Beta-blockers in i-PAH

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
A. Vonk Noordegraaf, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01246037
First received: November 18, 2010
Last updated: January 13, 2014
Last verified: January 2014
  Purpose

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', www.fk.cvz.nl) and treatment will be monitored along the guidelines of the American Heart Association.


Condition Intervention Phase
Idiopathic Pulmonary Arterial Hypertension
Drug: Bisoprolol
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Beta-blocker Therapy in Idiopathic Pulmonary Arterial Hypertension

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • Effectivity [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    The primary efficacy endpoint is improvement in RV function as reflected by RVEF determined by means of cardiac MRI.

  • Safety [ Time Frame: continue ] [ Designated as safety issue: Yes ]
    Safety of Bisoprolol treatment in iPAH patients is not taken as a primary endpoint but seen as a precondition for this study and will be closely monitored. Dose titration will be guided by possible side effects.


Secondary Outcome Measures:
  • Is Bisoprolol treatment effective in reducing sympathetic overdrive? [ Time Frame: 0,6,12 months ] [ Designated as safety issue: No ]
    Herefore the investigators use a C11-Hed-, H2O15- and a C11-acetate- nuclear scan

  • Is Bisoprolol effective in reversing maladaptive remodeling of the right ventricular wall, and does Bisoprolol thereby improve the diastolic properties of the right ventricle? [ Time Frame: 0,6 and 12 months ] [ Designated as safety issue: No ]
    Pressure-Volume loops will be reconstructed from the combined right heart catheterization data and MRI measurements

  • Is Bisoprolol treatment effective in improving the perfusion and mechanical efficiency (oxygen consumption per joule) of the heart? [ Time Frame: 0,6,12 months ] [ Designated as safety issue: No ]
    Perfusion will be measured by using the H2O tracer. Oxygen consumption of the right ventricle will be estimated from the uptake of the acetate tracer. Right ventricular power output will be derived from the right heart catheterization data.

  • Is Bisoprolol effective in improving exercise capacity? [ Time Frame: Every two weeks ] [ Designated as safety issue: No ]
    This will be measured by means of the maximal oxygen uptake which is measured by means of the incremental cardiopulmonary exercise test and six minute walking distance.


Estimated Enrollment: 30
Study Start Date: February 2011
Estimated Study Completion Date: April 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: First placebo
First half year placebo, second half year bisoprolol
Drug: Bisoprolol
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' and monitored according to the ACC/AHA/ESC guidelines. Up titration will be performed under the responsibilities of an experienced heart failure cardiologist and pulmonologist.
Experimental: First Bisoprolol
First half year bisoprolol, second half year placebo
Drug: Bisoprolol
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' and monitored according to the ACC/AHA/ESC guidelines. Up titration will be performed under the responsibilities of an experienced heart failure cardiologist and pulmonologist.

  Hide Detailed Description

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 ACC/AHA/ESC 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 1,25 mg Bisoprolol once daily. Every two weeks dosage is increased by 1,25 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 <60b/min
  • 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 his/her 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Idiopathic PAH patients
  • Stable on PAH specific treatment defined

    • No change in PAH specific treatment in the past 6 months
    • No change in functional class in the past 6 months
    • <10 % change in 6 minute walk distance in the past 6 months
  • Functional class 2 or 3
  • In sinus rhythm

Exclusion Criteria:

  • History of systemic hypertension, ischaemic heart disease, valvular disease or cardiomyopathy.
  • Asthma
  • Use of concomitant medication other than diuretics, Acenocoumarol and PAH targeted therapy
  • History of cardiac arrhythmias or the use of anti-arrhythmic drugs
  • Sick sinus syndrome
  • systolic hypotension < 90 mmHg
  • AV-block
  • Clinically relevant sinus-bradycardia
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01246037

Locations
Netherlands
VUmc
Amsterdam, Netherlands
Sponsors and Collaborators
VU University Medical Center
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Anton Vonk Noordegraaf, Prof. MD PhD VU University Medical Center, pulmonary department
  More Information

No publications provided

Responsible Party: A. Vonk Noordegraaf, Prof. dr., VU University Medical Center
ClinicalTrials.gov Identifier: NCT01246037     History of Changes
Other Study ID Numbers: 2010-262
Study First Received: November 18, 2010
Last Updated: January 13, 2014
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by VU University Medical Center:
Pulmonary Arterial Hypertension
Beta-blocker
Adrenergic Receptor Antagonist

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Adrenergic beta-Antagonists
Bisoprolol
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic beta-1 Receptor Antagonists

ClinicalTrials.gov processed this record on September 22, 2014