None listed
Conditions
Brief summary
Pulmonary Arterial Hypertension (PAH) is a medical disorder in which pressure in the blood vessels going from the right side of the heart to the lungs (the pulmonary arteries) is elevated. The symptoms associated with PAH are tiredness, dizziness, and shortness of breath. These symptoms increase over time due to deterioration of the right ventricle of the heart. Prostacyclin is a naturally occurring hormone like fatty acid which has been found diminished in patients with PAH. Treatment for PAH in Australia include drugs to dilate the blood vessels in the pulmonary artery i.e. Bosentan, Revatio, prostacyclin analogues (a manufactured drug similar in action to naturally occurring prostacyclin), Warfarin is used to thin the blood, oxygen and lung transplantation are all treatment options. UT-15C is a prostacyclin analogue that has been developed in an oral form. Prostacyclin analogues are currently only available in intravenous and subcutaneous (injected under the skin) forms and have been shown to be a potent vasodilator and an inhibitor of platelet aggregation. These proven forms of treatment for PAH come with additional risks and administration complications. An oral form of the drug would be far more suitable and safer for the patient. The aim of this study is to assess the effect of UT-15C sustained release (SR) on exercise capacity compared to placebo (as measured by the change in 6 minute walk distance after 16 weeks of treatment in patients with PAH currently receiving approved treatment. Approximately 300 patients will be recruited for this study, world wide. They will be randomized in a one to one placebo/active drug for 16 weeks of treatment. They will then be offered a place in the open label study planned for 36 months. The protocol for this has been submitted in a separate application. It is hoped that using a combination treatment of PAH with therapies targeting different mechanisms of action has great promise in addressing the multiple pathophysiologic mechanisms that are implicated in PAH. These combinations may produce an additive effect or enhance and prolong the effect of other therapeutic agents.
Interventions
Multi-center, randomized, double-blind, placebo-controlled, 16-week study in subjects with PAH currently receiving oral therapy for the treatment of PAH.
Stratification of the population will occur in three groups:
• Subjects currently receiving approved endothelin receptor antagonist (ERA) and approved phosphodiesterase-5 (PDE-5)
inhibitor therapy willing to maintain current therapy for the duration of the study
• Subjects currently receiving approved ERA therapy alone willing to maintain curre
Multi-center, randomized, double-blind, placebo-controlled, 16-week study in subjects with PAH currently receiving oral therapy for the treatment of PAH. Stratification of the population will occur in three groups: • Subjects currently receiving approved endothelin receptor antagonist (ERA) and approved phosphodiesterase-5 (PDE-5) inhibitor therapy willing to maintain current therapy for the duration of the study • Subjects currently receiving approved ERA therapy alone willing to maintain current therapy for the duration of the study • Subjects currently receiving approved PDE-5 inhibitor therapy alone willing to maintain current therapy for the duration of the study. All subjects must be taking a PDE-5 inhibitor, ERA, or the combination for a minimum duration of 90 days and at the current dose(s) for at least 30 days prior to Baseline. All subjects should remain on the same pulmonary hypertension medications (i.e. PDE-5 inhibitor, ERA etc.) and doses as were used at Baseline throughout the study. Active treatment is UT-15C SR tablets provided in 1 mg, 5 mg, or 10 mg strengths for the 16-week Treatment Phase. Treatment will be initiated at 1 mg twice daily (every 12 hours +/- 1 hour) with dose escalation of an additional 1 mg twice daily every 5 days if clinically indicated based upon adverse events and symptoms of PAH according to protocol-defined guidelines. Doses should be maximized throughout the Treatment Phase up to a maximum dose of 16 mg twice daily at the end of 16-weeks. All study drug should be administered with the morning and evening doses of background therapy immediately following (~10 minutes) breakfast and dinner.
Sponsors
United Therapeutics Corporation
Study design
Allocation
Randomised controlled trial
Intervention model
Factorial
Primary purpose
Treatment
Masking
Blinded (masking used)
Eligibility
Sex/Gender
All
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. The subject weighs a minimum of 45 kilograms at Screening. 2. The subject, if female, is physiologically incapable of childbearing or practicing an acceptable method of birth control (i.e., surgical sterilization, approved hormonal contraceptives, barrier methods [such as a condom or diaphragm] used with a spermicide, or an intrauterine device}.For women of childbearing potential, a negative serum pregnancy test will be required at Screening. 3. The subject has a diagnosis of symptomatic Idiopathic or Familial PAH (including PAH associated with appetite suppressant use), PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired = 5 years), PAH associated with Collagen Vascular Disease, or PAH associated with HIV. 4. The subject, if HIV positive, has a CD4 lymphocyte count = 200 within 30 days of Baseline and is receiving current standard of care anti-retroviral or other effective medication for treatment of HIV. 5. The subject must have a Baseline 6-Minute Walk distance of between 100 and 400 meters, inclusive. 6. The subject may benefit from the introduction of additional therapy (e.g. a prostacyclin) as determined by their medical provider. 7. The subject must have been optimally treated with approved oral therapies. Specifically, the subject:a. Has been receiving approved PDE-5 inhibitor or approved ERA therapy alone for at least 90 days and at the current stable dose for 30 days prior to Baseline and is willing to remain on PDE-5 inhibitor or ERA alone and at the same dose for the duration of the 16- week Treatment Phase orb. Has been receiving the combination of approved PDE-5 inhibitor and approved ERA therapy for at least 90 days prior to Baseline with both treatments at the current stable dose at least 30 days prior to Baseline and is willing to remain on the combination of PDE-5 inhibitor and ERA at the same dose for the duration of the 16-week Treatment Phase. 8. The subject must be optimally treated with conventional pulmonary hypertension therapy (anticoagulant, diuretic, oxygen, digoxin, etc) using the same regimen for at least 30 days prior to Baseline. 9. The subject has previously undergone a cardiac catheterization and been documented to have a mean pulmonary artery pressure (PAPm) > 25 mmHg, a pulmonary capillary wedge pressure (PCWP) or a left ventricular end diastolic pressure (LVEDP) < 15 mmHg, and pulmonary vascularresistance (PVR) > 3 Wood units and absence of unrepaired congenital heart disease. 10. The subject has previously undergone echocardiography with evidence of normal left systolic and diastolic ventricular function, and absence of any clinically significant left sided heart disease (e.g. mitral valve stenosis). 11. The subject has a previous chest radiograph, ventilation perfusion scan, high resolution computerized tomography scan, or pulmonary angiography that are consistent with the diagnosis of PAH (i.e., low probability of pulmonary embolism; absence of major perfusion defects). 12. In the opinion of the Principal Investigator, the subject is able to communicate effectively with study personnel, and is considered reliable, willing and likely to be cooperative with protocol requirements. 13. The subject voluntarily gives informed consent to participate in the study.
Exclusion criteria
1. The subject is pregnant or lactating.2. The subject has received epoprostenol, treprostinil, iloprost, beraprost, or any other prostacyclin therapy within 30 days of Baseline (except if used during acute vasoreactivity testing).3. The subject has had a new type of chronic therapy (including but not limited to oxygen, a different category of vasodilator, diuretic, digoxin) for pulmonary hypertension added within 30 days of Baseline.4. The subject has had any PAH medication except for anticoagulants discontinued within 30 days of Baseline.5. The subject has any disease associated with pulmonary arterial hypertension other than collagen vascular disease, HIV, or repaired congenital systemic-to-pulmonary shunts (repaired = 5 years)(e.g. portal hypertension, chronic thromboembolic disease, etc.).6. The subject has a current diagnosis of uncontrolled sleep apnea as defined by their physician.7. The subject has chronic renal insufficiency as defined by either a Screening creatinine value greater than 2.5 mg/dL (221 µmol/L) or the requirement for dialysis.8. The subject has anemia as defined by a Screening hemoglobin value of less than 10 g/dL.9. The subject has a history or current evidence of left-sided heart disease including previous myocardial infarction, or evidence of current left-sided heart disease as defined by PCWPm or LVEDP > 15 mmHg or left ventricular ejection fraction (LVEF) < 40% as assessed by either multigated angiogram (MUGA), angiography or echocardiography, or left ventricular (LV) shortening fraction < 22% as assessed by echocardiography, or symptomatic coronary artery disease (i.e., demonstratable ischemia either at rest or during exercise).10. The subject has significant parenchymal lung disease as evidenced by pulmonary function tests done within 6 months of Baseline as defined by any one of the following:a. Total Lung Capacity < 60% (predicted), orb. If Total Lung Capacity is between 60% and 70% of predicted, a high resolution CT scan must be performed to document diffuse interstitial fibrosis or alveolitis orc. Forced expiratory volume/forced vital capacity (FEV/FVC) ratio < 50%11. The subject has uncontrolled systemic hypertension as evidenced by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg.12. The subject has a musculoskeletal disorder (e.g. hip replacement, artificial leg, etc.) or any other disease that is likely to limit ambulation, or is connected to a machine that is not portable.13. The subject has an unstable psychiatric condition or is mentally incapable of understanding the objectives, nature, or consequences of the trial, or has any condition which in the Investigator’s opinion would constitute an unacceptable risk to the subject’s safety.14. The subject is receiving an investigational drug, has an investigational device in place (except a Chronicle® device if in place and without complications for 30 days prior to Screening), or has participated in an investigational drug or device study within 30 days prior to Screening.
Outcome results
None listed