Efficacy Study of Riociguat and Its Effects on Exercise Performance and Pulmonary Artery Pressure at High Altitude
| Status: | Completed |
|---|---|
| Conditions: | High Blood Pressure (Hypertension), High Blood Pressure (Hypertension), Other Indications |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Other |
| Healthy: | No |
| Age Range: | 18 - 40 |
| Updated: | 4/21/2016 |
| Start Date: | January 2014 |
| End Date: | December 2015 |
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.
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.
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.
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.
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).
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Durham, North Carolina 27710
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