The hypothesis of the study is that at least one dose of CP 690 550 is superior to placebo (inactive drug) in inducing remission in patients with moderate to severe ulcerative colitis.
BACKGROUND: Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation.
METHODS: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1.
RESULTS: The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500.
CONCLUSIONS: Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.).
BACKGROUND: Tofacitinib, a novel, oral Janus kinase inhibitor, demonstrated a dose‐dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC). The objective of the current study was to determine the effect of tofacitinib on patient‐reported outcomes (PROs). METHODS: Eligible patients (≥18 years of age) with a diagnosis of active UC (total Mayo score of 6‐12 points and moderately‐to‐severely active disease on sigmoidoscopy) were randomized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg, 3 mg, 10 mg, or 15 mg, or placebo twice daily (BID) for 8 weeks. PROs were assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient‐Reported Treatment Impact (IBD PRTI) survey. RESULTS: At Week 8, mean IBDQ total scores had improved relative to baseline across all five treatment groups (baseline range 123.2‐134.5; Week 8 range 149.6‐175.4). Improvement from baseline was significantly greater (P = 0.001) for tofacitinib 15 mg BID versus placebo. For tofacitinib 15 mg BID, most patients reported satisfaction or extreme satisfaction, definite preference for tofacitinib, and definite willingness to use tofacitinib again on the IBD PRTI at week 8. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission. CONCLUSIONS: Short‐term treatment with tofacitinib BID was associated with dose‐dependent improvement in health‐related quality of life and patient preferences for tofacitinib. The results complement previously reported efficacy and safety data for the Phase II study. (NCT 00787202, November 6, 2008).
BACKGROUND & AIMS: Accurate biomarkers of disease activity and therapeutic response can be valuable for clinical trials. We performed a post hoc analysis of data from a phase 2 trial to assess the relationship between the concentration of fecal calprotectin (FCP) and clinical and endoscopic outcomes of patients with moderate to severe ulcerative colitis receiving tofacitinib. METHODS: In a double‐blind, placebo‐controlled, phase 2 trial, 194 patients were assigned randomly to groups given tofacitinib (0.5, 3, 10, or 15 mg twice daily) or placebo. Clinical and endoscopic outcomes were assessed at week 8 using the Mayo scoring system. Receiver operating characteristics were used to evaluate the relationships between FCP concentration and clinical and endoscopic outcomes, and to determine the FCP cut‐off concentration that correlated with patient outcome. RESULTS: Week 8 median concentrations of FCP were significantly lower in responders than in nonresponders (P < .001): clinical response, 156 vs 725 mg/kg; clinical remission, 64 vs 617 mg/kg; endoscopic remission, 44 vs 489 mg/kg; and mucosal healing, 127 vs 753 mg/kg. Area‐under‐the‐curve values for FCP receiver operating characteristic models were 0.80 for clinical remission, 0.81 for endoscopic remission, and 0.78 for mucosal healing. An FCP cut‐off value of 150 mg/kg achieved the highest summation of sensitivity and specificity for clinical remission (0.68 and 0.79, respectively; κ coefficient, 0.44) and endoscopic remission (0.79 and 0.75, respectively; κ coefficient, 0.38). CONCLUSIONS: Concentrations of FCP correlate with clinical and endoscopic outcomes of patients with moderate to severe ulcerative colitis receiving tofacitinib, although at an individual level the agreement was moderate. FCP concentration with a cut‐off value of 150 mg/kg had only fair to good accuracy in classifying clinical and endoscopic outcomes in a clinical trial. ClinicalTrials.gov no: NCT00787202.
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.
Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The safety and efficacy of tofacitinib for the treatment of moderate to severe UC was evaluated in OCTAVE induction and maintenance Phase 3, randomized, placebo-controlled studies.1 Long-term safety and efficacy of tofacitinib for UC are being evaluated in an ongoing, open-label, long-term extension study.2 We present an updated integrated analysis of the safety profile of tofacitinib observed during the UC global clinical development program, with tofacitinib exposure up to 4.4 years. Methods: Patients who received placebo, tofacitinib 5 or 10 mg twice daily (BID) were analyzed as 3 cohorts: Induction (Phase 2/3 induction, N=1220); Maintenance (Phase 3 maintenance, N=592); and Overall (patients receiving tofacitinib 5 or 10 mg BID in Phase 2, Phase 3, or the open-label, long-term extension study, N=1157; 1613 patient-years of exposure). Data are shown as of December 2016. Proportions and incidence rates (IRs; patients with events per 100 patient-years) were evaluated for adverse events of special interest. Opportunistic infections, malignancies, major adverse cardiovascular events, and gastrointestinal perforations were reviewed by independent adjudication committees. Results: 1157 patients received ≥1 dose of tofacitinib 5 or 10 mg BID with 1613 patient-years of tofacitinib exposure and up to 4.4 years of treatment. Demographics and disease characteristics were generally similar among the treatment groups in each cohort. In induction studies, adverse events of special interest were similar for tofacitinib and placebo groups. In the Maintenance cohort, the IR of herpes zoster was numerically higher with tofacitinib 5 mg BID (2.1) and significantly higher with tofacitinib 10 mg BID (6.6) vs placebo (1.0). IRs for other adverse events of interest were similar across treatment groups. For the Overall cohort, the majority of patients (N=971, 84%) received an average dose of tofacitinib 10 mg BID. IRs for adverse events of special interest were: death, 0.2; serious infection, 2.0; opportunistic infections, 1.3; herpes zoster, 4.1; malignancy (excl. non-melanoma skin cancer), 0.5; non-melanoma skin cancer, 0.7; major adverse cardiovascular events, 0.2; and gastrointestinal perforations, 0.2. Conclusion: Tofacitinib treatment in patients with UC was associated with dose-dependent risk of herpes zoster. These results show an overall manageable safety profile of tofacitinib 5 and 10 mg BID in the UC program, generally similar to that previously reported in the tofacitinib rheumatoid arthritis program and to that of other UC therapies including biologics. References: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-36. 2. Lichtenstein GR et al. Am J Gastroenterol 2017;112(S1):Abstract 714. [Table Presented]
AIMS: Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose‐ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC. METHODS: One‐ and two‐compartment pharmacokinetic models, with first‐order absorption and elimination, were evaluated to describe plasma tofacitinib concentration‐time data at baseline and week 8. Relationships between tofacitinib exposure (dose, average plasma drug concentration during a dosing interval at steady state [Cav,ss ] and trough plasma concentration at steady state [Ctrough,ss ]) and week 8 efficacy endpoints were characterized using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates. RESULTS: Plasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and Cav,ss values were not significantly different between baseline and week 8. Dose, Cav,ss and Ctrough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual Cav,ss values were similar between clinical remitters and nonremitters at predicted efficacious doses (10 and 15 mg twice daily). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg twice daily for patients with baseline Mayo score >8 and ≤8 were 39% (95% CI: 7‐70) and 21% (‐2‐50), respectively. CONCLUSIONS: Exposure‐response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.
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.
INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated integrated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical program as of Sep 2018. METHODS: NMSC events were evaluated from 4 randomized, placebo-controlled studies (Phase [P] 2 and P3 induction studies [NCT00787202; NCT01465763; NCT01458951], a 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); Overall (patients [pts] receiving ≥1 dose of tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, or ongoing OLE studies). For P3 studies, a blinded independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. RESULTS: 1124 pts were evaluated for NMSC (P3 studies only), with 2399 PY of tofacitinib exposure and up to 6.1 years of treatment. NMSC occurred in 2 Induction tofacitinib-treated pts, 1 Maintenance placebo-treated pt (IR 0.97), 3 Maintenance 10 mg BID pts (IR 1.91), and 19 Overall Cohort pts (IR 0.78). 10 pts had squamous cell carcinoma (SCC) and 12 pts had basal cell carcinoma (BCC); 3 pts had both SCC and BCC (Table). No NMSC was metastatic or led to discontinuation. The Overall Cohort showed higher IRs for pts aged ≥50 years vs other subgroups and for pts with prior tumor necrosis factor inhibitor treatment, or prior immunosuppressant use vs those without (Table 1). Prior NMSC (hazard ratio [HR] 10.95; 95% CI 3.72, 32.24; P < 0.0001) and age (HR per 10-year increase 2.10; 95% CI 1.41, 3.13; P = 0.0003) were significant risk factors for NMSC. CONCLUSION: NMSC events were infrequent in the tofacitinib UC program, and were more likely to occur in pts with prior NMSC, and with increasing age - known NMSC risk factors.4 NMSC IRs were similar to those reported for tofacitinib in rheumatoid arthritis5 and for biologic UC treatments.6. (Figure Presented).
INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). 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 yrs 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.1,2 We report the incidence of DVT and PE in the tofacitinib UC clinical program, as of Sep 2018. METHODS: DVT and PE events were evaluated from 4 randomized placebo-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).3-5 Three cohorts were analyzed: Induction (P2/P3 induction studies), Maintenance (P3 maintenance study), and Overall (pts receiving tofacitinib 5 or 10 mg BID in P2, P3, or OLE studies). Incidence rates (unique pts with events per 100 pt-yrs [PY] of exposure) were evaluated. For Overall Cohort analysis, pts were categorized based on the average daily dose of tofacitinib: predominant dose (PD) tofacitinib 5 mg or 10 mg BID. RESULTS: 1157 pts were evaluated for DVT and PE, with 2404 PY of tofacitinib exposure and up to 6.1 yrs of treatment. In the Induction and Maintenance Cohorts, 2 pts had DVT and 2 had PE; all had received placebo in the study (Table 1). In the Overall Cohort, DVT occurred in 1 pt and PE in 4 pts during the OLE study; all pts had received PD of tofacitinib 10 mg BID. All pts with PE and DVT had risk factors for venous thrombosis (Table 1). CONCLUSION: In this post hoc analysis of pts with UC during tofacitinib exposure, 4 pts had PE and 1 pt had DVT, all of which occurred during the OLE study, in pts treated with PD of tofacitinib 10 mg BID (83% of Overall Cohort pts received a PD of tofacitinib 10 mg BID) with risk factors for venous thrombotic events. This analysis is limited by small sample size and limited drug exposure, and further study is needed. (Figure Presented).
INTRODUCTION: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Fecal calprotectin (FCP) levels correlated with clinical and endoscopic outcomes at Week (Wk) 8 in patients (pts) with moderately to severely active UC receiving tofacitinib in a Phase 2 study (1). In these post hoc analyses, we aimed to determine if FCP levels, C-reactive protein (CRP) levels, or partial Mayo score (PMS) can be early predictors of clinical or endoscopic outcomes in a Phase 2, randomized, double-blind, placebo-controlled study (NCT00787202) (2). METHODS: FCP levels and PMS at baseline, Wk 2, and Wk 4, and CRP levels at baseline and Wk 4 were analyzed based on whether pts with moderately to severely active UC treated with tofacitinib 10 mg twice daily (BID) had clinical response, clinical remission, mucosal healing, or endoscopic remission at Wk 8. Univariate logistic regression analyses were used to evaluate if FCP levels (log transformed), CRP levels (log transformed), or PMS were associated with each outcome. RESULTS: In pts treated with tofacitinib 10 mg BID (N = 28), numerically greater decreases from baseline were observed in FCP levels and PMS at Wks 2 and 4 in pts who achieved clinical response, clinical remission, mucosal healing, and endoscopic remission at Wk 8 vs those who did not. FCP levels at Wk 2 decreased by>50% from baseline in pts who achieved endoscopic remission. Numerically greater decreases from baseline were observed in CRP levels at Wk 4 in pts who achieved clinical response and mucosal healing at Wk 8 vs those who did not (Table 1). In pts treated with tofacitinib 10 mg BID, logistic regression results (shown as odds ratio [95% confidence interval]) showed that PMS at Wk 2 (0.496 [0.288, 0.856]; P=0.0117) and Wk 4 (0.463 [0.251, 0.853]; P=0.0135), and CRP levels at Wk 4 (0.582 [0.342, 0.990]; P=0.0460), were significantly associated with clinical remission at Wk 8, and that PMS at Wk 4 (0.572 [0.345, 0.948]; P=0.0302) was significantly associated with clinical response at Wk 8. CONCLUSION: These post hoc analyses of a Phase 2 study showed that decreases as early as Wk 2 in FCP levels and PMS, and as early as Wk 4 in CRP levels, may be predictors of improved clinical and endoscopic outcomes in pts with moderately to severely active UC treated with tofacitinib 10 mg BID, although definitive conclusions cannot be drawn due to low pt numbers.
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).
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.
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).
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
INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Patients (pts) with UC are susceptible to C. difficile infection (CDI) (1). In the tofacitinib UC clinical program, previous analyses showed CDI rates among tofacitinib-treated pts to be similar or numerically lower than placebo (PBO)-treated pts and pts treated with immunomodulators and TNFi in a generally comparable claims-based observational cohort (2). Here, we present an updated analysis of CDI in the tofacitinib UC clinical program. METHODS: CDI events were evaluated from 4 randomized, 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). 3 cohorts were analyzed: Induction (P2/P3 induction studies), Maintenance (P3 maintenance study) and Overall (pts receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3 or OLE studies; analyzed by pts receiving $ 1 dose of tofacitinib and predominant dose [PD; 5 or 10 mg BID based on average daily dose <15 mg or $ 15 mg, respectively]; data as of May 2019, database not locked). Proportions and incidence rates (unique pts with events per 100 pt-yrs [PY] of exposure) of CDI were evaluated. All pts underwent CDI screening; a positive test excluded pts from program entry. RESULTS: The Overall Cohort comprised 1,157 pts who received $ 1 dose of tofacitinib 5 or 10 mg BID, representing 2,581 PY of tofacitinib exposure and up to 6.8 yrs of treatment. CDI occurred in 3 pts in the Induction Cohort (PBO, n = 1; tofacitinib 10 mg BID, n = 2), 3 pts in the Maintenance Cohort (PBO, n = 3; CDI occurred 68, 81 and 98 days following initiation of PBO) and 9 pts in the Overall Cohort (PD tofacitinib 10 mg BID, n = 9; Table 1). Overall Cohort pts with CDI were mild (n = 4) or moderate (n = 5) in severity; 6 pts continued study treatment without interruption, 1 temporarily discontinued and 2 permanently discontinued. CDI resolved with treatment in 8 pts and CDI was still present in 1 pt at the time of study discontinuation. Two events were reported as serious AEs due to hospitalization. CONCLUSION: In the tofacitinib UC program, CDI rates among pts receiving tofacitinib have remained stable since the previous data cut (2) and are comparable to those reported for other advanced therapies (3).
The hypothesis of the study is that at least one dose of CP 690 550 is superior to placebo (inactive drug) in inducing remission in patients with moderate to severe ulcerative colitis.
