Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000669796
Ethics application status
Approved
Date submitted
28/03/2022
Date registered
9/05/2022
Date last updated
20/09/2022
Date data sharing statement initially provided
9/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Intranasal insulin for neurocognition in bipolar disorder
Scientific title
The efficacy of adjunctive intranasal insulin for the treatment of neurocognitive dysfunction in bipolar disorder: A 12-week double blind randomised placebo controlled clinical trial.
Secondary ID [1] 306831 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bipolar disorder 325618 0
neurocognition 325619 0
Condition category
Condition code
Mental Health 322976 322976 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention includes intranasal insulin, Levemir (Determir). Insulin is a standard treatment for diabetes, and has been extensively investigated for cognitive function in clinical trials. Delivery through the nasal has advantages in bypassing the peripheral bloodstream, allowing direct delivery to the brain, without systematic insulin increases. The role of insulin in cognitive function has been demonstrated in several populations, and has shown to be a safe, tolerable, and effective treatment for cognition. Levemir is a long acting insulin, when administered via inhalation, the onset of and duration of action is between 3-4 hours and 6-23 hours, respectively.

40 international units (IU) of inhaled insulin Levemir will be self-administered daily. Each dose will consist of 20IU (each actuation or puff being 10IU, 1 puff administered per nostril), two times per day (before breakfast, before dinner), evenly between nostrils, for 12 weeks.

During the trial, participants will be requested to log drug administration in an app. At completion of the trial, bottles wil be returned and assessed for adherence.
Intervention code [1] 323123 0
Treatment: Drugs
Comparator / control treatment
Participants randomised to the control group will self-administer a matched placebo equivalent for 12 weeks. The placebo product will consist of a commercially available nasal spray containing sodium chloride (9mg/ml; 0.9mg per spray), the product will be repackaged so that the appearance, administration method, dosage, and instructions are identical to the active condition. Two puffs will be admninistered two times per day (before breakfast and dinner), thus 3.6mg per day. To ensure blinding, the placebo spray bottles will be matched in all aspects.
Control group
Placebo

Outcomes
Primary outcome [1] 330745 0
Global neurocognitive function assessed by a cognitive battery- the MATRICS Consensus Cognitive Battery (MCCB), Delis–Kaplan Executive Function System (D-KEFS) Stroop task, and the Trails Making Task B (TMB). A composite primary outcome score will be derived, which covers eight neurocognitive domains (speed of processing, visual memory, verbal memory, attention, working memory, reasoning & problem solving, social cognition, and executive function).
Timepoint [1] 330745 0
12 weeks post intervention commencement
Secondary outcome [1] 407414 0
Psychosocial functioning assessed by - the Social and Occupational Functioning Scale (SOFAS).
Timepoint [1] 407414 0
12 weeks post intervention commencement
Secondary outcome [2] 407797 0
Quality of life- assessed by the Assessment of Quality of Life- Eight Dimensions (aQoL- 8D).
Timepoint [2] 407797 0
12 weeks post intervention commencement
Secondary outcome [3] 408329 0
Quality of life- assessed by the Manchester Short Assessment of Quality of Life (MANSA).
Timepoint [3] 408329 0
12 weeks post intervention commencement
Secondary outcome [4] 408330 0
Psychosocial functioning assessed by- the functional assessment screening tool (FAST).
Timepoint [4] 408330 0
12 weeks post intervention commencement
Secondary outcome [5] 409386 0
Cognition inhibition assessed by- Hayling task
Timepoint [5] 409386 0
12 weeks post intervention commencement
Secondary outcome [6] 409387 0
Apperceptive reasoning as assessed by- Brixton task
Timepoint [6] 409387 0
12 weeks post intervention commencement
Secondary outcome [7] 409388 0
Subjective cognition- assessed by Cognitive complaints in bipolar disorder rating assessment (COBRA)
Timepoint [7] 409388 0
12 weeks post intervention commencement

Eligibility
Key inclusion criteria
i) Aged between 18-55 years (inclusive)
ii) Primary diagnosis of bipolar disorder type I or II according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)
iii) Score <12 on the Montgomery-Asberg Depression Rating Scale (MADRS) and <8 on the Young Mania Rating Scale (YMRS) to ensure euthymia
iv) Perform atleast 1.0 standard deviations below the normative mean on the Screen for Cognitive Impairment in Psychiatry (SCIP)
v) Demonstrate an estimated IQ >79 assessed by the Weschler Abbreviated Scale of Intelligence (WASI) to ensure that study instructions can be understood
vi) Have been stabilised on psychotropic medications for 4 weeks, if prescribed
vii) Utilising effective contraception if female and of childbearing age
viii) Have capacity to consent to the study
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i) Concurrent DSM-5 diagnosis (including personality disorders) as the primary clinical concern determined by a treating clinician
ii) Not fluent in, or able to read English
iii) Enrolled in any other intervention study
iv) Clinically significant untreated medical condition (e.g., cardiovascular, gastrointestinal, haematological, renal, hepatic, respiratory or endocrine illnesses)
v) A history of neurological trauma resulting in loss of consciousness >10 minutes, or previously diagnosed with any known neurological disorder
vi) Currently pregnant or breastfeeding
vii) Ongoing sinus condition
viii) Untreated hypo / hyperthyroidism
ix) Current or history of diabetes mellitus type I or type II or hypo / hyperglycaemia
x) Currently taking corticosteroids, anticholinergics, or anti-diabetic medication
xi) Electroconvulsive therapy in the preceding 6 months
xii) Substance or alcohol abuse/ dependence in the last 3 months (meeting DSM-5 criteria)
xiii) Body mass index (BMI) equal or greater than 40 kg / m2
xiv) Actively suicidal or deemed at suicide risk as evaluated by their treating clinician or screening clinical assessments.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment will be maintained. A statistician will allocate participants to two different groups. An independent researcher will allocate the groups to each intervention.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified by age and sex, and computer generated by a statistician. Individuals will be allocated to one of four groups (young female, older female, young male, older male) so that randomisation to treatment and placebo is balanced within groups. The allocation of the groups will be assigned by an independent researcher, so that all researchers remain blinded to the treatment allocation.
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
Descriptive statistics will be used to summarise assessments of recruitment (including successful screening), drop-out and intervention completion. Baseline values for the
two groups will be compared using chi-squared tests of association for categorical variables (or Fisher’s exact test for small samples) and univariate ANOVA tests (or Kruskal-Wallis tests) for continuous variables.

For the primary analysis, an intention-to-treat (ITT) analysis will be conducted using repeated measures linear mixed models with individuals entered as a random effect to account for correlated readings. The dependent variable will be the global MCCB score (including the TMTB, D-KEFS Stroop), and the independent variables will be Group (intranasal insulin versus placebo), Visit (baseline, 12 weeks), and the interaction term Visit by Group (together with any clinical variables found to significantly differ between the groups at baseline). The same analytic approach will be used for the secondary outcomes. Exploratory analyses will be performed by re-running the models with the cognitive domain scores from the MCCB to examine for improvements in other cognitive abilities. Finally, a mediation analysis will be conducted using the process macro to determine whether changes in any of the MCCB domain scores mediate the relationship between the treatment groups and improvements in quality of life and psychosocial functioning.

Additional exploratory analysis will be conducted using primary, secondary and additional neurocognitive outcomes (Hayling, Brixton, Cognitive complaints in bipolar disorder rating assessment (COBRA)).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2022
Actual
Date of last participant enrolment
Anticipated
1/06/2024
Actual
Date of last data collection
Anticipated
1/09/2024
Actual
Sample size
Target
44
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 22788 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 38074 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 310894 0
Charities/Societies/Foundations
Name [1] 310894 0
Milken Institute
Country [1] 310894 0
United States of America
Primary sponsor type
University
Name
Swinburne University of Technology
Address
John Street, Hawthorn, 3122, VIC
Country
Australia
Secondary sponsor category [1] 312403 0
None
Name [1] 312403 0
Address [1] 312403 0
Country [1] 312403 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310454 0
Swinburne Human Research Ethics Committee
Ethics committee address [1] 310454 0
Ethics committee country [1] 310454 0
Australia
Date submitted for ethics approval [1] 310454 0
08/04/2022
Approval date [1] 310454 0
10/06/2022
Ethics approval number [1] 310454 0
20226331-10081

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117726 0
Prof Susan Rossell
Address 117726 0
Centre for Mental Health, Swinburne University of Technology, John Street, Hawthorn, 3122, VIC
Country 117726 0
Australia
Phone 117726 0
+613 9214 8173
Fax 117726 0
Email 117726 0
[email protected]
Contact person for public queries
Name 117727 0
Nicola Acevedo
Address 117727 0
Centre for Mental Health, Swinburne University of Technology, John Street, Hawthorn, 3122, VIC
Country 117727 0
Australia
Phone 117727 0
+613 9214 3687
Fax 117727 0
Email 117727 0
[email protected]
Contact person for scientific queries
Name 117728 0
Susan Rossell
Address 117728 0
Centre for Mental Health, Swinburne University of Technology, John Street, Hawthorn, 3122, VIC
Country 117728 0
Australia
Phone 117728 0
+613 9214 8173
Fax 117728 0
Email 117728 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The current trial is a small scale study, aggragate group data will be analysed and interpreted to investigate the treatment efficacy.


What supporting documents are/will be available?




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.