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

NCT00820352 | Completed Phase 3

• 2 other identifiers: BO-001EUDRACT Number: 2008-005514-40
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 7

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.

Conditions

Heart Failure, Diastolic; Hypertension, Pulmonary

Keywords

HFNEF; HFPEF; Secondary Pulmonary Hypertension; Endothelin Receptor Blockade

Outcome Measures

Primary Outcomes (1)

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

  12 weeks

Secondary Outcomes (6)

• change in 6 minute walking distance after 24 weeks (12 weeks bosentan or placebo treatment and 12 weeks follow-up)

  24 weeks

• changes in hemodynamics assessed by echocardiography after 12 and 24 weeks

  24 weeks

• time to clinical worsening after 12 and 24 weeks

  24 weeks

• levels of NTpBNP, CRP and Endothelin-1 after 12 and 24 weeks

  24 weeks

• Quality of Life assessment (SF-36 and Minnesota Living With Heart Failure Score) after 12 and 24 weeks

  24 weeks

Study Arms (2)

bosentan

ACTIVE COMPARATOR

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

Drug: bosentan

placebo

PLACEBO COMPARATOR

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

Drug: placebo

Interventions

bosentan DRUG

4 weeks of oral bosentan 62,5 mg b.i.d., followed by 8 weeks of 125 mg b.i.d.

Also known as: Ro 47.0203

bosentan

placebo DRUG

placebo twice a day for 12 weeks

placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Teaching Hospital Hall in Tirol: lead

Study Sites (7)

Hospital Mostviertel Waidhofen/Ybbs

Waidhofen an der Thaya, Lower Austria, 3340, Austria

Location

University Teaching Hospital Hall i.T.

Hall I. T., Tyrol, 6060, Austria

Location

University Teaching Hospital of the Elisabethinen, Linz

Linz, Upper Austria, 4010, Austria

Location

Hospital Wels/Grieskirchen

Wels, Upper Austria, 4600, Austria

Location

Hospital Hohenems

Hohenems, 6845, Austria

Location

Hospital Natters

Natters, 6161, Austria

Location

University Hospital Salzburg

Salzburg, 5020, Austria

Location

Related Publications (20)

• Kjaergaard J, Akkan D, Iversen KK, Kjoller E, Kober L, Torp-Pedersen C, Hassager C. Prognostic importance of pulmonary hypertension in patients with heart failure. Am J Cardiol. 2007 Apr 15;99(8):1146-50. doi: 10.1016/j.amjcard.2006.11.052. Epub 2007 Mar 8.

  PMID: 17437745 BACKGROUND

• Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006 Jul 20;355(3):251-9. doi: 10.1056/NEJMoa052256.

  PMID: 16855265 BACKGROUND

• Shah SJ, Gheorghiade M. Heart failure with preserved ejection fraction: treat now by treating comorbidities. JAMA. 2008 Jul 23;300(4):431-3. doi: 10.1001/jama.300.4.431. No abstract available.

  PMID: 18647986 BACKGROUND

• Sanderson JE. Heart failure with a normal ejection fraction. Heart. 2007 Feb;93(2):155-8. doi: 10.1136/hrt.2005.074187. Epub 2005 Dec 30.

  PMID: 16387829 BACKGROUND

• Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, Yip T, Lau ST, Lau CP, Tang MO, Yu CM, Sanderson JE. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008 May;94(5):573-80. doi: 10.1136/hrt.2007.117978. Epub 2008 Jan 20.

  PMID: 18208835 BACKGROUND

• Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006 Jul 20;355(3):260-9. doi: 10.1056/NEJMoa051530.

  PMID: 16855266 BACKGROUND

• Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in the community. JAMA. 2006 Nov 8;296(18):2209-16. doi: 10.1001/jama.296.18.2209.

  PMID: 17090767 BACKGROUND

• Tribouilloy C, Rusinaru D, Mahjoub H, Souliere V, Levy F, Peltier M, Slama M, Massy Z. Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population-based study. Eur Heart J. 2008 Feb;29(3):339-47. doi: 10.1093/eurheartj/ehm554. Epub 2007 Dec 22.

  PMID: 18156618 BACKGROUND

• Sweitzer NK, Lopatin M, Yancy CW, Mills RM, Stevenson LW. Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (> or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions. Am J Cardiol. 2008 Apr 15;101(8):1151-6. doi: 10.1016/j.amjcard.2007.12.014. Epub 2008 Feb 20.

  PMID: 18394450 BACKGROUND

• Onishi K, Ohno M, Little WC, Cheng CP. Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure. J Pharmacol Exp Ther. 1999 Mar;288(3):1214-22.

  PMID: 10027861 BACKGROUND

• Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation. 2000 Oct 3;102(14):1718-23. doi: 10.1161/01.cir.102.14.1718.

  PMID: 11015353 BACKGROUND

• Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007 Oct 2;116(14):1555-62. doi: 10.1161/CIRCULATIONAHA.107.716373. Epub 2007 Sep 4.

  PMID: 17785618 BACKGROUND

• Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004 Feb 1;61(2):227-37. doi: 10.1016/j.cardiores.2003.11.026.

  PMID: 14736539 BACKGROUND

• Cowburn PJ, Cleland JG. Endothelin antagonists for chronic heart failure: do they have a role? Eur Heart J. 2001 Oct;22(19):1772-84. doi: 10.1053/euhj.2000.2557. No abstract available.

  PMID: 11549299 BACKGROUND

• Cowburn PJ, Cleland JG, McDonagh TA, McArthur JD, Dargie HJ, Morton JJ. Comparison of selective ET(A) and ET(B) receptor antagonists in patients with chronic heart failure. Eur J Heart Fail. 2005 Jan;7(1):37-42. doi: 10.1016/j.ejheart.2004.08.001.

  PMID: 15642529 BACKGROUND

• Opitz CF, Ewert R, Kirch W, Pittrow D. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J. 2008 Aug;29(16):1936-48. doi: 10.1093/eurheartj/ehn234. Epub 2008 Jun 17.

  PMID: 18562303 BACKGROUND

• Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M; Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006 Jul 4;114(1):48-54. doi: 10.1161/CIRCULATIONAHA.106.630715. Epub 2006 Jun 26.

  PMID: 16801459 BACKGROUND

• Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar 21;346(12):896-903. doi: 10.1056/NEJMoa012212.

  PMID: 11907289 BACKGROUND

• Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, Tapson VF, Rubin LJ. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. 2003 Jul;124(1):247-54. doi: 10.1378/chest.124.1.247.

  PMID: 12853530 BACKGROUND

• Zolk O, Quattek J, Sitzler G, Schrader T, Nickenig G, Schnabel P, Shimada K, Takahashi M, Bohm M. Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure. Circulation. 1999 Apr 27;99(16):2118-23. doi: 10.1161/01.cir.99.16.2118.

  PMID: 10217651 BACKGROUND

MeSH Terms

Conditions

Heart Failure, Diastolic; Hypertension, Pulmonary

Interventions

Bosentan

Condition Hierarchy (Ancestors)

Heart Failure; Heart Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Wilhelm Grander, M.D.

  University Teaching Hospital Hall i.T.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: principal investigator

Study Record Dates

• First Submitted: January 8, 2009
• First Posted: January 12, 2009
• Study Start: January 1, 2009
• Primary Completion: June 1, 2014
• Study Completion: June 1, 2014
• Last Updated: June 30, 2014

Record last verified: 2014-06

Locations

AU (7)