Clinical trial NCT04062565: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: University of Arizona
Sponsor class: OTHER
First posted: 2019-08-20
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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).

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).

Primary outcomes:
measure: Change in stroke volume/end systolic volume (SV/ESV)
timeFrame: Baseline to 3 months
Secondary outcomes:
measure: Change in pulmonary and cardiac pressures
timeFrame: Baseline to 3 months
measure: Change in pulmonary blood flow
timeFrame: Baseline to 3 months
measure: Change in end-systolic elastance/arterial elastance (Ees/Ea)
timeFrame: Baseline to 3 months
measure: Change in Right Ventricle (RV) diastolic stiffness (Beta)
timeFrame: Baseline to 3 months
measure: Change in 6 minute walk distance
timeFrame: Baseline to 3 months
measure: Change in brain natriuretic peptide (BNP)
timeFrame: Baseline to 3 months
measure: Change in magnetic resonance imaging (MRI) right ventricle volumes
timeFrame: Baseline to 3 months
measure: Change in Cardio pulmonary Exercise Testing (CPET)
timeFrame: 3 months
measure: Change in derived VO2 max
timeFrame: 3 months
measure: Change in derived Ve/VCO2
timeFrame: 3 months
measure: Change in adverse event profile
timeFrame: Baseline to 3 months
measure: Change in composite time to clinical worsening
timeFrame: Baseline to 3 months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
Study officials:
affiliation: University of Arizona
name: Franz Rischard, DO
role: PRINCIPAL_INVESTIGATOR
References: