Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE (BICYCLE)

A Randomized Placebo Controlled Trial to Analyze Changes in Pulmonary Arterial Pressures at Peak Exercise in Congenital Heart Disease Patients With Exercise-induced Pulmonary Arterial Hypertension Before and After Treatment With Bosentan, Compared to Placebo

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.

Study Overview

• Status: Unknown
• Conditions: Pulmonary Arterial Hypertension; Congenital Heart Disease
• Intervention / Treatment: Drug: Placebo; Drug: Bosentan

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105AZ
      • Academic Medical Centre

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:

• 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

Exclusion Criteria:

• 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
• Any cardiac operation < 6 months before inclusion
• PAH of any aetiology other than the one specified in the inclusion criteria
• 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)
• Subjects with known intolerance to bosentan or their constituents

• Prohibited medication: any medication listed below which has not been discontinued at least 30 days prior to inclusion

  • Unspecified or other significant medication (glibenclamide or immunosuppression)
  • PAH therapy (endothelin receptor antagonists, PDE-5 inhibitors, prostanoids)
  • Medication which is not compatible with bosentan or interferes with its metabolism (inhibitors or inducers of CYP2C9, CYP3A4) or medication which may interfere with bosentan treatment according to the investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo tablet	Drug: Placebo
Active Comparator: Bosentan; Tracleer, 125-mg orange-white, round, biconvex, film-coated tablets	Drug: Bosentan; 125-mg orange-white, round, biconvex, film-coated tablets; Other Names: Tracleer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiopulmonary exercise capacity	o i.e. peak oxygen consumption, VE/VCO2 ratio, O2 pulse	26 weeks
Pulmonary hemodynamics	o i.e. systolic pulmonary arterial pressure, pulmonary vascular resistance, pressure-flow relationships during and at peak exercise	26 weeks
Right ventricular function	o i.e. TAPSE, TEI index, TDI-S, right ventricular dimensions	26 weeks
Laboratory parameters	o i.e. NT-pro BNP, troponin T	26 weeks
NYHA functional class		26 weeks
Quality of life	o assessed by TAAQOL-CHD, SF-36 and Minnesota CHD-HF questionnaire	26 weeks
Demographics	age, gender, marital status, work, income.; assessed by demographic questionnaire	26 weeks

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: 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

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Anticipated): February 1, 2018
• Study Completion (Anticipated): June 1, 2018

Study Registration Dates

• First Submitted: April 5, 2013
• First Submitted That Met QC Criteria: April 5, 2013
• First Posted (Estimate): April 9, 2013

Study Record Updates

• Last Update Posted (Actual): August 16, 2017
• Last Update Submitted That Met QC Criteria: August 14, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Hypertension, Pulmonary; Cardiovascular Abnormalities; Heart Diseases; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: NL 42568.018.12