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

Primary Purpose

Pulmonary Arterial Hypertension, Congenital Heart Disease

Status
Unknown status
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Bosentan
Placebo
Sponsored by
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension

Eligibility Criteria

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

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

Sites / Locations

  • Academic Medical Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Bosentan

Placebo

Arm Description

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

Placebo tablet

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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

Full Information

First Posted
April 5, 2013
Last Updated
August 14, 2017
Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
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1. Study Identification

Unique Protocol Identification Number
NCT01827059
Brief Title
Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE
Acronym
BICYCLE
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2017
Overall Recruitment Status
Unknown status
Study Start Date
October 2013 (undefined)
Primary Completion Date
February 2018 (Anticipated)
Study Completion Date
June 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension, Congenital Heart Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bosentan
Arm Type
Active Comparator
Arm Description
Tracleer, 125-mg orange-white, round, biconvex, film-coated tablets
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo tablet
Intervention Type
Drug
Intervention Name(s)
Bosentan
Other Intervention Name(s)
Tracleer
Intervention Description
125-mg orange-white, round, biconvex, film-coated tablets
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Change in mean pulmonary arterial pressure (mPAP) at peak exercise
Description
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)
Time Frame
26 weeks
Secondary Outcome Measure Information:
Title
Cardiopulmonary exercise capacity
Description
o i.e. peak oxygen consumption, VE/VCO2 ratio, O2 pulse
Time Frame
26 weeks
Title
Pulmonary hemodynamics
Description
o i.e. systolic pulmonary arterial pressure, pulmonary vascular resistance, pressure-flow relationships during and at peak exercise
Time Frame
26 weeks
Title
Right ventricular function
Description
o i.e. TAPSE, TEI index, TDI-S, right ventricular dimensions
Time Frame
26 weeks
Title
Laboratory parameters
Description
o i.e. NT-pro BNP, troponin T
Time Frame
26 weeks
Title
NYHA functional class
Time Frame
26 weeks
Title
Quality of life
Description
o assessed by TAAQOL-CHD, SF-36 and Minnesota CHD-HF questionnaire
Time Frame
26 weeks
Title
Demographics
Description
age, gender, marital status, work, income. assessed by demographic questionnaire
Time Frame
26 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
A.C.J.M. van Riel, MD
Organizational Affiliation
Academic Medical Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
B.J. Bouma, MD, PhD
Organizational Affiliation
Academic Medical Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
B.J.M. Mulder, MD, PhD
Organizational Affiliation
Academic Medical Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Academic Medical Centre
City
Amsterdam
State/Province
Noord-Holland
ZIP/Postal Code
1105AZ
Country
Netherlands

12. IPD Sharing Statement

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Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE

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