TAMARA was the first phase IIIb study preceding the approval of tocilizumab in January 2009 to be performed in a setting close to real-life medical care and confirmed the rapid and sustained improvement in signs and symptoms of RA with tocilizumab as well as a manageable safety profile.
The TAMARA study was conducted in 286 patients with active RA who had received 1–4 previous DMARDs; in 41.6% treatment had failed with a TNF antagonist. Concomitant DMARD therapy was continued, which was most often methotrexate (72.0%) but 19.6% of the patients were treated with leflunomide, reflecting the ‘real-life’ scenario. The high number of protocol deviations also reflects a ‘real-life’ scenario, but only a few patients had to be withdrawn from the study. Protocol violations did not influence study outcome parameters as the results of the ITT and PP populations were virtually identical.
The TAMARA study confirmed the good efficacy observed in different patient populations in previous studies (see table 4 in the online supplement).11–13 15 16
Treatment showed a very early onset of action as the mean DAS28 decreased by 40±20% after the first tocilizumab infusion. At week 24, 57% of the patients had achieved the primary end point of LDAS and 47.6% even achieved DAS remission. Remarkably, 79.2% of the patients in our study had high RA activity with a DAS28 >5.1 at baseline. Of important clinical relevance is the fact that tocilizumab treatment was particularly beneficial in these patients, 42% of whom achieved DAS28 remission by week 24. Furthermore, the quality of life as reflected by the HAQ-DI, SF-36 and fatigue score also improved. In all, 75% of the patients reported an overall satisfaction with the treatment.
Because of the strong effect of tocilizumab on the acute phase reactants (APR), it is a matter of debate whether the high remission rates resulting from tocilizumab are mainly driven by the reduction in APR. This can be rebutted by the strong decrease in the number of swollen and tender joints as well as the high percentage of patients (26%) with no TJC and no SJC ().
Subgroup analyses revealed a comparable clinical response in RF-positive and RF-negative patients that has not been reported previously. Patients with concomitant leflunomide treatment did not differ from the whole cohort with regard to efficacy parameters and safety, indicating that leflunomide may represent a suitable concomitant DMARD.
Not unexpectedly, patients who had failed with previous DMARDs showed a better clinical response than patients who had shown an inadequate response to previous TNF antagonists, possibly because of their longer disease duration, the earlier use of tocilizumab or because they may have had a less refractory form of RA.
The treatment with tocilizumab was well tolerated. The incidence rates of all AEs (83.9%) and of drug-related AEs (66.1%) as well as the incidence of serious infections were as expected from the published reports. Most of the AEs were mild or moderate and resolved by the end of the study. The only unexpected serious AE in this study was a relapse of a pre-existing but previously undiagnosed case of multiple sclerosis (MS) which was rated as drug-related. This patient had a history of several neurological disorders (including unspecified foci on the MRI), but the diagnosis of MS was not established before the study. Reassessment of the medical charts, however, confirmed the pre-existence of a relapsing-remitting MS and the serious AE was changed to ‘MS-relapse’. Thus, a causal relationship with tocilizumab could not be excluded.
This study was performed in a setting close to real-life medical care; however the non-controlled design and the short observation period of 24 weeks provide only limited data with respect to long-term efficacy and potential safety issues. Nevertheless, studies close to real-life medical care in usual clinical practice in a heterogeneous patient population have a high degree of relevance as results of controlled studies do not always match with daily medical care. Only 21–33% of patients in the German RABBIT register treated with biological agents would have been eligible for the major trials with TNFα antagonists. In the clinical setting, the indications for treatment with biological agents were not identical to the inclusion criteria for trials, and there was a smaller relative improvement achieved in the patients with RA who would not have fulfilled the inclusion criteria of the trials.18
Interestingly, the heterogeneous patient population from the TAMARA study showed even better efficacy results than patients from previously published controlled studies (see table 4 in the online supplement). We therefore believe that these data confirm that tocilizumab represents an important treatment option for patients with RA in a real-life setting.