A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF THE ADDITION OF INHALED ILOPROST IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH) RECEIVING ORAL SILDENAFIL - VISION

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2005-006192-13-GB
• Date of registration: 21/03/2006
• Prospective Registration: Yes
• Primary sponsor: Actelion Pharmaceuticals US, Inc.
• Public title: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF THE ADDITION OF INHALED ILOPROST IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH) RECEIVING ORAL SILDENAFIL - VISION
• Scientific title: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF THE ADDITION OF INHALED ILOPROST IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH) RECEIVING ORAL SILDENAFIL - VISION
• Date of first enrolment: 22/06/2006
• Target sample size: 180
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-006192-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Germany, Italy, Portugal, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
Patients may be included in the study only if they meet all of the following:
1. Able and willing to give written informed consent and comply with study requirements.
2. Male or female patients aged 18-85 years
3. Have a current diagnosis of symptomatic PAH classified by one of the following: a) IPAH or FPAH; b) PAH associated with one of the following connective tissue diseases and mild or no lung parenchymal disease: scleroderma spectrum of disease, systemic lupus erythematosis, or mixed connective tissue disease, c) PAH associated with repaired atrial septal defect (ASD), ventricular septal defect (VSD), or patent ductus arteriosus (PDA) = 1 year post-operative from Screening, d) PAH associated with HIV, or e) PAH associated with the use of anorexigens (e.g. fenfluramine-phentermine)
4. On a stable dose regimen of sildenafil, at doses between 60 mg and 300 mg/day in divided doses, for at least 12 weeks prior to screening, and tolerating sildenafil without clinically significant side effects
5. Screening 6-MWD of 100-450 meters
6. Have a cardiac catheterization either at baseline or within the previous 3 years consistent with PAH, with the following values: a) mean pulmonary artery pressure (mPAP) at rest > 25 mm Hg, b) pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure = 15 mm Hg, and c) pulmonary vascular resistance (PVR) = 240 dynes·sec·cm-5
7. Have pulmonary function tests showing FEV1/FVC ratio > 50% AND either a) total lung capacity > 70% predicted, or b) total lung capacity between 60% and 70% predicted, with no more than mild patchy interstitial lung disease on lung imaging
8. If HIV-seropositive, must have been stable with a) no concomitant active opportunistic infections and an undetectable viral load for the 6 months prior to screening, b) CD4+ T cell count > 200/mm3 and no change in antiviral regimen for the 3 months prior to screening, c) no change in antiviral regimen anticipated during the course of the study, and d) no use of inhaled pentamidine
9. Documented evidence of absence of thromboembolic disease (i.e., low probability for pulmonary embolism) using methodology such as pulmonary angiogram, ventilation perfusion scan, or chest CT scan within 3 years of screening
10. If on corticosteroids, be receiving a stable dose of = 20 mg/day of prednisone or equivalent for at least 1 month prior to screening
11. Women of childbearing potential must agree to use an adequate method of contraception during the study and for one month after the last dose of study drug
12. Those patients receiving bosentan concurrently with sildenafil at the time of screening must have been on bosentan for at least 16 weeks, with stable liver transaminases (< 2X upper limit of normal) and on stable dose (maximum 125 mg BID) for at least the last 8 weeks prior to screening

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:
Patients meeting any of the following criteria are not eligible to participate in the study:
1. Pulmonary arterial hypertension related to any etiology other than those specified in the inclusion criteria (including portopulmonary)
2. Receipt of any prostacyclin or prostacyclin analogue within 12 weeks before screening
3. Discontinuation of bosentan or other endothelin antagonist within 12 weeks before screening
4. Change in sildenafil dose within 12 weeks before screening
5. Any clinically significant ocular abnormality during screening examination that could be potentially related to sildenafil use (e.g. retinal abnormalities or visual defects)
6. History of poor tolerability to sildenafil
7. Untreated or inadequately treated obstructive sleep apnea
8. History of left-sided heart disease, including any of the following:
- aortic or mitral valve disease;
- pericardial constriction;
- restrictive or congestive cardiomyopathy;
- diastolic dysfunction syndrome;
- left ventricular ejection fraction < 40% by multigated radionucleotide angiogram
(MUGA), angiography, or echocardiography;
- left ventricular shortening fraction < 22% by echocardiography;
- symptomatic coronary disease with demonstrable ischemia;
- life-threatening cardiac arrhythmias
9. Cerebrovascular events (e.g. transient ischemic attack or stroke) within 6 months of screening
10. Chest X-Ray showing medically relevant disease other than findings consistent with PAH
11. Receipt of atrial septostomy within 6 months of screening
12. Any condition other than PAH which might affect the patient’s ability to perform a 6-MWT
13. Clinically relevant obstructive lung disease (e.g. asthma or COPD)
14. Clinically relevant abnormal laboratory values at screening that, in the opinion of the investigator, would compromise the evaluation of efficacy and/or safety of the study drug
15. Treatment with an investigational drug or device which has not received regulatory approval within 120 days before screening
16. Uncontrolled systemic hypertension as evidenced by systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg on repeated measurement
17. Systemic hypotension with systolic BP < 95 mmHg
18. Chronic renal insufficiency as defined by a creatinine of > 2.5 mg/dL or the requirement for dialysis
19. Chronic liver disease or cirrhosis, including porto-pulmonary hypertension
20. Clinically relevant bleeding disorder or active bleeding
21. Psychiatric, addictive, or other disorder that compromises the ability to give informed consent for participating in this study
22. Pregnant or breastfeeding
23. The addition or discontinuation of any new type of chronic treatment for PAH including, but not limited to calcium channel blockers within 12 weeks before screening; or vasodilators, digitalis, diuretics, oxygen, or investigational treatments within 30 days before screening; for all of these except diuretics, the dose must have been stable for 7 days prior to baseline. Anti-coagulant therapy may be modified at any time.
24. Concomitant use of medications that are contraindicated with sildenafil, including regular or intermittent use of organic nitrates
25. Are study investigators, study staff, or their immediate families
26. Concomitant therapy with medications contraindicated by bosentan labeling (cyclosporine, glyburide)
27. Any malignancy that may impact survival (<1 year expected survival), infiltrate the lungs, require contradicted or excluded concomitant medications, or caus

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

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension (PAH) is a condition that is characterized by increased pulmonary arterial pressure and vascular resistance that can lead to right ventricular failure and death.
MedDRA version: 8.1 Level: LLT Classification code 10037400 Term: Pulmonary hypertension

Intervention(s)

Trade Name: Ventavis
Product Name: Iloprost (Ventavis®)
Pharmaceutical Form: Inhalation vapour, solution
INN or Proposed INN: Iloprost
CAS Number: 78919-13-8
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Inhalation vapour, solution
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Primary end point(s): The primary measure will be the change in 6-Minute Walk Distance (6-MWD) from baseline, measured after inhalation, following 16 weeks of combination therapy with inhaled iloprost (administered 6 times per day) and sildenafil vs. inhaled placebo plus sildenafil

Secondary Objective: 1.Change from baseline in 6-MWD measured after inhalation at Week 16 of inhaled iloprost (4 x/day) plus sildenafil vs. placebo plus sildenafil
2.Change from baseline in NYHA/WHO class assessed at Week 16 of inhaled iloprost (6x/day) plus sildenafil vs. placebo plus sildenafil
3.Time to clinical worsening with inhaled iloprost (6x/day) plus sildenafil vs. placebo plus sildenafil, where clinical worsening is defined by: death due to PAH, hospitalization by worsening PAH, or any early discontinuation due to worsening PAH, initiation of additional PAH-specific therapy (such as systemic prostanoids), or performance of lung or heart-lung transplantation or atrial septostomy
4.Change from baseline in NYHA/WHO class assessed at Week 16 with inhaled iloprost (4x/day) plus sildenafil vs. placebo plus sildenafil
5.Time to clinical worsening with inhaled iloprost (4x/day) plus sildenafil vs. placebo plus sildenafil, (clinical worsening is defined above)

Main Objective: The primary objective of this study is to assess the efficacy of the addition of inhaled iloprost vs. placebo in patients with PAH receiving sildenafil. The primary measure will be the change in 6-Minute Walk Distance (6-MWD) from baseline, measured after inhalation, following 16 weeks of combination therapy with inhaled iloprost (administered 6 times per day) and sildenafil vs. inhaled placebo plus sildenafil.

Secondary ID(s)

C200-006