A 12-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C Sustained Release Tablets in Subjects with Pulmonary Arterial Hypertension - FREEDOM-M

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-000801-50-AT
• Date of registration: 17/01/2007
• Prospective Registration: Yes
• Primary sponsor: United Therapeutics Corporation
• Public title: A 12-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C Sustained Release Tablets in Subjects with Pulmonary Arterial Hypertension - FREEDOM-M
• Scientific title: A 12-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C Sustained Release Tablets in Subjects with Pulmonary Arterial Hypertension - FREEDOM-M
• Date of first enrolment: 19/02/2007
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-000801-50
• 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, Italy, Netherlands

Key inclusion & exclusion criteria

Inclusion criteria:
1. The subject is between the ages of 12 and 75 years of age at Screening.
2. The subject weighs a minimum of 40 kilograms with a Body Mass Index (BMI) less than 45 kg/m² at Screening.
3. The subject, if female, is physiologically incapable of childbearing or practicing an acceptable method of birth control as deemed appropriate by the physician or institution (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/toxin 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 200 and 425 meters, inclusive.
7. The subject may benefit from the introduction of therapy (e.g. a prostacyclin) as determined by their medical provider.
8. The subject must be optimally treated with conventional pulmonary hypertension therapy (e.g. oral vasodilators, oxygen, digoxin, etc) with no additions, discontinuations, or dose changes for at least 14 days prior to Baseline (excluding anticoagulants). Diuretics may be adjusted, but not discontinued or added, within 14 days of 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 vascular resistance (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 will voluntarily give informed consent to participate in the study.

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:
1. The subject is pregnant or lactating.
2. The subject has previously received a prostacyclin (except if used during acute vasoreactivity testing), endothelin receptor antagonist, or phosphodiesterase-5 inhibitor within 30 days of Baseline.
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 14 days of Baseline.
4. The subject has had any PAH medication except for anticoagulants discontinued within 14 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, pulmonary veno-occlusive disease, etc.) or has had an atrial septostomy.
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 ischemic heart disease (defined as either symptomatic or requiring anti-anginal therapy or experienced a myocardial infarction within the previous 3 years), or left ventricular dysfunction as evidenced by a mean PCWP (or a left ventricular end diastolic pressure) > 15 mmHg or left ventricular ejection fraction < 40% as assessed by either multigated angiogram (MUGA), angiography or echocardiography. Patients with abnormal left ventricular function attributable entirely to impaired left ventricular filling due to the effects of right ventricular overload (i.e. right ventricular hypertrophy and/or dilatation) will not be excluded.
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/toxin 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
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
Current Sponsor code: UT-15C SR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
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
Current Sponsor code: UT-15C SR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.25-
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
Current Sponsor code: UT-15C SR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.125-
Pharmaceutical form of the placebo: Coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

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

- change in 6-Minute Walk Distance (i.e., distance traversed during the 6-Minute Walk Test) from Baseline to Week 12 between UT-15C SR and placebo

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. ERA, PDE-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 12) in subjects with PAH who are not currently receiving endothelin receptor antagonist (ERA), phosphodiesterase (PDE)-5 inhibitor, prostacyclin therapy, or any combination. The change in 6-Minute Walk distance will be evaluated primarily for subjects with access to 0.25 mg tablets at the time of randimization, and secondarily for the overall population.

Secondary ID(s)

TDE-PH-302