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

• ClinicalTrials.gov Identifier: NCT05029050
• Recruitment Status: Recruiting
• First Posted: August 31, 2021
• Last Update Posted: January 12, 2023
• Sponsor: Oslo University Hospital
• Collaborators: Haukeland University Hospital; University Hospital of North Norway; UMC Utrecht; Sahlgrenska University Hospital, Sweden; St. Olavs Hospital
• Information provided by (Responsible Party): Bjørn Erik Neerland, MD, Oslo University Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Delirium; Cognitive Decline; Frailty	Drug: Dexmedetomidine; Drug: Clonidine; Drug: Natriumchlorid	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 900 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Alpha 2 Adrenergic Receptor Agonists for the Prevention of Delirium and Cognitive Decline After Open Heart Surgery (ALPHA2PREVENT): Randomised Controlled Trial.
• Actual Study Start Date: January 17, 2022
• Estimated Primary Completion Date: July 2024
• Estimated Study Completion Date: January 2025

Arms and Interventions

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: Dexdor; Precedex; 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

Outcome Measures

Primary Outcome Measures :

1. Postoperative delirium [ Time Frame: Up to 7 days ]
   Cumulative incidence of postoperative delirium, as diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria

Secondary Outcome Measures :

1. Incidence of coma [ Time Frame: Up to 7 days ]
   Incidence of coma, as measured by Richmond Agitation Sedation Scale (-5 to +5)
2. Incidence of death, coma or postoperative delirium [ Time Frame: Up to 7 days ]
   Incidence of death, coma or postoperative delirium, as described above
3. Number of delirium days postoperatively [ Time Frame: Up to 7 days ]
   Number of delirium days postoperatively, as diagnosed according to DSM-5 criteria
4. Delirium severity [ Time Frame: Up to 7 days ]
   Delirium severity, as measured by Confusion Assessment Method for Intensive Care Units-7 (CAM-ICU)-7
5. Motor activity patterns [ Time Frame: 6 months ]
   Motor activity patterns, assessed with body worn accelerometers
6. Change in cognitive function between inclusion and after 1 and 6 months [ Time Frame: 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
7. Change in patient rated health status between inclusion and after 1 and 6 months [ Time Frame: 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
8. Serum concentrations of NFL and p-tau181 [ Time Frame: 5 days postoperatively ]
   Comparison to inclusion of serum concentrations of neurofilament light (NFL) and p-tau181 1, 3 and 5 days postoperatively
9. Estimate associations between frailty and the other endpoints [ Time Frame: 6 months ]
   Estimate associations between frailty and the other endpoints, as described above
10. Safety and tolerability [ Time Frame: 6 months ]
    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
11. Interaction between preoperative frailty and treatment on delirium and the other endpoints [ Time Frame: 6 months ]
    Interaction between preoperative frailty and treatment on delirium and the other endpoints, as described above
12. Change in frailty status between inclusion and after 1 and 6 months [ Time Frame: 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
13. Comparison of change in frailty status between inclusion and after 1 and 6 months [ Time Frame: 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.

Other Outcome Measures:

1. Additional biomarkers [ Time Frame: 5 days postoperatively ]
   Additional biomarkers of neural injury, inflammation or neurotransmission may be explored

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: Torgeir Bruun Wyller, Professor; +4791166682; t.b.wyller@medisin.uio.no

Contact: Bjørn Erik Neerland, PhD; +47 90078979; bjonee@ous-hf.no

Locations

Norway

Haukeland University Hospital; Recruiting

Bergen, Norway

Contact: Øyvind Sverre Svendsen, MD, PhD

Oslo University Hospital Rikshospitalet; Recruiting

Oslo, Norway

Contact: Hilde Margrethe Norum, MD, PhD

Oslo University Hospital Ullevål; Recruiting

Oslo, Norway

Contact: Svein Aslak Landsverk, MD, PhD

University Hospital of North Norway; Recruiting

Tromsø, Norway

Contact: Astrid Kristine Kjerstad, MD

St Olav University Hospital; Recruiting

Trondheim, Norway

Contact: Nils Kristian Skjærvold, MD, PhD

Sponsors and Collaborators

Oslo University Hospital

Haukeland University Hospital

University Hospital of North Norway

UMC Utrecht

Sahlgrenska University Hospital, Sweden

St. Olavs Hospital

Investigators

• Principal Investigator: Torgeir Bruun Wyller, Professor; Oslo University Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Bjørn Erik Neerland, MD, Medical doctor, postdoctoral researcher, Oslo University Hospital
• ClinicalTrials.gov Identifier: NCT05029050
• Other Study ID Numbers: 2021-001645-12; 2021-001645-12 ( EudraCT Number )
• First Posted: August 31, 2021
• Last Update Posted: January 12, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• 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

Keywords provided by Bjørn Erik Neerland, MD, Oslo University Hospital:

delirium; cognitive decline; frailty; heart surgery

Additional relevant MeSH terms:

Delirium; Frailty; Cognitive Dysfunction; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Pathologic Processes; Cognition Disorders; Clonidine; Dexmedetomidine; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Sympatholytics; Autonomic Agents