Results
A total of 400 patients were screened and 380 patients were included in CareRA. Seventy-five per cent of these patients were included in non-university centres. No differences in demographic and clinical characteristics were observed between screened and included patients. In total, 290 patients were allocated to the high-risk group and randomly assigned to treatment in the COBRA Classic (98), COBRA Slim (98) and COBRA Avant-Garde (94) arm. Randomisation resulted in similar baseline characteristics between groups (Table 1).
Figure 2 describes the patient disposition from screening until W16.
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Figure 2.
Patient disposition flow chart.
Efficacy
Primary Outcome. Remission was achieved in 70.4% (68/98) COBRA Classic patients, 73.5% (72/98) COBRA Slim patients and 68.1% (64/94) COBRA Avant-Garde patients (p=0.713) at W16 (figure 3A).
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Figure 3.
Remission and disease activity over 16 weeks. (A) The proportion of patients in remission per treatment arm at weeks 4, 8 and 16. (B) The area under the curve of DAS28(CRP) per treatment arm during 16 weeks of treatment. DAS28(CRP), 28 joint disease activity score calculated with C-reactive protein.
Secondary Outcomes. At W16, a good EULAR response was reached in 79.6% of Classic patients, 79.6% of Slim patients and 76.6% of Avant-Garde patients (p=0.844). A clinically meaningful HAQ response was reached in 84.7% of Classic patients, 86.7% of Slim patients and 76.6% of Avant-Garde patients (p=0.271). HAQ was equal to zero in 45.9% of Classic patients, 42.9% of Slim patients and 48.9% of Avant-Garde patients (p=0.700) (Table 2).
Likewise, complete case analysis (without missing data imputation) of the primary and secondary outcomes revealed no significant differences between the three treatment arms (data not shown).
Area Under the Curve. The mean±SD AUC for DAS28(CRP) from baseline to W16 was 10.66±3.41, 11.05±3.39 and 10.72±2.96 for the Classic, Slim and Avant-Garde, respectively (p=0.521) (figure 3B).
Treatment Adaptations According to Protocol. During the first 16 weeks of therapy, treatment adaptations were performed in 19.4%, 22.4% and 14.9% in the Classic, Slim and Avant-Garde arm, respectively (p=0.407). Of these patients requiring treatment adaptations at W8, 50.0%, 87.5% and 60.0% in the Classic, Slim and Avant-Garde arm, respectively, reached the low-disease activity target at W16 (p=0.086). Of 61 patients requiring per protocol treatment adaptation at W8, 39% (24/61) had no change in therapy because of contraindications or because the treating physician judged the disease sufficiently controlled. These 24 patients received no other medication and stayed on the initial strategy without treatment adaptation. Intra-articular GC injections were given in 3.1% of Classic patients, 5.1% of Slim patients and 5.1% of Avant-Garde patients (p=0.703).
Safety
Therapy-related AEs were registered in 171 out of the 290 patients (59%) during the first 16 weeks of treatment. These were reported in 61.2% of Classic, in 46.9% of Slim and in 69.1% of Avant-Garde patients (p=0.006). The total number of AEs related to Classic, Slim and Avant-Garde treatment was 148, 70 and 130, respectively, with a similar distribution for discomfort and toxicity (Table 3).