Ignite Creation Date:
2024-05-05 @ 11:03 PM
Last Modification Date:
2024-10-26 @ 10:28 AM
Study NCT ID:
NCT01246037
Status:
UNKNOWN
Last Update Posted:
2014-01-14
First Post:
2010-11-18
Brief Title:
Beta-blockers in i-PAH
Sponsor:
Amsterdam UMC location VUmc
Organization:
Amsterdam UMC location VUmc
Study Overview
Official Title:
Beta-blocker Therapy in Idiopathic Pulmonary Arterial Hypertension
Status:
UNKNOWN
Status Verified Date:
2014-01
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The main question of this study is Is selective beta-blocker treatment safe and effective in reducing sympathetic overdrive thereby improving RV function and remodeling in patients with iPAH
In addition to the determination of RVEF the investigators will explore how beta-blocker therapy affects sympathetic overdrive remodeling of the RV single beat elastance exercise capacity and mechanical efficiency
30 iPAH patients will be randomized to either Bisoprolol- or placebo-treatment in a double-blinded fashion A cross-over trial design will be used to increase the power of the study and to assess long-term effects of Bisoprolol-treatment and -withdrawal The medication will be given in an escalating dose regimen as described in the farmacotherapeutisch kompas wwwfkcvznl and treatment will be monitored along the guidelines of the American Heart Association
In addition to the determination of RVEF the investigators will explore how beta-blocker therapy affects sympathetic overdrive remodeling of the RV single beat elastance exercise capacity and mechanical efficiency
30 iPAH patients will be randomized to either Bisoprolol- or placebo-treatment in a double-blinded fashion A cross-over trial design will be used to increase the power of the study and to assess long-term effects of Bisoprolol-treatment and -withdrawal The medication will be given in an escalating dose regimen as described in the farmacotherapeutisch kompas wwwfkcvznl and treatment will be monitored along the guidelines of the American Heart Association
Detailed Description:
This is a clinical study aimed to provide a proof of concept of the safety and efficacy of beta-blocker treatment in PAH-associated right ventricular failure
The protocol of the proposed double blinded cross over design
The reasons for not choosing an initial open phase 1 study but to start directly with a placebo controlled study are
1 Although the drug is considered contraindicated in the studied patient population it is very common for PAH patients to receive beta-blocker therapy in an uncontrolled way without reports of serious side effects until now
2 Dose titration in the study will be performed on the basis of side-effects and at this moment the investigators cannot predict the optimal dose which is both safe and efficacious Therefore safety assessment can only be performed in combination with the assessment of pharmaceutical effectiveness
After obtaining informed consent 30 idiopathic PAH patients NYHA II-III will be randomly assigned to either the placebo group or beta-blocker therapy For the randomization and study blinding the investigators will use a VUMC computer based procedure in close collaboration with the VUMC pharmacy
In the first 4 months of study the dose of the drug will be gradually increased the titration scheme is based on the farmacotherapeutisch kompas described below and monitored according to the ACCAHAESC guidelines Up titration will be performed under the responsibilities of an experienced heart failure cardiologist and pulmonologist
MEASUREMENTS Time points 1 3 and 5 6 months periods this includes a complete assessment of the patient
Clinical assessment physical examination NYHA class ECG routine lab including NT-proBNP and urine tests for proteinuria
Imaging of right ventricular function the primary measure of this study will be right ventricular ejection fraction measured by means of MRI Additional MRI and echocardiographic measurements will be performed the complete study protocols are added as supplements
Right Heart Catheterization performed under local anesthesia Measurements of pressures in the pulmonary artery right ventricle and right atrium while patients are breathing room air and at end-expiration
Exercise capacity by means of a maximal incremental cycle testing CardioPulmonary Exercise Test to measure maximal work load VO2 max anaerobic threshold heart rate response oxygen pulse and ventilatory efficiency And by means of 6 minute walking distance
Heart Rate Variability HRV
Nuclear scanning a comprised PET protocol will be performed to measure 11C-acetaat oxygen-15-labeled water H215O and ¹¹C-HED uptake in the right ventricle A summary of the protocol is added as a supplement
UP-TITRATION PHASE first 4 months either on placebo or Bisoprolol patients will be monitored every second week under supervision of an experienced pulmonologist specialized in PAH and a cardiologist specialized in chronic heart failure during a visit to the outpatient clinic If no contra-indications are found the dose will be increased to the next step
The investigators will start with a dosage of 125 mg Bisoprolol once daily Every two weeks dosage is increased by 125 mg until maximum dosage of 10 mg once a day is reached or as high as tolerated by the patient
Increasing the dosage will be stopped or if needed the dosage will be reduced in case of
systolic systemic pressure 90 mmHg
clinical progression in heart failure
clinically relevant bradycardia or 60bmin
progression of complaints
drop in 6 minute walk distance 15 The titration procedure for the placebo will be the same as for titration of Bisoprolol The dosage of the medication will be altered for maximal four months and after this the patients will use a stable dose for the rest of the six month period
Every clinical visit will at least contain a clinical assessment assessment of NYHA class 6 minute walk distance ECG and a Minnesota quality of life questionnaire Every fourth week NT-proBNP kidney- and liver functions will be assessed In addition the patient will be instructed to use a diary to record hisher symptoms and body weight
STABLE PHASE It is expected that up to 4 months are required to reach an acceptable dose of Bisoprolol After this up-titration phase the patient will be followed closely during the remaining part of the six month period using a stable medication dose The monitoring includes continuation of the diary monthly visits to the outpatient clinic including the measurements as described in the up-titration phase and a telephone call every 4 weeks in between office visits
CROSS OVER After six months new measurements will be done Thereafter the medication will be tapered down in a two week period and than finally stopped This will be done to prevent the patients for possible side effects rebound tachycardia of stopping their medication The same tapering down procedure will be performed after the third set of measurements
The protocol of the proposed double blinded cross over design
The reasons for not choosing an initial open phase 1 study but to start directly with a placebo controlled study are
1 Although the drug is considered contraindicated in the studied patient population it is very common for PAH patients to receive beta-blocker therapy in an uncontrolled way without reports of serious side effects until now
2 Dose titration in the study will be performed on the basis of side-effects and at this moment the investigators cannot predict the optimal dose which is both safe and efficacious Therefore safety assessment can only be performed in combination with the assessment of pharmaceutical effectiveness
After obtaining informed consent 30 idiopathic PAH patients NYHA II-III will be randomly assigned to either the placebo group or beta-blocker therapy For the randomization and study blinding the investigators will use a VUMC computer based procedure in close collaboration with the VUMC pharmacy
In the first 4 months of study the dose of the drug will be gradually increased the titration scheme is based on the farmacotherapeutisch kompas described below and monitored according to the ACCAHAESC guidelines Up titration will be performed under the responsibilities of an experienced heart failure cardiologist and pulmonologist
MEASUREMENTS Time points 1 3 and 5 6 months periods this includes a complete assessment of the patient
Clinical assessment physical examination NYHA class ECG routine lab including NT-proBNP and urine tests for proteinuria
Imaging of right ventricular function the primary measure of this study will be right ventricular ejection fraction measured by means of MRI Additional MRI and echocardiographic measurements will be performed the complete study protocols are added as supplements
Right Heart Catheterization performed under local anesthesia Measurements of pressures in the pulmonary artery right ventricle and right atrium while patients are breathing room air and at end-expiration
Exercise capacity by means of a maximal incremental cycle testing CardioPulmonary Exercise Test to measure maximal work load VO2 max anaerobic threshold heart rate response oxygen pulse and ventilatory efficiency And by means of 6 minute walking distance
Heart Rate Variability HRV
Nuclear scanning a comprised PET protocol will be performed to measure 11C-acetaat oxygen-15-labeled water H215O and ¹¹C-HED uptake in the right ventricle A summary of the protocol is added as a supplement
UP-TITRATION PHASE first 4 months either on placebo or Bisoprolol patients will be monitored every second week under supervision of an experienced pulmonologist specialized in PAH and a cardiologist specialized in chronic heart failure during a visit to the outpatient clinic If no contra-indications are found the dose will be increased to the next step
The investigators will start with a dosage of 125 mg Bisoprolol once daily Every two weeks dosage is increased by 125 mg until maximum dosage of 10 mg once a day is reached or as high as tolerated by the patient
Increasing the dosage will be stopped or if needed the dosage will be reduced in case of
systolic systemic pressure 90 mmHg
clinical progression in heart failure
clinically relevant bradycardia or 60bmin
progression of complaints
drop in 6 minute walk distance 15 The titration procedure for the placebo will be the same as for titration of Bisoprolol The dosage of the medication will be altered for maximal four months and after this the patients will use a stable dose for the rest of the six month period
Every clinical visit will at least contain a clinical assessment assessment of NYHA class 6 minute walk distance ECG and a Minnesota quality of life questionnaire Every fourth week NT-proBNP kidney- and liver functions will be assessed In addition the patient will be instructed to use a diary to record hisher symptoms and body weight
STABLE PHASE It is expected that up to 4 months are required to reach an acceptable dose of Bisoprolol After this up-titration phase the patient will be followed closely during the remaining part of the six month period using a stable medication dose The monitoring includes continuation of the diary monthly visits to the outpatient clinic including the measurements as described in the up-titration phase and a telephone call every 4 weeks in between office visits
CROSS OVER After six months new measurements will be done Thereafter the medication will be tapered down in a two week period and than finally stopped This will be done to prevent the patients for possible side effects rebound tachycardia of stopping their medication The same tapering down procedure will be performed after the third set of measurements
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None