5-HT3 Receptor Antagonist and Respiratory Drive in Patients With ARDS (DRIVE)

Effect of a 5-HT3 Receptor Antagonist on Respiratory Drive in Spontaneously Breathing Mechanically Ventilated Patients With Acute Respiratory Distress Syndrome (ARDS): a Pilot Proof-of-concept Crossover Non-randomized Controlled Trial

This is a pilot study aimed at acquiring primary physiological data, describing and estimating the effects of a 5-HT3 receptor antagonist (ondansetron) on respiratory drive in patients with acute respiratory distress syndrome (ARDS). The results of this study will determine the interest and feasibility of assessing the clinical applications of ondansetron in reducing patient self-inflicted lung injury (P-SILI) in ARDS, in subsequent studies.

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Ondansetron

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Virginie Williams; Phone Number: 583327 514-338-2222; Email: virginie.williams.cnmtl@ssss.gouv.qc.ca

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H4J1C5
      • Recruiting
      • Hôpital Sacré-Coeur de Montréal
      • Contact: Virginie Williams, PhD; Phone Number: 583327 514-338-2222; Email: virginie.williams.cnmtl@ssss.gouv.qc.ca
      • Principal Investigator: Yiorgos Alexandros Cavayas, MD MSc FRCPC
      • Sub-Investigator: David Williamson, BPharm PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patient (18-75 years old)

• Berlin Criteria for Acute Respiratory Distress Syndrome (ARDS) (1):

  • Hypoxemic respiratory failure with a patrial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2 ratio) < 300
  • Bilateral opacities not fully explained by effusions, lung/lobar collapse, or nodules on chest imaging that appeared within 7 days of a known clinical insult
  • Respiratory failure not fully explained by cardiac failure or fluid overload
• Has been mechanically ventilated > 48 hours
• Planned to remain mechanically ventilated for the next 24 hours
• Currently on Pressure Support Ventilation or planning to go on pressure support ventilation in the next 24 hours

Exclusion Criteria:

• Having received a 5-HT3 antagonist in the last 24 hours, or planning to use one in the next 24 hours
• Recently treated for bleeding varices, stricture, hematemesis, esophageal trauma, recent esophageal surgery or other contraindication for nasogastric tube placement
• Severe coagulopathy (platelet count< 10 000 or International Normalized Ratio (INR) > 3)
• Neuromuscular disease that impairs ability to ventilate spontaneously (including C5 or higher spinal cord injury, amyotrophic lateral sclerosis, Guillain-Barre syndrome or myasthenia gravis)
• Treating clinician refusal, or unwillingness to commit to pressure support ventilation for at least 6 hours.
• Pregnancy
• Liver cirrhosis (Child B or C) or other severe impairment of hepatic function
• Congestive heart failure
• Bradyarrhythmia (baseline pulse<55/min)
• Known long QT syndrome
• QTc prolongation>450 msec, noted on prior or screening ECG, or who are taking medication known to cause QT prolongation
• Hypersensitivity or other known intolerance to ondansetron or other 5-HT3 antagonists

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; All participants will receive a single injection of placebo, followed, three hours later, by a single injection of ondansetron.	Drug: Placebo; Single intravenous dose of 10 mL of sodium chloride (NaCl) 0.9% over 15 minutes.; Other Names: Sodium chloride; NaCl 0.9%; Normal Saline
Active Comparator: Ondansetron; All participants will receive a single injection of placebo, followed, three hours later, by a single injection of ondansetron.	Drug: Ondansetron; Single intravenous dose of ondansetron hydrochloride dihydrate 0.15 mg/kg (maximum 16 mg) in 10 mL of NaCl 0.9% over 15 minutes.; Other Names: Ondansetron hydrochloride dihydrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pressure-time product of the esophageal pressure per minute	Difference in mean pressure-time product of the esophageal pressure per minute between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Respiratory rate	Difference in mean respiratory rate between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Tidal volume	Difference in mean tidal volume between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Pressure-time product of the esophageal pressure per breath	Difference in mean pressure-time product of the esophageal pressure per breath between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Esophageal pressure swings	Difference in mean esophageal pressure swings between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Transpulmonary pressure swings	Difference in mean transpulmonary pressure swings between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Estimated occlusion pressure at 0.1 msec (P0.1)	Difference in mean estimated occlusion pressure at 0.1 msec (P0.1) between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Peak electrical activity of the diaphragm (Eadi)	Difference in mean peak Eadi between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Area under the Eadi curve	Difference in area under the Eadi curve between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
End-tidal CO2 (EtCO2)	Difference in mean EtCO2 between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Volume of expired CO2 (VCO2)	Difference in mean VCO2 between placebo phase and ondansetron phase	Continuous measurement during each 2-hour phase
Oxygen saturation estimated by pulse oximetry (SpO2)	Difference in mean SpO2 between placebo phase and ondansetron phase	Measurement every 5 minutes during each 2-hour phase
Partial pressure of carbon dioxide in arterial blood (PaCO2)	Difference in mean PaCO2 between placebo phase and ondansetron phase	Measurement every 30 minutes during each 2-hour phase
Partial pressure of oxygen in arterial blood (PaO2)	Difference in mean PaO2 between placebo phase and ondansetron phase	Measurement every 30 minutes during each 2-hour phase
Heart rate	Difference in mean heart rate between placebo phase and ondansetron phase	Measurement every 5 minutes during each 2-hour phase
Mean arterial pressure (MAP)	Difference in mean MAP between placebo phase and ondansetron phase	Measurement every 5 minutes during each 2-hour phase
Corrected QT length (QTc)	Difference in QTc between placebo phase and ondansetron phase	Measurement once (at the 1 hour-mark) during each 2-hour phase
Temperature	Difference in mean temperature between placebo phase and ondansetron phase	Hourly measurement during each 2-hour phase
Richmond Agitation and Sedation Scale (RASS)	Difference in mean Richmond Agitation and Sedation Scale (RASS) between placebo phase and ondansetron phase. This scale goes from -5 (unraousable) to +4 (combative).	Hourly measurement during each 2-hour phase
Critical care Pain Observation Tool (CPOT)	Difference in mean Critical care Pain Observation Tool (CPOT) between placebo phase and ondansetron phase. This scale goes from 0 (lowest pain level) to 10 (highest pain level).	Hourly measurement during each 2-hour phase

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Enrolment	Number of eligible patients and enrolled patients.	Monthly through study completion (estimated 6 months)

Collaborators and Investigators

• Sponsor: Hopital du Sacre-Coeur de Montreal
• Collaborators: Fonds de la Recherche en Santé du Québec
• Investigators: Principal Investigator: Yiorgos Alexandros Cavayas, MD MSc FRCPC, Hopital du Sacré Coeur de Montréal, Centre de recherche du centre intégré universitaire de santé et services sociaux du Nord-de-l'Ile-de-Montréal

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2022
• Primary Completion (Estimated): March 6, 2024
• Study Completion (Estimated): May 6, 2024

Study Registration Dates

• First Submitted: August 17, 2022
• First Submitted That Met QC Criteria: August 22, 2022
• First Posted (Actual): August 24, 2022

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 26, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: ARDS; Ondansetron
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Serotonin Agents; Serotonin Antagonists; Serotonin 5-HT3 Receptor Antagonists; Antipruritics; Ondansetron
• Other Study ID Numbers: 2023-2502

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No