Maintenance of Remission With Tofacitinib Therapy in

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Maintenance of Remission With Tofacitinib Therapy inPatients With Ulcerative Colitis

Jean-Frederic Colombel,* Mark T. Osterman,‡ Andrew J. Thorpe,§

Leonardo Salese,§ Chudy I. Nduaka,§ Haiying Zhang,§ Nervin Lawendy,§

Gary S. Friedman,§ Daniel Quirk,§ Chinyu Su,§ and Walter Reinischjj
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*Icahn School of Medicine at Mount Sinai, New York, New York; ‡University of Pennsylvania, Perelman School of Medicine,Philadelphia, Pennsylvania; §Pfizer, Collegeville, Pennsylvania; and ||Medical University of Vienna, Vienna, Austria
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BACKGROUND & AIMS:
Abbreviations used in this papeconfidence interval; FAS, full anrate; LOCF, last observation cadiovascular events; NMSC, nonimputation; OLE, open-label,score; TNFi, tumor necrosis fac

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Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerativecolitis (UC). The efficacy and safety of tofacitinib in patients with moderate to severe UC, up to 1year, have been reported. We investigated maintenance of efficacy in patients in remission after52 weeks of maintenance treatment in the pivotal phase 3 study (OCTAVE Sustain); these pa-tients received open-label, long-term treatment with tofacitinib 5 mg twice daily.

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METHODS: 98
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Patients with moderate to severe UC who completed a 52-week, phase 3 maintenance study(OCTAVE Sustain) were eligible to enroll into the ongoing, phase 3, multicenter, open-label,long-term extension (OCTAVE Open). We analyzed data from 142 patients who were inremission following tofacitinib treatment in OCTAVE Sustain who received tofacitinib 5 mgtwice daily during OCTAVE Open. We assessed efficacy (including remission [based on totalMayo score], endoscopic improvement, clinical response, and partial Mayo score up to month36 of OCTAVE Open) and safety data.

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RESULTS:
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After 12 months of tofacitinib 5 mg twice daily in OCTAVE Open, 68.3% of patients were inremission, 73.9% had endoscopic improvement, and 77.5% had a clinical response. At month36, 50.4%, of the patients were in remission, 55.3% had endoscopic improvement, and 56.0%had a clinical response. The safety profile of tofacitinib 5 mg twice daily revealed no new safetyrisks associated with long-term exposure up to 36 months.

r: AE, adverse event; BID, twice daily; CI,alysis set; HZ, herpes zoster; IR, incidencerried forward; MACE, major adverse car-melanoma skin cancer; NRI, nonresponderlong-term extension; PMS, partial Mayotor inhibitor; UC, ulcerative colitis.

© 2020 by the AGA Institute1542-3565/$36.00

https://doi.org/10.1016/j.cgh.2020.10.004

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CONCLUSIONS:
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Efficacy endpoints were maintained for up to 36 months, regardless of prior tofacitinib dose,including patients who reduced from tofacitinib 10 mg to 5 mg twice daily upon OCTAVE Openentry. No new safety risks were identified. ClinicalTrials.gov: OCTAVE Sustain (NCT01458574);OCTAVE Open (NCT01470612).

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Keywords: (3–4); JAK inhibitor; inflammatory bowel disease; response to therapy; active disease. 181
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Patients with ulcerative colitis (UC) often requirelifelong medical therapy to control symptoms and

to avoid disease deterioration, hospitalization, andcolectomy.1 Remission, defined in both symptomatic andendoscopic terms, represents a preferred goal of UCmedical management strategies,2 with the ultimate goalbeing to achieve a sustained and durable period ofsteroid-free remission.3

Tofacitinib is an oral, small molecule Janus kinaseinhibitor for the treatment of UC. The efficacy and safetyof tofacitinib have been demonstrated in two 8-week,phase 3 induction studies (OCTAVE Induction 1 study[NCT01465763] and OCTAVE Induction 2 study[NCT01458951]) and a 52-week, phase 3 maintenancestudy (the OCTAVE Sustain study [NCT01458574]) inpatients with moderate to severe UC.4 Patients whocompleted the OCTAVE Sustain study, or had earlytreatment withdrawal due to treatment failure, wereeligible to enroll into the open-label, long-term extension(OLE) study (OCTAVE Open study [NCT01470612]).Study treatment was assigned depending on the patients’remission status at baseline of the OCTAVE Open study,with patients in remission assigned to receive tofacitinib5 mg twice daily (BID), and patients who did not meetthe remission definition assigned to receive tofacitinib 10mg BID. The efficacy and safety of tofacitinib treatmentin 2 patient subpopulations from the OCTAVE Openstudy that enrolled patients from the OCTAVE Induction1 or 2 studies or the OCTAVE Sustain study have previ-ously been reported.5 These analyses, reported by Sandset al,5 included 2 subgroups of patients: (1) tofacitinibinduction responders in remission following 52 weeks oftofacitinib 10 mg BID maintenance treatment and sub-sequently reduced to tofacitinib 5 mg BID (the dose de-escalation group) and (2) tofacitinib induction re-sponders who experienced treatment failure whilereceiving tofacitinib 5 mg BID maintenance treatmentand subsequently increased to tofacitinib 10 mg BID (thedose escalation group). The primary aim of the currentanalysis was to investigate the maintenance of efficacy byexamining a cohort of patients in remission after 52weeks of tofacitinib treatment in the OCTAVE Sustainstudy, who subsequently received open-label, long-termtreatment with tofacitinib 5 mg BID in the OCTAVE Openstudy. Maintenance of efficacy was assessed through themeasurement of remission, endoscopic improvement,clinical response, and partial Mayo score (PMS). Patients’steroid status was assessed throughout the OCTAVEOpen study. The secondary aim was to report safety datafor all patients who received tofacitinib 5 mg BID in the

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OCTAVE Open study (including those who entered theOCTAVE Sustain study in remission following treatmentwith placebo in the OCTAVE Sustain study).

Materials and Methods

Study Design

The OCTAVE Open study is an ongoing, phase 3,multicenter, OLE study that enrolled patients whocompleted or demonstrated treatment failure in theOCTAVE Sustain study, as well as patients whocompleted the OCTAVE Induction 1 and 2 studieswithout clinical response (Supplementary Figure 1).4

Here, we report efficacy and safety data (up to May2019) for patients who had completed the OCTAVESustain study and met the criteria for remission (definedas a total Mayo score �2, no individual subscore >1, anda rectal bleeding subscore of 0) at week 52 and receivedopen-label treatment with tofacitinib 5 mg BID duringthe OCTAVE Open study, independent of which treat-ment arm of the OCTAVE Sustain study they enteredfrom (Figure 1). Remission status at week 52 of theOCTAVE Sustain study was based on centrally read Mayoendoscopic subscore. For further study design details,see the Supplementary Methods.

Ethical Considerations

All studies were conducted in compliance with theDeclaration of Helsinki and the International Conferenceon Harmonisation Good Clinical Practice Guidelines, andwere approved by the institutional review boards orindependent ethics committees at each of the investiga-tional centers participating in the studies, or a centralinstitutional review board. All patients provided writteninformed consent.

Patient Disposition

Inclusion and exclusion criteria for the OCTAVE In-duction 1 and 2 and OCTAVE Sustain studies have beendescribed previously.4 Briefly, eligible patients were �18years of age, with a confirmed diagnosis of moderate tosevere UC (total Mayo score of 6–12, with a rectalbleeding subscore of 1–3 and an endoscopic subscore of2–3) for �4 months and had failed treatment with, orwere intolerant to, at least 1 of the following: oral orintravenous corticosteroids, azathioprine or 6-

7 December 2020 � 7:19 pm � ce OB

https://clinicaltrials.gov/ct2/show/NCT01465763




What You Need to Know

BackgroundWe evaluated the effects of long-term treatment withtofacitinib—an oral, small molecule Janus kinaseinhibitor in patient with ulcerative colitis.

FindingsMost patients who achieved remission after main-tenance treatment with either tofacitinib 5 mg or 10mg twice daily for 52 weeks maintained remissionover 36 months with tofacitinib 5 mg twice daily inan open-label, long-term extension study.

Implications for patient careFindings of the durability of efficacy with tofacitinib5 mg twice daily supports its use in long-termmaintenance therapy for patients with ulcerativecolitis in remission after 52 weeks of maintenancetherapy.

- 2020 Tofacitinib Maintenance of Remission in UC 3

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mercaptopurine, or tumor necrosis factor inhibitors(TNFis) (infliximab or adalimumab).

Efficacy Assessments

Efficacy assessments utilized the Mayo score. In theOCTAVE clinical program, any friability on the endoscopysubscore meant a scoring of �2. For definitions ofremission, endoscopic improvement, and clinicalresponse, see the Supplementary Methods.

Remission, endoscopic improvement, and clinicalresponse were assessed at months 2 (centrally readendoscopy), 12, 24, and 36 (based on locally readendoscopic subscores) from baseline of the OCTAVEOpen study (endoscopic readings in the OCTAVE Sustainstudy were centrally read).

PMS remission was defined as a PMS �2 with noindividual subscore >1. PMS remission was assessed atvarious time points up to month 36 from baseline of theOCTAVE Open study.

Safety Assessments

During the course of treatment with tofacitinib 5 mgBID, safety outcomes were assessed, and the incidenceand severity of adverse events (AEs), classified in theMedical Dictionary for Regulatory Activities, includingAEs of special interest, were reported. See theSupplementary Methods for further details of AEs ofspecial interest. Patients underwent a 4-week safetyfollow-up evaluation after the last dose of studymedication.

Statistical Analysis

All data were analyzed descriptively. The full analysisset (FAS) was defined as all patients who received atleast 1 dose of study drug in the OCTAVE Open study.

Figure 1. Prior OCTAVE Induction and OCTAVE Sustain study tOpen study. For patients confirmed to be experiencing a flareincreased from 5 to 10 mg BID for the remaining treatment periopoints from baseline of the OCTAVE Sustain study, accompanieof �1 point, after a minimum of 8 weeks of treatment. Full schSupplementary Figure 1. aOne patient who was in remission at wmg BID) received tofacitinib 10 mg BID in the OCTAVE Open s

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Efficacy outcomes were analyzed in the maintenanceremission subpopulation (patients who had receivedtofacitinib 5 or 10 mg BID during the OCTAVE Sustainstudy) of the FAS. Nonresponder imputation (NRI) wasapplied after a patient discontinued the study or after thedose escalation, and last observation carried forward(LOCF) imputation was applied after a patient advancedto a subsequent study up to the visit they would havereached if they had remained in the study. No imputationfor missing data was applied for ongoing patients, exceptNRI for intermittent missing data (NRI-LOCF). Observedcase data are also presented. Data after the dose esca-lation were excluded for the observed case.

Safety was assessed in all patients who received atleast 1 dose of tofacitinib 5 mg BID in the OCTAVE Openstudy, with no imputation for missing data.

reatments of patients in remission at baseline of the OCTAVEin the OCTAVE Open study, the tofacitinib dose could be

d. A flare was defined as an increase in total Mayo score of �3d by an increase in rectal bleeding and endoscopic subscoresematic details of the OCTAVE clinical program are shown ineek 52 of the OCTAVE Sustain study (treated with tofacitinib 5tudy.


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All authors had access to the study data and reviewedand approved the final manuscript.

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Results

Patient Characteristics

At week 52 of the OCTAVE Sustain study, based oncentral endoscopic reading, 163 patients were in remis-sion (maintenance remission subpopulation) and wereassigned to receive tofacitinib 5 mg BID during theOCTAVE Open study. Of the OCTAVE Open maintenanceremission subpopulation, 142 patients received tofaciti-nib 5 mg BID (n ¼ 66) or tofacitinib 10 mg BID (n ¼ 76)in the OCTAVE Sustain study (Figure 1). Twenty-onepatients within the maintenance remission subpopula-tion received placebo during the OCTAVE Sustain study;these patients were included in the baseline

Table 1. Patient Demographics and Baseline and ClinicalCharacteristics (FAS)

Maintenance RemissionSubpopulation (n ¼ 163)a

Female 75 (46.0)

Age, y 44.8 � 14.7

RaceWhite 125 (76.7)Asian 25 (15.3)Other 8 (4.9)Unspecified 5 (3.1)

BMI, kg/m2 25.7 � 4.8

Duration of diagnosis, y 7.7 � 6.6

RegionEurope 96 (58.9)North America 32 (19.6)Other 35 (21.5)

Treatment assignment inthe OCTAVE Sustain studyTofacitinib 5 mg BID 66 (40.5)Tofacitinib 10 mg BID 76 (46.6)Placebo BID 21 (12.9)

Corticosteroid-free atOCTAVE Open study baseline

162 (99.4)b

5-aminosalicylates useat OCTAVE Open study baseline

124 (76.1)

Total Mayo score 1.0 � 0.7

PMS 0.4 � 0.5

Values are n (%) or mean � SD.BID, twice daily; BMI, body mass index; FAS, full analysis set; OCTAVE, ��;PMS, partial Mayo score.aOne patient who was in remission at week 52 of the OCTAVE Sustain studyreceived tofacitinib 10 mg BID as a protocol deviation.bOne patient was receiving prednisone 7.5 mg daily at baseline of the OCTAVEOpen study.


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demographics and clinical characteristics, and in thediscontinuations, but were not included within the effi-cacy analyses. Twelve patients who were not in remis-sion according to central endoscopic reading at entryinto the OCTAVE Open study also received tofacitinib 5mg BID but were not included in efficacy analyses pre-sented here.

Baseline demographics and disease characteristics forpatients in the maintenance remission subpopulation arepresented in Table 1. At baseline of the OCTAVE Openstudy, 162 of 163 patients were not receiving concomi-tant corticosteroids. See the Supplementary Results forfurther information relating to concomitantcorticosteroids.

Efficacy

The proportions of patients in the maintenanceremission subpopulation achieving remission, endo-scopic improvement, or clinical response during theOCTAVE Open study are shown in Figure 2. Observeddata show that rates of remission and endoscopicimprovement were generally maintained and broadlysimilar, irrespective of whether patients had receivedtofacitinib 5 or 10 mg BID during the OCTAVE Sustainstudy (Figure 2). PMS remission was maintained overtime in the majority of patients, and rates were similar,irrespective of whether patients had received tofacitinib5 or 10 mg BID during the OCTAVE Sustain study(Figure 3).

Ad hoc analysis of the maintenance of remissionpopulation showed that similar proportions of patientsmaintained remission or endoscopic improvementregardless of prior TNFi treatment status (Figure 2).

Within the maintenance remission subpopulation, 67(41.1%) patients discontinued treatment in the OCTAVEOpen study; see the Supplementary Results for furtherinformation relating to patient discontinuations.

Length of Time in Remission

Demographics and baseline characteristics weregenerally similar among patients in remission vs patientsnot in remission at month 12 of the OCTAVE Open study(Supplementary Table 1). Analysis of patients whoreduced tofacitinib dose from 10 to 5 mg BID in theOCTAVE Open study, by duration of remission, showsthat patients with a longer duration of remission in theOCTAVE Sustain study were more likely to stay inremission (Figure 4).

Dose Increase Due to Flare

Among the maintenance remission subpopulation,tofacitinib dose was increased from 5 to 10 mg BID dueto flare in 41 patients, of whom 37 had received tofaci-tinib (14 patients received tofacitinib 5 mg BID and 23


Figure 2. ProportionQ6 ofpatients in the mainte-nance remission subpop-ulation who achievedremission or endoscopicimprovement, anddemonstrated clinicalresponse following treat-ment with tofacitinib 5 mgBID in the OCTAVE Openstudy by maintenancedose and prior TNFi treat-ment status (FAS; NRI-LOCF and observedcase). All values are perlocal read of endoscopy.Remission was defined asa total Mayo score �2 withno individual subscore >1,and a rectal bleeding sub-score of 0. Clinicalresponse was defined as adecrease from inductionstudy baseline total Mayoscore of �3 points and�30%, plus a decrease inrectal bleeding subscoreof �1 point or an absoluterectal bleeding subscoreof 0 or 1. NRI was appliedafter a patient dis-continued, and last obser-vation carried forwardimputation was appliedafter a patient advanced toa subsequent study up tothe visit they would havereached if they had stayedin the study. No imputationfor missing data wasapplied for ongoing pa-tients, except NRI forintermittent missing data.


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patients received tofacitinib 10 mg BID) during theOCTAVE Sustain study. Following dose escalation, 75.0%(n ¼ 30 of 40), 77.4% (n ¼ 24 of 31), 89.3% (n ¼ 25 of


28), and 95.0% (n ¼ 19 of 20) of patients achieved PMSremission at months 3, 6, 9, and 12, respectively(observed data). Corresponding NRI data were 73.2%


Figure 3. Proportion ofpatients in the mainte-nance remission subpop-ulation who achieved PMSremission over timefollowing treatment withtofacitinib 5 mg BID in theOCTAVE Open study (FAS;NRI-LOCF and observedcase populations). PMSremission was defined as aPMS of �2 points, with noindividual subscore >1.


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(n ¼ 30 of 41), 58.5% (n ¼ 24 of 41), 64.1% (n ¼ 25 of39), and 48.7% (n ¼ 19 of 39), respectively(Supplementary Figure 2).

Safety

A total of 175 patients (163 patients in the mainte-nance of remission subpopulation [including the 142 pa-tients who received tofacitinib during the OCTAVE Sustainstudy and 12 placebo-treated patients, all of whom enteredthe OCTAVE Open study in remission] and 12 patientsreceiving tofacitinib 5 mg BID as protocol deviations) wereassigned to receive tofacitinib 5 mg BID in the OCTAVEOpen study, of whom 86.9% reported treatment-emergentAEs (Table 2). The most frequently reported treatment-emergent AEs by preferred term were “nasopharyngitis”(reported in 38 [21.7%] patients) and “worsening of UC”(reported in 41 [23.4%] patients). AEs in the tofacitinib 5mg BID subpopulation of OCTAVE Open showed no time-dependent increase when compared with safety datafrom OCTAVE Sustain study patients treated with


tofacitinib 5 or 10 mg BID (Table 2). The majority of in-fections were mild or moderate.

In patients receiving tofacitinib 5 mg BID during theOCTAVE Open study, herpes zoster (HZ) (nonserious andserious) occurred in 11 patients with an incidence rate(IR) (unique patients with events per 100 patient-yearsof exposure) of 2.1 (95% confidence interval [CI],1.1–3.8); 1 of these HZ events was reported as a seriousAE. A total of 6 (3.4%) patients had serious infections(IR, 1.1; 95% CI 0.4–2.5) ; 5 (2.9%) patients had malig-nancy (excluding nonmelanoma skin cancer [NMSC])events (IR, 1.0; 95% CI, 0.3–2.2), and 5 (2.9%) patientshad NMSC events (IR, 1.0; 95% CI, 0.3–2.3). One patienthad complicated appendicitis (adjudicated as a gastro-intestinal perforation). Of note, there were no events ofdeep vein thrombosis, pulmonary embolism, or death inpatients receiving tofacitinib 5 mg BID during theOCTAVE Open study. For further details on AEs, see theSupplementary Results.

In patients who required dose escalation due to flare,there was 1 case each of serious infection, HZ


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Figure 4. Proportion of patients who maintained remission at month 12 of the OCTAVE Open study, by duration of remission.Data are shown for patients who achieved remission at week 52 of the OCTAVE Sustain study with tofacitinib 10 mg BID andthen reduced to 5 mg BID in the OCTAVE Open study. Remission was defined as a total Mayo score �2 with no individualsubscore >1, and a rectal bleeding subscore of 0. Remission status in the OCTAVE Sustain study was based on central readof endoscopy: <6 months prior to dose reduction was defined as remission at week 52, but not week 24, regardless ofremission status at the OCTAVE Sustain study baseline; 6 to <12 months prior to dose reduction was defined as remission atboth weeks 24 and 52, but not at the OCTAVE Sustain study baseline; �12 months prior to dose reduction was defined asremission at the OCTAVE Sustain study baseline, week 24, and week 52.


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(nonserious; opportunistic infection), and malignancy(Supplementary Table 2).
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Discussion

Tofacitinib is an oral, small molecule Janus kinaseinhibitor for the treatment of UC. This report presentspost hoc analysis of data from an OLE study of tofacitinibin a subpopulation of patients with moderate to severeUC meeting remission criteria following completion ofthe 52-week OCTAVE Sustain study,4 extending previousefficacy and safety findings by a further 36 months.Among patients who achieved remission during mainte-nance treatment, tofacitinib 5 mg BID demonstrateddurability of efficacy, with the majority of patientsmaintaining remission over 36 months in the OCTAVEOpen study, as evidenced across a range of endpointsincluding remission, endoscopic improvement, PMSremission, and clinical response. Rates of remission,endoscopic improvement, PMS remission, and clinicalresponse were sustained over 36 months of treatment,regardless of whether patients had previously receivedtofacitinib 5 or 10 mg BID during maintenance treatmentand regardless of their prior TNFi treatment status.

The maintenance of clinical response and clinicalremission are historically important goals in the man-agement of patients with UC. The OCTAVE study pro-tocols were approved prior to the publication of the U.S.Food and Drug Administration guidance for clinical trialendpoints6 and incorporated a more stringent definitionof remission (with the inclusion of a rectal bleeding


subscore of 0) than that used in other studies.4 Rates ofendoscopic improvement (defined as a Mayo endoscopicsubscore of 0 or 1) in the current analysis generally re-flected those of remission, suggesting the validity of thisendpoint in clinical practice. The use of PMS remission,which may represent a more practical outcome measure,given its avoidance of endoscopy, was associated withslightly higher remission rates over 12 months.

Data reported here, in which a high proportion ofpatients who demonstrated a response following 8weeks of tofacitinib treatment achieved and remained inremission following 3 years of treatment, are similar tothose reported in patients with other UC treatments.7–10

Of note, there are limited data from head-to-head studiescomparing long-term efficacy of approved agents,11 andprimary outcome measures were different acrossstudies, making direct comparisons difficult.

A high proportion of patients maintained remissionfollowing tofacitinib dose reduction from 10 mg BID inthe OCTAVE Sustain study to 5 mg BID in the OCTAVEOpen study. These open-label, uncontrolled data suggestthat once remission has been achieved on tofacitinib 10mg BID maintenance treatment, tofacitinib dose could bereduced while maintaining remission. The ad hoc anal-ysis presented here showed that length of time inremission may require consideration prior to dosereduction; however, these analyses are limited by thesmall patient numbers.

The majority of patients who entered the OCTAVEOpen study in remission and had their tofacitinib doseincreased from 5 to 10 mg BID due to flare achieved PMSremission by month 3 postdose increase; however, these


Table 2. Summary of Safety Outcomes in the Tofacitinib 5 mg BID Treatment Group in the OCTAVE Open Study and, forComparison, the Tofacitinib 5 and 10 mg BID Treatment Groups in the OCTAVE Sustain Study

OCTAVE Open StudyaOCTAVE

Sustain Study

Tofacitinib5 mg BID (n ¼ 175)



Median duration of tofacitinib, d 1170 363.5 368

TEAEs 152 (86.9) 143 (72.2) 156 (79.6)

Deaths 0 (0.0), 0.0 (0.0–0.7) 0 (0.0), 0.0 (0.0–2.5) 0 (0.0), 0.0 (0.0–2.4)

SAEsb 33 (18.9) 10 (5.1) 11 (5.6)

Severe AEs 20 (11.4) 14 (7.1) 15 (7.7)

AEs leading to discontinuation 20 (11.4) 18 (9.1) 19 (9.7)

Infections 102 (58.3), 33.9 (27.6–41.1) 71 (35.9), 62.5 (48.9–78.9) 78 (39.8), 72.8 (57.6–90.9)

HZ (nonserious and serious)c 11 (6.3), 2.1 (1.1–3.8) 3 (1.5), 2.1 (0.4–6.0) 10 (5.1), 6.6 (3.2–12.2)

Serious infections 6 (3.4), 1.1 (0.4–2.5) 2 (1.0), 1.4 (0.2–4.9) 1 (0.5), 0.6 (0.0–3.5)

Opportunistic infectionsd,e 4 (2.3), 0.8 (0.2–2.0) 2 (1.0), 1.4 (0.2–4.9) 4 (2.0), 2.6 (0.7–6.7)

Serious HZ 1 (0.6), 0.2 (0.0–1.1) 0 (0.0), 0.0 (0.0–2.5) 0 (0.0), 0.0 (0.0–2.4)

Malignancies (excluding NMSC)d 5 (2.9), 1.0 (0.3–2.2) 0 (0.0), 0.0 (0.0–2.5) 0 (0.0), 0.0 (0.0–2.4)

NMSCd 5 (2.9), 1.0 (0.3–2.3) 0 (0.0), 0.0 (0.0–2.5) 3 (1.5), 1.9 (0.4–5.6)

Gastrointestinal perforationsd,f 1 (0.6), 0.2 (0.0–1.1) 0 (0.0), 0.0 (0.0–2.5) 0 (0.0), 0.0 (0.0–2.4)

MACEd 2 (1.1), 0.4 (0.1–1.4) 1 (0.5), 0.7 (0.0–3.8) 1 (0.5), 0.6 (0.0–3.5)

DVT 0 (0.0), 0.0 (0.0–0.7) 0 (0.0), 0.0 (0.0–2.5) 0 (0.0), 0.0 (0.0–2.4)

PE 0 (0.0), 0.0 (0.0–0.7) 0 (0.0), 0.0 (0.0–2.5) 0 (0.0), 0.0 (0.0–2.4)

Values are n (%) or incidence rate (95% confidence interval), unless otherwise indicated. Incidence rate is defined as unique patients with events per 100 patient-years of exposure; associated 95% confidence intervals were obtained by the exact Poisson method.AE, adverse event; BID, twice daily; DVT, deep vein thrombosis; HZ, herpes zoster; MACE, major adverse cardiovascular events; NMSC, nonmelanoma skincancer; PE, pulmonary embolism; SAE, serious adverse event; TEAE, treatment-emergent adverse event.aData are reported as per the May 27, 2019, data cut.bAccording to Investigator’s assessment.cRefer to the Supplementary Methods for preferred terms.dPer adjudication by specialist review committee.eExcludes tuberculosis and herpes zoster with 2 adjacent dermatomes.fExcludes preferred terms of pilonidal cyst, perirectal abscess, rectal abscess, anal abscess, perineal abscess, and any preferred terms using the term fistula.


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post hoc analyses are limited by the small sample size.Owing to the protocol design, endoscopy data in thesepatients who dose escalated were not available within a3-month window period.

The safety profile of tofacitinib 5 mg BID demonstratedno new safety risks associated with long-term exposure upto 36 months. Safety outcomes during the OCTAVE Openstudy were comparable to those of the OCTAVE Sustainstudy.4 Tofacitinib has been associated with an increasedrisk of HZ, but is not influenced by treatment duration.12,13

The majority of patients who had HZ were able to continuetofacitinib treatment or resume treatment following tem-porary discontinuation, consistent with the management ofHZ across other tofacitinib clinical programs.13 Safety inpatients who required dose escalation due to flare wasgenerally consistent with that observed in the OCTAVESustain study.4


Patients with inflammatory bowel disease receivingthiopurines have been reported to be at increased risk ofcertain types of malignancy, including lymphoma14 andNMSC.15 Observational data have shown the risk ofNMSC associated with thiopurines to continue followingdiscontinuation.15 In the maintenance of remission sub-population, 5 patients had malignancies (excludingNMSC), including 1 patient with diffuse large B celllymphoma. All patients with malignancies had priorexposure to thiopurines or TNFis; this was also true for 4of the 5 patients who had NMSC.

The remission status of patients completing theOCTAVE Sustain study was determined via central readendoscopy,4 whereas the OCTAVE Open study utilizedlocal endoscopy readings. Interpretation of endoscopicfindings by a local or central reader has the potential fordiscord between readings. During the OCTAVE Sustain


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study, both locally and centrally read endoscopies wereperformed, both of which demonstrated the efficacy oftofacitinib as maintenance therapy vs placebo. Overall,local and central endoscopy readings were consistent,although efficacy by local endoscopy was numericallyhigher than when assessed by central endoscopy.16 TheOCTAVE Open study is an open-label study with noplacebo group; this has the potential to introduce bias inendoscopy outcomes. The analyses presented here onlyfocus on patients who were in remission at the end of theOCTAVE Sustain study and did not include those whomay have had a clinical response and were not inremission.

In conclusion, this post hoc analysis of data from theOCTAVE Open study demonstrated the durability of ef-ficacy with tofacitinib 5 mg BID and supports long-termmaintenance with tofacitinib 5 mg BID up to 36 monthsin patients who were in remission after 52 weeks ofmaintenance therapy. Efficacy rates were sustained over36 months of treatment, regardless of whether patientshad previously received tofacitinib 5 or 10 mg BID dur-ing maintenance treatment and regardless of their priorTNFi treatment status.

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Supplementary Material

Note: To access the supplementary material accom-panying this article, visit the online version of ClinicalGastroenterology and Hepatology at www.cghjournal.org,and at https://doi.org/10.1016/j.cgh.2020.10.004.

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1. O’Connor A, Moss AC. Current and emerging maintenancetherapies for ulcerative colitis. Expert Rev Gastroenterol Hepatol2014;8:359–368.

2. Bressler B, Marshall JK, Bernstein CN, et al. Clinical practiceguidelines for the medical management of nonhospitalized ul-cerative colitis: the Toronto consensus. Gastroenterology 2015;148:1035–1058.

3. Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG clinicalguideline: ulcerative colitis in adults. Am J Gastroenterol 2019;114:384–413.

4. Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as inductionand maintenance therapy for ulcerative colitis. N Engl J Med2017;376:1723–1736.

5. Sands BE, Armuzzi A, Marshall JK, et al. Efficacy and safety oftofacitinib dose de-escalation and dose escalation for patientswith ulcerative colitis: results from OCTAVE Open. AlimentPharmacol Ther 2020;51:271–280.

6. U.S. Food and Drug Administration. Ulcerative colitis: clinicaltrial endpoints guidance for industry. 2016. Available at: https://www.fda.gov/media/99526/download. Accessed April 8, 2020.

7. Loftus EV Jr, Colombel JF, Feagan BG, et al. Long-term efficacyof vedolizumab for ulcerative colitis. J Crohns Colitis 2017;11:400–411.

8. Noman M, Ferrante M, Bisschops R, et al. Vedolizumab induceslong-term mucosal healing in patients with Crohn’s disease andulcerative colitis. J Crohns Colitis 2017;11:1085–1089.


9. Colombel JF, Sandborn WJ, Ghosh S, et al. Four-year mainte-nance treatment with adalimumab in patients with moderately toseverely active ulcerative colitis: data from ULTRA 1, 2, and 3.Am J Gastroenterol 2014;109:1771–1780.

10. Reinisch W, Colombel JF, Gibson PR, et al. Continuous clinicalresponse is associated with a change of disease course in pa-tients with moderate to severe ulcerative colitis treated withgolimumab. Inflamm Bowel Dis 2019;25:163–171.

11. Schreiber S, Peyrin-Biroulet L, Loftus EV Jr, et al. OP34 VAR-SITY: A double-blind, double-dummy, randomised, controlledtrial of vedolizumab versus adalimumab in patients with activeulcerative colitis [abstract]. J Crohns Colitis 2019;13:S612–S613.

12. Winthrop KL, Melmed GY, Vermeire S, et al. Herpes zosterinfection in patients with ulcerative colitis receiving tofacitinib.Inflamm Bowel Dis 2018;24:2258–2265.

13. Colombel JF. Herpes zoster in patients receiving JAK inhibitorsfor ulcerative colitis: mechanism, epidemiology, management,and prevention. Inflamm Bowel Dis 2018;24:2172–2182.

14. Kotlyar DS, Lewis JD, Beaugerie L, et al. Risk of lymphoma inpatients with inflammatory bowel disease treated with azathio-prine and 6-mercaptopurine: a meta-analysis. Clin GastroenterolHepatol 2015;13:847–858.e4; quiz e48–e50.

15. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased riskfor nonmelanoma skin cancers in patients who receive thio-purines for inflammatory bowel disease. Gastroenterology 2011;141:1621–1628.

16. Feagan BG, Vermeire S, Sandborn WJ, et al. Tofacitinib formaintenance therapy in patients with active ulcerative colitis inthe phase 3 OCTAVE Sustain trial: results by local and centralendoscopic assessments [abstract]. Am J Gastroenterol 2017;112:S329–S330.

Reprint RequestsAddress requests for reprints to: Nervin Lawendy, PharmD, Pfizer Inc, 500Arcola Road, Collegeville, PA 19426. e-mail: [email protected]; fax:��.

AcknowledgmentsThe authors would like to thank the patients, investigators, and study teamsinvolved in the OCTAVE clinical program. Upon request, and subject to certaincriteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provideaccess to individual de-identified participant data from Pfizer-sponsored globalinterventional clinical studies conducted for medicines, vaccines, and medicaldevices (1) for indications that have been approved in the United States and/orEuropean Union or (2) in programs that have been terminated (ie, developmentfor all indications has been discontinued). Pfizer will also consider requests forthe protocol, data dictionary, and statistical analysis plan. Data may berequested from Pfizer trials 24 months after study completion. The de-identifiedparticipant data will be made available to researchers whose proposals meetthe research criteria and other conditions, and for which an exception does notapply, via a secure portal. To gain access, data requestors must enter into adata access agreement with Pfizer.

Conflicts of InterestThese authors disclose the following: Jean-Frederic Colombel has acted as aconsultant for AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim,Celgene, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech,Gilead, Janssen, MedImmune, Merck & Co, Nextbiotix, Novartis, OtsukaPharmaceutical Development and Commercialization, Pfizer, Protagonist,Second Genome, Seres Therapeutics, Shire, Takeda, and Theradiag; hasreceived financial support for research from AbbVie, Intestinal Biotech Devel-opment, and Janssen and Janssen; and has participated in speakers’ bureausfor AbbVie, Celgene, Ferring Pharmaceuticals, Genfit, and Takeda. Mark T.Osterman has acted as an advisory board member for AbbVie, Elan, Janssen,Lycera, Merck & Co, Pfizer, Takeda, and UCB. Andrew J. Thorpe, LeonardoSalese, Chudy I. Nduaka, Haiying Zhang, Nervin Lawendy, Gary S. Friedman,Daniel Quirk, and Chinyu Su are employees and stockholders of Pfizer. WalterReinisch has acted as a consultant for 4SC, Abbott Laboratories, AbbVie,Aesca, Amgen, AM Pharma, AOP Orphan, Arena Pharmaceuticals, Astellas,AstraZeneca, Avaxia, Bioclinica, Biogen IDEC, Boehringer Ingelheim,


http://www.cghjournal.org


https://www.fda.gov/media/99526/download

https://www.fda.gov/media/99526/download

mailto:[email protected]

https://www.pfizer.com/science/clinical-trials/trial-data-and-results

https://www.pfizer.com/science/clinical-trials/trial-data-and-results

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Bristol-Myers Squibb, Celgene, Cellerix, Celltrion, Centocor, ChemoCentryx,Covance, Danone Austria, Elan, Eli Lilly, Ernst & Young, Falk Pharma GMbH,Ferring Pharmaceuticals, Galapagos, Genentech, Gilead, Grünenthal, ICON,Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko KirinPharma, Lipid Therapeutics, LivaNova, Mallinckrodt, MedAhead, MedImmune,Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestlé, Novartis,Ocera, Otsuka, Parexel, PDL, Pfizer, Pharmacosmos, Philip Morris Institute,Proctor & Gamble, Prometheus Laboratories, Protagonist, Provention, RobartsClinical Trials, Roland Berger GmBH, Sandoz, Schering-Plough, SecondGenome, Seres Therapeutics, SetPoint Medical, Sigmoid, Takeda, Therakos,TiGenix, UCB, Vifor, Zealand, and Zyngenia; he has participated in speakers’bureaus for Abbott Laboratories, AbbVie, Aesca, Aptalis, Astellas, Celltrion,Centocor, Danone Austria, Elan, Falk Pharma GMbH, Ferring Pharmaceuticals,Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL,Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos,Vifor, and Yakult; he has received financial support for research from Abbott


Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GMbH, Immundiagnostik,and MSD; and he has acted as an advisory board member for 4SC, AbbottLaboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca,Avaxia, Biogen IDEC, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene,Cellerix, Celltrion, Centocor, ChemoCentryx, Danone Austria, Elan, FerringPharmaceuticals, Galapagos, Genentech, Grünenthal, Inova, Janssen, John-son & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune,Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestlé, Novartis,Ocera, Otsuka, PDL, Pfizer, Pharmacosmos, Proctor & Gamble, PrometheusLaboratories, Sandoz, Schering-Plough, Second Genome, SetPoint Medical,Takeda, Therakos, TiGenix, UCB, Zealand, and Zyngenia.

FundingThis study was sponsored by and funding for medical writing support wasprovided by Pfizer.


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Q9

- 2020 Tofacitinib Maintenance of Remission in UC 10.e1

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Supplementary Methods

Dose Increase Due to Flare

At or after month 2 of the OCTAVE Open study,patients experiencing a flare could dose escalate tofa-citinib from 5 to 10 mg twice daily (BID). A flare wasdefined as an increase in total Mayo score of �3 pointsfrom baseline of the OCTAVE Sustain study, accompa-nied by an increase in rectal bleeding and site-readendoscopic subscore of �1 point, after a minimum of8 weeks of treatment in the OCTAVE Open study. Pa-tients who increased tofacitinib dose from 5 to 10 mgBID due to flare were excluded from the observed dataefficacy analysis, but treated as nonresponder imputa-tion (NRI) after dose escalation for NRI and lastobservation carried forward (NRI-LOCF) imputationdata.

Concomitant Medication

Patients were permitted to use concomitant oral 5-aminosalicylates or sulfasalazine.

Prohibited medications included azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, mycophe-nolate, tacrolimus, interferon, tumor necrosis factor in-hibitors, intravenous or rectally administeredcorticosteroids, and natalizumab, vedolizumab, or otherantiadhesion molecule therapy. Patients were permittedto use concomitant oral corticosteroids up to 25 mg/d during induction but had to undergo mandatorytapering during maintenance. If the patients entered theOCTAVE Open study on oral corticosteroids, taperingwas mandatory.1

If the patient was unable to tolerate tapering below10 mg/d, corticosteroids were permitted if the dosedid not exceed 10 mg/d. Once corticosteroid-freestatus was achieved, reinitiation of oral corticoste-roid therapy above 10 mg/d was considered rescuetherapy, and patients were required to discontinuefrom the study.

Study Discontinuation

Patients within the maintenance of remission cohortwere required to withdraw from the study if they initi-ated a new therapy for ulcerative colitis (UC), underwentsurgery for UC, or remained on corticosteroids exceeding15 mg/d of prednisone or equivalent after month 3, or ifthere were any safety concerns.

Mayo Score

Efficacy assessments utilized the Mayo score, whichranges from 0 to 12 points and comprises 4 subscores(graded from 0 to 3): stool frequency, rectal bleeding,and mucosal appearance on endoscopy (centrally read),


and physician global assessment. The partial Mayo scoremeasures disease activity in UC without endoscopy, andranges from 0 to 9 points. It comprises 3 subscores(graded from 0 to 3): stool frequency, rectal bleeding,and physician global assessment.

Efficacy Endpoints

Remission was defined as a total Mayo score �2 withno individual subscore >1, and a rectal bleeding sub-score of 0. Endoscopic improvement was defined as aMayo endoscopic subscore of 0 or 1 (defined as mucosalhealing in the OCTAVE study protocols. In the OCTAVEclinical program, any friability on the endoscopy sub-score meant a scoring of �2. Clinical response wasdefined as a decrease from induction study baseline totalMayo score of �3 points and �30%, plus a decrease inrectal bleeding subscore of �1 point or an absolute rectalbleeding subscore of 0 or 1.

Adverse Events of Special Interest

Adverse events (AEs) of special interest includedserious infection events (any infection AE that requiredthe infection to be classified as a serious AE [SAE]),herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, gastrointestinalperforations, and major adverse cardiovascular events.In order to harmonize and standardize endpointassessment, opportunistic infections, major adverse car-diovascular events, malignancy, and gastrointestinalperforation events were based on adjudication byspecialist review committees.

HZ AEs corresponded to the system organ class ofinfections and infestations; preferred terms included“Herpes zoster,” “Herpes zoster disseminated,” “Her-pes zoster cutaneous disseminated,” “OphthalmicHerpes zoster,” “Herpes zoster oticus,” “Genital Her-pes zoster,” “Herpes zoster pharyngitis,” “Herpeszoster necrotizing retinopathy,” “Herpes zoster infec-tion neurological,” “Herpes zoster meningitis,” “Her-pes zoster meningomyelitis,” and “Herpes zostermeningoencephalitis.”

Supplementary Results

Concomitant Corticosteroids

One patient who was receiving prednisone 7.5 mgdaily was enrolled into the OCTAVE Open study as aprotocol deviation. One patient who was not receivingcorticosteroids at baseline of the OCTAVE Open studyreceived prednisone (20 mg/d) for 2 days (days 36 and37) during the OCTAVE Open study. Neither of thesepatients met the criteria for patient withdrawal, and bothcontinued to participate in the study.


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Discontinuations

Within the maintenance remission subpopulation, 67(41.1%) patients discontinued treatment in the OCTAVEOpen study: 26 of 67 (38.8%) patients discontinued forstudy drug–related reasons, and 41 of 67 (61.2%) dis-continued for nonstudy drug–related reasons. Of thepatients who withdrew due to reasons related to thestudy drug, 15 (9.2%) discontinued due to insufficientclinical response, and 11 (6.7%) discontinued due to AEs(excluding worsening of UC). Of the 15 patients whodiscontinued due to insufficient clinical response, 3 hadreceived placebo during the OCTAVE Sustain study, 6had received tofacitinib 5 mg BID, and 6 had receivedtofacitinib 10 mg BID. One patient who discontinued inthe OCTAVE Open study was enrolled directly from theOCTAVE Induction study and assigned to tofacitinib 5 mgBID as a protocol deviation. Nonstudy drug–relatedreasons for study discontinuation included AEs (n ¼ 5of 41, 12.2%), patient no longer willing to participate(n ¼ 16 of 41, 39.0%), protocol violation (n ¼ 2 of 41,4.9%), lost to follow-up (n ¼ 2 of 41, 4.9%), pregnancy(n ¼ 2 of 41, 4.9%), and other reasons (n ¼ 14 of 41,34.1%) (including enrollment into postmarketingsurveillance).

Safety

A total of 6 (3.4%) patients had serious infections;however, there was no specific clustering, with 1 eventeach of appendicitis, gastroenteritis norovirus, HZ,necrotizing fasciitis, pulmonary mycosis, and tonsillitis.


Five patients who received tofacitinib 5 mg BIDduring the OCTAVE Open study had malignancy(excluding NMSC) events, including 1 event each of lungcancer, cervical dysplasia, and diffuse large B cell lym-phoma, and 2 patients had breast cancer. All patientsdiscontinued in the study, with the exception of the pa-tient with cervical dysplasia. Three patients with malig-nancy events had prior immunosuppressant therapy use,and 2 had prior tumor necrosis factor inhibitor use.

Of the 11 patients with HZ, 3 patients had receivedtofacitinib 10 mg BID during the OCTAVE Sustain study,4 patients had received tofacitinib 5 mg BID, and 4 pa-tients had received placebo. Two patients discontinuedthe study due to HZ events, and 2 required temporarydiscontinuation of treatment; all other patientscontinued in the study and treatment was not inter-rupted. Five patients who received tofacitinib 5 mg BIDduring the OCTAVE Open study had NMSC events; 4patients had prior immunosuppressant use, and 2 hadprior tumor necrosis factor inhibitor use.

Three patients, all of whom had a history of NMSC,had multiple NMSC events during the OCTAVE Openstudy. One patient developed appendicitis on day 10 ofthe OCTAVE Open study, underwent an appendectomy,and was adjudicated as a gastrointestinal perforation.

Tofacitinib was discontinued following this event,which was deemed unrelated to the study drug.

7 De

References
1. Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction
and maintenance therapy for ulcerative colitis. N Engl J Med2017;376:1723–1736.

cember 2020 � 7:19 pm � ce OB

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Supplementary Figure 2. Proportion of patients in the maintenance remission–dose escalation subpopulation with partialMayo score (PMS) remission. PMS remission was defined as a PMS �2 with no individual subscore >1. Error bars are exactbinomial 90% confidence intervals (Clopper-Pearson method). Nonresponder imputation (NRI) was applied after a patientdiscontinued the study, and last observation carried forward (LOCF) imputation was applied after a patient advanced to asubsequent study up to the visit they would have reached if they had remained in the study. No imputation for missing datawas applied for ongoing patients, except NRI for intermittent missing data (NRI-LOCF).

web4C=FPO

Supplementary Figure 1. Study design (overview of the phase 3 OCTAVE Q8program). aFinal complete efficacy assessment atweek 8 of 52. Treatment continued up to week 9 of 53. bClinical response in the OCTAVE Induction 1 and 2 studies wasdefined as a decrease from baseline total Mayo score of �3 points and �30%, plus a decrease in rectal bleeding subscore of�1 point or an absolute rectal bleeding subscore of 0 or 1. cStudy A3921139 (OCTAVE Open study) is ongoing. dRemissionwas defined as a total Mayo score �2 with no individual subscore >1, and a rectal bleeding subscore of 0. In the OCTAVEOpen study, 12 patients not in remission at OCTAVE Open study entry received tofacitinib 5 mg twice daily (BID) and 1 patientin remission at OCTAVE Open study entry received tofacitinib 10 mg BID as protocol deviations.

FLA 5.6.0 DTD � YJCGH57542_proof � 17 December 2020 � 7:19 pm � ce OB


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Supplementary Table 1. Patient Characteristics by OCTAVE Open Study Month 12 Remission Status Among Patients WhoAchieved Remission During OCTAVE Sustain Study

OCTAVE Open Study Month 12 Remission Status (as Observed)a

OCTAVE Sustain Study: Tofacitinib 10 mg BID OCTAVE Sustain Study: Tofacitinib 5 mg BID

In Remission(n ¼ 56)

Not in Remission(n ¼ 12)

In Remission(n ¼ 49)

Not in Remission(n ¼ 8)

Male 25 (45) 5 (42) 28 (57) 6 (75)

Age at OCTAVE Inductionstudy baseline, y

46.0 � 14.8 42.4 � 16.2 44.5 � 14.4 38.1 � 16.7

Total Mayo score at OCTAVEInduction study baseline

8.7 � 1.6 8.0 � 1.3 8.5 � 1.5 8.8 � 1.9

Endoscopic subscore atOCTAVE Open study baseline

0 17 (30) 5 (42) 23 (47) 3 (38)

1 39 (70) 7 (58) 26 (53) 5 (63)

CRP at OCTAVEOpen study baseline

<3 mg/L 49/56 (88) 9/10 (90) 41/49 (84) 7/8 (88)

�3 mg/L 7/56 (13) 1/10 (10) 8/49 (16) 1/8 (13)

Extent of disease atOCTAVE Induction study baseline

Proctosigmoiditis 11/55 (20) 5/12 (42) 9/49 (18) 1/8 (13)

Left-sided colitis 16/55 (29) 5/12 (42) 14/49 (29) 4/8 (50)

Extensive colitis/pancolitis 28/55 (51) 2/12 (17) 26/49 (53) 3/8 (38)

Prior TNFi failure at OCTAVEInduction study baseline

25 (45) 6 (50) 14 (29) 2 (25)

Values are n (%), mean � SD, or n/n (%).Remission was defined as a total Mayo score �2 with no individual subscore >1, and a rectal bleeding subscore of 0. PMS remission was defined as a PMS of �2with no individual subscore >1.BID, twice daily; CRP, C-reactive protein; PMS, partial Mayo score; TNFi, tumor necrosis factor inhibitor.aRemission status in the OCTAVE Open study was based on local read of endoscopy.


10.e4 Colombel et al Clinical Gastroenterology and Hepatology Vol. -, No. -

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Supplementary Table 2. Summary of Safety Outcomes in the Maintenance Remission-Dose Escalation Subpopulation of theOCTAVE Open Study

Tofacitinib Maintenance Remission-DoseEscalation Subpopulation (n ¼ 41)a

AEs 40 (97.6)

SAEsb 6 (14.6)

AEs leading to discontinuation 4 (9.8)

Deathsc 0 (0.0), 0.0 (0.0–3.0)

Serious infections 1 (2.4), 0.8 (0.0–4.6)

HZ (nonserious and serious) 1 (2.4), 0.8 (0.0–4.6)

Opportunistic infectionsd 1 (2.4), 0.8 (0.0–4.6)

Non-HZ opportunistic infectionsd 0 (0.0), 0.0 (0.0–3.0)

Malignancies (excluding NMSC)c,d 1 (2.4), 0.8 (0.0–4.6)

NMSCc,d 3 (7.3), 2.6 (0.5–7.5)

MACEc,d 0 (0.0), 0.0 (0.0–3.0)

DVT 0 (0.0), 0.0 (0.0–3.0)

PE 0 (0.0), 0.0 (0.0–3.0)

Values are n (%) or incidence rate (95% confidence interval).Incidence rate is defined as unique patients with events per 100 patient-years of exposure; associated 95% confidence intervals were obtained by the exactPoisson method.AE, adverse event; DVT, deep vein thrombosis; HZ, herpes zoster; MACE, major adverse cardiovascular events; NMSC, nonmelanoma skin cancer; PE, pulmonaryembolism; SAE, serious adverse event.aData are reported as per the May 27, 2019, data cut.bAccording to Investigator’s assessment.cAll events, including those that are outside the 28-day risk period, are included.dPer adjudication by specialist review committee.



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Maintenance of Remission With Tofacitinib Therapy in