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

This study has been completed.
Sponsor:
Collaborator:
Northwestern University
Information provided by (Responsible Party):
Roham T. Zamanian, Stanford University
ClinicalTrials.gov Identifier:
NCT01305252
First received: November 2, 2010
Last updated: April 27, 2017
Last verified: April 2017
  Purpose

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

Condition Intervention Phase
Hypertension, Pulmonary Drug: treprostinil inhalations Drug: tadalafil Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Roham T. Zamanian, Stanford University:

Primary Outcome Measures:
  • Change in Right Ventricular Ejection Fraction [ Time Frame: 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:
  • 6 Minute Walk Distance [ Time Frame: 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) [ Time Frame: Baseline and 24 weeks ]
    Change from baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)

  • Change in NYHA/WHO Class [ Time Frame: 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) [ Time Frame: Baseline and 24 weeks ]
    B-type Natriuretic peptide measures the percent change from baseline.


Enrollment: 21
Study Start Date: July 2010
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: tadalafil alone
tadalafil 40mg QD(Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated).
Drug: tadalafil
tadalafil 20mg QD PO increasing to 40mg QD as tolerated
Other Name: Adcirca
Active Comparator: tadalafil and 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.
Drug: treprostinil inhalations
Treprostinil inhalation QID starting at 3 breaths per inhalation & gradually increasing to 9 breaths. Each breath provides approximately 6mcg of treprostinil.
Other Name: Tyvaso
Drug: tadalafil
tadalafil 20mg QD PO increasing to 40mg QD as tolerated
Other Name: Adcirca

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

Ages Eligible for Study:   18 Years to 69 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01305252

Locations
United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60208
Sponsors and Collaborators
Stanford University
Northwestern University
Investigators
Principal Investigator: Roham T. Zamanian Stanford University
  More Information

Responsible Party: Roham T. Zamanian, Principle Investigator, Stanford University
ClinicalTrials.gov Identifier: NCT01305252     History of Changes
Other Study ID Numbers: SU-07152010-6565
IRB protocol # 18305
Study First Received: November 2, 2010
Results First Received: November 21, 2016
Last Updated: April 27, 2017

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Tadalafil
Treprostinil
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Antihypertensive Agents

ClinicalTrials.gov processed this record on July 24, 2017