INTERVENTION: Trade Name: RoActemra Pharmaceutical Form: Concentrate for solution for infusion Pharmaceutical form of the placebo: Concentrate for solution for infusion Route of administration of the placebo: Intravenous use Trade Name: Methotrexate 'Lederle' 2,5mg tablets Pharmaceutical Form: Tablet Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use CONDITION: Rheumatoid Arthritis ; MedDRA version: 15.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders INCLUSION CRITERIA: 1. Male or non‐pregnant, non‐nursing female 2. = 18 years of age 3. Early RA (disease symptoms <1 year) according to the revised 1987 ACR and/or ACR/EULAR classification criteria of 2010 for RA 4. Disease activity measured by DAS28 = 2,6 5. Patients able and willing to give written informed consent and comply with the requirements of the study protocol 6. Immunization status current for pneumovax, influenza as assessed according to standard of care for RA patients receiving a biological agent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range PRIMARY OUTCOME: Main Objective: To compare the number of patients with early RA who achieve sustained remission with three different regimens: tocilizumab combined with tightly controlled MTX, tightly controlled MTX as monotherapy and tocilizumab as monotherapy. The main focus is the contrast between the combination therapy and the MTX monotherapy followed by the contrast between the two monotherapy treatments. Primary end point(s): Primary endpoint of the present study is the sustained remission rate (SRR), i.e. the proportion of patients with early RA who achieve sustained remission.; In individual patients, sustained remission is considered to be achieved if an uninterrupted period of approximately 6 months (at least 23 weeks) can be identified, over which: ; •At least 6 DAS28 values are available, including one at the beginning and one at the end of the period; •All values are <2.6, with the exception of up to 2 values which can be between 2.6 and 3.2 provided that the investigator considers the patient to be in clinical remission for RA and documents the reason for the RA‐unrelated elevation of DAS28 (such as an infection); Secondary Objective: To compare the progression of radiographic characteristics of joint damage among the three treatment strategies by use of the change in SharpvanderHeijde score.; ; To compare clinical efficacy between the three treatment strategies by use of the ACR and EULAR response criteria.; ; To study safety in the context of the three treatment strategies, including the: ; ‐ occurrence of serious adverse events leading to withdrawal. ; ‐ occurrence of serious infections ; ‐ number of patients who are unable to use adequate dosage of MTX due to increase of liver enzymes ; ; To study differences in changes in functional disability, fatigue, quality of life and cost effectiveness in the three treatment strategy groups by use of the: Dutch consensus HAQ, the FACIT‐fatigue, the IPQR, the SF‐36, VAS pain and general wellbeing Questionnaires, a Dutch Healthcare resource use and work participation questionnaire, and the EuroQol (EQ5D) questionnaire. ;
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.
<b>BACKGROUND: </b>For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines.<b>METHODS: </b>We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137.<b>FINDINGS: </b>Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study.<b>INTERPRETATION: </b>For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards.<b>Funding: </b>Roche Nederland BV.
OBJECTIVE: To evaluate the effect of initiation of tocilizumab, with or without MTX, compared with MTX alone on patient-reported outcomes (PROs), in DMARD-naïve patients with early RA.
METHODS: In U-Act-Early, patients initiated treat-to-target step-up MTX, tocilizumab or tocilizumab plus MTX therapy. PROs assessed included the Functional Assessment of Chronic Illness Therapy-Fatigue, 36-item Short Form (SF-36), five dimensional EuroQol (EQ-5D) and the Revised Illness Perception Questionnaire. Differences between strategy groups over time and proportions of patients exceeding minimum clinically important differences (MCID) were evaluated.
RESULTS: During the 2-year study period, significant improvements were found in the tocilizumab strategies in the SF-36 physical component score (tocilizumab, P = 0.012; tocilizumab plus MTX, P = 0.044) and EQ-5D score (tocilizumab plus MTX, P = 0.020) when compared with the MTX strategy. No significant differences were noted in other PROs (P ⩾ 0.052, except for the domain 'identity' in the Illness Perception Questionnaire; tocilizumab vs MTX, P = 0.048). The proportions of patients achieving MCID in SF-36 physical component score were significantly higher at 12 and 52 weeks (P ⩽ 0.049) in the tocilizumab arms when compared with the MTX arm. At week 24, the proportion achieving MCID in EQ-5D was significantly higher in the tocilizumab plus MTX arm vs the MTX arm (P = 0.045).
CONCLUSION: Initiation of treat-to-target tocilizumab therapy resulted in significantly improved PROs, especially within the first 24 weeks, when compared with initiation of MTX therapy. Also on the patients' level, initiating tocilizumab may be considered as a valuable strategy in DMARD-naïve patients with early RA.
TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01034137.
Trade Name: RoActemra Pharmaceutical Form: Concentrate for solution for infusion Pharmaceutical form of the placebo: Concentrate for solution for infusion Route of administration of the placebo: Intravenous use Trade Name: Methotrexate 'Lederle' 2,5mg tablets Pharmaceutical Form: Tablet Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use
CONDITION:
Rheumatoid Arthritis ; MedDRA version: 15.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders
INCLUSION CRITERIA:
1. Male or non‐pregnant, non‐nursing female 2. = 18 years of age 3. Early RA (disease symptoms <1 year) according to the revised 1987 ACR and/or ACR/EULAR classification criteria of 2010 for RA 4. Disease activity measured by DAS28 = 2,6 5. Patients able and willing to give written informed consent and comply with the requirements of the study protocol 6. Immunization status current for pneumovax, influenza as assessed according to standard of care for RA patients receiving a biological agent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
PRIMARY OUTCOME:
Main Objective: To compare the number of patients with early RA who achieve sustained remission with three different regimens: tocilizumab combined with tightly controlled MTX, tightly controlled MTX as monotherapy and tocilizumab as monotherapy. The main focus is the contrast between the combination therapy and the MTX monotherapy followed by the contrast between the two monotherapy treatments. Primary end point(s): Primary endpoint of the present study is the sustained remission rate (SRR), i.e. the proportion of patients with early RA who achieve sustained remission.; In individual patients, sustained remission is considered to be achieved if an uninterrupted period of approximately 6 months (at least 23 weeks) can be identified, over which: ; •At least 6 DAS28 values are available, including one at the beginning and one at the end of the period; •All values are <2.6, with the exception of up to 2 values which can be between 2.6 and 3.2 provided that the investigator considers the patient to be in clinical remission for RA and documents the reason for the RA‐unrelated elevation of DAS28 (such as an infection); Secondary Objective: To compare the progression of radiographic characteristics of joint damage among the three treatment strategies by use of the change in SharpvanderHeijde score.; ; To compare clinical efficacy between the three treatment strategies by use of the ACR and EULAR response criteria.; ; To study safety in the context of the three treatment strategies, including the: ; ‐ occurrence of serious adverse events leading to withdrawal. ; ‐ occurrence of serious infections ; ‐ number of patients who are unable to use adequate dosage of MTX due to increase of liver enzymes ; ; To study differences in changes in functional disability, fatigue, quality of life and cost effectiveness in the three treatment strategy groups by use of the: Dutch consensus HAQ, the FACIT‐fatigue, the IPQR, the SF‐36, VAS pain and general wellbeing Questionnaires, a Dutch Healthcare resource use and work participation questionnaire, and the EuroQol (EQ5D) questionnaire. ;
