Infusion of Prostacyclin vs Placebo for 72-hours in Mechanically Ventilated Patients With Acute Respiratory Failure (COMBAT-ARF)

Efficacy and Safety of 72-hour Infusion of Prostacyclin (1 ng/kg/Min) in Mechanically Ventilated Patients With Infectious Pulmonary Endotheliopathy - a Multicenter Randomized, Placebo-controlled, Blinded, Investigator-initiated Trial

The purpose of this clinical trial is to investigate the efficacy and safety of continuous intravenous administration of low dose iloprost versus placebo for 72-hours, in 450 mechanically ventilated patients with infectious respiratory failure. The study hypothesis is that iloprost may be beneficial as an endothelial rescue treatment as it is anticipated to deactivate the endothelium and restore vascular integrity in patients suffering from respiratory failure caused by endothelial breakdown, ultimately improving survival.

Study Overview

• Status: Not yet recruiting
• Conditions: Endothelial Dysfunction; Acute Respiratory Failure; Pulmonary Infection
• Intervention / Treatment: Drug: Iloprost; Drug: Isotonic saline

Detailed Description

Acute respiratory failure (ARF) is common in critically ill patients and 50% of all intensive care unit patients require mechanical ventilation. ARF occurs in a heterogenous patient group, most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and major surgery. Despite improvements in intensive care capabilities, ARF mortality remains high and the only treatment option, to date, is supportive care. A recent Cochrane analysis (2018) found no evidence for that any drug was effective in reducing deaths in mechanically ventilated patients with ARF, highlighting the high unmet medical need.

Given that the pulmonary system, apart from the brain, is the most highly vascularized vital organ in the body, extensive endothelial damage is a central feature of acute respiratory distress syndrome (ARDS) with respiratory failure being the rationale for the current study. Evidence support that iloprost infusion significantly improved endothelial function and integrity in mechanically ventilated patients with COVID-19 infection with reducing 28-day mortality by 50%.

The main objective in this clinical trial is to investigate whether continuous infusion of low dose iloprost at a dose of 1 ng/kg/min for 72-hours is safe and significantly reduce all-cause mortality at day 28.

Patients that are eligible for this trial will be temporarily incompetent due to acute severe illness relating to respiratory failure.

During the trial, patient will be given continuous infusion of low dose iloprost or placebo for 72 hours during their stay at the intensive care unit (ICU) and additional blood samples will be obtained at baseline, 24-, 48 and 72-hours.

This trial is conducted in accordance with the Helsinki 2 Declaration and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline for Good Clinical Practice (ICH-GCP) and in compliance with the protocol. As part of the quality assurance on-site monitoring visit will be performed by the an independent GCP-unit including source data verification. Standard Operation Procedure (SOP) will address protocol specific procedures.

• Study Type: Interventional
• Enrollment (Estimated): 450
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pär I Johansson, MD, DMSc; Phone Number: +4535452030; Email: per.johansson@regionh.dk
• Study Contact Backup: Name: Kristine H Pedersen, MSc. Pharm.; Phone Number: +4535453489; Email: kristine.holst.pedersen.01@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital
    • Contact: Niels E Clausen, MD
    • Principal Investigator: Niels E Clausen, MD
  • Herlev, Denmark, 2730
    • Dept. of Intensive Care, Copenhagen University Hospital Herlev
    • Contact: Peter Soee-Jensen, MD
    • Principal Investigator: Peter Soee-Jensen, MD
  • Hillerød, Denmark, 3400
    • Dept. of Anaesthesia and Intensive Care, Nordsjaelands Hospital
    • Principal Investigator: Morten Bestle, MD
    • Contact: Morten Bestle, MD
  • Køge, Denmark, 4600
    • Department of Anesthesia and Intensive Care Medicine, Zealand University Hospital
    • Contact: Lars Peter K Andersen, MD, PhD
    • Principal Investigator: Lars Peter K Andersen, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult intensive care patients (age ≥ 18 years)
• Suspected pulmonary infection
• Need for mechanical ventilation (< 24 hours from time of screening)
• soluble thrombomodulin (sTM) ≥ 4 ng/mL in blood plasma

Exclusion Criteria:

• Withdrawal from active therapy
• Pregnancy (non-pregnancy confirmed by patient having a negative urine- or plasma Choriogonadotropin (hCG) or being postmenopausal defined as females at 60 years old or beyond or at the investigators discretion)
• Septic shock according to the Sepsis 3 criteria AND a sTM> 10 ng/ml
• Known hypersensitivity to iloprost or to any of the other ingredients.
• Previously included in this trial or a prostacyclin trial within 30 days
• Life-threatening bleeding defined by the treating physician
• Known severe heart failure (NYHA class IV)
• Suspected acute coronary syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Iloprost; Patients randomized to active treatment (n=225 patients) will receive continuous infusion of iloprost for 72 hours after inclusion or until discharge to ward or death, whichever comes first.	Drug: Iloprost; Continuously infusion for 72 hours at 3 ml/hours. Treatment dose 1 ng/kg/min; Other Names: Ilomedin
Placebo Comparator: Isotonic saline; Patients randomized to placebo treatment (n=225 patients) will receive continuous infusion of placebo for 72 hours after inclusion or until discharge to ward or death, whichever comes first.	Drug: Isotonic saline; Continuously infusion for 72 hours at 3 ml/hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day mortality	All-cause mortality at day 28	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-day mortality	All-cause mortality at day 90	Day 90
Vasopressor-free days	Days alive without vasopressor in the ICU within 28- and 90 days	Until ICU discharge, maximun 90 days after randomization]
Renal replacement-free days	Days alive without renal replacement in the ICU within 28- and 90 days	Until ICU discharge, maximun 90 days after randomization]
Mechanical ventilation free days	Days alive without mechanical ventilation in the ICU within 28- and 90 days	Until ICU discharge, maximun 90 days after randomization]
Serious adverse reactions (SARs)	Total number and numbers of patient with one or more serious adverse reactions within the first 7 days	Until day 7 after randomization
Serious adverse events (SAEs)	Total numbers and numbers of patients with one or more serious adverse events within the first 7 days	Until day 7 after randomization

Collaborators and Investigators

• Sponsor: Pär Johansson
• Investigators: Study Director: Pär I Johansson, MD, DMSc, Rigshospitalet, Denmark; Principal Investigator: Peter Soee-Jensen, MD, +4538682458

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: March 13, 2024
• First Submitted That Met QC Criteria: March 13, 2024
• First Posted (Actual): March 20, 2024

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: SHINE; Endotheliopathy
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Respiratory Insufficiency; Respiratory Distress Syndrome; Vasodilator Agents; Platelet Aggregation Inhibitors; Iloprost
• Other Study ID Numbers: COMBAT-ARF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No