FormalPara Key Points for Decision Makers

Patients receiving tofacitinib 5 mg twice-daily maintenance therapy achieved consistent improvement in key measures of ulcerative colitis disease activity reported by patients, namely the severity of rectal bleeding and frequency of stools.

Improvement of physical symptoms was paired with improvement in quality of life related to health in patients receiving tofacitinib 5 mg twice daily.

Long-term management of ulcerative colitis symptoms can be achieved with the lower maintenance dose of tofacitinib 5 mg twice daily.

1 Introduction

Ulcerative colitis (UC) is a chronic, relapsing–remitting inflammatory disease of the colon [1], with rectal bleeding and increased stool frequency as hallmark symptoms [2]. Patient-reported outcomes (PROs) are self-administered assessments of disease activity without interpretation by a clinician and are a primary method to assess symptomatic relief. The rectal bleeding subscore (RBS) and stool frequency subscore (SFS), which are part of the overall Mayo score to assess disease activity, are commonly used PROs in randomized controlled trials and are being used more often in clinical practice [3].

Determining the durability of UC therapies to maintain symptomatic improvement in rectal bleeding and stool frequency is clinically important, as these outcome measures can be surrogates for overall endoscopic disease activity [4]. Moreover, rectal bleeding and stool frequency improvements are recognized as a goal in the treat-to-target strategy, which is described in the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE)-II guidelines [4, 5]. It has also been shown, through two global UC Narrative surveys completed by UC patients and physicians, that discussion of symptoms experienced since the previous visit is a top priority at appointments for both patients and physicians, and reduction of symptoms is a top priority for patients’ medication satisfaction [6, 7]. Additionally, it is known that UC negatively impacts health-related quality of life (HRQoL) [8]. Improvement in HRQoL alongside clinical response is a major long-term treatment goal of UC and is included as a recommendation in the STRIDE-II treat-to-target strategy [5, 9]. Therefore, the long-term reporting of RBS and SFS PROs and HRQoL outcomes such as the Inflammatory Bowel Disease Questionnaire (IBDQ) are clinically relevant for both patients and physicians.

Tofacitinib is an oral small molecule Janus kinase (JAK) inhibitor for the treatment of UC. It is a first-generation inhibitor of JAK that has functional selectivity for JAK1 and JAK3 signaling over JAK2 [10]. The efficacy and safety of tofacitinib have been evaluated in three phase III, randomized, placebo-controlled studies (OCTAVE Induction 1 and 2 and OCTAVE Sustain) [11], and an open-label, long-term extension study (OCTAVE Open), in patients with moderately to severely active UC [12]. Previous post hoc analysis of the tofacitinib phase III induction studies demonstrated a significant improvement in RBS and SFS versus placebo within 3 days of treatment [13].

These post hoc analyses from the OCTAVE program explore the long-term effect of tofacitinib on PRO measurements, including RBS, SFS, and IBDQ, in patients with UC.

2 Methods

2.1 Patients and Study Design

All studies were registered on http://www.ClinicalTrials.gov (NCT01465763, NCT01458951, NCT01458574, and NCT01470612). Full details of OCTAVE Induction 1 and 2, OCTAVE Sustain, and OCTAVE Open study designs have been reported previously [11, 14]. Patients in OCTAVE Induction 1 and 2 received placebo or tofacitinib 10 mg twice daily for 8 weeks. Responders from OCTAVE Induction 1 and 2 could enter OCTAVE Sustain and were randomized to receive placebo, tofacitinib 5 mg twice daily, or tofacitinib 10 mg twice daily for 52 weeks. Patients in remission at Week 52 of OCTAVE Sustain were assigned to receive tofacitinib 5 mg twice daily in OCTAVE Open.

These analyses include patients who received tofacitinib 5 mg twice daily in OCTAVE Open, regardless of prior treatment in OCTAVE Sustain. This population was used for these analyses, as it was important to determine long-term PROs in patients receiving the lower maintenance dose of tofacitinib. These patients (per protocol) had clinical response at Week 8 of OCTAVE Induction 1 or 2 and completed Week 52 of OCTAVE Sustain in remission. Analyses from OCTAVE Induction 1 and 2 and OCTAVE Sustain were also performed and are presented here for additional context. Clinical response was defined as a decrease from induction study baseline total Mayo score of ≥3 points and ≥30%, with a decrease in RBS of ≥1 point or an absolute RBS of 0 or 1. Remission was defined as a total Mayo score of ≤2, with no individual subscore >1 and an RBS of 0.

Inclusion and exclusion criteria have been described previously [11, 14]. Briefly, for patients to be eligible to enter the studies, they had to be ≥18 years of age with a diagnosis of UC for ≥4 months (phase III OCTAVE Induction 1 and 2) and have had moderately to severely active UC at induction program entry (defined as a total Mayo score of 6–12, with an RBS of 1–3 and an endoscopic subscore of 2 or 3) [11].

During OCTAVE Sustain and OCTAVE Open, tapering of oral corticosteroids was mandatory.

2.2 Efficacy Assessments

Efficacy endpoints analyzed were RBS = 0, SFS ≤ 1, SFS = 0, the composites of RBS = 0 and SFS ≤ 1, and partial Mayo score (PMS) remission (PMS ≤ 2 with no individual subscore >1). PMS (including RBS, SFS, and Physician Global Assessment [PGA] subscore) was assessed at baseline to Week 8 (also baseline of OCTAVE Sustain) of OCTAVE Induction 1 and 2; Week 4 to Week 52 of OCTAVE Sustain; and baseline and Months 1, 4, 6, 9, 15, 18, 21, 27, 30, 33, 39, 42, 45, and 48 in OCTAVE Open. The total Mayo score (including RBS, SFS, PGA, and endoscopic subscore) was assessed at baseline and Week 8 of OCTAVE Induction 1 and 2; Week 24 and Week 52 of OCTAVE Sustain; and baseline and Months 2, 12, 24, and 36 of OCTAVE Open.

2.3 Health-Related Quality-of-Life (HRQoL) Assessments

HRQoL outcomes in OCTAVE Induction 1 and 2 and OCTAVE Sustain have been reported previously [15]. IBDQ remission was defined as an IBDQ total score of ≥170. The IBDQ provides a total score (ranging from 32 to 224; higher scores indicate a better HRQoL) and four domain scores: bowel symptoms (10 items, scored from 10 to 70), systemic symptoms (5 items, scored from 5 to 35), emotional function (12 items, scored from 12 to 84), and social function (5 items, scored from 5 to 35). The IBDQ was self-administered by patients at baseline, Week 4, and Week 8 of OCTAVE Induction 1 and 2, from Week 8 to Week 52 of OCTAVE Sustain, and at Months 2, 6, 12, 18, 24, 30, 36, and 48 of OCTAVE Open.

2.4 Statistical Analyses

In these post hoc analyses, proportions of patients with RBS = 0, SFS ≤ 1, and SFS = 0, PMS remission (PMS ≤ 2 with no individual subscore > 1), and IBDQ remission (total score of ≥ 170) were analyzed over time. Data from OCTAVE Induction 1 and 2 and OCTAVE Sustain were analyzed by non-responder imputation (NRI). For OCTAVE Open, NRI was applied after a patient discontinued, and last observation carried forward (LOCF) imputation was applied after a patient advanced to a subsequent study up to the visit they would have reached if they had stayed in the study; no imputation for missing data was applied for ongoing patients except NRI for intermittent missing data. Observed case data are also reported. The analyses of patients from OCTAVE Open included data up to Month 48, as follow-up data were limited (≤40 patients) beyond Month 60.

2.5 Correlation Analyses

Exploratory point-biserial correlation analyses were used to assess the correlation between HRQoL and efficacy outcomes at Week 8 of OCTAVE Induction 1 and 2, and Week 52 of OCTAVE Sustain. IBDQ total score was used as a dichotomous variable (<170 vs. ≥170), and efficacy outcomes, including RBS, SFS, and PMS, were used as continuous variables (observed cases).

2.6 Study Ethics and Patient Consent

All studies were conducted in compliance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice Guidelines, and approved by the Institutional Review Board and/or Independent Ethics Committee at each investigational center participating in the studies or at a central Institutional Review Board. All patients provided written informed consent.

3 Results

3.1 Patients

In OCTAVE Open, 142 patients who were in remission at baseline (per protocol) after receiving 52 weeks of tofacitinib maintenance therapy in OCTAVE Sustain, and 21 patients in remission after receiving 52 weeks of placebo therapy, were assigned to receive tofacitinib 5 mg twice daily. An additional 12 patients were assigned to tofacitinib 5 mg twice daily as protocol deviations owing to reasons such as patient eligibility not being confirmed prior to enrollment or tofacitinib dosage changes being performed outside of the protocol guidelines, making a total of 175 patients.

Baseline demographics and clinical characteristics of the tofacitinib 5 mg twice-daily patient group of OCTAVE Open are shown in Table 1. The mean age of patients treated with tofacitinib 5 mg twice daily was 44.5 years (standard deviation [SD] 14.6), and at OCTAVE Open baseline, the mean total Mayo score was 1.2 (SD 0.9). In the tofacitinib 5 mg twice-daily patient group, 74 (42.3%) and 116 (66.3%) patients had prior tumor necrosis factor inhibitor (TNFi) exposure and immunosuppressant use, and 66 (37.7%) and 110 (62.9%) patients had TNFi and immunosuppressant failure, respectively.

Table 1 Baseline demographics and clinical characteristics of patients treated with tofacitinib 5 mg twice daily in OCTAVE Open
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The number of patients assigned to treatment in OCTAVE Induction 1 and 2, and OCTAVE Sustain, are described in Online Resource 1.

3.2 Rectal Bleeding and Stool Frequency Patient-Reported Outcomes (PROs) in the OCTAVE Clinical Program

At baseline of OCTAVE Open, in patients assigned to tofacitinib 5 mg twice-daily treatment who entered OCTAVE Open in remission (per protocol), 172 (98.3%) and 175 (100%) had RBS = 0 and SFS ≤ 1, respectively. Based on NRI-LOCF, at Months 12, 24, 36, and 48, respectively, 149 (85.1%), 124 (70.9%), 115 (65.7%), and 95 (54.3%) patients maintained or achieved RBS = 0 (Fig. 1). Corresponding values based on observed cases were 149 (N = 158, 94.3%), 124 (N = 134, 92.5%), 109 (N = 117, 93.2%), and 86 ( N = 92, 93.5%) patients (Fig. 1). Of the 142 patients who were in remission after receiving 52 weeks of tofacitinib 5 mg twice-daily maintenance therapy in OCTAVE Sustain, based on NRI-LOCF and observed cases, 142 (100%) patients had RBS = 0 at baseline of OCTAVE Open. At Month 48, based on NRI-LOCF and observed cases, respectively, 65 (45.8%) and 57 (N = 60, 95.0%) patients maintained RBS = 0.

Fig. 1
figure 1

Proportions of tofacitinib 5 mg twice daily-treated patients in remission at baseline with RBS = 0a in OCTAVE Open (FAS, NRI-LOCF, and observed). NRI was used for missing data at all visits and LOCF was used for visits after a patient advanced to the next study. aThe RBS ranges from 0 to 3; an RBS of 0 equates to no blood seen, and the daily bleeding score represents the most severe bleeding of the day. BL baseline, FAS full analysis set, N number of patients treated in each treatment group, n number of patients with the specified response within the given category, NRI-LOCF non-responder imputation, last observation carried forward, RBS rectal bleeding subscore

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At Months 12, 24, 36, and 48, respectively, 151 (86.3%), 129 (73.7%), 119 (68.0%), and 96 (54.9%) patients maintained or achieved SFS ≤ 1 (NRI-LOCF) [Fig. 2]. At Months 12, 24, 36, and 48, respectively, 151 (N = 158, 95.6%), 129 ( N = 134, 96.3%), 114 (N = 117, 97.4%), and 88 (N = 92, 95.7%) patients maintained or achieved SFS ≤ 1 (observed) [Fig. 2]. Of the 142 patients who were in remission after receiving 52 weeks of tofacitinib 5 mg twice-daily maintenance therapy in OCTAVE Sustain, based on NRI-LOCF and observed cases, 142 (100%) patients had SFS ≤ 1 at baseline of OCTAVE Open. At Month 48, based on NRI-LOCF and observed cases, respectively, 70 (49.3%) and 58 (N = 60, 96.7%) patients maintained SFS ≤ 1.

Fig. 2
figure 2

Proportions of tofacitinib 5 mg twice daily-treated patients in remission at baseline with SFS ≤ 1a in OCTAVE Open (FAS, NRI-LOCF, and observed). NRI was used for missing data at all visits and LOCF was used for visits after a patient advanced to the next study. aThe SFS ranges from 0 to 3; an SFS of 0 equates to a normal number of stools for the patient, and an SFS of 1 equates to one to two stools more than normal. Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency. Normal number of bowel movements represents the number of bowel movements when not having a flare. BL baseline, FAS full analysis set, N number of patients treated in each treatment group, n number of patients with the specified response within the given category, NRI-LOCF non-responder imputation, last observation carried forward, SFS stool frequency subscore

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The composite endpoints of RBS = 0 and SFS ≤ 1, based on NRI-LOCF, was achieved in 172 (98.3%) patients at baseline of OCTAVE Open and 84 (48.0%) patients at Month 48. Corresponding values, based on observed cases, were 172 (98.3%) and 84 (N = 92, 91.3%) patients.

At baseline of OCTAVE Open, in patients assigned to tofacitinib 5 mg twice-daily treatment, 113 (64.6%) had SFS = 0 (see Online Resource 2). SFS = 0 was achieved or maintained in 66 (37.7%; NRI-LOCF) and 61 (N = 92, 66.3%; observed) patients at Month 48 (see Online Resource 2). Furthermore, at baseline of OCTAVE Open, in patients assigned to tofacitinib 5 mg twice-daily treatment, 174 (99.4%) were in PMS remission (see Online Resource 3). PMS remission was achieved or maintained in 95 (54.3%; NRI-LOCF) and 87 (N = 92, 94.6%; observed) patients at Month 48 (see Online Resource 3).

Based on NRI at Week 8 of OCTAVE Induction 1 and 2, and Week 52 of OCTAVE Sustain, higher proportions of patients receiving tofacitinib 10 mg twice daily (and tofacitinib 5 mg twice daily in OCTAVE Sustain) achieved RBS = 0 and SFS ≤ 1 than among those receiving placebo (see Online Resources 4 and 5).

3.3 HRQoL PROs in the OCTAVE Clinical Program

In patients in OCTAVE Open assigned to tofacitinib 5 mg twice-daily treatment, 165 (94.3%) patients were in IBDQ remission at baseline (Fig. 3). Based on NRI-LOCF, by Month 48, 93 (53.1%) patients maintained or achieved IBDQ remission. Based on LOCF, the mean (SD) changes from baseline to Month 48 in the IBDQ bowel function, emotional status, systemic symptoms, and social function domains were −3.3 (10.1), −3.4 (10.4), −1.8 (5.1), and −1.7 (5.1), respectively. Based on observed cases, by Month 48, 87 (83.7%) patients were in IBDQ remission (Fig. 3) and the mean (SD) changes from baseline to Month 48 in the IBDQ bowel function, emotional status, systemic symptoms, and social function domains were −1.1 (8.1), −1.7 (8.3), −0.9 (4.1), and −0.8 (4.3), respectively. Of the 142 patients who were in remission after receiving 52 weeks of tofacitinib 5 mg twice-daily maintenance therapy in OCTAVE Sustain, based on NRI-LOCF and observed cases, 136 (95.8%) patients were in IBDQ remission at baseline of OCTAVE Open. At Month 48, based on NRI-LOCF and observed cases, respectively, 64 (45.1%) and 56 (N = 62; 90.3%) patients achieved or maintained IBDQ remission.

Fig. 3
figure 3

Proportions of tofacitinib 5 mg twice daily-treated patients in remission at baseline with IBDQ remissiona in OCTAVE Open (FAS, NRI-LOCF, and observed). NRI was used for missing data at all visits and LOCF was used for visits after a patient advanced to the next study. a IBDQ remission was defined as an IBDQ total score of ≥ 170. BL baseline, FAS full analysis set, IBDQ Inflammatory Bowel Disease Questionnaire, N number of patients treated in each treatment group, n number of patients with the specified response within the given category, NRI-LOCF non-responder imputation, last observation carried forward

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Based on NRI-LOCF at Week 8 of OCTAVE Induction 1 and 2, and Week 52 of OCTAVE Sustain, higher proportions of patients receiving tofacitinib 10 mg twice daily (and tofacitinib 5 mg twice daily in OCTAVE Sustain) were in IBDQ remission than among those receiving placebo (see Online Resources 4 and 5) [11].

3.4 Correlation between Rectal Bleeding, Stool Frequency, Partial Mayo Score PROs, and Inflammatory Bowel Disease Questionnaire in the OCTAVE Program

Correlation analyses were conducted between IBDQ total score and RBS, SFS, and PMS. In OCTAVE Induction 1 and 2, RBS, SFS, and PMS had inverse correlations with IBDQ total score in patients treated with tofacitinib 10 mg twice daily or placebo (see Online Resource 6).

In OCTAVE Sustain, RBS, SFS, and PMS scores all had an inverse correlation with IBDQ total scores for all treatment groups (see Online Resource 7).

4 Discussion

We assessed the long-term effect of tofacitinib on rectal bleeding and stool frequency PROs, in addition to long-term disease-specific HRQoL (IBDQ) outcomes in the OCTAVE clinical program, complementing the previously completed studies demonstrating rapid response to tofacitinib treatment [13]. These analyses demonstrated that the majority of patients entering OCTAVE Open in remission achieved or maintained an RBS = 0 and SFS ≤ 1 up to Month 48 when receiving tofacitinib 5 mg twice daily. Importantly, for those patients who received tofacitinib treatment during OCTAVE Sustain, this time point represented at least 5 years of overall tofacitinib treatment in the OCTAVE clinical program.

More than half of patients who entered into OCTAVE Open in remission demonstrated continued normalization of rectal bleeding or improvement in stool frequency for 4 years. This is especially noteworthy, given that disease activity was moderate to severe (mean total Mayo scores ranging from 8.9 to 9.1) [11] for all patients entering the OCTAVE clinical program, and 66 (37.7%) patients in this OCTAVE Open subgroup had prior TNFi failure, which is considered a patient population more challenging to treat than a population without prior TNFi exposure [16].

The proportion of patients achieving or maintaining SFS = 0 was lower than those achieving or maintaining RBS = 0 or SFS ≤ 1. It is well known that normalization of stool frequency can be difficult to achieve [2]; one systematic review and meta-analysis suggested that patients in endoscopic remission were unlikely to have both an RBS and SFS of 0, with only 40% of patients in endoscopic remission achieving SFS = 0 and 36% showing a complete absence of symptoms [17]. The difficulty of achieving the complete normalization of stool frequency may be due to inflammation at the histological level [17], or due to remodeling of the colonic wall resulting from long-standing inflammation [18].

In addition to improvements in rectal bleeding and stool frequency, many patients achieved or maintained PMS remission at Month 48 of OCTAVE Open. Consistent with the Mayo score PRO components, IBDQ remission was also achieved or maintained in many patients at Month 48. Together, these results show the durability of the response to tofacitinib with regard to key UC PROs.

Induction and long-term maintenance of symptomatic remission defined by PROs remain important goals in the management of UC. To date, there have been few studies to demonstrate the long-term effect of UC therapies on rectal bleeding and stool frequency. The efficacy of the biologic therapy ustekinumab showed that the composite endpoint of RBS = 0 and SFS ≤ 1 was achieved by around 65% of patients up to Week 92 based on NRI analysis [19]. Our findings indicate that in OCTAVE Open, 95 (54.3%), 96 (54.9%), and 84 (48.0%) patients, respectively, achieved RBS = 0, SFS ≤ 1, and composite endpoints of RBS = 0 and SFS ≤ 1 at Month 48, based on NRI-LOCF analysis. Similarly, a post hoc analysis of the GEMINI 1 study of the integrin α4 β7, inhibitor, vedolizumab, in patients with UC found that at Week 52, RBS = 0 was achieved by 57% of patients, based on observed cases [20]. Moreover, observed data from a long-term extension study (which followed a 54-week or 30-week maintenance study) of patients with UC receiving infliximab showed that at the assessment at 1 year, 62% of patients had durability of response [21]. At Week 52 of OCTAVE Open, 94% of 5 mg twice daily-treated patients achieved RBS = 0. Although there have been no prospective head-to-head studies comparing long-term efficacy of tofacitinib to infliximab, vedolizumab, or ustekinumab, our results are generally consistent with these other advanced therapies for moderate to severe UC.

An update of the 2015 STRIDE guidelines included new findings that acknowledge that restoration of quality of life is one of the most important long-term treatment targets for patients with UC [5]. Our analyses indicated that over half of patients receiving tofacitinib 5 mg twice-daily treatment who entered OCTAVE Open in remission (per protocol) remained in IBDQ remission at Month 48, consistent with the observed improvements in RBS and SFS. PMS remission was also maintained in the majority of patients at Month 48. It is noteworthy to recognize that PMS includes the PGA, representing a clinician-reported assessment of disease activity. In recently updated regulatory guidance, the PGA has been identified as a key limitation of the Mayo score, although it may still have relevance in practice management as it represents the clinician’s perspective of their patient’s disease activity [22]. Previous analyses have indicated that in patients treated with tofacitinib, early improvement in PGA subscore is consistent with improvements in the PROs of rectal bleeding and stool frequency [23].

The limitations of these analyses include that they are post hoc and that the self-reported nature of the endpoints of interest could be impacted by reference bias. Moreover, the majority of data were from the open-label, long-term extension study, which has inherent limitations. In addition, PROs that have been reported to be perceived as the most important by patients with UC, such as nausea, stool urgency, and pain [24, 25], were not analyzed in this study.

5 Conclusion

Overall, these data show durability of response with tofacitinib 5 mg twice daily, with robust and sustained normalization of rectal bleeding, and improvement in stool frequency for up to 4 years of follow-up in OCTAVE Open. This response was accompanied by long-term improvements in the IBDQ total score. As improving and resolving rectal bleeding and stool frequency in UC are defined therapeutic targets, these findings reiterate that maintenance treatment with tofacitinib 5 mg twice daily is appropriate for the long-term management of UC.