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

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ClinicalTrials.gov Identifier: NCT04062565
Recruitment Status : Recruiting
First Posted : August 20, 2019
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Franz Rischard, DO, University of Arizona

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

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Treprostinil Injectable Product Drug: Riociguat Pill Phase 3

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : March 25, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: Experimental
Treprostinil and Riociguat
Drug: Treprostinil Injectable Product
Injection
Other Name: Remodulin

Drug: Riociguat Pill
Tablet
Other Name: Adempas




Primary Outcome Measures :
  1. Change in stroke volume/end systolic volume (SV/ESV) [ Time Frame: Baseline to 3 months ]
    Change in stroke volume/end systolic volume (SV/ESV)


Secondary Outcome Measures :
  1. Change in pulmonary and cardiac pressures [ Time Frame: Baseline to 3 months ]
    Increase or decrease in pressures

  2. Change in pulmonary blood flow [ Time Frame: Baseline to 3 months ]
    Increase or decrease in pulmonary blood flow

  3. Change in end-systolic elastance/arterial elastance (Ees/Ea) [ Time Frame: Baseline to 3 months ]
    Change in the interaction of the right heart and lung blood vessels

  4. Change in Right Ventricle (RV) diastolic stiffness (Beta) [ Time Frame: Baseline to 3 months ]
    Change in how stiff the wall of the right heart is at the end of relaxation

  5. Change in 6 minute walk distance [ Time Frame: Baseline to 3 months ]
    Change in how far a participant can walk during a self paced 6 minute walk test

  6. Change in brain natriuretic peptide (BNP) [ Time Frame: Baseline to 3 months ]
    Change in biomarker BNP that examines stretch on the right heart

  7. Change in magnetic resonance imaging (MRI) right ventricle volumes [ Time Frame: Baseline to 3 months ]
    Change in the volume ejected per beat and the end systolic and diastolic values of the right heart

  8. Change in Cardio pulmonary Exercise Testing (CPET) [ Time Frame: 3 months ]
    Change in how much oxygen the body consumes at peak exercise

  9. Change in derived VO2 max [ Time Frame: 3 months ]
    Change in how much oxygen the body consumes at peak exercise

  10. Change in derived Ve/VCO2 [ Time Frame: 3 months ]
    Change in how much oxygen the body consumes at peak exercise

  11. Change in adverse event profile [ Time Frame: Baseline to 3 months ]
    Change in side effects or other adverse events between combination therapy and historical control

  12. Change in composite time to clinical worsening [ Time Frame: Baseline to 3 months ]
    Difference relative to historical control in the time from diagnosis to followup, hospitalization, death or transplant



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04062565


Contacts
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Contact: Valerie Boss, MS 520-626-8305 vbloss@email.arizona.edu

Locations
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United States, Arizona
University of Arizona Recruiting
Tucson, Arizona, United States, 85724
Contact: Valerie Bloss, MS    520-626-8305    vbloss@email.arizona.edu   
Principal Investigator: Franz Rischard, DO         
Sponsors and Collaborators
University of Arizona
Investigators
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Principal Investigator: Franz Rischard, DO University of Arizona

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Responsible Party: Franz Rischard, DO, Director, University of Arizona Pulmonary Hypertension Program, University of Arizona
ClinicalTrials.gov Identifier: NCT04062565     History of Changes
Other Study ID Numbers: 1812168816
First Posted: August 20, 2019    Key Record Dates
Last Update Posted: August 20, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Familial Primary Pulmonary Hypertension
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Treprostinil
Riociguat
Antihypertensive Agents
Enzyme Activators
Molecular Mechanisms of Pharmacological Action