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.
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
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
900
Continous intravenous infusion
Continous intravenous infusion
Continous intravenous infusion NaCl
Haukeland University Hospital
Bergen, Norway
RECRUITINGOslo University Hospital Rikshospitalet
Oslo, Norway
RECRUITINGOslo University Hospital Ullevål
Oslo, Norway
RECRUITINGPostoperative delirium
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
Incidence of coma
Incidence of coma, as measured by Richmond Agitation Sedation Scale (-5 to +5)
Time frame: Up to 7 days
Incidence of death, coma or postoperative delirium
Incidence of death, coma or postoperative delirium, as described above
Time frame: Up to 7 days
Number of delirium days postoperatively
Number of delirium days postoperatively, as diagnosed according to DSM-5 criteria
Time frame: Up to 7 days
Delirium severity
Delirium severity, as measured by Confusion Assessment Method for Intensive Care Units-7 (CAM-ICU)-7
Time frame: Up to 7 days
Motor activity patterns
Motor activity patterns, assessed with body worn accelerometers
Time frame: 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
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University Hospital of North Norway
Tromsø, Norway
RECRUITINGSt Olav University Hospital
Trondheim, Norway
RECRUITINGTime frame: 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
Time frame: 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
Time frame: 5 days postoperatively
Estimate associations between frailty and the other endpoints
Estimate associations between frailty and the other endpoints, as described above
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 6 months