Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE

NCT01827059 | Unknown Phase 2

• 1 other identifier: NL 42568.018.12
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

SUMMARY Rationale: Pulmonary arterial hypertension (PAH) can be a rapidly progressive disorder and is associated with a high mortality rate, despite medical intervention. With the availability of effective therapy, early disease detection is an important strategic objective to improve treatment outcomes. Resting echocardiography is currently the recommended screening modality for high-risk population groups. However, it is clear that abnormalities in resting hemodynamics (and symptoms) are late sequelae of the pathobiological processes that begin in the distal pulmonary arteries. Exercise stress may unmask early pulmonary vascular dysfunction, however the definition, clinical significance, and natural history of 'exercise PAH' remain undefined. However, based on clinical experience and literature the prevalence is estimated at \~ 20%.Treatment with endothelin receptor blockers has shown a beneficial influence on the clinical performance in patients with exercise induced PAH due to systemic sclerosis and primary pulmonary hypertension. Whether endothelin receptor blockers decrease pulmonary pressures and improve clinical outcome in patients with exercise induced pulmonary arterial hypertension due to congenital heart disease is unknown. Objective: Identify congenital heart disease patients with exercise-induced pulmonary arterial hypertension. Analyze changes in pulmonary arterial pressures at peak exercise in patients with exercise induced pulmonary arterial hypertension before and after treatment with bosentan, compared to placebo. Study design: Randomized placebo controlled trial with a study period of 26 weeks. Study population: Adult congenital heart disease patients with exercise induced pulmonary arterial hypertension (n=40) from the Academic Medical Centre, Amsterdam. Intervention: After randomization one group (n=20) receives a 125 mg tablet of Bosentan twice daily for 6 months. The other group (n=20) receives placebo for 6 months. Main study parameters/endpoints: To determine wether bosentan (endothelin receptor inhibitor) decreases mean pulmonary arterial pressure at peak exercise in adult congenital heart disease patients with exercise induced pulmonary arterial hypertension. Furthermore the change in cardiopulmonary exercise capacity and right ventricular function will be investigated. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: All investigations, blood analysis excepted, are non-invasive and free of risk. The burden for the patients mainly consists of the time that is consumed by the investigations, namely: history taking + physical examination (15 min); Quality-of-Life- score (15 min); laboratory tests (electrolytes, creatinine, urea, albumin and neurohormones, troponin T); 12 lead electrocardiogram (10 min); exercise echocardiography (30 min); cardiovascular exercise testing (30 min). The trial medication has a potential risk of liver damage, which will be monitored regularly by laboratory testing of liver transaminases.

Conditions

Pulmonary Arterial Hypertension; Congenital Heart Disease

Outcome Measures

Primary Outcomes (1)

• Change in mean pulmonary arterial pressure (mPAP) at peak exercise

  * measured by means of transthoracic echocardiography at 3 and 6 months followup: mPAP = 0.6 x systolic PAP. * peak exercise is defined as 80% of maximum calculated heart rate: peak exercise=0.8\*(220-age)

  26 weeks

Secondary Outcomes (7)

• Cardiopulmonary exercise capacity

  26 weeks

• Pulmonary hemodynamics

  26 weeks

• Right ventricular function

  26 weeks

• Laboratory parameters

  26 weeks

• NYHA functional class

  26 weeks

Study Arms (2)

Bosentan

ACTIVE COMPARATOR

Tracleer, 125-mg orange-white, round, biconvex, film-coated tablets

Drug: Bosentan

Placebo

PLACEBO COMPARATOR

Placebo tablet

Drug: Placebo

Interventions

Bosentan DRUG

125-mg orange-white, round, biconvex, film-coated tablets

Also known as: Tracleer

Bosentan

Placebo DRUG

Placebo

Eligibility Criteria

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

You may qualify if:

• adult (\>18 years) and mentally competent
• Open or closed septal defect (ASD I/II, VSD, AVSD)
• Open or closed systemic-to-pulmonary shunt (PDA, PAPVC)
• Negative pregnancy test
• Presence of X-PAH
• One of the following criteria, at peak exercise.
• mPAP \> 34 mmHg with CO ≤ 10 l/min
• mPAP \> 40 mmHg with CO ≤ 15 l/min
• mPAP \> 45 mmHg with CO ≤ 20 l/min
• mPAP \> 50 mmHg with CO ≤ 30 l/min
• a PVR (slope pressure/flow plot) of \> 3 mmHg/l/min

You may not qualify if:

• Incapable of giving informed consent
• Pregnancy or lactation (a pregnancy test is offered to every female patient within fertile age)
• Women of child-bearing age who are sexually active without practising reliable methods of contraception. The use of oral contraceptives only, is not considered reliable. Reliable methods include concomitant use of oral contraceptives and condoms ("Double Dutch"), and those methods with a less than 1% chance of pregnancy during typical use20, including intrauterine contraceptives (Copper T, Mirena), Implanon, and sterilization.
• Substance abuse (alcohol, medicines, drugs)
• Subjects who are not able to perform cardiopulmonary exercise testing
• Left ventricular ejection fraction \< 30%
• Significant impairment of renal function (GFR \< 30 ml/min/1.73m2)
• Moderate to severe liver disease: Child Pugh class B or C
• Raised plasma transaminases level \> three times upper normal limit
• Arterial hypotension (systolic blood pressure \< 85mmHg)
• Anaemia (Hb \< 10g/L, or \<6.21 mmol/L)
• Significant valvular disease, other than tricuspid or pulmonary regurgitation
• Chronic lung disease or total lung capacity \< 80% predicted value
• History of significant pulmonary embolism
• Other relevant diseases (HIV infection, Hep B/C infection)

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead

Study Sites (1)

Academic Medical Centre

Amsterdam, North Holland, 1105AZ, Netherlands

Location

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Heart Defects, Congenital

Interventions

Bosentan

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

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

• A.C.J.M. van Riel, MD

  Academic Medical Centre

  PRINCIPAL INVESTIGATOR

• B.J. Bouma, MD, PhD

  Academic Medical Centre

  PRINCIPAL INVESTIGATOR

• B.J.M. Mulder, MD, PhD

  Academic Medical Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• 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: Dr. B.J. Bouma, MD, PhD

Study Record Dates

• First Submitted: April 5, 2013
• First Posted: April 9, 2013
• Study Start: October 1, 2013
• Primary Completion: February 1, 2018
• Study Completion: June 1, 2018
• Last Updated: August 16, 2017

Record last verified: 2017-08

Locations

NL (1)