Patient disposition and baseline characteristics
In total, 2653 patients received abatacept and 1485 received placebo in the controlled periods; 7044 patients received abatacept in the cumulative periods. Extent of exposure and patient baseline characteristics during the controlled periods of the clinical trials have been reported previously . In the cumulative period, demographic and disease characteristics as well as concomitant medications were similar to those seen in the controlled periods for abatacept (Table 1): mean (SD) age was 51.5 (12.6) and 51.7 (12.4), respectively; 80.6% and 79.1% of patients were female. Mean (SD) duration of exposure to abatacept in the controlled and cumulative periods, respectively, was 10.8 (3.3) and 36.9 (26.2) months with 2356.6 and 21335 total patient-years of exposure.
Tables 2 and 3 present the number and percentage of patients and IR (95% CI) for overall OI and the individual OIs reported in the double-blind and cumulative periods.
Overall OI IR (95% CI) for abatacept was similar and the corresponding 95% CIs were overlapping in both controlled (0.17 [0.05–0.43]) and cumulative (0.21 [0.15–0.28]) periods.
Overall, 222 potential OI cases were evaluated and adjudicated.
In the controlled periods, the numbers of OIs reported were low for abatacept and placebo (4 [0.2%] and 7 [0.5%] cases, respectively). There were only single occurrences of OI events reported. None resulted in death or discontinuation.
The IR for overall OI for abatacept was lower compared with the IR for placebo (0.17 [0.05–0.43] versus 0.56 [0.22–1.15], respectively).
There were 45 (0.6%) OI events reported, with an IR (95% CI) of 0.21 (0.15, 0.28). The most frequently reported OIs were esophageal candidiasis (n = 7 [0.1%], IR [95% CI]: 0.03 [0.01, 0.07]) and pulmonary TB (n = 6 [0.1%], IR [95% CI]: 0.03 [0.01, 0.06]). Of these, 19 were defined as SAEs, with an IR of 0.1 (95% CI 0.05–0.14).
There were 2 cases of TB in the abatacept (n = 1) and placebo (n = 1) groups during the controlled periods (IR [95% CI] of abatacept and placebo, respectively, 0.04 [0–0.2] and 0.08 [0–0.4]).
During the cumulative period, TB was reported in 16 (0.2%) abatacept-treated patients (IR [95% CI]: 0.08 [0.05–0.12]). There were 6 cases of pulmonary TB; most of the patients (83%) were female with an age range of 39–64 years; geographically, cases were reported from Brazil (n = 1), Korea (n = 1), Mexico (n = 2), Portugal (n = 1) and Thailand (n = 1). One case of pulmonary TB resulted in death.
Five (31.3%) cases of TB were extrapulmonary (bone, lymph node, peritoneal, pleurisy). Most of the patients (60%) were female with an age range of 47–55 years; cases were reported from Argentina (n = 2), Brazil (n = 1), South Africa (n = 1) and Thailand (n = 1).
There were 2 cases of unspecified TB; both patients were female and aged 35 and 55 years (cases reported from Mexico [n = 1] and Peru [n = 1]).
Three (18.8%) cases of latent TB were reported; 2 (67%) patients were male, aged 43, 62 and 71 years, with cases reported from Mexico (n = 2) and Taiwan (n = 1). Cases of latent TB were not included in the IR of overall OIs.
Herpes simplex virus and herpes zoster
Of the 284 herpes cases, 13 were reported as SAEs of herpes (9 zoster, 1 simplex, 1 dermatitis, 1 ophthalmic and 1 virus infection). Herpes zoster was reported as a standard adverse event; therefore, additional clinical details were not collected. None of the herpes zoster cases were included in the overall OI IR.
Herpes simplex and zoster were reported numerically more often with abatacept versus placebo in the controlled periods. There were 57 (2.1%) and 22 (1.5%) cases of herpes simplex and 44 (1.7%) and 21 (1.4%) cases of herpes zoster reported in the abatacept and placebo groups during the controlled periods. The IRs were similar and the corresponding 95% CIs were overlapping for herpes simplex IR [95% CI]: 2.5 [1.9–3.2] vs 1.8 [1.1–2.7] and herpes zoster IR [95% CI]: 1.9 [1.4–2.5] vs 1.7 [1.1–2.6], respectively.
In the cumulative periods, the IRs (95% CI) for abatacept were lower for both herpes simplex (1.48 [1.32–1.65]) and herpes zoster (1.53 ([1.36–1.71]) compared with the IRs in the controlled periods. All AEs coded as herpes during the controlled periods were non-serious, except for 2 cases of herpes zoster infections (mild/grade I) with abatacept treatment, of which one was deemed probably related to treatment by the investigator, resulting in discontinuation of abatacept During the cumulative periods, most of the AEs coded as herpes were herpes zoster and all were non-serious.