A Study of the Effectiveness of Sitaxsentan Sodium in Patients With Diastolic Heart Failure

A PHASE 2 RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED EXPLORATORY EFFICACY STUDY OF SITAXSENTAN SODIUM TO IMPROVE IMPAIRED EXERCISE TOLERANCE IN SUBJECTS WITH DIASTOLIC HEART FAILURE

The aim of this study was to determine whether long-term (≥ 6 months at the target dose) blockade of ETA receptors using sitaxsentan showed functional benefit in subjects with chronic Heart Failure and an Left Ventricular Ejection Fraction ≥50%.

Study Overview

• Status: Completed
• Conditions: Diastolic Heart Failure
• Intervention / Treatment: Drug: Sitexsentin sodium; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B1W8
      • St Michael's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • SMBD Jewish General Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Mobile, Alabama, United States, 36608
      • Mobile Heart Specialists, PC
    • Mobile, Alabama, United States, 36608
      • Preventative and Research Cardiloogy Providence Hospital
  • Alaska
    • Little Rock, Alaska, United States, 72205
      • Central Arkansas Veterans HCS
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Arizona Pulmonary Specialists, Ltd
    • Tucson, Arizona, United States, 85715
      • Southwest Heart
    • Tucson, Arizona, United States, 85715
      • Parkview Research Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Services/Cardiology Department
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California Medical Center
    • Orange, California, United States, 92868
      • Orange County Heart Institute and Research Center
    • Sacramento, California, United States, 95825
      • Sacramento Heart & Vascular Medical Associates
    • San Diego, California, United States, 92103-8411
      • University of California
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School of Medicine, Cardiovascular Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20011
      • Capital City Research, CCRW
  • Florida
    • Orlando, Florida, United States, 32803
      • Florida Heart Group Pa
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago
    • Peoria, Illinois, United States, 61606
      • Methodist Medical Center
  • Maine
    • Auburn, Maine, United States, 04210
      • Cardiovascular Consultants of Maine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Pulmonary and Critical Care Unit
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417-2309
      • VA Med Ctr Minneapolis
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis University Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington Univ. School of Medicine
  • Nebraska
    • Lincoln, Nebraska, United States, 68526
      • Nebraska Heart Institute
  • New Hampshire
    • Manchester, New Hampshire, United States, 03102
      • Catholic Medical Center d/b/a New England Heart Institute
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • Buffalo, New York, United States, 14221-5838
      • Buffalo Cardipul Assoc
    • New York, New York, United States, 10032
      • Columbia University Medical Center, New York Presbyterian Hospital
    • Troy, New York, United States, 112180
      • Capital Cardiology Associates
  • North Carolina
    • Charlotte, North Carolina, United States, 28204-3288
      • Mid Carolina Cardiology
    • Huntersville, North Carolina, United States, 28078
      • Mid Carolina Cardiology
    • Winston-Salem, North Carolina, United States, 27157-1045
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43210-1252
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Oklahoma Foundation for Cardiovascular Research
  • Oregon
    • Portland, Oregon, United States, 97220
      • The Oregon Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Advanced Heart Failure & Transplant Center
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • RHJ VA Medical Center
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Black Hills Clinical Research Center
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Stern Cardiovascular Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine Pulmonary Section
    • Houston, Texas, United States, 77030
      • Kelsey Seybold Clinic
    • Houston, Texas, United States, 77030
      • Methodist DeBakey Heart Center
  • Utah
    • Murray, Utah, United States, 84157
      • Intermountain Medical Center (a.k.a. LDS Hospital)
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Medical College of Virginia
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital & Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 or older with chronic heart failure and evidence of diastolic dysfunction on echocardiogram, heart imaging, and a minimum exercise tolerance average time of 120 seconds on two treadmill tests within 2 weeks of enrollment

Exclusion Criteria:

• unstable cardiovascular disease within 4 weeks of screening, history of heart attack, cardiac by-pass surgery or percutaneous intervention, stent placement, within 3 months of screening or amyloidosis, hypertrophic obstructive or restrictive cardiomyopathy, or constrictive pericarditis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; placebo identical to the study drug in description, dose and duration
Experimental: Sitaxsentan sodium	Drug: Sitexsentin sodium; sitaxsentan 100 mg (target dose) 0rally once daily. A 10-week Run-In Phase was conducted where dosing commenced at 25 mg daily for 2 weeks, and then was stepped up to 50 mg daily for 2 weeks, to 75 mg daily for 2 weeks and then to 100 mg daily for 2 weeks, with an additional 2-week stabilization period (10 weeks total) to a target study dose of 100 mg daily. During the Run-In Phase, if a subject was not able to tolerate upward dose titration to the target dose of 100 mg, the investigator may have elected to continue at the current dosage or reduce the dosage of sitaxsentan or placebo to the subject's immediate prior dose. During the Maintenance Phase, subjects received the highest titrated dose reached of study drug and continued it through the last day of Week M24 of the Maintenance Phase (14 weeks)- total study drug treatment duration= 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Treadmill Exercise Time at Maintenance Phase Week 24	Treadmill exercise test is used to assess the functional capacity of participants with cardiac disease. Treadmill exercise test was conducted using the 2 minute incremental Naughton protocol. The Naughton protocol starts with a 2 minute warm-up. The speed of treadmill is set to 1 mile per hour (mph) and the incline is set to 0. After the warm-up, the speed is set at 2 mph for the remainder of the test. The test consists of six, 2 minute intervals. The grade starts at 0 for the first interval, and increases by 3.5 percent every 2 minutes. The change in total exercise time (in seconds) during the treadmill test was reported.	Baseline, Week 24 (Maintenance Phase)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Ratio of Transmitral Inflow Velocity (E) to Early Diastolic Velocity of the Mitral Annulus (E') at Maintenance Phase Week 24	Ratio of E to E' is used as a predictor of first cardiac events. Ratio of E to E' was measured using imaging techniques based on Doppler principles. Transmitral inflow velocity was measured by Doppler echocardiography (ECHO) and the early diastolic velocity of the mitral annulus was measured by tissue Doppler imaging (TDI).	Baseline, Week 24 (Maintenance Phase)
Change From Baseline in Left Ventricular Mass at Maintenance Phase Week 24	Left ventricular mass was used as a parameter for the assessment of cardiac function. An increase in left ventricular mass leads to ventricular hypertrophy which is a prognostic factor of cardiovascular morbidity and mortality. Left ventricular mass was measured by ECHO, which was calculated as (1.04 * [{left ventricular end diastolic diameter (LVEDD) + septal diastolic thickness + post wall diastolic thickness}^3 - LVEDD^3]) * 0.8 + 0.6. Left ventricular mass was assessed for the two ECHO modes: parasternal long-axis two dimensional (PLAX 2D) mode and parasternal short-axis view motion (PSAX M) mode.	Baseline, Week 24 (Maintenance Phase)
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Total Score at Maintenance Phase Week 24	The MLHF is a 21-item questionnaire which used to evaluate QoL in participants suffering from heart failure. The participants were asked to evaluate how their heart condition affected their life during the past month. Each of the 21 items were assessed on a 6-point scale, where 0 = no affect and 5 = very much affected. The MLHF QoL total score was calculated as the sum of the 21 individual QoL questions. The MLHF QoL total score ranged from 0 to 105, where higher scores indicated worse health condition.	Baseline, Week 24 (Maintenance Phase)
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Physical Score at Maintenance Phase Week 24	The MLHF is a 21-item questionnaire which is used to evaluate QoL in participants suffering from heart failure. The participants were asked to evaluate how their heart condition affected their life during the past month. Each of the 21 items were assessed on a 6-point scale, where 0 = no affect and 5 = very much affected. The MLHF QoL physical score was calculated as the sum of the 8 physical domain QoL questions. The MLHF QoL physical score ranged from 0 to 40, where higher scores indicated worse health condition.	Baseline, Week 24 (Maintenance Phase)
Change From Baseline in Minnesota Living With Heart Failure (MLHF) Questionnaire - Quality of Life (QoL) Emotional Score at Maintenance Phase Week 24	The MLHF is a 21-item questionnaire which is used to evaluate QoL in participants suffering from heart failure. The participants were asked to evaluate how their heart condition affected their life during the past month. Each of the 21 items were assessed on a 6-point scale, where 0 = no affect and 5 = very much affected. The MLHF QoL emotional score was calculated as the sum of the 5 emotional domain QoL questions. The MLHF QoL emotional score ranged from 0 to 25, where higher scores indicated worse health condition.	Baseline, Week M24 (Maintenance Phase)
Number of Participants With Change From Baseline in New York Heart Association (NYHA) Functional Class at Maintenance Phase Week 24	Participants were classified by NYHA functional class. NYHA class I: participants with cardiac disease but without resulting limitations of physical activity, NYHA class II: participants with cardiac disease resulting in slight limitation of physical activity, NYHA class III: participants with cardiac disease resulting in marked limitation of physical activity, NYHA class IV: participants with cardiac disease resulting in inability to carry on any physical activity without discomfort. Baseline was reported by NYHA functional class and the change from baseline in the functional class was reported as improvement (positive change from baseline), no change and deterioration (negative change from baseline).	Baseline, Week 24 (Maintenance Phase)

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Zile MR, Bourge RC, Redfield MM, Zhou D, Baicu CF, Little WC. Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction. JACC Heart Fail. 2014 Apr;2(2):123-30. doi: 10.1016/j.jchf.2013.12.002. Epub 2014 Feb 26.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2006
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: March 16, 2006
• First Submitted That Met QC Criteria: March 16, 2006
• First Posted (Estimate): March 17, 2006

Study Record Updates

• Last Update Posted (Actual): January 4, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Diastolic
• Other Study ID Numbers: B1321006; FDHF01 (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.