Hypertension, Pulmonary Clinical Trial
Official title:
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.
Status | Completed |
Enrollment | 28 |
Est. completion date | December 2015 |
Est. primary completion date | December 2015 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | Both |
Age group | 18 Years to 40 Years |
Eligibility |
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). |
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label
Country | Name | City | State |
---|---|---|---|
United States | Duke Center for Hyperbaric Medicine and Environmental Physiology, Trent Drive, Building CR2, Room 0584, Box 3823, | Durham | North Carolina |
Lead Sponsor | Collaborator |
---|---|
Richard Moon |
United States,
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. — View Citation
Allen BW, Stamler JS, Piantadosi CA. Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation. Trends Mol Med. 2009 Oct;15(10):452-60. doi: 10.1016/j.molmed.2009.08.002. Epub 2009 Sep 24. Review. — View Citation
Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med. 1991 Oct 31;325(18):1284-9. — View Citation
Beidleman BA, Muza SR, Fulco CS, Cymerman A, Ditzler D, Stulz D, Staab JE, Skrinar GS, Lewis SF, Sawka MN. Intermittent altitude exposures reduce acute mountain sickness at 4300 m. Clin Sci (Lond). 2004 Mar;106(3):321-8. — View Citation
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. — View Citation
Follmann M, Griebenow N, Hahn MG, Hartung I, Mais FJ, Mittendorf J, Schäfer 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. Review. — View Citation
Forster PJ. Effect of different ascent profiles on performance at 4,200 m elevation. Aviat Space Environ Med. 1985 Aug;56(8):758-64. — View Citation
Frey R, Mück W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol. 2008 Aug;48(8):926-34. doi: 10.1177/0091270008319793. Epub 2008 Jun 2. — View Citation
Frezza EE, Mezghebe H. Indications and complications of arterial catheter use in surgical or medical intensive care units: analysis of 4932 patients. Am Surg. 1998 Feb;64(2):127-31. — View Citation
Gale GE, Torre-Bueno JR, Moon RE, Saltzman HA, Wagner PD. Ventilation-perfusion inequality in normal humans during exercise at sea level and simulated altitude. J Appl Physiol (1985). 1985 Mar;58(3):978-88. — View Citation
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. — View Citation
Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/NEJMoa1209655. — View Citation
Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, Seeger W, Grimminger F. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med. 2004 Aug 3;141(3):169-77. — View Citation
Hornbein TF, Townes BD, Schoene RB, Sutton JR, Houston CS. The cost to the central nervous system of climbing to extremely high altitude. N Engl J Med. 1989 Dec 21;321(25):1714-9. — View Citation
Hughson RL, Yamamoto Y, McCullough RE, Sutton JR, Reeves JT. Sympathetic and parasympathetic indicators of heart rate control at altitude studied by spectral analysis. J Appl Physiol (1985). 1994 Dec;77(6):2537-42. — View Citation
Jensen LA, Onyskiw JE, Prasad NG. Meta-analysis of arterial oxygen saturation monitoring by pulse oximetry in adults. Heart Lung. 1998 Nov-Dec;27(6):387-408. — View Citation
Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008 Feb;7(2):156-67. doi: 10.1038/nrd2466. Review. — View Citation
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. Review. — View Citation
McMahon TJ, Ahearn GS, Moya MP, Gow AJ, Huang YC, Luchsinger BP, Nudelman R, Yan Y, Krichman AD, Bashore TM, Califf RM, Singel DJ, Piantadosi CA, Tapson VF, Stamler JS. A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension. Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14801-6. Epub 2005 Oct 3. — View Citation
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. Epub 2002 Jun 3. — View Citation
Mummery HJ, Stolp BW, deL Dear G, Doar PO, Natoli MJ, Boso AE, Archibald JD, Hobbs GW, El-Moalem HE, Moon RE. Effects of age and exercise on physiological dead space during simulated dives at 2.8 ATA. J Appl Physiol (1985). 2003 Feb;94(2):507-17. Epub 2002 Oct 11. — View Citation
Richalet JP, Gratadour P, Robach P, Pham I, Déchaux M, Joncquiert-Latarjet A, Mollard P, Brugniaux J, Cornolo J. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med. 2005 Feb 1;171(3):275-81. Epub 2004 Oct 29. — View Citation
Rock PB, Johnson TS, Cymerman A, Burse RL, Falk LJ, Fulco CS. Effect of dexamethasone on symptoms of acute mountain sickness at Pikes Peak, Colorado (4,300 m). Aviat Space Environ Med. 1987 Jul;58(7):668-72. — View Citation
Rubin LJ, Naeije R. Sildenafil for enhanced performance at high altitude? Ann Intern Med. 2004 Aug 3;141(3):233-5. — View Citation
Sampson JB, Cymerman A, Burse RL, Maher JT, Rock PB. Procedures for the measurement of acute mountain sickness. Aviat Space Environ Med. 1983 Dec;54(12 Pt 1):1063-73. — View Citation
Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger GR, Fikrle A, Ballmer PE, Nicod P, Bärtsch P. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med. 1996 Mar 7;334(10):624-9. — View Citation
Slogoff S, Keats AS, Arlund C. On the safety of radial artery cannulation. Anesthesiology. 1983 Jul;59(1):42-7. — View Citation
Torre-Bueno JR, Wagner PD, Saltzman HA, Gale GE, Moon RE. Diffusion limitation in normal humans during exercise at sea level and simulated altitude. J Appl Physiol (1985). 1985 Mar;58(3):989-95. — View Citation
Valentine RJ, Modrall JG, Clagett GP. Hand ischemia after radial artery cannulation. J Am Coll Surg. 2005 Jul;201(1):18-22. — View Citation
Wagner PD, Gale GE, Moon RE, Torre-Bueno JR, Stolp BW, Saltzman HA. Pulmonary gas exchange in humans exercising at sea level and simulated altitude. J Appl Physiol (1985). 1986 Jul;61(1):260-70. — View Citation
West JB. Improving oxygenation at high altitude: acclimatization and O2 enrichment. High Alt Med Biol. 2003 Fall;4(3):389-98. — View Citation
* Note: There are 31 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Change from Baseline in Pulmonary Artery Pressure | Subject pulmonary artery pressures will be continuously monitored via pulmonary 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. | Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat | Yes |
Secondary | Change from Baseline in Radial Arterial Pressure | 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. | Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat | Yes |
Secondary | Change from Baseline in Arterial Oxygen Saturation (PaO2) | 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. | Measured Periodically During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat | Yes |
Secondary | Change from Baseline in 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). 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. | Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat | Yes |
Secondary | Change from Baseline in Work Rate at Exhaustion | 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. | Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat | No |
Secondary | Change from Baseline in Cardiac Output | 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. | Measured Continuously During Baseline Exercise Testing and Again 3 Hours Later Throughout Exercise Testing After Administration of Riociguat | Yes |
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT04095286 -
Relative Bioavailability Study of Marketed and Lower Dose Ambrisentan in Healthy Adult Participants
|
Phase 1 | |
Enrolling by invitation |
NCT03683186 -
A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
|
Phase 3 | |
Completed |
NCT02191137 -
Measuring Outcomes In Patients With Pulmonary Arterial Hypertension Not on Active Treatment (MOTION)
|
Phase 4 | |
Completed |
NCT01959828 -
Confirmatory Study of IK-3001 in Japanese Subjects With Peri-/Post-op Pulmonary Hypertension Assoc. With Cardiac Surgery
|
Phase 3 | |
Withdrawn |
NCT01202045 -
Stress Echocardiography in the Detection of Pulmonary Arterial Hypertension in Systemic Sclerosis Patients
|
N/A | |
Completed |
NCT01121458 -
Clevidipine for Vasoreactivity Evaluation of the Pulmonary Arterial Bed
|
Phase 4 | |
Completed |
NCT00963027 -
Effect of Esomeprazole on the Pharmacokinetics of Oral Treprostinil
|
Phase 1 | |
Completed |
NCT00963001 -
Effect of Food on the Pharmacokinetics of Oral Treprostinil
|
Phase 1 | |
Terminated |
NCT00825266 -
Insulin Resistance in Pulmonary Arterial Hypertension
|
Phase 4 | |
Terminated |
NCT00384865 -
A Study of Aspirin and Simvastatin in Pulmonary Arterial Hypertension
|
Phase 2 | |
Active, not recruiting |
NCT03926572 -
Acute Decompensation of Pulmonary Hypertension
|
N/A | |
Completed |
NCT02826252 -
Examination of Ventavis (Iloprost) Inhalation Behavior Using the I-Neb AAD System in Patients With Pulmonary Arterial Hypertension When Switching the Iloprost Nebulizer Solution for Inhalation From 10 μg/mL (V10) to 20 μg/mL (V20)
|
N/A | |
Completed |
NCT02545465 -
A Study to Understand the Treatment Patterns in Patients With Pulmonary Arterial Hypertension or Chronic Thromboembolic Pulmonary Hypertension During a Switch of Treatment to Adempas in Real-life Clinical Practice
|
N/A | |
Recruiting |
NCT04498299 -
Stress Echocardiography in Patients Recovery From Mild COVID-19 Illness
|
||
Recruiting |
NCT02558582 -
Effect of Exercise Training in Patients With Pulmonary Hypertension
|
N/A | |
Active, not recruiting |
NCT02562235 -
Riociguat in Children With Pulmonary Arterial Hypertension (PAH)
|
Phase 3 | |
Completed |
NCT02755298 -
Chronic Clinical Effect of Acetazolamide
|
Phase 2/Phase 3 | |
Terminated |
NCT03043976 -
Using Step Count to Enhance Daily Physical Activity in Pulmonary Hypertension
|
N/A | |
Completed |
NCT02576002 -
Epidemiology and Treatment Patterns of Paediatric PAH (Pulmonary Arterial Hypertension)
|
N/A | |
Completed |
NCT01178073 -
A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
|
Phase 3 |