DISCUSSION
tiredness, anemia
ADVERSE EVENTS, SECONDARY, TSS, ANEMIA
Here, we employed MMRM methodology with accompanying individual item‐level analyses using a continuous endpoint to examine longitudinal changes in MF domain‐level symptoms in each of the phase III SIMPLIFY trials of momelotinib. The benefits of using the MMRM approach are that it (1) estimates TSS treatment effect as a continuous variable and provides greater statistical power and clinically relevant granularity, (2) incorporates longitudinal data from every 4‐week period leading up to Week 24 (not just the terminal 4 weeks), (3) does not automatically assign a non‐responder status to patients with missing data but rather models the outcome at each time point where data are present, and (4) quantifies the overall degree of benefit experienced by each patient. Thus, this MMRM model provides an improved understanding of symptom response and the degree of benefit experienced by each patient, when compared with the dichotomous landmark symptom response endpoint traditionally used in MF clinical trials. The benefit of using individual item‐level data is to comprehensively inform the baseline severity and response to treatment over time of symptoms that compose the TSS. Future technological advances, such as the development of an application for patients to self‐monitor their symptoms, may be useful for clinical practice. Findings from these MMRM and individual item analyses demonstrate comparable symptom improvement on the MPN‐SAF TSS between the momelotinib and ruxolitinib treatment arms in SIMPLIFY‐1 and greater improvement in the momelotinib group compared with the BAT group in SIMPLIFY‐2, supporting the clinical relevance of symptom benefits with momelotinib for JAK inhibitor‐naïve and JAK inhibitor‐exposed patients with MF.Several design nuances in the SIMPLIFY‐1 trial limited the interpretability of the symptom response outcome. First, the prespecified TSS endpoint was based on a 50%‐responder definition, with the non‐inferiority margin based on historical data of a six‐item score from the MPN‐SAF to measure TSS, whereas the seven‐item score from the modified MPN‐SAF v2.0 was used to determine responder rate in SIMPLIFY‐1. The six‐item score does not include tiredness, typically the most severe and prevalent item. The SIMPLIFY‐1 secondary endpoint of TSS response rate at Week 24 failed to demonstrate non‐inferiority for momelotinib versus ruxolitinib. Second, baseline severity on the MPN‐SAF TSS was not an inclusion criterion in SIMPLIFY‐1, which led to a substantial number of asymptomatic patients entering the trial. For those patients, an a priori maintenance hypothesis was not considered. This may also have resulted in variations in symptom improvement between the momelotinib and ruxolitinib arms because (1) the 50% improvement threshold required for response may be achieved by vastly different absolute scores when patients with high and low baseline TSS are analyzed alongside each other; and (2) TSS was not a stratification factor, which resulted in a numerically higher mean baseline TSS in patients in the momelotinib arm than the ruxolitinib arm. This was evidenced by our results herein showing that the momelotinib and ruxolitinib groups achieved very similar absolute change in TSS from baseline when excluding patients with very low TSS (<10) at baseline. Additionally, missing data may have also contributed to the variation in symptom improvement between the momelotinib and ruxolitinib arms. More patients in the momelotinib arm discontinued treatment early due to low‐grade adverse events, which resulted in an imbalance in early discontinuation rates between the treatment arms (momelotinib: 15%; ruxolitinib: 6%). The SIMPLIFY‐1 study protocol included a ruxolitinib‐oriented dose modification schema, which likely led to higher rates of dose reductions and interruptions, but lower rates of early discontinuation due to low‐grade adverse events with ruxolitinib. Because patients who discontinued prior to Week 24 were considered non‐responders in the TSS analysis, this contributed to a lower TSS response rate at Week 24 in the momelotinib arm. Furthermore, change from baseline was not considered in the primary or key secondary endpoint strategy. Scores were dichotomized into responder categories rather than using the full score variability (e.g., heterogeneity of variance was not assessed).There were also several design nuances in the SIMPLIFY‐2 study that limited the interpretability of the PROs. Specifically, the only prespecified MPN‐SAF TSS endpoint performed was based on a 50%‐responder definition; the new analyses in this report augment this standard TSS response definition. Also, SIMPLIFY‐2 was an open‐label study, which could be regarded with more bias than a blinded trial. However, to address this potential bias, multiple item and domain level analyses were conducted and the impact of the open‐label design on symptomatic benefit appeared negligible, as observed in similar studies.In both SIMPLIFY‐1 and SIMPLIFY‐2, the items on the MPN‐SAF TSS were assumed unidimensional in the scoring; however, the face validity review demonstrates heterogeneity across the instrument. Furthermore, the studies were not powered to assess differences in individual items of TSS, which vary in prevalence. One limitation of the MMRM model is that it assumes a missing observation is equally likely to be a response or a non‐response, regardless of the health status of the patient, whereas the dichotomous approach assumes that all patients with missing data are not responders. However, it is not possible to confirm whether MMRM modeling yielded results that more closely reflect the true treatment differences than the dichotomous approach.Beyond these limitations, evidence from the SIMPLIFY studies demonstrates that momelotinib provides comprehensive improvements in symptoms with a similar magnitude across trials, reduction in spleen size, decreased anemia, and reduced transfusions.Findings from the SIMPLIFY trials support the demonstration of symptomatic improvement in terms of statistical results and clinically meaningful interpretation. Metrics for deriving between‐ and within‐patient analysis contextualize the TSS findings providing further confidence in the symptomatic benefit of momelotinib. Pertinent findings from the analyses described in this report were considered in the design of the PRO‐specific statistical analysis plan for the MOMENTUM phase III study (NCT04173494) to ensure appropriate interpretation of the symptom data arising from that study.Overall, results from SIMPLIFY‐1 illustrate that the momelotinib‐treated patients had similar symptom benefits to ruxolitinib treatment groups for both the overall and symptomatic populations. Differences between treatments were small relative to the derived non‐inferiority margin. The magnitude of improvement for each item was similar, with some symptoms favoring momelotinib treatment and others favoring ruxolitinib. Results from SIMPLIFY‐2 support the finding that momelotinib significantly improves MF symptoms compared with the BAT group, where 88.5% of patients were treated with ruxolitinib. The magnitude of symptom response for patients treated with momelotinib was similar in both SIMPLIFY studies, demonstrating that momelotinib provides robust symptom benefit in JAK inhibitor‐naïve patients and in those with prior JAK inhibitor treatment. This study, together with other evidence from SIMPLIFY‐1 and SIMPLIFY‐2, demonstrates that momelotinib addresses the key hallmark features of MF and the unmet medical needs for patients with MF.