Back to resultsDexmedetomidine or Clonidine Infusion for Prevention of Delirium After Open Heart Surgery (ALPHA2PREVENT)
Primary Purpose
Delirium, Cognitive Decline, Frailty
Status
Recruiting
Phase
Phase 4
Locations
Norway
Study Type
Interventional
Intervention
Dexmedetomidine
Clonidine
Natriumchlorid
Sponsored by
About this trial
This is an interventional prevention trial for Delirium focused on measuring delirium, cognitive decline, frailty, heart surgery
Eligibility Criteria
Inclusion Criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
- Participant must be ≥70 years old at the time of signing the informed consent.
- 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.
Participant must be capable of giving signed informed consent.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
- Preoperative delirium
- Known hypersensitivity to the active ingredient or components of the product
- 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
- Uncontrolled hypotension
- Ischemic stroke or transitory ischemic attack the last month or critical peripheral ischemia
- Acute coronary syndrome last 24 hours. Acute coronary syndrome is defined according to international guidelines
- Left ventricular ejection fraction < 40%
- Severe renal impairment (estimated GFR <20ml/min) or expected requirement for renal replacement therapy
- Severe hepatic dysfunction (liver enzyme three times the upper limit of normal together with a serum albumin concentration below the normal reference limit)
- Reduced peripheral autonomous activity (e.g. spinal cord injury)
- Current use of tricyclic antidepressants, monoamine reuptake inhibitors or ciclosporin
- Endocarditis or sepsis
- Pheochromocytoma
- Planned deep hypothermia and circulatory arrest
- Emergency surgery, defined as less than 24 hours from admission to surgery
- Previously included in this study
- Not speaking or reading Norwegian
- Any other condition as evaluated by the treating physician
Sites / Locations
- Haukeland University HospitalRecruiting
- Oslo University Hospital RikshospitaletRecruiting
- Oslo University Hospital UllevålRecruiting
- University Hospital of North NorwayRecruiting
- St Olav University HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Dexmedetomidine (D)
Clonidine (C)
Placebo (P)
Arm 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.
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.
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.
Outcomes
Primary Outcome Measures
Postoperative delirium
Cumulative incidence of postoperative delirium, as diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria
Secondary Outcome Measures
Incidence of coma
Incidence of coma, as measured by Richmond Agitation Sedation Scale (-5 to +5)
Incidence of death, coma or postoperative delirium
Incidence of death, coma or postoperative delirium, as described above
Number of delirium days postoperatively
Number of delirium days postoperatively, as diagnosed according to DSM-5 criteria
Delirium severity
Delirium severity, as measured by Confusion Assessment Method for Intensive Care Units-7 (CAM-ICU)-7
Motor activity patterns
Motor activity patterns, assessed with body worn accelerometers
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
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
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
Estimate associations between frailty and the other endpoints
Estimate associations between frailty and the other endpoints, as described above
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
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
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
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.
Full Information
NCT ID
NCT05029050
First Posted
August 21, 2021
Last Updated
January 30, 2023
Sponsor
Oslo University Hospital
Collaborators
Haukeland University Hospital, University Hospital of North Norway, UMC Utrecht, Sahlgrenska University Hospital, Sweden, St. Olavs Hospital
1. Study Identification
Unique Protocol Identification Number
NCT05029050
Brief Title
Dexmedetomidine or Clonidine Infusion for Prevention of Delirium After Open Heart Surgery
Acronym
ALPHA2PREVENT
Official Title
Alpha 2 Adrenergic Receptor Agonists for the Prevention of Delirium and Cognitive Decline After Open Heart Surgery (ALPHA2PREVENT): Randomised Controlled Trial.
Study Type
Interventional
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 17, 2022 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
January 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Oslo University Hospital
Collaborators
Haukeland University Hospital, University Hospital of North Norway, UMC Utrecht, Sahlgrenska University Hospital, Sweden, St. Olavs Hospital
4. Oversight
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
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Delirium, Cognitive Decline, Frailty
Keywords
delirium, cognitive decline, frailty, heart surgery
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
900 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Dexmedetomidine (D)
Arm Type
Experimental
Arm 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.
Arm Title
Clonidine (C)
Arm Type
Experimental
Arm 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.
Arm Title
Placebo (P)
Arm Type
Placebo Comparator
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Dexmedetomidine
Other Intervention Name(s)
Dexdor, Precedex, N05C M18
Intervention Description
Continous intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Clonidine
Other Intervention Name(s)
Catapresan, Catapressan, N02C X02
Intervention Description
Continous intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Natriumchlorid
Other Intervention Name(s)
Saline, NaCl 9mg/ml
Intervention Description
Continous intravenous infusion NaCl
Primary Outcome Measure Information:
Title
Postoperative delirium
Description
Cumulative incidence of postoperative delirium, as diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria
Time Frame
Up to 7 days
Secondary Outcome Measure Information:
Title
Incidence of coma
Description
Incidence of coma, as measured by Richmond Agitation Sedation Scale (-5 to +5)
Time Frame
Up to 7 days
Title
Incidence of death, coma or postoperative delirium
Description
Incidence of death, coma or postoperative delirium, as described above
Time Frame
Up to 7 days
Title
Number of delirium days postoperatively
Description
Number of delirium days postoperatively, as diagnosed according to DSM-5 criteria
Time Frame
Up to 7 days
Title
Delirium severity
Description
Delirium severity, as measured by Confusion Assessment Method for Intensive Care Units-7 (CAM-ICU)-7
Time Frame
Up to 7 days
Title
Motor activity patterns
Description
Motor activity patterns, assessed with body worn accelerometers
Time Frame
6 months
Title
Change in cognitive function between inclusion and after 1 and 6 months
Description
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
Time Frame
6 months
Title
Change in patient rated health status between inclusion and after 1 and 6 months
Description
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
Time Frame
6 months
Title
Serum concentrations of NFL and p-tau181
Description
Comparison to inclusion of serum concentrations of neurofilament light (NFL) and p-tau181 1, 3 and 5 days postoperatively
Time Frame
5 days postoperatively
Title
Estimate associations between frailty and the other endpoints
Description
Estimate associations between frailty and the other endpoints, as described above
Time Frame
6 months
Title
Safety and tolerability
Description
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
Time Frame
6 months
Title
Interaction between preoperative frailty and treatment on delirium and the other endpoints
Description
Interaction between preoperative frailty and treatment on delirium and the other endpoints, as described above
Time Frame
6 months
Title
Change in frailty status between inclusion and after 1 and 6 months
Description
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
Time Frame
6 months
Title
Comparison of change in frailty status between inclusion and after 1 and 6 months
Description
Comparison of change in frailty status between inclusion and after 1 and 6 months (as described above) between patients with or without postoperative delirium.
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Additional biomarkers
Description
Additional biomarkers of neural injury, inflammation or neurotransmission may be explored
Time Frame
5 days postoperatively
10. Eligibility
Sex
All
Minimum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
Participant must be ≥70 years old at the time of signing the informed consent.
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.
Participant must be capable of giving signed informed consent.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
Preoperative delirium
Known hypersensitivity to the active ingredient or components of the product
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
Uncontrolled hypotension
Ischemic stroke or transitory ischemic attack the last month or critical peripheral ischemia
Acute coronary syndrome last 24 hours. Acute coronary syndrome is defined according to international guidelines
Left ventricular ejection fraction < 40%
Severe renal impairment (estimated GFR <20ml/min) or expected requirement for renal replacement therapy
Severe hepatic dysfunction (liver enzyme three times the upper limit of normal together with a serum albumin concentration below the normal reference limit)
Reduced peripheral autonomous activity (e.g. spinal cord injury)
Current use of tricyclic antidepressants, monoamine reuptake inhibitors or ciclosporin
Endocarditis or sepsis
Pheochromocytoma
Planned deep hypothermia and circulatory arrest
Emergency surgery, defined as less than 24 hours from admission to surgery
Previously included in this study
Not speaking or reading Norwegian
Any other condition as evaluated by the treating physician
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bjørn Erik Neerland, PhD
Phone
+4790078979
Email
bjonee@ous-hf.no
First Name & Middle Initial & Last Name or Official Title & Degree
Torgeir Bruun Wyller, Professor
Phone
+4791166682
Email
t.b.wyller@medisin.uio.no
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bjørn Erik Neerland, PhD
Organizational Affiliation
Oslo University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Haukeland University Hospital
City
Bergen
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Øyvind Sverre Svendsen, MD, PhD
Facility Name
Oslo University Hospital Rikshospitalet
City
Oslo
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hilde Margrethe Norum, MD, PhD
Facility Name
Oslo University Hospital Ullevål
City
Oslo
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Svein Aslak Landsverk, MD, PhD
Facility Name
University Hospital of North Norway
City
Tromsø
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Astrid Kristine Kjerstad, MD
Facility Name
St Olav University Hospital
City
Trondheim
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nils Kristian Skjærvold, MD, PhD
12. IPD Sharing Statement
Plan to Share IPD
Yes
Citations:
PubMed Identifier
35725264
Citation
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.
Results Reference
derived
Learn more about this trial
Dexmedetomidine or Clonidine Infusion for Prevention of Delirium After Open Heart Surgery
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