Early sedation with dexmedetomidine vs. placebo in older ventilated critically ill patients
| ISRCTN | ISRCTN37114000 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN37114000 |
| EudraCT/CTIS number | 2022-501157-36 |
| IRAS number | 1008709 |
| Secondary identifying numbers | YS004, IRAS 1008709 |
- Submission date
- 13/02/2024
- Registration date
- 10/04/2024
- Last edited
- 15/05/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Other
Plain English Summary
Background and study aims
Most ICU patients who need a breathing machine (ventilator) to help them breathe require sedation with one or more sedative (calming) drugs, given as continuous drip into a vein. Currently, there is no agreement amongst doctors around the world about the best choice of sedative drug or the best way to manage sedation. Many of the commonly used sedative drugs have side effects and are thought to be associated with longer time on the ventilator, longer stay in the ICU, leading to delirium (a confused state often including hallucinations) and decreased mental awareness after recovery from critical illness. Dexmedetomidine is a commonly used sedative drugs that can be used alone or in combination, to keep ICU patients comfortable while on a ventilator. The purpose of this study is to evaluate dexmedetomidine, which might improve survival and recovery for older patients who require sedation in ICU.
Who can participate?
Patients will be able to participate in this trial if they are aged 65 or older and they require mechanical ventilation for more than 24 hours.
What does the study involve?
This is a type of study called a randomised controlled trial.
Hospitals with intensive care units that treat these patients will be involved in this trial. Half of the patients will be given DEX and the other half will be given a placebo (which looks the same as DEX but does not have any active ingredient). Results will be compared between the two groups. We will find out whether DEX is better than placebo by measuring outcomes such as whether the patient lives, whether they experience delirium (which means they have confused thinking and a lack of awareness of their surroundings), how long they are ventilated for, and whether they experience injury to their kidneys.
The trial is set to start in 2024 in the United Kingdom and is anticipated to conclude by the end of 2026. Participants in the trial will be contacted for an assessment at 90 days and six months after enrolment to see how well they have recovered.
What are the possible benefits and risks of participating?
Patients participating in this trial are heavily dependent on medical care. Therefore, they would receive sedative medications including study medication to facilitate safety, pain relief, comfort, and necessary therapeutic procedures. In addition, these patients would be allowed to be visited by their families and close relatives to facilitate their comfort.
These patients are usually monitored minute by minute in intensive care environments and cared for by highly specialised and trained intensive care practitioners and bedside carers. Common risks involved in the trial includes low or high blood pressure, and drop in heart rate. These variations in blood pressure and heart rate are continuously monitored by intensive care staff who are trained to promptly treat these conditions appropriately.
Other risks involved are no different from those experienced in the routine care of critically ill patients in the intensive care unit. All data collected from participants will be de-identified, stored in a password-protected and encrypted database accessible exclusively to authorised trial personnel, ensuring minimal risk of privacy breaches. Monash University has approved a data protection assessment to safeguard participant confidentiality.
The drug (DEX) used in the study are used within standard clinical practice within critical care units internationally. The sedative drugs used are to reduce discomfort and distress associated with ventilation, the patient will not be distressed by receiving the study intervention or standard care. The assessments needed for the study are the same as would be in standard clinical practice. There should be very little burden on the patient for participating in the study, the phone calls at 6 months should only be a mild inconvenience.
Where is the study run from?
Monash Medical Centre (Australia)
When is the study starting and how long is it expected to run for?
February 2024 to December 2026
Who is funding the study?
National Health and Medical Research Council (Australia)
Who is the main contact?
Prof Yahya Shehabi, yahya.shehabi@monashhealth.org
Dr Matt Wise, mattwise@doctors.org.uk
Contact information
Principal Investigator
Level 5, E Block, Monash Medical Centre 246 Clayton Road
Clayton
3168
Australia
| Phone | +61 (419)296 986 |
|---|---|
| Yahya.Shehabi@monash.edu |
Public, Scientific
Critical Care Medicine, University Hospital of Wales, Heath Park Way
Cardiff
CF14 4XW
United Kingdom
| Phone | +44 29 2074 7747 |
|---|---|
| Mattwise@doctors.org.uk |
Study information
| Study design | Interventional double blind randomized parallel group placebo controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Hospital |
| Study type | Safety, Efficacy |
| Scientific title | Sedation Practice in Intensive Care Evaluation-SPICE IV. Early Sedation with Dexmedetomidine vs. Placebo in Older Ventilated Critically Ill Patients. A Prospective, Multi-Centre, Double-Blind, Randomized, Controlled Trial |
| Study acronym | SPICE IV |
| Study hypothesis | Primary objective: To evaluate mortality and other key clinical outcomes in older patients (65 years and older) receiving early sedation with dexmedetomidine as the primary sedative agent. The primary outcome measure is 90-day all-cause mortality. Secondary objective: To assess the effect of dexmedetomidine on ventilator free days, coma and delirium free days, major adverse kidney events (MAKE-28) at day 28, duration of ventilation, and hospital stay in survivors. |
| Ethics approval(s) |
Approved 09/04/2024, Wales REC 3 (HCRW, Castlebridge 4, Cardiff, CF11 9AB, United Kingdom; +44 (0)2922941107; Wales.REC3@wales.nhs.uk), ref: 24/WA/0065 |
| Condition | Critically ill patients who are 65 years of age and older, and expected to be ventilated for more than 24 hours in an intensive care unit and are dependent on high level medical care including vasopressors, and sedative agents. |
| Intervention | Intravenous infusion of dexmedetomidine or saline as placebo will be started shortly after randomisation, at a recommended dose equivalent to 1 mcg/kg/h without a loading dose. The infusion will be adjusted between 0 and 1 mcg/kg/hr to achieve target sedation assessed by the Richmond Agitation Sedation Scale (RASS). The default target is RASS score of -1 to+1. The infusion would continue in intensive care until sedation is no longer required or to a max of 28-days whichever comes first. All study participants will receive standard routine care. The need for ongoing sedation will be determined by the attending clinician based on frequent clinical assessment. Adherence to the intervention will be monitored by onsite research support staff and the study PI at individual sites. In addition, monitoring through study website via built in queries will be regularly conducted. The comparator is placebo in the form of equivalent volume of normal saline will be used. As the study design is double-blind, staff, including clinicians and bedside carers will be blinded to the intervention. The study algorithm prescribes a sedation target for participants. Therefore, additional supplemental sedatives would be added, as per usual or routine care in ICU, to achieve desired sedation target. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacoeconomic, Therapy |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Dexmedetomidine |
| Primary outcome measure | 90-day all-cause mortality measured using phone follow-up by the sites research support staff at 90-days following randomisation |
| Secondary outcome measures | 1. Number of days alive and free of coma and delirium at 28 days collected through medical records and direct patient assessment for delirium, coma at 28 days following randomisation 2. Number of days alive and ventilator free at 28 days collected directly from medical records and entered into study database at 28 days following randomisation 3. Major Adverse Kidney Events at 28 days (Mortality + Acute Kidney Injury > stage II, defined by Kidney Disease Improving Global Outcome (KDIGO) definition) collected directly from medical records and entered into study database at 28 days following randomisation 4. Duration of mechanical ventilation in survivors collected directly from medical records and entered into study database at ICU discharge 5. Hospital length of stay in survivors collected directly from medical records and entered into study database at Hospital discharge |
| Overall study start date | 08/02/2024 |
| Overall study end date | 29/12/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Senior |
| Lower age limit | 65 Years |
| Sex | Both |
| Target number of participants | 3,500 |
| Participant inclusion criteria | 1. Age ≥ 65 years 2. Intubated and receiving invasive mechanical ventilation in an intensive care unit 3. The treating clinicians believe that the patient will remain intubated and ventilated until the day after tomorrow (unlikely to be extubated next day) 4. The patient requires immediate ongoing sedative medication for comfort, safety and to facilitate the delivery of life support measures. |
| Participant exclusion criteria | 1. Has been intubated (excluding time spent intubated within an operating theatre or transport) for greater than 12 hours, with an additional 6 hours grace period, a total of 18 hours, in an intensive care unit 2. Proven or suspected acute primary brain lesion such as traumatic brain injury, intracranial haemorrhage, stroke, or hypoxic brain injury 3. Proven or suspected spinal cord injury or other pathology that may result in permanent or prolonged weakness 4. Admission with a suspected or proven drug overdose or burns. 5. Administration of ongoing neuromuscular blockade 6. Mean arterial blood (MAP) pressure that is less than 50 mmHg despite adequate resuscitation and vasopressor therapy at time of randomization 7. Heart rate less than 55 beats per minute unless the patient is being treated with a betablocker or a high grade atrio-ventricular block in the absence of a functioning pacemaker 8. Known sensitivity to dexmedetomidine 9. Acute fulminant hepatic failure 10. Death is deemed to be imminent or inevitable during this admission and either the attending physician, patient or substitute decision maker is not committed to active treatment 11. Patient has an underlying disease that makes survival to 90 days unlikely 12. Previously enrolled in the SPICE IV study |
| Recruitment start date | 31/12/2023 |
| Recruitment end date | 31/12/2026 |
Locations
Countries of recruitment
- Brazil
- Canada
- England
- Ireland
- Kuwait
- Malaysia
- Netherlands
- New Zealand
- Northern Ireland
- Saudi Arabia
- Switzerland
- Taiwan
- United Kingdom
- Wales
Study participating centres
Heath Park
Cardiff
Cardiff
CF14 4XW
United Kingdom
Blackshaw road
London
SW17 0QT
United Kingdom
Prescot Street
Liverpool
L7 8XP
United Kingdom
Belfast
BT12 6BA
United Kingdom
Denmark Hill
London
SE5 9RS
United Kingdom
London
W6 8RF
United Kingdom
Crownhill
Plymouth
PL6 8DH
United Kingdom
Oxford Road
Manchester
M13 9WL
United Kingdom
Winchester
SO22 5DG
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Upper Maudlin Street
Bristol
BS2 8HW
United Kingdom
Barrack Road
Exeter
EX2 5DW
United Kingdom
London
E1 2ES
United Kingdom
Sponsor information
Hospital/treatment centre
Cardiff Joint Research Office
Cardiff
CF14 4XW
Wales
United Kingdom
| Phone | +44 2921 02921846327 |
|---|---|
| Research.Development@wales.nhs.uk | |
| Website | http://www.cardiffandvaleuhb.wales.nhs.uk/home |
"ROR" |
https://ror.org/0489f6q08 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- NHMRC
- Location
- Australia
Results and Publications
| Intention to publish date | 29/12/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Peer reviewed scientific journals Conference presentation Submission to regulatory authorities |
| IPD sharing plan | 1. Any research access to or use of shared SPICE IV data or information must be in accordance with the consent obtained, which includes consent to future use of data 2. Independent applications for the secondary use of data from the SPICE IV trial should be sent to the Chief Principal Investigator or his delegate from Monash University School of Clinical Sciences for review by the SPICE IV management committee. Applicants should be aware of the following: a. Data sharing requests can be received 6 months after publication and for up to 36 months after publication b. Applications should include a defined protocol and analysis plan c. All applications will be evaluated on a case-by-case basis and according to established principles, including the current NHMRC’s ‘National Statement on Ethical Conduct in Human Research 2007 (updated 2018)’ d. Only data underlying the published tables, figures and the supplementary material may be available for sharing e. Only data where direct and indirect identifiers are removed will be shared f. Applicants must provide a data management plan in accordance with the current NHRMC’s ‘National Statement on Ethical Conduct in Human Research 2007 (updated 2018) and include details on banking or sharing of the data or information, and, in particular, of any confidentiality agreements or other conditions on the identifiability or re-use of the data or information. g. The decision will be communicated within 6 weeks of application 3. Data sharing applications for the purpose of any forms of meta-analysis and/or systematic reviews, are expected to be collaborative in nature with a defined dataset. Such applications can be submitted to the Chief Principal Investigator or his delegate from Monash University School of Clinical Sciences and are not restricted to any time frame. |
Editorial Notes
15/05/2024: Ethics approval added.
13/02/2024: Trial's existence confirmed by NHS HRA.
