Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure: Extent of Renal Damage

Phase 3

Withdrawn

• Conditions: Heart Failure; Pulmonary Hypertension
• Interventions: Drug: Placebo; Drug: Tadalafil

• Registration Number: NCT01960153
• Lead Sponsor: Massachusetts General Hospital

Brief Summary

PITCH-ER is an ancillary study of PITCH-HF (NCT01910389). The goal of the PITCH-ER ancillary study is to evaluate the rate of decline in renal function and frequency of development of acute kidney injury (AKI) in patients enrolled in PITCH-HF (who have heart failure and pulmonary hypertension) treated with chronic tadalafil treatment compared to placebo.

Detailed Description

The National Heart, Lung, and Blood Institute (NHLBI)-funded parent study (PITCH-HF) is the first well-controlled, randomized, large-scale trial studying the effect of tadalafil, an FDA-approved selective phosphodiesterase type 5 inhibitor (PDE5i), on cardiovascular and heart failure-related deaths and hospitalizations in patients with heart failure and secondary pulmonary hypertension.

Both chronic kidney disease (CKD), as reflected by albuminuria and reduced estimated glomerular filtration rate (eGFR) and acute kidney injury (AKI) significantly contribute to morbidity and mortality in the population of patients who will be enrolled in PITCH-HF. Therapies that alter the course of renal disease in patients with heart failure are lacking. The biology of treatment with PDE5i strongly suggests a potential protective effect of these agents on renal function.

This ancillary PITCH-ER study leverages the PITCH-HF infrastructure and randomization, adding only longitudinal collection of subjects' urine samples to 5 timepoints throughout the study. With these urine samples collected, PITCH-ER will address 2 major patient-oriented questions:

1. Does chronic tadalafil treatment slow the rate of GFR decline and/or modify the development/progression of albuminuria vs placebo? To answer this question, longitudinal measures of eGFR utilizing state-of-the-art equations that incorporate serum creatinine and cystatin C and spot urine albumin-to-creatinine ratios (UACR) will be measured.

2. Does PDE5i treatment reduce AKI frequency and/or the magnitude of urinary biomarker changes reflecting subclinical renal injury vs placebo? An AKI adjudication committee will monitor the incidence of AKI events and their severity using the Kidney Disease Improving Global Outcomes (KDIGO) consensus criteria. Subclinical renal injury will be detected using validated urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury marker 1 (KIM-1).

Since 30% of the overall PITCH-HF population will likely have diabetes (which amplifies the risk for renal injury in HF patients), PITCH-ER will repeat analyses in the population stratified by baseline diabetes status as secondary endpoints.

Study Timeline

• Study Start: 2013-10
• Study First Submitted: 2013-10-08
• Study First Submitted QC: 2013-10-08
• Study First Posted: 2013-10-10
• Status Verified: 2017-09
• Last Update Submitted: 2017-09-09
• Last Update Posted: 2017-09-12
• Primary Completion: 2017-12
• Study Completion: 2018-05

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• All subjects eligible for enrollment into the PITCH-HF parent trial are eligible to enroll in this ancillary study (Refer to PITCH-HF NCT01910389 for specific eligibility criteria)

Exclusion Criteria

• Subjects who are not eligible for enrollment into the PITCH-HF parent trial may not enroll in this ancillary study (Refer to PITCH-HF NCT01910389 for specific eligibility criteria)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo of tadalafil. Subjects will take one tablet once per day and will be titrated to two tablets once per day after one week. Subjects are on study drug for the duration of the trial.
Tadalafil	Tadalafil	Tadalafil is supplied in 20 mg tablets. Subjects will take 20 mg (one tablet) once per day and will be titrated to 40 mg (two tablets once per day) after one week. Subjects are on study drug for the duration of the trial.

Primary Outcome Measures

Name	Time	Method
Change in renal function	Baseline to 48 months	Between-group differences in changes from baseline in: (1a) eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and (1b) spot urine albumin-to-creatinine ratio (UACR)
Incidence of acute kidney injury (AKI) events (clinical and subclinical)	Baseline to 48 months	Impact of treatment on (2a) incidence of AKI events (adjudicated) based on new Kidney Disease Improving Global Outcomes criteria; and (2b) changes from baseline in the urine biomarkers of subclinical kidney injury: Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Marker 1 (KIM-1).

Secondary Outcome Measures

Name	Time	Method
Changes in renal function stratified by diabetes/no diabetes	Baseline to 48 months	As for the primary outcome, measurements will be eGFR and UACR
Incidence of AKI events stratified by diabetes/no diabetes	Baseline to 48 months	As for the primary outcome, AKI events will be adjudicated and N-GAL and KIM-1 will be measured

Trial Locations

Locations (1)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States