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Beta Blockers for Treatment of Pulmonary Arterial Hypertension in Children

Primary Purpose

Pulmonary Arterial Hypertension

Status
Withdrawn
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Carvedilol
Sponsored by
The Hospital for Sick Children
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring Pulmonary Arterial Hypertension (PAH, Pediatrics, Right Heart Failure (RHF), Carvedilol, Beta-blockers

Eligibility Criteria

8 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must be ≥ 8 and ≤ 17.5 years of age at the time of study enrollment.
  • Patients must have a mean pulmonary artery pressure of greater than 25mmHg at rest in a setting of normal pulmonary arterial wedge pressure of 15mmHg or less with a PVR index greater than 3 Woods units•m2 at last hemodynamic study.
  • Patients must be diagnosed with any of the following:Idiopathic PAH (IPAH), PAH associated with repaired congenital heart disease, PAH associated with minor congenital heart disease (small interventricular communication, small interarterial communication, small ductus arteriosis)
  • Patients must be clinically stable (i.e. no treatment changes) for the last 3 months
  • Patients must have no or minimal evidence of fluid overload or volume depletion judged by clinical evaluation (with or without diuretic treatment)
  • Written informed consent

Exclusion Criteria:

  • Patients who are unable to perform a six minute walk test (6MWT)
  • Patients with a known history of pulmonary hypertension secondary to venoocclusive disease and/or capillary hemangiomatosis; pulmonary hypertensions owing to left heart disease
  • Patients who have previously received treatment with an intravenous positive inotropic agent in the last 3 months
  • Patients who are currently receiving β-blockers
  • Patients with a known history of reactive airways disease (bronchial asthma or relate bronchospastic conditions)
  • Patients with chronic obstructive pulmonary disease (COPD)
  • Patients with a known history of adverse reaction to β-blockers
  • Patients with a heart block on ECG or resting heart rate < 60 bpm
  • Patients with systemic hypotension (below 5th percentile for age) are not eligible as follows: 1-10 years old: systolic blood pressure defined as < [70 + (2 x age in years)] mmHg; Older than 10 years: systolic blood pressure < 90 mmHg
  • Patients with coagulopathy (INR < 1.5 or platelet count <50,000/mm3)
  • Patients with a known history of severe hepatic impairment (defined by the presence of ascites, esophageal varices, jaundice or spider angiomata)
  • Patients with severe renal insufficiency (defined as creatinine clearance < 30 mL/min/m2)
  • Patients with a known malignancy or other co-morbidity expected to limit survival or to limit the ability to complete the study
  • Patients with trisomy 21
  • Patients with a known history of sick sinus syndrome
  • Patients with a known history of moderate or severe primary obstructive valvular heart disease
  • Patients with a known history of diabetes
  • Female patients who are pregnant of breast-feeding

Sites / Locations

  • The Hospital for Sick Children

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Carvedilol

Arm Description

Outcomes

Primary Outcome Measures

Incidence of Adverse Events
-Incidence of major adverse effects defined as bradycardia, hypotension, and syncope, worsening of symptoms, disease state and death

Secondary Outcome Measures

Improvement in the six minute walk test (6MWT) and cardiopulmonary exercise testing (CPX)
This will be measured by the difference in walking distance in the 6MWT and peak oxygen consumption in the CPX, between the baseline condition before the study and after 6 months with maintenance dose of carvedilol.
Improvement in echocardiogram and magnetic resonance imaging (MRI) parameters
The echocardiogram will be a subjective assessment of the right valve (RV) fractional area of change through TAPSE. The MRI will measure the RV ejection fraction. Both indicators will measure the different between the baseline condition before the study and after 6 months with maintenance dose of carvedilol.
Feasibility of carvedilol
Proportion of patients achieving target maintenance dose of carvedilol Proportion of patients requiring dose adjustment due to bradycardia and/or hypertension Proportion of patients stopping treatment with carvedilol due to serious adverse events

Full Information

First Posted
October 31, 2012
Last Updated
December 30, 2015
Sponsor
The Hospital for Sick Children
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1. Study Identification

Unique Protocol Identification Number
NCT01723371
Brief Title
Beta Blockers for Treatment of Pulmonary Arterial Hypertension in Children
Official Title
Beta Blockers for Treatment of Pulmonary Arterial Hypertension in Children
Study Type
Interventional

2. Study Status

Record Verification Date
December 2015
Overall Recruitment Status
Withdrawn
Why Stopped
Due to lack of enrollment.
Study Start Date
September 2012 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Hospital for Sick Children

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This study will determine the safety and feasibility of using a β-blocker (in this case carvedilol) in the treatment of pediatric patients with Left Heart Failure (LHF) in children with Pulmonary Arterial Hypertension (PAH). Carvedilol affects the nervous system, the same system that is highly activated in response to stress in patients with PAH. Each patient is administered a dosage of carvedilol, according to their weight. This dosage is increased incrementally over the span of the study, if the patient responds well to the drug. The study will determine whether the potential adverse side effects of carvedilol outweigh the possible positive results in reducing LHF. The hypothesis of this study predicts that carvedilol will have positive effects in treating LHF, similar to their use in treatment of Right Heart Failure (RHF). This is a single-centered pilot study. Each patient will be studied for approximately 31 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
Keywords
Pulmonary Arterial Hypertension (PAH, Pediatrics, Right Heart Failure (RHF), Carvedilol, Beta-blockers

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Carvedilol
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Carvedilol
Intervention Description
Carvedilol will be administered orally. The initial dose of carvedilol will be 0.05mg/kg/day divided into 2 doses. After two weeks, at subsequent weekly study visits, the dose of carvedilol will be increased incrementally to 0.1mg/kg in Week 2, 0.2mg/kg in Week 3, 0.4mg/kg in Week 4, 0.6mg/kg in Week 5, and 0.8mg/kg in Week 6, when the target dose of 0.8mg/kg/day (if weight is less than 62.5kg) or 50mg/day (if weight is greater than 62.5kg) is achieved. This dosage, assuming no adverse effects, will be maintained between Weeks 6 and 30 of the study. After the maintenance period from Week 6 to 30, patients will be weaned over 5 to 7 days or continued on a non-study drug supply.
Primary Outcome Measure Information:
Title
Incidence of Adverse Events
Description
-Incidence of major adverse effects defined as bradycardia, hypotension, and syncope, worsening of symptoms, disease state and death
Time Frame
Throughout study (Baseline to week 31)
Secondary Outcome Measure Information:
Title
Improvement in the six minute walk test (6MWT) and cardiopulmonary exercise testing (CPX)
Description
This will be measured by the difference in walking distance in the 6MWT and peak oxygen consumption in the CPX, between the baseline condition before the study and after 6 months with maintenance dose of carvedilol.
Time Frame
Change over 6 months
Title
Improvement in echocardiogram and magnetic resonance imaging (MRI) parameters
Description
The echocardiogram will be a subjective assessment of the right valve (RV) fractional area of change through TAPSE. The MRI will measure the RV ejection fraction. Both indicators will measure the different between the baseline condition before the study and after 6 months with maintenance dose of carvedilol.
Time Frame
Change over 6 months
Title
Feasibility of carvedilol
Description
Proportion of patients achieving target maintenance dose of carvedilol Proportion of patients requiring dose adjustment due to bradycardia and/or hypertension Proportion of patients stopping treatment with carvedilol due to serious adverse events
Time Frame
Baseline, Week 0, 2, 3, 4, 5, 6, 10, 18, 22, 30, 31

10. Eligibility

Sex
All
Minimum Age & Unit of Time
8 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must be ≥ 8 and ≤ 17.5 years of age at the time of study enrollment. Patients must have a mean pulmonary artery pressure of greater than 25mmHg at rest in a setting of normal pulmonary arterial wedge pressure of 15mmHg or less with a PVR index greater than 3 Woods units•m2 at last hemodynamic study. Patients must be diagnosed with any of the following:Idiopathic PAH (IPAH), PAH associated with repaired congenital heart disease, PAH associated with minor congenital heart disease (small interventricular communication, small interarterial communication, small ductus arteriosis) Patients must be clinically stable (i.e. no treatment changes) for the last 3 months Patients must have no or minimal evidence of fluid overload or volume depletion judged by clinical evaluation (with or without diuretic treatment) Written informed consent Exclusion Criteria: Patients who are unable to perform a six minute walk test (6MWT) Patients with a known history of pulmonary hypertension secondary to venoocclusive disease and/or capillary hemangiomatosis; pulmonary hypertensions owing to left heart disease Patients who have previously received treatment with an intravenous positive inotropic agent in the last 3 months Patients who are currently receiving β-blockers Patients with a known history of reactive airways disease (bronchial asthma or relate bronchospastic conditions) Patients with chronic obstructive pulmonary disease (COPD) Patients with a known history of adverse reaction to β-blockers Patients with a heart block on ECG or resting heart rate < 60 bpm Patients with systemic hypotension (below 5th percentile for age) are not eligible as follows: 1-10 years old: systolic blood pressure defined as < [70 + (2 x age in years)] mmHg; Older than 10 years: systolic blood pressure < 90 mmHg Patients with coagulopathy (INR < 1.5 or platelet count <50,000/mm3) Patients with a known history of severe hepatic impairment (defined by the presence of ascites, esophageal varices, jaundice or spider angiomata) Patients with severe renal insufficiency (defined as creatinine clearance < 30 mL/min/m2) Patients with a known malignancy or other co-morbidity expected to limit survival or to limit the ability to complete the study Patients with trisomy 21 Patients with a known history of sick sinus syndrome Patients with a known history of moderate or severe primary obstructive valvular heart disease Patients with a known history of diabetes Female patients who are pregnant of breast-feeding
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark Friedberg, MD
Organizational Affiliation
The Hospital for Sick Children
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada

12. IPD Sharing Statement

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Beta Blockers for Treatment of Pulmonary Arterial Hypertension in Children

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