Maxime Verhoeven

134 Chapter 7 (13%/20%) values in a year, as well as (population) uncertainty in outcomes, we used the following approach, which has been suggested to be optimal in this situation. 14 As first step, 10,000 bootstrap samples (with replacement) were taken per treatment strategy arm. In the second step, single imputation of the missing yearly QALY and cost estimates was performed per bootstrap sample (see Supplementary Data S2 for details). Analysis Baseline (inclusion in U-Act-Early) characteristics of the strategy groups were described for the ‘intention-to-treat’ (ITT) population and the population as included in the PTFU. Mean values (2.5 and 97.5 percentiles) of costs per category and QALYs were calculated for the treatment strategy groups as well as for the differences of TCZ+MTX and TCZ, both compared to MTX over a 2-year (trial period) and 5-year (trial + PTFU) time horizon. Incremental cost effectiveness ratios (ICER: calculated as difference in costs between two strategies divided by difference in effectiveness, expressed as € per QALY gained) were estimated. A healthcare perspective (i.e., including only healthcare cost) as well as societal perspectives (i.e., including non-healthcare cost like costs related to productivity) were used for this estimation. The primary analysis uses the ITT population of U-Act-Early (n=317) and the follow-up period of 5 years. Results were illustrated in cost effectiveness planes. The distribution of simulations over the quadrants in these planes was also calculated and illustrates if TCZ(+MTX) is cost-effective compared to MTX (e.g., south east quadrant indicates lower costs with higher effectiveness (TCZ(+MTX) is dominant compared to MTX)). Cost effectiveness acceptability curves (CEACs) were constructed to illustrate the probability of TCZ(+MTX) being cost-effective compared to MTX at different willingness to pay (WTP; price society is willing to pay for a gain of 1 QALY) thresholds. Sensitivity and scenario analyses To evaluate the impact of missing data, a complete case analysis was performed (i.e., using data from PTFU population) as sensitivity analyses. To investigate the sensitivity of the results to treatment effect, we assumed QALYs were 0.05 higher and lower, respectively, in the TCZ strategies. We also performed a sensitivity analysis using discount rates of 4% per year for both costs and QALYs, as is generally in line with international guidelines. Moreover the following scenario analyses were performed. As TCZ has recently become available as a subcutaneous injection, making an admission day no longer necessary, we performed a scenario analysis assuming that TCZ is given subcutaneously instead of intravenously, resulting in a reduction of 23% of the (total) price (Supplementary Table 1). Furthermore, a scenario analysis was performed in which, in