Alpha 2 adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): randomised controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oslo University Hospital HF

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

10 Sep 2024 → ongoing

Decision date (initial)

2024-09-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

The national programme for clinical therapy research in the specialist health service, KLINBEFORSK

External identifiers

EU CT number

2023-510212-39-00

EudraCT number

2021-001645-12

ClinicalTrials.gov

NCT05029050

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Prophylaxis, Therapy, Efficacy

To prevent postoperative delirium

Secondary objectives 14

1. To prevent coma or postoperative (p.o.) delirium
2. To reduce the duration of p.o. delirium and delirium severity
3. To prevent cognitive decline and reduced patient rated health status 1 and 6 months p.o.
4. To prevent a p.o. increase in biomarkers of neuronal injury
5. To estimate the associations of preoperative frailty status and the other endpoints described above
6. To estimate the associations of preoperative frailty status and risk for adverse effects of dexmedetomidine and clonidine treatment
7. To assess preoperative frailty status as a predictive marker of effect or of adverse effects of dexmedetomidine and clonidine treatment
8. To compare the tolerability and safety of clonidine and dexmedetomidine with placebo and with each other
9. To prevent progression of frailty 1 and 6 months p.o.
10. To assess p.o delirium as a risk factor for progression of frailty status 1 and 6 months p.o.
11. To describe preoperative EEG in patients who develop delirium as opposed to those who do not
12. To gain further insight in the pathophysiology of delirium as assessed by EEG
13. To describe incidence of organ failure in an elderly cardiac surgery population
14. To prevent incidence and severity of organ failure after cardiac surgery

Conditions and MedDRA coding

Delirium

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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 of any of these procedures. 3. Participant must be capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria 18

1. Preoperative delirium (present at time of potential inclusion)
2. Known hypersensitivity to the active ingredient or components of the product
3. 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
4. Uncontrolled hypotension
5. Ischemic stroke or transitory ischemic attack the last month or critical peripheral ischemia
6. Acute coronary syndrome last 24 hours. Acute coronary syndrome is defined according to international guidelines
7. Left ventricular ejection fraction < 40%
8. Severe renal impairment (estimated GFR < 20 ml/min) or expected requirement for renal replacement therapy
9. Severe hepatic dysfunction (liver enzyme three times the upper limit of normal together with a serum albumin concentration below the normal reference limit
10. Reduced peripheral autonomous activity (e.g. spinal cord injury)
11. Current use of tricyclic antidepressants, monoamine reuptake inhibitors or ciclosporin
12. Endocarditis or sepsis
13. Pheochromocytoma
14. Planned deep hypothermia and circulatory arrest
15. Emergency surgery, defined as less than 24 hours from admission to surgery
16. Previously included in this study
17. Not speaking or reading Norwegian
18. Any other condition as evaluated by the treating physician

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Cumulative incidence of postoperative delirium, as diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria

Secondary endpoints 17

1. Incidence of coma or postoperative delirium, as measured by Richmond Agitation Sedation Scale (RASS) and according to DSM-5 criteria
2. Incidence of death, coma or postoperative delirium, as described above
3. Number of delirium days postoperatively, as diagnosed according to DSM-5 criteria
4. Delirium severity, as measured by Confusion Assessment Method for Intensive Care Units-7 (CAM-ICU)-7, Observational Scale of Level of Arousal (OSLA) and RASS
5. Motor activity patterns, assessed with body worn accelerometers
6. 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, as assessed by the EQ-5D-5L questionnaire preoperatively and 1 and 6 months postoperatively
8. 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, as described above
10. 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, as described above
12. Change in frailty status between inclusion and after 1 and 6 months, as graded by the frailty index (FI) and essential frailty toolset (EFT), 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 (as described above) between patients with or without postoperative delirium.
14. Comparison of changes in EEG pattern from preoperatively to postoperatively in patients who do and do not develop delirium.
15. Comparison of postoperative EEG in patients who do and do not develop delirium and the association with exposure to dexmedetomidine vs clonidine vs placebo
16. Additional biomarkers of neural injury, inflammation or neurotransmission may be explored
17. Sequential Organ Failure Assessment (SOFA) score

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oslo University Hospital HF

Sponsor organisation

Oslo University Hospital HF

Address

Taarnbygget, Kirkeveien 166 Kirkeveien 166

City

Oslo

Postcode

0450

Country

Norway

Scientific contact point

Organisation

Oslo University Hospital HF

Contact name

Bjørn Erik Neerland

Public contact point

Organisation

Oslo University Hospital HF

Contact name

Bjørn Erik Neerland

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications