Trial to Evaluate Parenteral Treprostinil and Riociguat on Right Ventriculo-vascular Coupling and Morphology in Those With Advanced PAH

Study Overview
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Brief Summary
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The purpose of this study is to determine if there is a greater effect to patients with advanced pulmonary arterial hypertension (PAH) by using a combination of two drugs, Treprostinil and Riociquat versus Treprostinil alone

Detailed Description
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The purpose of this study is to evaluate the combined effect of parenteral treprostinil (TRE) and riociguat (RIO) versus parenteral TRE alone on right ventricular (RV)-pulmonary artery (PA) interaction (RVPA coupling) and global RV function in patients with advanced pulmonary arterial hypertension (PAH).

Official Title
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A Prospective Trial to Evaluate Up-front Parenteral Treprostinil and Riociguat on Right Ventriculo-vascular Coupling and Morphology in Patients With Advanced Pulmonary Arterial Hypertension (IIR-3810)

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Treprostinil Injectable Product
* Drug: Riociguat Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: WHO Category I PAH Resting mPAP ≥ 25 mmHg with a wedge pressure of ≤ 15mmHg during right heart catheterization. Need for parenteral TRE as determined by the PH specialist caring for the patient Exclusion Criteria: Patients with a mean arterial pressure <60, and/or requiring vasopressor support Patients whom expected device (i.e. ECMO, RVAD) assistance or early pulmonary transplantation (within 3 months) seems inevitable Patients with a left ventricular ejection fraction <50% or clinical, echocardiographic, and/or catheterization data consistent with heart failure with preserved ejection fraction (HFpEF) and/or moderate-severe aortic or mitral valve abnormality Patients with severe restrictive lung disease (FVC<70% predicted) and/or obstructive lung disease (FEV1 <70% predicted and FEV1/FVC <70%). Patients with a history of pulmonary embolism within the last three months or evidence of chronic pulmonary embolism. Patients with a known contraindication to right heart catheterization. Patients whom have received active or previous pulmonary vasoactive medication within the previous 12 weeks. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis. Pulmonary Hypertension belonging to groups 2 to 5 of the WHO classification. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C. Estimated creatinine clearance < 30 mL/min Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal. Hemoglobin < 75% of the lower limit of the normal range. Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements. Pregnant or breast-feeding. Females must either abstain from intercourse (when it is in line with their preferred and usual lifestyle), or Use 2 medically acceptable, highly effective forms of contraception for the duration of study, and at least 30 after discontinuing study drug. Known concomitant life-threatening disease with a life expectancy < 12 months. Body weight < 40 kg and/or >150 kg. Any condition that prevents compliance with the protocol or adherence to therapy. Concurrent therapy with strong CYP3A4 inhibitors/inducers (i.e. protease inhibitors, azole antibiotics, macrolides), theophylline, and any medication in the PI's opinion may substantially potentiate the hypotensive effect of RIO. Treatment with nitrates of any kind within the 4 weeks prior to enrollment. Known hypersensitivity to drugs of the same class as TRE and/or RIO, or any of their excipients. Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization. Recent (<6 months) hemoptysis and/or history of severe hemoptysis requiring intervention (bronchial artery embolization).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: All participants will receive Treprostinil 2-3 times per day as tolerated. Subsequently, participants will receive Riociguat at 0.5 mg taken orally three times a day. Participants will receive the first dose inpatient prior to discharge. Participants will continue on a 2 ng/kg/min increase every other day for one week. Riociguat will subsequently be increased by 0.5 mg taken orally three times a day the following week as tolerated. Increases in Treprostinil and Riociguat will then alternate weeks such that only one medication is changed per week.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Treprostinil and Riociguat | Drug: Treprostinil Injectable Product<br>* Injection<br>* Other names: Remodulin;Drug: Riociguat Pill<br>* Tablet<br>* Other names: Adempas;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in stroke volume/end systolic volume (SV/ESV) | Change in stroke volume/end systolic volume (SV/ESV) | Baseline to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pulmonary and cardiac pressures | Increase or decrease in pressures | Baseline to 3 months | 
| Change in pulmonary blood flow | Increase or decrease in pulmonary blood flow | Baseline to 3 months | 
| Change in end-systolic elastance/arterial elastance (Ees/Ea) | Change in the interaction of the right heart and lung blood vessels | Baseline to 3 months | 
| Change in Right Ventricle (RV) diastolic stiffness (Beta) | Change in how stiff the wall of the right heart is at the end of relaxation | Baseline to 3 months | 
| Change in 6 minute walk distance | Change in how far a participant can walk during a self paced 6 minute walk test | Baseline to 3 months | 
| Change in brain natriuretic peptide (BNP) | Change in biomarker BNP that examines stretch on the right heart | Baseline to 3 months | 
| Change in magnetic resonance imaging (MRI) right ventricle volumes | Change in the volume ejected per beat and the end systolic and diastolic values of the right heart | Baseline to 3 months | 
| Change in Cardio pulmonary Exercise Testing (CPET) | Change in how much oxygen the body consumes at peak exercise | 3 months | 
| Change in derived VO2 max | Change in how much oxygen the body consumes at peak exercise | 3 months | 
| Change in derived Ve/VCO2 | Change in how much oxygen the body consumes at peak exercise | 3 months | 
| Change in adverse event profile | Change in side effects or other adverse events between combination therapy and historical control | Baseline to 3 months | 
| Change in composite time to clinical worsening | Difference relative to historical control in the time from diagnosis to followup, hospitalization, death or transplant | Baseline to 3 months |