Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Sandborn WJ

PROVIDER: S-EPMC6899755 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Sandborn William J WJ Panés Julian J Sands Bruce E BE Reinisch Walter W Su Chinyu C Lawendy Nervin N Koram Nana N Fan Haiyun H Jones Thomas V TV Modesto Irene I Quirk Daniel D Danese Silvio S

Alimentary pharmacology & therapeutics 20191009 10

<h4>Background</h4>Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC).<h4>Aim</h4>To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme.<h4>Methods</h4>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 ov ...[more]

PMID: 31599001

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Project description:IntroductionThis post hoc analysis evaluated influenza adverse events (AEs) across rheumatoid arthritis (RA), ulcerative colitis (UC), and psoriatic arthritis (PsA) tofacitinib clinical programs.MethodsAvailable data from phase 1, randomized phase 2/3/3b/4 clinical trials (completed by 2018), and long-term extension (LTE) studies (up to May 2019) in patients with RA, UC, and PsA were included [randomized or Overall (phase 1-3b/4 and LTE studies) tofacitinib cohorts]. Incidence rates (IRs; events per 100 patient-years) of combined influenza AEs (seasons 2004/2005 to 2018/2019) were analyzed, including by tofacitinib dose [5 or 10 mg twice daily (BID)] and age (< 65 versus ≥ 65 years). Logistic regression models evaluated risk factors for influenza AEs in the RA Overall tofacitinib cohort.ResultsIn randomized cohorts, combined influenza AE IRs were generally similar across tofacitinib, adalimumab, methotrexate, and placebo groups, across indications. Among Overall tofacitinib cohorts, combined influenza AE IRs with tofacitinib 5/10 mg BID, respectively, were higher in the UC (3.66/5.09) versus RA (2.38/2.19) and PsA (1.74/1.29) cohorts. IRs were generally similar across tofacitinib dose and age groups. Most influenza AEs were nonserious and did not require changes to tofacitinib treatment. Significant risk factors for influenza AEs in patients with RA were geographic region, baseline oral corticosteroid and methotrexate use, and tofacitinib dose.ConclusionsIn the RA, UC, and PsA clinical programs, combined influenza AE IRs were highest in UC, while in each indication they were generally similar across tofacitinib, placebo, and comparator groups. Influenza AEs were predominantly nonserious and not associated with changes to tofacitinib treatment.Trial registration numbersNCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.

Project description:Background and aimsTofacitinib is an oral small molecule Janus kinase [JAK] inhibitor for the treatment of ulcerative colitis. We report an integrated summary of tofacitinib safety [exposure: ≤7.8 years] from the global clinical programme.MethodsPatients receiving tofacitinib 5 or 10 mg twice daily [BID] from completed phase [P]2/3 placebo-controlled studies, an open-label, long-term extension study [final data cut-off: August 24, 2020], and interim analysis of a P3b/4 study (interim data cut-off: February 20, 2020; Overall plus P3b/4 [2020] Cohort) were included. Proportions with adverse events [AEs] and serious AEs, and incidence rates [IRs; unique patients with events/100 patient-years] for deaths and AEs of special interest [AESI] were evaluated. Opportunistic infections, malignancies, major adverse cardiovascular events [MACE] and gastrointestinal perforations were adjudicated.ResultsIn total, 1157 patients received one or more dose of tofacitinib (mean duration: 946.9 days); 955/1157 [83%] received a predominant dose of 10 mg BID; 412/1157 [35.6%] received tofacitinib for >4 years; 992/1157 [85.7%] had AEs, 244/1157 [21.1%] had serious AEs and 134/1157 (11.6%) discontinued use due to AEs. IRs [95% confidence intervals] for all tofacitinib doses were: deaths, 0.23 [0.09-0.46]; serious infections, 1.69 [1.26-2.21]; herpes zoster [non-serious and serious], 3.30 [2.67-4.04]; opportunistic infections, 1.03 [0.70-1.46]; malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 [0.55-1.24]; NMSC, 0.73 [0.45-1.10]; MACE, 0.29 [0.13-0.55]; deep vein thrombosis, 0.03 [0.00-0.18]; pulmonary embolism, 0.19 [0.07-0.42]; gastrointestinal perforations, 0.10 [0.02-0.28].ConclusionsAESI IRs were stable to 7.8 years and generally <2.0 in the Overall plus P3b/4 [2020] Cohort, with the exception of herpes zoster [a known risk of tofacitinib treatment]. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304JCC Topic/keyword selection: 3. Clinical trials.

Project description:OBJECTIVES:Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ?50 years and with ?1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within. METHODS:This post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years' exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed. RESULTS:12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all tofacitinib cohorts' average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09-0.27) and 0.15 (0.09-0.22)); PE (0.12 (0.06-0.22) and 0.13 (0.08-0.21)); ATE (0.32 (0.22-0.46) and 0.38 (0.28-0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00-0.36) and 0.06 (0.02-0.15)); PE (0.13 (0.02-0.47) and 0.09 (0.04-0.19)); ATE (0.52 (0.22-1.02) and 0.22 (0.13-0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00-0.28) and 0.13 (0.00-0.70)); PE (0.08 (0.00-0.43) and 0.00 (0.00-0.46)); ATE (0.31 (0.08-0.79) and 0.38 (0.08-1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database. CONCLUSIONS:DVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32-0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13-0.41)).

Dataset Information

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

Publications

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

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