Kukulka M.,Takeda Development Center Americas Inc. |
Nudurupati S.,Takeda Development Center Americas Inc. |
Perez M.C.,Takeda Development Center Americas Inc.
Clinical and Experimental Gastroenterology | Year: 2017
Background: Dexlansoprazole is a proton pump inhibitor (PPI) approved for use in dual delayed-release capsule and orally disintegrating tablet (ODT) formulations. Aim: To assess effects of food, water, and route of administration on the bioavailability of dexlansoprazole 30-mg ODT. Methods: Two separate open-label, phase 1, single-dose crossover studies were conducted in healthy adults. In study 1, pharmacokinetic parameters were analyzed in participants receiving dexlansoprazole ODT in a fed or fasted state with and without water. In study 2, the bioavailability of dexlansoprazole after administration via oral syringe or nasogastric (NG) tube, or after swallowing intact with water was compared to ODT administration in the fasted state, swallowed without water. Blood samples for determining dexlansoprazole plasma concentrations and pharmacokinetic parameter estimates were collected before and after dosing. Results: Equivalent values for area under the plasma concentration-time curve (AUC) were observed in the fed and fasted states, but the maximum observed plasma concentration (Cmax) was 38% lower in the fed state; therefore, bioequivalence was not achieved. A water rinse following standard ODT administration decreased dexlansoprazole bioavailability, with lower Cmax and AUC values than when ODT was administered without a water rinse. Bioequivalence was demonstrated when comparing the alternative routes of administration, including via oral syringe or NG tube with standard ODT administration. Unlike with a water rinse, bioequivalence to standard ODT administration (i.e., without water) was demonstrated when swallowing the ODT intact with water. Rates of adverse events were comparable irrespective of administration route in the fasted state (6.7%-9.3%) and were 12% higher in the fed state than in the fasted state. Conclusion: The AUC from the dexlansoprazole ODT was equivalent when administered in the fed and fasted states. Equivalent systemic exposure to dexlansoprazole was achieved regardless of the administration route. © 2017 Kukulka et al.
Dong X.,Takeda Development Center Americas Inc. |
Kong L.,Penn State College of Medicine |
Wahed A.S.,University of Pittsburgh
Statistics in Medicine | Year: 2016
Biomarkers are often measured over time in epidemiological studies and clinical trials for better understanding of the mechanism of diseases. In large cohort studies, case-cohort sampling provides a cost effective method to collect expensive biomarker data for revealing the relationship between biomarker trajectories and time to event. However, biomarker measurements are often limited by the sensitivity and precision of a given assay, resulting in data that are censored at detection limits and prone to measurement errors. Additionally, the occurrence of an event of interest may preclude biomarkers from being further evaluated. Inappropriate handling of these types of data can lead to biased conclusions. Under a classical case cohort design, we propose a modified likelihood-based approach to accommodate these special features of longitudinal biomarker measurements in the accelerated failure time models. The maximum likelihood estimators based on the full likelihood function are obtained by Gaussian quadrature method. We evaluate the performance of our case-cohort estimator and compare its relative efficiency to the full cohort estimator through simulation studies. The proposed method is further illustrated using the data from a biomarker study of sepsis among patients with community acquired pneumonia. © 2016 John Wiley & Sons, Ltd.
Lin Y.,Takeda Development Center Americas Inc.
Contemporary Clinical Trials Communications | Year: 2016
Responder analysis is in common use in clinical trials, and has been described and endorsed in regulatory guidance documents, especially in trials where "soft" clinical endpoints such as rating scales are used. The procedure is useful, because responder rates can be understood more intuitively than a difference in means of rating scales. However, two major issues arise: 1) such dichotomized outcomes are inefficient in terms of using the information available and can seriously reduce the power of the study; and 2) the results of clinical trials depend considerably on the response cutoff chosen, yet in many disease areas there is no consensus as to what is the most appropriate cutoff. This article addresses these two issues, offering a novel approach for responder analysis that could both improve the power of responder analysis and explore different responder cutoffs if an agreed-upon common cutoff is not present. Specifically, we propose a statistically rigorous clinical trial design that pre-specifies multiple tests of responder rates between treatment groups based on a range of pre-specified responder cutoffs, and uses the minimum of the p-values for formal inference. The critical value for hypothesis testing comes from permutation distributions. Simulation studies are carried out to examine the finite sample performance of the proposed method. We demonstrate that the new method substantially improves the power of responder analysis, and in certain cases, yields power that is approaching the analysis using the original continuous (or ordinal) measure. © 2016 Published by Elsevier Inc.
Zhang S.,Takeda Development Center Americas Inc.
Pediatric Rheumatology | Year: 2016
Mevalonate kinase deficiency (MKD), a very rare autosomal recessive autoinflammatory disease with multiple organ involvement, presents clinically as hyperimmunoglobulinemia D syndrome (HIDS), a less severe phenotype and more common form, and mevalonic aciduria (MVA), a more severe phenotype and rare form. MKD is characterized by recurrent febrile attacks that are frequently accompanied by lymphadenopathy, gastrointestinal symptoms, arthralgia, myalgia, skin rash, and aphthous ulcers. Patients with MVA also have intrauterine growth retardation, congenital defects (cataracts, shortened limbs, and dysmorphic craniofacial features), neurological disease, and failure to thrive. Mean age at onset of symptoms is within the first year of life. There is a delay by several years between symptom onset and diagnosis, which is in part attributable to the initial misdiagnosis due to the rarity and nonspecific clinical manifestations of disease. The frequency of recurrent febrile attacks is highest in childhood and gradually decreases after adolescence. MKD is associated with rare long-term complications such as type AA amyloidosis, joint contractures, abdominal adhesions, renal angiomyolipoma, and severe pneumococcal infections. Frequent febrile attacks significantly impair several aspects of patients' and caregivers' quality of life, with an adverse impact on patients' daily activities, education, and employment. Lifespan is generally normal for HIDS whereas MVA can be fatal in early childhood. © 2016 Zhang.
Del Prato S.,University of Pisa |
Camisasca R.,Takeda Development Center Europe Ltd. |
Wilson C.,Takeda Development Center Americas Inc. |
Fleck P.,Takeda Development Center Americas Inc.
Diabetes, Obesity and Metabolism | Year: 2014
Aims: To evaluate the long-term durability of the efficacy of alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin. Methods: This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18-80 years to 104 weeks of treatment with metformin in addition to alogliptin 12.5 mg once daily (n = 880), alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks. Results: The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were -0.68%, -0.72% and -0.59% for alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p<0.001); alogliptin 25 mg met superiority criteria (p=0.010)]. Fasting plasma glucose concentration decreased by 0.05 and 0.18 mmol/l for alogliptin 12.5 and 25 mg, respectively, and increased by 0.30 mmol/l for glipizide (p < 0.001 for both comparisons with glipizide). Mean weight changes were -0.68, -0.89 and 0.95 kg for alogliptin 12.5 and 25 mg and glipizide, respectively (p < 0.001 for both comparisons with glipizide). Hypoglycaemia occurred in 23.2% of patients in the glipizide group vs. 2.5 and 1.4% of patients in the alogliptin 12.5 and 25 mg groups, respectively. Pancreatitis occurred in one patient in the alogliptin 25 mg group and three in the glipizide group. Conclusions: Alogliptin efficacy was sustained over 2 years in patients with inadequate glycaemic control on metformin alone. © 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Lin J.H.,Takeda Development Center Americas Inc. |
Giovannucci E.,Harvard University
Current Colorectal Cancer Reports | Year: 2014
Colorectal cancers are a group of heterogeneous disorders that involve interactions among environmental influences, germ-line susceptibility factors, and accumulated genetic and epigenetic changes in the colorectal epithelium. This review provides background on environmental exposure and molecular pathways during colorectal cancer pathogenesis. Additionally, the review discusses the interplay between these risk factors in the context of colorectal cancer development and progression. Smoking, obesity, and regular aspirin use appear to have profound effects on colorectal cancer initiation and prognosis through the activation of pathways targeting gene methylation, inflammation, insulin mitogenesis, and cell proliferation. New data on other types of exposure and molecular changes will continue to improve our understanding of the cause of colorectal cancer, leading to novel therapeutic and preventive strategies and ultimate reduction in disease burden. © 2014 Springer Science+Business Media.
Jacobsen P.L.,Takeda Development Center Americas Inc. |
Harper L.,CNS Healthcare |
Chrones L.,Takeda Development Center Americas Inc. |
Chan S.,Takeda Development Center Americas Inc. |
Mahableshwarkar A.R.,Takeda Development Center Americas Inc.
International Clinical Psychopharmacology | Year: 2015
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. © 2015 Wolters Kluwer Health, Inc.
Lin Y.,Takeda Development Center Americas Inc. |
Zhu M.,Abbvie Inc. |
Su Z.,Deerfield Institute
Contemporary Clinical Trials | Year: 2015
Randomization is fundamental to the design and conduct of clinical trials. Simple randomization ensures independence among subject treatment assignments and prevents potential selection biases, yet it does not guarantee balance in covariate distributions across treatment groups. Ensuring balance in important prognostic covariates across treatment groups is desirable for many reasons. A broad class of randomization methods for achieving balance are reviewed in this paper; these include block randomization, stratified randomization, minimization, and dynamic hierarchical randomization. Practical considerations arising from experience with using the techniques are described. A review of randomization methods used in practice in recent randomized clinical trials is also provided. © 2015 Elsevier Inc. All rights reserved.
Pratley R.E.,Sanford Burnham Institute for Medical Research |
Fleck P.,Takeda Development Center Americas Inc. |
Wilson C.,Takeda Development Center Americas Inc.
Diabetes, Obesity and Metabolism | Year: 2014
Aim: To evaluate the efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin plus metformin (A+M) initial combination therapy versus either as monotherapy in drug-naïve T2DM patients. Methods: This international, randomized, double-blind, placebo-controlled, 26-week study involved T2DM patients with hyperglycaemia (HbA1c 7.5-10.0%) following diet/exercise therapy. Patients (N=784) received placebo, alogliptin (A, 12.5mg BID or 25mg QD), metformin (M, 500 or 1000mg BID) or A+M (12.5/500 or 12.5/1000mg BID); placebo, A25 for secondary analyses only. Endpoints: week26 changes from baseline in HbA1c (primary), fasting plasma glucose (FPG) and 2-h postprandial glucose (PPG); incidences of clinical response and hyperglycaemic rescue. Results: Week 26 mean HbA1c reductions from baseline (8.45%) were -1.22 and -1.55% with A+M 12.5/500 and 12.5/1000 versus -0.56, -0.65, and -1.11% with A12.5, M500 and M1000 (p<0.001, A+M vs. component monotherapies). FPG reductions were -1.76 and -2.55 mmol/L with 12.5/500 and 12.5/1000 versus -0.54, -0.64 and -1.78 mmol/L with A12.5, M500 and M1000 (p<0.05, A+M vs. component monotherapies). Significantly more A+M-treated patients achieved HbA1c<7% (47.1-59.5% vs. 20.2-34.3% with monotherapy), significantly fewer required hyperglycaemic rescue (2.6-12.3% vs. 10.8-22.9% with monotherapy). A+M caused only mild/moderate hypoglycaemia (1.9-5.3%) and weight loss (0.6-1.2kg). Conclusions: Alogliptin plus metformin initial combination therapy was well tolerated yet more efficacious in controlling glycaemia in drug-naïve T2DM patients than either as monotherapy. © 2014 John Wiley & Sons Ltd.
Liang H.,Takeda Development Center Americas Inc. |
Vallarino C.,Takeda Development Center Americas Inc. |
Joseph G.,Takeda Development Center Americas Inc. |
Manne S.,Takeda Development Center Americas Inc. |
And 2 more authors.
Diabetes Care | Year: 2014
OBJECTIVE: To compare the risk of subsequent myocardial infarction (MI) between patients with and without type 2 diabetes mellitus (T2DM) in a retrospective cohort study. RESEARCH DESIGN AND METHODS: Patients with their first MI recorded in the U.K. General Practice Research Database in 1997-2008 were classified as T2DM, diagnosed before or within 28 days after the date of the first recordedMI (i.e., the index date), or non-T2DM. Patients diagnosed within 28 days after the index date were assumed to have developed T2DM at baseline (i.e., before the index date). The primary outcome was the first subsequentMI. The secondary outcomes were all-cause death and a composite of all-cause death or subsequent MI. Cox proportional hazards models were fit to obtain hazard ratios (HRs) for all outcomes. RESULTS: A total of 7,411 T2DM (median age 72 years; men 63.4%) and 48,726 non-T2DM patients (median age 69 years; men 65.3%) were included. The crude incidences (per 1,000 patient-years) in T2DMvs. non-T2DMwere 32.8 vs. 22.8 for subsequent MI, 83.7 vs. 52.1 for all-cause death, and 106.5 vs. 69.9 for the composite end point. The adjusted HRs for subsequent MI, all-cause death, and their combination were 1.41 (95% CI 1.27-1.56), 1.50 (1.41-1.60), and 1.42 (1.34-1.50), respectively, in women and 1.23 (1.14-1.34), 1.40 (1.33-1.47), and 1.33 (1.27-1.39) in men. CONCLUSIONS: Compared with non-T2DM, T2DM was associated with an increased risk for subsequent MI, all-cause death, and their composite end point. The risk tends to be higher in women than in men. © 2014 by the American Diabetes Association.