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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Delirium; Frailty; Cognitive Decline
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Clonidine; Drug: Natriumchlorid

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.

• Study Type: Interventional
• Enrollment (Estimated): 900
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Torgeir Bruun Wyller, Professor; Phone Number: +4791166682; Email: t.b.wyller@medisin.uio.no
• Study Contact Backup: Name: Bjørn Erik Neerland, PhD; Phone Number: +4790078979; Email: bjonee@ous-hf.no

Study Locations

• Norway
  • Bergen, Norway
    • Recruiting
    • Haukeland University Hospital
    • Contact: Øyvind Sverre Svendsen, MD, PhD
  • Oslo, Norway
    • Recruiting
    • Oslo University Hospital Rikshospitalet
    • Contact: Hilde Margrethe Norum, MD, PhD
  • Oslo, Norway
    • Recruiting
    • Oslo University Hospital Ullevål
    • Contact: Svein Aslak Landsverk, MD, PhD
  • Tromsø, Norway
    • Recruiting
    • University Hospital of North Norway
    • Contact: Astrid Kristine Kjerstad, MD
  • Trondheim, Norway
    • Recruiting
    • St Olav University Hospital
    • Contact: Nils Kristian Skjærvold, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine (D); 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.	Drug: Dexmedetomidine; Continous intravenous infusion; Other Names: Precedex; Dexdor; N05C M18
Experimental: Clonidine (C); 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.	Drug: Clonidine; Continous intravenous infusion; Other Names: Catapresan; Catapressan; N02C X02
Placebo Comparator: Placebo (P); 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.	Drug: Natriumchlorid; Continous intravenous infusion NaCl; Other Names: Saline; NaCl 9mg/ml

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of coma	Incidence of coma, as measured by Richmond Agitation Sedation Scale (-5 to +5)	Up to 7 days
Incidence of death, coma or postoperative delirium	Incidence of death, coma or postoperative delirium, as described above	Up to 7 days
Number of delirium days postoperatively	Number of delirium days postoperatively, as diagnosed according to DSM-5 criteria	Up to 7 days
Delirium severity	Delirium severity, as measured by Confusion Assessment Method for Intensive Care Units-7 (CAM-ICU)-7	Up to 7 days
Motor activity patterns	Motor activity patterns, assessed with body worn accelerometers	6 months
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
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
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
Estimate associations between frailty and the other endpoints	Estimate associations between frailty and the other endpoints, as described above	6 months
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
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
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Additional biomarkers	Additional biomarkers of neural injury, inflammation or neurotransmission may be explored	5 days postoperatively

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: University Hospital of North Norway; UMC Utrecht; Sahlgrenska University Hospital, Sweden; Haukeland University Hospital; St. Olavs Hospital
• Investigators: Principal Investigator: Bjørn Erik Neerland, PhD, Oslo University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2022
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: August 21, 2021
• First Submitted That Met QC Criteria: August 25, 2021
• First Posted (Actual): August 31, 2021

Study Record Updates

• Last Update Posted (Actual): April 30, 2024
• Last Update Submitted That Met QC Criteria: April 29, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: delirium; frailty; cognitive decline; heart surgery
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognition Disorders; Delirium; Cognitive Dysfunction; Frailty; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Sympatholytics; Dexmedetomidine; Clonidine
• Other Study ID Numbers: 2021-001645-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No