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

Condition(s) targeted: Pulmonary Hypertension

Intervention: Vardenafil (Drug); Placebo (Drug); Vardenafil (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Tongji University

Official(s) and/or principal investigator(s):
Zhi-Cheng Jing, MD, Principal Investigator, Affiliation: Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, China

Overall contact:
Zhi-Cheng Jing, MD, Phone: +86 13901927267, Email: jingzhicheng@gmail.com

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

Official title: Multi-Centre, Prospective, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Treatment of Pulmonary Arterial Hypertension With Vardenafil in China

Study design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: The change in exercise capacity, as measured by the total distance walked in six minutes

Secondary outcome:

The reduction of mean pulmonary-artery pressure(mPAP)and pulmonary vascular resistance(PVR)

The increase of cardiac output(CO)

The increase of Peripheral Saturation of oxygen(SPO2)

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)

The change in World Health Organization (WHO) functional classification of pulmonary arterial hypertension (an adaptation of the New York Heart Association classification)

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)

Detailed 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.

Minimum age: 12 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Subjects aged 16-65.

- 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.

Zhi-Cheng Jing, MD, Phone: +86 13901927267, Email: jingzhicheng@gmail.com

Shanghai Pulmonary Hospital ,Tongji University, Shanghai 200433, China; Not yet recruiting
Zhi-Cheng Jing, MD, Phone: +86 13901927267, Email: jingzhicheng@gmail.com
Xi-Qi Xu, MD, Phone: +86 13916769755, Email: xuxiqi0928@yahoo.com.cn
Zhi-Cheng Jing, MD, Principal Investigator

Shanghai Pulmonary Hospital, Shanghai 200433, China; Recruiting
Xin JIANG, MD, Phone: +86-21-65115006, Email: jxcs983@163.com

Related publications:

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Olschewski H, Simonneau G, Galie 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.

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.

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.

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.

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. Summary for patients in: Ann Intern Med. 2002 Apr 2;136(7):I35.

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.

Galie 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.

Ghofrani HA, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadaş 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.

Starting date: July 2008
Ending date: December 2009
Last updated: May 28, 2009