A 48-week Study of the Effect of Dual Therapy (Inhaled Treprostinil and Tadafafil) Versus Monotherapy (Tadalafil).

Phase 4

Completed

• Conditions: Hypertension, Pulmonary
• Interventions: Drug: treprostinil inhalations; Drug: tadalafil

• Registration Number: NCT01305252
• Lead Sponsor: Stanford University

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.

Study Timeline

• Study Start: 2010-07
• Study First Submitted: 2010-11-02
• Study First Submitted QC: 2011-02-24
• Study First Posted: 2011-02-28
• Primary Completion: 2014-09
• Study Completion: 2014-09
• Results First Submitted: 2016-11-21
• Status Verified: 2017-04
• Results First Submitted QC: 2017-04-27
• Last Update Submitted: 2017-04-27
• Results First Posted: 2017-06-02
• Last Update Posted: 2017-06-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

Not provided

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
tadalafil and treprostinil inhalations	treprostinil inhalations	Treprostinil inhalation QID starting at 3 breaths per inhalation \& gradually increasing to 9 breaths.Each breath provides approximately 6 mcg of treprostinil.Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated.
tadalafil alone	tadalafil	tadalafil 40mg QD(Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated).
tadalafil and treprostinil inhalations	tadalafil	Treprostinil inhalation QID starting at 3 breaths per inhalation \& gradually increasing to 9 breaths.Each breath provides approximately 6 mcg of treprostinil.Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated.

Primary Outcome Measures

Name	Time	Method
Change in Right Ventricular Ejection Fraction	Basline and 24 weeks	Effect of dual-upfront therapies versus mono-therapy on percent change of right ventricular function assesed by cardiac MRI (cMRI) at 24 weeks compared with the baseline.

Secondary Outcome Measures

Name	Time	Method
Change in NYHA/WHO Class	Baseline and 48 week	At 48 week,WHO/NYHA functional class was assessed for change in WHO/NYHA functional class.Change NYHA is measured as decrease or increase in NYHA class in the subjects compared with baseline.; NYHA /WHO functional class is described below: NYHA functional class I:no symptoms and no limitation in ordinary physical activity NYHA functional class II:Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity NYHA functional class III:Marked limitation in activity due to symptoms, even during less-than-ordinary activity NYHA functional class IV:Severe limitations. Experiences symptoms even while at rest A higher functional class represent worse symptoms.
B-type Natriuretic Peptide (BNP)	Baseline and 24 weeks	B-type Natriuretic peptide measures the percent change from baseline.
6 Minute Walk Distance	Baseline and 24 weeks	Change in 6MWD during 24 week period compared between Tada and Tada+iTre.
N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)	Baseline and 24 weeks	Change from baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)

Trial Locations

Locations (2)

Stanford University School of Medicine; 🇺🇸 Stanford, California, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States