Efficacy Study of Riociguat and Its Effects on Exercise Performance and Pulmonary Artery Pressure at High Altitude
Condition: Hypertension, Pulmonary; Altitude Sickness
MeSH terms: Hypertension, Pulmonary; Altitude Sickness
Study type: Interventional
Phase: Phase 4

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 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.
    

Intervention name(s): Riociguat
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Adempas; NDA 204819
Intervention MeSH terms: Riociguat
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Guanylate Cyclase; Pulmonary Edema of Mountaineers; Mountaineering; Performance-Enhancing Substances; Athletic Performance