Ondansetron for the Prevention of Patient Self-Inflicted Lung Injury in Patients With ARDS - Pilot RCT (OSIRIS-1)

A Pilot, Randomized, Controlled Clinical Trial Evaluating Ondansetron for the Prevention of Patient Self-Inflicted Lung Injury Through Inhibition of Respiratory Drive in Patients With Acute Respiratory Distress Syndrome (OSIRIS-1)

Acute Respiratory Distress Syndrome (ARDS) is a serious condition where the lungs become inflamed, leading to severe breathing difficulties. Despite advances in medical care, ARDS remains a life-threatening illness with a high risk of death and long-term complications. One way doctors help ARDS patients is by using special ventilation techniques to protect the lungs from further damage. However, this often requires heavy sedation or even paralyzing medications, which can lead to other problems like delirium, muscle weakness, and longer hospital stays. Allowing patients to breathe on their own might offer benefits, but it also comes with risks. Many ARDS patients have a very strong urge to breathe, which can cause them to overexert their lungs, potentially leading to additional lung damage, known as patient selfinflicted lung injury (P-SILI). Our early research suggests that a medication called ondansetron, commonly used to prevent nausea, might help reduce this strong breathing drive in ARDS patients, possibly preventing further lung injury. The OSIRIS research program is designed to explore whether ondansetron can protect ARDS patients from P-SILI, ultimately improving their chances of survival and reducing long-term complications. The first part of this program, OSIRIS-1, is a small pilot study where we will test the feasibility of running a larger, more definitive trial. We will randomly assign ARDS patients to receive either ondansetron or a placebo, given intravenously four times a day, and monitor their heart rhythms closely to ensure safety. We will also track how well patients stick to the study plan and whether ondansetron helps reduce their breathing drive and lung strain. If successful, this research could lead to new ways of treating ARDS that rely less on heavy sedation, potentially improving outcomes for these critically ill patients and setting the stage for larger, more comprehensive studies in the future.

Study Overview

• Status: Not yet recruiting
• Conditions: ARDS (Acute Respiratory Distress Syndrome); Invasive Mechanical Ventilation; Patient-Self Inflicted Lung Injury
• Intervention / Treatment: Drug: Ondansetron hydrochloride 8 mg IV Q8H; Drug: 0.9 % Normal Saline 10 ml

Detailed Description

BACKGROUND: Acute Respiratory Distress Syndrome (ARDS) is a life-threatening inflammatory lung condition with high mortality and long-term morbidity. Lung-protective ventilation - targeting low tidal volumes and driving pressures - is one of the few proven interventions but often requires deep sedation and neuromuscular blockade (NMB), which are associated with delirium, ICU-acquired weakness, and prolonged ICU stays. Maintaining spontaneous breathing can offer physiological advantages but is frequently limited by excessive respiratory drive, which increases the risk of patient self-inflicted lung injury (P-SILI). Lung inflammation leading to stimulation and sensitization of pulmonary vagal afferent Cfibers could contribute to excessive respiratory effort. Stimulation of pulmonary C-fibers by serotonin increases respiratory rate in animal models through 5-HT receptors. Our previous data suggest that 3 ondansetron, a 5-HT receptor antagonist, attenuates respiratory drive and effort. We hypothesize that 3 this effect may reduce the need for sedation and paralysis, minimize P-SILI, and ultimately improve outcomes in ARDS.

OBJECTIVES: The overarching goal of the OSIRIS research program is to evaluate whether regular intravenous ondansetron can improve patient-important outcomes (survival, ventilator-free days and long term neurocognitive function) in patients with ARDS. With the OSIRIS-1 pilot study, our objective is to assess:

Feasibility:

[RQ1] What is the adherence to the study protocol? [PRIMARY] [RQ2] What is the completeness of the data collection? [RQ3] What is the recruitment rate?

Preliminary mechanistic efficacy and safety:

[RQ4] Does it decrease respiratory effort? [RQ5] Does it reduce exposure to sedatives, opioids and neuromuscular blockers? [RQ6] Is the intervention safe?

METHODS: OSIRIS-1 is a multicenter, double-blind, parallel-group, phase 2 and feasibility pilot RCT. We will enroll 76 invasively mechanically ventilated adults with moderate-to-severe ARDS (PaO :FiO2 < 200). Participants will be randomized to receive ondansetron 8 mg IV or placebo every 8 hours until liberation from invasive mechanical ventilation. Feasibility will be assessed through protocol adherence (defined as scheduled doses administered within ±2 hours), completeness of key clinical outcomes (ventilator-free days, coma/delirium-free days, 90-day survival), and site-level recruitment metrics. For preliminary efficacy, we will estimate respiratory drive using Pmus (derived from occlusion pressure, ΔPocc), measured three times daily by respiratory therapists. We will also measure P0.1, respiratory rate, and other ventilatory parameters. For safety, we will monitor the occurrence of ventricular arrhythmias, serotonin syndrome, and other serious adverse events.

IMPACT: OSIRIS-1 will provide essential data on mechanistic efficacy, safety, and feasibility to inform the design of a future large-scale trial evaluating patient-important outcomes. By targeting respiratory drive pharmacologically, we may enable safer spontaneous breathing, reduce the harms of oversedation and paralysis, and ultimately improve outcomes in ARDS.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Virginie Williams, PhD; Phone Number: 5833272 514-338-2222; Email: eresi.cnmtl@ssss.gouv.qc.ca

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4J 1C5
      • Hopital Du Sacre-Coeur de Montreal
      • Contact: Virginie Williams, PhD; Phone Number: 5833272 514-338-2222; Email: eresi.cnmtl@ssss.gouv.qc.ca
      • Principal Investigator: Yiorgos Alexandros Cavayas, MD MSc

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Moderate-to-severe ARDS with all of the following:
• Hypoxemic respiratory failure with PaO2:FiO2 < 200 (on IMV with PEEP ≥ 5)
• Precipitated within 1 week of an acute condition
• Bilateral opacities on chest radiography and computed tomography or bilateral B lines and/or consolidations on ultrasound not fully explained by effusions, atelectasis, or nodules/masses
• Pulmonary edema not exclusively or primarily attributable to cardiogenic pulmonary edema/fluid overload
• Hypoxemia/gas exchange abnormalities not primarily attributable to atelectasis
• IMV initiated < 96 hours
• Extubation not anticipated within 24 hours

Exclusion Criteria:

• Neuromuscular disease impairing spontaneous breathing
• Pregnancy
• Liver cirrhosis (Child B or C) or other severe impairment of hepatic function
• Bradycardia (baseline pulse<50/min) on screening day
• Known long QT syndrome
• History of sustained ventricular tachycardia
• Active digestive / abdominal infection44
• QTc prolongation > 470 msec in men and > 480 msec in women on screening day
• On a medication at high risk of QT prolongation (Table 5)50
• On two or more serotonergic medications (Table 6)51
• Hypersensitivity / intolerance to 5-HT3 antagonists
• Patient deemed unlikely to survive past 24 hours or being transitioned to a fully palliative philosophy of care

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: Ondansetron; The first dose of intravenous ondansetron will be administered within 24 hours of randomization, every 8 hours, for duration of invasive mechanical ventilation.	Drug: Ondansetron hydrochloride 8 mg IV Q8H; Participants randomized to the ondansetron arm will receive ondansetron hydrochloride dihydrate 8 mg IV every 8 hours, administered in 10 mL of 0.9% sodium chloride in prepared syringes over 15 minutes.
Placebo Comparator: Placebo; The first dose of intravenous placebo will be administered within 24 hours of randomization, every 8 hours, for duration of invasive mechanical ventilation.	Drug: 0.9 % Normal Saline 10 ml; Participants randomized to the placebo arm will receive 10 mL of 0.9% sodium chloride in prepared syringes administered over 15 minutes every 8 hours, matching the appearance, volume, and administration modalities of ondansetron to maintain blinding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
protocol adherence	Adherence will be measured as the proportion of scheduled doses (±2h window) administered; protocol-defined withholdings (e.g., electrophysiological disturbances) will be documented but not counted as non-adherence.	duration of intervention (duration of invasive mechanical ventilation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Outcome data completeness	Data completeness for 90 day survival, 28 day ventilator-free days, and 14 day coma-and-delirium-free days.	90 days
Enrolment rate	Patients enrolled by site by 12-month period	Duration of the study

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pmus	Pmus will be estimated by the occlusion pressure maneuvre, measured 3 times per day.	duration of the intervention (duration of invasive mechanical ventilation)
P0.1	P0.1 will be measured 3 times per day.	duration of the intervention (duration of invasive mechanical ventilation)
Respiratory Rate	Respiratory Rate will be measured 3 times per day.	duration of the intervention (duration of invasive mechanical ventilation)
Tidal volume	Tidal volume will be measured 3 times per day.	duration of the intervention (duration of invasive mechanical ventilation)
PaO2:FiO2 ratio	PaO2:FiO2 ratio will be measured 3 times per day.	duration of the intervention (duration of invasive mechanical ventilation)
Number of days of deep sedation	A deep sedation will be defined as a day in which a Richmond Agitation and Sedation Scale (RASS) of -4 or -5 was present for the majority of the day	duration of the intervention (duration of invasive mechanical ventilation)
Average daily oral morphine equivalent	All opiates received during a given day will be converted in oral morphine equivalent and summed up.	duration of the intervention (duration of invasive mechanical ventilation)
Days with NMB administration	Defined by having received any dose or neuromuscular blocker during a given day.	duration of the intervention (duration of invasive mechanical ventilation)
Sustained Ventricular Arrhythmia	Defined as ventricular tachycardia or fibrillation sustained for ≥30 seconds or requiring termination due to hemodynamic compromise in <30 seconds.	duration of the intervention (duration of invasive mechanical ventilation)
Serotonin Syndrome	Serotonin syndrome (ie, serotonin toxicity) is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning. Serotonin syndrome may involve a spectrum of clinical findings, which often include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.	duration of the intervention (duration of invasive mechanical ventilation)
90-day survival	Being alive at 90 days	90 days
Ventilator-Free Days	Number of days alive and free of mechanical ventilation in the first 28 days with death before day 28 counted as 0	28 days
Coma-and-delirium-free days	Number of days alive without delirium nor coma from any cause in the first 14 days	14 days

Collaborators and Investigators

• Sponsor: Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal
• Investigators: Principal Investigator: Yiorgos Alexandros Cavayas, MD MSc, Centre Intégré Universitaire de Santé et Services Sociaux du Nord-de-l'Ile-de-Montréal - Hôpital du Sacré-Coeur de Montréal; Principal Investigator: David Williamson, BPharm, PhD, Centre Intégré Universitaire de Santé et Services Sociaux du Nord-de-l'Ile-de-Montréal - Hôpital du Sacré-Coeur de Montréal

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: May 8, 2026
• First Submitted That Met QC Criteria: May 8, 2026
• First Posted (Actual): May 14, 2026

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: ondansetron; respiratory drive; respiratory effort; 5HT3 antagonist
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Injury; Acute Lung Injury; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Azoles; Imidazoles; Indoles; Crystalloid Solutions; Isotonic Solutions; Solutions; Heterocyclic Compounds, 3-Ring; Carbazoles; Ondansetron; Saline Solution
• Other Study ID Numbers: MP-32-2026-3061

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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