Clinical Trial: Efficacy Study of Riociguat and Its Effects on Exercise Performance and Pulmonary Artery Pressure at High Altitude

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: The Effect of Riociguat on Gas Exchange, Exercise Performance, and Pulmonary Artery Pressure During Acute Altitude Exposure

Brief Summary: During ascent to high altitude there is a physiologic response to hypoxia that results in an elevated pulmonary arterial pressure associated with decreased exercise performance, altitude-induced pulmonary hypertension, and high altitude pulmonary edema (HAPE). Riociguat is a novel agent from Bayer Pharmaceuticals that has already demonstrated effectiveness in the treatment of pulmonary hypertension, and it may prove to be beneficial in cases of altitude-induced pulmonary hypertension or HAPE. This research study, composed of 20 healthy volunteers ages 18-40 years, will attempt to mimic the decreased oxygen supply and elevated pulmonary artery pressures found in conditions of high altitude, allowing observation of the effects of riociguat and exercise on pulmonary arterial pressure, arterial oxygenation, and exercise performance. Prior to entering the hypobaric chamber, subjects will have radial arterial lines and pulmonary artery catheters placed to obtain arterial and pulmonary artery pressure measurements. Subjects will then enter the hypobaric chamber and perform exercise tolerance tests at a simulated altitude of 15,000 feet on an electrically braked ergometer (exercise bike) before and after administration of riociguat. If, after administration of riociguat and exposure to a simulated altitude of 15,000 feet, the exercise performance is improved and observed pulmonary artery pressures are lower than those measurements seen prior to administration of riociguat, this could lead to development of a prophylactic and/or treatment strategy for HAPE and high-altitude pulmonary hypertension. Statistical analysis will compare the variables of pulmonary artery pressure, radial arterial pressure, ventilation rate, cardiac output, PaO2, and work rate at exhaustion before and after administration of the drug riociguat. The investigator's hypothesis is that riociguat will decrease pulmonary artery pressure and improve gas exchange and exercise performance at altitude.

Detailed Summary:

Background and Significance:

Impairment of exercise performance during hypoxemia due to altitude exposure or lung disease is caused primarily by reduced oxygen delivery to the exercising muscles, due to the reduction in arterial oxygen content. This reduction in arterial oxygen content is due to reduced alveolar PO2 and ventilation/perfusion (VA/Q) mismatch, and to some extent alveolar to end-capillary diffusion impairment. Ultimately, hypoxemia results in secondary diffuse pulmonary vasoconstriction (hypoxic pulmonary vasoconstriction, HPV), which in turn causes pulmonary hypertension. This secondary pulmonary hypertension is believed to worsen VA/Q mismatch, further reducing the PO2, suggesting that pharmacologic blockade of HPV could increase PO2 (e.g. during altitude exposure) and thus improve exercise performance. Reduction in pulmonary artery pressure (PAP) in individuals susceptible to high altitude pulmonary edema (HAPE) could also facilitate both prevention and treatment of HAPE.

Sildenafil is commonly used to treat pulmonary hypertension, including pulmonary hypertension that occurs due to altitude exposure, with variable success in treating cases of altitude-induced pulmonary hypertension and HAPE. Sildenafil works via blockade of blocks phosphodiesterase-5 (PDE-5) in pulmonary arterioles, causing an increase in cGMP. When cGMP is activated by nitric oxide (NO) it induces vasodilatation, and indeed, sildenafil administration during altitude exposure does increase arterial oxygenation slightly. However, attempting to block HPV with sildenafil by using a pathway that requires NO can only be realized if there is sufficient NO available to produce cGMP. During hypoxia endogenous levels of NO are depleted due to impaired endothelial NO synthesis. This may explain the inconsistent effects of sildenafil when used to im
Sponsor: Richard Moon

Current Primary Outcome: Mean Pulmonary Artery Pressure [ Time Frame: At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test ]

Original Primary Outcome: Change from Baseline in Pulmonary Artery Pressure [ Time Frame: Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat ]

Current Secondary Outcome:

• Mean Radial Arterial Pressure [ Time Frame: At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test ]
  Subject systemic arterial pressures will be continuously monitored via radial artery catheterization during the VO2max exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet. Exercise level will be increased every 3 minutes until test termination criteria are achieved. Measurements will be obtained at rest, every 3 minutes during the exercise test (referred to as a stage below) and at 5 minutes post exercise. Results will be reported as a 30 second average. Subjects in the Riociguat cohorts will be tested prior to receiving drug and 90 minutes after receiving drug (midway through a three hour rest period between altitude exposures).
• Mean Arterial Oxygen Saturation (SaO2) [ Time Frame: At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test ]
  Subject arterial oxygen saturation (SaO2) will be periodically monitored at fixed intervals via arterial blood gas measurements during the VO2max exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet. Measurements will be obtained at rest, every 3 minutes during the exercise test (referred to as a stage below) and at 5 minutes post exercise. Results will be reported as a 30 second average. Subjects in the Riociguat cohorts will be tested prior to receiving drug and 90 minutes after receiving drug (midway through a three hour rest period between altitude exposures).
• Mean Ventilation Rate [ Time Frame: At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test ]
  Subject ventilation rates will be monitored continuously using a multi-channel A/D converter (PowerLab™) connected to a personal computer, using Chart™ software (ADInstruments, Colorado Springs, CO) during the VO2max exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet. Exercise level will be increased every 3 minutes until test termination criteria are achieved. Measurements will be obtained at rest, every 3 minutes during the exercise test (referred to as a stage below) and at 5 minutes post exercise. Results will be reported as a 30 second average. Subjects in the Riociguat cohorts will be tested prior to receiving drug and 90 minutes after receiving drug (midway through a three hour rest period between altitude exposures).
• Mean Work Rate at Exhaustion [ Time Frame: At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test ]
  Subject work rates at exhaustion (in watts) will be continuously monitored using an ergometer (exercise bicycle) during the VO2max exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet. Exercise level will be increased every 3 minutes until test termination criteria are achieved. Measurements will be obtained at rest, every 3 minutes during the exercise test (referred to as a stage below) and at 5 minutes post exercise. Results will be reported as a 30 second average. Subjects in the Riociguat cohorts will be tested prior to receiving drug and 90 minutes after receiving drug (midway through a three hour rest period between altitude exposures).
• Cardiac Output [ Time Frame: At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test ]
  Arterial blood samples will be obtained before, during, and after the VO2max exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet. Exercise level will be increased every 3 minutes until test termination criteria are achieved. Samples will be obtained during the fifth minute of rest prior to exercise, during the third minute of each exercise level (referred to as stage below) and during the fifth minute post exercise. Cardiac output (CO) will be calculated using the Fick Principle: CO = V̇O2/(CaO2 - Cv̄O2) where CaO2 and Cv̄O2 represent the arterial and mixed venous oxygen content, respectively. CaO2 and CvO2 will be determined from analysis of the arterial blood samples using an IL GEM 4000 analyzer. VO2 will be reported as the final 30 secon average value of each stage. Subjects in the Riociguat cohorts will be tested prior to receiving drug and 90 minutes after receiving drug (midway through a three hour rest period between altitude exposures).

Original Secondary Outcome:

• Change from Baseline in Radial Arterial Pressure [ Time Frame: Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat ]
  Subject systemic arterial pressures will be continuously monitored via radial artery catheterization. Measurements obtained during initial exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet will be compared with measurements obtained during exercise testing at the same altitude after administration of Riociguat.
• Change from Baseline in Arterial Oxygen Saturation (PaO2) [ Time Frame: Measured Periodically During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat ]
  Subject arterial oxygen saturation (PaO2) will be periodically monitored at fixed intervals via arterial blood gas measurements. Measurements obtained during initial exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet will be compared with measurements obtained during exercise testing at the same altitude after administration of Riociguat.
• Change from Baseline in Ventilation Rate [ Time Frame: Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat ]
  Subject ventilation rates will be monitored continuously using a multi-channel A/D converter (PowerLab™) connected to a personal computer, using Chart™ software (ADInstruments, Colorado Springs, CO). Measurements obtained during initial exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet will be compared with measurements obtained during exercise testing at the same altitude after administration of Riociguat.
• Change from Baseline in Work Rate at Exhaustion [ Time Frame: Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat ]
  Subject work rates at exhaustion (in watts) will be continuously monitored using an ergometer (exercise bicycle). Measurements obtained during initial exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet will be compared with measurements obtained during exercise testing at the same altitude after administration of Riociguat.
• Change from Baseline in Cardiac Output [ Time Frame: Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat ]
  Subjects cardiac output will be continuously monitored using a multi-channel A/D converter (PowerLab™) connected to a personal computer, using Chart™ software (ADInstruments, Colorado Springs, CO). Measurements obtained during initial exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet will be compared with measurements obtained during exercise testing at the same altitude after administration of Riociguat.

Dates:
Date Received: December 18, 2013
Date Started: January 2014
Date Completion:
Last Updated: March 1, 2017
Last Verified: March 2017