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

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

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.

Study Overview

• Status: Completed
• Conditions: Altitude Sickness; Hypertension, Pulmonary
• Intervention / Treatment: Drug: Riociguat

Detailed Description

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 improve oxygenation and performance at altitude.

Endogenous concentration of unbound NO is actually quite low, and most of the biological effects of NO are mediated through formation of S-nitrosothiols (SNOs) such as S-nitrosohemoglobin (SNO-Hb). NO binds to hemoglobin in a PO2-dependent manner, forming SNO-Hb so that when PO2 is low, NO-Hb binding is less avid and SNO-Hb is depleted. Depletion of SNO-Hb during hypoxia has been proposed as a mechanism that augments HPV, and indeed hypoxia has been shown to induce low levels of SNO-Hb. It is quite possible that the reduction in available endogenous NO and depletion of SNO-Hb during hypoxia limits the effect of the cGMP mechanism by which sildenafil works. Thus, an agent which can activate cGMP during periods of hypoxia when NO and SNO-Hb are depleted should be more effective in treating altitude-induced pulmonary hypertension.

Riociguat is a stimulator of soluble guanylate cyclase that bypasses the NO pathway and is currently approved by the FDA for treatment of pulmonary hypertension. Riociguat exhibits a dual mode of action that i.) stabilizes the reduced form of the nitrosyl-heme complex, enhancing the NO-cGMP signaling pathway in the absence of endogenous NO and ii.) acts in synergy with endogenous NO by increasing sGC sensitivity to NO. Essentially, riociguat stimulates sGC to produce cGMP in the absence of NO, and it is a mechanism by which pulmonary vascular resistance could be attenuated during altitude-induced pulmonary hypertension. It has recently been shown to augment exercise performance and decrease pulmonary artery pressure in both primary pulmonary hypertension and pulmonary arterial hypertension (PAH) due to chronic thromboembolic disease. Lowering pulmonary artery pressure could improve pulmonary gas exchange and performance at altitude, which has significant implications for those living at altitude, conducting military operations, altitude trekkers and high-altitude rescue teams. Direct stimulation of sGC also represents a promising alternative therapeutic strategy for those susceptible to high altitude pulmonary edema (HAPE) when current treatment modalities of nifedipine and sildenafil are ineffective and oxygen is unavailable. By itself or in combination with sildenafil, riociguat could produce a significant advance in exercise performance during altitude exposure and provide a substantial improvement over the current therapeutic options in the prevention and treatment of HAPE.

Design and Procedures:

This investigation will consist of 20 normal subjects. Medical screening will exclude cardiac and pulmonary disease, pregnancy and sickle cell disease/trait in African Americans.

Subjects will be instrumented with radial arterial lines and pulmonary artery catheters and will perform a VO2 max test on a bicycle ergometer in a hypobaric chamber at a simulated altitude of 15,000 feet.

Following the VO2 max test, subjects will return to ground level for a 3-hour rest period. At 90 minutes subjects will be administered riociguat 0.5 mg or 1.0 mg orally. Once study subjects are at therapeutic levels of riociguat (30 to 90 minutes after oral administration), they will repeat the VO2 max test at 15,000 feet. The dosing of riociguat will start at the lowest recommended individual dose (0.5 mg) for the first three subjects. If there are no side effects and no clinically important difference in either PAP (5 mmHg decrease in mean PAP) or PaO2 (5 mmHg increase) during exercise, then for the remaining subjects the dose will be increased to 1.0 mg.

During the incremental exercise test arterial and mixed blood samples will be analyzed for PO2, PCO2, pH, O2 saturation and hemoglobin. Exhaled gas will be collected continuously and analyzed for O2 and CO2 concentrations and exhaled volume. Cardiac output will be calculated using Fick. Pulmonary and systemic vascular resistances will be calculated from the cardiac output and intravascular pressures.

Outcome measures will be VO2max, maximum mechanical work rate, pulmonary and systemic arterial pressures, cardiac output, oxygen delivery and arterial blood gases.

Benefits:

Further understanding of the mechanism of hypoxic pulmonary vasoconstriction will aid in prognosis and treatment in conditions of increased pulmonary vascular resistance such as congenital heart disease, pulmonary arterial hypertension, and COPD, in addition to high-altitude pulmonary hypertension and high-altitude pulmonary edema (HAPE). Furthermore, the current treatment modalities for HAPE have demonstrated variable and/or limited effectiveness, so riociguat could potentially be used to prevent or treat HAPE in susceptible individuals. Additionally, riociguat could substantially improve exercise performance in those who must operate in conditions of high-altitude, such as those conducting military operations or working in high-altitude rescue teams.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Center for Hyperbaric Medicine and Environmental Physiology, Trent Drive, Building CR2, Room 0584, Box 3823,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy males and females
• Non-smoking
• Non-pregnant females
• Ages 18 - 40 years old

Exclusion Criteria:

• Serious pulmonary or cardiovascular comorbidities
• Pregnant women
• VO2max < 35 mL/kg per minute
• Sickle cell trait or disease
• Smokers
• Lung disease
• Hypertension
• Cardiac disease and left bundle branch block
• Taking nitrates, nitric oxide donors (such as amyl nitrite), and phosphodiesterase (PDE) inhibitors (including specific PDE-5 inhibitors, such as sildenafil, tadalafil, or vardenafil, or non-specific PDE inhibitors, such as dipyridamole or theophylline).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Riociguat 0.5 mg; Riociguat 0.5 mg tablets, one-time oral dose of 0.5 mg	Drug: Riociguat; After completion of first V02 max test at altitude, subjects will have a 3-hour rest period. Riociguat will be administered at the 90-minute mark of this rest period.; Other Names: Adempas; NDA 204819
Experimental: Riociguat 1.0 mg; Riociguat 0.5 mg tablets, one-time oral dose of 1.0 mg	Drug: Riociguat; After completion of first V02 max test at altitude, subjects will have a 3-hour rest period. Riociguat will be administered at the 90-minute mark of this rest period.; Other Names: Adempas; NDA 204819
No Intervention: Control arm; No drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Pulmonary Artery Pressure	Subject pulmonary artery pressures will be continuously monitored 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).	At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Radial Arterial Pressure	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).	At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test
Mean Arterial Oxygen Saturation (SaO2)	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).	At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test
Mean Ventilation Rate	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).	At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test
Mean Work Rate at Exhaustion	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).	At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test
Cardiac Output	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).	At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test

Collaborators and Investigators

• Sponsor: Richard Moon

Publications and helpful links

General Publications

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• McMahon TJ, Moon RE, Luschinger BP, Carraway MS, Stone AE, Stolp BW, Gow AJ, Pawloski JR, Watke P, Singel DJ, Piantadosi CA, Stamler JS. Nitric oxide in the human respiratory cycle. Nat Med. 2002 Jul;8(7):711-7. doi: 10.1038/nm718. Epub 2002 Jun 3.
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• Droma Y, Hanaoka M, Ota M, Katsuyama Y, Koizumi T, Fujimoto K, Kobayashi T, Kubo K. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema. Circulation. 2002 Aug 13;106(7):826-30. doi: 10.1161/01.cir.0000024409.30143.70.
• Ahsan A, Charu R, Pasha MA, Norboo T, Charu R, Afrin F, Ahsan A, Baig MA. eNOS allelic variants at the same locus associate with HAPE and adaptation. Thorax. 2004 Nov;59(11):1000-2. doi: 10.1136/thx.2004.029124. No abstract available.
• Luo Y, Chen Y, Zhang Y, Zhou Q, Gao Y. Association of endothelial nitric oxide synthase (eNOS) G894T polymorphism with high altitude pulmonary edema susceptibility: a meta-analysis. Wilderness Environ Med. 2012 Sep;23(3):270-4. doi: 10.1016/j.wem.2012.03.007. Epub 2012 Jul 13.
• Follmann M, Griebenow N, Hahn MG, Hartung I, Mais FJ, Mittendorf J, Schafer M, Schirok H, Stasch JP, Stoll F, Straub A. The chemistry and biology of soluble guanylate cyclase stimulators and activators. Angew Chem Int Ed Engl. 2013 Sep 2;52(36):9442-62. doi: 10.1002/anie.201302588. Epub 2013 Aug 20.
• Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29. doi: 10.1056/NEJMoa1209657.
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Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: December 18, 2013
• First Submitted That Met QC Criteria: December 27, 2013
• First Posted (Estimate): December 31, 2013

Study Record Updates

• Last Update Posted (Actual): April 12, 2017
• Last Update Submitted That Met QC Criteria: March 1, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Athletic Performance; Guanylate Cyclase; Pulmonary Edema of Mountaineers; Mountaineering; Performance-Enhancing Substances
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Hypertension; Altitude Sickness; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: Pro00049150