Clinical trial NCT01305252: A 48-week Study of the Effect of Dual Therapy (Inhaled Treprostinil and Tadafafil) Versus Monotherapy (Tadalafil).
Official title: CombinatiON Up-FRON t Therapy for PAH - A Phase 4, Randomized, Multicenter Study of Inhaled Treprostinil in Treatment naïve Pulmonary Arterial Hypertension Patients Starting on Tadalafil
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension, Pulmonary
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Northwestern University
First posted: 2011-02-28
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The Study Hypothesis:

Aggressive, upfront, dual therapy for treatment-naïve NYHA I/II/III PAH is superior to a traditional "step-up" approach.

The study will evaluate:

1. Impact of dual, upfront, therapy on cardiovascular parameters in PAH as gauged by cardiac magnetic resonance imaging (cMRI) at 24 weeks and event free survival at outcome at 48 weeks.
2. Value of novel biomarkers (NT-pro BNP, Mts1/S100A4, and insulin resistance) and cutting-edge imaging technologies (cardiac MRI) as newer endpoints for clinical trials in PAH.
3. Utility of longer clinical trial design with the use of combined clinical events as time to clinical worsening surrogate

Detailed description: This is a 48 week interventional study evaluating the effect of Dual therapy ( Treprostinil inhalations and Tadalafil) versus Mono therapy (Tadalafil). The impact of the therapy on cardiovascular parameters in PAH measured at 24 weeks and event free survival outcome at 48 weeks.

Eligibility criteria: Inclusion criteria:

1. Age 18 and \< 75 years at baseline visit.
2. Diagnosis of Idiopathic PAH, Heritable PAH (including Hereditary Hemorrhagic Telangiectasia), Associated PAH (including collagen vascular disorders, drug+toxin exposure, repaired congenital heart disease repaired \> 5 years, portopulmonary disease, and human immunodeficiency virus (HIV) infection not on protease inhibitor).
3. PAH treatment naïve including any prostacycline, endothelin receptor antagonist, or phosphodiesterase inhibitors within 12 months prior to enrollment.
4. Previous Right Heart Catheterization that documented:

   1. Mean PAP; 25 mmHg.
   2. Pulmonary capillary wedge pressure \< 15 mmHg.
   3. Pulmonary Vascular Resistance; 3.0 Wood units or 240 dynes/sec/cm5 5.6MW distances; 150 m and \< 450 meters.

6. WHO functional class II or III as judged by principal investigators.

Exclusion Criteria:

Exclusion criteria:

1. Group II - V pulmonary hypertension.
2. PAH with unrepaired congenital heart defect.
3. Current or prior PAH treatments within the last 6-12 months including experimental PAH therapies (including but not limited to tyrosine kinase inhibitors, rho-kinase inhibitors, phosphodiesterase inhibitors, prostacycline, or cGMP modulators).
4. TLC \< 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease.
5. FEV1 / FVC \< 70% predicted and FEV1 \< 60% predicted
6. Significant left-sided heart disease (based on pre-trial Echocardiogram):

   1. Significant aortic or mitral valve disease
   2. Diastolic dysfunction ; Grade II C.LV systolic function \< 45%

   d. Pericardial constriction e. Restrictive cardiomyopathy f. Significant coronary disease with demonstrable ischemia
7. Chronic renal insufficiency defined as an estimated creatinine clearance \< 30 ml/min (by MDRD equation)
8. Current atrial arrhythmias
9. Uncontrolled systemic hypertension: SBP \> 160 mm or DBP \> 100mm
10. Severe hypotension: SBP \< 80 mmHg.
11. Pregnant or breast-feeding
12. Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions
13. Co-morbid conditions that would impair a patient's exercise performance and ability to assess WHO functional class, including but not limited to chronic low-back pain or peripheral musculoskeletal problems.
14. Contraindications for magnetic resonance imaging, including significant claustrophobia, implanted metallic objects, or others as per Appendix X).
15. Known allergy to treprostinil or tadalafil.
16. Active oral nitrate use.
17. Diabetes mellitus.
18. Planned initiation of cardiac or pulmonary rehabilitation during period of study.

Primary outcomes:
measure: Change in Right Ventricular Ejection Fraction
timeFrame: Basline and 24 weeks
Secondary outcomes:
measure: 6 Minute Walk Distance
timeFrame: Baseline and 24 weeks
measure: N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
timeFrame: Baseline and 24 weeks
measure: Change in NYHA/WHO Class
timeFrame: Baseline and 48 week
measure: B-type Natriuretic Peptide (BNP)
timeFrame: Baseline and 24 weeks
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
Study officials:
affiliation: Stanford University
name: Roham T. Zamanian
role: PRINCIPAL_INVESTIGATOR
References: