Between December 19, 2018 and January 5, 2021, 935 participants were screened and 621 eligible participants were randomized to study treatment (TCZ, N = 155; TCZ→BAT1806/BIIB800, N = 154; BAT1806/BIIB800, N = 312; Fig. 1). Of the 621 randomized participants, 577 (92.9%) completed TP1 and entered TP2 (N = 145 [93.5%], N = 142 [92.2%], and N = 290 [92.9%], respectively); overall, 89.4% (555/621) of participants completed the study. Demographic and clinical characteristics remained balanced at week 24 (Table 1).

The treatment groups were similar prior to the start of TP2 also in terms of intercurrent events (type and occurrence percentage) (Supplemental Fig. 1) [5, 6].

Proportions of ACR20, ACR50, and ACR70 responders were similar between treatment groups throughout TP2 (Fig. 2). At week 48, the proportions of participants who achieved ACR20 in the TCZ, TCZ→BAT1806/BIIB800, and BAT1806/BIIB800 groups were 87.8% (122/139), 90.3% (121/134), and 90.4% (253/280), respectively. The proportions of participants who achieved ACR50 at week 48 were 61.9% (86/139), 70.1% (94/134), and 70.4% (197/280), respectively, and for ACR70 were 38.8% (54/139), 49.3% (66/134), and 46.1% (129/280), respectively.

DAS28 (ESR and CRP) responses at each time point in TP2 were similar across the three treatment groups (Fig. 3, Supplemental Table 1).

The treatment groups displayed similar longitudinal trajectories in terms of DAS28-ESR and DAS28-CRP responses (Supplemental Fig. 2A–D). From the MMRM analyses, no differences between treatment arms with regards to DAS28-ESR and DAS28-CRP were observed, with overlapping 95% CIs at all time points. At week 48, mean (standard deviation [SD]) changes in DAS28-ESR were − 3.7 (1.5), − 4.1 (1.4), and − 4.2 (1.5) in the TCZ, TCZ→BAT1806/BIIB800, and BAT1806/BIIB800 groups, respectively. At week 48, mean (SD) changes in DAS28-CRP were − 3.1 (1.1), − 3.4 (1.2), and − 3.4 (1.2), respectively.

In the PK analysis, Ctrough geometric mean values for the TCZ, TCZ→BAT1806/BIIB800, and BAT1806/BIIB800 groups were 12.4 μg/mL (coefficient of variation [CV]% 180.7), 12.7 μg/mL (CV% 157.0), and 13.1 µg/mL (CV% 126.5), respectively, at week 28, and 13.5 µg/mL (CV% 121.0), 13.4 µg/mL (CV% 125.1), and 12.3 µg/mL (CV% 150.6), respectively, at week 44.

In TP2, 345 (59.8%) participants experienced a total of 1179 AEs, including 323 events in 91 (62.8%), 287 events in 92 (64.8%), and 569 events in 162 (55.9%) participants in the TCZ, TCZ→BAT1806/BIIB800, and BAT1806/BIIB800 groups, respectively (Table 2). Overall, 344 (59.6%) participants reported 1163 TEAEs; 318 TEAEs in 90 (62.1%) participants in the TCZ group, 286 TEAEs in 92 (64.8%) participants in the TCZ→BAT1806/BIIB800 group, and 559 TEAEs in 162 (55.9%) participants in the BAT1806/BIIB800 group. The most common TEAEs in TP2 across treatment groups were upper respiratory tract infection, reported by 41 of 577 (7.1%) participants, and leukopenia, reported in 40 of 577 (6.9%) participants. Related TEAEs occurred in 59 (40.7%), 64 (45.1%), and 112 (38.6%) participants in the TCZ, TCZ→BAT1806/BIIB800, and BAT1806/BIIB800 groups, respectively. Most were mild in severity (mild: 56 [38.6%] participants, 56 [39.4%] participants, and 101 [34.8%] participants, respectively; moderate: 14 [9.7%] participants, 18 [12.7%] participants, and 26 [9.0%] participants, respectively; severe: 2 [1.4%] participants, 0 [0%] participants, and 1 [0.3%] participants, respectively). Five serious TEAEs were reported in four (2.8%) participants in the TCZ group, five serious TEAEs in five (3.5%) participants in the TCZ→BAT1806/BIIB800 group, and nine serious TEAEs in eight (2.8%) participants in the BAT1806/BIIB800 group.

The only serious TEAE to occur in more than one participant in any one treatment group was tooth abscess, which occurred in two participants in each of the treatment groups. Of the serious TEAEs, one (pneumonia) in the TCZ group, one (laryngitis) in the TCZ→BAT1806/BIIB800 group, and two (pneumonia and salpingo-oophoritis) in the BAT1806/BIIB800 group were considered by the investigator to be possibly related to study treatment (Table 3). There were no fatal events in TP2.

In TP2, 18.6% (27/145), 16.2% (23/142), and 21.0% (61/290) of participants in the TCZ, TCZ→BAT1806/BIIB800, and BAT1806/BIIB800 groups, respectively, had ≥ 1 positive ADA result at any time point. Across the treatment groups, the majority of ADA-positive participants reported titers of < 20 or 20. All ADA-positive tests were also positive for nAbs, with the exception of a single result in the TCZ group. The point prevalence for participants testing positive for ADAs remained stable in all treatment groups, and the majority of positive cases transitioned from positive to negative across the study period (Fig. 4). At week 52 (8 weeks after the last dose of study drug), 11 (7.9%), 2 (1.5%), and 16 (5.7%) participants were ADA-positive in the TCZ, TCZ→BAT1806/BIIB800, and BAT1806/BIIB800 groups, respectively; the majority of these participants were also positive for nAbs at this time point (10 [7.2%], 2 [1.5%], and 15 [5.4%], respectively).