Clinical trial NCT00494533: Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
Official title: Treprostinil for Untreated Symptomatic PAH Trial: A 12-Week Multicenter Randomized Double-Blind Placebo-Controlled Trial of the Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Keywords: pulmonary arterial hypertension
prostacyclin analogue
intravenous
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Asian Clinical Trials
First posted: 2007-06-29
Enrollment: 45
Sex: ALL
Minimum age (years): 16
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Multi-center, double-blind, placebo-controlled, randomized, parallel study comparing continuous intravenous (IV) Remodulin® to placebo in patients with pulmonary arterial hypertension either primary (PPH) or associated with human immunodeficiency virus (HIV) infection or collagen vascular disease).


Eligibility criteria: Inclusion Criteria: Patients Must

1. Between 16- 75 years of age.
2. Male or, if female, physiologically incapable of childbearing or utilizing birth control.
3. Have current diagnosis of symptom-limited NYHA Functional Class III/IV PAH that is:

   * PPH ("idiopathic" or familial PAH); or
   * PAH associated with collagen vascular disease (confirmed by antinuclear antibody titer or acceptable test); or
   * PAH associated with HIV infection (confirmed by serological test).
4. If HIV positive, have CD4 lymphocyte count ≥ 200 at baseline and receiving current SOC anti-retroviral or effective medication for HIV infection.
5. Optimally treated with conventional PH therapy and clinically stable for at least 1 month prior to baseline.
6. Have ventilation/perfusion scan, contrast-enhanced CT scan, or pulmonary angiogram after onset of PAH that rules out pulmonary embolism.
7. Have cardiac catheterization in last 3 months (or at Baseline) showing:

   * PAPm \> 35 mmHg (at rest) \&
   * PCWPm (or LV end diastolic pressure) \< 16 mmHg \&
   * PVR \> 5 mmHg/L/min.
8. Have echocardiogram in last 3 months consistent with PH, specifically:

   * evidence of RV hypertrophy or dilation \&
   * evidence of normal LV function \&
   * absence of mitral valve stenosis.
9. Have chest radiograph consistent with PH performed in last 3 months. Radiograph must show clear lung fields or no more than patchy interstitial infiltrates.
10. Unless contraindicated, able to receive one of following anticoagulants: warfarin to achieve INR between 1.5-2.5 or heparin to produce aPTT between 1.3-1.5 times control, unless higher levels clinically indicated.
11. Mentally and physically capable of learning to administer Study Drug using ambulatory intravenous infusion pump and central venous access, or have trained caregiver.
12. If on corticosteroids, receiving stable dose of 20 mg/day of prednisone (or equivalent dose of another steroid) for at least 1 month prior to entry.

Exclusion Criteria: Patients must not:

1. Nursing or pregnant (women of childbearing potential have negative pregnancy test).
2. Have had new type of chronic therapy (including but not limited to oxygen, different category of vasodilator, diuretic, digoxin) for PH, except for anticoagulants, added in last month.
3. Be scheduled for heart-lung transplant.
4. Have any PH medication except for anticoagulants discontinued in week prior to study entry.
5. Have received any chronic prostaglandin or prostaglandin analogue (including intravenous/inhaled/oral: epoprostenol, iloprost, beraprost, etc.), any phosphodiesterase inhibitor therapy such as sildenafil, or any endothelin antagonist therapy such as bosentan, in past 30 days.
6. Have PH associated with chronic thromboembolic disease; or chronic obstructive lung diseases or hypoxemia; or evidence of significant parenchymal lung disease as evidenced by PFTs in last 3 months as follows (any one of following):

   * TLC \< 60% (predicted) or high resolution CT documenting diffuse interstitial fibrosis or alveolitis
   * FEV1/FVC ratio \< 50%
7. Have Portal Hypertension.
8. Have history of uncontrolled Sleep Apnea, defined as oxygen desaturation less than 90% at night, in past 3 months.
9. Have history of left-sided heart disease including:

   * Aortic or mitral valve disease or
   * Pericardial constriction or
   * Restrictive or congestive cardiomyopathy; or have evidence of current left-sided heart disease defined by:
   * PCWPm or LV end diastolic pressure \> 16 mmHg or
   * LVEF \< 40% by MUGA, angiography or echocardiography or
   * LV Shortening Fraction \< 22% by echocardiography or
   * Symptomatic coronary disease (demonstrable ischemia).
10. Have any disease other than HIV or connective tissue disease associated with PH (e.g. sickle cell anemia, schistosomiasis).
11. Have active AIDS or tuberculosis.
12. Have musculoskeletal disorder (e.g. arthritis, artificial leg, etc.) or any other disease thought to limit ambulation, or connected to machine which is not portable.
13. Have baseline exercise capacity of \<50 m or \>325 m as measured by 6-Minute Walk Test.
14. Have uncontrolled systemic hypertension as evidenced by systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg.
15. Have used prescription appetite suppressants in 3 months of study entry.
16. Have chronic renal insufficiency defined by creatinine \>2.5 mg/dL or requiring dialysis.
17. Receiving an investigational drug (other than acute challenge with epoprostenol), have in place an investigational device, or have participated in investigational drug/device study in past 30 days.
18. Have presence of any physiological or mental condition which contraindicates administration of Remodulin.

Primary outcomes:
measure: Six-minute walk distance
timeFrame: Twelve Weeks
Secondary outcomes:
measure: Borg Dyspnea Score
timeFrame: Twelve Weeks
measure: Dyspnea-Fatigue Index
timeFrame: Twelve weeks
measure: NYHA Functional Class
timeFrame: Twelve Weeks
measure: Clinical Worsening
timeFrame: Twelve Weeks
measure: Combined Walk and Borg Dyspnea Score
timeFrame: 12 Weeks
Other outcomes:
Locations:
city: Ahmedabad
country: India
facility: SAL Hospital & Medical Institute
city: Bangalore
country: India
facility: Narayana Hrudayalaya Inst. Of Cardiac Sciences
city: Chennai
country: India
facility: Apollo Hospitals
city: Chennai
country: India
facility: K. S. Hospital
city: Chennai
country: India
facility: Sri Ramachandra Medical College
city: Hyderabad
country: India
facility: Medwin Heart Institute
city: Hyderabad
country: India
facility: Yashoda Super Specialty Hospital
city: Kolkata
country: India
facility: Apollo Gleneagles Hospital
city: Mangalore
country: India
facility: KMC Hospital
city: Manipal
country: India
facility: Kasturba Medical College
city: Mumbai
country: India
facility: KEM Hospital
city: New Delhi
country: India
facility: G. B. Pant Hospital & Maulana Azad Med. College
city: Pune
country: India
facility: Ruby Hall Clinic
city: Secunderabad
country: India
facility: Krishna Institute of Medical Sciences
Study officials:
affiliation: United Therapeutics
name: Michael Wade, Ph.D.
role: STUDY_DIRECTOR
References:
citation: Hiremath J, Thanikachalam S, Parikh K, Shanmugasundaram S, Bangera S, Shapiro L, Pott GB, Vnencak-Jones CL, Arneson C, Wade M, White RJ; TRUST Study Group. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant. 2010 Feb;29(2):137-49. doi: 10.1016/j.healun.2009.09.005.