Filgotinib Improved Health-Related Quality of Life and Led to Comprehensive Disease Control in Individuals with Ulcerative Colitis: Data from the SELECTION Trial

Abstract Background and Aims Ulcerative colitis [UC] impacts patients’ health-related quality of life [HRQoL]. We assessed HRQoL and an exploratory patient-level composite endpoint (‘Comprehensive Disease Control’ [CDC]) in individuals receiving filgotinib [an oral JAK1 preferential inhibitor] in the SELECTION trial. Methods In SELECTION [NCT02914522], a double-blind, randomized, placebo-controlled, phase 2b/3 trial, adults with moderately to severely active UC received once-daily filgotinib 200 mg, filgotinib 100 mg or placebo for 11 weeks in Induction Study A [biologic-naïve] or B [biologic-experienced]. Filgotinib responders [week 10 clinical remission/response] were re-randomized to their filgotinib regimen or placebo for the 48-week Maintenance Study. We assessed week 10 and week 58 SF-36, EQ-5D, WPAI and IBDQ scores. Achievement of CDC (patient-level partial Mayo Clinic Score [pMCS] remission [pMCS ≤2, no individual rectal bleeding, stool frequency or physician’s global assessment subscore >1], endoscopic improvement [endoscopic subscore ≤1], faecal calprotectin <150 µg/g and IBDQ score ≥170) and its association with HRQoL and histological outcomes were also explored. Results Analyses included 382 biologic-naïve and 404 biologic-experienced patients. Filgotinib 200 mg induced and maintained improvements vs placebo in SF-36, EQ-5D, WPAI and IBDQ scores, and restored HRQoL by week 10. Proportionally more filgotinib 200 mg- than placebo-treated patients achieved CDC at weeks 10 and 58 [p < 0.01]. CDC was associated with clinically important improvements in HRQoL and histological remission over both periods. Conclusions Filgotinib 200 mg results in short- and long-term improvements in HRQoL. High-level improvement of HRQoL relates to a stringent composite endpoint suggesting meaningful disease control in a subset of filgotinib-treated individuals. ClinicalTrials.gov identifier: NCT02914522


Introduction
Ulcerative colitis [UC] is an inflammatory bowel disease of the colonic mucosa that negatively affects patients' health-related quality of life [HRQoL]. 1,2 Approximately half of patients develop a complex course of disease, with chronic activity or frequent relapses, despite advanced therapy. 3 Common UC symptoms, including diarrhoea, haematochezia, abdominal pain, urgency, tenesmus, anaemia and fatigue, are important determinants of HRQoL that negatively affect psychological, physical, sexual and social functioning. 1,[4][5][6][7][8] Reduced HRQoL is in turn one of the strongest factors affecting work productivity loss among employed patients with UC. 9 Patients consider the ability to improve HRQoL to be among the most important attributes of a UC treatment. 10 Accordingly, long-term treatment goals now include improvement/normalization of HRQoL, in addition to conventional targets such as the induction and maintenance of clinical remission, endoscopic mucosal healing and symptom relief. 11 Although most clinical trials conducted in patients with UC evaluate each of these outcomes, they are often assessed independently of one another, and at the level of the overall patient population, rather than as composite measures at the patient level. While these global assessments are useful for assessing the overall efficacy of a therapy, a composite, patientlevel endpoint would be a valuable tool for clinicians in assessing the diverse targets specified by treatment guidelines [including HRQoL measures related to the patient's function and well-being, 12 as well as symptoms and objective disease activity].
Filgotinib is an oral Janus kinase [JAK] 1 preferential inhibitor that has been approved in the European Union and the UK for the treatment of adults with moderately to severely active UC. 13, 14 In the phase 2b/3 SELECTION trial, filgotinib 200 mg was efficacious in inducing and maintaining remission in biologic-naïve and biologic-experienced patients with UC. 15 In these exploratory and post hoc analyses of SELECTION data, we examined the effect of filgotinib on generic HRQoL (measured using 36-Item Short-Form Survey  and EuroQol 5-dimension [EQ-5D] scores), disease-specific HRQoL (measured using the Inflammatory Bowel Disease Questionnaire [IBDQ] score) and work productivity (measured using Work Productivity and Activity Impairment [WPAI] questionnaire scores), and examined the effect of filgotinib on restoration of generic HRQoL, as assessed using SF-36 scores. In addition, we explored disease control at the patient level by evaluating achievement of an exploratory composite endpoint, herein referred to as 'Comprehensive Disease Control' [CDC], comprising objective measures of disease activity and patient-reported outcomes. Finally, we assessed the correlation of this endpoint with generic HRQoL, work productivity scores and histological remission. SELECTION [NCT02914522] was a combined phase 2b/3 double-blind, randomized, placebo-controlled trial comprising two induction studies and a Maintenance Study. Details of the study design have been previously described by Feagan et al. 15 Eligible patients with moderately to severely active UC (Mayo endoscopic subscore ≥2, rectal bleeding subscore ≥1, stool frequency subscore ≥1, physician's global assessment subscore ≥2; total Mayo Clinic Score [tMCS] of [6][7][8][9][10][11][12] were enrolled into one of two induction studies: biologic-naïve patients entered Induction Study A and biologic-experienced patients entered Induction Study B. Patients were randomized 2:2:1 to receive filgotinib 200 mg, filgotinib 100 mg or placebo orally once daily for 11 weeks. Those who achieved either clinical remission or a tMCS response at week 10 [responders] were re-randomized 2:1 at week 11 to continue their induction filgotinib regimen or receive placebo in the Maintenance Study through week 58. Placebo responders continued to receive placebo. Clinical remission was defined as a Mayo endoscopic subscore of 0 or 1, a rectal bleeding subscore of 0 and at least a 1-point decrease in stool frequency subscore from induction baseline to achieve a subscore of 0 or 1. tMCS response was defined as a reduction of at least 3 points in tMCS and at least 30% from induction baseline, with an accompanying decrease in rectal bleeding subscore of at least 1 point, or an absolute rectal bleeding subscore of 0 or 1. Full details of the inclusion and exclusion criteria for enrolment into the induction and maintenance studies have been given by Feagan et al. 15 Week 10 non-responders were excluded from the Maintenance Study but could enter the ongoing long-term extension study, SELECTIONLTE [NCT02914535]. Each study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki. All patients provided written informed consent before any study procedures were carried out.

Pre-specified exploratory analyses
As part of pre-specified exploratory analyses of SELECTION, changes from induction/maintenance baseline in the following outcomes were assessed at weeks 10 and 58: generic HRQoL, as measured by SF-36 physical component summary [PCS], mental component summary [MCS] and subscale scores, as well as EQ-5D visual analogue scale [VAS] and EQ-5D 5-level [-5L] UK utility scores; and disease-specific HRQoL, as measured by IBDQ total score and subscores.

Post hoc analyses 2.3.1. Achievement of MCIDs in HRQoL outcomes
The proportions of patients achieving the minimal clinically important difference [MCID] in the following measures at weeks 10 and 58 were assessed: SF-36 PCS score, SF-36 MCS score, EQ-5D VAS score, EQ-5D UK utility score, IBDQ total score, combined IBDQ and SF-36 scores [achievement of the MCID in each of IBDQ total score, SF-36 PCS score, and SF-36 MCS score], and WPAI activity impairment score. In addition, the proportions of patients who were in employment at induction baseline and who achieved the MCID in WPAI absenteeism, presenteeism and work productivity loss scores were assessed at weeks 10 and 58. EQ-5D-5L values were standardized to the EQ-5D 3-level [-3L] according to the algorithm proposed by van Hout et al., 16 and scored using the corresponding EQ-5D-3L UK value set to derive health utilities based on the UK population. 17 19 ; and (4) IBDQ remission [IBDQ total score ≥170]. The proportions of patients who achieved minimal clinically important improvements from induction baseline to week 10 and minimal clinically important declines from maintenance pre-baseline [week 11] to week 58 in SF-36, EQ-5D and WPAI scores were assessed among those who achieved CDC and those who did not. In addition, the proportions of patients in histological remission [Geboes score ≤2B.0] within each group were assessed at weeks 10 and 58.

Statistical analyses
These analyses were conducted using the SELECTION induction and maintenance full analysis sets. 15 For the induction studies, the full analysis sets included all randomized patients who received at least one dose of the study drug within that study. For the Maintenance Study, the full analysis set included all patients randomized to either filgotinib 200 mg or filgotinib 100 mg in the induction studies who achieved clinical remission or a tMCS response at week 10, and who were re-randomized in the Maintenance Study [and received at least one dose of the study drug in the Maintenance Study].
Patient demographics and baseline characteristics were analysed using descriptive statistics. Changes from induction baseline to week 10 and from maintenance baseline to week 58 were calculated for each HRQoL measure using leastsquares [LS] mean changes with 95% confidence intervals [CIs]. Differences in LS mean changes were estimated using analysis of covariance adjusted for baseline HRQoL measures and stratification factors. Treatment assignments and analyses were stratified in Induction Study A by day 1 use of oral systemic corticosteroids and use of immunosuppressants [6-mercaptopurine, azathioprine and methotrexate]; in Induction Study B, by the same factors as in Induction Study A, and by previous exposure to one vs more than one biologic; and in the Maintenance Study, by the same factors as in Induction Study A, and by participation in Induction Study A or B. Binary assessment of the proportion of patients achieving the MCID in each of the HRQoL measures at weeks 10 and 58 was performed using Cochran-Mantel-Haenszel tests. No adjustment for multiple comparisons was made. A logistic regression model was used to calculate odds ratios with 95% CIs for restoration of SF-36-defined HRQoL at week 10 and maintenance of normal SF-36-defined HRQoL at week 58 for filgotinib 200 mg compared with placebo. The proportions of patients who achieved CDC at weeks 10 and 58, and the proportions of patients who had minimal clinically important improvements and declines in HRQoL measures from induction baseline to week 10 and from maintenance baseline to week 58, respectively, among CDC achievers and non-achievers, were compared using Pearson's chi-squared test.
All missing data were imputed using a last observation carried forward approach, except for the proportions of patients in IBDQ remission, for which non-responder imputation was used. Because these were exploratory and post hoc analyses, all p values are considered nominal.

Patient disposition and baseline characteristics
These analyses included 382 and 404 patients from Induction Studies A and B, respectively, and 297 patients from the Maintenance Study. Patient baseline demographic and disease characteristics were similar between treatment groups within each induction study [ Table 1]. In addition, mean SF-36, EQ-5D, IBDQ and WPAI scores were similar across treatment groups and studies at induction baseline, with mean IBDQ total scores of <170.

Primary HRQoL analyses 3.2.1. SF-36
At week 10, patients who had received filgotinib 200 mg had greater LS mean increases from induction baseline in SF-36 PCS and MCS scores than those who had received placebo [p < 0.01] [ Figure 1A-D]. Treatment differences were numerically larger among biologic-experienced than biologic-naïve patients. Similar results were observed for all SF-36 subscales [Supplementary Figure 1A Table 2].
In a further analysis, we assessed restoration of HRQoL as measured using SF-36 scores. Among patients with an SF-36 PCS or MCS score of <40 at induction baseline, a greater proportion of those treated with filgotinib 200 mg than those treated with placebo achieved restoration of SF-36-defined HRQoL [SF-36 PCS or MCS score ≥40] by week 10 in the biologic-naïve and biologic-experienced populations [all p < 0.05] [Supplementary Table 2]. At week 58, normal HRQoL was maintained in numerically higher proportions of patients treated with filgotinib 200 mg compared with placebo, though the differences in proportions were not nominally significant.

EQ-5D
At week 10, filgotinib 200 mg-treated patients had a greater LS mean increase from induction baseline in EQ-5D VAS and EQ-5D-5L UK utility scores than placebo-treated patients, in both the biologic-naïve and biologic-experienced populations [all p < 0.0001] [ Figure 1E-H]. A treatment effect of filgotinib 200 mg compared with placebo on the proportion of patients who achieved the MCID in EQ-5D VAS was observed in both patient populations [biologic-naïve, p = 0.0004; biologicexperienced, p < 0.0001], and on the proportion of patients who achieved the MCID in EQ-5D-5L UK utility score in the biologic-experienced population [p < 0.0001] [ Table 2].
At week 58, patients in the filgotinib 200 mg group experienced LS mean increases from maintenance baseline in EQ-5D VAS and EQ-5D-5L UK utility scores, whereas patients in the respective placebo group experienced LS mean decreases [EQ-5D VAS, p = 0.0030; EQ-5D-5L UK utility, p = 0.0171] [ Figure  2C and D]. In addition, greater proportions of filgotinib 200 mg-treated than placebo-treated patients achieved the MCID in both EQ-5D measures [both p < 0.0001] [ Table 2].

WPAI
Greater proportions of patients who received filgotinib 200 mg than those who received placebo achieved the MCID in WPAI activity impairment score at week 10 [biologic-naïve, p = 0.0123; biologic-experienced, p = 0.0006] and at week 58 [p < 0.0001] [ Table 2]. Among patients who were employed at induction baseline, greater proportions of those treated with filgotinib 200 mg than those treated with placebo achieved the MCID for both presenteeism [p < 0.0001] and work productivity loss [p = 0.0002] scores at week 58.

Proportions of patients experiencing minimal clinically important improvements and declines in HRQoL and work productivity measures by CDC achievement
To evaluate the association between CDC achievement and HRQoL, we assessed clinically important improvements from induction baseline to week 10, and clinically important declines from maintenance baseline to week 58, in generic HRQoL and work productivity outcomes. Greater proportions of patients who achieved CDC at week 10 than those who did not achieve CDC experienced minimal clinically important improvements from induction baseline in the following measures: SF-36 PCS, SF-36 MCS and all SF-36 subscale scores, EQ-5D VAS and EQ-5D-5L UK utility scores, and WPAI activity impairment score [all p < 0.05] [ Table  4 and Supplementary Table 3]. Differences were observed among biologic-naïve patients in each of these measures, and among biologic-experienced patients in SF-36 PCS score; in SF-36 physical role limitations, bodily pain, general health perceptions and mental health subscale scores; and in EQ-5D VAS score [all p < 0.05]. Among patients who were employed at induction baseline, greater proportions of CDC achievers than non-achievers at week 10 also achieved clinically important improvements from induction baseline in WPAI absenteeism, presenteeism and work productivity loss scores [all p < 0.05], with differences observed among biologic-naïve patients [all p < 0.05]. At week 58, a lower proportion of CDC achievers than non-achievers experienced clinically important declines from maintenance baseline in SF-36 bodily pain and social functioning subscale scores, and in EQ-5D VAS and WPAI activity impairment scores [all p < 0.05] [ Table 4 and Supplementary Table 3]. In addition, among patients who were employed at induction baseline, a lower proportion of CDC achievers than non-achievers had a clinically important decline in WPAI presenteeism score [p < 0.05].

Proportions of patients in histological remission among CDC achievers vs non-achievers
To assess the relationship between achievement of CDC and histomorphology [as an objective marker of disease activity], the proportions of patients who did and did not achieve CDC who were in histological remission were investigated. At week 10, greater proportions of CDC achievers than non-achievers were in histological remission [biologic-naïve: 75.5% vs 21.4%; biologic-experienced: 57.1% vs 14.2%; both p < 0.001] [ Figure 3]. In addition, at week 58, greater proportions of patients who achieved CDC were in histological remission, compared with those who did not achieve CDC [86.3% vs 18.3%, p < 0.001].  20 Whilst this finding does underscore the relationship between the different outcomes, it also suggests that there are additional dimensions to the effect of disease on HRQoL outside of those relating to gut dysfunction.

Discussion
Restoration of HRQoL is now among the long-term treatment targets recommended for UC. 11 Notably, patients treated with filgotinib 200 mg in SELECTION experienced considerable improvements across the broad range of HRQoL measures included in these analyses [SF-36, EQ-5D and IBDQ] during both induction and maintenance, vs placebo. When considering the proportion of patients demonstrating restoration of overall HRQoL (determined as SF-36 PCS or MCS score ≥40) this generally improved following treatment with filgotinib. This reached nominal significance relative to placebo in the induction phase (p < 0.05), whereas in the maintenance phase it did not. A possible explanation for this could be that participants who were randomized to receive placebo in the maintenance phase had already received filgotinib in the induction phase and were in response and/or remission at the beginning of the maintenance phase. Indeed, analysis of disease worsening revealed that of patients who received filgotinib 200 mg in the induction phase before being withdrawn to placebo in the maintenance phase, only 50% demonstrated significant disease worsening during the maintenance phase, suggesting that filgotinib still exerted some therapeutic effects 58 weeks later (data unpublished at present).
Treatment differences in HRQoL improvements at week 10 were numerically larger in biologic-experienced than biologicnaïve patients, despite the former group having a lower response rate [53.1% and 66.5% of biologic-experienced and biologic-naïve filgotinib 200 mg-treated patients achieved an MCS response at week 10, respectively 15] . This may reflect the finding that biologic-experienced patients had more severe disease and thus a greater unmet treatment need than biologic-naïve patients [77.8% and 55.8% had an induction baseline Mayo endoscopic subscore of 3, respectively], and therefore perceived any treatment benefits to be greater. In addition, the benefit of filgotinib 200 mg on WPAI outcomes provides evidence that approximately a quarter of patients had improvements in health status that allowed them to return to their normal working lives. Induction treatment with filgotinib 200 mg was also shown to restore HRQoL after 10 weeks compared with placebo in a proportion of patients with low induction baseline SF-36 scores.
To assess the benefits of filgotinib 200 mg at the patient level, we combined endpoints that are treatment targets specified by the STRIDE-II guidelines, 11 and that are typically reported as part of independent cross-sectional analyses. A greater proportion of patients treated with filgotinib 200 mg than those treated with placebo simultaneously achieved each of the four CDC components [pMCS remission, endoscopic improvement, inflammatory biomarker remission and IBDQ remission], at both week 10 and week 58. The cut-off of faecal calprotectin 150 µg/g was chosen because any value above this level is considered to be indicative of active disease, and associated with an increased risk of disease flares. 19 The proportion of patients who achieved CDC was lower than the proportion of those who achieved each of the individual components. This indicates that the combination of the four outcomes [clinical, endoscopic, biomarker and patient-reported] was difficult to attain. Importantly, CDC was achieved in parallel with short-and long-term improvements in HRQoL, as shown by clinically important improvements in SF-36 and EQ-5D scores at week 10 that were sustained in high proportions of CDC achievers by week 58. This result suggests that achievement of CDC may be associated with restoration of HRQoL. In addition, achievement of CDC was associated with histological remission, a gold standard morphological measure of disease activity, 21 indicating that patients who achieved the endpoint may have had controlled disease at the cellular level. Indeed, previous analyses by our group have demonstrated a significant association between histological remission and endoscopic improvement, a well-established clinical endpoint (data not shown). Further work, including prospective trials and assessment of risk-benefit profiles in patient subpopulations, is required to validate our exploratory composite endpoint. Nevertheless, these initial observations point to the potential of assessing multiple established outcomes within individuals as an approach for measuring multidimensional disease control that relates to the patient's overall health status.
Limitations of these analyses include that HRQoL measures were assessed at only two time points. Future studies could assess individual patient trajectories using multiple endpoint data at various time points [from the beginning of treatment through to CDC], in order to evaluate disease burden and fluctuations over time, and to determine early indicators of a positive/negative disease course. A further limitation was that only responders entered the Maintenance Study, owing to the re-randomization trial design. This introduces bias due to the exclusion of non-responders. Nevertheless, this was not considered a major issue, as the purpose of the maintenance phase was to evaluate the perpetuation of previously identified therapeutic benefit arising from the induction phase. It is also worth noting that for the group who received induction filgotinib and maintenance placebo, as noted above, it cannot be ruled out that priming with filgotinib impacted the disease trajectory during maintenance when filgotinib treatment ceased. However, if anything this is likely to favour an underestimation of the benefits of filgotinib. In addition, this is a study design that is frequently employed in UC trials as it allows for evaluation of different treatment durations whilst minimizing the time that any individual patients spend on the placebo. This is important as withholding of favourable care would present ethical issues.
Analyses evaluating the composite endpoint were exploratory and require formal external validation, for example reliability testing. This is particularly true considering the response to filgotinib of inflammatory biomarkers. These are well-established indicators of active disease, as well as being the least invasive of all the objective endpoints, and the lack of concordance of their profiles with other disease markers warrants further investigation. Alternatively, our data could suggest the threshold for inflammatory biomarker remission could be made less stringent, given that clinically significant improvements to HRQoL and endoscopic improvement were achieved in this study without the criterion for inflammatory biomarker remission being met. Nevertheless, it could be speculated that assessment of multiple established UC outcomes within a composite endpoint may be valuable for clinicians managing patients with UC, as treatment shifts towards a more personalized and patient-centred approach. 22,23 Such composite efficacy measures assessing disease control within individuals could fuel a new generation of algorithm trials that help guide decisions on the sequential use of targeted therapies, and could aid in cost-effectiveness evaluations.

Conclusions
Based upon data from the SELECTION trial, filgotinib 200 mg resulted in short-and long-term improvements in generic and disease-specific HRQoL. Filgotinib 200 mg led to some patients achieving a stringent exploratory composite endpoint that may be associated with both improved HRQoL and histological remission. Further work is required to validate this exploratory endpoint.