Safety and Efficacy of GFB-887, a TRPC5 Channel Inhibitor, in Patients With Focal Segmental Glomerulosclerosis, Treatment-Resistant Minimal Change Disease, or Diabetic Nephropathy: TRACTION-2 Trial Design.

Introduction: A critical unmet need exists for precision therapies for chronic kidney disease. GFB-887 is a podocyte-targeting, small molecule inhibitor of transient receptor potential canonical-5 (TRPC5) designed specifically to treat patients with glomerular kidney diseases characterized by an overactivation of the TRPC5-Rac1 pathway. In a first-in-human study, GFB-887 was found to be safe and well tolerated, had a pharmacokinetic (PK) profile allowing once-daily dosing, and dose dependently decreased urinary Rac1 in healthy adults.

The NOCTURNE Randomized Trial Comparing 2 Tolvaptan Formulations.

Introduction: Tolvaptan, a treatment for autosomal dominant polycystic kidney disease (ADPKD), inhibits vasopressin V2 receptor signaling, which causes aquaretic adverse events (AAEs). The short-term efficacy and tolerability of a once-daily, modified-release (MR) formulation was assessed relative to the twice-daily, immediate-release (IR) formulation.

Methods: This Phase 2 multicenter, randomized (1:1:1:1), placebo-controlled, double-blind, placebo-masked, parallel-group study (NCT01451827) compared tolvaptan MR 50 mg once daily or tolvaptan MR 80 mg once daily with tolvaptan IR 60/30 mg daily split dose and placebo over 8 weeks in 177 subjects.

A Randomized Trial of Modified-Release Versus Immediate-Release Tolvaptan in ADPKD.

Introduction: Tolvaptan, for treatment of autosomal dominant polycystic kidney disease (ADPKD), is provided as immediate-release (IR) tablets administered twice daily in split-dose regimens to suppress urine osmolality to <300 mOsm/kg. A modified-release (MR) formulation was developed for once-daily (QD) dosing to increase compliance and mitigate urinary symptom burden. This phase 2, dose-ranging study (NCT01210560) compared pharmacokinetics, pharmacodynamics, and tolerability of several MR regimens with IR in patients with ADPKD.

Plasma copeptin levels predict disease progression and tolvaptan efficacy in autosomal dominant polycystic kidney disease.

In the TEMPO 3:4 Trial, treatment with tolvaptan, a vasopressin V2 receptor antagonist, slowed the increase in total kidney volume and decline in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether plasma copeptin levels, a marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy. This post hoc analysis included 1,280 TEMPO 3:4 participants (aged 18-50 years, estimated creatinine clearance ≥60 ml/min and total kidney volume ≥750 mL) who had plasma samples available at baseline for measurement of copeptin using an automated immunofluorescence assay.

Standardizing total kidney volume measurements for clinical trials of autosomal dominant polycystic kidney disease.

Background: The ability of unstandardized methods to track kidney growth in clinical trials for autosomal dominant polycystic kidney disease (ADPKD) has not been critically evaluated.

Methods: The Tolvaptan Efficacy and Safety Management of ADPKD and its Outcomes (TEMPO) 3:4 study involved baseline and annual magnetic resonance follow-up imaging yearly for 3 years. Total kidney volume (TKV) measurements were performed on these four time points in addition to the baseline imaging in TEMPO 4:4, initially by Perceptive Informatics (Waltham, MA, USA) using planimetry (original dataset) and for this study by the Mayo Translational PKD Center using semiautomated and complementary automated methods (sequential dataset).

Long-Term Administration of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease.

Background And Objectives: In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy.

Design, Setting, Participants, & Measurements: One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic.

Tolerability of Aquaretic-Related Symptoms Following Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Results From TEMPO 3:4.

Introduction: In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance.

Methods: A analysis of tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4.

Development of the Autosomal Dominant Polycystic Kidney Disease Impact Scale: A New Health-Related Quality-of-Life Instrument.

Background: The impact of autosomal dominant polycystic kidney disease (ADPKD) on health-related quality of life (HRQoL) is not well understood due to a lack of instruments specific to the condition.

Study Design: Content for a new self-administered patient-reported outcome (PRO) questionnaire to assess ADPKD-related HRQoL was developed through clinical expert and patient focus group discussions. The new PRO instrument was administered to study patients with ADPKD to evaluate its reliability and validity.

A Drug Development Tool for Trial Enrichment in Patients With Autosomal Dominant Polycystic Kidney Disease.

Introduction: Total kidney volume (TKV) is a promising imaging biomarker for tracking and predicting the natural history of patients with autosomal dominant polycystic kidney disease.

Methods: A drug development tool was developed by linking longitudinal TKV measurements to the probability of a 30% decline of estimated glomerular filtration rate (eGFR) or end-stage renal disease. Drug development tools were developed based on observational data collected over multiple decades for an eGFR decline and end-stage renal disease in 641 and 866 patients with autosomal dominant polycystic kidney disease, respectively.

Total Kidney Volume Is a Prognostic Biomarker of Renal Function Decline and Progression to End-Stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease.

Introduction: Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. TKV is a promising imaging biomarker for tracking and predicting the natural history of autosomal dominant polycystic kidney disease. The prognostic value of TKV was evaluated, in combination with age and eGFR, for the outcomes of 30% decline in eGFR and progression to ESRD.

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

Background: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown.

Methods: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial.

Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial.

Background: The PROPKD score has been proposed to stratify the risk of progression to end-stage renal disease in autosomal dominant polycystic kidney disease (ADPKD) subjects. We aimed to assess its prognostic value in a genotyped subgroup of subjects from the Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (TEMPO3/4) trial.

Methods: In the post hoc analysis, PKD1 and PKD2 were screened in 770 subjects and the PROPKD score was calculated in mutation-positive subjects (male: 1 point; hypertension <35 years: 2 points; first urologic event <35 years: 2 points; nontruncating PKD1 mutation: 2 points; truncating PKD1 mutation: 4 points).

Performance of an Artificial Multi-observer Deep Neural Network for Fully Automated Segmentation of Polycystic Kidneys.

Deep learning techniques are being rapidly applied to medical imaging tasks-from organ and lesion segmentation to tissue and tumor classification. These techniques are becoming the leading algorithmic approaches to solve inherently difficult image processing tasks. Currently, the most critical requirement for successful implementation lies in the need for relatively large datasets that can be used for training the deep learning networks.

Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial.

Background: In TEMPO 3:4, the vasopressin V2 receptor antagonist tolvaptan slowed total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline relative to placebo.

Methods: TEMPO 4:4 was designed to provide an additional 2 years of data on the long-term safety and efficacy of tolvaptan in subjects completing TEMPO 3:4. The objective was to assess the disease-modifying effects of tolvaptan on TKV and eGFR end-points including change from baseline over the combined duration of TEMPO 3:4 and TEMPO 4:4, and non-inferiority of slopes during TEMPO 4:4.

Tolvaptan use in cancer patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone: a post hoc analysis of the SALT-1 and SALT-2 trials.

Hyponatremia is a common electrolyte disorder in cancer patients and has been associated with poor prognosis. A frequent cause of cancer-related hyponatremia is the syndrome of inappropriate antidiuretic hormone (SIADH). This study was a post hoc subgroup analysis of the SALT-1 (Study of Ascending Levels of Tolvaptan in Hyponatremia) and SALT-2 clinical trials.

Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial.

In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2-receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient-reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split-dose regimen: a single ascending-dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split-dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8-week open-label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg).

Rationale and Design of a Clinical Trial Investigating Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease.

Background: In TEMPO 3:4, the vasopressin V2-receptor antagonist tolvaptan slowed kidney growth and function decline in autosomal dominant polycystic kidney disease (ADPKD) patients with relatively preserved kidney function.

Methods: Prospective, phase 3b, multi-center, randomized-withdrawal, placebo-controlled, double-blind trial of tolvaptan in ADPKD patients with late stage 2 to early stage 4 chronic kidney disease (CKD). The primary endpoint was estimated glomerular filtration rate (eGFR) change from pre-treatment baseline to post-treatment follow-up.

Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial.

The vasopressin-cAMP-osmolality axis is abnormal in autosomal dominant polycystic kidney disease (ADPKD). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial, a 3-year randomized, placebo-controlled trial in adults, the vasopressin V2 receptor antagonist tolvaptan slowed ADPKD progression in patients with preserved GFR. Here, we investigated the determinants of baseline urine osmolality (Uosm) and its value as a severity marker of ADPKD, the factors influencing the response to tolvaptan, and whether change in Uosm associated with key trial end points.

Tolvaptan and Kidney Pain in Patients With Autosomal Dominant Polycystic Kidney Disease: Secondary Analysis From a Randomized Controlled Trial.

Background: Kidney pain is a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD), and data from the TEMPO 3:4 trial suggested that tolvaptan, a vasopressin V2 receptor antagonist, may have a positive effect on kidney pain in this patient group. Because pain is difficult to measure, the incidence of kidney pain leading to objective medical interventions was used in the present study to assess pain.

Study Design: Secondary analysis from a randomized controlled trial.

Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial.

Background: The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable.

Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease: The TEMPO 3:4 Clinical Trial.

Introduction: Patients with slowly progressive autosomal dominant polycystic kidney disease (ADPKD) are unlikely to experience outcomes during randomized controlled trials (RCTs). An image classification of ADPKD into typical (diffuse cyst distribution) class 1A to E (by age- and height-adjusted total kidney volume [TKV]) and atypical (asymmetric cyst distribution) class 2 was proposed for prognostic enrichment design, recommending inclusion of only classes 1C to 1E in RCTs.

Methods: A exploratory analysis was conducted of the TEMPO 3:4 Trial, a prospective, randomized, double-blinded, controlled clinical trial in adult subjects with ADPKD, an estimated creatinine clearance >60 ml/min and total kidney volume >750 ml.