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Sildenafil Trial in Children and Young Adults With CF

Primary Purpose

Cystic Fibrosis With Mild to Moderate Lung Disease, CMRI of Lung Perfusion, Lung Perfusion

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Sildenafil
Sponsored by
Children's Hospital Medical Center, Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cystic Fibrosis With Mild to Moderate Lung Disease focused on measuring Cystic Fibrosis, CF, CMRI, vascularization, perfusion

Eligibility Criteria

8 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

Research subjects must meet the following inclusion criteria:

  • Age 8 years to age 21 years
  • Weight > 20kg
  • Diagnosis of cystic fibrosis confirmed by a prior sweat chloride evaluation of > 60 mmol/liter or by two identified CFTR mutations on genetic analysis
  • Able to perform acceptable and repeatable spirometry per American Thoracic Society/European Respiratory Society (ATS/ERS) joint consensus criteria.
  • Have valid spirometry data for at least 3 years
  • Must have mild to moderate lung disease (Mild lung disease will be defined as an FEV1%p of 80-99% predicted. Moderate lung disease will be defined as an FEV1%p of 60-79% predicted.)
  • If under the age of 18, the subject must assent to participation in the study, and the subject's parent or guardian must be able to give written informed consent and comply with the requirements of the study protocol
  • If 18 years of age or older, the subject must be able to give written parental permission and comply with the requirements of the study protocol
  • For female subjects: negative serum pregnancy test and must be willing to use contraception during study participation
  • Able to tolerate MRI without sedation
  • Subjects who are on alternating monthly on/off cycles of inhaled antibiotics must be willing to be off of inhaled antibiotic therapy for one "on" cycle.
  • Must be currently enrolled in CCHMC IRB#: 2008-0926
  • Normal Vitamin K status (PT/IND, PIVKA, etc) at screening

Exclusion Criteria

Research subjects will be excluded from the study based on:

  • History of CF-related liver disease with portal hypertension
  • Currently smoking cigarettes or other tobacco products
  • Use of daytime oxygen supplementation
  • Previous organ transplantation
  • Unstable or uncontrolled hypertension
  • Ongoing use of oral corticosteroids
  • For female subjects: pregnancy or lactation and unwillingness to use contraception during study participation
  • Any hemodynamically significant congenital or acquired cardiac disease or significant cardiomyopathy, hematologic disease (i.e. hemoglobinopathies), or pulmonary disease associated with an increased risk of pulmonary perfusion defects or pulmonary hypertension other than as an outcome of CF
  • History of renal and/or hepatic insufficiency, defined as cystatin-C level that exceeds normal range and a previous diagnosis of liver cirrhosis.
  • History of uncontrolled asthma defined as oral steroid dependent
  • History of hypersensitivity to gadolinium (Magnevist)
  • Contraindications specific to MRI including a history of claustrophobia, cardiac pacemaker, or other non-MRI compatible surgical implants (This includes neuro-stimulators containing electrical circuitry, or which generate electrical signals and/or have moving metal parts, and metal orthopedic pins or plates. The research coordinator and/or the MRI technologist will screen all subjects using the standard checklist of medical history and safety questions used by the Radiology Department in routine clinical scans.)
  • Daily use of montelukast and ibuprofen
  • Use of nitrate medicines or other drugs known to have unsafe interactions with Sildenafil
  • Known allergy to Sildenafil
  • Inability to comply with study procedures

  • History of the following:

    1. Tinnitus or hearing impairment
    2. CF exacerbation within the preceding two months
    3. Ulcer, severe gastritis, or prior GI bleed
    4. Recurrent epistaxis
    5. Diabetes or abnormal OGTT (risk of retinal hemorrhage with sildenafil is highest in diabetics)

Laboratory Exclusion Criteria for research subjects (based on history or blood work before first MRI):

  • Positive sputum, epiglottic, or bronchoalveolar lavage culture for Mycobacterium abscessus during the 2 years prior to enrollment
  • A positive serum pregnancy test
  • Serum creatinine > two times the upper limit of normal for age
  • A serum Cystatin C < 60 ml/min/1.73m2
  • Vitamin K outside of normal range

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Sildenafil

    Arm Description

    15 subjects will receive 8 week course of Sildenafil administered at a dose of 20 mg per dose three times per day.

    Outcomes

    Primary Outcome Measures

    Increase pulmonary perfusion
    • Increase of pulmonary perfusion by a minimum of 15% as measured by gadolinium contrast MRI with segmental perfusion and scored on a continuous scale;

    Secondary Outcome Measures

    Improved lung function
    • Improved exercise performance as measured by the following variables: Ventilatory equivalent of O2 and CO2 (VEO2 and VECO2) Maximum oxygen consumption (VO2 max)

    Full Information

    First Posted
    September 1, 2010
    Last Updated
    December 10, 2012
    Sponsor
    Children's Hospital Medical Center, Cincinnati
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01194232
    Brief Title
    Sildenafil Trial in Children and Young Adults With CF
    Official Title
    Randomized Controlled Study of Sildenafil in Children and Young Adults With Mild to Moderate Cystic Fibrosis Lung Disease
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    December 2012
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Funding, MedWatch change to study drug
    Study Start Date
    August 2012 (undefined)
    Primary Completion Date
    December 2012 (Actual)
    Study Completion Date
    December 2012 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Children's Hospital Medical Center, Cincinnati

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Cystic Fibrosis (CF), the most common inherited disease in Caucasians, is characterized by chronic pulmonary inflammation and progressive loss of gas exchange units that eventually results in respiratory failure. There is strong evidence that, in CF, abnormally low perfusion carries a high risk of death independent from the presence of pulmonary hypertension. However, the evolution of pulmonary vascular disease in CF and how it might contribute to the rate of decline in lung function is not known. Our knowledge remains limited to the results of old observational studies which concluded that the major causes of pulmonary vascular remodeling and hypertension in CF are hypoxic respiratory failure and destruction of lung tissue. Our recent data obtained by state-of-the-art Magnetic Resonance Imaging (MRI) of the pulmonary circulation, challenges the existing paradigm. We demonstrate that in the absence of hypoxia, significant changes in pulmonary perfusion and in surrogate measures of vascular resistance as well as in collateral blood flow begin early in the course of CF. Newly developed therapeutics have altered dramatically the course of patients suffering from pulmonary vascular disease. Through this 8 week trial, we will examine by Magnetic Resonance Imaging the effect of Sildenafil on pulmonary perfusion and systemic vascularization of the lungs in subjects with mild to moderate disease.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Cystic Fibrosis With Mild to Moderate Lung Disease, CMRI of Lung Perfusion, Lung Perfusion, Lung Vascularization
    Keywords
    Cystic Fibrosis, CF, CMRI, vascularization, perfusion

    7. Study Design

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

    8. Arms, Groups, and Interventions

    Arm Title
    Sildenafil
    Arm Type
    Experimental
    Arm Description
    15 subjects will receive 8 week course of Sildenafil administered at a dose of 20 mg per dose three times per day.
    Intervention Type
    Drug
    Intervention Name(s)
    Sildenafil
    Intervention Description
    8 week course of Sildenafil administered at a dose of 1 mg / Kg three times a day with a maximum dose of 20 mg per dose.
    Primary Outcome Measure Information:
    Title
    Increase pulmonary perfusion
    Description
    • Increase of pulmonary perfusion by a minimum of 15% as measured by gadolinium contrast MRI with segmental perfusion and scored on a continuous scale;
    Time Frame
    8 week visit
    Secondary Outcome Measure Information:
    Title
    Improved lung function
    Description
    • Improved exercise performance as measured by the following variables: Ventilatory equivalent of O2 and CO2 (VEO2 and VECO2) Maximum oxygen consumption (VO2 max)
    Time Frame
    8 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    8 Years
    Maximum Age & Unit of Time
    21 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria Research subjects must meet the following inclusion criteria: Age 8 years to age 21 years Weight > 20kg Diagnosis of cystic fibrosis confirmed by a prior sweat chloride evaluation of > 60 mmol/liter or by two identified CFTR mutations on genetic analysis Able to perform acceptable and repeatable spirometry per American Thoracic Society/European Respiratory Society (ATS/ERS) joint consensus criteria. Have valid spirometry data for at least 3 years Must have mild to moderate lung disease (Mild lung disease will be defined as an FEV1%p of 80-99% predicted. Moderate lung disease will be defined as an FEV1%p of 60-79% predicted.) If under the age of 18, the subject must assent to participation in the study, and the subject's parent or guardian must be able to give written informed consent and comply with the requirements of the study protocol If 18 years of age or older, the subject must be able to give written parental permission and comply with the requirements of the study protocol For female subjects: negative serum pregnancy test and must be willing to use contraception during study participation Able to tolerate MRI without sedation Subjects who are on alternating monthly on/off cycles of inhaled antibiotics must be willing to be off of inhaled antibiotic therapy for one "on" cycle. Must be currently enrolled in CCHMC IRB#: 2008-0926 Normal Vitamin K status (PT/IND, PIVKA, etc) at screening Exclusion Criteria Research subjects will be excluded from the study based on: History of CF-related liver disease with portal hypertension Currently smoking cigarettes or other tobacco products Use of daytime oxygen supplementation Previous organ transplantation Unstable or uncontrolled hypertension Ongoing use of oral corticosteroids For female subjects: pregnancy or lactation and unwillingness to use contraception during study participation Any hemodynamically significant congenital or acquired cardiac disease or significant cardiomyopathy, hematologic disease (i.e. hemoglobinopathies), or pulmonary disease associated with an increased risk of pulmonary perfusion defects or pulmonary hypertension other than as an outcome of CF History of renal and/or hepatic insufficiency, defined as cystatin-C level that exceeds normal range and a previous diagnosis of liver cirrhosis. History of uncontrolled asthma defined as oral steroid dependent History of hypersensitivity to gadolinium (Magnevist) Contraindications specific to MRI including a history of claustrophobia, cardiac pacemaker, or other non-MRI compatible surgical implants (This includes neuro-stimulators containing electrical circuitry, or which generate electrical signals and/or have moving metal parts, and metal orthopedic pins or plates. The research coordinator and/or the MRI technologist will screen all subjects using the standard checklist of medical history and safety questions used by the Radiology Department in routine clinical scans.) Daily use of montelukast and ibuprofen Use of nitrate medicines or other drugs known to have unsafe interactions with Sildenafil Known allergy to Sildenafil Inability to comply with study procedures History of the following: Tinnitus or hearing impairment CF exacerbation within the preceding two months Ulcer, severe gastritis, or prior GI bleed Recurrent epistaxis Diabetes or abnormal OGTT (risk of retinal hemorrhage with sildenafil is highest in diabetics) Laboratory Exclusion Criteria for research subjects (based on history or blood work before first MRI): Positive sputum, epiglottic, or bronchoalveolar lavage culture for Mycobacterium abscessus during the 2 years prior to enrollment A positive serum pregnancy test Serum creatinine > two times the upper limit of normal for age A serum Cystatin C < 60 ml/min/1.73m2 Vitamin K outside of normal range

    12. IPD Sharing Statement

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    Sildenafil Trial in Children and Young Adults With CF

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