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

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ClinicalTrials.gov Identifier: NCT01305252
Recruitment Status : Completed
First Posted : February 28, 2011
Results First Posted : June 2, 2017
Last Update Posted : June 2, 2017
Sponsor:
Collaborator:
Northwestern University
Information provided by (Responsible Party):
Roham T. Zamanian, Stanford University

Tracking Information
First Submitted Date  ICMJE November 2, 2010
First Posted Date  ICMJE February 28, 2011
Results First Submitted Date  ICMJE November 21, 2016
Results First Posted Date  ICMJE June 2, 2017
Last Update Posted Date June 2, 2017
Study Start Date  ICMJE July 2010
Actual Primary Completion Date September 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 27, 2017)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 24, 2011)
  • 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. [ Time Frame: 24 weeks ]
  • Changed in RVEDV by cardiac MRI [ Time Frame: 24 Weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2017)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2011)
  • NT-pro BNP [ Time Frame: 24 weeks ]
  • Time to clinical worsening [ Time Frame: 48 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A 48-week Study of the Effect of Dual Therapy (Inhaled Treprostinil and Tadafafil) Versus Monotherapy (Tadalafil).
Official Title  ICMJE 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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Hypertension, Pulmonary
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Active Comparator: tadalafil alone
    tadalafil 40mg QD(Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated).
    Intervention: Drug: tadalafil
  • 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.
    Interventions:
    • Drug: treprostinil inhalations
    • Drug: tadalafil
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 27, 2017)
21
Original Estimated Enrollment  ICMJE
 (submitted: February 24, 2011)
30
Actual Study Completion Date  ICMJE September 2014
Actual Primary Completion Date September 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 69 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01305252
Other Study ID Numbers  ICMJE SU-07152010-6565
IRB protocol # 18305
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Roham T. Zamanian, Stanford University
Original Responsible Party Roham T. Zamanian, Stanford University School of Medicine
Current Study Sponsor  ICMJE Stanford University
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Northwestern University
Investigators  ICMJE
Principal Investigator: Roham T. Zamanian Stanford University
PRS Account Stanford University
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP