The Efficacy and Safety of Vardenafil in the Treatment of Pulmonary Arterial Hypertension

Pulmonary Hypertension Clinical Trial

— EVALUATION  

Official title:

Multi-centre, Prospective, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Treatment of Pulmonary Arterial Hypertension With Vardenafil in China

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00718952
• Other study ID #: EVALUATION-01
• Status: Completed
• Phase: Phase 3
• First received: July 18, 2008
• Last updated: February 11, 2010
• Start date: July 2008
• Est. completion date: February 2010

Study information

• Verified date: February 2010
• Source: Tongji University
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of vardenafil in the treatment of pulmonary arterial hypertension.

Description:

Pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure ≥25 mmHg with a pulmonary capillary wedge pressure ≤15 mmHg measured by cardiac catheterization, is a disorder that may occur either in the setting of a variety of underlying medical conditions or as a disease that uniquely affects the pulmonary circulation. Irrespective of its etiologies, PAH is a serious and often progressive disorder that results in right ventricular dysfunction and impairment in activity tolerance, and may lead to right-heart failure and death. The pathogenesis of PAH is complex and incompletely understood, but includes both genetic and environmental factors that alter vascular structure and function.

In recent years, several new drugs have been developed for the treatment of pulmonary arterial hypertension (PAH), including continuous intravenous epoprostenol, inhaled iloprost, subcutaneous trepostinil, oral bosentan, and oral beraprost. In addition, there is increasing evidence for the therapeutic effectiveness of the phosphodiesterase-5 (PDE-5) inhibitor sildenafil in PAH. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide (NO) .The phosphodiesterases have different tissue distributions and substrate affinities. Interestingly, PDE-5 is abundantly expressed in lung tissue, thus offering as target molecule for PAH treatment concepts.

The three commercially available PDE-5 inhibitors (sildenafil, vardenafil, and tadalafil) are currently approved for the treatment of erectile dysfunction . These inhibitors are now receiving attention for their activity in the pulmonary vasculature. Sildenafil has been proved to improve the exercise capacity and pulmonary hemodynamics of PAH patients, however, there are few reports regarding the use of vardenafil or tadalafil on the pulmonary vasculature. Although sildenafil, vardenafil, and tadalafil act on the same enzyme, these drugs exhibit different pharmacokinetics and selectivity, and therefore may not be equally efficacious in the pulmonary vascular bed. As vardenafil has a more than 20-fold greater potency than sildenafil for inhibiting purified PDE-5, we assume that it will show more favorable clinical and side-effect profiles in treating PAH.

This is a prospective, randomized, placebo-controlled, pilot study to evaluate the efficacy and safety of vardenafil in the treatment of pulmonary arterial hypertension.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: February 2010
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years to 65 Years

Eligibility

Inclusion Criteria:

• Subjects aged 12-65.

• Confirmed idiopathic pulmonary hypertension, connective tissue disease associated pulmonary hypertension, congenital heart disease(with Eisenmenger syndrome) associated pulmonary hypertension.

• Baseline 6-minutes walking distance 150m-550m.

• WHO pulmonary hypertension function II-III with non-responder to calcium channel blockers.

• Documented written informed consent.

Exclusion Criteria:

• The other types of pulmonary hypertension.

• Subjects who refuse to subscribe written informed consents or can't cooperate with the trial well.

• Subjects with serious acute or chronic disease involved liver, kidney, and brain or have to use potent CYP3A4-inhibitor or nitrate to treat the underlying diseases.

• Subjects who are currently treated with sildenafil for PAH or taking sildenafil or tadalafil.

• Other contraindications in package insert.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Vardenafil
vardenafil tablet 5mg once-daily orally in the first 4 weeks while 5mg twice-daily orally in the following 8 weeks.
• Placebo
Placebo tablet 5mg once-daily orally in the first 4 weeks while 5mg twice-daily orally in the following 8 weeks.
• Vardenafil
Patients in all the 2 arms will take vardenafil tablet 5mg twice-daily orally from week 13 to week 24(open-label).

Locations

Country	Name	City	State
China	Beijing Shijitan Hospital, Peking University	Beijing	Beijing
China	Peking Union Hospital, Peking Union Medical College	Beijing	Beijing
China	Peking University First Hospital	Beijing	Beijing
China	Peking University First Hospital	Beijing	Beijing
China	Xiangya Hospital, Central-South University	Changsha	Hunan
China	The First Clinical College of Harbin Medical University	Harbin	Heilongjiang
China	Renji Hospital, Shanghai Jiaotong University	Shanghai	Shanghai
China	Shanghai Pulmonary Hospital ,Tongji University	Shanghai
China	The General Hospital of Shenyang Military Command	Shenyang	Liaoning
China	The First Affiliated Hospital of Medical College of Xian Jiaotong University	Xi'an	Shanxi

Sponsors (1)

Lead Sponsor	Collaborator
Tongji University

Country where clinical trial is conducted

China, 

References & Publications (9)

Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996 Feb 1;334(5):296-301. — View Citation

Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005 Nov 17;353(20):2148-57. Erratum in: N Engl J Med. 2006 Jun 1;354(22):2400-1. — View Citation

Galiè N, Humbert M, Vachiéry JL, Vizza CD, Kneussl M, Manes A, Sitbon O, Torbicki A, Delcroix M, Naeije R, Hoeper M, Chaouat A, Morand S, Besse B, Simonneau G; Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002 May 1;39(9):1496-502. — View Citation

Ghofrani HA, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadas B, Schermuly RT, Weissmann N, Seeger W, Grimminger F. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol. 2004 Oct 6;44(7):1488-96. — View Citation

Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, Seeger W, Grimminger F. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med. 2002 Apr 2;136(7):515-22. — View Citation

Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation. 2002 May 21;105(20):2398-403. — View Citation

Olschewski H, Simonneau G, Galiè N, Higenbottam T, Naeije R, Rubin LJ, Nikkho S, Speich R, Hoeper MM, Behr J, Winkler J, Sitbon O, Popov W, Ghofrani HA, Manes A, Kiely DG, Ewert R, Meyer A, Corris PA, Delcroix M, Gomez-Sanchez M, Siedentop H, Seeger W; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002 Aug 1;347(5):322-9. — View Citation

Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar 21;346(12):896-903. Erratum in: N Engl J Med 2002 Apr 18;346(16):1258. — View Citation

Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002 Mar 15;165(6):800-4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The change in exercise capacity, as measured by the total distance walked in six minutes		at week 12 and week 24	No
Secondary	The reduction of mean pulmonary-artery pressure(mPAP)and pulmonary vascular resistance(PVR)		at week 12 and week 24	No
Secondary	The increase of cardiac output(CO)		at week 12 and week 24	No
Secondary	The increase of Peripheral Saturation of oxygen(SPO2)		at week 12 and week 24	No
Secondary	The change in the Borg dyspnea index(a measure of perceived breathlessness on a scale of 0 to 10, with higher values indicating more severe dyspnea)		at week 12 and week 24	No
Secondary	The change in World Health Organization (WHO) functional classification of pulmonary arterial hypertension (an adaptation of the New York Heart Association classification)		at week 12 and week 24	No
Secondary	Time from randomization to clinical worsening(defined as death, transplantation,hospitalization for PAH and worse right heart failure,acute heart failure,or vardenafil allergy,or worsening leading to discontinuation,need for epoprostenol or bosentan)		From baseline to week 24	Yes