Beta Blockers for Treatment of Pulmonary Arterial Hypertension in Children - Full Text View

Purpose

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.

Condition	Intervention	Phase
Pulmonary Arterial Hypertension	Drug: Carvedilol	Phase 1 Phase 2


Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Beta Blockers for Treatment of Pulmonary Arterial Hypertension in Children

Resource links provided by NLM:

Genetics Home Reference related topics: pulmonary arterial hypertension

Drug Information available for: Carvedilol Carvedilol hydrochloride Adrenergic beta-Antagonists

Genetic and Rare Diseases Information Center resources: Pulmonary Arterial Hypertension

U.S. FDA Resources

Further study details as provided by The Hospital for Sick Children:

Primary Outcome Measures:

Incidence of Adverse Events [ Time Frame: Throughout study (Baseline to week 31) ] [ Designated as safety issue: Yes ]
-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) [ Time Frame: Change over 6 months ] [ Designated as safety issue: No ]
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 [ Time Frame: Change over 6 months ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline, Week 0, 2, 3, 4, 5, 6, 10, 18, 22, 30, 31 ] [ Designated as safety issue: No ]
- 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


Enrollment:	0
Study Start Date:	September 2012
Primary Completion Date:	September 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Carvedilol	Drug: Carvedilol 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.

Arms

Assigned Interventions

Experimental: Carvedilol

Drug: Carvedilol

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.

Eligibility


Ages Eligible for Study:	8 Years to 17 Years (Child)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

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: NCT01723371

Locations


Canada, Ontario
The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8

Sponsors and Collaborators

The Hospital for Sick Children

Investigators


Principal Investigator:	Mark Friedberg, MD	The Hospital for Sick Children

More Information


Responsible Party:	Mark Friedberg, Staff Cardiologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier:	NCT01723371 History of Changes
Other Study ID Numbers:	1000031903
Study First Received:	October 31, 2012
Last Updated:	December 30, 2015
Health Authority:	Canada: Health Canada

Keywords provided by The Hospital for Sick Children:


Pulmonary Arterial Hypertension (PAH Pediatrics Right Heart Failure (RHF) Carvedilol Beta-blockers

Additional relevant MeSH terms:


Hypertension Familial Primary Pulmonary Hypertension Vascular Diseases Cardiovascular Diseases Hypertension, Pulmonary Lung Diseases Respiratory Tract Diseases Carvedilol Adrenergic beta-Antagonists	Adrenergic Antagonists Adrenergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Antihypertensive Agents Vasodilator Agents Adrenergic alpha-1 Receptor Antagonists Adrenergic alpha-Antagonists

ClinicalTrials.gov processed this record on September 26, 2016