A Phase 2/3 interventional study of Ondansetron hydrochloride 8 mg IV Q8H and 0.9 % Normal Saline 10 ml in ARDS (Acute Respiratory Distress Syndrome), Invasive Mechanical Ventilation and Patient-Self Inflicted Lung Injury, sponsored by Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal. Not yet recruiting at 1 site in Canada. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2026-05-14.
Sponsored by Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal · Phase 2/3, Interventional, and Treatment
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.
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.
989 studies on the registry are indexed under Acute Lung Injury; 156 are open to participants now.
This study's planned enrollment of 76 is above the median of 54 across 561 interventional studies indexed under Acute Lung Injury.
Browse Acute Lung Injury studies →Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal is the lead sponsor of 31 studies on the registry; 15 are open to participants now.
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Exclusion Criteria:
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
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 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.
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.
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.
Time frame: duration of intervention (duration of invasive mechanical ventilation)
Outcome data completeness
Data completeness for 90 day survival, 28 day ventilator-free days, and 14 day coma-and-delirium-free days.
Time frame: 90 days
Enrolment rate
Patients enrolled by site by 12-month period
Time frame: Duration of the study
Pmus
Pmus will be estimated by the occlusion pressure maneuvre, measured 3 times per day.
Time frame: duration of the intervention (duration of invasive mechanical ventilation)
P0.1
P0.1 will be measured 3 times per day.
Time frame: duration of the intervention (duration of invasive mechanical ventilation)
Respiratory Rate
Respiratory Rate will be measured 3 times per day.
Time frame: duration of the intervention (duration of invasive mechanical ventilation)
Tidal volume
Tidal volume will be measured 3 times per day.
Time frame: duration of the intervention (duration of invasive mechanical ventilation)
PaO2:FiO2 ratio
PaO2:FiO2 ratio will be measured 3 times per day.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: duration of the intervention (duration of invasive mechanical ventilation)
90-day survival
Being alive at 90 days
Time frame: 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
Time frame: 28 days
Coma-and-delirium-free days
Number of days alive without delirium nor coma from any cause in the first 14 days
Time frame: 14 days
Plan to share: Undecided
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Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal