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Advair HFA in Healthy and HAPE Predisposed Subjects (SWIFTARC)

Primary Purpose

Altitude Edema

Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Advair HFA
Placebo
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Altitude Edema focused on measuring salmeterol, fluticasone, exercise performance, high altitude pulmonary edema, hypoxia

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Written informed consent signed prior to entry into the study. Male or female age 18-50 years of age BMI ≥ 20 and < 35 kg/m2 Agreement to comply with the study-required interventions and treatment during the full duration of the study. In good health as determined by screening medical history, physical examination, vital signs (blood pressure, heart rate, respiratory rate and temperature), clinical laboratory tests (CBC, PT (INR)/PTT, TSH, Total Bilirubin, blood chemistries, urine drug screening), and a resting 12-lead Electrocardiogram with a 10 second rhythm strip. Adequate peripheral venous access for IV insertion and blood sample collection (assessments will be made prior to undergoing further assessments). HAPE-susceptible individuals (Study 2 only) must have had a medically documented (hospital admission or emergency room visit) HAPE episode characterized by noncardiogenic pulmonary edema and hypoxemia that occurred during high altitude travel in Colorado and must reside below 3,000 feet (unacclimatized individuals; non-Colorado residents). HAPE-resistant individuals (Study 2 only) will have had no evidence of HAPE during high altitude travel in Colorado, and must reside below 3,000 feet (unacclimatized; often being travel partners of HAPE-susceptible subjects). Healthy controls (Study 1 only) will all be Colorado residents. Exclusion Criteria: Currently participating in or has been enrolled in another clinical trial within the last 30 days (observational studies are acceptable). Donation of any blood or plasma in the last month, or donation of >500mL of blood within the 3 months preceding study drug administration. Female subjects of childbearing potential with positive serum pregnancy (beta human chorionic gonadotropin) test, who are breastfeeding, plan to become pregnant during the study, or decline to either be abstinent or use highly effective birth control if they have sexual intercourse with a male partner (ie, oral contraceptives; contraceptive patches, implants, injections, and rings; intrauterine devices [IUD], both IUDs hormonally-impregnated and untreated) throughout the study and for at least 1 month after study completion; Known history of impaired liver function Clinically significant laboratory abnormalities (one retest is allowed at the discretion of the Investigator and Medical Monitor), defined as: Impaired renal function (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) as estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at screening.(81) Serum Potassium < 3.2 mM AST or ALT > 2x upper reference limit INR > 1.5 Fasting serum triglycerides > 500 mg/dL (lipemic serum affects assays) TSH < 0.5 or > 5 mU/L Hemoglobin < 12.0 g/dL Bilirubin > 2, unless consistent with Gilbert's disorder (indirect bilirubinemia) Platelet count < 100,000/µL Any other abnormality deemed by the Investigator to exceed normal safety limits for this study or exclude subject participation. Cardiovascular conditions: Clinically significant abnormal electrocardiogram at screening: ▪ Clinically significant abnormal ECG results including but not limited to complete left or right bundle branch block; other ventricular conduction block (except for incomplete bundle branch blocks, QRS duration < 0.12 sec) ; 2nd degree or 3rd degree atrioventricular (AV) block; sustained ventricular arrhythmia; sustained atrial arrhythmia; two or more PVC in a row; pattern of ST elevation felt consistent with cardiac ischemia; or any condition deemed clinically significant by a study investigator Any history of congenital or acquired long QT syndrome Any history of uncorrected re-entrant supraventricular tachycardia, atrial fibrillation, sinus tachycardia (> 100 bpm at rest), or ventricular tachycardia. Evidence of conduction abnormality including QTc prolongation on ECG, defined as > 450 msec for men and > 470 msec for women Unstable angina pectoris, history of myocardial infarction (MI), transient ischemic attack (TIA) or stroke within 3 months prior to screening, or subjects who have ever undergone percutaneous coronary intervention or a coronary artery bypass or who are due to undergo these procedures at the time of screening, as evidence of atherosclerotic cardiovascular disease (ASCVD). New York Heart Association Functional Class I-IV congestive heart failure (any congestive heart failure) Use of any blood thinner (e.g. novel oral anticoagulant, coumadin/warfarin). Use of aspirin is acceptable for study and will not need to be discontinued prior to involvement in the study. Use of a P2Y12 inhibitor (such as clopidogrel) is also not permitted due to bleeding risks. Use of any phosphodiesterase-5 inhibitors (as prescribed medications or obtained by other means) such as sildenafil, tadalafil, or vardenafil (as they may enhance hypoxic exercise performance) Infectious conditions: o Active COVID-19 or any viral upper respiratory infection suspected by symptoms and/or confirmed by nasal swab PCR or rapid antigen within the past 30 days. Subjects will be screened for COVID-19 at study entry by nasal swab antigen test on day 0 regardless of symptoms. A subject with recent COVID-19 will be allowed to participate provided that the diagnosis was made more than 30 days previously, COVID-related symptoms have been absent for 20 or more days, and an antigen test on day 0 is negative. Concomitant Medications: Nonselective beta-blockers including propranolol, carvedilol, and labetalol (due to antagonization of beta-2 agonist effects) Use of any inhaled or oral beta-2 receptor agonists, or oral theophylline Non-potassium sparing diuretics (due to hypokalemia risks) The use of any medication known to be a strong inhibitor or strong inducer of CYP 3A4/5 enzymes (cytochrome P450 isoenzymes) that metabolize salmeterol.(66) Also, any medication that has been reported to have a major or moderate interaction with salmeterol or fluticasone(82) Use of monoamine oxidase inhibitors or tricyclic antidepressants within 2 weeks of screening Prescription amphetamines or other sympathetic stimulants used for disorders such as narcolepsy, somnolence, or attention deficit disorder History of claustrophobia or post traumatic stress disorder that would limit use of gas breathing masks or mouthpieces. Essential tremor limiting handwriting, or any tremor requiring medication.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Advair HFA (salmeterol 126 ug/fluticasone 270 ug) twice daily for up to 7 days

    Placebo

    Arm Description

    Participants will inhale salmeterol 126 ug and fluticasone 270 ug twice daily for up to 7 days

    Participants will inhale placebo (same puff number) twice daily for up to 7 days

    Outcomes

    Primary Outcome Measures

    VO2 max
    peak oxygen consumption with exercise

    Secondary Outcome Measures

    Aa Gradient
    alveolar-arterial oxygen Gradient during peak hypoxic exercise
    blood lactate
    peak arterial blood lactate during peak hypoxic exercise
    nadir PaO2
    lowest arterial partial pressure of oxygen during peak hypoxic exercise
    highest PaO2
    highest arterial partial pressure of oxygen during peak hypoxic exercise
    MPAP
    highest mean pulmonary arterial pressure during hypoxic exercise
    cardiac output
    highest cardiac output during hypoxic exercise

    Full Information

    First Posted
    September 8, 2023
    Last Updated
    September 8, 2023
    Sponsor
    University of Colorado, Denver
    Collaborators
    United States Department of Defense, MTEC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06040268
    Brief Title
    Advair HFA in Healthy and HAPE Predisposed Subjects
    Acronym
    SWIFTARC
    Official Title
    A Double-Blinded, Placebo-Controlled, Randomized, 2 Period, Crossover Phase 1/2a Study to Test the Safety and Efficacy of Advair HFA (Salmeterol and Fluticasone) in Resting and Exercising Healthy and High Altitude Pulmonary Edema (HAPE) Predisposed Subjects
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    November 1, 2023 (Anticipated)
    Primary Completion Date
    November 1, 2026 (Anticipated)
    Study Completion Date
    November 15, 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    University of Colorado, Denver
    Collaborators
    United States Department of Defense, MTEC

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The current protocol is composed of two studies. The first study is designed to carefully evaluate the safety of high-dose salmeterol/fluticasone administration over 7 days, as well as the efficacy of the study drug to increase exercise performance, in healthy individuals exercising under hypoxic, simulated high-altitude conditions (Phase 1/2a study). The second study will examine sensitive measures of cardiopulmonary function using invasive cardiopulmonary testing, in both HAPE-sensitive and HAPE-resistant individuals, to assess the potential efficacy of salmeterol/fluticasone to prevent pulmonary edema and to enhance exercise capacity (Phase 2a) in these individuals.
    Detailed Description
    Both Study 1 and Study 2 are double-blinded, randomized, placebo-controlled, two-period, crossover studies. Study 1 (Phase 1/2a) is a Double-Blinded, Placebo-Controlled, Randomized, 2 Period, Crossover study examining safety and efficacy in healthy subjects dosed with salmeterol/fluticasone 126mcg/270mcg twice daily vs. placebo, for 7 days. Subjects will exercise under hypoxic conditions one time during each study period with the primary efficacy outcome being maximal oxygen uptake (VO2max), and secondary outcomes of PaO2, Aa gradient, and blood lactate levels. Continuous cardiac monitoring will occur during study drug dosing and for 5 days after drug discontinuation. ECGs and safety lab tests will be assessed at key intervals during drug dosing. A pause in enrollment will occur for a planned DSMB safety analysis after four subjects have completed Study 1. There will also be a full review of safety data once Study 1 is complete prior to initiating Study 2. Study 2 (Phase 2a) is a Double-Blinded, Placebo-Controlled, Randomized, 2 Period, Crossover study examining efficacy and safety in both healthy (HAPE-resistant) and HAPE-susceptible subjects dosed with salmeterol/fluticasone 126mcg/270mcg twice daily. Subjects will take study drug for two days prior to hypoxic exercise testing in each period of this study, then discontinue study drug when the exercise is completed. Efficacy assessments will include VO2 max (primary outcome), right heart catheter measurements, PaO2, A-a gradients, and blood lactate. For both studies, investigators and subjects will be blinded to assignment group (order of study drug vs. placebo).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Altitude Edema
    Keywords
    salmeterol, fluticasone, exercise performance, high altitude pulmonary edema, hypoxia

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Crossover Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    60 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Advair HFA (salmeterol 126 ug/fluticasone 270 ug) twice daily for up to 7 days
    Arm Type
    Experimental
    Arm Description
    Participants will inhale salmeterol 126 ug and fluticasone 270 ug twice daily for up to 7 days
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Participants will inhale placebo (same puff number) twice daily for up to 7 days
    Intervention Type
    Drug
    Intervention Name(s)
    Advair HFA
    Other Intervention Name(s)
    salmeterol/fluticasone
    Intervention Description
    6 puffs (total: salmeterol 126 ug and fluticasone 270 ug) twice daily
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    HFA134a inhaler
    Primary Outcome Measure Information:
    Title
    VO2 max
    Description
    peak oxygen consumption with exercise
    Time Frame
    day 3 of treatment
    Secondary Outcome Measure Information:
    Title
    Aa Gradient
    Description
    alveolar-arterial oxygen Gradient during peak hypoxic exercise
    Time Frame
    day 3 of treatment
    Title
    blood lactate
    Description
    peak arterial blood lactate during peak hypoxic exercise
    Time Frame
    day 3 of treatment
    Title
    nadir PaO2
    Description
    lowest arterial partial pressure of oxygen during peak hypoxic exercise
    Time Frame
    day 3 of treatment
    Title
    highest PaO2
    Description
    highest arterial partial pressure of oxygen during peak hypoxic exercise
    Time Frame
    day 3 of treatment
    Title
    MPAP
    Description
    highest mean pulmonary arterial pressure during hypoxic exercise
    Time Frame
    day 3 of treatment
    Title
    cardiac output
    Description
    highest cardiac output during hypoxic exercise
    Time Frame
    day 3 of treatment
    Other Pre-specified Outcome Measures:
    Title
    Cardiac rhythm
    Description
    Safety as measured by number of subjects with symptomatic ectopy on continuous cardiac monitoring
    Time Frame
    Up to 7 days of treatment
    Title
    Cardiac rhythm
    Description
    Safety as measured by number of subjects with asymptomatic ectopy/tachyarrythmias on continuous cardiac monitoring
    Time Frame
    Up to 7 days of treatment
    Title
    Serum potassium
    Description
    Safety as measured by number of subjects with serum potassium < 3.3
    Time Frame
    Up to 7 days of treatment
    Title
    QTc
    Description
    Safety as measured by number of subjects with QTc interval prolongation > 30 msec on 12-lead EKG
    Time Frame
    Up to 7 days of treatment
    Title
    Drug discontinuation
    Description
    Number of subjects with adverse event-related study drug discontinuation (compared to placebo)
    Time Frame
    up to 7 days of treatment

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    50 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    Inclusion Criteria: Written informed consent signed prior to entry into the study. Male or female age 18-50 years of age BMI ≥ 20 and < 35 kg/m2 Agreement to comply with the study-required interventions and treatment during the full duration of the study. In good health as determined by screening medical history, physical examination, vital signs (blood pressure, heart rate, respiratory rate and temperature), clinical laboratory tests (CBC, PT (INR)/PTT, TSH, Total Bilirubin, blood chemistries, urine drug screening), and a resting 12-lead Electrocardiogram with a 10 second rhythm strip. Adequate peripheral venous access for IV insertion and blood sample collection (assessments will be made prior to undergoing further assessments). HAPE-susceptible individuals (Study 2 only) must have had a medically documented (hospital admission or emergency room visit) HAPE episode characterized by noncardiogenic pulmonary edema and hypoxemia that occurred during high altitude travel in Colorado and must reside below 3,000 feet (unacclimatized individuals; non-Colorado residents). HAPE-resistant individuals (Study 2 only) will have had no evidence of HAPE during high altitude travel in Colorado, and must reside below 3,000 feet (unacclimatized; often being travel partners of HAPE-susceptible subjects). Healthy controls (Study 1 only) will all be Colorado residents. Exclusion Criteria: Currently participating in or has been enrolled in another clinical trial within the last 30 days (observational studies are acceptable). Donation of any blood or plasma in the last month, or donation of >500mL of blood within the 3 months preceding study drug administration. Female subjects of childbearing potential with positive serum pregnancy (beta human chorionic gonadotropin) test, who are breastfeeding, plan to become pregnant during the study, or decline to either be abstinent or use highly effective birth control if they have sexual intercourse with a male partner (ie, oral contraceptives; contraceptive patches, implants, injections, and rings; intrauterine devices [IUD], both IUDs hormonally-impregnated and untreated) throughout the study and for at least 1 month after study completion; Known history of impaired liver function Clinically significant laboratory abnormalities (one retest is allowed at the discretion of the Investigator and Medical Monitor), defined as: Impaired renal function (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) as estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at screening.(81) Serum Potassium < 3.2 mM AST or ALT > 2x upper reference limit INR > 1.5 Fasting serum triglycerides > 500 mg/dL (lipemic serum affects assays) TSH < 0.5 or > 5 mU/L Hemoglobin < 12.0 g/dL Bilirubin > 2, unless consistent with Gilbert's disorder (indirect bilirubinemia) Platelet count < 100,000/µL Any other abnormality deemed by the Investigator to exceed normal safety limits for this study or exclude subject participation. Cardiovascular conditions: Clinically significant abnormal electrocardiogram at screening: ▪ Clinically significant abnormal ECG results including but not limited to complete left or right bundle branch block; other ventricular conduction block (except for incomplete bundle branch blocks, QRS duration < 0.12 sec) ; 2nd degree or 3rd degree atrioventricular (AV) block; sustained ventricular arrhythmia; sustained atrial arrhythmia; two or more PVC in a row; pattern of ST elevation felt consistent with cardiac ischemia; or any condition deemed clinically significant by a study investigator Any history of congenital or acquired long QT syndrome Any history of uncorrected re-entrant supraventricular tachycardia, atrial fibrillation, sinus tachycardia (> 100 bpm at rest), or ventricular tachycardia. Evidence of conduction abnormality including QTc prolongation on ECG, defined as > 450 msec for men and > 470 msec for women Unstable angina pectoris, history of myocardial infarction (MI), transient ischemic attack (TIA) or stroke within 3 months prior to screening, or subjects who have ever undergone percutaneous coronary intervention or a coronary artery bypass or who are due to undergo these procedures at the time of screening, as evidence of atherosclerotic cardiovascular disease (ASCVD). New York Heart Association Functional Class I-IV congestive heart failure (any congestive heart failure) Use of any blood thinner (e.g. novel oral anticoagulant, coumadin/warfarin). Use of aspirin is acceptable for study and will not need to be discontinued prior to involvement in the study. Use of a P2Y12 inhibitor (such as clopidogrel) is also not permitted due to bleeding risks. Use of any phosphodiesterase-5 inhibitors (as prescribed medications or obtained by other means) such as sildenafil, tadalafil, or vardenafil (as they may enhance hypoxic exercise performance) Infectious conditions: o Active COVID-19 or any viral upper respiratory infection suspected by symptoms and/or confirmed by nasal swab PCR or rapid antigen within the past 30 days. Subjects will be screened for COVID-19 at study entry by nasal swab antigen test on day 0 regardless of symptoms. A subject with recent COVID-19 will be allowed to participate provided that the diagnosis was made more than 30 days previously, COVID-related symptoms have been absent for 20 or more days, and an antigen test on day 0 is negative. Concomitant Medications: Nonselective beta-blockers including propranolol, carvedilol, and labetalol (due to antagonization of beta-2 agonist effects) Use of any inhaled or oral beta-2 receptor agonists, or oral theophylline Non-potassium sparing diuretics (due to hypokalemia risks) The use of any medication known to be a strong inhibitor or strong inducer of CYP 3A4/5 enzymes (cytochrome P450 isoenzymes) that metabolize salmeterol.(66) Also, any medication that has been reported to have a major or moderate interaction with salmeterol or fluticasone(82) Use of monoamine oxidase inhibitors or tricyclic antidepressants within 2 weeks of screening Prescription amphetamines or other sympathetic stimulants used for disorders such as narcolepsy, somnolence, or attention deficit disorder History of claustrophobia or post traumatic stress disorder that would limit use of gas breathing masks or mouthpieces. Essential tremor limiting handwriting, or any tremor requiring medication.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    James P Maloney, MD
    Phone
    3037246072
    Email
    james.maloney@ucdenver.edu
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    James P Maloney, MD
    Organizational Affiliation
    Univ. of Colorado, Denver
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No

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