Introduction
Ulcerative colitis (UC) is a chronic, immune-mediated disease, which is characterized by recurrent periods of relapsing and remitting symptoms, including diarrhea, fecal urgency, and rectal bleeding [
1,
2]. Given the chronic nature of the disease, patients with UC require long-term therapy, with the ultimate goal of inducing and maintaining sustained steroid-free remission.
With progress in understanding the mechanisms behind UC immunopathogenesis, the number of treatment options for patients with UC has expanded [
3‐
5]. The choice of therapy for patients with UC is predicated on disease severity and the benefit–risk profile of medical therapy [
6]. The concept of personalized therapy is based on the premise of identifying specific clinical or laboratory variables capable of identifying patients who may respond to certain treatments. While personalized medicine for UC is not yet well developed, this could further streamline future therapeutic choices [
7,
8].
Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of UC. The efficacy and safety of tofacitinib 10 mg twice daily (BID) in patients with moderately to severely active UC were demonstrated in an 8-week phase II induction study (NCT00787202) [
9], two 8-week phase III induction studies (OCTAVE Induction 1 and 2; NCT01465763 and NCT01458951) [
10], and a 52-week phase III maintenance study (OCTAVE Sustain; NCT01458574) [
10], and were evaluated further in an open-label long-term extension study (OCTAVE Open; NCT01470612) [
11] and a phase IIIb/IV study (RIVETING; NCT03281304) [
12].
The use of various statistical techniques can aid in the development of models to predict the outcomes of patients with UC treated with tofacitinib, which could assist healthcare professionals in decisions on benefits and risks including in the context of dosing. This is particularly important because the lowest effective tofacitinib dose should be used for maintenance therapy in patients with UC [
13]. A previous analysis of data from patients with UC in OCTAVE Induction 1 and 2 who received 8 weeks of induction therapy with tofacitinib 10 mg BID demonstrated that early and clinically meaningful predictions of responder status were possible using these techniques [
14].
The aim of this post hoc analysis was to assess whether similar techniques could be used to predict early and long-term outcomes of tofacitinib 5 or 10 mg BID as maintenance therapy in patients with UC who had previously responded to tofacitinib 10 mg BID induction therapy. Outcomes included loss of response and steroid-free remission at week 8 and week 52 of OCTAVE Sustain, respectively, as well as differences in loss of response/discontinuation patterns between treatment groups. This analysis also assessed delayed response in patients who did not respond to the initial 8-week induction therapy.
Discussion
This post hoc analysis of data from patients with UC in OCTAVE Sustain and OCTAVE Open utilized statistical modeling to predict patient loss of responder status (based on change in PMS) at week 8 of OCTAVE Sustain, steroid-free remission (based on PMS) at week 52 of OCTAVE Sustain, and delayed response at week 8 of OCTAVE Open. In all analyses, AUROC values were below the threshold for accurate prediction of response (AUROC value < 0.9), and there were no notable differences in model outcomes when 2- and 3-point changes in PMS were used as definitions of response. The AUROC values were moderately acceptable at discriminating responders vs non-responders (i.e., AUROC > 0.8) in the prediction modeling analyses that used the whole dataset, including data from baseline to week 8 of OCTAVE Induction 1 and 2. However, models validated using the training–testing split or the cross-validation datasets generally had AUROC values below the threshold for moderate to accurate prediction (AUROC values < 0.8) [
17,
18]. Comparisons of the two active treatment arms of OCTAVE Sustain (tofacitinib 5 and 10 mg BID) demonstrated that patient characteristics associated with responses to treatment were generally similar when evaluated using the variables that were available in this clinical trial. However, the variables that were identified as important within a particular model should be interpreted with caution. As the overall performance of the models was rather poor, the variables that were driving the outcomes could also not be considered specific enough to discriminate between the tofacitinib 5 and 10 mg BID groups. However, the variables listed such as age, PMS, and corticosteroid use have been previously described as factors associated with UC disease activity [
14,
21,
22]. Despite the multiple efforts that were made to refine the research methodology by applying advanced prediction modeling methods and multi-omic approaches, which allows for more robust prediction by combining individual components and sharpening the approach to disease prediction, further refinement is suggested [
23‐
25].
Notably, among patients with an increase in total Mayo score from study baseline to week 52 of OCTAVE Sustain, the rectal bleeding subscore was identified as the primary determinant of disease worsening. By contrast, among patients with a decrease in total Mayo score from study baseline to week 52 of OCTAVE Sustain, the endoscopic subscore was identified as the primary determinant of improvement.
A previous assessment of data from OCTAVE Induction 1 and 2 used statistical modeling techniques to identify predictors of early treatment response among patients receiving induction therapy with tofacitinib 10 mg BID [
14]. This study reported that logistic regression and random forest models were able to predict week 4 and week 8 responder status using only four measures (PMS, partial Mayo subscores, total cholesterol, and C-reactive protein) at different timepoints. An early change in the PMS was identified as the most important predictor of responder status. Here, we explored the extent to which treatment outcomes after week 8 of OCTAVE Induction 1 and 2 could be predicted on the basis of a change in PMS, as well as steroid-free remission (based on PMS) or delayed response among patients with UC. Patients included in this analysis were receiving either tofacitinib 5 or 10 mg BID as maintenance therapy or placebo in OCTAVE Sustain, or were non-responders at the end of OCTAVE Induction 1 and 2 and received extended induction for an additional 8 weeks in OCTAVE Open. There is no unambiguous reason why the models in this analysis were unable to accurately predict treatment response; however, factors such as the inclusion/exclusion criteria for the patient population in the global OCTAVE clinical program, number of patients analyzed, study design (i.e., omission of variables that could have been more predictive), the subjective nature of patient-reported symptoms in the PMS, and flare severity may have influenced the models’ predictive capabilities.
Visualization of remission and discontinuation patterns across treatment groups demonstrated that disease activity patterns were generally similar in patients receiving tofacitinib 5 or 10 mg BID among TNFi-naïve patients. These visualizations suggest that the differences in measurable disease activity characteristics between the tofacitinib treatment groups were too small to be accurately assessed, even with advanced data analysis techniques. The relatively low patient numbers included in this analysis may also have influenced the performance of the models, and this was partly confirmed by the small increase in power with the models that utilized the whole set of patients.
Previous studies have evaluated the role of biomarkers, such as fecal calprotectin, in predicting endoscopic response and possible relapse among patients with UC [
26,
27]. A prospective, real-world study of patients with UC in Spain demonstrated that fecal calprotectin levels could act as a potential surrogate marker for endoscopic remission [
27]. The absence of such biomarkers in the OCTAVE clinical program may have influenced the overall predictive value of the models, and future studies might consider including a different array of variables.
This analysis included visualizations of disease activity and discontinuation patterns that provided some insight into the effects of maintenance treatment over time. Notably, while patients who received tofacitinib 5 or 10 mg BID exhibited generally similar patterns of response, patients who received placebo demonstrated a distinct outcome pattern, compared with those who received tofacitinib, and this is consistent with previously reported results of induction study efficacy data [
10].
Furthermore, the visualizations established that a change in rectal bleeding subscore was the primary determinant of disease worsening, as indicated by an increase in total Mayo score between baseline and week 52 of OCTAVE Sustain. This is consistent with a previous meta-analysis, which found that a normal rectal bleeding subscore correlated with the achievement of endoscopic remission among patients with UC [
28]. The rectal bleeding subscore is a semiquantitative, subjective, patient-reported variable that has demonstrated fair correlation with endoscopic activity in patients with UC [
29]. However, similar to stool frequency, it is subject to substantial bias. Conversely, endoscopic activity (measured using the Mayo endoscopic subscore) is relatively objective and, in the global OCTAVE clinical program, was reviewed centrally. Here, the rectal bleeding subscore was not normally distributed. It is possible that the variance in the total Mayo score among patients with disease worsening was driven by a subgroup of outliers who were reporting higher rectal bleeding subscores compared with other variables, such as stool frequency, Physician Global Assessment, and endoscopic subscores, which either remained the same or improved. However, a change in the rectal bleeding subscore may be an early indicator of change in disease activity in patients with UC [
30]. Furthermore, a strong correlation between clinical symptoms and endoscopic disease severity has been reported [
31]. Therefore, it is possible that improvements in the endoscopic subscore may be indicative of an improvement in a patient’s clinical symptoms.
This study had some limitations. Firstly, the number of patients included in this prediction analysis was relatively small, especially in some treatment subgroups, which limits the ability to interpret the data. Also, the prediction models have not been confirmed or validated by other data sources. External validation is key to determining the reproducibility and generalizability of the models to other patient populations. In addition, all patients who enrolled in OCTAVE Sustain had at least achieved a clinical response following OCTAVE Induction 1 and 2, and this may have contributed to the generally similar patterns of response with both tofacitinib doses in OCTAVE Sustain. Finally, this study only included data from patients who met the inclusion/exclusion criteria for the global OCTAVE clinical program. This may limit the generalizability of the results in the general population of patients with UC, and further studies that include prospective and real-world validation of the predictive models should be performed.
Acknowledgments
The authors would like to thank the patients, investigators, and study teams involved in the OCTAVE trials.
Disclosures
Michael Chiorean has served as a speaker for AbbVie, Bristol Myers Squibb, Janssen, Medtronic, Pfizer Inc, and Takeda; and has served as a consultant for AbbVie, Arena, Bristol Myers Squibb, Eli Lilly, Janssen, Medtronic, Pfizer Inc, Prometheus, and Takeda. Marco Daperno has received personal fees from AbbVie, Chiesi, Ferring, Janssen, MSD, Pfizer Inc, and Quintiles; has received grants and personal fees from Takeda; has received non-financial support from SOFAR; and has been involved in clinical trials for Eli Lilly, Galapagos, Gilead, Janssen, MSD, Roche, and Takeda. Charlie W. Lees has served as a speaker for AbbVie, Dr Falk, Ferring, Hospira, Janssen, MSD, Pfizer Inc, Shire, Takeda, and Warner-Chilcott; has served as a consultant for AbbVie, Dr Falk, Gilead, GSK, Hospira, Iterative Scopes, Janssen, MSD, Oshi Health, Pfizer Inc, Pharmacosmos, Takeda, Topivert, Trellus Health, and Vifor Pharma; and has received research funding from AbbVie and Gilead. Gianluca Bonfonti has a contract with Health Services Consulting Corporation, which was a paid contractor to Pfizer in connection with the formal analysis of this manuscript. Dimitrios Soudis, Irene Modesto, and J. Jasper Deuring are employees of, and own stocks and shares in, Pfizer Inc. Roger A. Edwards is a Principal in Health Services Consulting Corporation, which was a paid contractor to Pfizer in connection with the formal analysis of this manuscript.