Double-Blinded, Placebo-Controlled, Randomized, 2 Period, Crossover Phase 1/2a Study Testing Safety/Efficacy of Advair HFA (Salmeterol, Fluticasone) in Resting & Exercising Healthy & High Altitude Pulmonary Edema (HAPE) Predisposed Subjects
Overview
- Phase
- Phase 1
- Intervention
- Placebo
- Conditions
- Altitude Edema
- Sponsor
- University of Colorado, Denver
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- VO2 max
- Status
- Recruiting
- Last Updated
- 7 months ago
Overview
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 (Advair HFA) versus placebo (hydrofluoroalkane, HFA) 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 arterial partial pressure of oxygen (PaO2), alveolar-arterial oxygen (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 data and safety monitoring board (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).
Investigators
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, protime (PT) (INR)/partial thromboplastin time (PTT), thyroid stimulating hormone (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 \> 500 milliliters (ml) 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 - both hormonally-impregnated and untreated devices) 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 as estimated glomerular filtration rate \< 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 millimolar (mM)
- •aspartate aminotransferase (AST) or alanine transaminase (ALT) \> 2x upper reference limit
- •international normalized ratio (INR) \> 1.5
- •Fasting serum triglycerides \> 500 mg/dL (lipemic serum affects assays)
Arms & Interventions
Placebo
Participants will inhale placebo (same puff number) twice daily for up to 7 days
Intervention: Placebo
Advair HFA (salmeterol 126 ug/fluticasone 270 ug) twice daily for up to 7 days
Participants will inhale salmeterol 126 ug and fluticasone 270 ug twice daily for up to 7 days
Intervention: Advair HFA
Outcomes
Primary Outcomes
VO2 max
Time Frame: day 3 of treatment
peak oxygen consumption with exercise
Secondary Outcomes
- MPAP(day 3 of treatment)
- nadir PaO2(day 3 of treatment)
- highest PaO2(day 3 of treatment)
- Aa Gradient(day 3 of treatment)
- blood lactate(day 3 of treatment)
- cardiac output(day 3 of treatment)