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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05029050
Recruitment Status : Recruiting
First Posted : August 31, 2021
Last Update Posted : January 12, 2023
Sponsor:
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

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.

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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

Resource links provided by the National Library of Medicine


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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05029050


Contacts
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Contact: Torgeir Bruun Wyller, Professor +4791166682 t.b.wyller@medisin.uio.no
Contact: Bjørn Erik Neerland, PhD +47 90078979 bjonee@ous-hf.no

Locations
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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
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Principal Investigator: Torgeir Bruun Wyller, Professor Oslo University Hospital
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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    Key Record Dates
Last Update Posted: January 12, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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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:
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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