Dexmedetomidine or Clonidine Infusion for Prevention of Delirium After Open Heart Surgery (ALPHA2PREVENT)

University of Oslo (UIO)

Status and phase: Enrolling; Phase 4

Conditions: Delirium; Cognitive Decline; Frailty

Treatments: Drug: Clonidine; Drug: Natriumchlorid; Drug: Dexmedetomidine

Study type: Interventional

Funder types: Other

Identifiers

NCT05029050

2021-001645-12 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 900 estimated patients

Sex: All

Ages: 70+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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900 participants in 3 patient groups, including a placebo group

Dexmedetomidine (D)

Experimental group

Description:

Continuous intravenous infusion of dexmedetomidine 0.4 μg/kg/hour from the start of cardiopulmonary bypass and during surgery, followed by 0.2 μg/kg/hour until discharge from the ICU or 24 hours postoperatively, whichever happens first.

Treatment:

Drug: Dexmedetomidine

Clonidine (C)

Experimental group

Description:

Continuous intravenous infusion of clonidine 0.4 μg/kg/hour from the start of cardiopulmonary bypass and during surgery, followed by 0.2 μg/kg/hour until discharge from the ICU or 24 hours postoperatively, whichever happens first.

Treatment:

Drug: Clonidine

Placebo (P)

Placebo Comparator group

Description:

Continuous intravenous infusion of saline 0.4 μg/kg/hour from the start of cardiopulmonary bypass and during surgery, followed by 0.2 μg/kg/hour until discharge from the ICU or 24 hours postoperatively, whichever happens first.

Treatment:

Drug: Natriumchlorid