Clinical trial NCT06259565: Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults
Official title: Non-invasive Ventilation and Dexmedetomidine in Critically Ill Adults: An International Pragmatic Randomized Controlled Trial (inDEX Trial)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Non-Invasive Ventilation
Lead sponsor: St. Joseph's Healthcare Hamilton
Sponsor class: OTHER
First posted: 2024-02-14
Enrollment: 846
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients randomized to the experimental arm will receive dexmedetomidine. 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 to 4). The study drug will always be titrated to the lowest possible dose with preserved effect. Each bag will be composed of two 100 mcg/mL dexmedetomidine vials (2ml vials) mixed in a 96mL 0.9% sodium chloride mini-bag (4mcg/ml) and labeled as per Health Canada guidance for labelling pharmaceutical drugs for use in humans.

The trial protocol does not allow an initial bolus of dexmedetomidine for safety reasons.
Primary purpose: TREATMENT

Brief summary: 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.

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 vanguard 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.

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.

Eligibility criteria: 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. Death is deemed imminent and inevitable
6. Patient is currently on a dexmedetomidine infusion for a duration of \> 12 hours
7. Previously enrolled in the inDEX trial
8. Acute liver failure with hepatic encephalopathy INR \> 3 and/or bilirubin \> 300
9. Current pregnancy or breast feeding
10. Known allergy to dexmedetomidine
11. Treating physician does not believe that participation in the trial is in the best interest of the patient (reasons for refusal will be captured)
12. Patients receiving Amphotericin B or Diazepam

Primary outcomes:
measure: NIV Failure
timeFrame: 28 days
Secondary outcomes:
measure: Physiologic outcomes: Incidence of delirium
timeFrame: 28 days
measure: Physiologic outcomes: Incidence of agitation
timeFrame: 28 days
measure: Major morbidity or mortality outcomes: Intubation
timeFrame: 14 days
measure: Major morbidity or mortality outcomes: ICU Mortality
timeFrame: 28 days
measure: Major morbidity or mortality outcomes: Hospital Mortality
timeFrame: 90 days
Other outcomes:
measure: Functional Outcome: EQ-5D-5L
timeFrame: 90 days
measure: Functional Outcome: EQ-VAS
timeFrame: 90 days
measure: Functional Outcome: Clinical Frailty Scale
timeFrame: 90 days
measure: Hospital outcomes
timeFrame: 90 days
Locations:
city: Surrey
country: Canada
facility: Fraser Health Authority
state: British Columbia
city: Brockville
country: Canada
facility: Brockville General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Hospital and Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sinai Health System
state: Ontario
Study officials:
affiliation: St. Joseph's Healthcare Hamilton
name: Kimberley Lewis, MD
role: PRINCIPAL_INVESTIGATOR
References: