MOZART (non-controlled clinical trial to evaluate the effectiveness of TCZ in patients with moderate to severe RA and in candidates for a biologic in monotherapy) (EudraCT: 2013-004051-20, and ClinicalTrials.gov: NCT02087696). This is a 32-week prospective non-controlled multicenter study to assess the effectiveness and safety of intravenous (iv) TCZ monotherapy in MTX-intolerant RA patients with moderate-severe activity.

All RA patients included in this study fulfilled the ACR classification criteria. Patients recruited from 20 rheumatology units in Spain between June 2014 and November 2016 were consecutively registered into this study and were followed during 24 weeks. Inclusion criteria were: moderate to severe RA (DAS28≥3.2), inadequate clinical response to a stable dose of synthetic DMARDs or failure to respond to one or two biologics for a period ≥8 weeks, oral glucocorticoids (GCs) ≤10mg prednisone or equivalent with a stable dose for at least one month prior to TCZ treatment.

RA patients were enrolled if had intolerance, contraindication or lack of adherence to MTX. The intolerance to MTX was evaluated using the UKU Side Effects Rating Scale.13 Lack of adherence to MTX was evaluated using the Morisky Green Levine Test.14 Patients were excluded if presented a hepatitis C virus infection, active diverticulitis, latent tuberculosis (positive PPD or suspicious chest X-ray), women pregnant or breastfeeding. Additional information regarding selection criteria are available in the Supplementary Material section (Table 1S).

Enrolled patients, who had MTX stopped 4 weeks before the baseline visit, were scheduled for eight visits (weeks 0, 4, 8, 12, 16, 20, 24, and a visit at week 32 to evaluate safety).

All enrolled patients were offered to initiate open-label iv treatment with TCZ 8mg/kg in monotherapy per protocol every 4 weeks for 6 months from June 2014 to April 2017. Patients who presented abnormal laboratory parameters (liver enzymes, absolute neutrophil counts and/or platelet counts) during treatment with TCZ, had their doses adjusted in accordance with the TCZ drug information sheet.

Demographic data, including date of diagnosis, comorbidities, current and previous treatments for RA were collected from the medical charts. The following parameters were evaluated at 0, 4, 8, 12, 24 and 32 weeks: tender joint count (TJC) 28, swollen joint count (SJC) 28, patient's global assessment (Pt-GA) of disease activity, physician's global assessment (Ph-GA) of disease activity, ESR, CRP, Health Assessment Questionnaire (HAQ), Short Form 36 Health Survey (SF-36), and fatigue by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Disease activity was assessed by the Disease Activity Score (DAS28), the Clinical Disease Activity Index (CDAI) and the Simple Disease Activity Index (SDAI), which were calculated according to their formula.

The primary endpoint was the EULAR response after 24 weeks of TCZ treatment. The EULAR response criteria classify patients as good, moderate, or non-responders using the individual amount of change determined by the DAS28-ESR and the DAS28-ESR value (low, moderate, or high) and can also be applied using the DAS28-ESR (Table 2S, Supplementary Material).15,16

Secondary endpoints were: (1) effectiveness of TCZ after 24 weeks according to the American College of Rheumatology 20%, 50%, and 70% improvement (ACR 20/50/70) criteria; (2) to compare response to TCZ in monotherapy according to previous treatment with biologics; and (3) to assess the safety of TCZ by adverse events reported by patients or recorded by researchers.

This study was developed in accordance with the protocol and guidelines of Good Clinical Practice and was carried out following the principles outlined in the Helsinki Declaration (v.2013). The study protocol was approved by the Ethics Committee for Clinical Research of the Hospital University Vall d’Hebron, Barcelona, Spain (Approval number: ID-RTF010). All patients provided written informed consent to participate in the study and to publish the data obtained.

In order to obtain an estimation whereby 78% of patients achieved a moderate or good EULAR response, with 10% accuracy and a 95% confidence interval, it was necessary to include 109 patients in the study. By assuming a loss rate of 10%, the total number of recruited patients needed to achieve the primary objective was 122. When 93 patients were recruited, the statistic power to reach 78% of a good or moderate EULAR response was 0.76, at which point the scientific committee halted further inclusion. A flow chart of patient inclusion is shown in Fig. 1.

Fig. 1.

Flowchart of patients included in the study_2.

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To evaluate one of the secondary objectives, patients were stratified into two cohorts: cohort A, patients naïve to biologics (n=50); and cohort B, patients who previously received 1 or 2 biologics for RA treatment (n=43).

An analysis of frequency of qualitative and quantitative variables was performed. Qualitative variables were expressed in percentage and absolute values, and quantitative variables were expressed as a means plus standard deviation.

Effectiveness of TCZ treatment in monotherapy was assessed based on the percentage of patients who achieved moderate and good EULAR responses after 24 weeks of treatment.

An intention-to-treat analysis was conducted. If a patient terminated treatment before week 24, he/she was evaluated as a responder or non-responder according to the results obtained from the last registered visit.

To assess the effectiveness of reducing the DAS28-ESR, the median score at baseline was compared to that at week 24 using the two-sided Student t-test for related samples. In order to evaluate whether patients in cohorts A and B could obtain different effectiveness results, an ANCOVA was performed.

All patients receiving at least one TCZ dose were included in the safety analysis. A description of the AEs recorded throughout the study period was performed.

IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp. was used to conduct the statistical analyses.

A total of 93 were enrolled of whom 84 were eligible for the effectiveness analysis. Table 1 summarizes the sociodemographic characteristics of the patients. The mean age of patients included was 54.4 years (SD: 12.8) with 83.3% of the participants being women. 46 (54.8%) patients were naïve to biological. Patients naïve to biologics were older than those previously treated with these compounds (57.9±12.5 vs 51.5±12.4 years), albeit with shorter disease durations (6.4±6.6 vs 13.3±11.5 years). Among the patients included, 77 (91.7%) were intolerant to MTX, 4 (4.8%) had contraindications to this drug and 1 (1.2%) showed a lack of adherence to MTX. The DAS28 at the entrance to the study was 5.5±1.1, with no differences between biologic naive and non-naive patients. Other RA activity indexes such as CDAI or SDAI, the counts of tender and swollen joints, acute phase reactants or functional capacity as assessed by HAQ did not reveal any differences between biologic naïve and non-naïve patients. Most patients (78.6%) had been receiving corticosteroids treatment at doses lower than 10mg/day of Prednisone or equivalent. The previous use of biologics and disease activity at study enrollment did not influence the percentage of patients with intolerance, contraindications or lack of adherence.

Ninety-three point eight percent of the patients analyzed had a good or moderate EULAR response. When stratifying by previous biologics treatment, a numerically higher percentage of naive patients showed a response (95.5%) compared to those with prior biologics use (91.7%) (p=0.53). When analyzing effectivenes according to moderate or good response, most patients showed a moderate response (Tables 2 and 3). This was true when analyzed either globally (92.5%) or separately by the previous use or non-use of biologics (93.2% vs 91.7%) (Table 3). Fig. 2 shows the mean variation in DAS28-ESR throughout the study with respect to baseline, which proved similar between patients naïve to biologics and those previously treated with biologics. An analysis has been carried out to evaluate the effectiveness of Tocilizumab, separating the results of the response variables by weeks to differentiate patients naïve to biological therapy versus patients who received prior treatment with biological therapy and where it can also be seen that naive patients had in every week a higher percentage of patients with EULAR response (Table 4). Fifty-eight point five percent of the naïve to biological patients reached remission and thirty-eight point 2 percent of the patients with previous biological therapy (Table 3). The rates of ACR response criteria are available in Table 2. TCZ was discontinued in 11 patients due to inefficacy and in the Table 5 also shows the causes of withdrawals of the patients and the mean time until leaving the study.

Fig. 2.

Mean variation in DAS28 ESR.

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A total 89 AEs were recorded in a total of 50 patients. Eighty-six percent were non-serious and occurred mainly in biologic naïve patients. Fourteen serious AEs (SAEs) were recorded during the study; these corresponded to 6 patients, with 8 of them being drug-related SAEs. Four of these 6 patients discontinued TCZ due to serious adverse drug reactions. Three patients presented RA reactivation characterized by musculoskeletal pain and peripheral joint swelling, type IV hypersensitivity reaction, syncope, colonic abscess, rash, diverticular perforation, myelopathy, spinal stenosis, spinal osteoarthritis, vocal cord paresis, lower extremity fracture, and/or spontaneous miscarriage (Table 6). No opportunistic infections, deaths, neoplasms or major adverse cardiovascular events (MACE) were reported during the study.