The Effects of Ambrisentan on Exercise Capacity in Fontan Patients

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01971580
• Collaborator: (none)
• Enrollment: 28
• Location: 1
• Arms: 2
• Duration (Months): 33
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Hypothesis:

Patients with a Fontan type palliation are limited by preload, or the rate at which blood returns to the heart after passively traversing the pulmonary capillary bed. By decreasing pulmonary vascular resistance using an endothelin receptor antagonist, both ventricular filling pressures and volumes will increase with a simultaneous decrease in systemic impedance to flow and decrease in central venous pressures, leading to an improved capacity to increase cardiac output, and thereby an improvement in patient functional status.

Patients who are candidates for the study will be randomized to a double-blind single crossover study. Therapy with either ambrisentan or placebo will be continued for 12 weeks, with a 2 week washout period between treatment periods. Subjects will be subjected to a VO2 max test to evaluate exercise capacity at enrolment, and on the last day of each treatment period. As a component of the VO2 max testing the patient's VE, VCO2, VE/VCO2 slope, ventilatory anaerobic threshold (VAT), peak work, efficiency, and other physiologic parameters as typically obtained from cardiopulmonary testing will be assessed. In addition, each patient will be asked to complete an SF-36 quality of life questionnaire at enrollment, and on the last day of each study period.

Condition or Disease	Intervention/Treatment	Phase
Single Ventricle Fontan Palliation	Drug: Ambrisentan	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effects of Ambrisentan on Exercise Capacity in Fontan Patients
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Other: Ambrisentan first, Placebo second These patients will be randomized to have ambrisentan during the first study period, and placebo during the second study period.	Drug: Ambrisentan; Other Names: Letaris
Other: Placebo first, Ambrisentan second These patients will be randomized to have placebo during the first study period, and ambrisentan during the second study period.	Drug: Ambrisentan; Other Names: Letaris

Outcome Measures

Primary Outcome Measures

1. Change in VO2 Max [Baseline compared to 12 weeks therapy with either ambrisentan or placebo]

Secondary Outcome Measures

1. Quality of Life [12 weeks]

   Change in Rand 36-item Short Form (SF-36) physical function score (0-100). On the Rand SF-36 questionnaire, a score closer to 100 (higher) suggests lesser disability, while a score closer to 0 (lower) suggests more disability.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients over 18 years of age followed at the Center for Adults with Congenital Heart Disease at Washington University School of Medicine or at Saint Louis Childrens Hospital who have had a Fontan-type of palliation with single ventricular physiology.

2. Patients must not within the last year have been treated with an endothelin receptor antagonist, phosphodiesterase 5 antagonist, or prostacyclin analogue.

3. Female patients must not be pregnant, and during the study period must be using effective contraception (including barrier method with spermicide, intrauterine device, implanon, oral contraceptives) if fertile.

4. In the physicians opinion patients must be able to complete a VO2 max test to achieve an RER of >1.0

5. In the physicians opinion patients must be socially and intellectually able to adhere to the treatment regimen and follow-up

6. Patients must be intellectually able to reliably complete an SF-36 questionnaire on quality of life.

7. Patients must be clinically stable for at least 3 months prior to enrolment.

8. Patients must not have had surgery within 6 months prior to enrolment, and have no planned surgery for the study period.

9. Patients must provide informed consent.

Exclusion Criteria:

1. Patients under 18 years of age.

2. Patients who are pregnant, nursing, or who in the physician's opinion are likely to become pregnant.

3. Patients who are clinically unstable.

4. Patients who have previously been treated with either an endothelin receptor antagonist and stopped due to adverse side effects.

5. Patients with an AST or ALT of >3 x normal.

6. Patients having any known contraindication to the initiation of ambrisentan.

7. Patients with a calculated creatinine clearance of <60ml/min

8. Patients with a serum hemoglobin concentration of <10mg/dl

9. Patients with a poorly controlled cardiac arrhythmia

10. Patients who are unable to provide independent informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ari Cedars, Assistant Professor of Medicine, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01971580
• Other Study ID Numbers: IN-US-300-D076
• First Posted: Oct 29, 2013
• Last Update Posted: May 7, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Univentricular Heart; Ambrisentan

Study Results

Participant Flow

Recruitment Details	Patients were recruited from Washington University School of Medicine Adult Congenital Heart Disease clinic between 10/2012 and 11/2014

Arm/Group Title	Ambrisentan First, Placebo Second	Placebo First, Ambrisentan Second
Arm/Group Description	These patients will be randomized to have ambrisentan during the first study period, and placebo during the second study period. Ambrisentan	These patients will be randomized to have placebo during the first study period, and ambrisentan during the second study period. Ambrisentan
Period Title: Overall Study
STARTED	14	14
COMPLETED	10	9
NOT COMPLETED	4	5

Baseline Characteristics

Arm/Group Title	Ambrisentan First, Placebo Second	Placebo First, Ambrisentan Second	Total
Arm/Group Description	These patients will be randomized to have ambrisentan during the first study period, and placebo during the second study period. Ambrisentan	These patients will be randomized to have placebo during the first study period, and ambrisentan during the second study period. Ambrisentan	Total of all reporting groups
Overall Participants	14	14	28
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	14 100%	28 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	7 50%	4 28.6%	11 39.3%
Male	7 50%	10 71.4%	17 60.7%

Outcome Measures

1. Primary Outcome

Title	Change in VO2 Max
Time Frame	Baseline compared to 12 weeks therapy with either ambrisentan or placebo

Outcome Measure Data

Analysis Population Description

In this crossover study, all patients received both ambrisentan and placebo. Data was analyzed comparing baseline measures to those after the period on ambrisentan and baseline measures to those after the period on placebo.

Arm/Group Title	On Ambrisentan Therapy	On Placebo
Arm/Group Description	After Ambrisentan compared to baseline	After Placebo compared to baseline
Measure Participants	19	19
Mean (95% Confidence Interval) [Change in ml/kg min]	1.33	0.745

2. Secondary Outcome

Title	Quality of Life
Description	Change in Rand 36-item Short Form (SF-36) physical function score (0-100). On the Rand SF-36 questionnaire, a score closer to 100 (higher) suggests lesser disability, while a score closer to 0 (lower) suggests more disability.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

In this crossover study, all patients received both therapies. Analysis was performed comparing baseline to after indicated therapy

Arm/Group Title	On Ambrisentan Therapy	On Placebo
Arm/Group Description	Baseline compared to after period of ambrisentan therapy	Baseline compared to after placebo therapy
Measure Participants	19	19
Mean (95% Confidence Interval) [Change in score from baseline]	3.75	0.195

Adverse Events

Time Frame	During the study period and for one month after the completion of the study protocol, an average of 30 weeks.
Arm/Group Title	On Ambrisentan Therapy		On Placebo
Arm/Group Description	Events that occurred while on ambrisentan therapy		Events that occurred while on placebo therapy
All Cause Mortality
	On Ambrisentan Therapy		On Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)
Serious Adverse Events
	On Ambrisentan Therapy		On Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/19 (0%)
Gastrointestinal disorders
Gastroenteritis and acidosis	1/19 (5.3%)	1	0/19 (0%)	0
Other (Not Including Serious) Adverse Events
	On Ambrisentan Therapy		On Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/19 (68.4%)		14/19 (73.7%)
Cardiac disorders
chest pain	0/19 (0%)	0	2/19 (10.5%)	2
Gastrointestinal disorders
nausea	4/19 (21.1%)	4	2/19 (10.5%)	2
abdominal pain	1/19 (5.3%)	1	0/19 (0%)	0
diarrhea	1/19 (5.3%)	1	2/19 (10.5%)	2
General disorders
fatigue	1/19 (5.3%)	1	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
arthralgia	0/19 (0%)	0	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Rhinitis or Pharyngitis	6/19 (31.6%)	6	8/19 (42.1%)	8
cough/dyspnea	4/19 (21.1%)	4	3/19 (15.8%)	3
Skin and subcutaneous tissue disorders
edema	3/19 (15.8%)	3	2/19 (10.5%)	2
rash	2/19 (10.5%)	2	3/19 (15.8%)	3

Limitations/Caveats

Large dropout rate. Small sample size. Many individuals did not achieve the target RER during cardiopulmonary exercise testing.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.