Clinical trial NCT06319274: Infusion of Prostacyclin Vs Placebo for 72-hours in Mechanically Ventilated Patients with Acute Respiratory Failure
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Respiratory Failure
Endothelial Dysfunction
Pulmonary Infection
Keywords: Endotheliopathy
SHINE
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2024-03-20
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomization active/placebo (1:1) parallel arms
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 28-day mortality
timeFrame: Day 28
Secondary outcomes:
measure: 90-day mortality
timeFrame: Day 90
measure: Vasopressor-free days
timeFrame: Until ICU discharge, maximun 90 days after randomization]
measure: Renal replacement-free days
timeFrame: Until ICU discharge, maximun 90 days after randomization]
measure: Mechanical ventilation free days
timeFrame: Until ICU discharge, maximun 90 days after randomization]
measure: Serious adverse reactions (SARs)
timeFrame: Until day 7 after randomization
measure: Serious adverse events (SAEs)
timeFrame: Until day 7 after randomization
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital
city: Herlev
country: Denmark
facility: Dept. of Intensive Care, Copenhagen University Hospital Herlev
city: Hillerød
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Nordsjaelands Hospital
city: Køge
country: Denmark
facility: Department of Anesthesia and Intensive Care Medicine, Zealand University Hospital
Study officials:
affiliation: Rigshospitalet, Denmark
name: Pär I Johansson, MD, DMSc
role: STUDY_DIRECTOR
affiliation: +4538682458
name: Peter Soee-Jensen, MD
role: PRINCIPAL_INVESTIGATOR
References: