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Trial registered on ANZCTR

Registration number

ACTRN12625000368437

Ethics application status

Approved

Date submitted

16/04/2025

Date registered

28/04/2025

Date last updated

28/04/2025

Date data sharing statement initially provided

28/04/2025

Type of registration

Prospectively registered

Titles & IDs

Public title

Intranasal insulin for prevention of perioperative delirium in femoral fracture surgery

Scientific title

A phase II single site, triple blind randomised placebo-controlled trial of short-acting intranasal insulin for the prevention of delirium in older patients undergoing surgery for femoral fracture

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Delirium

Condition category

Condition code

Neurological

Other neurological disorders

Surgery

Other surgery

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Nebulised intranasal insulin.

Drug: insulin aspart.
Dose: 30 international units (0.3mL) twice daily.
Device: Nasal drug delivery device (Teleflex MAD NasalTM Intranasal Mucosal Atomization Device).

Administration: Administration to a nostril twice daily (morning and evening) assisted by registered nurse.
Duration: Commence treatment on enrolment until day 3 post-surgery.
Monitoring adherence: Ward nurses will undergo training in preparation for the trial to ensure adherence to the trial protocol as well as consistent drug administration and documentation. Missed doses and tolerability will be documented by the nurses on electronic medical records and this will be reviewed by the study team.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Diluent placebo

Drug: Diluent (glycerin 16 mg, metacresol 1.6 mg, phenol 0.65 mg and sodium phosphate dibasic 3.8 mg dissolved in 1 ml distilled water)
Dose: 0.3mL twice daily.
Device: Nasal drug delivery device (Teleflex MAD NasalTM Intranasal Mucosal Atomization Device).

Administration: Administration to a nostril twice daily (morning and evening) assisted by registered nurse.
Duration: Commence treatment on enrolment until day 3 post-surgery.
Monitoring adherence: Ward nurses will undergo training in preparation for the trial to ensure adherence to the trial protocol as well as consistent drug administration and documentation. Missed doses and tolerability will be documented by the nurses on electronic medical records and this will be reviewed by the study team.

Control group

Placebo

Outcomes

Primary outcome [1]

Incidence of delirium.

Timepoint [1]

Daily assessment will be conducted from admission until day 4 postoperatively.

Secondary outcome [1]

Duration of delirium.

Timepoint [1]

Daily assessment until day 4 postoperatively. If delirium is present and persists on day 4 postoperatively, then assessment will be continued at least five times per week until delirium resolves, transfer to other hospital or hospital discharge.

Secondary outcome [2]

Severity of delirium.

Timepoint [2]

Daily assessment until day 4 postoperatively. If delirium is present and persists on day 4 postoperatively, the assessment will be continued at least five times per week until delirium resolves, transfer to other hospital or hospital discharge.

Secondary outcome [3]

Acute and total length of hospital stay.

Timepoint [3]

At discharge from hospital.

Secondary outcome [4]

Hospital-acquired complications.

Timepoint [4]

At discharge from hospital.

Secondary outcome [5]

New admission to a residential aged care facility.

Timepoint [5]

At discharge from hospital, at 4 month telephone follow up and at 12 months follow up.

Secondary outcome [6]

Incidence of cognitive decline at 12 months follow up (from admission).

Timepoint [6]

On admission (MMSE) and at 12 months (ACE-R) follow up.

Secondary outcome [7]

New onset dementia at 12 months follow up (from admission).

Timepoint [7]

On admission (MMSE) and at 12 months (ACE-R) follow up.

Secondary outcome [8]

Mortality rates.

Timepoint [8]

During admission, at 4 month telephone follow up and at 12 months follow up.

Secondary outcome [9]

Preserved activities of daily living at 12 months from baseline.

Timepoint [9]

At 12 months follow up.

Secondary outcome [10]

Health care utilisation and cost of care.

Timepoint [10]

At 4 and 12 months follow-up.

Secondary outcome [11]

Quality of Life.

Timepoint [11]

At 4 month telephone follow-up and at 12 months follow up.

Secondary outcome [12]

Patients and caregiver emotional distress.

Timepoint [12]

At Discharge.

Secondary outcome [13]

Depression.

Timepoint [13]

At 12 months follow up.

Eligibility

Key inclusion criteria

Aged 75 years or older, or aged 65-74 years with pre-existing cognitive impairment and/or frailty (clinical frailty scale (CFS) >4).
Undergoing orthopaedic surgery for femoral fractures (neck of femur, femoral shaft, distal femur and periprosthetic fractures of the femur).
Receiving inpatient care at the Prince of Wales Hospital.
Informed consent obtained.

Minimum age

65 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Prevalent delirium on admission to hospital diagnosed by a geriatrician or advanced trainee in geriatric medicine using the DSM-V criteria.
Expected prognosis is less than 7 days lifespan assessed by admitting medical consultant opinion.
Allergy to insulin formulation.
A structural abnormality precluding the use of nasal drug delivery device.
Unable to participate in cognitive testing and unable to establish whether the participant is at their neurocognitive baseline (i.e. at baseline cognition and function if pre-existing cognitive impairment) according to available sources of evidence (e.g. corroborative history from carer in addition to staff assessment on patient’s interaction, level of consciousness and fluctuations).
Participant objects to treatment.

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)

Allocation will be undertaken by staff in the hospital pharmacy as per the randomisation schedule.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation will be conducted using randomly permuted block randomisation with variable block sizes of 4-8 using a computer algorithm.

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 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

Power analysis (with 5% significance and 80% power) was performed using Australian Hip Fracture Registry data for delirium rates in this population. A total of 216 participants will be required based on reducing incidence of post-operative delirium by 50% (from 34% to 17%) and allowing for a 5% dropout rate.
A statistical analysis plan will be developed and signed by the investigators prior to study completion and published in Open Science Framework (OSF). The primary analysis will be undertaken by researchers blind to group allocation.
An intention-to-treat approach will be adopted for all analyses and statistical significance assumed at the level of 5% (P<0.05). A Poisson or negative binomial regression will be used to test the differences in delirium incidence as well as hospital acquired complications between the arms depending on the distribution. The primary analysis will be replicated by another member of the research team or a statistician. Baseline characteristics will be reported for the overall population and separately for each group.
For descriptive statistics, continuous variables will be reported as mean with standard deviation or median and interquartile range, depending on their distribution. For between group comparisons, Student’s t-test and Mann-Whitney U tests will be adopted for normally and non-normally distributed data, respectively. Categorical/binary variables will be presented as frequency and percentages and will be analysed using the chi-squared or Fisher’s exact test. Depending on adherence, a per protocol analysis may be undertaken.
A priori subgroup analysis will be performed on the primary and secondary outcomes for the following groups:
• Baseline CFS
• History of cognitive impairment
• Baseline residential status
• Use of central nervous system medications at the point of admission
• Baseline functional independence
• Baseline ASA grade
• Adherence to treatment
• Depth of sedation
• Type and/or duration of anaesthesia (general vs regional anaesthetics)
• Anaesthetic agents
• Pre-existing comorbidities/CCI
• APOE4 status

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

28/04/2025

Actual

Date of last participant enrolment

Anticipated

27/04/2029

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

216

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Prince of Wales Hospital - Randwick

Recruitment postcode(s) [1]

2031 - Randwick

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

The Julia Lowy Foundation

Address [1]

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Prince of Wales Hospital Foundation

Address [2]

Country [2]

Australia

Primary sponsor type

Individual

Name

Prof Gideon A Caplan, The Prince of Wales Hospital

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

South Eastern Sydney Local Health District HREC

Ethics committee address [1]

https://www.seslhd.health.nsw.gov.au/services-clinics/directory/research-home/ethics

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

09/01/2024

Approval date [1]

29/02/2024

Ethics approval number [1]

2024/ETH00005

Summary

Brief summary

Delirium is a transient and fluctuating cause of cerebral dysfunction and manifests with a wide range of cognitive and behavioural abnormalities. Delirium is associated with both increased morbidity and mortality and is a medical emergency. 

The sequelae of delirium are multiple and significant and extend well beyond the acute hospital stay. Delirium is associated with higher rates of death, medical complications, longer hospital stays, functional and cognitive decline and admission to residential aged care facilities. 

There are no registered pharmacological agents for the prevention or management of delirium. Pharmacological management is currently focused on symptomatic control with antipsychotics, as thus far, the cerebral abnormalities causing delirium have been poorly elucidated.

We hypothesise that intranasal insulin, via its neuromodulatory effects, will reduce the rate of delirium leading to improved outcomes for patients and decreased costs of patient care in hospital. 

This RCT aims to evaluate the use of short-acting intranasal insulin in the prevention of delirium in patients undergoing orthopaedic surgery for femoral fractures. We will also assess the effect of intranasal insulin on duration and severity of delirium, acute and total hospital length of stay, complications, new residential aged care facility placement, cognitive decline, new onset of dementia, mortality, function, cost of care, quality of life (QoL) and emotional/mental impact on patients and caregivers.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Gideon A Caplan

Address

Department of Geriatric Medicine South Wing Edmund Blackett Building The Prince of Wales Hospital Barker Street Randwick NSW 2031

Country

Australia

Phone

+61293824252

Fax

[email protected]

Contact person for public queries

Name

Gideon A Caplan

Address

Department of Geriatric Medicine South Wing Edmund Blackett Building The Prince of Wales Hospital Barker Street Randwick NSW 2031

Country

Australia

Phone

+61293824252

Fax

[email protected]

Contact person for scientific queries

Name

Gideon A Caplan

Address

Department of Geriatric Medicine South Wing Edmund Blackett Building The Prince of Wales Hospital Barker Street Randwick NSW 2031

Country

Australia

Phone

+61293824252

Fax

[email protected]

Data sharing statement

Will the study consider sharing individual participant data?

Yes

Will there be any conditions when requesting access to individual participant data?

Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
• Requires a scientifically sound proposal or protocol
• Requires approval by an ethics committee
• Requires a data sharing agreement between data requester and trial custodian or sponsor

What individual participant data might be shared?

• All de-identified individual participant data

What types of analyses could be done with individual participant data?

• Any type of analysis (i.e. no restrictions on data re-use)

When can requests for individual participant data be made (start and end dates)?

From:
After publication of main results
To:
Not yet decided

Where can requests to access individual participant data be made, or data be obtained directly?

• Email of trial custodian, sponsor or committee: [email protected]

Are there extra considerations when requesting access to individual participant data?

What supporting documents are/will be available?

No Supporting Document Provided

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.

Trial Review

Documents added manually

Documents added automatically