OCTAVE 1
Alternative name: OCTAVE INDUCTION 1,
Phase: 3 /
ID: 623cc2537aaac8401707cd2e
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A Study Evaluating The Efficacy And Safety Of CP-690,550 In Patients With Moderate To Severe Ulcerative Colitis

Autori Pfizer
Registry of Trials ClinicalTrials.gov
Year 2011
Links Registry of Trials
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This study is designed to evaluate the efficacy and safety of tofacitinib (CP-690,550) in patients with moderate to severe ulcerative colitis who have failed or be intolerant to one of following treatments for ulcerative colitis: oral steroids, azathiopurine/6-mercaptopurine, or anti-TNF-alpha therapy.

Primary study

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Direct and Indirect Effects of Tofacitinib on Treatment Satisfaction in Patients with Ulcerative Colitis

Giornale Journal of Crohn's & colitis
Year 2016
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BACKGROUND AND AIMS: This mediation modelling analysis evaluated direct and indirect effects of tofacitinib, an oral, small molecule Janus kinase inhibitor under investigation for ulcerative colitis, on patient treatment satisfaction. METHODS: Data from an 8‐week randomized Phase 2 trial [NCT00787202] in adults with moderate‐to‐severe, active ulcerative colitis receiving twice‐daily tofacitinib 0.5‐15mg [n=146] or placebo [n=48] were analysed in patient‐reported [n=149] and clinician‐reported [n=170] outcomes‐based mediation models. Binary predictor variable: Treatment [pooled active treatment vs placebo]. Eventual dependent variable: Week 8 patient treatment satisfaction [measured on a five‐point Likert scale]. Mediators of treatment effect on satisfaction: Week 8 Inflammatory Bowel Disease Questionnaire domains [Bowel Symptoms, Emotional Health, Social Function and Systemic Symptoms] and Mayo scale domains [Stool Frequency, Rectal Bleeding, Physician's Global Assessment and Endoscopic Disease Activity] for patient‐reported and clinician‐reported models, respectively. RESULTS: Overall tofacitinib indirect effect on satisfaction via Inflammatory Bowel Disease Questionnaire domains was 40.5% [p<0.05] and via Mayo scale domains was 84.0% [p<0.01] for patient‐reported and clinician‐reported models, respectively. Bowel function had the most important indirect effect: of the total tofacitinib effect on satisfaction, 32.4% [p=0.05] was indirectly mediated via Bowel Symptoms; and 30.0% [p=0.04] via Stool Frequency. In total, 59.5% [p<0.01] and only 16.0% [p=0.56] of tofacitinib's effect on satisfaction was unrelated to Inflammatory Bowel Disease Questionnaire and Mayo scale domains in the patient‐reported and clinician‐reported models, respectively. CONCLUSIONS: Bowel function is an important factor for patient treatment satisfaction with tofacitinib. Treatment effect on patient satisfaction was almost completely mediated via improvement in Mayo scale domains.

Primary study

Unclassified

Tofacitinib for induction therapy in patients with active ulcerative colitis in two phase 3 clinical trials: results by local and central endoscopic assessments

Giornale
Year 2016
Links DOI www.cochranelibrary.com
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Introduction: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). Two Phase 3 randomised placebo‐controlled studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951) demonstrated efficacy of tofacitinib 10 mg twice daily (BID) vs placebo as induction therapy for patients with moderately to severely active UC.1. Aims & Methods: We describe here the clinical efficacy endpoints assessed by local endoscopy readings along with the previously reported results assessed by central readings. Patients in OCTAVE Induction 1 and 2 were randomised (4:1) to receive treatment with tofacitinib 10 mg BID or placebo for up to 9 weeks (wks). Patients were ≥18 years old with moderately to severely active UC (baseline Mayo score ≥6, rectal bleeding subscore ≥1 and endoscopic subscore ≥2). Patient eligibility was assessed based on central endoscopic reading. Patients had previous failure or intolerance to treatment with ≥1 of corticosteroids, thiopurines, or tumour necrosis factor inhibitors. The following efficacy endpoints were assessed at Wk 8: mucosal healing (defined as Mayo endoscopic subscore ≥1), remission (study primary endpoint, defined as Mayo score ≤2, no subscore 41 and rectal bleeding subscore of 0) and clinical response (decrease from baseline Mayo score of ≥3 points and ≥30%, plus decrease in rectal bleeding subscore ≥1 or absolute subscore ≥1). Clinical outcomes were measured using both local (ie site) and central endoscopic readings at baseline and Wk 8. Results: At Wk 8, significantly more patients receiving tofacitinib 10mg BID achieved mucosal healing in both studies vs placebo as demonstrated by both central and local endoscopic readings (Table). Similar results were observed with remission and clinical response at Wk 8. The observed rates as well as the magnitude of treatment differences based on local endoscopic reading were generally higher than those assessed by central reading. There was good agreement between locally and centrally read endoscopic subscores (kappa=0.63 (95% CI 0.58, 0.67) and 0.62 (95% CI 0.57, 0.67) in OCTAVE Induction 1 and 2, respectively). Conclusion: In patients with moderately to severely active UC, who were qualified for both Phase 3 studies on central reading, treatment effects observed with local endoscopic readings were similar or slightly higher and, overall, consistent with central readings. Both methods demonstrated the significant effect of tofacitinib vs placebo for induction therapy.

Primary study

Unclassified

Tofacitinib for induction therapy in patients with active ulcerative colitis in two phase 3 clinical trials: results by local and central endoscopic assessments

Giornale American journal of gastroenterology
Year 2016
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Introduction: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). Two Phase 3 randomized placebo‐controlled studies (OCTAVE Induction 1 and 2: NCT01465763, NCT01458951) demonstrated efficacy of tofacitinib 10 mg twice daily (BID) vs placebo as induction therapy for patients (pts) with moderately to severely active UC.1 Here, we describe clinical efficacy endpoints assessed by local endoscopy readings along with the previously reported results assessed by central readings. Methods: Pts in both studies were randomized (4:1) to receive tofacitinib 10 mg BID or placebo for up to 9 weeks (wks). Pts were ≥18 years old with moderately to severely active UC (baseline Mayo score ≥6, rectal bleeding subscore ≥1 and endoscopic subscore ≥2). Pt eligibility was assessed based on central endoscopic reading. Pts had previous failure or intolerance to treatment with ≥1 of corticosteroids, thiopurines, or tumor necrosis factor inhibitors. The following efficacy endpoints were assessed at Wk 8: remission (primary endpoint; Mayo score ≤2, no subscore >1 and rectal bleeding subscore of 0), mucosal healing (Mayo endoscopic subscore ≤1) and clinical response (decrease from baseline Mayo score of ≥3 points and ≥30%, plus decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1). Clinical outcomes were measured using both local (ie site) and central endoscopic readings at baseline and Wk 8. Results: At Wk 8, significantly more pts receiving tofacitinib 10 mg BID achieved remission in both studies vs placebo as demonstrated by both central and local endoscopic readings (Table). Similar results were observed with mucosal healing and clinical response at Wk 8. The observed rates as well as the magnitude of treatment differences based on local endoscopic reading were generally higher than those assessed by central reading. There was good agreement between locally and centrally read endoscopic subscores (kappa = 0.63 (95% CI 0.58, 0.67) and 0.62 (95% CI 0.57, 0.67) in OCTAVE Induction 1 and 2, respectively). Conclusion: In pts with moderately to severely active UC, who were qualified for both studies on central reading, treatment effects observed with local endoscopic readings were similar or slightly higher, and consistent with central readings. Both methods demonstrated the significant effect of tofacitinib vs placebo for induction therapy. (Figure Presented).

Primary study

Unclassified

Tofacitinib has induction efficacy in moderately to severely active ulcerative colitis, regardless of prior TNF inhibitor therapy

Giornale
Year 2016
Links DOI www.cochranelibrary.com
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Introduction: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). Two Phase 3 randomized placebo (PBO)‐controlled studies (OCTAVE Induction 1 and 2: NCT01465763, NCT01458951) demonstrated efficacy of tofacitinib 10 mg twice daily (BID) vs PBO as induction therapy for patients (pts) with moderate to severe UC.1 Here, we assessed the effect of TNF inhibitor (TNFi) therapy and disease severity on clinical efficacy and patient‐reported outcomes (PROs). Methods: Adults with moderately to severely active UC (Mayo score ≥6, rectal bleeding subscore ≥1 and endoscopic subscore ≥2) and prior failure/intolerance to ≥1 of corticosteroids, thiopurines or TNFi were randomized (4:1) to receive tofacitinib 10 mg or PBO BID for up to 9 weeks (wks). Efficacy endpoints at Wk 8 included: remission (Mayo score ≤2, no subscore>1 and rectal bleeding subscore of0), mucosal healing at Wk 8 (Mayo endoscopic subscore≤1), clinical response (decrease from baseline Mayo score of ≥3 points and ≥30%, plus decrease in rectal bleeding subscore≥1 or absolute subscore ≤1). PROs at Wk 8 included IBDQ remission (total score ≥170) and IBDQ response (≥16‐point increase from baseline). For binary endpoints, comparison of tofacitinib vs PBO was assessed using the Cochran‐ Mantel‐Haenszel (CMH) chi‐square test stratified by study, prior TNFi therapy, baseline corticosteroid use and geographic region. Within each subgroup, the CMH chi‐square test stratified by study was used. Results: Significantly more pts achieved remission, mucosal healing and clinical response at Wk 8 with tofacitinib 10 mg BID vs PBO (all p < 0.0001). The difference generally remained significant regardless of prior TNFi exposure, prior TNFi failure, primary or secondary TNFi failure or baseline Mayo score (≥9 or < 9). For all three endpoints, greater effects were observed when comparing secondary vs primary TNFi failure and baseline Mayo score < 9 vs ≥9 subpopulations. IBDQ remission and response were significantly greater with tofacitinib 10 mg BID vs PBO at Wk 8 regardless of prior TNFi exposure/ prior TNFi failure. Conclusion: Tofacitinib 10 mg BID demonstrated efficacy vs PBO, regardless of prior TNFi therapy or baseline disease severity, in pts with moderately and severely active UC. PRO results were similar in pts with/without prior TNFi exposure or failure.

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

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

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]

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

Correlation of Lipid Levels with Reduction in Inflammation in Patients with Ulcerative Colitis: Data from the Tofacitinib Octave Clinical Trials

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). Mild lipid elevations - with no evidence suggesting correlation with major cardiovascular events - have been seen in tofacitinib-treated patients.1,2 We evaluated relationships between inflammatory status and lipid levels in tofacitinib-treated patients with UC. Methods: This analysis included patients from two randomized, placebo-controlled tofacitinib induction trials in patients with moderate to severe UC (OCTAVE Induction 1 & 2, NCT01465763 & NCT01458951). Correlation of Week 8 changes from baseline in lipid parameters (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and total cholesterol) with Week 8 changes from baseline in C-reactive protein, and with the proportions of patients with mucosal healing (Mayo endoscopic subscore ≤1) and remission (total Mayo score ≤2, no individual subscore >1 and rectal bleeding subscore = 0) at Week 8, were determined. Results: In OCTAVE Induction 1 & 2, 234 patients received placebo and 905 patients received tofacitinib 10 mg twice daily (BID). Consistent with previously reported data,2 there were greater increases from baseline in lipid levels, decreases from baseline in C-reactive protein, and greater rates of mucosal healing and remission at Week 8 with tofacitinib 10 mg BID vs placebo (Table). The Pearson correlation coefficients at Week 8 between C-reactive protein and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and total cholesterol levels were significantly different from zero for both placebo-treated patients (low-density lipoprotein cholesterol: -0.23; high-density lipoprotein cholesterol: -0.34; total cholesterol: -0.36) and tofacitinib-treated patients (low-density lipoprotein cholesterol: -0.19; high-density lipoprotein cholesterol: -0.25; total cholesterol: -0.27). For tofacitinib-treated patients, correlation coefficients at Week 8 between mucosal healing and high-density lipoprotein cholesterol (0.12) and total cholesterol (0.09), and between remission and high-density lipoprotein cholesterol (0.08), were significantly different from zero. Conclusion: There was significant negative but small correlation between lipid and C-reactive protein changes in the tofacitinib and placebo groups. These data suggest that lipid changes seen in patients treated with tofacitinib may be partially due to the beneficial effect of reduced inflammation. More studies are warranted to better understand these correlations. References: 1. Charles-Schoeman C et al. Semin Arthritis Rheum 2016;46:261-71. 2. Sandborn WJ et al. N Engl J Med 2017;376:1723-36. [Table Presented]

Primary study

Unclassified

Tofacitinib Achieves Symptomatic Improvement within 3 Days in Moderately to Severely Active Ulcerative Colitis, Regardless of Prior Tumour Necrosis Factor Inhibitor Treatment Status: Results from Octave Induction 1 & 2

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). We evaluated the timing of onset of symptomatic improvement in a post-hoc analysis of patient-reported diary data and evaluated treatment effect in patients with and without prior failure of tumor necrosis factor inhibitor therapy. Methods: OCTAVE Induction 1 & 2 (NCT01465763; NCT01458951) were identical, randomized, placebo-controlled Phase 3 trials in adult patients with moderately to severely active UC who had failed or were intolerant to steroids, immunomodulators, or tumor necrosis factor inhibitors. Patients received placebo (N=234) or tofacitinib 10 mg twice daily (N=905) for 8 weeks. Pooled data for OCTAVE Induction 1 & 2 are presented. During the study, patients recorded their number of bowel movements per day, and the presence and a description of any blood in the stools. Binary endpoints based on Mayo stool frequency and rectal bleeding subscores were compared using stratified Cochran-Mantel-Haenszel chi-square test, based on observed data. Subgroup analyses were conducted by prior tumor necrosis factor inhibitor failure status, baseline C-reactive protein, and corticosteroid use at baseline. Results: At baseline, the mean Mayo subscores for the placebo and tofacitinib groups were 2.5 for stool frequency and 1.6 for rectal bleeding. By Day 3, significantly more patients achieved each of the binary efficacy endpoints (defined in Table) with tofacitinib vs placebo (all p<0.05). Among patients with prior tumor necrosis factor inhibitor failure, 117 (26.8%) tofacitinib-treated patients had reduction from baseline stool frequency ≥1 at Day 3, vs 16 (14.0%) with placebo, and 133 (30.6%) tofacitinib-treated patients had reduction from baseline rectal bleeding ≥1 at Day 3, vs 14 (12.5%) with placebo. Subgroup analyses demonstrated generally consistent effects of tofacitinib treatment vs placebo, regardless of prior tumor necrosis factor inhibitor treatment failure status (Figure), baseline C-reactive protein, and corticosteroid use at baseline. Conclusion: Significant symptomatic improvements were observed with tofacitinib vs placebo as early as Day 3. A consistent treatment effect was observed regardless of whether patients had prior tumor necrosis factor inhibitor treatment failure. These results support the rapid onset of tofacitinib efficacy previously reported based on significant improvement vs placebo at 2 weeks in partial Mayo score, and extend this result to response at Day 3.1 Reference: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36. [Table Presented] [Figure Presented]

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
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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.

Primary study

Unclassified

Tofacitinib achieves symptomatic improvement within 3 days in moderately to severely active ulcerative colitis, regardless of prior tumour necrosis factor inhibitor treatment status: Results from OCTAVE induction 1 and 2

Giornale Journal of Crohn's & colitis
Year 2018
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Background: Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). We evaluated the timing of onset of symptomatic improvement in a post hoc analysis of patient-reported diary data and evaluated treatment effect in patients with and without prior failure of tumour necrosis factor inhibitor (TNFi) therapy. Methods: OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951) were identical, randomised, placebo-controlled Phase 3 trials in adult patients with moderately to severely active UC who had failed or were intolerant to steroids, immunomodulators or TNFi. Patients received placebo (n = 234) or tofacitinib 10 mg twice daily (N = 905) for 8 weeks. Pooled data for OCTAVE Induction 1 and 2 are presented. During the study, patients recorded their number of bowel movements per day, and the presence and a description of any blood in the stools. Binary endpoints based on Mayo stool frequency (SF) and rectal bleeding (RB) subscores were compared using stratified Cochran-Mantel-Haenszel chi-square test, based on observed data. Subgroup analyses were conducted by prior TNFi failure status, baseline C-reactive protein (CRP) and corticosteroid use at baseline. Results: At baseline, the mean Mayo subscores for the placebo and tofacitinib groups were 2.5 for SF and 1.6 for RB. By Day 3, significantly more patients achieved each of the binary efficacy endpoints (defined in Table) with tofacitinib vs. placebo (all p < 0.05). Among patients with prior TNFi failure, 117 (26.8%) tofacitinib-treated patients had reduction from baseline SF ≥1 at Day 3, vs. 16 (14.0%) with placebo, and 133 (30.6%) tofacitinib-treated patients had reduction from baseline RB ≥1 at Day 3, vs. 14 (12.5%) with placebo. Subgroup analyses demonstrated generally consistent effects of tofacitinib treatment vs. placebo, regardless of prior TNFi treatment failure status (Figure), baseline CRP and corticosteroid use at baseline. Conclusions: Significant symptomatic improvements were observed with tofacitinib vs. placebo as early as Day 3. A consistent treatment effect was observed regardless of whether patients had prior TNFi treatment failure. These results support the rapid onset of tofacitinib efficacy previously reported based on significant improvement vs. placebo at 2 weeks in partial Mayo score, and extend this result to response at Day 3.1.

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
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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

EFFICACY OF TOFACITINIB MAINTENANCE THERAPY FOR ULCERATIVE COLITIS IN REMITTING PATIENTS VS PATIENTS WITH CLINICAL RESPONSE AFTER 8 WEEKS OF INDUCTION TREATMENT

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 (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 rerandomized at baseline to receive placebo, tofacitinib 5 or 10 mg twice daily (BID) in the double-blind, parallel-group, multicenter 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 analyzed 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 tumor 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 non-failure subpopulation was evident regardless of the maintenance baseline remission status (Table). Conclusion: 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. Reference: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36. [Table presented]

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).

Unclassified

MEASURING THE MEDIATING EFFECTS OF TOFACITINIB ON HEALTH STATUS IN ULCERATIVE COLITIS: DATA FROM THE OCTAVE PROGRAM

Giornale Gastroenterology
Year 2019
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BACKGROUND: The Mayo score (MS) is typically used to calculate ulcerative colitis (UC) clinical trial efficacy endpoints and includes 4 components: stool frequency, rectal bleeding, endoscopic appearance, and physician assessment. Although generic patient-reported outcome measures (PROMs) like the Short Form-36 (SF-36) are also frequently included in UC trials, it is unclear whether treatment effects on these measures are fully explained by MS changes or whether other unobserved variables are in play. Here, we explored the interrelationship among treatment, SF-36 domains and MS using a mediation modeling framework. METHODS: Pooled data at the end (week 8) of the two double-blind, identically designed induction studies of tofacitinib (OCTAVE Induction 1 & 2, NCT01465763 & NCT01458951) were used. Tofacitinib is an oral, small molecule Janus kinase inhibitor approved in several countries for the treatment of ulcerative colitis (UC). A mediation model was specified such that the MS components served as mediators between treatments (active treatment vs. placebo) and the eight SF-36 domain scores (bodily pain, general health, mental health, physical functioning, emotional role limitations, physical role limitations, social functioning, and vitality), which served as the outcomes. Our primary interest was the extent to which treatment affects the SF-36 domain outside of any change in MS components (i.e., the direct path). RESULTS: 1079 patients with moderately to severely active UC were included. For all SF-36 domains, the indirect path (i.e., the pathways from treatment to the MS components and then to each SF-36 domain score) was significant (all p<.05) and explained 65.6% (bodily pain) to 92.9% (mental health) of the total effect of the treatment on SF-36 domain scores. In other words, the majority of the total effect of treatment on the SF-36 scores was explained by changes in Mayo score components. Yet, for bodily pain (34.4%), physical role limitations (31.2%) and vitality (32.7%), the direct paths (i.e., the pathway from treatment directly to each SF-36 domain outside of any effect from changes in MS components) were also significant (all p<.05). No other direct effects were observed. CONCLUSIONS: Our study suggests that the MS, while important in capturing disease activity, does not fully mediate treatment effects on all SF-36 domains. Hence, the results indicate that tofacitinib can directly improve certain aspects of general health status – specifically, bodily pain, physical role limitation and vitality – outside of any benefit of improving stool frequency, rectal bleeding, endoscopic assessment, or physician assessment. These results reinforce the value of health status PROMs such as the SF-36 in capturing the full benefit of UC treatment.

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

Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis

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 for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post‐hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2). Methods: The studies comprised patients with moderate to severe active UC who were intolerant to, or failed by previous treatment with, corticosteroids, thiopurines, and/or tumor necrosis factor (TNF) antagonists. Patients received tofacitinib (10 mg twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo stool frequency and rectal bleeding subscores were calculated using diary data from the first 15 days of therapy. We analyzed data from subgroups including failure of prior anti‐TNF therapy, baseline corticosteroid use, and baseline serum levels of C‐reactive protein. Results: Mean changes were significantly greater in patients given tofacitinib vs placebo in reductions from baseline stool frequency subscore (tofacitinib: –0.27 vs placebo: –0.11; P < .01), total number of daily bowel movements (–1.06 vs –0.27; P < .0001), and rectal bleeding subscore (–0.30 vs –0.14; P < .01) by day 3. Compared with placebo, more tofacitinib‐treated patients had reductions from baseline in stool frequency subscore (by ≥1 point for tofacitinib, 241/837, 28.8% vs placebo, 39/218, 17.9%) (P < .01) and rectal bleeding subscore (by ≥1 point for tofacitinib, 266/830, 32.0% vs placebo, 43/214, 20.1%) (P < .01) by day 3. A consistent effect of tofacitinib was observed in all subgroups. Conclusions: In a post‐hoc analysis of data from phase 3 trials of induction therapy with tofacitinib in patients with UC, we found significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days. These findings indicate the rapid onset of effect of this drug in patients with UC. ClinicalTrials.gov no: NCT01465763 and NCT01458951.

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

Incidence of venous thrombo embolic events in patients with ulcerative colitis treated with to facitinib in the ulcerative colitis clinical development programme

Giornale
Year 2019
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Introduction: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The safety of tofacitinib for the treatment of moderate to severe UC was evaluated in a randomised, placebo‐controlled Phase (P) 2 induction study (NCT00787202),1 2 induction P3 studies (NCT01465763; NCT01458951), 1 maintenance P3 study (NCT01458574),2 and an ongoing, open‐label, long‐term extension (OLE) study (NCT01470612).3 A safety signal for pulmonary embolism (PE) was seen in the tofacitinib 10 mg twice daily (BID) arm of an FDA post‐marketing requirement study in rheumatoid arthritis designed to evaluate the long‐term risk of major cardiovascular events and malignancy. Patients (pts) eligible for this ongoing, open‐label, safety‐endpoint‐driven study had to be ≥50 years of age, have ≥1 cardiovascular risk factor and be on a stable dose of methotrexate. UC is a known risk factor for deep vein thrombosis (DVT) and PE, with reported incidence rates ranging from 0.07 to 0.30 and 0.04 to 0.20, respectively.4,5 Here, we report the incidence of DVT and PE in the tofacitinib UC clinical programme, as of Sep 2018. Aims & Methods: Pts who received placebo, tofacitinib 5 or 10 mg BID were analysed in three cohorts: Induction (P2/P3 induction studies, N=1220), Maintenance (P3 maintenance study, N=592) and Overall (pts receiving tofacitinib 5 or 10 mg BID in P2, P3 or ongoing OLE studies, N=1157). DVT and PE events were identified using preferred terms in the Standardised Medical Dictionary for Regulatory Activities query 'embolic and thrombotic events, venous' and incidence rates (unique pts with events per 100 ptyears [PY] of exposure) were evaluated. For Overall Cohort analysis, pts were categorised based on the average daily dose of tofacitinib: predominant dose (PD) tofacitinib 5 mg BID (average total daily dose < 15 mg) and PD tofacitinib 10 mg BID (average total daily dose ≥15 mg). Results: The Overall Cohort comprised 1157 pts who received ≥1 dose of tofacitinib 5 or 10 mg BID, with 2404 PY of tofacitinib exposure and up to a maximum of 6.1 years of treatment. Results for DVT and PE are shown in the Table. In the Induction and Maintenance Cohorts, 2 pts had DVT and 2 had PE; all had received placebo in the study. In the Overall Cohort, there was 1 pt with DVT and 4 pts with PE; all 5 pts had received PD of tofacitinib 10 mg BID and all events occurred during the OLE study. Pts with PE had the following notable medical history: 1 with prior DVT and PE, 1 with phlebothrombosis and stroke, 1 was receiving oral contraceptives for dysfunctional uterine bleeding, and 1 had cholangiocarcinoma and metastases to the peritoneum, and PE was the cause of death. The pt with DVT was diagnosed following a long‐haul flight and management of an infected leg wound sustained in a recent motorbike accident. Conclusion: In this post‐hoc analysis of pts from the OCTAVE programme, during tofacitinib exposure, 4 pts had PE and 1 pt had DVT. All of the events in pts taking tofacitinib occurred during the OLE study in pts treated with PD of tofacitinib 10 mg BID (83% of pts in the Overall Cohort received a PD of tofacitinib 10 mg BID) and with risk factors for thrombotic events. This post‐hoc analysis is limited by small sample size and limited drug exposure, and further study is needed. (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

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]

Unclassified

Tofacitinib for the treatment of ulcerative colitis: An update on the analysis of malignancy rates from the UC clinical program

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). We present an updated analysis of adjudicated malignancies in the UC clinical development program as of Sep 2018. METHODS: Malignancies were evaluated from 4 randomized placebo (PBO)-controlled studies (Phase [P] 2 and P3 induction studies [NCT00787202; NCT01465763; NCT01458951], 1 maintenance P3 study [NCT01458574]), and an ongoing, open-label, long-term extension (OLE) study (NCT01470612).1-3 Three cohorts were analyzed: Induction (P2/P3 induction studies), Maintenance (P3 maintenance study), and Overall (patients [pts] receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, or OLE studies). Proportions and incidence rates (IRs; unique pts with events per 100 ptyears [PY] of exposure) were evaluated for malignancies (excl. non-melanoma skin cancer [NMSC]) and NMSC. For Overall Cohort analysis, pts were categorized based on the average daily tofacitinib dose: predominant dose (PD) 5 or 10 mg BID. For P3 studies, an independent adjudication committee reviewed all potential malignancies. RESULTS: 1157 pts were evaluated for malignancies (2404 PY of tofacitinib exposure; up to 6.1 years of treatment). Malignancies (excl. NMSC) occurred in 0 Induction Cohort pts, 1 PBO-treated Maintenance Cohort pt, and 17 Overall Cohort pts (IR 0.69; 3 received a PD of tofacitinib 5 mg BID [IR 0.49] and 14 a PD of 10 mg BID [IR 0.75]; Table 1). NMSC occurred in 2 tofacitinib-treated Induction Cohort pts, 4 Maintenance Cohort pts (3 with 10 mg BID-treated pts, IR 1.91; and 1 PBOtreated pt, IR 0.97), and 19 Overall Cohort pts (IR 0.78; 4 had received a PD of 5 mg BID and 15 a PD of 10 mg BID). CONCLUSION: Malignancies (incl. NMSC) were observed with tofacitinib in UC. There was no malignancy type clustering (excl. NMSC). The IR of malignancies (excl. NMSC) reported here is similar to those previously reported for UC [4] - suggesting no treatment duration impact on the IR - and for tofacitinib in pts with rheumatoid arthritis and in pts with UC treated with biologics.5-7. (Figure 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
Links DOI www.cochranelibrary.com
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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].

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

Unclassified

DIAGNOSTIC ACCURACY OF RECTAL BLEEDING AND STOOL FREQUENCY IN PREDICTING MUCOSAL HEALING IN PATIENTS WITH ULCERATIVE COLITIS IN THE TOFACITINIB OCTAVE PHASE 3 INDUCTION STUDIES

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 patients with UC, associations between endoscopic findings and patient-reported outcomes, such as stool frequency (SF) and rectal bleeding (RB), are not well described. Here, we evaluated the diagnostic accuracy of Mayo SF and RB subscores to predict mucosal healing (MH) in OCTAVE Induction 1&2 (NCT01465763; NCT01458951). Methods: This post hoc analysis used data from OCTAVE Induction 1&2, two identical, randomized, placebo-controlled, 8-week, Phase 3 studies of tofacitinib for the treatment of patients with moderately to severely active UC.1 SF (Mayo subscore 0–3), RB (Mayo subscore 0–3), and endoscopic findings (Mayo endoscopic subscore [ES] 0–3) were assessed at baseline and at Week 8. MH and endoscopic normalization were defined as an ES of 0 or 1, or an ES of 0, respectively. Based on two-by-two contingency tables, diagnostic test characteristics for SF and RB were evaluated: positive and negative predictive values, sensitivity, and specificity. Kappa statistics (chance-corrected measure of agreement) and Pearson correlations (measure of association) were also calculated. All available data at Week 8 were used. Results: A total of 614 and 547 patients received treatment (tofacitinib 15 or 10 mg BID, or placebo) in OCTAVE Induction 1&2, respectively. Two-by-two contingency table analyses showed that dichotomized SF (0 vs ≥1) and RB (0 vs ≥1) were each or both not good predictors of MH (ES of 0 or 1 vs ≥2) or endoscopic normalization (ES 0 vs ≥1), as ≥1 of the four diagnostic test characteristics was <50% (Table). In OCTAVE Induction 1&2, weighted kappa statistics for SF (original metric 0–3) and RB (0–3) vs ES (0–3) indicated moderate agreement for SF (0.46 and 0.42, respectively), slight agreement for RB (0.19 and 0.15, respectively), and fair agreement for SF and RB (0.40 and 0.34, respectively). Correlations were 0.54 and 0.49 for SF, 0.46 and 0.37 for RB, and 0.57 and 0.51 for SF and RB (OCTAVE Induction 1&2, respectively), suggesting a modest-to-moderate association. Conclusion: In patients with UC treated with tofacitinib or placebo in OCTAVE Induction 1&2, SF and RB subscores had slight-to-moderate agreement with ES, but were not predictive of MH or endoscopic normalization. The presence of blood at Week 8 strongly indicated that patients had endoscopic activity, but the absence of blood was associated with MH in <50% of patients. Further analysis is needed to fully understand the relationship between SF, RB, and MH. Reference: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36

Primary study

Unclassified

C-REACTIVE PROTEIN LEVELS AND PARTIAL MAYO SCORE AS EARLY PREDICTORS OF CLINICAL AND ENDOSCOPIC OUTCOMES IN ADULT PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS TREATED WITH TOFACITINIB: A POST HOC ANALYSIS OF OCTAVE INDUCTION 1&2

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 a Phase 2 study, changes from baseline in C-reactive protein (CRP) levels as early as Week 4 and partial Mayo scores (PMS) as early as Week 2 were shown to correlate with clinical and endoscopic outcomes at Week 8 in patients with UC receiving tofacitinib.1 We aimed to determine if CRP levels and/or PMS can be early predictors of clinical or endoscopic outcomes at Week 8 in OCTAVE Induction 1&2 (NCT01465763; NCT01458951).2 Methods: In OCTAVE Induction 1&2, patients received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Mean CRP levels at baseline and Week 4, and PMS at baseline and Weeks 2 and 4, were analyzed by secondary endpoint (clinical response, clinical remission, mucosal healing, and endoscopic remission) status at Week 8. Univariate logistic regression analyses were performed to evaluate if CRP levels (log-transformed) or PMS were associated with these endpoints. Results: In patients treated with tofacitinib 10 mg BID, numerically greater decreases from baseline were observed in CRP levels at Week 4 in patients who achieved a clinical response at Week 8 vs those who did not achieve a clinical response (Table). Similarly, numerically greater decreases from baseline were observed in PMS at Weeks 2 and 4 in patients who achieved clinical response, clinical remission, mucosal healing, and endoscopic remission at Week 8 vs those who did not achieve these endpoints (Table). Logistic regression results showed that PMS at Weeks 2 and 4, and CRP levels at Week 4, were significantly (p<0.001) associated with a clinical response at Week 8 (odds ratio [95% confidence interval] 0.578 [0.529, 0.631]; 0.483 [0.437, 0.533]; 0.631 [0.572, 0.695], respectively). This was also true for clinical remission (0.523 [0.467, 0.587]; 0.426 [0.367, 0.495]; 0.582 [0.508, 0.666]), mucosal healing (0.650 [0.600, 0.705]; 0.599 [0.548, 0.655]; 0.576 [0.515, 0.643]), and endoscopic remission (0.659 [0.574, 0.756]; 0.604 [0.513, 0.712]; 0.663 [0.549, 0.802]) at Week 8. Conclusion: These post hoc analyses showed that PMS as early as Week 2 and CRP levels as early as Week 4 may be predictors of improved clinical and endoscopic outcomes in patients with moderately to severely active UC treated with tofacitinib 10 mg BID. These results are in alignment with the findings reported from the Phase 2 trial.1 References: 1. Dubinsky MC et al. Am J Gastroenterol 2019;114:Abstract 823 2. Sandborn WJ et al. N Engl J Med 2017;376:1723-36

Unclassified

Serum Lipid and C-Reactive Protein Levels by Treatment Response Following 8 Weeks of Tofacitinib Induction Therapy 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. Following 8 weeks of tofacitinib 10 mg twice daily (BID) in OCTAVE Induction 1&2, modest and reversible increases in serum lipid levels were reported in patients with UC, which were associated with reduced C-reactive protein (CRP) levels [1]. METHODS: OCTAVE Induction 1&2 (NCT01465763; NCT01458951) were 2 identical, 8-week, Phase 3 studies in which patients with moderately to severely active UC received tofacitinib 10 mg BID or placebo (total n = 1,139). In this post hoc analysis of the pooled induction studies, we assessed changes from baseline (CFB) in lipid levels (total cholesterol [total-c], high-density lipo-protein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c]) at Week 8 by responder and remitter status in patients who received tofacitinib 10 mg BID or placebo; analysis of variance was performed to estimate differences for responders or remitters vs non-responders. The association between CFB in lipid levels and CFB in CRP levels (log-transformed), by responder and remitter status, was assessed using a linear regression model at Week 8 in patients who received tofacitinib 10 mg BID. RESULTS: Increases in lipid levels from baseline to Week 8 were observed in responders, non-responders, and remitters (Table), which were greater with tofacitinib 10 mg BID vs placebo. There were significantly greater increases from baseline in total-c, HDL-c, and LDL-c for responders vs non-responders (all P < 0.0001), and in total-c and HDL-c for remitters vs non-responders (both P # 0.0001) in patients who received tofacitinib 10 mg BID (Table). Significant differences in lipid levels by responder and remitter status were not reported with placebo (data not shown). In patients who received tofacitinib 10 mg BID, linear regression modeling showed a significant association between CFB in total-c, HDL-c, and LDL-c and CFB in CRP in responders and non-responders, and between CFB in total-c and HDL-c and CFB in CRP in remitters (all P < 0.01) (Table). CONCLUSION: These data suggest an association between increases in lipid levels and tofacitinib responder and remitter status. Further research is necessary to determine if increases in lipid levels can be used as a surrogate marker of reduced inflammation, and to establish lipid levels as potential predictors of patient outcomes to tofacitinib treatment.

Primary study

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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

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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

Tofacitinib in Patients with Ulcerative Colitis: Inflammatory Bowel Disease Questionnaire Items in Phase 3 Randomized Controlled Induction Studies.

Giornale Inflammatory bowel diseases
Year 2021
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Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We examined the effect of tofacitinib induction treatment on Inflammatory Bowel Disease Questionnaire (IBDQ) items in adults with moderate to severe UC. Methods Data were pooled from the randomized, 8‑week, double-blind, phase 3 OCTAVE Induction 1 and 2 studies. The IBDQ was self-administered by patients at baseline, week 4, and week 8, with higher scores indicating better health-related quality of life (HRQoL). Change from baseline in IBDQ items was analyzed for 10 mg of tofacitinib twice daily (BID) vs placebo using a linear mixed-effects model, with no multiplicity adjustment performed. Effect sizes were calculated. Subgroup analyses by tumor necrosis factor inhibitor (TNFi) experience were performed. Results Significant improvements (nominal P &lt; 0.05) were observed in all IBDQ items with 10 mg of tofacitinib BID vs placebo at weeks 4 and 8. For the overall population, the largest treatment differences across all items were reported for "bowel movements been loose" at weeks 4 and 8, and "problem with rectal bleeding" at week 8 (mean treatment differences all 1.1; both in bowel symptoms domain). These items also showed the largest effect sizes. Treatment benefits were generally slightly numerically higher in TNFi-experienced vs TNFi-naïve patients. Conclusions Tofacitinib induction therapy improved all IBDQ items vs placebo in patients with UC, reflecting improvements in HRQoL, with greatest benefits reported in bowel symptoms domain items (Funded by Pfizer Inc; OCTAVE Induction 1 and OCTAVE Induction 2; ClinicalTrials.gov, NCT01465763 and NCT01458951, respectively).

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.

Unclassified

Diagnostic accuracy of patient-reported outcomes in predicting endoscopic subscore in patients with ulcerative colitis

Giornale GastroHep
Year 2021
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Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). In patients with UC, associations between endoscopic findings and UC symptoms are not well described. Aims: Post hoc analysis of data from two randomised, placebo-controlled, 8-week, phase 3 studies of tofacitinib for the treatment of patients with UC. Methods: Associations of stool frequency and rectal bleeding subscores with endoscopic improvement (Mayo endoscopic subscore ≤1) were assessed and relationships studied using regression analyses. Results: Analysis of two-by-two contingency tables showed that dichotomised stool frequency and rectal bleeding were each or both not good predictors of endoscopic improvement. Using stool frequency and/or rectal bleeding as predictors of endoscopic subscore, regression modelling analyses demonstrated a weak relationship between variables. However, a robust relationship was observed with endoscopic subscore as a predictor of stool frequency and rectal bleeding. In OCTAVE Induction 1, normal/inactive disease (endoscopic subscore 0) corresponded to a least-squares mean value of 0.05 for rectal bleeding (no blood), and severe disease (endoscopic subscore 3) corresponded to a value of 1.5 (interpreted as streaks of blood with stool <50% of the time [score of 1] or obvious blood with stool most of the time [score of 2]). OCTAVE Induction 2 results were similar. Conclusions: Results suggest that the likelihood of endoscopic improvement or normalisation is higher in patients with normal stool frequency and without rectal bleeding, but that these symptoms alone are not predictive of endoscopic improvement or normalisation, and endoscopy is needed for disease assessment. ClinicalTrials.gov: NCT01465763; NCT01458951.

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
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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
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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.