Hypertension, Pulmonary
Conditions
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.
Interventions
DRUGtreprostinil inhalations
Treprostinil inhalation QID starting at 3 breaths per inhalation & gradually increasing to 9 breaths. Each breath provides approximately 6mcg of treprostinil.
DRUGtadalafil
tadalafil 20mg QD PO increasing to 40mg QD as tolerated
Sponsors
Northwestern University
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tadalafil Alone tadalafil 40mg QD
tadalafil: tadalafil 20mg QD PO increasing to 40mg QD as tolerated | 10 |
| Tadalafil and Treprostinil Inhalations 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 | 11 |
| Total | 21 |
Baseline characteristics
| Characteristic | Tadalafil Alone | Tadalafil and Treprostinil Inhalations | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 11 Participants | 21 Participants |
| Age, Continuous | 51.6 years STANDARD_DEVIATION 11.4 | 52.1 years STANDARD_DEVIATION 9.7 | 51.9 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 10 | 8 / 11 |
| serious Total, serious adverse events | 1 / 10 | 0 / 11 |
Outcome results
Primary
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.
Time frame: Basline and 24 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tadalafil and Treprostinil Inhalations | Change in Right Ventricular Ejection Fraction | 7.45 percent change |
| Tadalafil Alone | Change in Right Ventricular Ejection Fraction | 2.8 percent change |
p-value: 0.03t-test, 2 sided
p-value: 0.17t-test, 2 sided
Secondary
6 Minute Walk Distance
Change in 6MWD during 24 week period compared between Tada and Tada+iTre.
Time frame: Baseline and 24 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tadalafil and Treprostinil Inhalations | 6 Minute Walk Distance | 82.63 meters |
| Tadalafil Alone | 6 Minute Walk Distance | 87.69 meters |
Secondary
B-type Natriuretic Peptide (BNP)
B-type Natriuretic peptide measures the percent change from baseline.
Time frame: Baseline and 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil and Treprostinil Inhalations | B-type Natriuretic Peptide (BNP) | 374 percent change | Standard Deviation 133.8 |
| Tadalafil Alone | B-type Natriuretic Peptide (BNP) | 295.6 percent change | Standard Deviation 133.2 |
Secondary
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.
Time frame: Baseline and 48 week
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tadalafil and Treprostinil Inhalations | Change in NYHA/WHO Class | 6 participants |
| Tadalafil Alone | Change in NYHA/WHO Class | 11 participants |
p-value: 0.03t-test, 2 sided
p-value: 0.33t-test, 2 sided
Secondary
N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
Change from baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
Time frame: Baseline and 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil and Treprostinil Inhalations | N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | 1239 pg/mL | Standard Deviation 1393 |
| Tadalafil Alone | N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | 988.4 pg/mL | Standard Deviation 827.6 |