Takeda Global Research and Development

Anderson, IL, United States

Takeda Global Research and Development

Anderson, IL, United States

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Bonner G.,Park Klinikum Bad Krozingen | Bakris G.L.,University of Chicago | Sica D.,Virginia Commonwealth University | Weber M.A.,Brooklyn College | And 5 more authors.
Journal of Human Hypertension | Year: 2013

Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150-180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57±11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg. Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1-2 hypertension with AZL-M was more effective than RAM and better tolerated. © 2013 Macmillan Publishers Limited All rights reserved.


Taylor W.J.,University of Otago | Singh J.A.,University of Alabama at Birmingham | Saag K.G.,University of Alabama at Birmingham | Dalbeth N.,University of Auckland | And 9 more authors.
Journal of Rheumatology | Year: 2011

Objective. To review a novel approach for constructing composite response criteria for use in chronic gout clinical trials that implements a method of multicriteria decision-making. Methods. Preliminary work with paper patient profiles led to a restricted set of core-set domains that were examined using 1000Minds™ by rheumatologists with an interest in gout, and (separately) by OMERACT registrants prior to OMERACT 10. These results and the 1000Minds approach were discussed during OMERACT 10 to help guide next steps in developing composite response criteria. Results. There were differences in how individual indicators of response were weighted between gout experts and OMERACT registrants. Gout experts placed more weight upon changes in uric acid levels, whereas OMERACT registrants placed more weight upon reducing flares. Discussion highlighted the need for a "pain" domain to be included, for "worsening" to be an additional level within each indicator, for a group process to determine the decision-making within a 1000Minds exercise, and for the value of patient involvement. Conclusion. Although there was not unanimous support for the 1000Minds approach to inform the construction of composite response criteria, there is sufficient interest to justify ongoing development of this methodology and its application to real clinical trial data. The Journal of Rheumatology Copyright © 2011. All rights reserved.


Dalbeth N.,University of Auckland | McQueen F.M.,University of Auckland | Singh J.A.,University of Alabama at Birmingham | MacDonald P.A.,Takeda Global Research and Development | And 9 more authors.
Journal of Rheumatology | Year: 2011

Despite the recognition that tophus regression is an important outcome measure in clinical trials of chronic gout, there is no agreed upon method of tophus measurement. A number of methods have been used in clinical trials of chronic gout, from simple physical measurement techniques to more complex advanced imaging methods. This article summarizes methods of tophus measurement and discusses their properties. Physical measurement using Vernier calipers meets most aspects of the Outcome Measures in Rheumatology (OMERACT) filter. Rigorous testing of the complex methods, particularly with respect to reliability and sensitivity to change, is needed to determine the appropriate use of these methods. Further information is also required regarding which method of physical measurement is best for use in future clinical trials. The need to develop and test a patient-reported outcome measure of tophus burden is also highlighted. The Journal of Rheumatology Copyright © 2011. All rights reserved.


Dalbeth N.,University of Auckland | Schauer C.,University of Auckland | MacDonald P.,Takeda Global Research and Development | Perez-Ruiz F.,Hospital Of Cruces | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective: To identify methods of tophus measurement for gout studies, summarise the properties of these methods and compile a detailed pictorial reference guide to demonstrate the methods. Methods: A systematic search strategy for methods of tophus measurement was formulated. For each method, papers were assessed by two reviewers to summarise information according to the specific components of the Outcomes Measures in Rheumatology (OMERACT) filter: feasibility, truth and discrimination. Detailed images were obtained to construct the reference guide. Results: Eight methods of tophus measurement were identified: counting the total number of tophi, physical measurement using tape measure, physical measurement using Vernier callipers, digital photography, ultrasonography (US), MRI, CT and dual energy CT. Feasibility aspects of the methods are well documented. Physical measurement techniques are more feasible than advanced imaging methods, but do not allow for assessment of intra-articular tophi or for data storage and central reading. The truth aspect of the filter has been documented for many methods, particularly Vernier callipers, US, MRI and CT. Reliability of most methods has been reported as very good or excellent. Sensitivity to change has been reported for all methods except MRI and CT. Conclusion: A variety of methods of tophus assessment have been described for use in clinical trials of chronic gout. Physical measurement techniques (particularly the Vernier calliper method) and US measurement of tophus size appear to meet most aspects of the OMERACT filter.


Stringer F.,Takeda Pharmaceutical | Dejongh J.,LAP and P Consultants BV | Dejongh J.,Leiden Amsterdam Center for Drug Research | Scott G.,Takeda Global Research and Development | And 2 more authors.
Journal of Clinical Pharmacology | Year: 2014

The pharmacokinetics of sipoglitazar, a peroxisome proliferator activated receptor agonist, are subject to high inter-individual variability resulting from a polymorphism of the UGT2B15 genotype. The aim of the current analysis was to apply a PK-PD model-based approach to evaluate the influence of UGT2B15 driven pharmacokinetic differences on the clinical response. Efficacy and safety of sipoglitazar compared to placebo were assessed in Type 2 Diabetes Mellitus patients in two Phase II randomized, double-blind studies (sipoglitazar once daily: 8, 16, 32, or 64 mg; sipoglitazar twice daily: 16 or 32 mg; rosiglitazone 8 mg once daily and placebo for 13 weeks; n = 780). Changes in fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels over time were described as a function of individual drug exposure using a simultaneous, cascading indirect response model structure. The effects on FPG and HbA1c could successfully be described for placebo, rosiglitazone, and sipoglitazar treated groups in all three UGT2B15 genotypes. Differences in drug effects between genotypes were fully explained by differences in drug exposure. The current PK-PD analysis confirms that UGT2B15 genotype is a major determinant for differences in FPG and HbA1c response to sipoglitazar treatment between Type 2 Diabetes mellitus patients, due to related differences in drug exposure. © 2013, The American College of Clinical Pharmacology.


Stringer F.,Takeda Pharmaceutical | Scott G.,Takeda Global Research and Development | Valbuena M.,Takeda Global Research and Development | Kinley J.,Takeda Global Research and Development | And 2 more authors.
European Journal of Clinical Pharmacology | Year: 2013

Purpose: Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar. Methods: Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug. Results: Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC0-∞ explained by UGT2B15 was 66.7 % (P < 0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant (UGT2B15*2/*2) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher). Conclusions: These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group. © 2012 Springer-Verlag.


Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Inzucchi S.E.,Yale University | Seufert J.,University Hospital Freiburg | Fleck P.R.,Takeda Global Research and Development | And 2 more authors.
Diabetes Care | Year: 2010

OBJECTIVE - To assess the efficacy and tolerability of alogliptin plus pioglitazone for initial combination therapy in drug-naïve type 2 diabetic patients. RESEARCH DESIGN AND METHODS - This 26-week, double-blind, parallel-group study randomized 655 patients with inadequately controlled type 2 diabetes to four arms: 25 mg alogliptin (A25) q.d. monotherapy, 30 mg pioglitazone (P30) q.d. monotherapy, or 12.5 (A12.5) or 25 mg alogliptin q.d. plus pioglitazone (P30) q.d. combination therapy. Primary efficacy was A1C change from baseline with the high-dose combination (A25 + P30) versus each monotherapy. RESULTS - Combination therapy with A25 + P30 resulted in greater reductions in A1C (-1.7 ± 0.1% from an 8.8% mean baseline) vs. A25 (-1.0 ± 0.1%, P<0.001) or P30 (-1.2 ± 0.1%, P < 0.001) and in fasting plasma glucose (-2.8 ± 0.2 mmol/l) vs. A25 (<1.4 ± 0.2 mmol/l, P < 0.001) or P30 (-2.1 ± 0.2 mmol/l, P = 0.006). The A25 + P30 safety profile was consistent with those of its component monotherapies. CONCLUSIONS - Alogliptin plus pioglitazone combination treatment appears to be an efficacious initial therapeutic option for type 2 diabetes. © 2010 by the American Diabetes Association.


De Fronzo R.A.,University of Texas at San Antonio | Burant C.F.,University of Michigan | Fleck P.,Takeda Global Research and Development | Wilson C.,Takeda Global Research and Development | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Optimal management of type 2 diabetes remains an elusive goal. Combination therapy addressing the core defects of impaired insulin secretion and insulin resistance shows promise in maintaining glycemic control. Objective: The aim of the study was to assess the efficacy and tolerability of alogliptin combined with pioglitazone in metformin-treated type 2 diabetic patients. Design, Setting, and Patients: We conducted a multicenter, randomized, double-blind, placebocontrolled, parallel-arm study in patients with type 2 diabetes. Interventions: The study consisted of 26-wk treatment with alogliptin (12.5 or 25 mg qd) alone or combined with pioglitazone (15, 30, or 45 mg qd) in 1554 patients on stable-dose metformin monotherapy (>1500 mg) with inadequate glycemic control. Main Outcome Measure: The primary endpoint was change in glycosylated hemoglobin (HbA1c) from baseline to wk 26. Secondary endpoints included changes in fasting plasma glucose and β-cell function. Primary analyses compared pioglitazone therapy [all doses pooled, pioglitazone alone (Pio alone); n = 387] with alogliptin 12.5 mg plus any dose of pioglitazone (A12.5 + P; n = 390) or alogliptin 25 mg plus any dose of pioglitazone (A25 + P; n = 390). Results: When added to metformin, the least squares mean change (LSMA) from baseline HbA1c was -0.9 ± 0.05% in the Pio-alone group and -1.4 ± 0.05% in both the A12.5 + P and A25 + P groups (P < 0.001 for both comparisons). A12.5 + P and A25 + P produced greater reductions in fasting plasma glucose (LSMA = -2.5 ± 0.1 mmol/liter for both) than Pio alone (LSMA = -1.6 ± 0.1 mmol/liter; P < 0.001). A12.5 + P and A25 + P significantly improved measures of β-cell function (proinsulin:insulin and homeostasis model assessment of β-cell function) compared to Pio alone, but had no effect on homeostasis model assessment of insulin resistance. The LSMA body weight was 1.8 ± 0.2, 1.9 ± 0.2, and 1.5 ± 0.2 kg in A12.5 + P, A25 + P, and Pio-alone groups, respectively. Hypoglycemia was reported by 1.0,1.5, and 2.1% of patients in the A12.5 + P, A25 + P, and Pio-alone groups, respectively. Conclusions: In type 2 diabetic patients inadequately controlled by metformin, the reduction in HbA1c by alogliptin and pioglitazone was additive. The decreases in HbA1c with A12.5 +P and A25 + P were similar. All treatments were well tolerated. Copyright © 2012 by The Endocrine Society.


Sun S.S.,Virginia Commonwealth University | Sabo R.,Virginia Commonwealth University | Arslanian S.,University of Pittsburgh | Wu R.,Takeda Global Research and Development | Sabo C.,Virginia Commonwealth University
Journal of Public Health (Germany) | Year: 2012

Objective To document age- and sex-related differences in the 16 phenotypes of risk factors for the metabolic syndrome (MS) among adults in the Fels Longitudinal Study (FLS). Methods Data on risk factors for the MS were analyzed in 471 white men and 503 white women in the FLS. We used the Cochran-Armitage test to compare age- and sex-related differences in the prevalence of the 16 diagnostic clusters of positive risk factors. Results Of the 974 subjects, 238 were found to meet diagnostic criteria for 15 of a possible 16 phenotypes of the MS. The prevalence of the MS was four times greater in subjects older than 40 years than in subjects 20-40 years old. Older subjects had more risk factors exceeding criterion values than younger subjects. Among those who met three-to-five criteria for the MS, younger subjects were more likely to have dyslipidemia, less likely to have high blood pressure (HBP), and two times less likely to have impaired fasting plasma glucose (IFG) than subjects 40+ years old. Older men were more likely than older women to have HBP and IFG. . We found that if one of the five risk factors reaches a criterion value, the values for the other four risk factors move closer to their own diagnostic criterion values in apparent synchrony. Conclusions Subjects 40+ years old are four times likelier to have the MS than younger subjects, and older men are at higher risk than older women. The mean values for each of the five risk factors get progressively worse as the number of risk factors meeting diagnostic criteria increases. Therefore, when one factor is found to meet its diagnostic criterion, levels of the other four risk factors should be measured. The different phenotypic patterns that comprise the MS should prompt clinicians to target specific risk factors for prevention or treatment. Certain phenotypes were found more commonly in women and certain others more commonly in men. Similarly, certain phenotypes were found more commonly in older than in younger age groups. These age- and sex-specific phenotypes should help clinicians to identify subjects at highest risk for certain risk factors and to initiate specifically tailored preventive and therapeutic interventions. Our observations should also stimulate clinical investigators and epidemiologists to ascertain what factors determine the sex and age specificity of certain phenotypes of the MS. © The Author(s) 2012.


Levin S.,Takeda Global Research and Development | McMahon E.,Pfizer | John-Baptiste A.,Pfizer | Bell R.R.,Pfizer
Toxicologic Pathology | Year: 2013

Eplerenone (Inspra®) is an aldosterone receptor antagonist approved for the treatment of hypertension and heart failure after a myocardial infarction. In vitro receptor binding and transactivation studies showed eplerenone had high selectivity for the mineralocorticoid receptor over other steroid receptors (glucocorticoid, androgen, and progesterone). The most sensitive off-target effect of orally administered eplerenone preclinically was prostate atrophy in dogs. Dose-related prostate atrophy was observed at eplerenone dosages ≥15 mg/kg/day for 13 weeks or longer. The no observed adverse effect level (NOAEL) for the prostate effect in dogs was 5 mg/kg/day. The maximal effect was seen by 13 weeks and the atrophy was reversible even after 1 year of daily treatment. An additional study demonstrated dogs with eplerenone-induced prostate atrophy (confirmed by intrarectal ultrasound) had slightly decreased semen volume but no compound-related effects on libido, semen protein content, sperm motility, daily sperm production, or epididymal sperm transit time. Four possible mechanisms for prostate effect were investigated: (1) inhibition of testosterone synthesis and secretion; (2) inhibition of 5α-reductase, the enzyme within the prostate that converts testosterone into the more active growth factor dihydrotestosterone (DHT); (3) competitive antagonism of the androgen receptor; and (4) inhibition of 5α-reductase or competitive antagonism of the androgen receptor by aldosterone, which increased in dogs treated with eplerenone. Data from these studies supported blockade of androgen receptors at suprapharmacological concentrations of eplerenone. Another mineralocorticoid blocker, spironolactone, had greater antiandrogenic activity than eplerenone both in vivo and in vitro, and it has well known clinically significant antiandrogenic effects in humans, whereas eplerenone does not. © 2013 by The Author(s).

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