Abstract
Background
We evaluated the health-related quality of life (HRQoL) benefits of upadacitinib (UPA) induction and maintenance treatment in a phase 3 study of patients with ulcerative colitis (UC) across a broad range of patient-centered outcomes.
Methods
Patients received UPA 45 mg once daily or placebo as induction treatment for 8 weeks. Patients who achieved clinical response were rerandomized to receive once daily UPA 15 mg, 30 mg, or placebo as maintenance treatment for 52 weeks. The percentages of patients reporting a clinically meaningful within-person change from baseline in the Ulcerative Colitis Symptoms Questionnaire, Inflammatory Bowel Disease Questionnaire, Work Productivity and Impairment Questionnaire, 36-Item Short Form Survey, and European Quality of Life-5 Dimension 5 Levels were evaluated at weeks 2 and 8 of induction and at weeks 0 and 52 of maintenance.
Results
Significant improvements from baseline in all HRQoL measures except the Work Productivity and Impairment Questionnaire–absenteeism were achieved with UPA (P < .001) vs placebo as early as week 2 of induction. These improvements were sustained at week 52 with significantly more patients treated with either 15 mg or 30 mg UPA vs placebo achieving meaningful within-person change in the Ulcerative Colitis Symptoms Questionnaire; Inflammatory Bowel Disease Questionnaire; overall work impairment, presenteeism, and activity impairment; both 36-Item Short Form Survey Physical and Mental Component Summaries; and European Quality of Life-5 Dimension 5 Levels (P < .001).
Conclusions
Induction treatment with UPA 45 mg significantly improved HRQoL measures. A significantly higher percentage of patients who responded to induction treatment with UPA maintained clinically meaningful improvements consistently across a wide range of HRQoL outcomes after 52 weeks of maintenance therapy with UPA (15 mg and 30 mg) compared with placebo. (ClinicalTrials.gov, Numbers: NCT02819635, NCT03653026).
Keywords: clinical trials, quality of life, socioeconomical and psychological endpoints
Key Messages.
What is already known?
Induction treatment with upadacitinib (UPA) has previously demonstrated improvement in health-related quality of life measures in a phase 2 clinical trial in patients with ulcerative colitis, but longer-term benefits through maintenance therapy and across a broader range of patient-reported outcomes remain unknown.
What is new here?
Induction treatment with UPA 45 mg significantly improved health-related quality of life measures across multiple patient-reported outcomes that measure inflammatory bowel disease symptoms, work productivity, physical and mental functioning, and general well-being that were maintained after 52 weeks of maintenance treatment with UPA (15 mg and 30 mg), compared with placebo.
How can this study help patient care?
The benefits identified in HRQoL with UPA treatment fulfill the recommendations of the STRIDE initiative that targets the restoration of quality of life as an important, long-term treatment goal for patients with inflammatory bowel disease, which is increasingly recognized as an important factor influencing patient preference regarding treatment options.
INTRODUCTION
Ulcerative colitis (UC) is a chronic, inflammatory disease that affects the mucosa of the colon and rectum. The clinical course varies and is characterized by exacerbation and remission.1,2 The prevalence of UC has been estimated to be as high as 286 cases per 100 000 persons in North America,3 with similar rates reported in Europe, at up to 291 cases per 100 000.1 In Asia, the prevalence of inflammatory bowel disease (IBD) has been estimated at up to 76 cases per 100 000; however, the incidence of IBD has been reported at 1.4 cases per 100 000 and rising.4
Patients with UC experience reduced health-related quality of life (HRQoL) compared with the general population and UC symptoms have been associated with patients experiencing disease-related physical and psychological burden, which may impact work productivity, off-work activity, and general well-being.5 Measures of HRQoL, including disease-specific tools such as the Inflammatory Bowel Disease Questionnaire (IBDQ) and more general measures like the European Quality of Life-5 Dimension 5 Levels (EQ-5D-5L), have correlated significantly with disease severity, and more active disease is associated with higher levels of work impairment and negative work productity.6,7 Improvements in patient-reported outcomes (PROs) are often a target for UC therapy; both the STRIDE-II (Selecting Therapeutic Targets in Inflammatory Bowel Disease-II) and SPIRIT (Selecting End Points for Disease–Modification Trials) consensus, which included clinician and patient participation, recommend that the primary therapeutic goal in IBD is to limit the impact of disease on patient’s quality of life.8,9 The use of advanced therapies as an effective treatment is supported by evidence that suggests that these have the potential to improve HRQoL.10,11
Janus kinase (JAK) inhibitors are a novel type of therapy for UC and other immune-mediated inflammatory diseases.12,13 Upadacitinib (UPA) is a selective and reversible JAK inhibitor approved by the U.S. Food and Drug Administration and European Medicines Agency for the treatment of adults with moderately to severely active UC. The efficacy of UPA has been demonstrated as an induction and maintenance treatment for inflammation and bowel symptoms in a placebo-controlled study of adult patients with moderate to severe UC and in induction studies of patients who had inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists.14,15
Induction treatment with UPA has demonstrated improvement in HRQoL measures in a phase 2 clinical trial, including the IBDQ and 36-Item Short Form Survey (SF-36), but longer-term benefits through maintenance therapy and across a broader range of PROs remain unknown.15
The aim of this study was to evaluate HRQoL of 8-week induction treatment with UPA across a broad range of PROs (IBD symptoms, work productivity, physical and mental quality of life, and general well-being), in a post hoc analysis of phase 3 studies, and to determine whether any demonstrated benefits are sustained with 52-week maintenance treatment for induction responders in patients with moderately to severely active UC.
METHODS
Study design and participants
Here, we report a post hoc analysis of UPA for induction and maintenance therapy in patients with UC. The U-ACHIEVE Induction (NCT02819635; substudy 2) and U-ACCOMPLISH (NCT03653026) studies were multicenter, randomized double-blind, placebo-controlled studies. Both studies had an 8-week double-blind induction period and an 8-week open-label extended induction period. Patients who achieved clinical response in either of these studies at the end of the induction period, as well as responders from U-ACHIEVE phase 2b (substudy 1) study, were evaluated in a 52-week maintenance study (U-ACHIEVE Maintenance study). Full details of these trials have been published previously.
Patients eligible for the UPA induction studies were 16 to 75 years of age with a diagnosis of UC for at least 90 days prior to baseline, confirmed by colonoscopy. Patients had moderately to severely active UC, defined as an adapted Mayo score of 5 to 9 points with an endoscopic subscore of 2 or 3, confirmed by a central reader. Patients were also required to have a history of an inadequate response; loss of response; or intolerance to aminosalicylates, corticosteroids, immunosuppressants, or biologic therapies. Patients were excluded if they had a diagnosis of Crohn’s disease or indeterminate colitis, UC limited to the rectum, clinical signs of fulminant colitis, toxic megacolon, or a history of colectomy. Patients who had previous exposure to JAK inhibitors were also excluded.
For the double-blind induction period (U-ACHIEVE Induction and U-ACCOMPLISH studies), patients were randomized 2:1 to oral administration of UPA 45 mg once daily (QD) or placebo for 8 weeks and continued to receive UPA 45 mg QD open-label treatment for 8 weeks if clinical response was not achieved at the end of the double-blind period. Patients who achieved clinical response after 8-week UPA 45 mg QD induction treatment in the 2 identical induction studies (U-ACHIEVE Induction and U-ACCOMPLISH), were rerandomized 1:1:1 to oral administration of QD UPA 15 mg, 30 mg, or placebo maintenance treatment (U-ACHIEVE Maintenance study). A clinical response was defined as a decrease of ≥2 points and ≥30% from baseline in the adapted Mayo score, and a decrease in rectal bleeding subscore ≥1 or an absolute rectal bleeding subscore ≤1. The baseline of the induction phase is defined as week 0. Baseline of the maintenance period (maintenance week 0) is week 8 for patients who achieved response after 8-week induction treatment with UPA, or week 16 for patients who achieved a response after the extended 16-week induction treatment.
Outcomes
The outcomes evaluated in this post hoc analysis were the percentage of patients achieving a clinically meaningful within-person change (MWPC) in each PRO at weeks 2 and 8 of the induction phase and at week 52 of the maintenance phase for the following HRQoL measures: Ulcerative Colitis Symptoms Questionnaire (UC-SQ), IBDQ, Work Productivity and Activity Impairment (WPAI) questionnaire (overall work impairment, absenteeism, presenteeism, and activity impairment), SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and EQ-5D-5L. Least squares (LS) mean change from baseline in each PRO at weeks 2 and 8 of induction and at week 52 of maintenance were also reported.
The UC-SQ is a 17-item instrument of intestinal and extraintestinal symptoms, including bowel movements, abdominal pain, blood in stool, fatigue, and problems with sleeping. The instrument was developed using a targeted literature review, and combined concept elicitation and cognitive interviews of patients with mild or in remission UC. Items were scored on a 0- to 4-point Likert-type scale indicating the frequency and intensity of each symptom. Overall scores were calculated by adding ratings of each item, with higher scores indicating greater severity. As part of the psychometric validation of this instrument based on UPA phase 2 data, patients’ individual UC-SQ change scores anchored on their impression of change (eg, “minimally improved”) and clinical remission, probability density functions, and empirical cumulative distribution functions were used to determine the MWPC threshold, estimated to be a ≥10-point decrease.
The IBDQ is a disease-specific tool comprising 32 Likert-scaled items (with 7-point response options ranging from 1 to 7), scored from 32 to 224, evaluating systemic symptoms, bowel symptoms, and emotional and social function.16,17 Higher scores indicated better HRQoL, and the percentage of patients with an increase in IBDQ score of ≥16 points (MWPC threshold)18 from baseline was reported at induction weeks 2 and 8 and at maintenance week 52. The percentage of patients achieving IBDQ remission (defined as IBDQ total score ≥170) and IBDQ response (an increase of IBDQ total score ≥16 from baseline) were also reported at induction weeks 2 and 8 and at maintenance week 52.
The WPAI is composed of 6 items across 4 domains: productivity loss (overall work impairment), absenteeism (work missed), presenteeism (work impairment or reduced effectiveness at work), and activity impairment (activities not including paid work, for example cleaning or shopping).19,20 Scores were reported as impairment percentages; higher numbers signifying more impairment and less productivity. The percentage of patients who achieved MWPC for improvement in the WPAI from baseline at weeks 2 and 8 of induction and week 52 of maintenance were reported. MWPC thresholds used were a decrease of ≥7.3% for overall work impairment, ≥6.5% decrease for absenteeism, ≥6.1% decrease for presenteeism, and ≥8.5% decrease for activity impairment.21,22
The SF-36 is a validated, self-administered HRQoL questionnaire with 36 items that includes 8 subscales evaluating different functions: physical and physical-role functioning, bodily pain, general health, vitality, social and emotional role-functioning, and mental health.23,24 Summary scores include a PCS score and an MCS score, with higher scores indicating a better outcome. The MWPC threshold used for SF-36 was a ≥4.1-point increase.25
The EQ-5D-5L is a validated instrument for evaluating HRQoL consisting of 5 dimensions, which include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.26 A single EQ-5D-5L summary index value for health status was generated, derived by applying weights to each of the levels in each dimension (full health = 1, death = 0). An increase in score of ≥0.0763 was used as the threshold for MWPC.27
Statistical analyses
Analyses for the induction studies were performed in the intention-to-treat (ITT) population that included all randomized patients who received at least 1 dose of the study drug. In the maintenance study, the ITT analysis set consisted of rerandomized 8-week UPA 45 mg QD induction responders who received at least 1 dose of the study drug in the maintenance study. Treatment groups were compared using 95% confidence intervals for adjusted differences, and P values were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (corticosteroid use at week 0 [yes or no], adapted Mayo score at induction baseline [≤7 or >7], clinical remission status at week 0 of maintenance [yes or no], biologics-inadequate response [Bio-IR] status at baseline [Bio-IR or non-Bio-IR]). Missing data were reported using nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19. LS mean change analyses were conducted using mixed-effects model repeat measurement for induction and return to baseline multiple imputation for maintenance.
Ethical requirements
This study was conducted in compliance with the protocol, International Conference on Harmonisation guidelines, applicable regulations, and guidelines governing clinical study conduct. As per Good Clinical Practice, the study protocol, informed consent forms, and all other explanatory materials were approved by the relevant ethics committees or institutional review boards at all study sites. All patients provided informed consent before study participation.
RESULTS
Study population
In the induction studies, a total of 988 patients were included in the ITT population for statistical analysis; 660 patients received UPA 45 mg QD and 328 patients received placebo. Baseline characteristics were balanced across treatment groups. At baseline, the median age of patients who received UPA was 41 vs 42 years among those receiving placebo, and female patients comprised 37.6% vs 37.8%, respectively (Table 1). Baseline HRQoL levels were balanced in both the placebo and UPA groups (Table 1).
Table 1.
Baseline demographics and HRQoL values (induction, ITT1 population).
| Placebo (n = 328) | UPA 45 mg QD (n = 660) | |
|---|---|---|
| Female | 124 (37.8) | 248 (37.6) |
| Age, y | 42.0 (17-76) | 41.0 (17-76) |
| Race | ||
| Caucasian | 224 (68.3) | 440 (66.7) |
| Black or African American | 10 (3.1) | 23 (3.5) |
| Asian | 87 (26.5) | 189 (28.6) |
| American Indian or Alaska Native | 3 (0.9) | 0 (0) |
| Native Hawaiian and other Pacific Islander | 1 (0.3) | 1 (0.1) |
| Multiple | 3 (0.9) | 7 (1.1) |
| Disease duration, y | 8.2 ± 8.0 | 7.9 ± 6.8 |
| Inadequate response to biologics | 167 (50.9) | 340 (51.5) |
| UC-SQ | ||
| n | 319 | 642 |
| Mean ± SD | 31.4 ± 10.86 | 32.3 (11.24) |
| Median (range) | 31.0 (2 to 60) | 32.0 (2 to 63) |
| IBDQ | ||
| n | 322 | 649 |
| Mean ± SD | 122.2 ± 34.65 | 122.5 ± 35.47 |
| Median (range) | 120.0 (46 to 202) | 122.0 (40 to 218) |
| WPAI—Overall | ||
| n | 197 | 408 |
| Mean ± SD | 52.8 ± 29.63 | 53.8 ± 28.41 |
| Median (range) | 52.3 (0 to 100) | 53.5 (0 to 100) |
| WPAI—absenteeism | ||
| n | 197 | 408 |
| Mean ± SD | 19.2 ± 29.44 | 19.6 ± 31.05 |
| Median (range) | 3.6 (0 to 100) | 3.2 (0 to 100) |
| WPAI—presenteeism | ||
| n | 182 | 372 |
| Mean ± SD | 43.5 ± 25.96 | 44.6 ± 23.58 |
| Median (range) | 40.0 (0 to 100) | 40.0 (0 to 100) |
| WPAI—activity impairment | ||
| n | 321 | 647 |
| Mean ± SD | 49.5 ± 26.29 | 51.6 ± 25.74 |
| Median (range) | 50.0 (0 to 100) | 50.0 (0 to 100) |
| SF-36—PCS | ||
| n | 321 | 647 |
| Mean ± SD | 43.1 ± 8.03 | 42.8 ± 7.78 |
| Median (range) | 43.3 (18.80 to 66.86) | 43.2 (14.21 to 65.37) |
| SF-36—MCS | ||
| n | 321 | 647 |
| Mean ± SD | 40.6 ± 10.99 | 40.6 ± 10.61 |
| Median (range) | 41.1 (12.71 to 65.04) | 40.8 (9.32 to 64.14) |
| EQ-5D-5L index value | ||
| n | 321 | 647 |
| Mean ± SD | 0.7 ± 0.21 | 0.7 ± 0.20 |
| Median (range) | 0.7 (-0.22 to 1) | 0.7 (-0.32 to 1) |
Values are n (%), median (range), or mean ± SD, unless otherwise indicated.
Abbreviations: EQ-5D-5L, European Quality of Life-5 Dimension 5 Levels; HRQoL, health-related quality of life; IBDQ, Inflammatory Bowel Disease Questionnaire; ITT, intention to treat; MCS, Mental Component Score; PCS, Physical Component Score; QD, once daily; SF-36, 36-Item Short Form Survey; UC-SQ, Ulcerative Colitis Symptoms Questionnaire; UPA, upadacitinib; WPAI, Work Productivity and Impairment Questionnaire.
For the maintenance phase, 451 patients who achieved a clinical response following treatment with 8-week UPA 45 mg QD were included in the primary analysis. A total of 149, 148, and 154 patients received placebo, UPA 15 mg, and UPA 30 mg QD, respectively, during the maintenance phase. Baseline PRO scores were balanced across UPA and placebo treatment groups at end of induction (week 0 of maintenance).
UC-SQ improvement with UPA
A significantly higher percentage of patients receiving induction treatment with UPA reported meaningful improvements in UC-SQ at both induction week 2 and induction week 8 compared with those receiving placebo (P < .001) (Figure 1A). The improvement in UC-SQ was sustained to week 52 with UPA maintenance treatment (15 mg and 30 mg) compared with placebo (P < .001)( Figure 1B). The high levels of improvement in UC-SQ seen at the end of induction therapy declined with placebo maintenance treatment to week 52 (from 81.4% at end of 8-week induction treatment to 29.7% at 52-week maintenance treatment). Mean change from baseline was also significantly higher across induction weeks 2 and 8 and at week 52 maintenance treatment with UPA compared with placebo (Tables S1 and S3).
Figure 1.
Percent of patients achieving meaningful within-person change (MWPC) relative to baseline for the Ulcerative Colitis Symptoms Questionnaire (A) at weeks 2 and 8 of induction treatment and (B) at weeks 0 and 52 of maintenance treatment. *End of 8-week induction treatment with upadacitinib (UPA) 45 mg once daily. MWPC is based on anchor and/or distribution analyses with the MWPC threshold for the Ulcerative Colitis Symptoms Questionnaire (≥10-point decrease). The 95% confidence intervals are shown in parentheses. PBO, placebo.
IBDQ improvement with UPA
A significantly higher percentage of patients receiving induction treatment with UPA achieved MWPC in IBDQ at both induction week 2 and induction week 8 compared with those receiving placebo (P < .001) (Figure 2A). Improvements in IBDQ seen in induction persisted with maintenance treatment at week 52, with a significantly higher percentage of patients achieving MWPC criteria (P < .001) with both 15 mg and 30 mg UPA compared with placebo (Figure 2B). Patients who received UPA 45 mg compared with placebo reported significantly improved and clinically meaningful improvement at week 8 in HRQoL measured by the IBDQ total score and all 4 domain scores: systemic symptoms (including fatigue), social and emotion function, and bowel symptoms (that included abdominal pain and bowel urgency) (Table S2). Patients treated with either UPA 15 mg or 30 mg in the 52-week maintenance also demonstrated significant and clinically meaningful improvement on the IBDQ total score and all 4 domain scores compared with placebo (Table S3). A significantly greater percentage of patients receiving induction treatment with UPA also achieved IBDQ remission at weeks 2 and 8, with a difference of 22.7% and 35.7%, respectively, compared with placebo. Higher rates of IBDQ remission continued with maintenance treatment to week 52 with a difference of 42.8% higher achievement of remission seen with UPA 30 mg treatment compared with placebo (Figure S1).
Figure 2.
Percent of patients achieving meaningful within-person change (MWPC) relative to baseline for the Inflammatory Bowel Disease Questionnaire (A) at weeks 2 and 8 of induction treatment and (B) at weeks 0 and 52 of maintenance treatment. *End of 8-week induction treatment with upadacitinib (UPA) 45 mg once daily. MWPC is based on anchor and/or distribution analyses with the MWPC threshold for the Inflammatory Bowel Disease Questionnaire (≥16-point increase) extracted from published literature. The 95% confidence intervals are shown in parentheses. PBO, placebo.
WPAI improvement with UPA
The percentage of patients achieving MWPC across WPAI domains of overall work impairment, presenteeism, and activity impairment were significantly higher with induction treatment with UPA compared with placebo (P < .001) (Figure 3A). Improvements in WPAI domains seen in induction persisted with UPA 15 mg and UPA 30 mg maintenance treatment to week 52 (Figure 3B). The percentage of patients achieving MWPC for absenteeism was numerically higher, but not significant, with UPA induction treatment compared with placebo (27.4% achieved MWPC with UPA compared with 20.5% with placebo at induction week 8; P = .059). LS mean change from baseline was significant across all domains except absenteeism at induction weeks 2 and 8 and overall work impairment at induction week 2 with UPA compared with placebo (Table S1). With maintenance treatment, significant improvements in absenteeism vs placebo were observed with UPA 15 mg (P = .028), but not with UPA 30 mg (P = .242), which may be explained by skewed distribution with a high proportion of zero values, statistical noise, and between-workplace effects. Variance in workplace policies and actual practice may have dominated the effects of UPA on well-being.
Figure 3.
Percent of patients achieving meaningful within-person change (MWPC) relative to baseline for the Work Productivity and Impairment Questionnaire (A) at weeks 2 and 8 of induction treatment and (B) at weeks 0 and 52 of maintenance treatment. *End of 8-week induction treatment with upadacitinib (UPA) 45 mg once daily. MWPC is based on anchor and/or distribution analyses with the MWPC threshold for the Work Productivity and Impairment Questionnaire extracted from published literature. The 95% confidence intervals are shown in parentheses. PBO, placebo.
SF-36 improvement with UPA
With induction treatment, significantly more patients achieved MWPC with UPA compared with placebo at induction weeks 2 and 8 in SF-36 PCS (P < .001). MWPC in SF-36 MCS was also more likely to be achieved at week 2 (P = .013) and week 8 (P < .001) with UPA induction treatment compared with placebo (Figure 4A). Fewer patients achieved clinically meaningful improvements in PCS and MCS scores who received placebo in the maintenance phase after the end of 8-week induction to maintenance week 52. In these patients, the percentage with a MWPC dropped from 68.5% at induction week 0 to 32.6% at maintenance week 52 for PCS and from 69.8% to 28.9% for MCS. In contrast, clinically meaningful improvements in PCS and MCS persisted in those patients who received maintenance treatment with UPA 15 mg or 30 mg. Similarly, LS mean change from baseline scores were significantly higher at induction weeks 2 and 8 and maintenance week 52 with UPA treatment compared with placebo (Table S1 and S3).
Figure 4.
Percent of patients achieving meaningful within-person change (MWPC) relative to baseline for the 36-Item Short Form Survey (A) at weeks 2 and 8 of induction treatment and (B) at weeks 0 and 52 of maintenance treatment. *End of 8-week induction treatment with upadacitinib (UPA) 45 mg once daily. MWPC is based on anchor and/or distribution analyses with the MWPC threshold for the 36-Item Short Form Survey (≥4.1-point increase) extracted from published literature. The 95% confidence intervals are shown in parentheses. MCS, Mental Component Summary; PBO, placebo; PCS, Physical Component Summary.
EQ-5D-5L improvement with UPA
Significantly more patients achieved MWPC for improvements in EQ-5D-5L with UPA induction treatment compared with placebo at both weeks 2 and 8 (P < .001) (Figure 5A). Improvement in EQ-5D-5L was sustained with maintenance UPA treatment (UPA 15 mg and UPA 30 mg) but not with placebo treatment from baseline maintenance to week 52 (P < .001) (Figure 5B). Significantly higher LS mean change scores for improvement in EQ-5D-5L with UPA treatment compared with placebo were also reported across induction weeks 2 and 8 and maintenance week 52 (Table S1 and S3).
Figure 5.
Percent of patients achieving meaningful within-person change (MWPC) relative to baseline for the European Quality of Life-5 Dimension 5 Levels (A) at weeks 2 and 8 of induction treatment and (B) at weeks 0 and 52 of maintenance treatment. *End of 8-week induction treatment with upadacitinib (UPA) 45 mg once daily. MWPC is based on anchor and/or distribution analyses with the MWPC threshold for the European Quality of Life-5 Dimension 5 Levels (≥0.0763-point increase) extracted from published literature. The 95% confidence intervals are shown in parentheses. PBO, placebo.
DISCUSSION
This post hoc analysis demonstrates that patients with moderately to severely active UC treated with UPA 8-week induction treatment achieve benefits across multiple HRQoL measures that are sustained with maintenance UPA treatment to 52 weeks, compared with placebo. Improvements were observed as early as week 2 and at week 8 of induction treatment, with significant clinically meaningful improvements seen across a broad range of PROs, capturing quality-of-life aspects that are both disease related (eg, UC-SQ and IBDQ) and more general (eg, EQ-5D-5L). These outcomes are considered particularly relevant and important to patients because they cover UC-related gastrointestinal symptoms (eg, urgency or frequency of bowel movements and abdominal pain) and nongastrointestinal symptoms (eg, joint pain, fatigue, and difficulty sleeping), physical and mental functioning, work productivity, and performance of everyday activities.
Improvements in all WPAI domains, apart from absenteeism, were observed in induction and persisted with UPA maintenance treatment to week 52. The nonsignificant result for absenteeism with UPA 30 mg may be related to the acceptability of absenteeism in different countries and workplaces. In addition, baseline levels of absenteeism were low relative to other WPAI domains (Table 1), leaving less opportunity for improvement. However, there may be greater potential impact on absenteeism in real-world settings, and future research may evaluate the real-world impact of UPA on absenteeism in specific countries and workplaces.
For patients who responded to induction therapy, the HRQoL benefits observed were sustained with UPA 15 mg and 30 mg maintenance treatment, compared with placebo, across a variety of HRQoL outcomes at 52 weeks. Statistically significant improvements in HRQoL were maintained with both 15 mg and 30 mg UPA treatment to 52 weeks. In contrast, the robust improvements in PROs demonstrated at the end of UPA induction treatment decline in patients receiving placebo maintenance treatment, highlighting that benefits seen in induction are reversible in the absence of UPA.
Sustained improvements in PROs are noteworthy because patients with UC have reported more depression, anxiety, and pain compared with the general population.28 Patients have also experienced a negative impact on social activities that may be attributed to the deterioration of HRQoL and to the stigmatism of IBD symptoms.29,30 Studies have shown that UC symptoms have a significant impact on patients’ everyday functioning, with work-related outcomes often highlighted, including absenteeism and impairment in productivity.22,31 In North America, the annual cost of lost productivity due to absence from work has been estimated at $1443 (range $85-$2350) for patients with UC,32 highlighting the importance of the sustained improvement in WPAI domains with UPA treatment observed in this study. Similar high costs have been reported in Europe for patients with IBD, with indirect costs from a loss of work productivity estimated at €1900 per patient per year.33
PROs are a direct measure of how patients feel or function, and as such they supplement information obtained from clinical effectiveness endpoints. The benefits identified in HRQoL with UPA treatment fulfill the recommendations of the STRIDE initiative that targets the restoration of quality of life as an important, long-term treatment goal for patients with IBD.9 The assessment of HRQoL is increasingly recognized as an important factor influencing patient preference regarding treatment options.
Benefits in HRQoL observed during the UPA phase 3 program were in agreement with those reported with alternative advanced therapies for the treatment of UC, including infliximab,34 vedolizumab,35 adalimumab,36 and tofacitinib,37 although the benefits demonstrated in this study were across a broader range of HRQoL measures.
Key strengths of this study are that the data analyzed are from randomized, double-blind phase 3 trials. Multiple validated PROs have been assessed, providing results across a wide range of HRQoL measures during induction and maintenance treatment with UPA. Clinically meaningful improvements were consistent across a broad range of PROs, demonstrating significant benefits of UPA compared with placebo. The SF-36, EQ-5D-5L, IBDQ, and WPAI are validated PROs with published MWPC thresholds,17,18,21,22,25,27 and publication of the UC-SQ validation study is in progress. The results of this study predominantly reflect the impact in Caucasian populations in keeping with the demographics of the clinical trial. Data beyond 52 weeks are needed to assess the long-term benefit of UPA therapy on HRQoL in patients with UC. Furthermore, the extent to which the efficacy of UPA to improve HRQoL is associated with its formulation as an oral medication instead of other modes of administration (intravenous or subcutaneous) remains an area of future research.
Conclusions
This study demonstrates that induction treatment with UPA 45 mg achieved significant and clinically meaningful improvements compared with placebo as early as induction week 2, across a variety of HRQoL assessments for patients with moderately to severely active UC. Significant clinically meaningful improvements across a broad range of HRQoL outcomes persisted with UPA (15 mg and 30 mg) maintenance treatment compared with placebo for 52 weeks. These improvements were observed across multiple PROs that measure IBD symptoms, work productivity, physical and mental functioning, and general well-being.
Supplementary Material
Acknowledgments
Medical writing assistance was provided by Sarah Hodgkinson, PhD, and Joann Hettasch, PhD, of Fishawack Facilitate Ltd, part of Fishawack Health, and was funded by AbbVie Inc. Part of this work was presented at the 17th Congress of the European Crohn’s and Colitis Organization (ECCO 2022), February 16-19, 2022, Virtual.
Contributor Information
Julian Panés, Inflammatory Bowel Disease Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
Edward V Loftus, Jr, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
Peter D R Higgins, Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
James O Lindsay, Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.
Wen Zhou, AbbVie Inc, North Chicago, IL, USA.
Xuan Yao,, AbbVie Inc, North Chicago, IL, USA.
Dapo Ilo, AbbVie Inc, North Chicago, IL, USA.
Charles Phillips, AbbVie Inc, North Chicago, IL, USA.
Jacinda Tran, AbbVie and the Comparative Health Outcomes, Policy, and Economics Institute, University of Washington, Seattle, WA, USA.
Yuri Sanchez Gonzalez, AbbVie Inc, North Chicago, IL, USA.
Séverine Vermeire, Department of Gastroenterology and Hepatology, University Hospital Leuven, Leuven, Belgium.
Funding
This work was supported by AbbVie. AbbVie sponsored the study; contributed to the design; participated in collection, analysis, and interpretation of data; and in writing, reviewing and approval of the final version. All authors had access to the data results, and participated in the development, review, and approval of this abstract. No honoraria or payments were made for authorship.
Conflicts of Interest
J.P. has received financial support for research, received lecture fee(s), and/or received consultancy fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, Genentech, GSK, Janssen, Mirum Pharma, Morphic Therapeutic, Origo, Pandion, Pfizer, Progenity, Revolo Biotherapeutics, Robarts, Roche, Takeda, Theravance, and Wassermann. E.V.L. has received financial support for research and/or consultancy fees from AbbVie, Amgen, Arena, BI, BMS, Calibr, Celgene, Celltrion Healthcare, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Scopes, Janssen, Lilly, Morphic Therapeutics, Ono Pharma, Pfizer, Protagonist, Receptos, Robarts Clinical Trials, Scipher, Sun, Surrozen, Takeda, Theravance, and UCB. P.D.R.H. has received consultancy fees and/or research funding from AbbVie, the Crohn’s and Colitis Foundation, Eli Lilly, Lycera, the National Institutes of Health, Pfizer, PRIME Medical Education, and Takeda. J.O.L. has served as consultant and on the advisory board for, received speaker fees from, received sponsorship for academic meetings from, and/or received investigator-led research grants from AbbVie, Allergan, Atlantic, BMS, Celgene, Celltrion, Ferring, Galapagos, Gilead, GSK, Janssen, Lilly, MSD, Napp, Norgine, Pfizer, Shire, Takeda, Tillotts, and Vifor Pharma. W.Z., X.Y, D.I., C.P., and Y.S.G. are full-time employees of AbbVie and may hold AbbVie stock and/or stock options. J.T. was a summer intern at AbbVie at the time this study was conducted, is currently an AbbVie contractor and PhD student at University of Washington, and has received financial support from the Agency for Healthcare Research and Quality, National Institutes of Health, ARCS Foundation, and the Washington Research Foundation. S.V. has received grants from AbbVie, J&J, Pfizer, Galapagos, and Takeda; has received consulting and/or speaking fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, and Zealand Pharma.
Data Availability
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis datasets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan, and execution of a Data Sharing Agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this article for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis datasets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan, and execution of a Data Sharing Agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this article for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.