OCTAVE Sustain
Alternative name: NCT01458574,
ID: 623cc7c77aaac8401707d0ac
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Primary study

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A Study Of Oral CP-690,550 As A Maintenance Therapy For Ulcerative Colitis

Autori Pfizer
Registry of Trials ClinicalTrials.gov
Year 2011
Links Registry of Trials
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The study proposes to assess whether compared to placebo, CP-690,550 is effective, safe, and tolerable maintenance therapy in subjects with Ulcerative Colitis (UC). The study proposes to assess whether compared to placebo, CP-690,550 maintenance therapy more effectively achieves mucosal healing and improves quality of life in subjects with UC.The study proposes to assess CP-690,550 pharmacokinetic exposure during maintenance therapy in subjects over the age of 18 years with UC.

Primary study

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Maintenance of quality of life improvement in a phase 3 study of tofacitinib for patients with moderately to severely active ulcerative colitis

Giornale Gut
Year 2017
Links DOI www.cochranelibrary.com
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Introduction Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib 10 mg twice daily (BID) improved quality of life (QoL) in the Phase 3 OCTAVE Induction 1 and 2 studies of patients (pts) with moderate to severe UC.1 Method OCTAVE Sustain (NCT01458574) was a Phase 3, 52 week, randomised, double-blind, placebo (Pbo)-controlled study in pts completing OCTAVE Induction 1 or 2 with clinical response (≥3 points and ≥30% decrease from baseline (BL) Mayo score plus decrease in rectal bleeding subscore (RBSS) of ≥1 or RBSS ≤1). Pts were re-randomised (1:1:1) to Pbo, tofacitinib 5 or 10 mg BID. QoL was assessed at Weeks 24 and 52 using the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ) and the Short Form-36 (SF-36v2, 1 week recall; 8 domain scores and Physical/Mental Component Summaries [PCS and MCS]). Clinically relevant endpoints including IBDQ Remission (IBDQ Score ≥170) and Response (≥16 point improvement from induction BL IBDQ Score) were compared by Cochran- Mantel-Haenszel chi-square test. Continuous endpoints were analysed using a linear mixed-effects model. Results OCTAVE Sustain randomised 593pts (Pbo: n=198; 5 mg BID: n=198; 10 mg BID: n=197). At Sustain BL, mean IBDQ total score ranged from 166.7-167.7, and mean SF-36 PCS and MCS ranged from 49.3-50.5 and 47.8-49.0, respectively, across groups. There was minimal change from BL at Week 24 and 52 in the total IBDQ scores in the tofacitinib groups, while there was a worsening (decrease) in the Pbo group. Both the tofacitinib 5 and 10 mg BID groups showed significant difference in change from Sustain BL in total IBDQ scores at Weeks 24 and 52 compared to Pbo (all p<0.001) (Table). Significantly more patients achieved IBDQ remission and response with both tofacitinib doses vs Pbo at all time points (all p<0.001) (Table). Mean changes from Sustain BL in SF-36 PCS and MCS and all individual domain scores showed similar benefit with both tofacitinib doses vs Pbo at Weeks 24 and 52 (all p<0.001) (Table). Conclusion For pts with moderate to severe UC and clinical response to induction therapy, significant and clinically meaningful improvements in QoL (IBDQ; SF-36) were maintained with tofacitinib 5 and 10 mg BID vs Pbo through 52 weeks maintenance therapy.

Primary study

Unclassified

Maintenance of quality of life improvement in a phase 3 study of tofacitinib for patients with moderately to severely active ulcerative colitis

Giornale Journal of Crohn's and Colitis
Year 2017
Links DOI www.cochranelibrary.com
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib 10 mg twice daily (BID) improved quality of life (QoL) in two Phase 3 induction studies of patients with moderately to severely active UC (OCTAVE Induction 1 & 2) [1]. Methods: OCTAVE Sustain (NCT01458574) was a Phase 3, randomised, double-blind, placebo-controlled study that enrolled patients who completed OCTAVE Induction 1 or 2 with clinical response (=3 points and =30% decrease from baseline (BL) Mayo score plus decrease in rectal bleeding subscore of =1 or rectal bleeding subscore =1). Patients were re-randomised (1:1:1) to placebo, tofacitinib 5 or 10 mg BID for 52 weeks. QoL was assessed at Weeks 24 and 52 using the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ) and the Short Form-36 (SF-36; version 2, 1-week recall; 8 domain scores summarised as Physical and Mental Component Summaries [PCS and MCS]). Clinically relevant endpoints including IBDQ Remission (IBDQ Score =170) and Response (=16-point improvement from induction study BL IBDQ Score), were compared by Cochran-Mantel-Haenszel chi-square test. Continuous endpoints were analysed using a linear mixed-effects model. Results: OCTAVE Sustain randomised 593 patients (placebo: n=198; 5 mg BID: n=198; 10 mg BID: n=197). At Sustain BL, across treatment groups, mean IBDQ total score ranged from 166.7167.7, and mean SF-36 PCS and MCS ranged from 49.350.5 and 47.849.0, respectively. IBDQ and SF-36 endpoints at Weeks 24 and 52 are shown in Table 1. There was no significant change from Sustain BL in total IBDQ scores at Weeks 24 and 52 with tofacitinib (Table 1). In contrast, IBDQ total score decreased with placebo (p<0.001 for all comparisons of tofacitinib vs placebo). Significantly more patients achieved IBDQ remission and response with both tofacitinib doses vs placebo at all time points (p<0.001 for all comparisons). Mean changes from Sustain BL in SF-36 PCS and MCS and all individual domain scores showed similar benefit with both tofacitinib doses vs placebo at Weeks 24 and 52 (p<0.001 for all comparisons). [Table presented] Conclusions: For patients with moderate to severe UC and clinical response to tofacitinib induction therapy, significant and clinically meaningful improvements in QoL (assessed by IBDQ and SF-36) were maintained with tofacitinib 5 and 10 mg BID vs placebo through 52 weeks of maintenance therapy.

Primary study

Unclassified

Tofacitinib, an oral Janus Kinase inhibitor, in the treatment of ulcerative colitis: open-label, long-term extension study

Conference United European Gastroenterology Journal
Year 2017
Links DOI www.cochranelibrary.com
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Introduction: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The efficacy and safety of tofacitinib was demonstrated as induction and maintenance therapy in three Phase 3, randomised, placebo‐controlled studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951; OCTAVE Sustain, NCT01458574) in patients (pts) with moderate to severe UC.1, 2 Aims & Methods: We present interim safety and efficacy data up to 3 years of treatment (as of 08 July 2016) from an ongoing Phase 3, multicentre, open‐label, long‐term extension study (OLE, NCT01470612) in pts who had completed or demonstrated treatment failure in OCTAVE Sustain, or who were non‐responders after completing OCTAVE Induction 1 or 2. Eligibility for this study was determined based on Week (Wk) 8 data from OCTAVE Induction 1 & 2, or Wk 52 data (for completers) or early termination data from OCTAVE Sustain. Pts who were in remission at Wk 52 of OCTAVE Sustain were assigned to tofacitinib 5mg twice daily (BID); all others were assigned 10 mg BID. At Month 2, all pts underwent endoscopy, and non‐responders from induction were mandated to withdraw if they did not show evidence of clinical response. Remission was defined by a Mayo score ≤2 with no individual subscore >1, and rectal bleeding subscore of 0. Binary efficacy endpoints were derived from Mayo score based on local‐read endoscopic subscore. Results: A total of 914 pts (5 mg BID, N=156 [17.1%]; 10mg BID, N=758 [82.9%]) received at least one dose of study drug, of whom 381 (41.7%) discontinued (reasons included adverse events [AEs]: 23 [2.5%] and insufficient clinical response: 283 [31.0%]). The most frequent AE leading to discontinuation was worsening of UC. Serious and severe AEs occurred in 10.4% and 7.8% of pts, respectively (5 and 10 mg BID groups combined). The two most frequent treatment‐ emergent AE (TEAE) system organ classes in both dose groups were 'infections and infestations' and 'gastrointestinal disorders'. The two most frequent TEAEs by preferred term were nasopharyngitis and worsening of UC. Serious infections AEs were reported in four (2.6%) and 14 (1.8%) pts in the 5 and 10mg BID groups, respectively. Malignancies excluding non‐melanoma skin cancer were reported in nine (1.2%) pts in the 10 mg BID group (with no clustering of malignancy type); none were reported in the 5mg BID group. No new safety risks were identified. The available data 'as observed' for remission and mucosal healing at Months 2, 12 and 24 are shown in the Table. Remission was defined as a Mayo score ≤2 with no individual subscore >1, and rectal bleeding subscore of 0; Mucosal healing was defined by a Mayo endoscopic subscore ≤1; AE, adverse event; FAS, full analysis set; GI, gastrointestinal; n, number of patients with the specified response within the given category; N, number of randomised patients in the total population; N1, number of patients in the specified category with non‐missing values; SAEs, serious adverse events; SOC, system organ class; TEAEs, treatment‐emergent adverse events; UC, ulcerative colitis. Conclusion: In pts with moderate to severe UC who remained in the OLE study, no new safety concerns emerged compared with those observed with tofacitinib in rheumatoid arthritis. The efficacy results from this OLE study support sustained efficacy with both tofacitinib 5 and 10 mg BID.

Unclassified

Pregnancy outcomes in the tofacitinib ulcerative colitis octave studies

Giornale
Year 2017
Links DOI www.cochranelibrary.com
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Introduction: Compared with controls, pregnant women with ulcerative colitis (UC) are at a higher risk of adverse outcomes incl. spontaneous abortion, preterm birth and low birth weight.1,2 Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for UC. Tofacitinib is feticidal and teratogenic in rats and rabbits at exposures 146 and 13 times, respectively, the human dose of 5 mg twice daily (BID). There are no adequate and well‐controlled studies of tofacitinib in pregnant women. Methods: We report pregnancy outcomes from 3 randomized, placebo (PBO)‐controlled studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951; OCTAVE Sustain, NCT01458574) and 1 ongoing open‐label extension study (OCTAVE long‐term study, NCT01470612) of tofacitinib monotherapy in patients (pts) with moderate to severe UC.3 Pregnancy outcomes following maternal or paternal exposure to tofacitinib 5 or 10 mg BID were identified from Pfizer's internal safety database up to March 23, 2017. Trial protocols required use of highly effective contraception for women of childbearing potential, and for the study drug to be discontinued in any female pts that became pregnant. Results: 1139 unique pts (incl. PBO) enrolled in the OCTAVE trials; 296 were women of childbearing age. There were 25 pregnancies reported with exposure to tofacitinib. Of these, 11 were cases of maternal exposure, all during the 1st trimester, including: 2 (18.2%) spontaneous abortions (5 mg BID, n=1; 10 mg BID, n=1), 2 (18.2%) medical terminations (both 10 mg BID), 4 (36.4%) healthy newborns (all 10 mg BID) and 3 (27.3%) lost to follow up (all 10 mg BID). Of the 14 cases of paternal exposure, 11 (78.6%) were healthy newborns (5 mg BID, n=2; 10 mg BID, n=9) and 3 (21.4%) were pending/ lost to follow up (5 mg BID, n=1; 10 mg BID, n=2). There were no cases of fetal death or congenital malformation. Conclusion: Based on limited data and follow up available, pregnancy and newborn outcomes among pts with UC with prenatal (maternal/paternal) exposure to tofacitinib appear to be similar to those reported for the UC population and those previously reported in pts with rheumatoid arthritis and psoriasis.4 Larger long‐term follow‐up studies are needed to examine safety of tofacitinib during pregnancy. (Table Presented).

Primary study

Unclassified

Efficacy and safety of oral tofacitinib as maintenance therapy in patients with moderate to severe ulcerative colitis: Results from a phase 3 randomised controlled trial

Giornale Journal of Crohn's & colitis
Year 2017
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Background: Tofacitinib is an oral, small molecule Janus kinase in-hibitor that is being investigated for ulcerative colitis (UC). Efficacy and safety of tofacitinib 10 mg twice daily (BID) were reported in OCTAVE Induction 1 & 2 [1]. Methods: OCTAVE Sustain (NCT01458574) was a Phase 3, ran-domised, double-blind, placebo (PBO)-controlled study that en-rolled PBO or tofacitinib patients (pts) who completed OCTAVE In-duction 1 or 2 with at least clinical response (≥3 points and ≥30% decrease from baseline (BL) Mayo score plus a decrease in rectal bleeding subscore of ≥1 or absolute rectal bleeding subscore ≤1). Pts were re-randomised (1:1:1) to maintenance treatment with PBO (N=198), tofacitinib 5 (N=198) or 10 mg BID (N=197) for 52 weeks (wks). The primary endpoint was remission (total Mayo score ≤2, no subscore >1, rectal bleeding subscore of 0) at Wk 52. Key secondary endpoints were mucosal healing (Mayo endoscopic subscore ≤1) at Wk 52, and sustained steroid-free remission (remission at Wks 24 and 52; no steroid use ≥4 wks prior to each visit) among pts in remission at BL. Results: At Wk 52, tofacitinib 5 and 10 mg BID had significantly greater effect vs PBO for the primary endpoint of remission, and secondary endpoints of mucosal healing, clinical response as well as sustained remission, sustained mucosal healing and sustained clinical response (Table; p<0.001 all comparisons). Among pts in remission at BL, both tofacitinib groups had significantly higher proportions of pts with sustained steroid-free remission vs PBO (p<0.001 all comparisons). Adverse event (AE), serious AE and serious infection rates were similar among all groups. Despite more frequent infections with tofacitinib vs PBO, discontinuations due to AEs were numerically lower for tofacitinib vs PBO. A dose dependent increase in herpes zoster (HZ) rate was observed. There were no deaths, malignancies (excluding non-melanoma skin cancer) or intestinal perforation AEs in either tofacitinib group. Changes in lipid and creatine kinase levels were consistent with results from tofacitinib studies in other popula-tions. Conclusions: Tofacitinib 5 and 10 mg BID were significantly more effective vs PBO as maintenance therapy over 52 wks in pts with moderately to severely active UC. Despite a dose-dependent increase in HZ, overall, AE rates were similar among both tofacitinib groups. No new safety findings emerged from those previously reported in studies of rheumatoid arthritis.

Primary study

Unclassified

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

Giornale The New England journal of medicine
Year 2017
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<b>BACKGROUND: </b>Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.<b>METHODS: </b>We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.<b>RESULTS: </b>In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P&lt;0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P&lt;0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.<b>CONCLUSIONS: </b>In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).

Unclassified

LOWER INCIDENCE OF HERPES ZOSTER IN VEDOLIZUMAB-TREATED VS TOFACITINIB-TREATED PATIENTS WITH ULCERATIVE COLITIS

Giornale Gastroenterology
Year 2018
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Background: Patients (pts) with inflammatory bowel disease (IBD) have an increased risk of herpes zoster (HZ) compared with healthy controls.1 Systemic immunosuppression with immunomodulators or anti-tumor necrosis factor (TNF) therapy are independent risk factors for HZ in IBD patients.1 In pts receiving higher doses of tofacitinib (TOFA), a non-selective Janus kinase (JAK) inhibitor, HZ rates in pts with ulcerative colitis (UC),2 rheumatoid arthritis,3 and psoriasis4 were higher than placebo (PBO). Vedolizumab (VDZ), a humanized monoclonal antibody with a gut-selective mechanism of action (MOA),5, 6 may be associated with a lower risk of HZ infection compared to immunosuppressants. This retrospective post hoc analysis compared the risk of HZ infection with VDZ and TOFA in UC pts. Methods: Reported adverse events of HZ from similarly designed randomized clinical trials for VDZ (GEMINI I, N=6207) and TOFA (OCTAVE SUSTAIN, N=3942) in pts with UC were analyzed. Pts aged ≥18 years with active UC who failed or were intolerant to ≥1 of the following were included in the studies: oral corticosteroids, azathioprine or 6-mercaptopurine, or anti-TNFα therapy.2,7The number needed to harm (NNH) value was derived from the number of pts receiving either active drug or PBO who developed HZ over 52 weeks (wks). Results: VDZ had a favorable NNH value (-2436 for the combined safety population; -257 for both intent-to-treat (ITT) treatment groups combined) demonstrating that VDZ may not be associated with increased risk of HZ infection compared with PBO. TOFA showed an increased risk for HZ infection compared with PBO (NNH=36 for TOFA 5 mg + 10 mg [Fig 1]). VDZ dosing every 4 wks had a NNH value of -126 while VDZ every 8 wks had a NNH of 3843 relative to PBO. Conclusions: In these analyses, the decreased risk of HZ for VDZ relative to TOFA is possibly due to the absence of systemic immunosuppression conferred by the gut-selective MOA of VDZ. Limitations include restricted data from 2 different studies with small sample sizes, the inability to access individual data to evaluate the effects of concomitant immunosuppression and age, and the heterogeneity of the VDZ combined ITT and non-ITT groups, where the ‘PBO’ arm represents patients who either took PBO straight through the study or VDZ induction responders who were re-randomized to PBO for maintenance. References: 1. Long MD, et al. Aliment Pharmacol Ther 2013;37:420-429. 2. Sandborn WJ et al. New Engl J Med 2017;376:1723-36. 3. Winthrop KL et al. Arthritis Rheumatol 2014;66:2675-84. 4. Winthrop KL et al. J Am Acad Dermatol 2017;77:302-309. 5. Wyant T et al. J Crohns Colitis 2016;10:1437-44. 6. Colombel JF et al. Gut 2015;1-13. 7. Feagan BG et al. New Engl J Med 2013;369:699-710. 8. Andrade C. J Clin Psychiatry 2015;76:e330-3. [Figure Presented]

Unclassified

Tofacitinib for the treatment of ulcerative colitis: Up to 4.4 years of safety data from global clinical trials

Giornale Journal of Crohn's and Colitis
Year 2018
Links DOI www.cochranelibrary.com
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Background: Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The safety and efficacy of tofacitinib for the treatment of moderate to severe UC was evaluated in OCTAVE induction and maintenance Phase (P) 3, randomised, placebo-controlled studies.1 Long-term safety and efficacy of tofacitinib for UC are being evaluated in an ongoing, open-label, long-term extension (OLE) study.2 We present an updated integrated analysis of the safety profile of tofacitinib observed during the UC global clinical development programme, with tofacitinib exposure up to 4.4 years. Methods: Patients who received placebo, tofacitinib 5 or 10 mg twice daily (BID) were analysed as three cohorts: induction (P2/P3 induction, n = 1220); maintenance (P3 maintenance, n = 592); and overall (patients receiving tofacitinib 5 or 10 mg BID in P2, P3, or the OLE study, n = 1157; 1613 patient-years [PY] of exposure). Data are shown as of December 2016. Proportions and incidence rates (IRs; patients with events per 100 PY) were evaluated for adverse events (AEs) of special interest. Opportunistic infections (OIs), malignancies, major adverse cardiovascular events (MACE), and gastrointestinal perforations (GIP) were reviewed by independent adjudication committees. Results: A total of 1157 patients received ≥1 dose of tofacitinib 5 or 10 mg BID with 1613 PY of tofacitinib exposure and up to 4.4 years of treatment. Demographics and disease characteristics were generally similar among the treatment groups in each cohort. In induction studies, AEs of special interest were similar for tofacitinib and placebo groups. In the maintenance cohort, IR of herpes zoster (HZ) was numerically higher with tofacitinib 5 mg BID (2.1) and significantly higher with tofacitinib 10 mg BID (6.6) vs. placebo (1.0). IRs for other AEs of interest were similar across treatment groups. For the Overall cohort, the majority of patients (N = 971, 84%) received an average dose of tofacitinib 10 mg BID. IRs for AEs of special interest were: death, 0.2; serious infection, 2.0; OIs, 1.3; HZ, 4.1; malignancy (excl. non-melanoma skin cancer [NMSC]), 0.5; NMSC, 0.7; MACE, 0.2; and GIP, 0.2. Conclusions: Tofacitinib treatment in patients with UC was associated with dose-dependent risk of HZ. These results show an overall manageable safety profile of tofacitinib 5 and 10 mg BID in the UC programme, generally similar to that previously reported in the tofacitinib rheumatoid arthritis programme and to that of other UC therapies including biologics.

Primary study

Unclassified

THE EFFECT OF TOFACITINIB ON SERUM LIPIDS AND CARDIOVASCULAR SAFETY IN PATIENTS WITH ULCERATIVE COLITIS - RESULTS FROM THE TOFACITINIB ULCERATIVE COLITIS CLINICAL PROGRAM

Giornale Gastroenterology
Year 2018
Links DOI www.cochranelibrary.com
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). We describe baseline cardiovascular (CV) risk, the effect of tofacitinib treatment on lipid concentrations, and incidence rates (IRs; patients with events per 100 patient-years) of major adverse CV events (MACE) in patients enrolled in the UC global development program. Methods: Analyses were performed for patients in 3 placebo-controlled induction studies (Ind), a 52-week placebo-controlled maintenance study, and an ongoing, open-label, long-term extension study (N=1157). Lipid concentrations were assessed at pre-induction baseline and up to Week 61 for responders to tofacitinib 10 mg twice daily (BID) in Ind who were randomized to tofacitinib 5 or 10 mg BID or placebo in Main. IRs and confidence intervals (CI) for MACE were calculated (follow-up to December 2016), including patients with ≥1 event per 100 patient-years of exposure. The distribution of CV risk factors and Reynolds Risk Score was determined for male patients ≤45 years and >45 years, and female patients ≤55 years and >55 years. Results: Mean patient age was 41.3 years. At baseline, Reynolds Risk Score was ≥10% in 24.4% of males >45 years and 6.4% of females >55 years. Most patients did not require lipid-lowering medication (Table). Dose-dependent increases in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglycerides were observed, which remained stable up to Week 61 in Main patients assigned to placebo, tofacitinib 5 mg BID and 10 mg BID; LDL-c: HDL-c and TC: HDL-c ratios were unchanged. In the overall clinical program, 4 MACE events were reported (IR 0.24; 95% CI 0.07, 0.62; males 3/668 [0.4%]; females 1/475 [0.2%]): 1 hemorrhagic stroke, 1 aortic dissection, 1 acute coronary syndrome, and 1 myocardial infarction. The aortic dissection resulted in death (patient had 1 CV risk factor). The hemorrhagic stroke led to permanent tofacitinib discontinuation. The myocardial infarction and acute coronary syndrome events led to temporary tofacitinib discontinuation (patients completed the study). These 3 patients had ≥4 CV risk factors at baseline, including hyperlipidemia. Conclusion: Tofacitinib treatment was associated with increases in TC, HDL-c, and LDL-c in patients with UC, while LDL-c: HDL-c and TC: HDL-c ratios were unaffected. These results are similar to those reported for rheumatoid arthritis. MACE events were infrequent, with rates similar to those reported in the tofacitinib rheumatoid arthritis program and for other UC agents; 3 of 4 patients had multiple CV risk factors. [Table Presented]

Unclassified

TOFACITINIB FOR THE TREATMENT OF ULCERATIVE COLITIS: UP TO 4.4 YEARS OF SAFETY DATA FROM GLOBAL CLINICAL TRIALS

Giornale Gastroenterology
Year 2018
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The safety and efficacy of tofacitinib for the treatment of moderate to severe UC was evaluated in OCTAVE induction and maintenance Phase 3, randomized, placebo-controlled studies.1 Long-term safety and efficacy of tofacitinib for UC are being evaluated in an ongoing, open-label, long-term extension study.2 We present an updated integrated analysis of the safety profile of tofacitinib observed during the UC global clinical development program, with tofacitinib exposure up to 4.4 years. Methods: Patients who received placebo, tofacitinib 5 or 10 mg twice daily (BID) were analyzed as 3 cohorts: Induction (Phase 2/3 induction, N=1220); Maintenance (Phase 3 maintenance, N=592); and Overall (patients receiving tofacitinib 5 or 10 mg BID in Phase 2, Phase 3, or the open-label, long-term extension study, N=1157; 1613 patient-years of exposure). Data are shown as of December 2016. Proportions and incidence rates (IRs; patients with events per 100 patient-years) were evaluated for adverse events of special interest. Opportunistic infections, malignancies, major adverse cardiovascular events, and gastrointestinal perforations were reviewed by independent adjudication committees. Results: 1157 patients received ≥1 dose of tofacitinib 5 or 10 mg BID with 1613 patient-years of tofacitinib exposure and up to 4.4 years of treatment. Demographics and disease characteristics were generally similar among the treatment groups in each cohort. In induction studies, adverse events of special interest were similar for tofacitinib and placebo groups. In the Maintenance cohort, the IR of herpes zoster was numerically higher with tofacitinib 5 mg BID (2.1) and significantly higher with tofacitinib 10 mg BID (6.6) vs placebo (1.0). IRs for other adverse events of interest were similar across treatment groups. For the Overall cohort, the majority of patients (N=971, 84%) received an average dose of tofacitinib 10 mg BID. IRs for adverse events of special interest were: death, 0.2; serious infection, 2.0; opportunistic infections, 1.3; herpes zoster, 4.1; malignancy (excl. non-melanoma skin cancer), 0.5; non-melanoma skin cancer, 0.7; major adverse cardiovascular events, 0.2; and gastrointestinal perforations, 0.2. Conclusion: Tofacitinib treatment in patients with UC was associated with dose-dependent risk of herpes zoster. These results show an overall manageable safety profile of tofacitinib 5 and 10 mg BID in the UC program, generally similar to that previously reported in the tofacitinib rheumatoid arthritis program and to that of other UC therapies including biologics. References: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36. 2. Lichtenstein GR et al. Am J Gastroenterol 2017;112(S1):Abstract 714. [Table Presented]

Primary study

Unclassified

Tofacitinib in Patients with Ulcerative Colitis: health-Related Quality of Life in Phase 3 Randomised Controlled Induction and Maintenance Studies

Giornale Journal of Crohn's & colitis
Year 2018
Links Pubmed DOI PubMed Central
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Background and Aims: Tofacitinib is an oral, small molecule Janus kinase [JAK] inhibitor that is being investigated for ulcerative colitis [UC]. We evaluated health‐related quality of life [HRQoL] in tofacitinib UC Phase 3 studies. Methods: Patients ≥ 18 years old in OCTAVE Induction 1 [N = 598] and 2 [N = 541] with moderately to severely active UC were randomised [1:4] to placebo or tofacitinib 10 mg twice daily [BID] for 8 weeks. Subsequently, OCTAVE Sustain re‐randomised [1:1:1] clinical responders [N = 593] from induction studies to placebo, tofacitinib 5 mg BID, or 10 mg BID, for 52 weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and SF‐36v2® Health Survey [SF‐36v2] assessed HRQoL. Results: In OCTAVE Induction 1 and 2, mean changes from baseline IBDQ were greater with tofacitinib 10 mg BID at Week 8 [28.9 and 31.5] versus placebo [15.4 and 17.2; p < 0.0001]; mean changes from baseline SF‐36v2 Physical and Mental Component Summaries [PCS/MCS] were also greater with 10 mg BID [PCS: 6.8 and 6.8; MCS: 6.8 and 7.6] versus placebo [PCS: 2.5 and 4.6; MCS: 3.5 and 4.4; p < 0.01]. In OCTAVE Sustain atWeek 52, changes in IBDQ were maintained with tofacitinib 5 mg [‐1.3] and 10 mg BID [0.6], and larger with placebo [‐20.2; p < 0.0001]. Changes in SF‐36v2 PCS/MCS were also maintained with 5 mg [PCS: 0.0; MCS: ‐1.0] and 10 mg BID [PCS: 0.3; MCS: 0.1] versus placebo [PCS: ‐5.2; MCS: ‐6.7; p < 0.0001] at Week 52 in OCTAVE Sustain. Conclusions: Tofacitinib 10 mg BID induction therapy significantly improved HRQoL versus placebo at Week 8. Improvements were maintained through 52 weeks' maintenance therapy with tofacitinib 5 mg and 10 mg BID. ClinicalTrials.gov registration numbers: NCT01465763, NCT01458951 and NCT01458574.

Primary study

Unclassified

Tofacitinib induction and maintenance therapy in East Asian patients with active ulcerative colitis: subgroup analyses from three phase 3 multinational studies

Giornale Intestinal research
Year 2018
Links Pubmed DOI PubMed Central www.cochranelibrary.com
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BACKGROUND/AIMS: Tofacitinib is an oral, small‐molecule Janus kinase inhibitor being investigated for ulcerative colitis (UC). In OCTAVE Induction 1 and 2, patients with moderately to severely active UC received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Clinical responders in OCTAVE Induction were re‐randomized to 52 weeks' therapy with placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID. METHODS: We conducted post‐hoc efficacy and safety analyses of East Asian patients in OCTAVE Induction 1 and 2 and OCTAVE Sustain. RESULTS: A total of 121 East Asian (Japan, Korea, and Taiwan) patients were randomized in OCTAVE Induction 1 and 2 (placebo, n=26; tofacitinib 10 mg BID, n=95), and 63 in OCTAVE Sustain (placebo, n=20; tofacitinib 5 mg BID, n=22; tofacitinib 10 mg BID, n=21). At week 8 of OCTAVE Induction 1 and 2, 18.9% of patients (18/95) achieved remission with tofacitinib 10 mg BID versus 3.8% (1/26) with placebo. In OCTAVE Sustain, the week 52 remission rates were 45.5% (10/22), 47.6% (10/21), and 15.0% (3/20) with 5 mg BID, 10 mg BID, and placebo, respectively. Adverse event rates were similar between groups in OCTAVE Induction and numerically higher with tofacitinib in OCTAVE Sustain. Serious adverse event rates were similar across groups in all studies. Infections were numerically more frequent with tofacitinib than placebo. Increases in serum lipid levels were observed with tofacitinib. CONCLUSIONS: In East Asian patients with UC, tofacitinib demonstrated numerically greater efficacy versus placebo as induction and maintenance therapy, with a safety profile consistent with the global study population. ClinicalTrials.gov: NCT01465763; NCT01458951; NCT01458574.

Primary study

Unclassified

Tofacitinib for the treatment of ulcerative colitis: Analysis of malignancy rates from the OCTAVE clinical programme

Giornale Journal of Crohn's and Colitis
Year 2018
Links DOI www.cochranelibrary.com
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The safety of tofacitinib for treatment of moderate to severe UC was evaluated in randomised, placebo-controlled induction Phase (P) 2 (NCT00787202), induction P3 (NCT01465763; NCT01458951) and maintenance P3 (NCT01458574) studies,1 and an ongoing, (Table presented) open-label, long-term extension (LTE) study (NCT01470612).2 Here, we present an integrated analysis of adjudicated malignancies observed in the UC clinical development programme. Methods: Patients who received placebo, tofacitinib 5 or 10 mg twice daily (BID) were analysed as three cohorts: Induction (P2/P3 induction studies, n = 1220); Maintenance (P3 maintenance study, n = 592); Overall (patients receiving tofacitinib 5 or 10 mg BID in P2, P3 or ongoing LTE studies, n = 1157). Data shown are as of 16 December 2016. Proportions and incidence rates (IRs; patients with events per 100 patient-years [PY] of exposure) were evaluated for malignancies (excl. non-melanoma skin cancer [NMSC]) and NMSC. An independent adjudication committee reviewed all potential malignancies. Results: 1157 patients with 1613 PY of tofacitinib exposure and ≤4.4 years of treatment (median 514 days, range 1-1606 days) received ≥1 dose of tofacitinib 5 or 10 mg BID (Table). There was no patient with malignancy (excl. NMSC) in the Induction cohort, 1 patient (placebo, breast cancer) in the Maintenance cohort and 8 patients in the Overall cohort (IR 0.48; 95% confidence interval [CI] 0.21, 0.95); all 10 mg BID. No clustering of malignancies (excl. NMSC) was noted. In tofacitinib-treated patients, NMSC was reported in: two (0.2%) Induction cohort patients, three Maintenance cohort patients (IR 1.91; 95% CI 0.39, 5.59) (all 10 mg BID) and 11 Overall cohort patients (IR 0.67; 95% CI 0.33, 1.19). NMSC IRs in the Maintenance cohort for tofacitinib 5 mg BID (IR 0.00; 95% CI 0.00, 2.48) were not higher than placebo (IR 0.97; 95% CI 0.02, 5.40). Of the 11 Overall cohort patients with NMSC, most (10/11) had been exposed to azathioprine or 6-mercaptopurine and most (10/11) failed treatment with tumour necrosis factor inhibitors. Conclusions: Malignancies occurred infrequently with tofacitinib treatment in the UC clinical programme. The malignancies (NMSC, and excl. NMSC) IRs were similar to those reported for tofacitinib in rheumatoid arthritis patients3 and for UC patients treated with biologics. A dose-dependent increased risk of NMSC could not be derived from the data.

Unclassified

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Malignancy Rates from the Octave Clinical Program

Giornale Gastroenterology
Year 2018
Links DOI www.cochranelibrary.com
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The safety of tofacitinib for treatment of moderate to severe UC was evaluated in randomized, placebo-controlled induction Phase (P) 2 (NCT00787202), induction P3 (NCT01465763; NCT01458951), and maintenance P3 (NCT01458574) studies,1 and an ongoing, open-label, long-term extension study (NCT01470612).2 Here, we present an integrated analysis of adjudicated malignancies observed in the UC clinical development program. Methods: Patients who received placebo, tofacitinib 5 or 10 mg twice daily (BID) were analyzed as 3 cohorts: Induction (P2/P3 induction studies, N=1220); Maintenance (P3 maintenance study, N=592); Overall (patients receiving tofacitinib 5 or 10 mg BID in P2, P3, or ongoing long-term extension studies, N=1157). Data shown are as of December 16 2016. Proportions and incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for malignancies (excl. non-melanoma skin cancer) and non-melanoma skin cancer. An independent adjudication committee reviewed all potential malignancies. Results: 1157 patients with 1613 patient-years of tofacitinib exposure and ≤4.4 years of treatment (median 514 days, range 1-1606 days) received ≥1 dose of tofacitinib 5 or 10 mg BID (Table). There was no patient with malignancy (excl. non-melanoma skin cancer) in the Induction cohort, 1 patient (placebo, breast cancer) in the Maintenance cohort, and 8 patients in the Overall cohort (IR 0.48; 95% confidence interval [CI] 0.21, 0.95); all 10 mg BID. No clustering of malignancies (excl. non-melanoma skin cancer) was noted. In tofacitinib-treated patients, non-melanoma skin cancer was reported in: 2 (0.2%) Induction cohort patients, 3 Maintenance cohort patients (IR 1.91; 95% CI 0.39, 5.59) (all 10 mg BID), and 11 Overall cohort patients (IR 0.67; 95% CI 0.33, 1.19). Non-melanoma skin cancer IRs in the Maintenance cohort for tofacitinib 5 mg BID (IR 0.00; 95% CI 0.00, 2.48) were not higher than placebo (IR 0.97; 95% CI 0.02, 5.40). Of the 11 Overall cohort patients with non-melanoma skin cancer, most (10/11) had been exposed to azathioprine or 6-mercaptopurine and most (10/11) failed treatment with tumor necrosis factor inhibitors. Conclusion: Malignancies occurred infrequently with tofacitinib treatment in the UC clinical program. The malignancies (non-melanoma skin cancer, and excl. non-melanoma skin cancer) IRs were similar to those reported for tofacitinib in rheumatoid arthritis patients3 and for UC patients treated with biologics. A dose-dependent increased risk of non-melanoma skin cancer could not be derived from the data. References: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36. 2. Lichtenstein GR et al. Am J Gastroenterol 2017;112(S1):Abstract 714. 3. Cohen SB et al. Ann Rheum Dis 2017;76:1253-62. [Table Presented]

Primary study

Unclassified

Analysis of the impact of body mass index on efficacy and safety in the tofacitinib OCTAVE ulcerative colitis programme

Giornale Journal of Crohn's and Colitis
Year 2019
Links DOI www.cochranelibrary.com
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Background: High body mass index (BMI) can be associated with increased risk of treatment failure in biologic-treated patients with ulcerative colitis (UC).1 Tofacitinib is an oral, small-molecule JAK inhibitor approved in several countries for the treatment of UC. We present analysis of BMI effect on tofacitinib efficacy and safety in the tofacitinib UC clinical programme. Methods: Data from two identical, 8-week (week) induction studies (OCTAVE Induction 1 and 2, NCT01465763 and NCT01458951)2 and a 52-week maintenance study (OCTAVE Sustain, NCT01458574)2 were analysed. Patients received placebo, tofacitinib 5 or 10 mg twice daily (BID). Patients were stratified by BMI <25, 25-<30 or ≥30 for analysis at Week 8 (Induction 1 and 2) and Week 52 (Sustain) for efficacy endpoints remission, clinical response and mucosal healing (MH), and for safety outcomes including infections. Results: Patient demographics and baseline characteristics were similar for placebo and tofacitinib groups. The majority of patients in each group had BMI <25 (table). In Induction 1 and 2 and Sustain, tofacitinib-treated patients had a gradual increase in body weight and BMI over time vs. placebo. In Induction 1 and 2, for tofacitinib 10 mg BID at Week 8, patients with BMI <25 had numerically higher proportions of remission vs. other BMI groups. Proportion of patients with MH was lower in BMI ≥30. Clinical response was similar in all BMI groups. At Sustain Week 52, for tofacitinib 5 mg BID, BMI 25-<30 had highest proportions of remission and MH; BMI ≥30 had highest proportion of sustained steroid-free remission and lowest proportion for MH and clinical response vs. other BMI groups. Clinical response was similar for all BMI groups. In Sustain, for tofacitinib 10 mg BID, BMI ≥30 had highest proportions of remission, sustained steroid-free remission, MH, and clinical response. For tofacitinib patients in Induction 1 and 2, opportunistic infections (OI) were rare; proportions were similar across BMI groups. BMI stratification for infections and serious infections (SI) was not available. In Sustain, for tofacitinib 5 and 10 mg BID, infections were numerically higher for BMI 25-<30 vs. others. There were few OI or SI, and proportions were similar among subgroups. Conclusions: The majority of patients with UC in the OCTAVE programme had BMI <25. In subgroup analyses by BMI, patients with high BMI receiving tofacitinib did not demonstrate lower efficacy endpoints or greater infection rates. However, limitations include low patient numbers in the BMI ≥30 group and rare OI/SI events. (Figure Presented).

Primary study

Unclassified

Improvement in patient-reported inflammatory bowel disease questionnaire outcomes, and relationship with disease activity, in tofacitinib treated patients with ulcerative colitis: Data from the OCTAVE clinical trials

Giornale Journal of Crohn's and Colitis
Year 2019
Links DOI www.cochranelibrary.com
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Background: Tofacitinib is an oral, small-molecule JAK inhibitor approved in several countries for the treatment of ulcerative colitis (UC). We assessed relationships between patient (pt)-reported Inflammatory Bowel Disease Questionnaire (IBDQ) outcomes and Mayo score (a widely used measure of clinical activity) in tofacitinib UC induction and maintenance studies. Methods: We analysed patients from two randomised, placebocontrolled, 8-week tofacitinib induction studies (OCTAVE Induction 1 and 2, NCT01465763 and NCT01458951) and a 52-week, randomised, placebo-controlled maintenance study (OCTAVE Sustain, NCT01458574). We evaluated IBDQ remission (total score ≥190) and response (≥30-point increase from baseline) at Week 8 (induction) and Weeks 24 and 52 (maintenance). These criteria are more stringent vs. previously reported IBDQ remission (total score ≥170) and response (≥16-point increase from baseline) thresholds. We evaluated relationships between IBDQ total scores and total Mayo scores at baseline and Week 8 (induction) and Weeks 24 and 52 (maintenance) using Spearman correlation. Results: In OCTAVE Induction 1 and 2, mean baseline IBDQ total score of each treatment ranged from 117.5 to 124.9. Statistically significant effects of treatment with tofacitinib 10 mg twice daily (BID) vs. placebo were observed at Week 8 for IBDQ remission (p < 0.05) and response (p < 0.0001) (Table 1). In OCTAVE Sustain, mean baseline IBDQ total score of each treatment ranged from 181.3 to 182.3. There were statistically significant maintenance treatment effects with 5 and 10 mg BID vs. placebo for IBDQ remission and response at Weeks 24 and 52 (all p < 0.0001; Table 2). Spearman correlation coefficients between IBDQ total score and total Mayo score in OCTAVE Induction 1 and 2 at Week 8 were -0.67 and -0.59, respectively. In OCTAVE Sustain, correlation coefficients were -0.57 at Week 24 and -0.40 at Week 52. Conclusions: For patients with moderate to severe UC, induction and maintenance therapy with tofacitinib resulted in statistically significant improvements in patient-reported quality of life vs. placebo, as measured using comparatively stringent IBDQ criteria. Moderate correlations between IBDQ and Mayo scores were observed from Week 8 in OCTAVE Induction to Week 52 in OCTAVE Sustain. (Table Presented) .

Primary study

Unclassified

ANALYSIS OF HEMATOLOGICAL CHANGES IN TOFACITINIB-TREATED PATIENTS WITH ULCERATIVE COLITIS ACROSS PHASE 3 INDUCTION AND MAINTENANCE STUDIES

Giornale Gastroenterology
Year 2019
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Background: Tofacitinib is an oral, small molecule JAK inhibitor approved in several countries, including the US, for the treatment of ulcerative colitis. Changes in hematological parameters in participants of OCTAVE Induction 1 & 2 (NCT01465763 & NCT01458951) and OCTAVE Sustain (NCT01458574)1 were evaluated. Methods: In OCTAVE Induction 1 & 2, patients (pts) received either placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks; clinical responders were re-randomized into OCTAVE Sustain for 52 weeks (received placebo, tofacitinib 5 or 10 mg BID). Mean absolute lymphocyte count (ALC), absolute neutrophil count (ANC), platelet count (PC), and hemoglobin (Hgb) level changes were analyzed. Hematological adverse events were evaluated. Results: Following 8 weeks of treatment (placebo or tofacitinib 10 mg BID) in OCTAVE Induction 1 & 2, Hgb levels, ALC, and ANC were stable, while PC declined from baseline (Table). Up to Week 52 of OCTAVE Sustain, Hgb levels increased and ALC, ANC, and PC declined in all groups (Table). During OCTAVE Induction 1 & 2, adverse events of anemia were reported in 22 (2.4%) tofacitinib-treated pts compared with 9 (3.8%) placebo-treated pts. During OCTAVE Sustain, the incidence rates (IRs; unique pts with events per 100 pt-years) of anemia were 2.91, 5.51, and 2.55 for placebo, tofacitinib 5 and 10 mg BID, respectively. No adverse events of neutropenia were reported during OCTAVE Induction 1 & 2. In OCTAVE Sustain, IRs were 0.00, 0.67, and 0.64 for placebo, tofacitinib 5 and 10 mg BID, respectively. During OCTAVE Induction 1 & 2, two (0.2%) tofacitinib-treated pts had adverse events of lymphopenia, and no adverse events of lymphopenia occurred during OCTAVE Sustain. Discontinuations due to laboratory abnormalities were low. Two (0.2%) tofacitinib-treated pts discontinued in OCTAVE Induction 1 & 2 due to ALC decline (two sequential readings <0.5 × 109/L), and five (0.6%) tofacitinib-treated pts discontinued due to Hgb decline (two sequential values <0.8 g/dL or >30% decrease from baseline), compared to Hgb decline in one (0.4%) placebo-treated pt. In OCTAVE Sustain, one (0.3%) pt discontinued due to Hgb decline. Conclusion: In OCTAVE Sustain, treatment with both tofacitinib doses resulted in decreased ALC, ANC, and PC, and increases in Hgb levels. There was no dose dependency in anemia or neutropenia IRs. Similar trends were observed in pts with rheumatoid arthritis treated with tofacitinib.2 Increases in Hgb were also found in pts with inflammatory bowel disease and rheumatoid arthritis treated with tumor necrosis factor inhibitors.3-5 References: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36. 2. Schulze-Koops H et al. Rheumatology 2017;56:46-57. 3. Koutroubakis IE et al. Inflamm Bowel Dis 2015;21:1587-93. 4. Rubin DT et al. Inflamm Bowel Dis 2012;18:818-25. 5. Doyle MK et al. Semin Arthritis Rheum 2009;39:123-31. [Table presented]

Primary study

Unclassified

Analysis of haematological changes in tofacitinib-treated patients with ulcerative colitis across Phase 3 induction and maintenance studies

Giornale Journal of Crohn's and Colitis
Year 2019
Links DOI www.cochranelibrary.com
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Background: Tofacitinib is an oral, small-molecule JAK inhibitor approved in several countries for the treatment of ulcerative colitis. Changes in haematological parameters in participants of OCTAVE Induction 1 and 2 (NCT01465763 and NCT01458951) and OCTAVE Sustain (NCT01458574)1 were evaluated. Methods: In OCTAVE Induction 1 and 2, patients received either placebo (PBO) or tofacitinib 10 mg twice Da ily (BID) for 8 weeks; clinical responders were re-randomised into OCTAVE Sustain for 52 weeks (received PBO, tofacitinib 5 or 10 mg BID). Mean absolute lymphocyte count (ALC), absolute neutrophil count (ANC), platelet count (PC) and haemoglobin (Hgb) level changes were analysed. Haematological adverse events (AEs) were evaluated. Results: Following 8 weeks of treatment (PBO or tofacitinib 10 mg BID) in OCTAVE Induction 1 and 2, Hgb levels, ALC and ANC were stable, while PC declined from baseline (Table). Up to Week 52 of OCTAVE Sustain, Hgb levels increased and ALC, ANC and PC declined in all groups (table). During OCTAVE Induction 1 and 2, AEs of anaemia were reported in 22 (2.4%) tofacitinib-treated patients compared with 9 (3.8%) placebo-treated patients. During OCTAVE Sustain, the incidence rates (IRs; unique patients with events per 100 patient-years) of anaemia were 2.91, 5.51, and 2.55 for PBO, tofacitinib 5 and 10 mg BID, respectively. No AEs of neutropenia were reported during OCTAVE Induction 1and2. In OCTAVE Sustain, IRs were 0.00, 0.67, and 0.64 for placebo, tofacitinib 5 and 10 mg BID, respectively. During OCTAVE Induction 1 and 2, 2 (0.2%) tofacitinib-treated patients had AEs of lymphopenia, and no AEs of lymphopenia occurred during OCTAVE Sustain. Discontinuations due to laboratory abnormalities were low. Two (0.2%) tofacitinib-treated patients discontinued in OCTAVE Induction 1 and 2 due to ALC decline (2 sequential readings <0.5 × 109/l) and 5 (0.6%) tofacitinib-treated patients discontinued due to Hgb decline (2 sequential values < 0.8 g/dl or >30% decrease from baseline), compared with Hgb decline in 1 (0.4%) PBO-treated patient. In OCTAVE Sustain, 1 (0.3%) pt discontinued due to Hgb decline. Conclusions: In OCTAVE Sustain, treatment with both tofacitinib doses resulted in decreased ALC, ANC and PC, and increases in Hgb levels. There was no dose dependency in anaemia or neutropenia IRs. Similar trends were observed in rheumatoid arthritis (RA) patients treated with tofacitinib.2 Increases in Hgb were also found in IBD and RA patients treated with TNFi.3-5.

Unclassified

Item-level improvements in inflammatory bowel disease questionnaire scores in patients with ulcerative colitis treated with tofacitinib induction therapy

Giornale American journal of gastroenterology
Year 2019
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INTRODUCTION: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Significant improvements have been reported in all Inflammatory Bowel Disease Questionnaire (IBDQ) domains for tofacitinib vs placebo (PBO) in patients (pts) with UC in OCTAVE Induction 1 & 2 and OCTAVE Sustain.1 The effect of tofacitinib on items within each IBDQ domain has not yet been analyzed. METHODS: We examined the effect of tofacitinib induction (10 mg twice daily [BID]) on individual IBDQ items in adults with moderate to severe UC. Data were pooled from the randomized, Phase 3 OCTAVE Induction 1 & 2 studies (NCT01465763 & NCT01458951).2 Pts self-administered the IBDQ at baseline (BL), Week (Wk) 4, and Wk 8. IBDQ domains are: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items); higher scores indicate better health-related quality of life (HRQoL).1,3 Change from BL (CFB) in IBDQ items was analyzed for tofacitinib vs PBO using a linear mixed-effects model, with fixed effects (treatment, study, prior tumor necrosis factor inhibitor treatment, BL corticosteroid use, geographical region, week, treatment-by-week interaction, and BL score) and a random effect (pts). No multiplicity adjustment was performed. RESULTS: Significant improvements (P < 0.05) were observed in all IBDQ items with tofacitinib 10 mg BID vs PBO at Wks 4 and 8. The largest treatment differences (CFB; domain) were: “bowel movements been loose” at Wks 4 and 8 and also “problem with rectal bleeding” at Wk 8 (all 1.1 points) for the bowel symptoms domain; “getting a good night's sleep” at Wk 4 (0.8) and 8 (0.9) for the systemic symptoms domain; “fear of not finding a washroom” at Wk 4 (0.6) and 8 (0.8) and also “felt embarrassed” and “felt angry” at Wk 4 (both 0.6) for the emotional function domain; and “avoid attending events” at Wk 4 (0.8) and 8 (1.0) and also “difficulty doing leisure/sports” at Wk 8 (1.0) for the social function domain (Table 1). CONCLUSION: Tofacitinib improved all bowel-related and systemic symptoms, and all emotional and social functioning IBDQ items vs PBO, highlighting the broad impact of tofacitinib on HRQoL. This analysis provides a useful perspective on the most improved IBDQ domains with tofacitinib induction therapy, which may facilitate patient-physician dialogue. (Figure Presented).

Primary study

Unclassified

Efficacy of tofacitinib maintenance therapy for ulcerative colitis in remitting patients vs. patients with clinical response after 8 weeks of induction treatment

Giornale Journal of Crohn's & colitis
Year 2019
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Background: Tofacitinib is an oral, small-molecule JAK inhibitor approved in several countries for the treatment of ulcerative colitis (UC). Here, we present data from the Phase 3 OCTAVE Sustain (NCT01458574) study,1 comparing the 52-week maintenance efficacy of tofacitinib in patients with UC who achieved baseline remission (ie, remitters), to that of those who achieved clinical response but not remission (ie, non-remitters) after 8 weeks of induction therapy. Methods: Patients who had achieved clinical response (≥3-point and ≥30% decrease from induction study baseline total Mayo score, plus a ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding subscore ≤1) after 8 weeks of therapy in OCTAVE Induction 1 or 2 (NCT01465763; NCT01458951) were re-randomised at baseline to receive placebo, tofacitinib 5 or 10 mg twice daily (BID) in the double-blind, parallel-group, multi-centre OCTAVE Sustain study. The proportion of patients in remission (total Mayo score ≤2 with no individual subscore >1, and a rectal bleeding subscore of 0), and the proportion of patients with mucosal healing (Mayo endoscopic subscore ≤1) at Week 52, were analysed in baseline remitters (n = 165) vs. non-remitters (n = 358), excluding patients treated with placebo who achieved clinical response at baseline. This analysis was also performed for prior tumour necrosis factor inhibitor (TNFi) failures (n = 234) and non-failures (n = 283), although the six patients who did not meet clinical response criteria at baseline of OCTAVE Sustain were also excluded. Results: A numerically higher proportion of tofacitinib-treated patients who were baseline remitters achieved remission at Week 52 vs. non-remitters, regardless of tofacitinib dose received or TNFi failure status. Similar findings were also observed for mucosal healing at Week 52. The relative increase in the observed treatment effect of tofacitinib 10 over 5 mg BID was generally similar between baseline remitters and non-remitters. Furthermore, the greater dose-related relative increase in efficacy in the TNFi failure vs. the TNFi nonfailure subpopulation was evident regardless of the maintenance baseline remission status (table). Conclusions: A numerically higher proportion of baseline remitters vs. non-remitters treated with tofacitinib achieved remission or mucosal healing at Week 52 in OCTAVE Sustain, although a large proportion of non-remitters and prior TNFi failures still achieved remission or mucosal healing at Week 52. (Table Presented) .

Primary study

Unclassified

Impact of prior immunosuppressant and tumor necrosis factor inhibitor therapies on tofacitinib efficacy and safety in patients with ulcerative colitis

Giornale American Journal of Gastroenterology
Year 2019
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BACKGROUND: Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The tofacitinib UC program comprises Phase (P)2 and P3 induction studies, a P3 maintenance study, and an ongoing open-label extension study (1). We report efficacy and safety of tofacitinib in the UC program in patients with/without prior tumor necrosis factor inhibitor (TNFi) failure and/or immunosuppressant failure. METHODS: Efficacy data are reported from OCTAVE Induction 1 and 2 (NCT01465763 and NCT01458951; pooled data), and OCTAVE Sustain (NCT01458574). We evaluated rates of remission stratified by prior TNFi failure (yes/no) and prior immunosuppressant failure (yes/no). Where there were sufficient adverse events (AEs) to analyze, effects of prior TNFi failure, and prior immunosuppressant exposure on AEs of special interest (herpes zoster [HZ], serious infections, and adjudicated non-melanoma skin cancer [NMSC]), were evaluated using Cox regression analysis in tofacitinib-treated patients in the UC program (December 2016 data cut; N = 1,157; 1,613 patient-years' exposure). RESULTS: Among 1,139 patients (placebo: n = 234; tofacitinib 10 mg BID: n = 905) treated in OCTAVE Induction 1 and 2, 51.7% had prior TNFi failure and 71.9% had prior immunosuppressant failure. For patients with TNFi failure, Week (Wk) 8 remission rates were: placebo: 0.8%; 10 mg BID: 11.4% (difference from placebo [Δ] =10.6%); rates for patients without TNFi failure were 11.8% and 24.1%, respectively (Δ = 12.3%). In patients with immunosuppressant failure, Wk8 remission rates were: placebo 3.2%; 10 mg BID: 15.6% (Δ = 12.4%); rates in patients without immunosuppressant failure were 11.8% and 23.0%, respectively (Δ = 11.1%). Among 593 patients treated in OCTAVE Sustain (placebo: n = 198; 5 mg BID: n = 198; 10 mg BID: n = 197), 44.7% had prior TNFi failure and 69.6% prior immunosuppressant failure at induction baseline. For patients with TNFi failure, Wk52 remission rates were: placebo: 11.2%; 5 mg BID: 24.1% (Δ = 12.9%); 10 mg BID: 36.6% (Δ = 25.3%); rates for patients without TNFi failure were: placebo: 11.0%; 5 mg BID: 41.7% (Δ = 30.7%); 10 mg BID: 44.2% (Δ = 33.2%). For patients with immunosuppressant failure, Wk52 remission rates were: placebo: 7.8%; 5 mg BID: 29.4% (Δ = 21.6%); 10 mg BID: 37.6% (Δ = 29.8%); rates for patients without immunosuppressant failure were: placebo 17.4%; 5 mg BID: 47.3% (Δ = 29.9%); 10 mg BID: 48.2% (Δ = 30.8%). Among all tofacitinibtreated patients in the UC program with prior TNFi failure, 505/583 (86.6%) had AEs and 92/583 (15.8%) had serious AEs. For patients without prior TNFi failure, 431/541 (79.7%) had AEs and 75/541 (13.9%) had serious AEs. Prior TNFi failure (hazard ratio [95% confidence interval]: 1.9 [1.2-3.2]) was identified as a significant risk factor for HZ, and for NMSC (11.3 [1.4-88.3]). Prior immunosuppressant exposure was not identified as a significant risk factor for AEs of special interest in Cox regression analyses. CONCLUSION(S): In patients with UC, prior TNFi/immunosuppressant failure did not preclude benefit from tofacitinib induction or maintenance therapy. Prior TNFi failure was associated with greater risk for HZ and NMSC. HZ cases in the UC program were typically non-complicated and manageable with standard antiviral therapy (2).

Primary study

Unclassified

IMPROVEMENT IN PATIENT-REPORTED INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE OUTCOMES, AND RELATIONSHIP WITH DISEASE ACTIVITY, IN TOFACITINIB-TREATED PATIENTS WITH ULCERATIVE COLITIS: DATA FROM THE OCTAVE CLINICAL TRIALS

Giornale Gastroenterology
Year 2019
Links DOI www.cochranelibrary.com
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Background: Tofacitinib is an oral, small molecule JAK inhibitor approved in several countries, including the US, for the treatment of ulcerative colitis (UC). We assessed relationships between patient-reported Inflammatory Bowel Disease Questionnaire (IBDQ) outcomes and Mayo score (a widely used measure of clinical activity) in tofacitinib UC induction and maintenance studies. Methods: We analyzed patients from two randomized, placebo-controlled, 8-week tofacitinib induction studies (OCTAVE Induction 1 & 2, NCT01465763 & NCT01458951) and a 52-week, randomized, placebo-controlled maintenance study (OCTAVE Sustain, NCT01458574). We evaluated IBDQ remission (total score ≥190) and response (≥30-point increase from baseline) at Week 8 (induction) and Weeks 24 and 52 (maintenance). These criteria are more stringent vs previously reported IBDQ remission (total score ≥170) and response (≥16-point increase from baseline) thresholds. We evaluated relationships between IBDQ total scores and total Mayo scores at baseline and Week 8 (induction) and Weeks 24 and 52 (maintenance) using Spearman correlation. Results: In OCTAVE Induction 1 & 2, mean baseline IBDQ total score of each treatment ranged from 117.5 to 124.9. Statistically significant effects of treatment with tofacitinib 10 mg twice daily (BID) vs placebo were observed at Week 8 for IBDQ remission (p<0.05) and response (p<0.0001) (Table 1). In OCTAVE Sustain, mean baseline IBDQ total score of each treatment ranged from 181.3 to 182.3. There were statistically significant maintenance treatment effects with 5 and 10 mg BID vs placebo for IBDQ remission and response at Weeks 24 and 52 (all p<0.0001; Table 2). Spearman correlation coefficients between IBDQ total score and total Mayo score in OCTAVE Induction 1 & 2 at Week 8 were -0.67 and -0.59, respectively. In OCTAVE Sustain, correlation coefficients were -0.57 at Week 24 and -0.40 at Week 52. Conclusion: For patients with moderate to severe UC, induction and maintenance therapy with tofacitinib resulted in statistically significant improvements in patient-reported quality of life vs placebo, as measured using comparatively stringent IBDQ criteria. Moderate correlations between IBDQ and Mayo scores were observed from Week 8 in OCTAVE Induction to Week 52 in OCTAVE Sustain. [Table presented] [Table presented]

Primary study

Unclassified

Extraintestinal manifestations at baseline, and effect of tofacitinib in patients with moderate to severe ulcerative colitis in the octave program

Giornale American Journal of Gastroenterology
Year 2019
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BACKGROUND: Extraintestinal manifestations (EIMs) occur in approximately one-third of patients with ulcerative colitis (UC) (1). Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. The effect of tofacitinib on EIMs is currently unknown. We explore whether tofacitinib treatment impacts EIMs in patients with moderate to severe UC enrolled in the Phase 3 OCTAVE clinical program. METHODS: We report data from three double-blind, placebo-controlled, Phase 3 studies in patients with moderate to severe UC: two 8-week induction studies (tofacitinib 10 mg twice daily [BID] or placebo; OCTAVE Induction 1&2, NCT01465763 and NCT01458951) and a 52-week maintenance study (tofacitinib 5 or 10 mg BID or placebo; OCTAVE Sustain, NCT01458574). The frequency and proportion of pre-defined quiescent prior and active EIMs at baseline, and the change from baseline in EIMs at the end of the treatment period (Week 8 or Week 52), or at early termination, were evaluated in patients with non-missing data. RESULTS: Overall, 1139 and 592 patients were randomized into OCTAVE Induction 1&2 and Sustain, of which 27.0% and 9.0% had a history of quiescent prior or active EIMs, respectively. At Week 8 of OCTAVE Induction 1&2, 4.6% of tofacitinib-treated patients and 5.3% of placebo-treated patients experienced a change (improvement, worsening, or new occurrence) from baseline in EIMs. At Week 52 of OCTAVE Sustain, 4.6%, 3.1%, and 7.3% of patients in the tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo groups experienced a change from Sustain baseline in EIMs, respectively. The most frequent active EIMs at Induction baseline were peripheral arthritis (11.2% of patients [127/1135]), sacroiliitis (1.0% of patients [11/1135]), and oral ulcers/stomatitis (0.7% of patients [8/1135]). In OCTAVE Induction 1&2, similar proportions of patients in each treatment group with active baseline peripheral arthritis experienced no change (tofacitinib 10 mg BID, 78/96 [81.3%]; placebo, 24/28 [85.7%]) or an improvement (15/96 [15.6%] and 4/28 [14.3%], respectively) from baseline at Week 8. Three (3.1%) tofacitinib-treated patients experienced worsening of symptoms compared with no placebo-treated patients. At OCTAVE Sustain baseline, 20 patients had active peripheral arthritis. The majority of these patients experienced no change in their peripheral arthritis at Week 52 (tofacitinib 5 mg BID, 5/6 [83.3%]; tofacitinib 10 mg BID, 2/3 [66.7%]; placebo, 9/11 [81.8%]). Two tofacitinib-treated patients experienced an improvement at Week 52 (tofacitinib 5 mg BID, 1/6 [16.7%]; tofacitinib 10 mg BID, 1/3 [33.3%]) and no tofacitinib-treated patients reported a worsening of symptoms. Two placebo-treated patients (2/11 [18.2%]) reported a worsening of symptoms and none reported improvement. CONCLUSION(S): In OCTAVE Induction 1&2 and OCTAVE Sustain, 27.0% and 9.0% of patients experienced EIMs at baseline, respectively. The most common active EIM was peripheral arthritis, for which the majority of patients in Induction and Sustain reported either no change or improvement from baseline. These post-hoc analyses should be interpreted with caution; they are limited by low patient numbers and collection of data via a predefined EIM list which did not include a specific arthralgia category (ie arthralgia may have been recorded as peripheral arthritis). Additional studies are required.

Primary study

Unclassified

Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials

Giornale Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Year 2019
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Background & Aims: Tofacitinib is an oral, small‐molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib‐treated patients with moderate to severe UC. Methods: Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open‐label, long‐term extension studies, n = 1157; 1613 patient‐years’ exposure). Incidence rates (IRs; patients with events per 100 patient‐years of exposure) were evaluated for select adverse events. Results: In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4–6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2–12.2) vs placebo (IR, 1.0, 95% CI, 0.0–5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1–0.6); serious infections, 2.0 (95% CI, 1.4–2.8); opportunistic infections, 1.3 (95% CI, 0.8–2.0); herpes zoster infection, 4.1 (95% CI, 3.1–5.2); malignancy (excluding non‐melanoma skin cancer), 0.7 (95% CI, 0.3–1.2); non‐melanoma skin cancer, 0.7 (95% CI, 0.3–1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1–0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0–0.5). Conclusions: In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow‐up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

Primary study

Unclassified

Tofacitinib efficacy in patients with moderate to severe ulcerative colitis: Subgroup analyses of OCTAVE Induction 1 and 2 and OCTAVE sustain by 5-aminosalicylates use

Giornale Journal of Crohn's and Colitis
Year 2019
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Background: Tofacitinib is an oral, small-molecule JAK inhibitor approved in several countries for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib were demonstrated in three Phase 3 trials (OCTAVE Induction 1 and 2, NCT01465763 and NCT01458951; OCTAVE Sustain, NCT01458574) in patients with moderate to severe UC [1]. In this post-hoc analysis, we explored tofacitinib efficacy for patients with (c5-ASA) and without (n5-ASA) concomitant 5-aminosalicylates use. Methods: In OCTAVE Induction 1 and 2, patients received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks; clinical responders were re-randomised into OCTAVE Sustain for 52 weeks and received placebo, tofacitinib 5 or 10 mg BID. c5-ASA were permitted at entry, provided doses were stable ≥4 weeks prior to and during the trials. Remission and mucosal healing were summarised at Week 8 (OCTAVE Induction 1 and 2) and Week 52 (OCTAVE Sustain) by c5-ASA status. Generalised linear models were used to compare the adjusted treatment effects between 5-ASA subgroups (Tables 1 and 2). Results: A smaller proportion of c5-ASA patients had prior tumour necrosis factor inhibitor (TNFi) and immunosuppressant failure compared with n5-ASA patients, at baseline of OCTAVE Induction and Sustain (OCTAVE Induction 1 and 2: TNFi failure 42.7% vs. 74.5%; immunosuppressant failure 69.4% vs. 78.3%; OCTAVE Sustain: TNFi failure 36% vs. 70%; immunosuppressant failure 67.9% vs. 80%). For both c5-ASA and n5-ASA subgroups, a higher proportion of tofacitinib-treated patients achieved efficacy endpoints, compared with placebo-treated patients, at Week 8 of OCTAVE Induction 1 and 2 and Week 52 of OCTAVE Sustain (Tables 1 and 2). Without controlling for baseline variables, higher treatment effects were observed within the c5-ASA subgroup compared with the n5-ASA subgroup; however, when controlled for prior TNFi and immunosuppressant failure (and baseline remission status in OCTAVE Sustain), the differences were not statistically significant in treatment effects between the 5-ASA subgroups in terms of adjusted odds ratios (Tables 1 and 2). Conclusions: When controlling for prior UC treatment status, efficacy of tofacitinib, based on adjusted odds ratios, was similar regardless of 5-ASA status. This analysis is limited by subgroup size differences. (Table Presented) .

Primary study

Unclassified

Tofacitinib as Induction and Maintenance Therapy in Japanese Patients with Active Ulcerative Colitis

Giornale Inflammatory intestinal diseases
Year 2019
Links Pubmed DOI PubMed Central www.cochranelibrary.com
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor approved in Japan for the treatment of ulcerative colitis (UC). Differences in the safety profile of tofacitinib in Japanese patients versus the global population, such as a higher risk of herpes zoster, have been reported. Objectives: We conducted post hoc analyses of tofacitinib treatment in Japanese patients with moderate-to-severe UC in two global phase III studies. Methods: In OCTAVE Induction 1 (NCT01465763), 62 patients were randomized to placebo or tofacitinib 10 mg twice daily (b.i.d.). In OCTAVE Sustain (NCT01458574), 39 patients with clinical response in OCTAVE Induction 1 were re-randomized to placebo, tofacitinib 5 mg, or 10 mg b.i.d. Efficacy endpoints included: remission (primary endpoint; total Mayo score ≤2; no individual subscore >1; rectal bleeding subscore 0); mucosal healing (Mayo endoscopic subscore ≤1); clinical response (≥30% and ≥3-point decrease from induction study baseline total Mayo score; decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1). Adverse events (AEs) and clinical laboratory parameters were recorded. Results: At week 8 of OCTAVE Induction 1, 22.4% of patients achieved remission with tofacitinib (placebo, 7.7%). At week 52 of OCTAVE Sustain, 31.3% and 66.7% of patients receiving tofacitinib 5 and 10 mg b.i.d., respectively, achieved remission (placebo, 9.1%). The occurrence of AEs or serious AEs in Japanese patients was generally similar to that in the global study population, with no new or unexpected safety risks observed. Conclusions: Although patient numbers were small, tofacitinib demonstrated numerically greater efficacy versus placebo among Japanese patients in OCTAVE Induction 1 and OCTAVE Sustain, with a safety profile consistent with that of the global study population.

Primary study

Unclassified

Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme.

Giornale Alimentary pharmacology & therapeutics
Year 2019
Links Pubmed DOI PubMed Central
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BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). AIM: To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme. METHODS: DVT and PE were evaluated from one phase 2 and two phase 3 induction studies, one phase 3 maintenance study and an ongoing, open-label, long-term extension (OLE) study (September 2018 datacut). Data were analysed in induction, maintenance and overall (patients receiving ≥ 1 dose of tofacitinib 5 or 10 mg b.d. in any phase 2, 3 or OLE study) cohorts. RESULTS: 1157 patients (2404 patient-years' exposure; ≤ 6.1 years' tofacitinib treatment) were evaluated in the overall cohort. In induction, one placebo-treated patient had DVT and one had PE; no tofacitinib-treated patients had DVT/PE. In maintenance, one placebo-treated patient had DVT and one had PE; no tofacitinib-treated patients had DVT/PE. In the overall cohort, one patient had DVT (incidence rate [patients with events/100 patient-years; 95% CI]: 0.04 [0.00-0.23]); four had PE (0.16 [0.04-0.41]); all received predominant dose tofacitinib 10 mg b.d.; all had venous thromboembolism risk factors alongside UC. CONCLUSIONS: In this post hoc analysis of patients with UC, during tofacitinib exposure, one patient had DVT and four had PE, all during the OLE study, on predominant dose 10 mg b.d. (83% of overall cohort patients received predominant dose 10 mg b.d.) with venous thromboembolism risk factors. This analysis is limited by small sample size and limited drug exposure; further studies are needed. ClinicalTrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Primary study

Unclassified

Tofacitinib for the treatment of ulcerative colitis: Up to 5.4 years of safety Da ta from global clinical trials

Giornale Journal of Crohn's and Colitis
Year 2019
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Background: Tofacitinib is an oral, small-molecule Janus kinase inhibitor approved in several countries for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib as UC induction and maintenance therapy were evaluated in Phase (P) 21 and P32 randomised, placebo-controlled studies, and in an ongoing, openlabel, long-term extension (OLE) study.3 We report up Da ted tofacitinib safety analyses from the UC programme, with exposure up to 5.4 years. Methods: Patients who received placebo, tofacitinib 5 or 10 mg twice Da ily (BID) were analysed as two cohorts: Maintenance (P3 maintenance, n = 592) and Overall (patients receiving tofacitinib 5 or 10 mg BID in P2, P3 or the OLE study, n = 1157; 2050.5 patientyears' exposure; Da ta at November 2017). Proportions and incidence rates (IR; unique patients with events per 100 patient-years) were evaluated for adverse events (AEs) of special interest. Opportunistic infections, malignancies, major adverse cardiovascular events (MACE) and gastrointestinal perforations were reviewed by independent adjudication committees. Results in the overall Ccohort based on the previous December 2016 Da ta cut are presented for context. Results: In total, 1157 patients received ≥1 dose of tofacitinib 5 or 10 mg BID. Demographics and disease characteristics were generally similar among treatment groups across cohorts. For the Overall Cohort, most patients (n = 956, 83%) received an average tofacitinib dose of 10 mg BID. IR for AEs of special interest were: death, 0.2; serious infection, 1.9; herpes zoster, 3.8; opportunistic infection, 1.2; malignancy (excluding non-melanoma skin cancer [NMSC]), 0.6; NMSC, 0.8; MACE, 0.3; and gastrointestinal perforation, 0.1. Conclusions: The safety profile of tofacitinib in patients with UC was manageable, and similar to the tofacitinib rheumatoid arthritis programme and that of other UC therapies including biologics. IR for AEs of special interest did not increase with longer exposure relative to previously reported analyses from the OCTAVE programme. A dose-dependent risk of herpes zoster was observed.

Primary study

Unclassified

EFFICACY AND SAFETY OF OPEN-LABEL TREATMENT WITH TOFACITINIB 10 MG TWICE DAILY IN PATIENTS WITH ULCERATIVE COLITIS WITH CLINICAL RESPONSE, BUT NOT REMISSION, AFTER 52 WEEKS OF MAINTENANCE THERAPY: DATA FROM THE OCTAVE STUDIES

Giornale Gastroenterology
Year 2019
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor approved in several countries, including the US, for the treatment of ulcerative colitis (UC). We evaluated the efficacy and safety of tofacitinib in patients with clinical response, but not remission, after 52 weeks of maintenance therapy in the OCTAVE Sustain study, who subsequently received tofacitinib 10 mg twice daily (BID) in an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open; data as of November 2017).1 Methods: We evaluated clinical response, remission, and mucosal healing based on Mayo score (using local endoscopic reading and non-responder imputation) in patients with clinical response but not remission (based on central endoscopic reading at Week 52 of OCTAVE Sustain) who received tofacitinib 10 mg BID in the OLE study. Efficacy is reported at Month 2, Month 12, and Month 24 of the OLE by subgroups of prior tumor necrosis factor inhibitor (TNFi) failure (yes/no). Safety was assessed throughout the study. Results: 82 patients were included in the analysis (18 received placebo in OCTAVE Sustain; 28 received tofacitinib 5 mg BID; 35 received 10 mg BID; 1 patient was randomized into OCTAVE Sustain in error and received 10 mg BID in the OLE). 38/82 (46.3%) had prior TNFi failure per induction baseline. Clinical response at Month 24 was maintained by 69.5% (41/59), 65.4% (17/26), and 72.7% (24/33) of patients overall, and with and without prior TNFi failure, respectively. By Month 2, the proportion of patients who had improved to remission, overall and for patients with and without prior TNFi failure, was 58.5% (48/82), 60.5% (23/38), and 56.8% (25/44), respectively. Month 2 remission rates were 77.8% (14/18) for patients who had received placebo in OCTAVE Sustain, 57.1% (16/28) for patients who had received 5 mg BID, and 50.0% (18/36) for patients who had received 10 mg BID (Figure). A summary of safety in the OLE clinical responder subpopulation is presented (Table). Conclusion: Over 50% of patients with UC who completed OCTAVE Sustain as clinical responders improved to remission within 2 months of receiving 10 mg BID in the OLE study. Efficacy was observed regardless of prior TNFi failure status. No new safety concerns associated with tofacitinib emerged with regard to the overall study population.1 Reference: 1. Lichtenstein GR et al. Am J Gastroenterol 2017;112(S1):Abstract 714. [Figure Presented] [Table Presented]

Primary study

Unclassified

ANALYSIS OF THE IMPACT OF BODY MASS INDEX ON EFFICACY AND SAFETY IN THE TOFACITINIB OCTAVE ULCERATIVE COLITIS PROGRAM

Giornale Gastroenterology
Year 2019
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Background: High body mass index (BMI) can be associated with increased risk of treatment failure in biologic-treated patients with ulcerative colitis (UC).1 Tofacitinib is an oral, small molecule JAK inhibitor approved in several countries, including the US, for the treatment of UC. We present analysis of BMI effect on tofacitinib efficacy and safety in the tofacitinib UC clinical program. Methods: Data from two identical, 8-week induction studies (OCTAVE Induction 1 & 2, NCT01465763 & NCT01458951)2 and a 52-week maintenance study (OCTAVE Sustain, NCT01458574)2 were analyzed. Patients received placebo, tofacitinib 5 or 10 mg twice daily (BID). Patients were stratified by BMI <25, 25?<30, or ≥30 for analysis at Week 8 (OCTAVE Induction 1&2) and Week 52 (OCTAVE Sustain) for efficacy endpoints remission, clinical response, and mucosal healing, and for safety outcomes including infections. Results: Patient demographics and baseline characteristics were similar for placebo and tofacitinib groups. The majority of patients in each group had BMI <25 (Table). In OCTAVE Induction 1 & 2 and OCTAVE Sustain, tofacitinib treated-patients had a gradual increase in body weight and BMI over time vs placebo. In OCTAVE Induction 1 & 2, for tofacitinib 10 mg BID at Week 8, patients with BMI <25 had numerically higher proportions of remission vs other BMI groups. The proportion of patients with mucosal healing was lower in BMI ≥30. Clinical response was similar in all BMI groups. At OCTAVE Sustain Week 52, for tofacitinib 5 mg BID, BMI 25?<30 had the highest proportions of remission and mucosal healing; BMI ≥30 had the highest proportion of sustained steroid-free remission and the lowest proportion for mucosal healing and clinical response, vs other BMI groups. Clinical response was similar for all BMI groups. In OCTAVE Sustain, for tofacitinib 10 mg BID, BMI ≥30 had the highest proportions of remission, sustained steroid-free remission, mucosal healing, and clinical response. For tofacitinib patients in OCTAVE Induction 1 & 2, opportunistic infections were rare; proportions were similar across BMI groups. BMI stratification for infections and serious infections was not available. In OCTAVE Sustain, for tofacitinib 5 and 10 mg BID, infections were numerically higher for BMI 25?<30 vs others. There were few opportunistic or serious infections, and proportions were similar among subgroups. Conclusion: The majority of patients with UC in the OCTAVE program had BMI <25. In subgroup analyses by BMI, patients with high BMI receiving tofacitinib did not demonstrate lower efficacy endpoints or greater infection rates. However, limitations include low patient numbers in the BMI ≥30 group and rare opportunistic/serious infection events. References: 1. Kurnool et al. Aliment Pharmacol Ther 2018;47:1472-9. 2. Sandborn et al. N Engl J Med 2017;376:1723-36. [Table Presented]

Primary study

Unclassified

Tofacitinib efficacy in patients with moderate to severe ulcerative colitis: Aubgroup analyses of octave induction 1 & 2 and octave sustain by 5-aminosalicylates use

Giornale American Journal of Gastroenterology
Year 2019
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INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib were demonstrated in 3 Phase 3 trials (OCTAVE Induction 1 & 2, NCT01465763 & NCT01458951; OCTAVE Sustain, NCT01458574) in patients (pts) with moderate to severe UC (1). In this post-hoc analysis, we explored tofacitinib efficacy for pts with (c5-ASA) and without (n5-ASA) concomitant 5-aminosalicylates use. METHODS: In OCTAVE Induction 1 & 2, pts received placebo (PBO) or tofacitinib 10 mg twice daily (BID) for 8 weeks; clinical responders were re-randomized into OCTAVE Sustain for 52 weeks and received PBO, tofacitinib 5 or 10 mg BID. c5-ASA were permitted at entry, provided doses were stable for ≥4 weeks prior to and during the trials. Remission and mucosal healing were summarized at Week 8 (OCTAVE Induction 1 & 2) and Week 52 (OCTAVE Sustain) by c5-ASA status. Generalized linear models were used to compare adjusted treatment effects between 5-ASA subgroups (Tables 1 and 2). RESULTS: A smaller proportion of c5-ASA pts had prior tumor necrosis factor inhibitor (TNFi) and immunosuppressant failure versus n5-ASA pts, at baseline of OCTAVE Induction and OCTAVE Sustain (OCTAVE Induction 1 & 2: TNFi failure, 42.7% vs 74.5%; immunosuppressant failure, 69.4% vs 78.3%; OCTAVE Sustain: TNFi failure, 36% vs 70%; immunosuppressant failure, 67.9% vs 80%). For both the 5-ASA subgroups, a higher proportion of tofacitinib-treated pts achieved efficacy endpoints, versus PBO-treated pts, at Week 8 of OCTAVE Induction 1 & 2 and Week 52 of OCTAVE Sustain (Tables 1 and 2). Without controlling for baseline variables, higher treatment effects were observed within the c5-ASA subgroup versus the n5-ASA subgroup. When controlled for prior TNFi and immunosuppressant failure (and baseline remission status in OCTAVE Sustain), the differences were not statistically significant in treatment effects between the 5-ASA subgroups in terms of adjusted odds ratios (Tables 1 and 2). CONCLUSION: When controlling for prior UC treatment status, efficacy of tofacitinib, based on adjusted odds ratios, was similar regardless of 5-ASA status. These post-hoc analyses were not intended to evaluate incremental benefit of 5-ASA as combination therapy for tofacitinib. (Table Presented).

Unclassified

An Update on the Analysis of Non-Melanoma Skin Cancer in the Tofacitinib Ulcerative Colitis Clinical Program as of May 2019

Giornale American Journal of Gastroenterology
Year 2020
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INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We present an updated [1] analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical program as of May 2019. METHODS: NMSC events were evaluated from 3 randomized, placebo-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951] and 1 maintenance P3 study [NCT01458574]) and an ongoing, open-label, long-term extension (OLE) study (NCT01470612). Three cohorts were analyzed: Induction (P3 induction studies), Maintenance (P3 maintenance study), and Overall (patients [pts] receiving tofacitinib 5 or 10 mg twice daily [BID] in P3 or OLE studies). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose < 15 mg or $ 15 mg, respectively (82.4% of pts assigned PD 10 mg BID). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for NMSC. A Cox proportional hazards model was used for risk factor analysis. RESULTS: 1,124 pts were evaluated for NMSC (2,576.4 PY of tofacitinib exposure; # 6.8 years of treatment). NMSC events in the Induction and Maintenance Cohorts were previously reported (Table) [1]. NMSC occurred in 19 Overall Cohort pts (IR 0.73 [95% confidence interval (CI) 0.44, 1.13]; PD tofacitinib 5 mg BID, n = 3, IR 0.45 [0.09, 1.30]; PD tofacitinib 10 mg BID, n = 16, IR 0.82 [0.47, 1.34]) (Table); no new cases since Sep 2018 [1]. No NMSC was metastatic or led to discontinuation. Prior NMSC (hazard ratio [HR] 9.09 [95% CI 2.98, 27.73]), prior tumor necrosis factor inhibitor (TNFi) failure (HR 3.32 [1.08, 10.20]), and age (per 10-year increase, HR 2.03 [1.37, 3.02]) were significant risk factors for NMSC. CONCLUSION: NMSC events were infrequent with tofacitinib treatment and more likely to occur in pts with prior NMSC, prior TNFi failure, and with increasing age - known NMSC risk factors [2]. Dose dependency of NMSC IR could not be concluded here, as dose changes were permitted. NMSC IRs were similar to those previously reported in the tofacitinib UC clinical program [1] and in pts with UC treated with biologics [3].

Primary study

Unclassified

Association between Duration of Latest Flare before Induction Treatment with Tofacitinib and Efficacy Outcomes in Patients with Ulcerative Colitis

Giornale American Journal of Gastroenterology
Year 2020
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INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. The duration of active disease prior to starting treatment may impact treatment effects. We evaluated the association between duration of the latest flare before starting tofacitinib therapy and efficacy outcomes in the tofacitinib UC clinical program. METHODS: Patients (pts) received tofacitinib 10 mg twice daily (BID) or placebo in OCTAVE Induction 1&2 (NCT01465763; NCT01458951) and responders received tofacitinib 5 or 10 mg BID or placebo during OCTAVE Sustain (final efficacy assessment at Wk52; NCT01458574). Pts were stratified by UC flare duration (ie duration of active disease; <3 and ≥3 mo) prior to enrollment in OCTAVE Induction 1&2. Differences between the change from baseline Mayo stool frequency subscore (SF), Mayo rectal bleeding subscore (RB), and partial Mayo score (PMS) at Wk2 of OCTAVE Induction 1&2 between flare duration groups were assessed using ANOVA. Associations between flare duration and efficacy endpoints were assessed using the Cochran-Mantel-Haenszel chi-squared test. RESULTS: Among the 905 pts who received tofacitinib 10 mg BID in OCTAVE Induction 1&2, 443 and 462 pts had flare durations of <3 and ≥3 mo, respectively. A higher proportion of pts with ≥3 mo flare duration had pancolitis (53.7%) vs pts with <3 mo flare duration (48.8%); this was also true for prior TNFi failure (60% vs 42%). Mean baseline total Mayo score in both groups was 9.0. In OCTAVE Induction 1&2, a numerically higher proportion of pts with <3 mo flare duration met efficacy endpoints vs pts with ≥3 mo, with a significant association. Changes from baseline SF, RB, and PMS at Wk2 were significantly greater in pts with <3 vs ≥3 mo flare duration. Among pts who received tofacitinib 5 mg BID in OCTAVE Sustain, a numerically higher proportion with <3 mo flare duration met efficacy endpoints at Wk52 vs pts with ≥3 mo; similar proportions of tofacitinib 10 mg BID-treated pts across flare duration groups met efficacy endpoints (Table). CONCLUSION: These post hoc analyses showed that latest flare duration was significantly associated with the efficacy of tofacitinib 10 mg BID induction therapy at Wk8, with shorter duration (,3 mo) associated with greater efficacy, potentially implying that a timely intervention during a new flare may, as expected, lead to a better outcome for induction. During maintenance, flare duration had less impact on efficacy, with similar responses at Wk52 between tofacitinib 10 mg BID groups.

Unclassified

684 INCIDENCE OF VENOUS THROMBOEMBOLIC EVENTS IN PATIENTS WITH ULCERATIVE COLITIS TREATED WITH TOFACITINIB IN THE ULCERATIVE COLITIS CLINICAL DEVELOPMENT PROGRAM: AN UPDATE AS OF MAY 2019

Giornale Gastroenterology
Year 2020
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. In data analyzed from a large, ongoing (data cut-off Feb 2019a; database unlocked; data may be subject to change), post-authorization safety study in patients (pts) with rheumatoid arthritis (≥50 yrs; ≥1 cardiovascular risk factor; enrolled on a stable dose of methotrexate), the incidence rate (IR; unique pts with events per 100 pt-yrs [PY]) of pulmonary embolism (PE) in pts treated with tofacitinib 10 mg BID (0.54 [95% confidence interval] 0.32, 0.87]) was numerically higher compared with 5 mg BID (0.27 [0.12, 0.52]) and statistically different from tumor necrosis factor inhibitors (0.09 [0.02, 0.26]). Corresponding IRs for deep vein thrombosis (DVT) were 0.38 (0.20, 0.67), 0.30 (0.14, 0.55), and 0.18 (0.07, 0.39).1 UC is a known risk factor for DVT and PE. Subsequently, updates to the tofacitinib prescribing information have been made, with venous thromboembolism added as a warning and adverse drug reaction. Here, we provide an update on the incidence of DVT and PE in the tofacitinib UC clinical development program, as of May 2019.2 Methods: DVT and PE events were evaluated from 4 randomized placebo-controlled studies (Phase [P]2/P3 induction studies and P3 maintenance study) and an ongoing, open-label, long-term extension (OLE) study.3,4 Three cohorts were analyzed: Induction, Maintenance, and Overall (pts receiving tofacitinib 5 or 10 mg BID in P2/P3/OLE studies; pts were categorized based on the average daily dose: predominant dose [PD] 5 or 10 mg BID). Results: 1,157 pts were evaluated for DVT and PE, with 2,581 PY of tofacitinib exposure and up to 6.8 yrs’ treatment. In the Induction and Maintenance Cohorts, 2 pts had DVT and 2 had PE; all were receiving placebo at the time of event (Tables). In the Overall Cohort, DVT occurred in 1 pt and PE in 4 pts during the OLE study, after ≥7 months of treatment; all pts had received PD 10 mg BID (83% of the Overall Cohort received PD 10 mg BID) and had other (non-UC) risk factors for venous thrombosis (Tables). Conclusion: IRs in the Overall Cohort have remained stable since the previously reported data cut.2 All of the events in tofacitinib pts (PD 10 mg BID) occurred during the OLE study and all had other (non-UC) risk factors for thromboembolic events. This analysis is limited by sample size and duration of drug exposure; further study is needed. aThe tofacitinib 10 mg BID arm of the study was discontinued in Feb 2019 and pts who re-consented and chose to remain in the study were switched to the 5 mg BID arm. References: 1. https://www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedure-annex-iii_en.pdf 2. Sandborn WJ et al. Aliment Pharmacol Ther 2019;50:1068-76 3. Sandborn WJ et al. N Engl J Med 2017;376:1723-36 4. Lichtenstein GR et al. Am J Gastroenterol 2019;114:Abstract 704

Primary study

Unclassified

EVALUATION OF THE EFFICACY OF TOFACITINIB IN PATIENTS WITH ULCERATIVE COLITIS UTILIZING THE MODIFIED MAYO SCORE: DATA FROM THE OCTAVE PROGRAM

Giornale Gastroenterology
Year 2020
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Introduction: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Safety and efficacy of tofacitinib were evaluated in 2 Phase 3 induction studies (OCTAVE Induction 1 & 2, & ), a 52-week (wk), Phase 3 maintenance study (OCTAVE Sustain, NCT01458574),1 and an ongoing open-label, long-term extension study (NCT01470612).2 In these trials, endpoint definitions were based on the conventional Mayo score comprising 4 subscores (stool frequency, rectal bleeding, endoscopic findings, Physician Global Assessment [PGA]). The FDA recommend the use of a modified Mayo (mMayo) score in which the PGA subscore is omitted (a subjective measure, and a recognized Mayo score limitation) as an endpoint measure for UC clinical trials.3 In this post hoc analysis, we assessed the efficacy of tofacitinib using endpoint definitions based on mMayo score. Methods: In OCTAVE Induction 1 & 2, patients received placebo or tofacitinib 10 mg twice daily (BID) for 8 wks; clinical responders were re-randomized into OCTAVE Sustain for 52 wks and received placebo, tofacitinib 5 or 10 mg BID. Trial endpoints included remission, symptomatic remission, and clinical remission (Table), assessed at Wk 8 in OCTAVE Induction 1 & 2 and Wk 52 in OCTAVE Sustain. Treatment effects (ie difference from placebo) using mMayo and Mayo scores were evaluated and compared. Results: In OCTAVE Induction 1 & 2, numerically more patients achieved remission using the mMayo score (7.7% placebo; 24.8% tofacitinib 10 mg BID) compared with the Mayo score (6.0% placebo; 17.6% tofacitinib 10 mg BID), with a greater difference from placebo with mMayo scores (Table). Likewise, the proportion of patients achieving clinical remission was numerically greater with mMayo scores (7.7% placebo; 25.0% tofacitinib 10 mg BID) compared with Mayo scores (6.0% placebo; 17.7% tofacitinib 10 mg BID), whereas the same proportion of patients achieved symptomatic remission with both scores. The same trends were noted in OCTAVE Sustain, with numerically more patients in placebo and tofacitinib groups achieving remission and clinical remission using mMayo scores compared with Mayo scores (Table), and symptomatic remission achieved by the same proportion of patients with both scores. Conclusion: In this post hoc analysis, a statistically significant effect of tofacitinib treatment vs placebo was demonstrated across endpoints based on the mMayo score, agreeing with previously reported data based on the Mayo score.1 Treatment effect sizes for endpoints based on the mMayo score without PGA were the same or numerically greater than corresponding endpoints based on the Mayo score. 1. Sandborn et al. N Engl J Med 2017;376:1723-36. 2. Lichtenstein et al. Am J Gastroenterol 2018;113(S1):571. 3. FDA. 2016. [Formula presented]

Unclassified

Tofacitinib for the Treatment of Ulcerative Colitis: Up to 6.8 Years of Safety Data from Global Clinical Trials

Giornale American Journal of Gastroenterology
Year 2020
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INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Efficacy and safety of tofacitinib were evaluated in randomized, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, and in an ongoing, open-label, long-term extension (OLE) study (NCT01470612) (1-3). We report updated tofacitinib safety analyses from the tofacitinib UC clinical program, with exposure up to 6.8 years. METHODS: Two cohorts were analyzed: P3 Maintenance (n = 592; patients [pts] receiving placebo, tofacitinib 5 or 10 mg twice daily [BID]) and Overall (n = 1,157; pts receiving tofacitinib 5 or 10 mg BID in P2/P3/OLE studies; data as of May 2019, database not locked). Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for adverse events (AEs) of special interest. Opportunistic infections (OIs), malignancies, major adverse cardiovascular events (MACE), and gastrointestinal (GI) perforations were reviewed by independent adjudication committees. RESULTS: Demographics, clinical characteristics, and safety data are shown in the table. In the Overall Cohort, 1,157 pts received $ 1 dose of tofacitinib 5 or 10 mg BID; most pts (n = 959, 83%) received an average dose of 10 mg BID. Median treatment duration was 623 (range 1-2,494) days (2,581.3 PY of exposure). IRs (95% confidence interval) for AEs of special interest were: deaths, 0.19 (0.06, 0.44); serious infections, 1.70 (1.24, 2.27); herpes zoster (non-serious and serious), 3.48 (2.79, 4.30); OIs, 1.07 (0.71, 1.55); malignancies (excl. non-melanoma skin cancer [NMSC]), 0.75 (0.46, 1.16); NMSC, 0.73 (0.44, 1.13); MACE, 0.26 (0.11, 0.54); deep vein thrombosis, 0.04 (0.00, 0.21); pulmonary embolism, 0.15 (0.04, 0.38); GI perforations, 0.11 (0.02, 0.33). Results in the Overall Cohort as per the previous Nov 2017 data cut are presented for context (4). CONCLUSION: The safety profile of tofacitinib in pts with UC was manageable and consistent with that of other UC therapies incl. biologics. Overall, IRs for AEs of interest have generally remained stable in the tofacitinib UC clinical program over an extended period of time (up to 6.8 years).

Primary study

Unclassified

IMPACT OF DISEASE DURATION ON TOFACITINIB EFFICACY IN PATIENTS WITH ULCERATIVE COLITIS

Giornale Gastroenterology
Year 2020
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Safety and efficacy of tofacitinib in patients with UC were evaluated in two Phase 3 induction studies (OCTAVE Induction 1&2; NCT01465763, NCT01458951), a 52-week, Phase 3 maintenance study (OCTAVE Sustain, NCT01458574),1 and an ongoing, open-label, long-term extension study (NCT01470612).2 We evaluated the impact of disease duration on tofacitinib efficacy in the OCTAVE trials. Methods: Patients received tofacitinib 10 mg twice daily (BID) or placebo in OCTAVE Induction 1&2, and responders at Week 8 were eligible to receive tofacitinib 5 or 10 mg BID or placebo during OCTAVE Sustain (final efficacy assessment at Week 52). Non-responders from OCTAVE Induction 1&2 and completers/treatment failures from OCTAVE Sustain could enter the OLE study. In the OLE study, patients who did not show clinical response to 8 weeks of tofacitinib 10 mg BID in OCTAVE Induction 1&2 (induction non-responders [IndNR]) received an additional 8 weeks of tofacitinib 10 mg BID; all patients underwent endoscopy at Month 2 (data as of September 2018). Patients were stratified by UC disease duration (<3, 3–6, and?>6 years) at OCTAVE Induction 1&2 baseline (ie prior to study treatment). Associations between disease duration category and efficacy endpoints were assessed using the Cochran-Mantel-Haenszel chi-squared test. Results: Among patients who received tofacitinib 10 mg BID in OCTAVE Induction 1&2, remission and mucosal healing rates at Week 8 were numerically higher in those with shorter disease duration than those with longer disease duration, but associations were not statistically significant (Table). Clinical response rates were similar across disease duration categories. At Week 52 of OCTAVE Sustain, remission and mucosal healing rates were highest in patients with the shortest disease duration (<3 years; Table). Among IndNR, the proportions of patients achieving efficacy endpoints at Month 2 of the OLE study were lowest in those with disease duration <3 years, but associations were not statistically significant (Table). Conclusion: In general, disease duration did not impact tofacitinib efficacy. Patients diagnosed with UC <3 years prior to starting tofacitinib treatment were numerically more likely to achieve remission and mucosal healing in induction and maintenance trials than those with longer disease duration, but the associations were not statistically significant. These analyses are post hoc and limited by the small sample size, and further data are needed to understand whether disease duration may have an impact on the response to tofacitinib treatment. References: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36 2. Lichtenstein GR et al. Am J Gastroenterol 2019;114:Abstract 704

Primary study

Unclassified

TIME TO LOSS OF EFFICACY AMONG PATIENTS IN REMISSION FOLLOWING INDUCTION TREATMENT WITH TOFACITINIB 10 MG BID WHO REDUCED TOFACITINIB DOSE OR DISCONTINUED TOFACITINIB IN OCTAVE SUSTAIN

Giornale Gastroenterology
Year 2020
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. Safety and efficacy of tofacitinib were evaluated in two Phase 3 induction studies (OCTAVE Induction 1&2; NCT01465763, NCT01458951), a 52-week, Phase 3 maintenance study (OCTAVE Sustain, NCT01458574), and an ongoing, open-label, long-term extension study (NCT01470612).1,2 Here, we assess time to treatment failure among patients in remission at the end of OCTAVE Induction 1&2 who enrolled in OCTAVE Sustain. Methods: In OCTAVE Induction 1&2, patients received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks; clinical responders were re-randomized to placebo, tofacitinib 5 or 10 mg BID in OCTAVE Sustain for 52 weeks. Kaplan-Meier method was used to estimate median time to treatment failure (withdrawal due to insufficient clinical response) in patients who received 10 mg BID in induction studies and entered OCTAVE Sustain in remission (a total Mayo score of ≤2 with no individual subscore?>1, and a rectal bleeding subscore of 0). Treatment failure: a ≥3-point increase from baseline total Mayo score, plus a ≥1-point increase in rectal bleeding subscore and endoscopic subscore (centrally read), and an absolute endoscopic subscore of ≥2 after ≥8 weeks of maintenance therapy. Results: Following induction, 156 patients in remission entered OCTAVE Sustain and received tofacitinib 5 mg BID (N=57) or 10 mg BID (N=50), or placebo (N=49). Estimated treatment failure rates are reported in the table. At Week 52, Kaplan-Meier rates of treatment failure were higher in patients who switched to placebo (81.8% [95% confidence interval 67.0, 90.4]) vs those who continued to receive tofacitinib 10 mg BID (25.6% [14.2, 38.6]) or reduced their dose to 5 mg BID (34.4% [21.8, 47.3]). Median time to treatment failure was 169 days for placebo and?>52 weeks for tofacitinib 5 and 10 mg BID (due to the low number of treatment failure events, exact median time to treatment failure was not available for tofacitinib 5 or 10 mg BID). Conclusion: For patients in remission following 8 weeks of induction treatment with tofacitinib 10 mg BID, median time to treatment failure for those who continued tofacitinib treatment (5 or 10 mg BID) was?>52 weeks. After treatment interruption (remission patients who were re-randomized to placebo), median time to treatment failure was 169 days; this was similar to previously published time-to-treatment-failure data for patients with clinical response (including remission) following 8 weeks of induction treatment with tofacitinib who were re-randomized to placebo.3 References: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36 2. Lichtenstein GR et al. Am J Gastroenterol 2019;114:Abstract 704 3. Dubinsky MC et al. Am J Gastroenterol 2018;113:Abstract 725

Unclassified

Tofacitinib Treatment Is Associated With Modest and Reversible Increases in Serum Lipids in Patients With Ulcerative Colitis.

Giornale Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Year 2020
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BACKGROUND & AIMS: Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We analyzed inflammation, lipid concentrations, and incidence rates of major adverse cardiovascular (CV) events (MACEs) in patients who received tofacitinib in worldwide studies. METHODS: We collected data from 1157 patients who participated in 3 8-week induction studies (1 phase-2 study and 2 phase-3 studies; patients received tofacitinib 10 mg twice daily or placebo), a 52-week phase-3 maintenance study of responders (patients received tofacitinib 5 or 10 mg twice daily or placebo), and an ongoing long-term extension study of patients who did and did not respond to induction or maintenance therapy (patients received tofacitinib 5 or 10 mg twice daily). Lipid concentrations were assessed from induction baseline to week 61 (week 52 of maintenance therapy). We calculated MACE incidence rates (patients with ≥1 event per 100 patient-years of exposure) and Reynolds risk score (RRS; a composite score used to determine CV risk) for patients given tofacitinib vs placebo. RESULTS: The mean RRS was <5% at baseline and week 8 of treatment with tofacitinib. At week 8, there were greater increases from baseline in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol in patients given tofacitinib compared with placebo. There were correlations between reduced levels of high-sensitivity C-reactive protein and increased serum concentrations of lipid in patients given tofacitinib or placebo (P < .001). Lipid concentrations were increased in patients given tofacitinib vs patients given placebo through week 61. Overall, ratios of low-density lipoprotein cholesterol to HDL-c and total cholesterol to HDL-c did not change significantly over the 61-week period. Four MACEs were reported; the incidence rate was 0.24 (95% CI, 0.07-0.62) and 3 of these patients had 4 or more CV risk factors. CONCLUSIONS: In an analysis of data from 5 trials of patients with UC who received tofacitinib, we found reversible increases in lipids with treatment and inverse correlations with reduced levels of high-sensitivity C-reactive protein. We did not find clinically meaningful changes in lipid ratios or RRS. MACEs were infrequent and not dose-related. Clinicaltrials.gov: A3921063 (NCT00787202); OCTAVE Induction 1 (NCT01465763); OCTAVE Induction 2 (NCT01458951); OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612).

Primary study

Unclassified

THE EFFECT OF TOFACITINIB ON SERUM LIPIDS AND CARDIOVASCULAR SAFETY IN PATIENTS WITH ULCERATIVE COLITIS - UPDATED RESULTS FROM THE TOFACITINIB ULCERATIVE COLITIS CLINICAL PROGRAM

Giornale Gastroenterology
Year 2020
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). In the tofacitinib UC clinical program, the majority of patients did not have cardiovascular risk factors at baseline, and increases in lipid levels occurred primarily during induction and remained elevated to Week 61 during maintenance; lipid ratios were relatively unchanged.1 Here, we present updated results of lipid levels in the ongoing, open-label, long-term extension (OLE) study (NCT01470612) and major adverse cardiovascular events (MACE) in the Phase 3/OLE tofacitinib UC clinical program. Methods: Lipid levels were assessed at multiple time points, and changes from OLE study baseline to Month 48 in the OLE study were evaluated. Lipid-lowering agent (LLA) use (proportion of patients) and adjudicated MACE (proportion of patients and incidence rate [IR; unique patients with events per 100 patient-years] with 95% confidence interval [CI]) were reported in patients with UC in two Phase 3, 8-week, placebo-controlled induction studies (OCTAVE Induction 1&2; NCT01465763, NCT01458951), a Phase 3, 52-week, placebo-controlled maintenance study (OCTAVE Sustain; NCT01458574), and the OLE study (data as of May 2019; database not locked). Results: No major changes in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides, LDL-c:HDL-c, and TC:HDL-c from OLE study baseline were observed at Month 48 of the OLE study (Table). In the Phase 3/OLE program (N=1,124), 7.7% of patients had a new LLA added and 1.9% of patients had their LLA dose increased. Seven MACE were reported (IR 0.26; 95% CI 0.11, 0.54; 2,654.66 patient-years); the IR has remained stable since December 2016 (IR 0.24; 95% CI 0.07, 0.62).1 Reported MACE were one each of myocardial infarction, acute myocardial infarction, acute coronary syndrome, cerebrovascular accident, hemorrhagic stroke, cerebellar hemorrhage, and aortic dissection. Both myocardial infarction events and the acute coronary syndrome event led to temporary tofacitinib discontinuation; the hemorrhagic stroke, cerebrovascular accident, and cerebellar hemorrhage led to permanent tofacitinib discontinuation; and the aortic dissection resulted in death. Of the seven patients with MACE, five had cardiovascular risk factors at baseline. Conclusion: At Month 48 of the OLE study, lipid levels and ratios remained generally unchanged from OLE study baseline following tofacitinib treatment. MACE were infrequent, with the IR remaining stable since the previous report.1 Limitations include low patient numbers and short tofacitinib exposure duration. Longer-term observation studies will further assess risk. Reference: 1. Sands BE et al. Clin Gastroenterol Hepatol 2019;Epub ahead of print

Primary study

Unclassified

Efficacy and Safety of Tofacitinib Retreatment for Ulcerative Colitis after Treatment Interruption: An Update of Results from the OCTAVE Clinical Trials

Giornale American Journal of Gastroenterology
Year 2020
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INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Patients (pts) may need to temporarily suspend tofacitinib treatment for several reasons, such as adverse events (AEs), pregnancy or surgery; thus, it is key to assess the efficacy/safety of retreatment after treatment interruption. METHODS: We provide an update (1) of tofacitinib retreatment efficacy and safety data after treatment interruption in the ongoing, open-label, long-term extension (OLE) study (NCT01470612; data as of May 2019, database not locked). We analyzed pts in the OLE study who had a clinical response after 8 wks of tofacitinib 10 mg twice daily (BID) in OCTAVE Induction 1&2 (NCT01465763; NCT01458951) then received placebo in OCTAVE Sustain (NCT01458574) and had treatment failure after Wk8 up to Wk52 and subsequently received tofacitinib 10 mg BID in the OLE study. Treatment failure was defined as a $ 3-point increase from OCTAVE Sustain baseline total Mayo score plus a $ 1-point increase in rectal bleeding subscore and endoscopic subscore (ES) and an absolute ES $ 2 points after $ 8 wks' treatment. We evaluated efficacy up to Month (Mo) 36 of the OLE study and AEs throughout the study. RESULTS: Of 917 pts treated for $ 2 mo in the OLE study, 100 entered the study with a clinical response to tofacitinib 10 mg BID in OCTAVE Induction 1 or 2 followed by treatment failure on placebo during OCTAVE Sustain; median time to treatment failure was 135 days. After receiving tofacitinib 10 mg BID in the OLE study, clinical response was recaptured at Mo2 in 74.3% (non-responder imputation and last observation carried forward [NRI-LOCF]) and 85.2% of pts (observed data; Table 1). At Mo 12, 24 and 36, 43.6%, 40.6% and 37.0% (NRI-LOCF) and 62.0%, 69.5% and 72.0% (observed data) of pts were in remission, respectively. In pts with prior TNFi failure, 80.4% had a clinical response at Mo 2 and 47.8%, 37.0% and 28.3% were in remission at Mo 12, 24 and 36 (NRI-LOCF), respectively. Corresponding observed data were 92.5%, 66.7%, 70.8% and 63.2%, respectively. Incidence rates for AEs are reported (Table 1). CONCLUSION: In this post hoc analysis, in pts with prior response to tofacitinib induction, retreatment with 10 mg BID after 8-52 wks' treatment interruption was efficacious and well-tolerated, with clinical response recaptured in the majority of pts by Mo 2 and in half of pts at Mo 36. The safety profile was generally consistent with that in the overall study population.

Primary study

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THE EFFECT OF TOFACITINIB ON EXTRAINTESTINAL MANIFESTATIONS AT BASELINE IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS IN THE OCTAVE PROGRAM

Giornale Gastroenterology
Year 2020
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Background: Extraintestinal manifestations (EIMs) occur in approximately one-third of patients (pts) with ulcerative colitis (UC).1 Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. The effect of tofacitinib on EIMs is currently unknown. We explore whether tofacitinib treatment impacts EIMs in pts with moderate to severe UC enrolled in the Phase 3 OCTAVE clinical program. Methods: We report data from 3 double-blind, placebo-controlled, Phase 3 studies in pts with moderate to severe UC: two 8-week (wk) induction studies (tofacitinib 10 mg twice daily [BID] or placebo; OCTAVE Induction 1&2, NCT01465763 and NCT01458951) and a 52-wk maintenance study (tofacitinib 5 or 10 mg BID or placebo; OCTAVE Sustain, NCT01458574). The frequency and proportion of predefined quiescent prior and active EIMs at baseline, and the change from baseline in EIMs at the end of the treatment period (Wk8 or Wk52), or at early termination, were evaluated. The predefined EIMs included arthritis but did not separate arthralgia. Results: Overall, 1,139 and 592 pts were randomized into OCTAVE Induction 1&2 and OCTAVE Sustain, of which 27.0% and 9.0% had a history of quiescent prior or active EIMs, respectively. At Wk8 of OCTAVE Induction 1&2, 4.6% of tofacitinib-treated pts and 5.3% of placebo-treated pts experienced a change (improvement, worsening, or new occurrence) from baseline in EIMs. At Wk52 of OCTAVE Sustain, 4.6%, 3.1%, and 7.3% of pts in the tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo groups experienced a change from baseline in EIMs, respectively. In OCTAVE Induction 1&2, the most frequent active EIMs at baseline were peripheral arthritis, sacroiliitis, and oral ulcer/stomatitis (Table). Similar proportions of pts in each treatment group with active baseline peripheral arthritis experienced no change or an improvement from baseline at Wk8 (Table). Three tofacitinib-treated pts experienced worsening symptoms compared with no placebo-treated pts. At OCTAVE Sustain baseline, 21 pts had active peripheral arthritis; the majority of these pts experienced no change in their peripheral arthritis at Wk52. Improved symptoms occurred in 2 tofacitinib-treated and no placebo-treated pts; worsened symptoms occurred in 2 placebo-treated and no tofacitinib-treated pts. Conclusion: In OCTAVE Induction 1&2 and OCTAVE Sustain, 27.0% and 9.0% of pts experienced EIMs at baseline, respectively. The most common active EIM was peripheral arthritis, for which the majority of pts in OCTAVE Induction 1&2 and OCTAVE Sustain reported either no change or improvement from baseline. These post hoc analyses should be interpreted with caution; they are limited by low pt numbers and a predefined EIM list. Additional studies are required. Reference: 1. Ungaro R et al. Lancet 2017;389:1756-70

Unclassified

Tofacitinib for the Treatment of Ulcerative Colitis: analysis of Infection Rates from the Ulcerative Colitis Clinical Programme

Giornale Journal of Crohn's & colitis
Year 2021
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BACKGROUND AND AIMS: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes. METHODS: Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib‐treated patients in induction, maintenance, or ongoing, open‐label, long‐term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient‐years] of serious infections [SIs], herpes zoster [HZ] [non‐serious and serious], and opportunistic infections [OIs] are reported [censored at time of event]. RESULTS: In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23‐7.00] for placebo and 1.35 [0.16‐4.87] and 0.64 [0.02‐3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02‐5.42], 2.05 [0.42‐6.00], and 6.64 [3.19‐12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non‐HZ OI IRs were 1.70 [1.24‐2.27], 3.48 [2.79‐4.30], and 0.15 [0.04‐0.38], respectively. No SIs resulted in death. CONCLUSIONS: During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non‐HZ OIs and viral infections were rare.

Unclassified

Agreement between local and central reading of endoscopic disease activity in ulcerative colitis: results from the tofacitinib OCTAVE trials

Giornale Alimentary pharmacology & therapeutics
Year 2021
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Background: Endoscopy is routine in trials of ulcerative colitis therapies. Aim: To investigate agreement between central and local Mayo endoscopic subscore (MES) reads in the OCTAVE programme. Methods: Flexible sigmoidoscopy was performed in tofacitinib induction (OCTAVE Induction 1&2, NCT01465763 and NCT01458951), maintenance (OCTAVE Sustain, NCT01458574) and open‐label, long‐term extension (OCTAVE Open, NCT01470612) studies. Kappa statistics and Bowker's tests evaluated agreement/disagreement between centrally and locally read MES, with potential determinants of differences analysed by logistic regression. Results: Moderate‐to‐substantial agreement was observed between central and local reads at screening (77.1% agreement; kappa 0.62 [95% confidence interval 0.59‐0.66]), OCTAVE Induction 1&2 week (Wk) 8 (63.8%; 0.62 [0.59‐0.66]), OCTAVE Sustain Wk 52 (55.6%; 0.56 [0.50‐0.62]) and for induction non‐responders at OCTAVE Open month 2 (59.9%; 0.54 [0.48‐0.60]). Where disagreements occurred, local reads were systematically lower than central reads at OCTAVE Induction 1&2 Wk 8, OCTAVE Sustain Wk 52 and OCTAVE Open month 2 (Bowker's P�<�0.0001); this difference was not observed at screening (P�=�0.0852). Using multivariable logistic regression, geographical region, C‐reactive protein (Wk 8), partial Mayo score (Wk 8) and prior tumour necrosis factor antagonist failure were associated with disparity at OCTAVE Induction 1&2 Wk 8 (P�<�0.05). In OCTAVE Induction 1&2 and OCTAVE Sustain, significantly higher proportions of patients endoscopic improvement, remission and endoscopic remission with tofacitinib vs placebo, using either central or local reads. Conclusion: Moderate‐to‐substantial agreement was observed between central and local endoscopic reads. Where disagreements occurred, local reads were systematically lower than central reads at most timepoints, suggesting potential bias. ClinicalTrials.gov identifier: NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Unclassified

Patient-reported outcome improvement with tofacitinib in the ulcerative colitis octave clinical program

Giornale American Journal of Gastroenterology
Year 2021
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Introduction: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. The OCTAVE clinical program included Phase 3 induction (OCTAVE Induction 1&2, NCT01465763 and NCT01458951) and maintenance (OCTAVE Sustain, NCT01458574) studies, and an open-label, long-term extension study (OCTAVE Open, NCT01470612).1,2 Stool frequency (SF) and rectal bleeding (RB) are important patient (pt)-reported outcomes (PROs) in measuring UC disease activity and treatment effect. Methods: This post hoc analysis reports long-term PRO measurements of RB and SF in pts from the OCTAVE clinical program. Analyses included pts from OCTAVE Induction 1&2, OCTAVE Sustain (responders from OCTAVE Induction 1&2), and OCTAVE Open (subpopulation in remission at Week [Wk]52 of OCTAVE Sustain, regardless of treatment). OCTAVE Open data from the final analyses (Aug 2020) are shown to Month (M)48. Endpoints included Mayo RB subscore (RBS)50, Mayo SF subscore (SFS)50 and ≤ 1, and partial Mayo score (PMS) remission (PMS ≤ 2 with no individual subscore> 1); analysis was descriptive (observed case). Results: After induction therapy, 62.8-64.0% of tofacitinib 10 mg BID-treated pts achieved RBS50 vs 37.0-42.9% of placebo (PBO)-treated pts, and 55.4-60.9% of tofacitinib 10 mg BID-treated pts achieved SFS ≤ 1 (21.7-23.6% achieved SFS50) vs 33.6-33.7% of PBO-treated pts (11.2-12.6% for SFS50). Among OCTAVE induction responders re-randomized to maintenance therapy, 85.2%, 92.0%, and 94.5% of pts had RBS50, 79.6%, 89.3%, and 88.2% had SFS ≤ 1, and 40.7%, 56.3%, and 51.2% had SFS50 at Wk52 of OCTAVE Sustain for PBO, tofacitinib 5 mg BID, and tofacitinib 10 mg BID, respectively. Among pts who entered OCTAVE Open in remission and who were assigned to tofacitinib 5 mg BID, 93.5%, 95.7%, and 66.3% of pts maintained or achieved RBS50, SFS ≤ 1, and SFS50, respectively, at M48 of OCTAVE Open. Additionally, 94.6% of these pts maintained PMS remission (which includes RBS and SFS) at M48. Conclusion: Most pts with UC demonstrated improvements in RBS and SFS after tofacitinib induction therapy. Among induction responders, the majority of pts maintained normalization or improvement in RB and/or SF in OCTAVE Sustain and up to M48 of OCTAVE Open. These data show robust and sustained improvement in key UC PROs with tofacitinib.

Primary study

Unclassified

Persistence of tofacitinib treatment in patients with ulcerative colitis who entered the open-label, long-term extension study, octave open in remission or with a clinical response

Giornale American Journal of Gastroenterology
Year 2021
Links DOI www.cochranelibrary.com
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Introduction: Drug survival in open-label, long-term extension (OLE) studies may provide important information on the long-term efficacy and tolerability of a therapy. Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Efficacy and safety were demonstrated in three Phase 3, randomized, PBO-controlled studies in patients (pts) with moderate to severe UC. A Phase 3, OLE study (OCTAVE Open, NCT01470612) included pts from OCTAVE Induction 1 & 2 and OCTAVE Sustain. Methods: Data on the persistence of tofacitinib treatment in the OLE study for pts who had a clinical response at Week (Wk) 52 of treatment with tofacitinib 5 or 10 mg BID, or PBO, in OCTAVE Sustain were evaluated. Data were analyzed for all responder pts and by remission status: responders who were also in remission (remitters; assigned to tofacitinib 5 mg BID per OLE study protocol), and responders who were not in remission (responders/non-remitters) at OLE baseline (assigned to tofacitinib 10 mg BID per OLE study protocol) (Figure 1). Duration of treatment in the OLE study varied by pt. Results: At baseline of the OLE study, there were 280 pts with a clinical response (all responders) which included 164 remitters and 116 responders/non-remitters who were treated for a maximum of 7 years in the OLE study (Table 1). Of these, 118 (42.1%) pts discontinued the OLE study (68/164 [41.5%] among remitters and 50/116 [43.1%] among responders/non-remitters) with a median time to discontinuation of 291 wks. Overall, the estimated 2-and 5-year tofacitinib persistence rates in the all-responder population were 73.9% and 54.5%, respectively. These rates were numerically higher in remitters (76.8% and 56.9%, respectively) vs responders/non-remitters (69.8% and 50.0%, respectively). During the OLE study, 43 (26.2%) remitters increased tofacitinib dose from 5 to 10 mg BID, and 15 (12.9%) responders/non-remitters decreased tofacitinib dose from 10 to 5 mg BID. Conclusion: With up to 7 years of follow-up, treatment persistence to tofacitinib was highest amongst pts who were responders/remitters compared with responders/non-remitters and the majority of pts continued to be on treatment at 5 years. Analyses are post hoc and limited by sample size. Further research will help to understand the reasons for continuation or discontinuation of tofacitinib treatment in pts with UC.

Unclassified

The impact of body mass index on efficacy and safety in the tofacitinib OCTAVE ulcerative colitis clinical programme.

Giornale Alimentary pharmacology & therapeutics
Year 2021
Links Pubmed DOI PubMed Central
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BACKGROUND: Obesity may affect efficacy and safety of biologic treatments for ulcerative colitis (UC). Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. AIMS: To assess efficacy and safety of tofacitinib in patients with UC, by baseline body mass index (BMI). METHODS: This post hoc analysis evaluated patients with UC receiving placebo or tofacitinib from the 8-week OCTAVE Induction 1 and 2 (NCT01465763, NCT01458951) and 52-week OCTAVE Sustain (NCT01458574) studies. Patients were stratified by BMI at OCTAVE Induction 1 and 2 baseline (<25, 25 to <30 and ≥30 kg/m2 ). Outcomes included remission, endoscopic improvement, clinical response, sustained steroid-free remission, Inflammatory Bowel Disease Questionnaire total score and Short Form-36 Health Survey scores. Adverse events were evaluated. RESULTS: At Week 8 of OCTAVE Induction 1 and 2, and Week 52 of OCTAVE Sustain, higher proportions of patients receiving tofacitinib 5 or 10 mg twice daily (b.d.) achieved clinical response vs placebo, regardless of baseline BMI subgroup (all P < 0.05). Proportions of patients achieving efficacy endpoints were generally similar across BMI subgroups; in univariate and multivariate regression analyses, BMI was not a significant predictor (all P ≥ 0.05; univariate BMI [continuous] odds ratio for remission: 0.98 [95% confidence interval 0.95, 1.02]). There was no consistent trend between BMI and adverse events. Among patients receiving tofacitinib 10 mg b.d. in OCTAVE Induction 1 and 2, serious infections were numerically greater in the BMI ≥30 subgroup (3.2%) vs other subgroups (0.4%). Limitations included small patient numbers in the BMI ≥30 subgroup. CONCLUSIONS: Efficacy and safety of tofacitinib were similar in patients with UC regardless of baseline BMI.

Primary study

Unclassified

Tofacitinib for the Treatment of Ulcerative Colitis: analysis of Nonmelanoma Skin Cancer Rates From the Ulcerative Colitis Clinical Program

Giornale Inflammatory bowel diseases
Year 2022
Links Pubmed DOI PubMed Central
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BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program. METHODS: Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo‐controlled studies: 2 identical, 8‐week induction studies (NCT01465763, NCT01458951), a 52‐week maintenance study (NCT01458574), and an open‐label, long‐term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient‐years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. RESULTS: Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient‐years of tofacitinib exposure; ≤6.8 years' treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10‐year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors. CONCLUSIONS: For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Unclassified

Efficacy and Safety of Tofacitinib in Ulcerative Colitis Based on Prior Tumor Necrosis Factor Inhibitor Failure Status

Giornale Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Year 2022
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BACKGROUND & AIMS: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We summarize efficacy and safety data of tofacitinib 5 or 10 mg twice daily (BID) in the UC clinical program, stratified by prior tumor necrosis factor inhibitor (TNFi) failure status. METHODS: Efficacy was assessed in the pooled Phase 3 OCTAVE Induction 1&2 studies (N=1,139), the Phase 3 OCTAVE Sustain maintenance study (N=593), and the dose escalation subpopulation of the open‐label, long‐term extension OCTAVE Open study (N=59). Safety was assessed in OCTAVE Sustain, the dose escalation subpopulation, and the Overall Cohort, which included patients from OCTAVE Induction 1&2, OCTAVE Sustain, and OCTAVE Open (N=1,124; no prior TNFi failure N=541; prior TNFi failure N=583; Phase 2 data were excluded when stratified by prior TNFi failure status). The dose escalation subpopulation received tofacitinib 10 mg BID in OCTAVE Induction 1&2, tofacitinib 5 mg BID in OCTAVE Sustain, and tofacitinib 10 mg BID in OCTAVE Open. RESULTS: Tofacitinib had greater efficacy than placebo, regardless of prior TNFi failure status. In OCTAVE Sustain and the Overall Cohort, herpes zoster [HZ] (non‐serious and serious) rates were numerically higher in tofacitinib‐treated patients with vs without prior TNFi failure. Dose escalation to tofacitinib 10 mg BID generally recaptured clinical response for most patients. HZ (non‐serious and serious) rates were numerically higher in the dose escalation subpopulation vs the Overall Cohort. CONCLUSION: Tofacitinib was efficacious in patients with UC regardless of prior TNFi failure status. HZ (non‐serious and serious) rates were numerically higher in patients who had previously failed TNFi. ClinicalTrials.gov: A3921063 (NCT00787202); OCTAVE Induction 1 (NCT01465763); OCTAVE Induction 2 (NCT01458951); OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612).