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

Delirium Clinical Trial

— ALPHA2PREVENT  

Official title:

Alpha 2 Adrenergic Receptor Agonists for the Prevention of Delirium and Cognitive Decline After Open Heart Surgery (ALPHA2PREVENT): Randomised Controlled Trial.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05029050
• Other study ID #: 2021-001645-12
• Secondary ID: 2021-001645-12
• Status: Recruiting
• Phase: Phase 4
• Start date: January 17, 2022
• Est. completion date: January 2025

Study information

• Verified date: January 2023
• Source: Oslo University Hospital
• Contact: Bjørn Erik Neerland, PhD
• Phone: +4790078979
• Email: bjonee[@]ous-hf.no
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 900
• Est. completion date: January 2025
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 70 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cognitive Decline
• Cognitive Dysfunction
• Delirium
• Frailty

Intervention

Drug:
• Dexmedetomidine
Continous intravenous infusion
• Clonidine
Continous intravenous infusion
• Natriumchlorid
Continous intravenous infusion NaCl

Locations

Country	Name	City	State
Norway	Haukeland University Hospital	Bergen
Norway	Oslo University Hospital Rikshospitalet	Oslo
Norway	Oslo University Hospital Ullevål	Oslo
Norway	University Hospital of North Norway	Tromsø
Norway	St Olav University Hospital	Trondheim

Sponsors (6)

Lead Sponsor	Collaborator
Oslo University Hospital	Haukeland University Hospital, Sahlgrenska University Hospital, Sweden, St. Olavs Hospital, UMC Utrecht, University Hospital of North Norway

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Additional biomarkers	Additional biomarkers of neural injury, inflammation or neurotransmission may be explored	5 days postoperatively
Primary	Postoperative delirium	Cumulative incidence of postoperative delirium, as diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria	Up to 7 days
Secondary	Incidence of coma	Incidence of coma, as measured by Richmond Agitation Sedation Scale (-5 to +5)	Up to 7 days
Secondary	Incidence of death, coma or postoperative delirium	Incidence of death, coma or postoperative delirium, as described above	Up to 7 days
Secondary	Number of delirium days postoperatively	Number of delirium days postoperatively, as diagnosed according to DSM-5 criteria	Up to 7 days
Secondary	Delirium severity	Delirium severity, as measured by Confusion Assessment Method for Intensive Care Units-7 (CAM-ICU)-7	Up to 7 days
Secondary	Motor activity patterns	Motor activity patterns, assessed with body worn accelerometers	6 months
Secondary	Change in cognitive function between inclusion and after 1 and 6 months	Change in cognitive function between inclusion and after 1 and 6 months, as graded by Montreal Cognitive Assessment (MoCA), 10-words memory task from The Consortium Establish a Registry for Alzheimer's Disease (CERAD), digit span tests, Trail making tests (TMT) A and B, semantic and phonemic verbal fluency, and measured repeatedly preoperatively and 1 and 6 months after surgery	6 months
Secondary	Change in patient rated health status between inclusion and after 1 and 6 months	Change in patient rated health status between inclusion and after 1 and 6 months, as assessed by the EQ-5D-5L questionnaire preoperatively and 1 and 6 months postoperatively	6 months
Secondary	Serum concentrations of NFL and p-tau181	Comparison to inclusion of serum concentrations of neurofilament light (NFL) and p-tau181 1, 3 and 5 days postoperatively	5 days postoperatively
Secondary	Estimate associations between frailty and the other endpoints	Estimate associations between frailty and the other endpoints, as described above	6 months
Secondary	Safety and tolerability	Safety and tolerability as determined by the numbers of Adverse Events (AEs), serious AEs (SAEs) and suspected unexpected serious adverse reactions (SUSARs), and vital signs; blood pressure (BP), heart rate (HR), peripheral oxygen saturation (SpO2) postoperatively	6 months
Secondary	Interaction between preoperative frailty and treatment on delirium and the other endpoints	Interaction between preoperative frailty and treatment on delirium and the other endpoints, as described above	6 months
Secondary	Change in frailty status between inclusion and after 1 and 6 months	Change in frailty status between inclusion and after 1 and 6 months, as graded by the frailty index (FI) and essential frailty toolset (EFT) (section 8.1.3), and measured repeatedly preoperatively and 1 and 6 months after surgery	6 months
Secondary	Comparison of change in frailty status between inclusion and after 1 and 6 months	Comparison of change in frailty status between inclusion and after 1 and 6 months (as described above) between patients with or without postoperative delirium.	6 months