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

Pär Johansson

Status and phase: Enrolling; Phase 2

Conditions: Endothelial Dysfunction; Pulmonary Infection; Acute Respiratory Failure

Treatments: Drug: Isotonic saline; Drug: Iloprost

Study type: Interventional

Funder types: Other

Identifiers

NCT06319274

COMBAT-ARF

Details and patient eligibility

About

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.

Full 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.

Enrollment: 450 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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450 participants in 2 patient groups, including a placebo group

Iloprost

Experimental group

Description:

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.

Treatment:

Drug: Iloprost

Isotonic saline

Placebo Comparator group

Description:

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.

Treatment:

Drug: Isotonic saline