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

Study Overview
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Brief Summary
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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%.

Official Title
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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

Conditions
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Diastolic Heart Failure

Intervention / Treatment
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* Drug: Sitexsentin sodium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitaxsentan sodium<br> | Drug: Sitexsentin sodium<br>* 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<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* placebo identical to the study drug in description, dose and duration<br>|

What is the study measuring?
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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) |