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

Official title

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)

Overview

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

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).

Interventions

• Drug Treprostinil Injectable Product
  Injection
• Drug Riociguat Pill
  Tablet

Primary outcome measures

• Change in stroke volume/end systolic volume (SV/ESV) [Time frame: Baseline to 3 months]

Secondary outcome measures (12)

• Change in pulmonary and cardiac pressures [Time frame: Baseline to 3 months]
• Change in pulmonary blood flow [Time frame: Baseline to 3 months]
• Change in end-systolic elastance/arterial elastance (Ees/Ea) [Time frame: Baseline to 3 months]
• Change in Right Ventricle (RV) diastolic stiffness (Beta) [Time frame: Baseline to 3 months]
• Change in 6 minute walk distance [Time frame: Baseline to 3 months]
• Change in brain natriuretic peptide (BNP) [Time frame: Baseline to 3 months]
• Change in magnetic resonance imaging (MRI) right ventricle volumes [Time frame: Baseline to 3 months]
• Change in Cardio pulmonary Exercise Testing (CPET) [Time frame: 3 months]
• Change in derived VO2 max [Time frame: 3 months]
• Change in derived Ve/VCO2 [Time frame: 3 months]
• Change in adverse event profile [Time frame: Baseline to 3 months]
• Change in composite time to clinical worsening [Time frame: Baseline to 3 months]

Eligibility criteria

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Arizona — Tucson

Identifiers

NCT: NCT04062565 · 1812168816

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗