A MULTINATIONAL, MULTICENTRE, RANDOMIZED, PARALLEL GROUP, DOUBLE-BLIND STUDY TO ASSESS THE EFFICACY AND SAFETY OF 1 MG, 5MG AND 20 MG TID OF ORAL SILDENAFIL IN THE TREATMENT OF SUBJECTS AGED 18 YEARS AND OVER WITH PULMONARY ARTERIAL HYPERTENSION (PAH) - N/A

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-006748-76-NL
• Date of registration: 01/11/2007
• Prospective Registration: Yes
• Primary sponsor: Pfizer Ltd. Ramsgate Road, Sandwich, Kent, UK
• Public title: A MULTINATIONAL, MULTICENTRE, RANDOMIZED, PARALLEL GROUP, DOUBLE-BLIND STUDY TO ASSESS THE EFFICACY AND SAFETY OF 1 MG, 5MG AND 20 MG TID OF ORAL SILDENAFIL IN THE TREATMENT OF SUBJECTS AGED 18 YEARS AND OVER WITH PULMONARY ARTERIAL HYPERTENSION (PAH) - N/A
• Scientific title: A MULTINATIONAL, MULTICENTRE, RANDOMIZED, PARALLEL GROUP, DOUBLE-BLIND STUDY TO ASSESS THE EFFICACY AND SAFETY OF 1 MG, 5MG AND 20 MG TID OF ORAL SILDENAFIL IN THE TREATMENT OF SUBJECTS AGED 18 YEARS AND OVER WITH PULMONARY ARTERIAL HYPERTENSION (PAH) - N/A
• Date of first enrolment: 23/04/2008
• Target sample size: 284
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-006748-76
• 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: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Standard dose of IMP

Countries of recruitment

Belgium, Bulgaria, Denmark, Greece, Italy, Latvia, Netherlands, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Subjects aged 18 and over with any of the following conditions:
• Idiopathic Primary Pulmonary Arterial Hypertension (IPAH)
• PAH secondary to connective tissue disease
• PAH with surgical repair (at least 5 years previously) of atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA) and aorto-pulmonary window

2. Subjects with a mean pulmonary artery pressure of greater than or equal to 25 mmHg and a pulmonary artery wedge pressure of less than or equal to 15 mmHg at rest (or in the event that PAWP is unobtainable, a left ventricular end diastolic pressure (LVEDP) of <14 mmHg and absence of any mitral stenosis on echocardiography) via right heart catherization performed within 12 weeks prior to randomization. Subjects who underwent right heart catheterization and who fulfil the following criteria:
• background therapy (class and dose of drug) has not been changed for at least 30 days prior to right heart catheterization measurement,
• the drugs and doses used for background therapy have not changed since catheterization for inclusion (subjects can undergo repeat right heart catheterization
prior to randomization).

3. Subjects whose baseline 6MWT distance is greater than or equal to 100 m and less than or equal to 450 m.

4. 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 four weeks after completion of the study or must be celibate or their partner must have had a vasectomy. The screening urine pregnancy test must be negative (if the urine pregnancy test is positive, a serum pregnancy test should be performed and the result should 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.

5. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

6. Subjects who have been informed of all pertinent aspects of the trial and have given (personally signed and dated) written informed consent to participate in the study before being screened for the study.
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. Subjects with significant 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 screening.

3. Subjects who have undergone atrial septostomy within 6 months prior to randomization.

4. Subjects with acutely decompensated heart failure within the previous 30 days prior to screening.

5. Subjects with a left ventricular ejection fraction (LVEF) less than 40% or LV shortening fraction <0.2 within 3 months prior to randomization.

6. Subjects with acute myocardial infarction within 3 months prior to randomization.

7. Subjects with uncontrolled brady- or tachyarrhythmias (e.g. sinus arrest, complete heart block, atrial fibrillation or flutter, frequent runs of ventricular tachycardia); placement of dual chamber pacemakers and/or implantable defibrillators <60 days prior to randomization.

8. Subjects whose 6 Minute Walk Distance may be limited by conditions other than PAH related dyspnoea or fatigue, e.g. claudication from vascular insufficiency or significant arthritis.

9. Subjects who are currently receiving any forms of chronic treatment for PAH such as prostacyclin, PDE-5 inhibitors, endothelin-receptor antagonists, nitrates or nitric oxide donors in any form, protease inhibitors such as ritonavir and saquinavir, ketoconazole, itraconazole, and alpha blockers. Subjects previously receiving any of these drugs must have stopped use for a period of at least 1 month prior to screening, except in the case of bosentan or prostacyclin (3 months).

Note: Acute vasodilator response testing with any short acting vasodilators such as prostacyclin, inhaled NO and sildenafil during right heart catheterization is permitted.

10. Subjects who have previously failed on chronic treatment with sildenafil therapy.

11. Subjects who have had a change of dose or class of standard background therapy used for treatment of PAH within 30 days prior to randomization. Exception is treatment with anticoagulants where a patient’s dose may need to be adjusted based on INR.

12. Pregnant or lactating women.

13. Subjects with a history of pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest CT scan.

14. Subjects with known hereditary degenerative retinal disorders or history of non-arteritic anterior ischaemic optic neuropathy.

15. Subjects with history of chronic lung diseases / restrictive lung disease (e.g. chronic obstructive pulmonary disease (COPD) or scleroderma) with impairment of lung function if total lung capacity (TLC) <60% predicted within 30 days of randomization.

16. Subjects at screening with impairment of renal function (serum creatinine > 2.5 mg/dL (>220 µmol/L)). This criterion may be satisfied by a creatinine result from the clinic’s local laboratory.

17. Subjects with hypotension defined as systolic arterial pressure <90 mmHg after sitting for 5 minutes at either screening or baseline.

18. Subjects with severe impairment of hepatic function, Child-P

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

Health Condition(s) or Problem(s) studied

Pulmonary arterial hypertension (PAH).
MedDRA version: 8.1 Level: LLT Classification code 10037400 Term: Pulmonary hypertension

Intervention(s)

Trade Name: Revatio
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sildenafil citrate
Other descriptive name: UK-92,480
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Trade Name: Revatio
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sildenafil citrate
Other descriptive name: UK-92,480
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: Revatio
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sildenafil citrate
Other descriptive name: UK-92,480
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-

Primary Outcome(s)

Primary end point(s): The change from baseline in the total distance walked during the 6MWT at Week 12 of the study

Main Objective: To demonstrate a dose response for 1 mg, 5 mg and 20 mg TID oral sildenafil for the
treatment of subjects with PAH.

Secondary Objective: • To assess the safety and tolerability of sildenafil (1 mg, 5 mg and 20 mg TID) after 12 weeks of treatment in subjects with PAH.

• To evaluate the effects of sildenafil (1 mg, 5 mg and 20 mg TID) on biomarkers of progression of PAH as measured by B-type natriuretic peptide (BNP)/pro-BNP levels and tricuspid annular plane systolic excursion (TAPSE)

• To determine the population pharmacokinetic parameters, and assess potential relationship of 6MWD, BNP/pro-BNP, TAPSE, PVRI and sildenafil exposure.

Secondary ID(s)

A1481244

N/A