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

8. mai 2026 oppdatert av: Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal

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.

Studieoversikt

Status

Har ikke rekruttert ennå

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

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.

Studietype

Intervensjonell

Registrering (Antatt)

76

Fase

  • Fase 2
  • Fase 3

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiekontakt

Studiesteder

  • Canada
    • Quebec
      • Montreal, Quebec, Canada, H4J 1C5
        • Hôpital du Sacré-Cœur de Montréal
        • Ta kontakt med:
        • Hovedetterforsker:
          • Yiorgos Alexandros Cavayas, MD MSc

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

  • Voksen
  • Eldre voksen

Tar imot friske frivillige

Nei

Beskrivelse

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

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Firemannsrom

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: Ondansetron
The first dose of intravenous ondansetron will be administered within 24 hours of randomization, every 8 hours, for duration of invasive mechanical ventilation.
Legemiddel: 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 komparator: Placebo
The first dose of intravenous placebo will be administered within 24 hours of randomization, every 8 hours, for duration of invasive mechanical ventilation.
Legemiddel: 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.

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
protocol adherence
Tidsramme: duration of intervention (duration of invasive mechanical ventilation)
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)

Sekundære resultatmål

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

Andre resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Pmus
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
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
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
P0.1 will be measured 3 times per day.
duration of the intervention (duration of invasive mechanical ventilation)
Respiratory Rate
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
Respiratory Rate will be measured 3 times per day.
duration of the intervention (duration of invasive mechanical ventilation)
Tidal volume
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
Tidal volume will be measured 3 times per day.
duration of the intervention (duration of invasive mechanical ventilation)
PaO2:FiO2 ratio
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
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
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
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
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
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
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
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
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
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
Tidsramme: duration of the intervention (duration of invasive mechanical ventilation)
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
Tidsramme: 90 days
Being alive at 90 days
90 days
Ventilator-Free Days
Tidsramme: 28 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
Tidsramme: 14 days
Number of days alive without delirium nor coma from any cause in the first 14 days
14 days

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal

Etterforskere

  • Hovedetterforsker: 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
  • Hovedetterforsker: 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

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Antatt)

1. oktober 2026

Primær fullføring (Antatt)

1. oktober 2028

Studiet fullført (Antatt)

1. oktober 2029

Datoer for studieregistrering

Først innsendt

8. mai 2026

Først innsendt som oppfylte QC-kriteriene

8. mai 2026

Først lagt ut (Faktiske)

14. mai 2026

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

14. mai 2026

Siste oppdatering sendt inn som oppfylte QC-kriteriene

8. mai 2026

Sist bekreftet

1. mai 2026

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • MP-32-2026-3061

Plan for individuelle deltakerdata (IPD)

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UBESLUTTE

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Nei

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

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