A 16-Week International, Multicenter, Double-Blind, Randomized, Placebo Controlled Comparison of the Efficacy 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 - FREEDOM-C

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-000800-17-IE
• Date of registration: 13/11/2006
• Prospective Registration: Yes
• Primary sponsor: United Therapeutics Corporation
• Public title: A 16-Week International, Multicenter, Double-Blind, Randomized, Placebo Controlled Comparison of the Efficacy 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 - FREEDOM-C
• Scientific title: A 16-Week International, Multicenter, Double-Blind, Randomized, Placebo Controlled Comparison of the Efficacy 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 - FREEDOM-C
• Date of first enrolment: 15/02/2007
• Target sample size: 300
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-000800-17
• 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: yes Other: no

Countries of recruitment

Austria, Belgium, France, Germany, Ireland, Italy, Netherlands, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. The subject is between the ages of 12 and 65 years of age at Screening.
2. The subject weighs a minimum of 45 kilograms at Screening.
3. 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.
4. 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.
5. 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.
6. The subject must have a Baseline 6-Minute Walk distance of between 100 and 400 meters, inclusive.
7. The subject may benefit from the introduction of additional therapy (e.g. a prostacyclin) as determined by their medical provider.
8. 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
or
b. 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.

9. 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.
10. 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 vascular resistance (PVR) > 3 Wood units and absence of unrepaired congenital heart disease.
11. 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).
12. 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).
13. 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.
14. The subject voluntarily gives informed consent to participate in the study.

Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of s
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), or
b. 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 or
c. 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.



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

Health Condition(s) or Problem(s) studied

Idiopathic or Familial pulmonary arterial hypertension (PAH), including PAH associated with: 1) Appetite suppressant use, or 2) Repaired congenital systemic-to-pulmonary shunts (repaired = 5 years), or 3) Collagen Vascular Disease (CVD), or 4) Human Immunodeficiency virus (HIV)
MedDRA version: 8.1 Level: PT Classification code 10037400 Term: Pulmonary hypertension

Intervention(s)

Product Name: Treprostinil Diethanolamine
Product Code: UT-15C SR
Pharmaceutical Form: Coated tablet
INN or Proposed INN: Treprostinil diethanolamine
Current Sponsor code: UT-15C SR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Coated tablet
Route of administration of the placebo: Oral use

Product Name: Treprostinil Diethanolamine
Product Code: UT-15C SR
Pharmaceutical Form: Coated tablet
INN or Proposed INN: Treprostinil diethanolamine
Current Sponsor code: UT-15C SR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: To assess the effect of UT-15C SR on the following:

- Combined Walk Distance/Borg Dyspnea Score
- Clinical Worsening*
- Borg Dyspnea Score
- Dyspnea-Fatigue Index
- World Health Organization (WHO) Functional Class
- Symptoms of PAH
- Safety (adverse events, clinical laboratory parameters, electrocardiogram findings)

*Definition of clinical worsening requires one of the following:
1. Death (all causes excluding accident)
2. Transplantation or atrial septostomy
3. Clinical deterioration as defined by:
a. Hospitalization as a result of PAH, or
b.= 20% decrease in 6-Minute Walk distance from Baseline (or too ill to walk) and a decrease in WHO Functional Class
And
c. Initiation of new PAH specific therapy (i.e., endothelin receptor antagonist, phosphodiesterase-5 inhibitor, prostacyclin).

Main Objective: 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 from Baseline to Week 16) in subjects with PAH.

Primary end point(s): The primary efficacy endpoint is:

- change in 6-Minute Walk Distance ( i.e distance traversed during the 6-minute walk test) from Baseline to Week 16 between UT-15C SR and placebo.

Secondary ID(s)

TDE-PH-301