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Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension (BADDHY)

Primary Purpose

Heart Failure, Diastolic, Hypertension, Pulmonary

Status
Completed
Phase
Phase 3
Locations
Austria
Study Type
Interventional
Intervention
bosentan
placebo
Sponsored by
University Teaching Hospital Hall in Tirol
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure, Diastolic focused on measuring HFNEF, HFPEF, Secondary Pulmonary Hypertension, Endothelin Receptor Blockade

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Clinically signs or history of congestive heart failure NYHA II-III (Fatigue, dyspnea on exertion, lung crepitations, pulmonary edema, ankle and or lower leg swelling, jugular pressure enhancement, hepatomegaly)
  • Echocardiographic signs of diastolic dysfunction (heart failure with normal ejection fraction)
  • Right ventricle enlargement with pulmonary hypertension
  • 6 minute walking distance > 150 m < 400 m
  • Right Heart Catheterization: Mean PAP > 25 mmHg, PCWP > 15 mmHg

Echocardiographic requirements for definition of heart failure with normal ejection fraction

  • E/E' > 15, or
  • E/E' > 8 + NTpBNP > 220 pg/ml, or
  • E/E' > 8 + E:A < 0.5 + DT > 280 ms or
  • Ard-Ad > 30 ms or
  • atrial enlargement or
  • atrial fibrillation
  • NTpBNP > 220 pg/ml + combination
  • IVRT - IVRTm < 0 septal und lateral

Echocardiographic requirements for pulmonary hypertension and right ventricle dysfunction

  • RVEDD > 30 mm short axis parasternal, and

  • one of the following:

    • Tricuspid valve regurgitation velocity (TRV) > 3 m/s;
    • RV-annular systolic velocity < 10 cm/sec (TDI)
    • TAPSE < 18 mm

Exclusion Criteria:

  • Patients who are not on guideline conform treatments for cardiovascular disease.
  • Left ventricle systolic dysfunction (EF < 50 %), aortic stenosis with peak gradient (instantane) > 40 mm Hg,moderate and severe aortic insufficiency
  • moderate and severe mitral regurgitation,
  • acute coronary disease, stable coronary artery disease or peripheral vascular disease limiting exercise.

  • Other causes of pulmonary - artery - hypertension:

    • relevant obstructive ventilatory disease > grade II (lung functions tests)
    • collagen disease (Tests: MSCT and ANA, ANCA),
    • chronic thrombo- embolic pulmonary arterial hypertension (MSCT),
    • sleep disorder.
    • HIV, HCV, HBV infection.
    • Drug related PAH.
  • Orthopaedic disease, immobility, inability to perform 6MWT and cancer.
  • Liver disease Child-Pugh B and C, three fold above normal elevated liver enzymes,
  • anaemia Hb < 10 mg/dl,
  • other specific treatment of pulmonary arterial hypertension including other endothelin receptor blockers, phosphodiesterase inhibitors, prostaglandins and L-arginin
  • drug therapy with glibenclamide, rifampicin, tacrolimus, sirolimus, cyclosporine A
  • known adverse reactions to bosentan and
  • pregnancy and lactation

Sites / Locations

  • Hospital Mostviertel Waidhofen/Ybbs
  • University Teaching Hospital Hall i.T.
  • University Teaching Hospital of the Elisabethinen, Linz
  • Hospital Wels/Grieskirchen
  • Hospital Hohenems
  • Hospital Natters
  • University Hospital Salzburg

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

bosentan

placebo

Arm Description

Patients in this arm receive bosentan twice a day for 12 weeks

patients in this arm receive 12 placebo twice a day for 12 weeks

Outcomes

Primary Outcome Measures

change in 6 minute waling distance after 12 weeks of bosentan (or placebo) treatment

Secondary Outcome Measures

change in 6 minute walking distance after 24 weeks (12 weeks bosentan or placebo treatment and 12 weeks follow-up)
changes in hemodynamics assessed by echocardiography after 12 and 24 weeks
time to clinical worsening after 12 and 24 weeks
levels of NTpBNP, CRP and Endothelin-1 after 12 and 24 weeks
Quality of Life assessment (SF-36 and Minnesota Living With Heart Failure Score) after 12 and 24 weeks
Adverse event count after 12 and 24 weeks

Full Information

First Posted
January 8, 2009
Last Updated
June 27, 2014
Sponsor
University Teaching Hospital Hall in Tirol
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1. Study Identification

Unique Protocol Identification Number
NCT00820352
Brief Title
Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension
Acronym
BADDHY
Official Title
Endothelin Receptor Blockade in Heart Failure With Diastolic Dysfunction and Pulmonary Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
January 2009 (undefined)
Primary Completion Date
June 2014 (Actual)
Study Completion Date
June 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Teaching Hospital Hall in Tirol

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Heart failure is a major medical and socioeconomic problem in western industrial countries, especially with aging populations. Heart failure with normal left ventricle systolic function (heart failure with preserved ejection fraction, HFPEF, heart failure with normal ejection fraction, HFNEF) are common causes of hospitalization mainly in the elderly population and are frequently associated with pulmonary hypertension. It is commonly seen, that patients with left heart disease and pulmonary hypertension with right ventricle dysfunction have a worse prognosis. The investigators hypothesize, that an additional treatment with Bosentan in this patients will improve their exercise capacity, symptoms, hemodynamics and quality of life.
Detailed Description
Heart Failure with preserved ejection fraction is with more than 50% of cases the most common form of heart failure. Typically patients are elderly women with arterial hypertension. Mortality, hospitalization rates due to heart failure and in-hospital complications do not differ significantly from patients with systolic heart failure. However there are some subgroups of HFPEF-patients with a worse prognosis, for example up to 30% of patients develop secondary pulmonary hypertension and thus right ventricle dysfunction. Increased right-ventricle systolic pressure is associated with increased mortality in patients with all forms of heart failure. There is a lack of evidence about HFPEF. Drugs for treating systolic heart failure showed no improvement in mortality and prognosis. Diuretics are just able to relieve symptoms. There are no clinical trials concerning HFPEF with secondary pulmonary hypertension. The endothelin system is not only activated in PAH, but also in pulmonary venous hypertension and congestive heart failure, where ET-1 levels rise with the severity of secondary pulmonary hypertension. Pulmonary congestion leads to endothelial dysfunction that results in increased levels of Endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor. In pulmonary arterial vessels the ETA receptor is the predominant receptor (ratio of ETA to ET B = 9:1), which is responsible for vasoconstriction and remodeling of the pulmonal vasculature. In heart failure the ETA receptor is upregulated. Elevated plasma ET-1 levels correlate with pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and inversely with peak exercise capacity. Recent clinical and laboratory findings indicate comparable pathophysiological mechanisms in pulmonary hypertension secondary to left ventricular dysfunction and pulmonary arterial hypertension. Yet, despite an expanding application in pulmonary artery hypertension, according to current opinion, the oral dual endothelin (ETA/ETB) antagonist bosentan is not indicated for PVH caused by left ventricle / left atrial pressure overload and preserved systolic function. However, there are several studies which show some effects of pulmonary vessel dilating drugs in PAH and left ventricle dysfunction.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Diastolic, Hypertension, Pulmonary
Keywords
HFNEF, HFPEF, Secondary Pulmonary Hypertension, Endothelin Receptor Blockade

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
bosentan
Arm Type
Active Comparator
Arm Description
Patients in this arm receive bosentan twice a day for 12 weeks
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
patients in this arm receive 12 placebo twice a day for 12 weeks
Intervention Type
Drug
Intervention Name(s)
bosentan
Other Intervention Name(s)
Ro 47.0203
Intervention Description
4 weeks of oral bosentan 62,5 mg b.i.d., followed by 8 weeks of 125 mg b.i.d.
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
placebo twice a day for 12 weeks
Primary Outcome Measure Information:
Title
change in 6 minute waling distance after 12 weeks of bosentan (or placebo) treatment
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
change in 6 minute walking distance after 24 weeks (12 weeks bosentan or placebo treatment and 12 weeks follow-up)
Time Frame
24 weeks
Title
changes in hemodynamics assessed by echocardiography after 12 and 24 weeks
Time Frame
24 weeks
Title
time to clinical worsening after 12 and 24 weeks
Time Frame
24 weeks
Title
levels of NTpBNP, CRP and Endothelin-1 after 12 and 24 weeks
Time Frame
24 weeks
Title
Quality of Life assessment (SF-36 and Minnesota Living With Heart Failure Score) after 12 and 24 weeks
Time Frame
24 weeks
Title
Adverse event count after 12 and 24 weeks
Time Frame
24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Clinically signs or history of congestive heart failure NYHA II-III (Fatigue, dyspnea on exertion, lung crepitations, pulmonary edema, ankle and or lower leg swelling, jugular pressure enhancement, hepatomegaly) Echocardiographic signs of diastolic dysfunction (heart failure with normal ejection fraction) Right ventricle enlargement with pulmonary hypertension 6 minute walking distance > 150 m < 400 m Right Heart Catheterization: Mean PAP > 25 mmHg, PCWP > 15 mmHg Echocardiographic requirements for definition of heart failure with normal ejection fraction E/E' > 15, or E/E' > 8 + NTpBNP > 220 pg/ml, or E/E' > 8 + E:A < 0.5 + DT > 280 ms or Ard-Ad > 30 ms or atrial enlargement or atrial fibrillation NTpBNP > 220 pg/ml + combination IVRT - IVRTm < 0 septal und lateral Echocardiographic requirements for pulmonary hypertension and right ventricle dysfunction RVEDD > 30 mm short axis parasternal, and one of the following: Tricuspid valve regurgitation velocity (TRV) > 3 m/s; RV-annular systolic velocity < 10 cm/sec (TDI) TAPSE < 18 mm Exclusion Criteria: Patients who are not on guideline conform treatments for cardiovascular disease. Left ventricle systolic dysfunction (EF < 50 %), aortic stenosis with peak gradient (instantane) > 40 mm Hg,moderate and severe aortic insufficiency moderate and severe mitral regurgitation, acute coronary disease, stable coronary artery disease or peripheral vascular disease limiting exercise. Other causes of pulmonary - artery - hypertension: relevant obstructive ventilatory disease > grade II (lung functions tests) collagen disease (Tests: MSCT and ANA, ANCA), chronic thrombo- embolic pulmonary arterial hypertension (MSCT), sleep disorder. HIV, HCV, HBV infection. Drug related PAH. Orthopaedic disease, immobility, inability to perform 6MWT and cancer. Liver disease Child-Pugh B and C, three fold above normal elevated liver enzymes, anaemia Hb < 10 mg/dl, other specific treatment of pulmonary arterial hypertension including other endothelin receptor blockers, phosphodiesterase inhibitors, prostaglandins and L-arginin drug therapy with glibenclamide, rifampicin, tacrolimus, sirolimus, cyclosporine A known adverse reactions to bosentan and pregnancy and lactation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wilhelm Grander, M.D.
Organizational Affiliation
University Teaching Hospital Hall i.T.
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Mostviertel Waidhofen/Ybbs
City
Waidhofen
State/Province
Lower Austria
ZIP/Postal Code
3340
Country
Austria
Facility Name
University Teaching Hospital Hall i.T.
City
Hall i. T.
State/Province
Tyrol
ZIP/Postal Code
6060
Country
Austria
Facility Name
University Teaching Hospital of the Elisabethinen, Linz
City
Linz
State/Province
Upper Austria
ZIP/Postal Code
4010
Country
Austria
Facility Name
Hospital Wels/Grieskirchen
City
Wels
State/Province
Upper Austria
ZIP/Postal Code
4600
Country
Austria
Facility Name
Hospital Hohenems
City
Hohenems
ZIP/Postal Code
6845
Country
Austria
Facility Name
Hospital Natters
City
Natters
ZIP/Postal Code
6161
Country
Austria
Facility Name
University Hospital Salzburg
City
Salzburg
ZIP/Postal Code
5020
Country
Austria

12. IPD Sharing Statement

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Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension

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