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)
28
Enrollment
1
Location
2
Arms
33
Duration (Months)
0.8
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
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

ArmIntervention/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

    SiteCityStateCountryPostal Code
    1Washington University School of MedicineSaint LouisMissouriUnited States63110

    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:

    Study Results

    Participant Flow

    Recruitment DetailsPatients were recruited from Washington University School of Medicine Adult Congenital Heart Disease clinic between 10/2012 and 11/2014
    Pre-assignment Detail
    Arm/Group TitleAmbrisentan First, Placebo SecondPlacebo First, Ambrisentan Second
    Arm/Group DescriptionThese patients will be randomized to have ambrisentan during the first study period, and placebo during the second study period. AmbrisentanThese patients will be randomized to have placebo during the first study period, and ambrisentan during the second study period. Ambrisentan
    Period Title: Overall Study
    STARTED1414
    COMPLETED109
    NOT COMPLETED45

    Baseline Characteristics

    Arm/Group TitleAmbrisentan First, Placebo SecondPlacebo First, Ambrisentan SecondTotal
    Arm/Group DescriptionThese patients will be randomized to have ambrisentan during the first study period, and placebo during the second study period. AmbrisentanThese patients will be randomized to have placebo during the first study period, and ambrisentan during the second study period. AmbrisentanTotal of all reporting groups
    Overall Participants141428
    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
    TitleChange in VO2 Max
    Description
    Time FrameBaseline 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 TitleOn Ambrisentan TherapyOn Placebo
    Arm/Group DescriptionAfter Ambrisentan compared to baselineAfter Placebo compared to baseline
    Measure Participants1919
    Mean (95% Confidence Interval) [Change in ml/kg min]
    1.33
    0.745
    2. Secondary Outcome
    TitleQuality of Life
    DescriptionChange 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 Frame12 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 TitleOn Ambrisentan TherapyOn Placebo
    Arm/Group DescriptionBaseline compared to after period of ambrisentan therapyBaseline compared to after placebo therapy
    Measure Participants1919
    Mean (95% Confidence Interval) [Change in score from baseline]
    3.75
    0.195

    Adverse Events

    Time FrameDuring the study period and for one month after the completion of the study protocol, an average of 30 weeks.
    Adverse Event Reporting Description
    Arm/Group TitleOn Ambrisentan TherapyOn Placebo
    Arm/Group DescriptionEvents that occurred while on ambrisentan therapyEvents that occurred while on placebo therapy
    All Cause Mortality
    On Ambrisentan TherapyOn Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/19 (0%) 0/19 (0%)
    Serious Adverse Events
    On Ambrisentan TherapyOn Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total1/19 (5.3%) 0/19 (0%)
    Gastrointestinal disorders
    Gastroenteritis and acidosis1/19 (5.3%) 10/19 (0%) 0
    Other (Not Including Serious) Adverse Events
    On Ambrisentan TherapyOn Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total13/19 (68.4%) 14/19 (73.7%)
    Cardiac disorders
    chest pain0/19 (0%) 02/19 (10.5%) 2
    Gastrointestinal disorders
    nausea4/19 (21.1%) 42/19 (10.5%) 2
    abdominal pain1/19 (5.3%) 10/19 (0%) 0
    diarrhea1/19 (5.3%) 12/19 (10.5%) 2
    General disorders
    fatigue1/19 (5.3%) 11/19 (5.3%) 1
    Musculoskeletal and connective tissue disorders
    arthralgia0/19 (0%) 01/19 (5.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Rhinitis or Pharyngitis6/19 (31.6%) 68/19 (42.1%) 8
    cough/dyspnea4/19 (21.1%) 43/19 (15.8%) 3
    Skin and subcutaneous tissue disorders
    edema3/19 (15.8%) 32/19 (10.5%) 2
    rash2/19 (10.5%) 23/19 (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.

    Results Point of Contact

    Name/TitleAri Cedars
    OrganizationUT Southwestern
    Phone3149224788
    Emailacedars97@gmail.com
    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