Clinical trial NCT01034137: A Study of Tocilizumab and Methotrexate in Combination or as Monotherapy in Treatment-Naïve Patients With Early Rheumatoid Arthritis
Official title: U-ACT-EARLY: A Multi-center, Randomized, Double Blind, Placebo Controlled Study to Evaluate Remission in DMARD and Biological naïve Early Rheumatoid Arthritis (RA) Subjects Treated With Tocilizumab (TCZ) Plus Tight Control Methotrexate (MTX) , TCZ Monotherapy or Tight Control MTX Monotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Keywords: Treat-to-target, tight control, strategy study, TCZ, MTX
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2009-12-17
Enrollment: 317
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: This randomized, double-blind, placebo-controlled study will compare the efficacy with regard to sustained remission and safety of tocilizumab and methotrexate, in combination or as monotherapy, in treatment-naïve patients with early rheumatoid arthritis. Patients will be randomized to receive either tocilizumab (8mg/kg iv every 4 weeks) plus weekly methotrexate (po in ascending doses), or tocilizumab (8mg/kg iv every 4 weeks) plus placebo, or methotrexate plus placebo. Anticipated time on study treatment is 2 years, and target sample size is 300.

Detailed description: Multi-center, randomized, double-blind, placebo-controlled (double placebo) three-arm parallel group, comparative study. Patients were randomized in a 1:1:1 ratio to one of the following treatments:

* TCZ 8 milligram (mg)/kilogram (kg) + MTX (Group I: TCZ+MTX)
* TCZ 8 mg/kg + placeboMTX (Group II: TCZ+placebo)
* MTX + placeboTCZ (Group III: MTX+placebo)

Randomization was stratified by participating center and baseline Disease Activity Score, scoring 28 joints (DAS28) level (\<5.1 vs. ≥5.1). Patients were evaluated every 4 weeks and at each visit a decision on dosage changes was made based on efficacy parameters (DAS28) and occurrence of adverse events (AEs). Patients received MTX/placeboMTX in climbing dosages. Hydroxychloroquine (HCQ) was added when remission was not reached with the maximum tolerable dosage (MTD) of MTX/placeboMTX. If after 12 additional weeks remission was not reached, HCQ was stopped and replaced by standard of care therapy (in Group I) or placebo therapy was replaced by the corresponding verum resulting in TCZ+MTX combination therapy (in Groups II and III). In case remission was reached, MTX/placeboMTX and TCZ/placeboTCZ had to be decreased. Patients were followed for a maximum of 24 months

Eligibility criteria: Inclusion Criteria:

* adult patients, \>/=18 years of age
* early rheumatoid arthritis (disease symptoms \<1 year) according to ACR criteria
* disease activity DAS28 \>2.6
* body weight \</=110kg, BMI \</=36

Exclusion Criteria:

* rheumatic autoimmune disease other than RA
* current inflammatory joint disease other than RA
* previous treatment with any DMARD or biologic drug used in the treatment of RA
* intra-articular, parenteral or oral glucocorticoids used for the arthritis

Primary outcomes:
measure: Percentage of Participants Achieving Sustained Remission Rate At Week 104
timeFrame: Week 104
Secondary outcomes:
measure: Median Time to First Sustained Remission
timeFrame: Up to Week 104
measure: Mean Duration of First Sustained Remission
timeFrame: Up to Week 104
measure: Number of Participants Achieving Disease Activity Score 28 Remission at Weeks 12, 24, 52, and 104
timeFrame: Weeks 12, 24, 52, and 104
measure: Median Time to First Disease Activity Score 28 Remission
timeFrame: Up to Week 104
measure: Percentage of Participants With Cumulative Remission Rate at Weeks 12, 24, 52, and 104
timeFrame: Weeks 12, 24, 52, and 104
measure: Mean Duration of First Disease Activity Score 28 Remission
timeFrame: Up to Week 104
measure: Absolute Change From Baseline in Disease Activity Score 28 at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52, and 104
measure: Median Change From Baseline in Clinical Disease Activity Index Score at Weeks 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 24, 52, and 104
measure: Median Change From Baseline in Simplified Disease Activity Index Scores at Weeks 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 24, 52, and 104
measure: Number of Participants With Good European League Against Rheumatism Response Rate at Weeks 24, 52, and 104
timeFrame: Weeks 24, 52, and 104
measure: Median Time to First European League Against Rheumatism Response
timeFrame: Up to Week 104
measure: Percentage of Participants With American College of Rheumatology 20 Response Rate at Weeks 12, 24, 52 and 104
timeFrame: Weeks 12, 24, 52 and 104
measure: Percentage of Participants With American College of Rheumatology 50 Response Rate at Weeks 12, 24, 52 and 104
timeFrame: Weeks 12, 24, 52 and 104
measure: Percentage of Participants With American College of Rheumatology 70 Response Rate at Weeks 12, 24, 52 and 104
timeFrame: Weeks 12, 24, 52 and 104
measure: Percentage of Participants With American College of Rheumatology 90 Response Rate at Weeks 12, 24, 52 and 104
timeFrame: Weeks 12, 24, 52 and 104
measure: Mean Percent Change From Baseline in the Swollen Joint Count (SJC) at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52, and 104
measure: Mean Percent Change From Baseline in the Tender Joint Count (TJC) at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52, and 104
measure: Mean Percent Change From Baseline in Patient Health Visual Analog Scale at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52, and 104
measure: Mean Percent Change From Baseline in The Physician Health Visual Analog Scale at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52, and 104
measure: Mean Percent Change From Baseline in Pain Visual Analog Scale at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52, and 104
measure: Mean Percent Change From Baseline in CRP at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52, and 104
measure: Mean Change From Baseline in Modified Sharp/Van Der Heijde Score at Weeks 52 and 104
timeFrame: From Baseline (Week 0) to Weeks 52 and 104
measure: Percentage of Participants Who Withdraw Due to Lack of Sufficient Therapeutic Response
timeFrame: Up to Week 104
measure: Number of Participants With Change in The Therapy Strategy During The Study
timeFrame: From Baseline to Week 104
measure: Mean Change From Baseline in The Dutch Consensus Health Assessment Questionnaire of Quality of Life at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52 and 104
measure: Mean Change From Baseline in The EuroQol Score of Quality of Life at Weeks 12, 24, 52 and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52 and 104
measure: Mean Change From Baseline in 36-Item Short Form Health Survey of Quality of Life at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52 and 104
measure: Mean Change From Baseline in Patient Global Health Visual Analog Scale Score of Quality of Life at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52 and 104
measure: Mean Change From Baseline in Physician Global Health Visual Analog Scale Score of Quality of Life at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52 and 104
measure: Mean Change From Baseline in Patient Pain Visual Analog Scale Score of Quality of Life at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52 and 104
measure: Mean Change From Baseline in Patient General Wellbeing Visual Analog Scale Score of Quality of Life at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52 and 104
measure: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue Score of Quality of Life at Weeks 12, 24, 52, and 104
timeFrame: From Baseline (Week 0) to Weeks 12, 24, 52 and 104
measure: Mean Change From Baseline in The Revised Illness Perception Questionnaire (IPQ-R) Score of Quality of Life at Week 12
timeFrame: From Baseline (Week 0) to Week 12
measure: Mean Change From Baseline in The IPQ-R Score of Quality of Life at Week 24
timeFrame: From Baseline (Week 0) to Week 24
measure: Mean Change From Baseline in The IPQ-R Score of Quality of Life at Week 52
timeFrame: From Baseline (Week 0) to Week 52
measure: Mean Change From Baseline in The IPQ-R Score of Quality of Life at Week 104
timeFrame: From Baseline (Week 0) to Week 104
measure: Number of Participants With Any Adverse Events, Any Serious Adverse Events, and Adverse Events Leading to Discontinuation
timeFrame: Up to Week 104
measure: Number of Participants With Clinically Significant Laboratory Values at Week 12
timeFrame: Week 12
measure: Number of Participants With Clinically Significant Laboratory Values at Week 24
timeFrame: Week 24
measure: Number of Participants With Clinically Significant Laboratory Values at Week 52
timeFrame: Week 52
measure: Number of Participants With Clinically Significant Laboratory Values at Week 104
timeFrame: Week 104
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
city: Amersfoort
country: Netherlands
city: Amsterdam
country: Netherlands
city: Apeldoorn
country: Netherlands
city: Breda
country: Netherlands
city: Den Helder
country: Netherlands
city: Emmeloord
country: Netherlands
city: Gorinchem
country: Netherlands
city: Gouda
country: Netherlands
city: Groningen
country: Netherlands
city: Haarlem
country: Netherlands
city: Heerlen
country: Netherlands
city: Hilversum
country: Netherlands
city: Hoofddorp
country: Netherlands
city: Leeuwarden
country: Netherlands
city: Leiden
country: Netherlands
city: Nieuwegein
country: Netherlands
city: Nijmegen
country: Netherlands
city: Sneek
country: Netherlands
city: Utrecht
country: Netherlands
city: Woerden
country: Netherlands
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
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citation: Teitsma XM, Yang W, Jacobs JWG, Petho-Schramm A, Borm MEA, Harms AC, Hankemeier T, van Laar JM, Bijlsma JWJ, Lafeber FPJG. Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology. Arthritis Res Ther. 2018 Oct 15;20(1):230. doi: 10.1186/s13075-018-1729-2.
citation: Teitsma XM, Jacobs JWG, Welsing PMJ, de Jong PHP, Hazes JMW, Weel AEAM, Petho-Schramm A, Borm MEA, van Laar JM, Lafeber FPJG, Bijlsma JWJ. Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors. Ann Rheum Dis. 2018 Sep;77(9):1261-1267. doi: 10.1136/annrheumdis-2018-213035. Epub 2018 May 14.
citation: Teitsma XM, Jacobs JWG, Welsing PMJ, Petho-Schramm A, Borm MEA, van Laar JM, Lafeber FPJG, Bijlsma JWJ. Radiographic joint damage in early rheumatoid arthritis patients: comparing tocilizumab- and methotrexate-based treat-to-target strategies. Rheumatology (Oxford). 2018 Feb 1;57(2):309-317. doi: 10.1093/rheumatology/kex386.
citation: Teitsma XM, Jacobs JWG, Welsing PMJ, Petho-Schramm A, Borm MEA, Hendriks L, Denissen NHAM, van Laar JM, Lafeber FPJG, Bijlsma JWJ. Patient-reported outcomes in newly diagnosed early rheumatoid arthritis patients treated to target with a tocilizumab- or methotrexate-based strategy. Rheumatology (Oxford). 2017 Dec 1;56(12):2179-2189. doi: 10.1093/rheumatology/kex319.
citation: Teitsma XM, Jacobs JWG, Mokry M, Borm MEA, Petho-Schramm A, van Laar JM, Bijlsma JWJ, Lafeber FPJ. Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy. Arthritis Res Ther. 2017 Jul 20;19(1):170. doi: 10.1186/s13075-017-1378-x.
citation: Bijlsma JWJ, Welsing PMJ, Woodworth TG, Middelink LM, Petho-Schramm A, Bernasconi C, Borm MEA, Wortel CH, Ter Borg EJ, Jahangier ZN, van der Laan WH, Bruyn GAW, Baudoin P, Wijngaarden S, Vos PAJM, Bos R, Starmans MJF, Griep EN, Griep-Wentink JRM, Allaart CF, Heurkens AHM, Teitsma XM, Tekstra J, Marijnissen ACA, Lafeber FPJ, Jacobs JWG. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016 Jul 23;388(10042):343-355. doi: 10.1016/S0140-6736(16)30363-4. Epub 2016 Jun 7.