by US in order to adequately assess disease activity(Baseline to weeks 2, 4, 8, 12, 16, 24, 32, 40, 54)
- Change in gray-scale (GS) scores for the whole US joint set(Baseline to weeks 2, 4, 8, 12, 16, 24, 32, 40, 54)
- Total PD score measured at 8 and 12 weeks is predictive to later clinical response at 24 and at 48 weeks(weeks 8, 12 , 24, 48)
- No radiographic progression assessed by Sharp/vdHeijde score(baseline to week 54)
- No new radiographic joint erosion at hands, wrists, ankles, feet(baseline to week 54)
- No new swollen joint assessed by clinical examination(baseline to week 54)
- No new radiographic joint chondrolysis at hands, wrists, ankles, feet(baseline to week 54)
- No new swollen joint assessed by ultrasound examination(baseline to week 54)
- Patient visual analog score for disease activity during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- DAS28 during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- Swollen joint count score during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- Physician visual analog score for disease activity during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- Health assessment questionnaire(HAQ) score during the induction and maintenance phase(baseline to week 2, 4, 8, 12, 16, 24, 48, 54)
- Number of participants with serious adverse events(SAEs), with treatment-related SAEs, with discontinuations due to SAEs, with adverse events (AEs) with treatment-related AEs, with discontinuations due to AEs, death as outcome.(Days 1 to 365 days)