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Long-term safety and tolerability of oral tofacitinib in patients with Crohn's disease: results from a phase 2, open-label, 48-week extension study.

ABSTRACT: BACKGROUND:Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease. AIMS:This 48-week open-label extension study primarily investigated long-term safety of tofacitinib 5 and 10 mg b.d. and secondarily investigated efficacy as maintenance therapy in patients with Crohn's disease. METHODS:Patients who had completed the phase 2b maintenance study, or withdrawn due to treatment failure, were enrolled. Patients in remission (Crohn's disease activity index <150) at baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. A single dose adjustment was allowed after 8 weeks' fixed, open-label treatment. RESULTS:Sixty-two patients received tofacitinib 5 mg b.d.; 88 received 10 mg b.d. Both groups had similar rates of adverse events and serious infections. Crohn's disease worsening was the most frequent adverse event for tofacitinib 5 (33.9%) and 10 mg b.d. (19.3%). Patients not in remission at baseline, receiving 10 mg b.d., had higher rates of serious adverse events (19.3%) and discontinuation attributed to insufficient clinical response (30.7%) vs 5 mg b.d. (8.1% and 9.7%, respectively). At week 48, of patients with baseline remission receiving 5 mg b.d., 87.9% maintained remission and 75.0% sustained remission as observed (46.8% and 38.7%, respectively, by non-responder imputation). Study design prevented between-dose efficacy comparisons. CONCLUSIONS:No new safety signals emerged. Although both doses showed generally similar safety outcomes for overall adverse events, serious adverse events were more frequent for tofacitinib 10 than 5 mg b.d. Discontinuation due to insufficient clinical response was lower among patients in remission at baseline. ClinicalTrials.gov: NCT01470599.

SUBMITTER: Panes J

PROVIDER: S-EPMC6646954 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Long-term safety and tolerability of oral tofacitinib in patients with Crohn's disease: results from a phase 2, open-label, 48-week extension study.

Panés Julián J D'Haens Geert R GR Higgins Peter D R PDR Mele Linda L Moscariello Michele M Chan Gary G Wang Wenjin W Niezychowski Wojciech W Su Chinyu C Maller Eric E

Alimentary pharmacology & therapeutics 20190201 3

<h4>Background</h4>Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease.<h4>Aims</h4>This 48-week open-label extension study primarily investigated long-term safety of tofacitinib 5 and 10 mg b.d. and secondarily investigated efficacy as maintenance therapy in patients with Crohn's disease.<h4>Methods</h4>Patients who had completed the phase 2b maintenance study, or withdrawn due to treatment failure, were enrolled. Patients in r ...[more]

PMID: 30663107

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Project description:Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery-Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ-4.2), the Clinical Global Impression Scale-Severity of Illness (Δ-1.2), and the Sheehan Disability Scale (Δ-4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period.

Project description:Abstract Objective To assess the safety and efficacy of Tesomet (tesofensine plus metoprolol) in adults with hypothalamic obesity, a rare disease with no approved therapy. Research Design and Methods Twenty-one adults with hypothalamic obesity (16 females, 5 males) were randomized to Tesomet (0.5 mg tesofensine/50 mg metoprolol) (n=14) or placebo (n=8) during a 24-week double-blind period. On completion of the double-blind period, 17 (81%) subjects (11 Tesomet; 6 placebo) entered in to a 24-week open-label extension period and were treated with Tesomet. The primary endpoint was safety while secondary endpoints included measures of body weight, waist circumference, and body composition. Trial NCT03845075. Results The most common adverse events following the 24-week double-blind period and the 24-week open-label extension period were sleep disorder, dizziness, dry mouth, and headache; the majority of these adverse events were mild to moderate in severity. No significant nor clinically meaningful changes in heart rate or blood pressure were observed during the study. On completion of the double-blind period mean change in body weight (kg) was -7.84 for the Tesomet group versus -0.34 kg for the placebo group (P=0. 03). At the end of the open-label extension period mean change in body weight (kg) from baseline was -6.34 for the Tesomet-Tesomet group and -6. 03 for the placebo-Tesomet group. On completion of the double-blind period mean change in waist circumference (cm) was -7. 09 cm for the Tesomet group versus -1.16 for the placebo group (P=NS). At the end of the open-label extension period mean change in waist circumference (cm) from baseline was -5.73 for the Tesomet-Tesomet group and -3. 04 for the placebo-Tesomet group. On completion of the double-blind period mean change in fat mass (kg) was -5.28 for the Tesomet group versus -1.11 for the placebo group (P=NS). At the end of the open-label extension period mean change in fat mass (kg) from baseline was -4.84 for the Tesomet-Tesomet group and -3.85 for the placebo-Tesomet group. On completion of the double-blind period mean change in lean tissue mass (kg) was -2.76 for the Tesomet group versus 0.36 for the placebo group (P<0. 01). At the end of the open-label extension period mean change in lean mass (kg) from baseline was -1.64 for the Tesomet-Tesomet group and -2.22 for the placebo-Tesomet group. Discussion Tesomet was generally well tolerated after 48 weeks treatment and resulted in clinically meaningful improvements in body weight and body composition measures in adults with hypothalamic obesity. In contrast to previous studies of tesofensine monotherapy in general obesity, no significant nor clinically meaningful changes in cardiovascular measures were observed during the study. Conclusion Tesomet is a promising new experimental treatment for hypothalamic obesity. A randomized, placebo controlled, multi-center, dose-finding, Phase 2b study has now been initiated. Presentation: No date and time listed

Project description:ObjectiveThe purpose of this study was to evaluate the safety and efficacy of asenapine in adolescents with schizophrenia.MethodsIn an 8 week, randomized, double-blind placebo-controlled trial, subjects (12-17 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria for schizophrenia were randomized 1:1:1 to placebo, asenapine 2.5 mg b.i.d., or asenapine 5 mg b.i.d. Subjects who completed the 8 week acute study could participate in a 26 week flexible-dose asenapine-only open-label extension (OLE).ResultsA similar percentage of subjects completed treatment on day 56 (2.5 mg b.i.d. (n=98): 83%; 5 mg b.i.d. [n=106]: 79%; placebo [n=102]: 79%). In the mixed model for repeated measures analysis of the primary end-point (with Hochberg correction for multiplicity), least squares (LS) mean differences between asenapine and placebo on the Positive and Negative Syndrome Scale (PANSS) total score at day 56 were not significant (-4.8 for 2.5 mg b.i.d., p=0.070; -5.6 for 5 mg b.i.d., p=0.064). Significant improvement in the Clinical Global Impressions-Severity score was observed in the 5 mg b.i.d. group versus placebo on day 56 (LS mean -0.3, p=0.024). In the acute phase, ≥7% weight gain and the composite event of somnolence, sedation, and hypersomnia were more common in both asenapine groups than in the placebo group. Akathisia, fasting glucose elevation, and extrapyramidal syndrome were more common in the 5 mg b.i.d. group than in the placebo group. There were no unexpected adverse events in the OLE, and PANSS total scores decreased by -16.1 points in the group previously treated with placebo (n=62) and by -11.2 points in the continuous asenapine group (n=131) from OLE baseline to week 26.ConclusionsAlthough improvements in PANSS total score at day 56 of the acute phase were numerically greater for both asenapine 2.5 and 5 mg b.i.d. than for placebo and were maintained in the OLE, the primary end-point did not achieve statistical significance in the acute phase. No new or unexpected safety concerns were detected during the acute phase or after an additional 26 weeks of asenapine treatment in the adolescent population with schizophrenia.Clinical trials registryNCT01190254 and NCT1190267 at ClinicalTrials.gov.

Project description:Introduction/objectivesWe assess the impact of switching versus staying on the same tofacitinib dose on efficacy and safety in patients with rheumatoid arthritis (RA).MethodsORAL Sequel was an open-label, long-term extension study of patients with RA receiving tofacitinib 5 or 10 mg BID for up to 9.5 years. Tofacitinib doses could be switched during the study at investigator discretion. In this post hoc analysis, data from ORAL Sequel were stratified into four groups: 5 → 10 mg BID (Dose-up); 5 mg BID (Stay-on 5); 10 → 5 mg BID (Dose-down); and 10 mg BID (Stay-on 10). Efficacy assessments over 12 months included: change from baseline in 4-component Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28), and DAS28 minimum clinically important difference, remission, and low disease activity (LDA) rates. Safety was assessed for the study duration.ResultsGenerally, DAS28 improvements and minimum clinically important difference rates were significantly greater (p < 0.05) in Dose-up versus Stay-on 5 up to month 12. DAS28 remission rates were significantly greater in Dose-up versus Stay-on 5 at month 12. Change from baseline in DAS28 was similar in Dose-down and Stay-on 10. No significant differences in DAS28 LDA rates were observed between groups. Safety data were similar overall across the four groups.ConclusionIn patients with RA receiving open-label tofacitinib, this analysis found that some benefited from increasing dose from 5 to 10 mg BID and did not find that reducing dose from 10 to 5 mg BID affected efficacy or that dose switching in either direction affected safety.Study registrationClinicalTrials.gov number NCT00413699. Registered December 20, 2006. https://clinicaltrials.gov/ct2/show/NCT00413699 Key Points • This post hoc analysis of data from the long-term extension study, ORAL Sequel, assessed the impact of dose switching between tofacitinib 5 and 10 mg twice daily (BID), at the investigator's discretion, on efficacy and safety in patients with rheumatoid arthritis (RA). • Dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID was not generally associated with a significant loss of efficacy. • Safety outcomes were generally consistent across dose groups and did not change markedly after switching dose in either direction. • These findings can help to inform physicians on what may be expected in terms of efficacy and safety when adjusting tofacitinib dose according to clinical need. The recommended tofacitinib dosage for the treatment of RA in most jurisdictions is 5 mg BID.

Dataset Information

Long-term safety and tolerability of oral tofacitinib in patients with Crohn's disease: results from a phase 2, open-label, 48-week extension study.

Publications

Long-term safety and tolerability of oral tofacitinib in patients with Crohn's disease: results from a phase 2, open-label, 48-week extension study.

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