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Trial registered on ANZCTR


Registration number
ACTRN12606000187549
Ethics application status
Not yet submitted
Date submitted
5/05/2006
Date registered
18/05/2006
Date last updated
18/05/2006
Type of registration
Prospectively registered

Titles & IDs
Public title
An Open-Label Extension Trial of UT-15C SR in Subjects with
Pulmonary Arterial Hypertension
Scientific title
An Open-Label Extension Trial of Treprostinil Diethanolamine Sustained Release (UT-15C SR) in Subjects with Pulmonary Arterial Hypertension to assess the long-term safety of UT-15C SR in study subjects and the effect of continued therapy with UT-15C SR on exercise capacity after one year of treatment.
Universal Trial Number (UTN)
Trial acronym
TDE-PH-304
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension (PAH) 1160 0
Condition category
Condition code
Cardiovascular 1245 1245 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multi-center, open-label study for eligible patients who participated in Protocol TDE-PH-301 and TDE-PH-302. The estimated study duration for each subject is up to 36 months from the point of transition from protocol TDE-PH-301 or TDE-PH-302 to the end of the open-label study. Treprostinil Diethanolamine Sustained Release (UT-15C SR) will be provided as 1, 5, and 10 mg tablets and will be labeled and packaged for open-label
administration.
Subjects who were randomized to UT-15C SR treatment group in the previous trial will begin open-label therapy at the same dose they were receiving at the final (Week 12/16) visit in the previous trial, and subsequent dose adjustments will be made based on symptoms of PAH and AEs.
Intervention code [1] 1022 0
Treatment: Drugs
Comparator / control treatment
For subjects who were randomized to placebo in either protocol TDE-PH-301 or TDE-PH-302, 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.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 1680 0
The study drug will be taken on a daily basis for 36 months on the open label study. The outcome will be measured by assessing the patient's improvement (Clinical Laboratory Assessments, Adverse Event Assessment, and A 6-Minute Walk Test with Borg Dyspnea Score) over the 36 months
Timepoint [1] 1680 0
At each visit to the clinic every 3 months over the 36 months.
Primary outcome [2] 1681 0
The study drug will be taken on a daily basis for 36 months on the open label study. The outcome will be measured by assessing the tolerance for the study drug over the 36 months
Timepoint [2] 1681 0
At each visit to the clinic every 3 months over the 36 months.
Secondary outcome [1] 3019 0
To assess the long-term safety of UT-15C SR in these subjects through assessment of adverse events and laboratory parameters.
Timepoint [1] 3019 0
At the visit 1 (three months after first dose of UT-15C SR; only for subjects randomized to placebo in previous study), visit 2 (six months after first dose of UT-15C SR), visit 3 (12 months after first dose of UT-15C SR), visit 4 (24 months after first dose of UT-15C SR), visit 5 (36 months after first dose of UT-15C SR).
Secondary outcome [2] 3020 0
To assess the effect of continued therapy with UT-15C SR on exercise capacity.
Timepoint [2] 3020 0
After one year of treatment.

Eligibility
Key inclusion criteria
Participation in study TDE-PH-301 or TDE-PH-302 is required. Subjects must complete all assessments in one of these two studies to be eligible. Subjects who permanently discontinued study drug during the previous study (TDE-PH-301 or TDE-PH-302) due to treatment related adverse events are not eligible for entry into this study, even if they completed all remaining study visits in the previous study.Subjects who permanently discontinued study drug during the Treatment Phase of Study TDE-PH-301 or TDE-PH-302 due to clinical worsening (as defined in those study protocols) and who did not undergopremature termination assessments prior to discontinuing study drug, and/or who did not complete all remaining study visits through the final scheduled visit, are also not eligible for entry into this study.Subjects who permanently discontinued study drug during the Treatment Phase of the previous study (TDE-PH-301 or TDE-PH-302) due to clinical worsening, who completed premature terminationassessments prior to discontinuing study drug, and who completed all remaining scheduled study visits, are eligible for entry into this study. However, if the subject received active drug during the TreatmentPhase of the previous study (TDE-PH-301 or TDE-PH-302), then the subject may not participate in this study, as the subject previously clinically worsened on active drug. If the subject received placebo duringthe Treatment Phase of the previous study, then the subject is eligible for this study and should start treatment UT-15C SR in the open-label study at 1 mg twice daily.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
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
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
30/11/2006
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
450
Accrual to date
Final
Recruitment outside Australia
Country [1] 308 0
United Kingdom
State/province [1] 308 0

Funding & Sponsors
Funding source category [1] 1360 0
Commercial sector/Industry
Name [1] 1360 0
United Therapeutics Corporation
Country [1] 1360 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] 1201 0
Commercial sector/Industry
Name [1] 1201 0
Icon Clinical Reasearch Organisation will represent the sponsor in Australia
Address [1] 1201 0
Country [1] 1201 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 2717 0
Heart/Lung Transplant Unit Xavier 4 St. Vincent’s Hospital
Ethics committee address [1] 2717 0
Ethics committee country [1] 2717 0
Australia
Date submitted for ethics approval [1] 2717 0
Approval date [1] 2717 0
Ethics approval number [1] 2717 0
Ethics committee name [2] 2718 0
Advanced Lung Disease Dept Royal Perth Hospital, South Metropolitan Area Health Service
Ethics committee address [2] 2718 0
Ethics committee country [2] 2718 0
Australia
Date submitted for ethics approval [2] 2718 0
Approval date [2] 2718 0
Ethics approval number [2] 2718 0
Ethics committee name [3] 2719 0
The Alfred Hospital
Ethics committee address [3] 2719 0
Ethics committee country [3] 2719 0
Australia
Date submitted for ethics approval [3] 2719 0
Approval date [3] 2719 0
Ethics approval number [3] 2719 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 35126 0
Address 35126 0
Country 35126 0
Phone 35126 0
Fax 35126 0
Email 35126 0
Contact person for public queries
Name 10211 0
Ms. Georgina Spence
Address 10211 0
United Therapeutics Europe Ltd, 26 Frederick Sanger Road
Guildford, Surrey
GU2 7YD
Country 10211 0
United Kingdom
Phone 10211 0
+44 1483 207785
Fax 10211 0
+44 1483 207781
Email 10211 0
[email protected]
Contact person for scientific queries
Name 1139 0
Ms. Georgina Spence
Address 1139 0
United Therapeutics Europe Ltd, 26 Frederick Sanger Road
Guildford, Surrey
United Kingdom
GU2 7YD
Country 1139 0
United Kingdom
Phone 1139 0
+44 1483 207785
Fax 1139 0
+44 1483 207781
Email 1139 0
[email protected]

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Results publications and other study-related documents

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