Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults (inDEX)

Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults: An International Pragmatic Randomized Controlled Trial (inDEX Trial)

Non-Invasive ventilation (NIV) is a life saving intervention for patients with acute respiratory failure (ARF). Some patients are not able to tolerate the NIV intervention and ultimately fail, requiring the use of invasive mechanical ventilation (IMV) and intubation. Sedation may improve a patient's NIV tolerance. However, this practice has not been adopted by intensivists as the risk of over-sedation resulting in respiratory depression, inability to protect the airway, and inadvertent need for intubation are all large deterrents of sedative use in NIV.

The Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults: a Pragmatic Randomized Controlled Trial (inDEX) is looking to evaluate the effectiveness of dexmedetomidine compared to placebo in reducing non-invasive ventilation failures in patients admitted to the hospital with acute respiratory failure.

Study Overview

• Status: Recruiting
• Conditions: Non-Invasive Ventilation
• Intervention / Treatment: Other: Placebo Control; Drug: Dexmedetomidine

Detailed Description

Acute respiratory failure (ARF) is a common reason for admission to an intensive care unit (ICU). Non-invasive positive pressure ventilation (NIV) is a life-saving intervention for selected patients with ARF. Compared to endotracheal intubation and invasive mechanical ventilation (IMV), NIV is safer, less invasive, preferred by most patients, and is associated with a reduced ICU length of stay (LOS), less pneumonia and mortality, and lower healthcare costs.

NIV failure can occur, necessitating IMV. Risk factors associated with NIV failure including intolerance, agitation, and delirium. Sedation is a potential solution for NIV intolerance, however the evidence is sparse and the risk of over-sedation resulting in respiratory depression, inability to protect the airway, and inadvertent need for intubation are all large deterrents.

Dexmedetomidine (Dex) is an α2-adrenergic agonist sedative commonly used in IMV that promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and reduces delirium. The investigators hypothesize that Dex, when compared to placebo, reduces NIV failure in hospitalized adults with ARF and agitation or NIV intolerance.

Overall Goal: To determine if Dex, compared to placebo, reduces the risk of NIV failure in patients that admitted to hospital with acute respiratory failure and are intolerant of NIV.

Target Population: 846 patients will be enrolled into the trial if they meet all the following criteria: 1) ≥18 years old; 2) Receiving any NIV modality for ARF of any etiology; 3) Admitted to ICU, PACU, step-down unit (surgical or medical), or emergency department; 4) Presence of one or more of the following: a) Agitation, b) Patient expresses intolerance or requests removal of NIV secondary to self-reported discomfort, anxiety, or claustrophobia, or c) Other reason that the physician feels the patient is intolerant of NIV or agitated not captured above, or feels that the patient will benefit from sedation (all reasons will be recorded).

Methods: The inDEX trial is a pragmatic, international, multi-centred, stratified, randomized, parallel-group, placebo-controlled trial. Patients, investigators, healthcare team, data collectors, outcome assessors, and the statistician will be blinded to trial arms. The trial will maximize external validity by including patients in a range of hospitals across the world. Patients randomized to the experimental arm will receive Dex while those randomized to the control arm will receive placebo.

Assessment: The primary outcome is NIV failure. The investigators define NIV failure as the proportion that require intubation or have died at 28 days.

• Study Type: Interventional
• Enrollment (Estimated): 846
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kimberley Lewis, MD; Phone Number: (289)775-7334; Email: kimberley.lewis@medportal.ca
• Study Contact Backup: Name: Jose Estrada; Email: jestrada@stjosham.on.ca

Study Locations

• Canada
  • British Columbia
    • Surrey, British Columbia, Canada, V3T 0H1
      • Not yet recruiting
      • Fraser Health Authority
      • Principal Investigator: Wesley Jang, MD
      • Contact: Patrick Altejos; Email: patrick.altejos@fraserhealth.ca
  • Ontario
    • Brockville, Ontario, Canada, K6V 1S8
      • Not yet recruiting
      • Brockville General Hospital
      • Contact: Tommy Li; Email: tli@brockvillegeneralhospital.ca
      • Principal Investigator: Mohammed Al-Amoudi, MD
    • Hamilton, Ontario, Canada, L8N 4A6
      • Recruiting
      • St. Joseph's Healthcare Hamilton
      • Principal Investigator: Kimberley Lewis, MD
      • Contact: Jose Estrada; Phone Number: 905-522-1155 Ext. 32873; Email: jestrada@stjosham.on.ca
      • Contact: Irene Armanious; Phone Number: 905-522-1155 Ext. 32873; Email: iarmanio@stjosham.on.ca
    • Hamilton, Ontario, Canada, L8V 1C3
      • Not yet recruiting
      • Juravinski Hospital and Cancer Centre
      • Principal Investigator: Bram Rochwerg, MD
      • Contact: Tina Millen; Email: millent@mcmaster.ca
    • Toronto, Ontario, Canada, M2K 1E1
      • Not yet recruiting
      • North York General Hospital
      • Contact: Mary Rahmat; Email: mary.rahmat@nygh.on.ca
      • Principal Investigator: Anna Geaea, MD
    • Toronto, Ontario, Canada, M5G 1X5
      • Not yet recruiting
      • Sinai Health System
      • Contact: Sumesh Shah; Email: sumesh.shah@sinaihealth.ca
      • Principal Investigator: Geetha Mehta, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥18 years
2. Patient receiving any NIV modality for acute respiratory failure of any etiology
3. Admitted to ICU, PACU, step-down unit (surgical or medical), or emergency department(with planned admission to a monitored setting) or equivalent unit where hemodynamics and respiratory status can be monitored, and NIV is permitted; and

4. Presence of one or more of the following after optimized NIV treatment:

   1. Agitation (Defined as a Richmond Agitation and Sedation Scale [RASS] score of ≥+2 or a Riker Sedation-Agitation Scale [SAS] score of ≥5) (Appendix 1 Table 2 and Table 3)
   2. Patient expresses intolerance or requests removal of NIV secondary to self-reported discomfort, anxiety, or claustrophobia
   3. Other reason that the physician judges the patient to be intolerant of NIV or agitated, not captured above, or feels that the patient would benefit from titrated sedation for other reasons.

Exclusion Criteria:

1. Absence of a functioning pacemaker with one of the following: a-Persistent bradycardia defined as a heart rate (HR) ≤60bpm; b-Second or third-degree heart block; or c- Tachybrady syndrome
2. Persistent hypotension, defined as a mean arterial pressure (MAP) ≤65mmHg despite volume resuscitation and vasopressors
3. Imminent need for endotracheal intubation as determined by healthcare team
4. Patient's goals of care do not include intubation and IMV
5. Patient is not for vasopressors or inotropic support
6. Death is deemed imminent and inevitable
7. Patient is currently on a dexmedetomidine infusion for a duration of > 12 hours
8. Previously enrolled in the inDEX trial
9. Acute liver failure with hepatic encephalopathy INR > 3 and/or bilirubin > 300
10. Current pregnancy or breast feeding
11. Known allergy to dexmedetomidine
12. Patients receiving Amphotericin B or Diazepam
13. Treating physician does not believe that participation in the trial is in the best interest of the patient (reasons for refusal will be captured)

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
Placebo Comparator: Placebo Control; Those in the control group will receive a placebo that is identical in colour and packaging and at equal volume to the intervention group. Each bag of placebo contains 100mL of 0.9% sodium chloride and labeled as per Health Canada guidance for labelling pharmaceutical drugs for use in humans	Other: Placebo Control; Those in the control group will receive a placebo that is identical in colour and packaging and at equal volume to the intervention group. Each bag of placebo contains 100mL of 0.9% sodium chloride and labeled as per Health Canada guidance for labelling pharmaceutical drugs for use in humans
Experimental: Dexmedetomidine Intervention; Dexmedetomidine (Dex) is an α2-adrenergic agonist sedative commonly used in IMV that promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and reduces delirium. Patients randomized to the experimental arm will receive dexmedetomidine. At initiation, a bolus will NOT be administered. In keeping with Health Canada Guidelines, we will start the infusion at a mid-range dose of 0.5mcg/kg/h with titration either up or down by 0.1mcg/kg/h every 20-30 minutes to a maximum rate of 1.2mcg/kg/h to maintain light sedation (RASS = -2 to +1 or SAS 3-4). Each bag will be composed of composed of dexmedetomidine 4mcg/mL(in 0.9% sodium chloride) prepared as a volume of 100mL and labeled as per Health Canada guidance for labelling pharmaceutical drugs for use in humans.	Drug: Dexmedetomidine; Dexmedetomidine (Dex) is an α2-adrenergic agonist sedative commonly used in invasive mechanical ventilation (IMV) that promotes patient wakefulness, has no effect on respiratory drive, has important analgesic properties, and reduces delirium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NIV Failure	The primary outcome is NIV failure, defined by either mortality or intubation	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physiologic outcomes: Incidence of delirium	Delirium assessed using the ICU-CAM or ICDSC every 12 hours during NIV and daily thereafter until ICU discharge	28 days
Physiologic outcomes: Incidence of agitation	Agitation defined as Richmond Agitation Sedation Scale (RASS) ≥2+ during NIV), where RASS scale ranges from -5 (unrousable) to +4 (combative).	28 days
Major morbidity or mortality outcomes: Intubation	Intubation	14 days
Major morbidity or mortality outcomes: ICU Mortality	ICU mortality	28 days
Major morbidity or mortality outcomes: Hospital Mortality	Hospital Mortality	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital outcomes	Hospital Length of Stay (LOS)	90 days
Functional Outcome: EQ-5D-5L	The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. EQ-5D-5L index scores range from -0.59 to 1, where 1 is the best possible health state	90 days
Functional Outcome: EQ-VAS	The EQ VAS records the patient's self-rated health on a vertical visual analogue scale where the endpoints are labelled 'The best health you can image' and 'The worst health you can image'. The VAS can be used as a quantitative measure of health outcome that reflects the patient's own judgement. EQ VAS scores range from 0 to 100, where 100 is the best possible health state.	90 days
Functional Outcome: Clinical Frailty Scale	The CFS summarizes the overall level of fitness or frailty of an older adult after they had been evaluated by a clinician. A score from 1 (very fit) to 9 (terminally ill) is given based on the descriptions and pictographs of activity and functional status.	90 days

Collaborators and Investigators

• Sponsor: St. Joseph's Healthcare Hamilton
• Collaborators: Population Health Research Institute
• Investigators: Principal Investigator: Kimberley Lewis, MD, St. Joseph's Healthcare Hamilton

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): January 31, 2030

Study Registration Dates

• First Submitted: December 27, 2023
• First Submitted That Met QC Criteria: February 6, 2024
• First Posted (Actual): February 14, 2024

Study Record Updates

• Last Update Posted (Estimated): September 10, 2025
• Last Update Submitted That Met QC Criteria: September 3, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Substandard Drugs; Pharmaceutical Preparations; Azoles; Imidazoles; Dexmedetomidine; Counterfeit Drugs
• Other Study ID Numbers: 4257

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