A multinational, multicentre, randomized, double-blind study to assess the efficacy and safety of oral sildenafil 20mg TID or placebo when added to Bosentan in the treatement of subjects , aged 18 years and above, with pulmonary arterial hypertension (PAH) - N/A

• Register: EUCTR
• Last refreshed on: 12 May 2014
• Main ID: EUCTR2006-001464-23-CZ
• Date of registration: 21/04/2006
• Prospective Registration: Yes
• Primary sponsor: Pfizer Ltd,Ramsgate Road,Sandwich CT13 9NJ
• Public title: A multinational, multicentre, randomized, double-blind study to assess the efficacy and safety of oral sildenafil 20mg TID or placebo when added to Bosentan in the treatement of subjects , aged 18 years and above, with pulmonary arterial hypertension (PAH) - N/A
• Scientific title: A multinational, multicentre, randomized, double-blind study to assess the efficacy and safety of oral sildenafil 20mg TID or placebo when added to Bosentan in the treatement of subjects , aged 18 years and above, with pulmonary arterial hypertension (PAH) - N/A
• Date of first enrolment: 08/06/2006
• Target sample size: 106
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-001464-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Second phase of the study will be open-label If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Czech Republic, Germany, Greece, Italy, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Subjects aged 18 and above at the time of the screening visit who have any of the following types of pulmonary arterial hypertension and functional class, and for which bosentan therapy is indicated according to EU Marketing Authorisation:
· Idiopathic ‘Primary’ Pulmonary Arterial Hypertension (PAH)
.Pulmonary Hypertension secondary to Scleroderma.
·Subjects with WHO functional class III prior to initiation of bosentan therapy.
2. Subjects must have been treated continually with a stable dose of bosentan (62.5mg bid or 125mg bid) for a minimum of three months prior to randomization.
3. Subject with a mean pulmonary artery pressure =25 mmHg and a pulmonary capillary wedge pressure of < 15 mmHg at rest, via right heart catheterization within 3 years prior to randomization.
4. Subjects whose baseline 6-Minute Walk Test distance is =100m and =450m.
5. Subjects who have given written informed consent to participate in the study before being screened for the study.
6. All women of childbearing potential must use adequate contraception (i.e. hormonal in conjunction with intrauterine device or barrier methods with spermicide) throughout the study and for the duration of their bosentan therapy or must be celibate or their partner must have had vasectomy. The screening serum pregnancy test must be negative. Women who have been surgically sterilized or are at least two years postmenopausal may be enrolled and do not need to use birth control.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria.
2. With the exception of bosentan therapy, subjects who are currently receiving any forms of chronic treatment for PAH such as any formulations of prostacyclin, PDE-5 inhibitors, other endothelin-receptor antagonists, nitrates or nitric oxide donors (e.g. arginine supplements) including nicorandil in any form or any potent CYP3A4 inhibitors (e.g. Cyclosporin A and Glibenclamide). Note: Acute vasodilator response testing with any short acting vasodilators such as prostacyclin or inhaled NO during right heart catherization is permitted.
3. Subjects with significant (i.e. > 2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation. Subjects with previous surgical replacement of a valve may be eligible for entry into the study after consultation with a Pfizer study clinician provided the following conditions are satisfied:
·That there was no evidence of PAH secondary to valvular disease prior to surgery.
·The prosthetic valve is functioning normally on echocardiography.
·The valve replacement occurred at least one year prior to randomization.
4. Subjects with acutely decompensated heart failure within 30 days prior to randomization.
5. Subjects with LV Ejection Fraction of <45% or LV shortening fraction of <0.2 within three months prior to randomization.
6. Subjects who have had a myocardial infarction within 6 months prior to randomization
7. Subjects who have had a change of dose or class of standard background therapy used for treatment of PAH (i.e. oxygen, calcium channel blockers, digoxin, diuretics) used for the treatment of PAH within 30 days prior to randomization. Note: a change in the dose or oral anticoagulant therapy within this timeframe to maintain the INR within the therapeutic range is acceptable.
8. Subjects with congenital heart disease (unless they fulfill inclusion 1.), pulmonaryhypertension due to thromboembolism, HIV or schistosomiasis.
9. Subjects who have undergone atrial septostomy within six months prior to randomization.
10. Subjects with uncontrolled brady- or tachyarrhythmias, placement of pacemakers orimplantable defibrillators <60 days prior to randomization.
11. Subjects whose 6 Minute Walk Test distance may be limited by conditions other than PAHrelated dyspnoea or fatigue e.g. claudication from vascular insufficiency or arthritis.
12. Pregnant or lactating women.
13. Subjects with a history or pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest CT scan.
14. Subjects with hypotension defined as systolic arterial pressure <90 mm Hg after sitting for 5 minutes at either screening or baseline.15. Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa)or history of non-arteritic ischemic optic neuropathy (NAION).
16. Subjects with history of chronic lung diseases / restrictive lung disease (e.g. COPD orscleroderma) with impairment of lung function as defined by TLC <60% and/or FEV1 =80% predicted within 30 days or randomization.
17. Subjects who have previously failed on bosentan or sildenafil therapy (defined as those subjects who had no evidence of clinical improvement whilst on the medicines, and no worsening in symptoms or clinical status, on discontinuation of the medicines).
18. Subjects at screening with impairment of renal function (serum creatinine > 2.5 X UpperLimits of Normal (ULN)).
19

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension
MedDRA version: 9.1 Level: LLT Classification code 10064911 Term: Pulmonary arterial hypertension

Intervention(s)

Trade Name: Revatio
Product Name: Revatio®
Product Code: UK-92,480
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Sildenafil
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: 1. To assess the safety and tolerability of sildenafil (20mg TID) or placebo, when added to subjects with PAH who are currently treated with bosentan, after 12 weeks of treatment.
2. To assess the safety and tolerability of the open label treatment of sildenafil (20mg TID) and bosentan therapy in subjects with PAH after 12 months of treatment.
3. To assess the effect on other clinical outcome measures (clinical worsening, Borg dyspnoea score and PAH functional class) after 12 weeks of treatment of sildenafil (20mg TID) or placebo when added to bosentan therapy in subjects with PAH.
4. To determine the population pharmacokinetic parameters of sildenafil and bosentan and to investigate potential pharmacokinetic interactions between the two compounds in the target patient population.
5. To investigate the PK/PD relationship between sildenafil and bosentan exposure on the 6-Minute Walk Test

Tertiary Objective
To investigate the effects on BNP and N-terminal pro-BNP

Primary end point(s): The change from baseline in the total distance walked during the 6-Minute Walk Test at Week 12 of the study.

Main Objective: To assess the effect on exercise capacity (as measured by the 6 Minute Walk Distance) after 12 weeks of treatment of sildenafil (20mg TID) or placebo when added to subjects with PAH who are stabilized on bosentan therapy

Secondary ID(s)

N/A

A1481243