Clinical trial NCT05029050: Dexmedetomidine or Clonidine Infusion for Prevention of Delirium After Open Heart Surgery
Official title: Alpha 2 Adrenergic Receptor Agonists for the Prevention of Delirium and Cognitive Decline After Open Heart Surgery (ALPHA2PREVENT): Randomised Controlled Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Delirium
Cognitive Decline
Frailty
Keywords: delirium
cognitive decline
frailty
heart surgery
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: Haukeland University Hospital
name: University Hospital of North Norway
name: UMC Utrecht
name: Sahlgrenska University Hospital
name: St. Olavs Hospital
First posted: 2021-08-31
Enrollment: 900
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A parallel-group treatment, five-centre, participant and investigator masked, three-arm study to assess the safety and effectiveness of dexmedetomidine or clonidine infusion compared to placebo for the prevention of delirium and cognitive decline in male and female participants aged 70+ scheduled for open heart surgery.
Primary purpose: PREVENTION

Brief summary: A parallel-group treatment, five-centre, participant and investigator masked, three-arm study to assess the safety and effectiveness of dexmedetomidine or clonidine infusion compared to placebo for the prevention of delirium and cognitive decline in male and female participants aged 70+ scheduled for open heart surgery.

Detailed description: Delirium is a major public health concern without therapeutic options. It is an acute disturbance of attention and cognition, precipitated by an acute somatic condition. Delirious patients are often subject to off-label treatment with psychotropic drugs that have dubious effects.

The intravenous alpha-2-adrenergic receptor agonist dexmedetomidine, attenuating sympathetic nervous system activity, shows promise as treatment for delirium, but its use is limited to intensive care units (ICU). Its long-term cognitive effects are unknown. Clonidine is a pharmacodynamically similar drug that can be given orally and has been used for decades as an antihypertensive agent, but is else sparsely studied.

ALPHA2PREVENT will be a three-armed randomised controlled trial to study 1) whether repurposing of clonidine can represent a novel treatment option for delirium, and 2) the possible effects of both dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns, patient rated outcome measures and biomarkers of neuronal injury.

Eligibility criteria: Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Participant must be ≥70 years old at the time of signing the informed consent.
2. Participant must be accepted for cardiac surgery with cardiopulmonary bypass. The surgical procedures may constitute 1) coronary bypass grafting, 2) tricuspid, mitral, or aortic valve replacement or repair, 3) surgery on the ascending aorta, and 4) the combination any of these procedures.
3. Participant must be capable of giving signed informed consent.

   Exclusion Criteria:

   Participants are excluded from the study if any of the following criteria apply:
4. Preoperative delirium
5. Known hypersensitivity to the active ingredient or components of the product
6. Bradycardia due to sick-sinus-syndrome, 2nd or 3rd degree AV-block (if not treated with pacemaker) or any other reason causing HR \<50 bpm at time of inclusion
7. Uncontrolled hypotension
8. Ischemic stroke or transitory ischemic attack the last month or critical peripheral ischemia
9. Acute coronary syndrome last 24 hours. Acute coronary syndrome is defined according to international guidelines
10. Left ventricular ejection fraction \< 40%
11. Severe renal impairment (estimated GFR \<20ml/min) or expected requirement for renal replacement therapy
12. Severe hepatic dysfunction (liver enzyme three times the upper limit of normal together with a serum albumin concentration below the normal reference limit)
13. Reduced peripheral autonomous activity (e.g. spinal cord injury)
14. Current use of tricyclic antidepressants, monoamine reuptake inhibitors or ciclosporin
15. Endocarditis or sepsis
16. Pheochromocytoma
17. Planned deep hypothermia and circulatory arrest
18. Emergency surgery, defined as less than 24 hours from admission to surgery
19. Previously included in this study
20. Not speaking or reading Norwegian
21. Any other condition as evaluated by the treating physician

Primary outcomes:
measure: Postoperative delirium
timeFrame: Up to 7 days
Secondary outcomes:
measure: Incidence of coma
timeFrame: Up to 7 days
measure: Incidence of death, coma or postoperative delirium
timeFrame: Up to 7 days
measure: Number of delirium days postoperatively
timeFrame: Up to 7 days
measure: Delirium severity
timeFrame: Up to 7 days
measure: Motor activity patterns
timeFrame: 6 months
measure: Change in cognitive function between inclusion and after 1 and 6 months
timeFrame: 6 months
measure: Change in patient rated health status between inclusion and after 1 and 6 months
timeFrame: 6 months
measure: Serum concentrations of NFL and p-tau181
timeFrame: 5 days postoperatively
measure: Estimate associations between frailty and the other endpoints
timeFrame: 6 months
measure: Safety and tolerability
timeFrame: 6 months
measure: Interaction between preoperative frailty and treatment on delirium and the other endpoints
timeFrame: 6 months
measure: Change in frailty status between inclusion and after 1 and 6 months
timeFrame: 6 months
measure: Comparison of change in frailty status between inclusion and after 1 and 6 months
timeFrame: 6 months
Other outcomes:
measure: Additional biomarkers
timeFrame: 5 days postoperatively
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital Rikshospitalet
city: Oslo
country: Norway
facility: Oslo University Hospital Ullevål
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Trondheim
country: Norway
facility: St Olav University Hospital
Study officials:
affiliation: Oslo University Hospital
name: Bjørn Erik Neerland, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Neerland BE, Busund R, Haaverstad R, Helbostad JL, Landsverk SA, Martinaityte I, Norum HM, Raeder J, Selbaek G, Simpson MR, Skaar E, Skjaervold NK, Skovlund E, Slooter AJ, Svendsen OS, Tonnessen T, Wahba A, Zetterberg H, Wyller TB. Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial. BMJ Open. 2022 Jun 20;12(6):e057460. doi: 10.1136/bmjopen-2021-057460.