Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12606000169549
Ethics application status
Approved
Date submitted
5/05/2006
Date registered
11/05/2006
Date last updated
11/05/2006
Type of registration
Prospectively registered

Titles & IDs
Public title
A 16-Week, International, Multicenter, Double-Blind, Randomized, Placebo-
Controlled Comparison of the Efficacy (by vasodilation of also inhibition of platelet aggregation) and Safety of Oral UT-15C
Sustained Release Tablets in Combination with an Endothelin Receptor
Antagonist and/or a Phosphodiesterase-5 Inhibitor in Subjects with
Pulmonary Arterial Hypertension
Scientific title
A 16-Week, International, Multicenter, Double-Blind, Randomized, Placebo-
Controlled Comparison of the Efficacy (by vasodilation of also inhibition of platelet aggregation) and Safety of Oral UT-15C
Sustained Release Tablets in Combination with an Endothelin Receptor
Antagonist and/or a Phosphodiesterase-5 Inhibitor in Subjects with
Pulmonary Arterial Hypertension
Universal Trial Number (UTN)
Trial acronym
TDE-PH-301
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension (PAH) 1142 0
Condition category
Condition code
Cardiovascular 1222 1222 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 1021 0
Treatment: Drugs
Comparator / control treatment
Placebo
Control group
Placebo

Outcomes
Primary outcome [1] 1657 0
To assess the effect of UT-15C sustained release (SR) on exercise capacity compared to placebo as measured by the change in the 6-Minute Walk distance in patients with PAH
Timepoint [1] 1657 0
At the visits at baseline, week 4, week 8, week 12, and week 16.
Secondary outcome [1] 2953 0
To assess the effect of UT-15C SR
Timepoint [1] 2953 0
During the visits Baseline, week 4, week 8, week 12, week 16
Secondary outcome [2] 2954 0
Combined Walk Distance/Borg Dyspnea Score
Timepoint [2] 2954 0
Secondary outcome [3] 2955 0
Clinical Worsening*
Timepoint [3] 2955 0
Baseline; week 16
Secondary outcome [4] 2956 0
Borg Dyspnea Score
Timepoint [4] 2956 0
During the visits Baseline, week 4, week 8, week 12, week 16
Secondary outcome [5] 2957 0
Dyspnea-Fatigue Index
Timepoint [5] 2957 0
During the visits Baseline, week 4, week 8, week 12, week 16
Secondary outcome [6] 2958 0
World Health Organization (WHO) Functional Class
Timepoint [6] 2958 0
During the visits Baseline, week 4, week 8, week 12, week 16
Secondary outcome [7] 2959 0
Symptoms of PAH
Timepoint [7] 2959 0
During the visits Baseline, week 4, week 8, week 12, week 16
Secondary outcome [8] 2960 0
Safety
Timepoint [8] 2960 0
Baseline, week 16 (adverse events, clinical laboratory parameters Baseline, week 8, week 16 electrocardiogram findings).

Eligibility
Key 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.
Minimum age
12 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation double blind envelopes will be used. The Pharmacy department will be used at each site to maintain the study blind.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The study is randomized 1:1 active to placebo. All subjects will be randomized using a centrally administered stratified permuted block randomization, stratified by background therapy (ERA alone, PDE- 5 inhibitor alone, and ERA + PDE-5 inhibitor) and Baseline 6-Minute Walk distance (= 350m and > 350m). Block sizes will be variable and not disclosed to investigators so that no inferences can be made about possible treatment assignments of current or future subjects. An Interactive Voice Response System (IVRS) will be utilized for the central randomization procedure.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/07/2006
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
300
Accrual to date
Final
Recruitment outside Australia
Country [1] 307 0
United Kingdom
State/province [1] 307 0

Funding & Sponsors
Funding source category [1] 1334 0
Commercial sector/Industry
Name [1] 1334 0
United Therapeutics Corporation
Country [1] 1334 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
United Therapeutics Corporation
Address
One Park Drive
P. O. Box 14186
Research Triangle Park NC 27709
Country
United States of America
Secondary sponsor category [1] 1177 0
Commercial sector/Industry
Name [1] 1177 0
Icon Clinical Reasearch Organisation will represent the sponsor in Australia
Address [1] 1177 0
Country [1] 1177 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 2681 0
Heart/Lung Transplant Unit Xavier 4 St. Vincent’s Hospital
Ethics committee address [1] 2681 0
Victoria Street Darlinghurst NSW 2010
Ethics committee country [1] 2681 0
Australia
Date submitted for ethics approval [1] 2681 0
Approval date [1] 2681 0
Ethics approval number [1] 2681 0
Ethics committee name [2] 2682 0
Advanced Lung Disease Dept Royal Perth Hospital, South Metropolitan Area Health Service
Ethics committee address [2] 2682 0
Wellington St, WA 6847
Ethics committee country [2] 2682 0
Australia
Date submitted for ethics approval [2] 2682 0
Approval date [2] 2682 0
Ethics approval number [2] 2682 0
Ethics committee name [3] 2683 0
The Alfred Hospital
Ethics committee address [3] 2683 0
5th Floor Commercial Rd Melbourne VIC 3004
Ethics committee country [3] 2683 0
Australia
Date submitted for ethics approval [3] 2683 0
Approval date [3] 2683 0
Ethics approval number [3] 2683 0

Summary
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 36032 0
Address 36032 0
Country 36032 0
Phone 36032 0
Fax 36032 0
Email 36032 0
Contact person for public queries
Name 10210 0
Ms. Georgina Spence
Address 10210 0
United Therapeutics Europe Ltd, 26 Frederick Sanger Road
Guildford, Surrey
GU2 7YD
Country 10210 0
United Kingdom
Phone 10210 0
+44 1483 207785
Fax 10210 0
+44 1483 207781
Email 10210 0
[email protected]
Contact person for scientific queries
Name 1138 0
Ms. Georgina Spence
Address 1138 0
United Therapeutics Europe Ltd 26 Frederick Sanger Road
Guildford Surrey
GU2 7YD
Country 1138 0
United Kingdom
Phone 1138 0
+44 1483 207785
Fax 1138 0
+44 1483 207781
Email 1138 0
[email protected]

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