Baseline characteristics and enrichment results from the SONAR trial.

Aim: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin-to-creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here.

Methods: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.

Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy.

Aims: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR), with a large variability between patients.

Longitudinal Assessment of the Effect of Atrasentan on Thoracic Bioimpedance in Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan.

Objective: We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan.

Study Design: We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics.

Relationship Between Atrasentan Concentrations and Urinary Albumin to Creatinine Ratio in Western and Japanese Patients With Diabetic Nephropathy.

Purpose: The objective of the current analyses was to characterize the pharmacokinetic properties of atrasentan and the exposure-response relationships for the efficacy end point, urinary albumin to creatinine ratio (UACR), and the treatment-emergent adverse event, peripheral edema, during 8 or 12 weeks of treatment.

Methods: Results from 3 Phase II, randomized, double-blind, placebo-controlled studies (N = 257) were used for the population pharmacokinetic and exposure-response models. Concentration-time and response data for efficacy and tolerability were analyzed using a nonlinear mixed-effects population analysis and logistic regression approaches.

The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy.

We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.

Comparison of exposure response relationship of atrasentan between North American and Asian populations.

Aims: The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan.

Materials And Methods: Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.

Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers.

Background: A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes.

Design: We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes.

Predictors of Atrasentan-Associated Fluid Retention and Change in Albuminuria in Patients with Diabetic Nephropathy.

Background And Objectives: Endothelin A receptor antagonists (ERAs) decrease residual albuminuria in patients with diabetic kidney disease; however, their clinical utility may be limited by fluid retention. Consequently, the primary objective of this study was to identify predictors for ERA-induced fluid retention among patients with type 2 diabetes and CKD. A secondary objective was to determine if the degree of fluid retention necessarily correlated with the magnitude of albuminuria reduction in those patients receiving ERAs.

The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy.

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.

A multicenter, open-label, observational study of testosterone gel (1%) in the treatment of adolescent boys with klinefelter syndrome or anorchia.

Purpose: To assess the safety and clinical outcomes of 6-month treatment with testosterone gel 1% therapy in adolescent boys with primary hypogonadism resulting from Klinefelter syndrome (KS) or anorchia.

Methods: This was a subgroup analysis of a multicenter, open-label study of adolescent boys (N = 86) with delayed puberty who received .5-5.

One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.

Introduction: A new formulation of testosterone gel (1.62% testosterone gel) with increased viscosity and reduced volume of application has been shown to be safe and efficacious after 182 days of use in a phase 3, double-blind study in adult hypogonadal males.

Aim: The objective of this study was to evaluate the efficacy and safety of the 1.

Serum testosterone levels in non-dosed females after secondary exposure to 1.62% testosterone gel: effects of clothing barrier on testosterone absorption.

Objective: To evaluate secondary exposure of testosterone transferred to females from a male partner, dosed with 1.62% testosterone gel after direct skin-to-skin contact with the application site, and to investigate the effect of wearing a t-shirt on testosterone transfer.

Research Design And Methods: Across three studies, a total of 72 healthy males applied 5.

Effect of application site, clothing barrier, and application site washing on testosterone transfer with a 1.62% testosterone gel.

Objectives: To evaluate the effect of application site location, clothing barrier, and application site washing on testosterone transfer from males dosed with 1.62% testosterone gel to female partners.

Research Design And Methods: Open-label, randomized, parallel group, crossover study performed in 24 healthy male/female couples.

Effects of skin washing on systemic absorption of testosterone in hypogonadal males after administration of 1.62% testosterone gel.

Objective: The impact of washing on the pharmacokinetics, systemic absorption and residual testosterone on the skin after application of a 1.62% testosterone gel was investigated in an open-label, randomized, three-way crossover study in hypogonadal men.

Research Design And Methods: Twenty-four hypogonadal men (total testosterone <300 ng/dL) applied 5 g of 1.

Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men.

Introduction: Male hypogonadism is a significant and growing problem that can be successfully treated with testosterone replacement therapy. A new formulation of testosterone gel (1.62%) was developed with increased viscosity, reduced volume of application, and increased skin permeation compared with other currently available testosterone gels.

Pharmacokinetics and relative bioavailability of absorbed testosterone after administration of a 1.62% testosterone gel to different application sites in men with hypogonadism.

Objective: To determine the pharmacokinetics, bioavailability, and safety of a new formulation (1.62%) of testosterone gel that produces eugonadal serum testosterone levels with use of a lower amount of gel than the currently available 1% gels.

Methods: In an open-label, randomized, 3-way crossover study, 36 male patients with hypogonadism applied 5 g of 1.

Combined esterified estrogens and methyltestosterone versus esterified estrogens alone in the treatment of loss of sexual interest in surgically menopausal women.

Objective: To compare the effect of esterified estrogens and methyltestosterone versus esterified estrogens alone on diminished sexual interest in surgically menopausal women.

Design: This randomized, double-blind study compared the effect of combined esterified estrogens (1.25 mg) and methyltestosterone (2.