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

Primary Purpose

Hypertension, Pulmonary

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

treprostinil inhalations

tadalafil

About this trial

This is an interventional treatment trial for Hypertension, Pulmonary

Eligibility Criteria

18 Years - 69 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Age 18 and < 75 years at baseline visit.
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).
PAH treatment naïve including any prostacycline, endothelin receptor antagonist, or phosphodiesterase inhibitors within 12 months prior to enrollment.
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:

Group II - V pulmonary hypertension.
PAH with unrepaired congenital heart defect.
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).
TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease.
FEV1 / FVC < 70% predicted and FEV1 < 60% predicted
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
Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min (by MDRD equation)
Current atrial arrhythmias
Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm
Severe hypotension: SBP < 80 mmHg.
Pregnant or breast-feeding
Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions
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.
Contraindications for magnetic resonance imaging, including significant claustrophobia, implanted metallic objects, or others as per Appendix X).
Known allergy to treprostinil or tadalafil.
Active oral nitrate use.
Diabetes mellitus.
Planned initiation of cardiac or pulmonary rehabilitation during period of study.

Sites / Locations

Stanford University School of Medicine
Northwestern University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

tadalafil alone

tadalafil and treprostinil inhalations

Arm Description

tadalafil 40mg QD(Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated).

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.

Outcomes

Primary Outcome Measures

Change in Right Ventricular Ejection Fraction

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

Change in 6MWD during 24 week period compared between Tada and Tada+iTre.

N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)

Change from baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)

Change in NYHA/WHO Class

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)

B-type Natriuretic peptide measures the percent change from baseline.

Full Information

NCT ID

NCT01305252

First Posted

November 2, 2010

Last Updated

April 27, 2017

Sponsor

Stanford University

Collaborators

Northwestern University

1. Study Identification

Unique Protocol Identification Number

NCT01305252

Brief Title

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

2. Study Status

Record Verification Date

April 2017

Overall Recruitment Status

Completed

Study Start Date

July 2010 (undefined)

Primary Completion Date

September 2014 (Actual)

Study Completion Date

September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Stanford University

Collaborators

Northwestern University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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: 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. 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertension, Pulmonary

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

tadalafil alone

Arm Type

Active Comparator

Arm Description

tadalafil 40mg QD(Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated).

Arm Title

tadalafil and treprostinil inhalations

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

treprostinil inhalations

Other Intervention Name(s)

Tyvaso

Intervention Description

Treprostinil inhalation QID starting at 3 breaths per inhalation & gradually increasing to 9 breaths. Each breath provides approximately 6mcg of treprostinil.

Intervention Type

Drug

Intervention Name(s)

tadalafil

Other Intervention Name(s)

Adcirca

Intervention Description

tadalafil 20mg QD PO increasing to 40mg QD as tolerated

Primary Outcome Measure Information:

Title

Change in Right Ventricular Ejection Fraction

Description

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.

Time Frame

Basline and 24 weeks

Secondary Outcome Measure Information:

Title

6 Minute Walk Distance

Description

Change in 6MWD during 24 week period compared between Tada and Tada+iTre.

Time Frame

Baseline and 24 weeks

Title

N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)

Description

Change from baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)

Time Frame

Baseline and 24 weeks

Title

Change in NYHA/WHO Class

Description

Time Frame

Baseline and 48 week

Title

B-type Natriuretic Peptide (BNP)

Description

B-type Natriuretic peptide measures the percent change from baseline.

Time Frame

Baseline and 24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

69 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Age 18 and < 75 years at baseline visit. 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). PAH treatment naïve including any prostacycline, endothelin receptor antagonist, or phosphodiesterase inhibitors within 12 months prior to enrollment. Previous Right Heart Catheterization that documented: Mean PAP; 25 mmHg. Pulmonary capillary wedge pressure < 15 mmHg. 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: Group II - V pulmonary hypertension. PAH with unrepaired congenital heart defect. 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). TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease. FEV1 / FVC < 70% predicted and FEV1 < 60% predicted Significant left-sided heart disease (based on pre-trial Echocardiogram): Significant aortic or mitral valve disease Diastolic dysfunction ; Grade II C.LV systolic function < 45% d. Pericardial constriction e. Restrictive cardiomyopathy f. Significant coronary disease with demonstrable ischemia Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min (by MDRD equation) Current atrial arrhythmias Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm Severe hypotension: SBP < 80 mmHg. Pregnant or breast-feeding Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions 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. Contraindications for magnetic resonance imaging, including significant claustrophobia, implanted metallic objects, or others as per Appendix X). Known allergy to treprostinil or tadalafil. Active oral nitrate use. Diabetes mellitus. Planned initiation of cardiac or pulmonary rehabilitation during period of study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Roham T. Zamanian

Organizational Affiliation

Stanford University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Stanford University School of Medicine

City

Stanford

State/Province

California

ZIP/Postal Code

94305

Country

United States

Facility Name

Northwestern University

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60208

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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