Inhaled Selective Pulmonary Vasodilators for Advanced Heart Failure Therapies and Lung Transplantation Outcomes (INSPIRE-FLO)

1. to conduct a clinical investigation to determine if inhaled epoprostenol (Veletri®, iEPO) and inhaled nitric oxide (iNO) will have similar impact on outcomes in adult patients undergoing durable LVAD placement, heart transplantation, or lung transplantation 2. to conduct a cost-capture analysis on the expense each drug incurs per patient.

Study Overview

• Status: Completed
• Conditions: Heart Transplant Surgery; Lung Transplant Surgery
• Intervention / Treatment: Drug: iNO; Drug: iEPO

Detailed Description

In adult cardiothoracic surgical patients, iNO is used to treat precapillary pulmonary hypertension (PH), right-sided heart failure (RHF), and ventilation-to-perfusion (V:Q) mismatch. Adult patients who undergo durable LVAD implantation (e.g. Heartware®, Heartmate 2®, or Heartmate 3®), cardiac transplantation for HFrEF, or those that have endured lung transplantation as a result of end-stage lung disease, compose the largest subpopulation which receives iPVD therapy at Duke University Hospital. iEPO may display an equivalent efficacy profile to iNO for pulmonary vasodilation and oxygenation and have a similar impact on clinical outcomes.

Subjects undergoing LVAD placement or heart transplantation (N=224) or lung transplantation (N=200) will be prospectively enrolled over a three-year period (one-year for follow-up). Patients will be randomly assigned 1:1 according to stratified randomization blocking either iNO or iEPO. Additional study procedures will involve data collection, blood, and tissue sampling.

• Study Type: Interventional
• Enrollment (Actual): 519
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Heart transplantation
• LVAD placement
• Lung Transplantation

Exclusion Criteria:

• Combined Organ Transplantation
• Age < 18 years old
• Pregnancy
• Known allergy to prostaglandin (rare)
• Refusal of blood products due to personal or religious preference
• Subject is enrolled in another study protocol, which does not allow randomization of PVD therapy

• Heart transplant or durable LVAD recipients with adult congenital heart disease (CHD)

  o Caveat: Does NOT meet exclusion criteria if the scheduled heart transplant or LVAD implantation is due to heart failure from a previous heart transplantation related to CHD, performed more than 90 days previous to the date of trial enrollment

• Heart transplant recipients diagnosed with Arrythmogenic Right Ventricular Cardiomyopathy
• Heart transplant recipients diagnosed with Acute Cardiac Allograft Rejection after a previous heart transplantation.
• Heart transplant or durable LVAD recipients with preoperative RVAD for right heart failure
• Patient is scheduled to undergo lung transplantation but has undergone heart transplantation in the previous 90 days
• Patient is scheduled to undergo durable LVAD implantation but has undergone heart transplantation in the previous 90 days
• Patient is scheduled to undergo heart transplantation but has undergone lung transplantation in the previous 90 days
• Patients with preoperative Venovenous ECMO as a bridge to lung transplantation
• Heart transplant or durable LVAD recipients with preoperative RVAD for right heart failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lung transplant with iNO	Drug: iNO; Subject will receive inhaled Nitric Oxide in this intervention; Other Names: Inhaled Nitric Oxide
Active Comparator: Lung transplant with iEPO	Drug: iEPO; Subject will receive inhaled Epoprostrenol in this intervention; Other Names: Inhaled Epoprostrenol
Active Comparator: Heart transplant & LVAD implantation with iNO	Drug: iNO; Subject will receive inhaled Nitric Oxide in this intervention; Other Names: Inhaled Nitric Oxide
Active Comparator: Heart transplant & LVAD implantation with iEPO	Drug: iEPO; Subject will receive inhaled Epoprostrenol in this intervention; Other Names: Inhaled Epoprostrenol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Grade 3 Primary Graft Dysfunction (PGD) for Lung Transplant Subjects	This is defined by the International Society of Heart and Lung Transplantation (ISHLT) as severe hypoxemia with a PaO2-to-FiO2 ratio < 200 or the presence of venovenous extracorporeal membrane oxygenation (VV ECMO) at a time-point within the first 72 hours after lung transplantation.	Up to 72 hours
Number of Participants With Moderate or Severe RV Failure for the LVAD Implantation Subjects and Severe RV Failure for Heart Transplantation Subjects	This is defined by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) score of moderate or severe right-heart failure for LVADS, and by the incidence of an RVAD placement or ECMO for RHF for heart transplants.	up to approximately 21 days after LVAD placement, up to approximately 30 days after heart transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Postoperative Mechanical Ventilation	Length of time from intubation until patient is extubated	up to approximately 90 days after index surgery
Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost	Data reflects a per patient cost in dollars that has been scaled to a unit of measure relative to the cost per hour of drug and multiplied by the duration of iPVD administration. In our study, iNO cost 7 times that of iEPO per hour, hence for each patient this outcome value is the duration of iPVD administration multiplied by 7 if a patient is randomized to iNO or multiplied by 1 if randomized to iEPO.	up to approximately 30 days after index surgery
Length of ICU Stay	Length of time from ICU admission from surgery until ICU discharge	up to approximately 90 days after index surgery
Length of Hospital Stay	Length of time from surgery to hospital discharge	up to approximately 1 year after index surgery
Number of Participants With Acute Kidney Injury	defined by Modified KDIGO-AKI definition: Increase in Serum Creatinine (Cr) by ≥0.3mg/dL within 48 hours; or; Increase in Cr to ≥1.5 times baseline; Urine output is not included as urine could be under-captured after Foley catheter removal	up to approximately 14 days
Number of Participants With In-hospital Mortality	Death that occurs during the hospital stay	up to approximately 1 year after index surgery
Number of Participants With Post-operative Mortality Within 30 Days	From the day of surgery to 30 days postoperatively.	up to approximately 30 days after index surgery
Number of Participants With Post-operative Mortality Within 90 Days	From the day of surgery to 90 days after index surgery	up to approximately 90 days after index surgery

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Principal Investigator: Kamrouz Ghadimi, MD, Duke Health

Publications and helpful links

General Publications

• Ghadimi K, Cappiello J, Cooter-Wright M, Haney JC, Reynolds JM, Bottiger BA, Klapper JA, Levy JH, Hartwig MG; INSPIRE-FLO Investigators. Inhaled Pulmonary Vasodilator Therapy in Adult Lung Transplant: A Randomized Clinical Trial. JAMA Surg. 2022 Jan 1;157(1):e215856. doi: 10.1001/jamasurg.2021.5856. Epub 2022 Jan 12.

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2017
• Primary Completion (Actual): October 5, 2020
• Study Completion (Actual): September 5, 2021

Study Registration Dates

• First Submitted: March 8, 2017
• First Submitted That Met QC Criteria: March 14, 2017
• First Posted (Actual): March 15, 2017

Study Record Updates

• Last Update Posted (Estimate): February 16, 2023
• Last Update Submitted That Met QC Criteria: February 14, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Heart and Lung transplantation surgery; Pulmonary vasodilation therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: Pro00078035

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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