Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000862741
Ethics application status
Approved
Date submitted
19/10/2021
Date registered
17/06/2022
Date last updated
19/09/2023
Date data sharing statement initially provided
17/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Managing Delirium with FLUvoxamine treatment in Non-Cardiac Surgical patients: a feasibility trial
Scientific title
Managing Delirium with FLUvoxamine treatment in Non-Cardiac Surgical patients: a feasibility trial
Secondary ID [1] 305551 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
MD FluNCS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Delirium 323942 0
Non-Cardiac Surgery 324212 0
Condition category
Condition code
Neurological 321455 321455 0 0
Other neurological disorders
Surgery 321456 321456 0 0
Other surgery
Mental Health 323766 323766 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral Fluvoxamine 100 mg tablets (immediate release)
Study drug (100mg Fluvoxamine tablet or placebo) will be administered at the following times:
1)Evening prior to surgery (if inpatient the study drug will be transferred to the ward for administration, registered nurses (RNs) will administer, witness and sign off once taken in the electronic medical record)(If the patient is at home the evening prior to surgery they will be dispensed the tablets for the pm before surgery and am of surgery from pharmacy - clinical trials unit. This will be self-reported adherence).
2) Day of surgery - Study drug to be taken morning of surgery and evening of surgery
3) Post-operative day 1 - Study drug to be taken morning and evening

On day of surgery if the patient is arriving in the morning they will be given the study drug by a registered nurse (RN) in admissions or they will self administer if not arriving until later. On the evening of surgery and post-operative day 1 the study drug will be administered, witnessed and signed off on the electronic medication chart by an RN.
Intervention code [1] 321946 0
Treatment: Drugs
Intervention code [2] 321947 0
Prevention
Comparator / control treatment
Placebo (oral glucose tablet)
Control group
Placebo

Outcomes
Primary outcome [1] 331500 0
Feasibility assessed as number of eligible participants enrolled per month at a single site (Royal Prince Alfred Hospital) by an audit of the study screening and recruitment log.
Timepoint [1] 331500 0
Assessed quarterly for the 12- month duration of the study.
Secondary outcome [1] 410080 0
Screening failures as documented in screening log and assessed by audit of screening log.
Timepoint [1] 410080 0
Assessed quarterly for the 12- month duration of the study.
Secondary outcome [2] 410081 0
Instance of post-operative delirium using the 3D Confusional Assessment Method (3D-CAM).
Timepoint [2] 410081 0
Assessed twice daily post-operative days 1-4
Secondary outcome [3] 410082 0
Assess the rate and severity of adverse events of fluvoxamine (assessment of adverse events/side effects will include pain scale, presence of nausea/vomiting, documentation by clinical staff of sleep disturbances, altered bowel movements, sweating, fatigue, anxiety/nervousness). This will be assessed by anaesthetic staff during the day of surgery, self-reports from the patient, assessed and monitored by research nursing staff during follow ups and monitored by registered nurses and medical staff on the ward or ICU.
Timepoint [3] 410082 0
Assessed on day of surgery by treating anaesthetic doctor and again in the evening of surgery by research staff, assessed daily by a member of the research staff or a registered nurse or medical staff on the ward/ICU. If adverse events are noted, the frequency of assessment will be increased at the direction of the principal investigator and treating team.
Secondary outcome [4] 410083 0
Examine instances of missed study drug doses due to adverse events as documented in the electronic medication records by registered nurses on the ward or self-reported by participant if not an inpatient.
Timepoint [4] 410083 0
Evening prior to surgery, AM and PM- Day of surgery, and AM/PM on post-operative day 1.
Secondary outcome [5] 410084 0
Assess the ability to acquire electroencephalogram (EEG). Assessed by auditing case record files/uploaded to secure server to confirm if completed.
Timepoint [5] 410084 0
EEG data will be collected intra-operatively and post-operative day 1
Secondary outcome [6] 410085 0
Differences in EEG slow wave activity, assessed by research staff during data analysis phase.
Timepoint [6] 410085 0
EEG data will be collected intra-operatively and post-operative day 1
Secondary outcome [7] 410086 0
Assess the ability to acquire plasma biomarkers by documentation in Biospecimen log in the Department Lab. Missing samples or issues with analysing samples will be documented in case record file.
Timepoint [7] 410086 0
Blood samples to be collected in the morning of surgery (around 1 hour post-study drug and before anaesthetic), in the mornings on post-operative days 1, 2, 3 and 4 (around 1 hour after the study drug on post-operative day one and in the morning between 0800-1000 on post-operative days 2, 3 and 4).
Secondary outcome [8] 410087 0
Group differences in plasma IL-8 and NfL
Timepoint [8] 410087 0
Blood samples to be collected in the morning of surgery (around 1 hour post-study drug and before anaesthetic), in the mornings on post-operative days 1 and 2 during follow up by research staff between 0600-1000.
Plasma aliquots will be processed on the morning of surgery and post operative days 1 and 2 and bio-banked in the department.
Secondary outcome [9] 410088 0
Assess the fraction of completed delirium assessments by auditing participant CRFs/RedCAP database for missing data sets.
Timepoint [9] 410088 0
Assessed daily on post-operative days 1-4.
Secondary outcome [10] 410090 0
Post-operative pain score assessed using numerical pain scale.
Timepoint [10] 410090 0
Assessed daily on post-operative days 1-4.
Secondary outcome [11] 410092 0
Differences in plasma CRP, White cell count and troponin, samples will be taken during routine blood collection when feasible or by a trained member of the research team.
Timepoint [11] 410092 0
Assessed daily on post-operatives days 1-4.
Secondary outcome [12] 410242 0
Severity of Delirium assessed using the Delirium Rating Scale (revised)
Timepoint [12] 410242 0
Assessed daily on post-operative days 1-4.
Secondary outcome [13] 410256 0
Assess the influence of fluvoxamine on post-operative change in cognition using the Modified Telephone Interview for Cognition (TICS-M)
Timepoint [13] 410256 0
Assessed on post-operative day 4 and 30.
Secondary outcome [14] 410257 0
Assessment of post-operative disability using the World Health Organisation Disability Assessment Schedule (WHODAS).
Timepoint [14] 410257 0
Assessed on post-operative day 4 and 30.
Secondary outcome [15] 410258 0
Assessment of influence of fluvoxamine on post-operative geriatric depression using the Geriatric Depression Scale (GDS15).
Timepoint [15] 410258 0
Assessed on post-operative day 4 and 30.
Secondary outcome [16] 410552 0
Instance of post-operative delirium using the Richmond Agitation and Sedation Scale (RASS).
Timepoint [16] 410552 0
Assessed daily on post-operative days 1-4.
Secondary outcome [17] 410553 0
Assess the influence of fluvoxamine on post-operative change in cognition using a verbal fluency assessment.
Timepoint [17] 410553 0
Assessed on post-operative days 4 and 30,
Secondary outcome [18] 410555 0
Blood loss during as reported by surgeons during the procedure as recorded on the post-operation report or in electronic medical records and as documented in electronic medical records by the treating medical team in post-operative phase.
Timepoint [18] 410555 0
Assessed following the procedure on day of surgery and daily on post-operative days 1-4.
Secondary outcome [19] 410556 0
Participant satisfaction with anaesthetic and research activities. Questionnaire self-administered or administered by research staff. The questionairre was designed by the principal investigator and his research team at University of Wisconsin specfically for his anaesthetic research projects.
Timepoint [19] 410556 0
Post-operative day 4.

Eligibility
Key inclusion criteria
Elective non-cardiac, non-intracranial surgical patients who are older than 60 years old with an expected length of hospital stay of >2 days
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Non-english speaking
Participants who may have received an investigational new drug within the last 7 days/weeks.
Participants who lack capacity to provide informed consent.
Participants with prior known intolerance/allergy to SSRIs or fluvoxamine.
Planned postoperative ventilation
Patients on medications that interact with fluvoxamine: hepatic metabolism by CYP1A2 (theophylline, clozapine, tizadine, olanzapine), metabolism inhibited by fluvoxamine (diazepam, alprazolam, phenytoin), sigma-1
agonists/antagonists (donepezil, sertraline), risk of serotonin syndrome (St John’s Wort, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs)

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants randomized using the randomization model in REDCAP. Study drug/placebo will be provided by an external pharmacy. Study drugs will be numbered and patients allocated to study drug using randomisation model. Unblinding will only occur when study finishes or if safety issues require,
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Based on an estimated 25% enrollment rate, then n=184 screen-positive patients will provide sufficient power to measure this proportion with a 95% confidence interval width of 13%. From our preliminary data, we expect successful enrollment of 46 patients across 2 sites over 9 months. This will allow estimation of the proportion of patients who will complete at least 80% of doses of fluvoxamine with a 95% confidence interval width of 23%, assuming a completion rate of 80%.
The DRS-R-98 score, 3D-CAMS, TICS-M, Verbal fluency, WHODAS and GDS15 will be analyzed by Mann-Whitney or t- test depending on distribution.
The incidence of delirium (on 3D-CAM), will be analysed by Fisher’s exact test.
EEG analysis will be conducted by pwelch calculation of power bands and Mann-Whitney or t-test depending on distribution.
The biomarkers (IL-8 and NfL [and CRP, WCC and troponin]) will be log transformed and will be analyzed by Mann- Whitney or t-test depending on distribution.
Rates of data loss will be established using point estimates and sample variance will be estimated in intention to treat analyses. For all analyses, a P below 0.05 will be considered statistically significant.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/09/2023
Actual
Date of last participant enrolment
Anticipated
2/06/2025
Actual
Date of last data collection
Anticipated
3/08/2026
Actual
Sample size
Target
46
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20770 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 35581 0
2050 - Camperdown
Recruitment outside Australia
Country [1] 24819 0
United States of America
State/province [1] 24819 0
Washington

Funding & Sponsors
Funding source category [1] 309916 0
Hospital
Name [1] 309916 0
Royal Prince Alfred Hospital
Country [1] 309916 0
Australia
Primary sponsor type
Hospital
Name
Royal Prince Alfred Hosptial
Address
Level 4, BLDG 89
50 Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 310963 0
None
Name [1] 310963 0
Address [1] 310963 0
Country [1] 310963 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309635 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 309635 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 309635 0
Australia
Date submitted for ethics approval [1] 309635 0
26/10/2021
Approval date [1] 309635 0
28/02/2023
Ethics approval number [1] 309635 0

Summary
Brief summary
Double-blind placebo-controlled randomised controlled feasibility trial to assess the feasibility of a larger multi-centre study. The rationale for the study are based on the known action of the drug fluvoxamine to reduce inflammation in the brain. The main objective of this pilot is to determine feasibility on a larger scale - including rate of recruitment, adherence to drug, ability to preform research activities and reporting adverse events related to the drug. As this is a pilot study our hypothesis is that more than 25% of patients approached will be happy to enrol in the study, 80% of enrolled participants will adhere to the study drug schedule and we will be able to collect measurable information on 90% of the participants. Secondary objectives include instance and severity of post-operative delirium, changes in EEG from intra-operative recording to and post-operative day 1, and collecting blood results/bio-markers associated with inflammation. Previous randomised control trials of prophylactic interventions to treat delirium have shown modest effectiveness.
The intervention (Fluvoxamine 100mg oral tablet) or placebo will be administered on the evening prior to surgery, day of surgery and post-operative day one. Participants will be asked to partake in cognitive assessments, delirium assessments and have routine bloods drawn as part of daily research activities.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114854 0
Prof Robert Sanders
Address 114854 0
Royal Prince Alfred Hospital
Department of Anaesthetics
Level 4, BLDG 89
50 Missenden Road
Camperdown NSW 2050
Country 114854 0
Australia
Phone 114854 0
+61 02 9515 8564
Fax 114854 0
Email 114854 0
robert.sanders@sydney.edu.au
Contact person for public queries
Name 114855 0
Miss Kaitlin Kramer
Address 114855 0
Royal Prince Alfred Hospital
Department of Anaesthetics
Level 4, BLDG 89
50 Missenden Road
Camperdown NSW 2050
Country 114855 0
Australia
Phone 114855 0
+61 02 9515 8789
Fax 114855 0
Email 114855 0
kaitlin.kramer@health.nsw.gov.au
Contact person for scientific queries
Name 114856 0
Prof Robert Sanders
Address 114856 0
Royal Prince Alfred Hospital
Department of Anaesthetics
Level 4, BLDG 89
50 Missenden Road
Camperdown NSW 2050
Country 114856 0
Australia
Phone 114856 0
+61 02 9515 8564
Fax 114856 0
Email 114856 0
robert.sanders@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16219Study protocol    382949-(Uploaded-17-06-2022-10-57-48)-Study-related document.pdf
16270Informed consent form    382949-(Uploaded-17-06-2022-10-58-26)-Study-related document.pdf
18534Ethical approval    382949-(Uploaded-08-07-2022-08-41-42)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.