A 48-week Study of the Effect of Dual Therapy (Inhaled Treprostinil and Tadafafil) Versus Monotherapy (Tadalafil), 2 FDA Approved Pulmonary Hypertension Medications

Hypertension, Pulmonary Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01305252
• Other study ID #: SU-07152010-6565
• Secondary ID: IRB protocol # 1
• Status: Active, not recruiting
• Phase: Phase 4
• First received: November 2, 2010
• Last updated: May 21, 2014
• Start date: July 2010
• Est. completion date: September 2014

Study information

• Verified date: May 2014
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 30
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 69 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary

Intervention

Drug:
• inhaled treprostinil
Treprostinil inhalation QID starting at 3 breaths per inhalation & gradually increasing to 9 breaths. Each breath provides approximately 6mcg of treprostinil.
• tadalafil
tadalafil 20mg QD PO increasing to 40mg QD as tolerated

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois
United States	Stanford University School of Medicine	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
Stanford University	Northwestern University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effect of dual-upfront therapies versus mono-therapy on parameters of right ventricular function as gauged by cMRI. Primary endpoint will be aimed at evaluating the mean change in RV end diastolic volume (RVEDV) at 24 weeks.		24 weeks	Yes
Primary	Changed in RVEDV by cardiac MRI		24 Weeks	No
Secondary	NT-pro BNP		24 weeks	No
Secondary	Time to clinical worsening		48 weeks	No