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Trial registered on ANZCTR


Registration number
ACTRN12618000496213
Ethics application status
Approved
Date submitted
16/03/2018
Date registered
5/04/2018
Date last updated
11/03/2019
Date data sharing statement initially provided
11/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Is dysfunction of brain blood vessels associated with cognitive impairment in type-1 diabetes?
Scientific title
Is dysfunction of brain blood vessels associated with cognitive impairment in type-1 diabetes?
Secondary ID [1] 294176 0
None
Universal Trial Number (UTN)
U1111-1209-9447
Trial acronym
iNeuroT1D
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes Mellitus 306805 0
Condition category
Condition code
Metabolic and Endocrine 305915 305915 0 0
Diabetes
Mental Health 306209 306209 0 0
Studies of normal psychology, cognitive function and behaviour

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
A pilot cross-sectional study involving Type 1 Diabetic (T1D) adults and age-matched non-diabetic controls will be conducted over two visits scheduled up to seven days apart.
Anthropometric measurements of height, weight and waist circumference will then be obtained prior to clinic Blood Pressure (BP) and arterial compliance (AC) measurements. We will obtain a finger-prick glucose reading from T1D to ensure that their blood glucose levels are at least 6.5mmol/L before proceeding with the rest of the assessments.
Participants will then be fitted with a headpiece with two ultrasound probes on both sides of the temporal region. This transcranial doppler (TCD) device will monitor the blood flow velocity in either the middle cerebral artery or the anterior cerebral artery. Participants will have their cerebral blood flow velocity recorded at rest. Participants will then perform a series of cognitive tasks continuously for approximately 70 mins, whilst the TCD device records changes in blood flow velocities. The neuropsychological test battery will consist of the Trail Making Task, the N-back task, Rey-Osterrieth complex figure, and the NIH Toolbox Battery of cognitive function.
Volunteers will arrive for the second visit and a blood sample will be obtained. They will complete paper-based questionnaires that will measure various subjective perceptions of their current mood states using the Profile of Mood States (POMS) Questionnaire and the Center for Epidemiological Studies Depression Scale (CES-D) and diabetes self-care. Volunteers will then proceed to do a 10-min auditory function test, the NIH Toolbox 9-hole Pegboard Dexterity test, and the Addenbrooke’s Cognitive Examination-III (a measure of global cognitive status) (ACE-III).
Intervention code [1] 300470 0
Not applicable
Comparator / control treatment
Adults with no diabetes
Control group
Active

Outcomes
Primary outcome [1] 304950 0
Composite Primary Outcome: Overall performance of a neuropsychological test battery, consisting of the Trail Making Task, the N-back task, Rey-Osterrieth complex figure, and the NIH Toolbox Battery of cognitive function.
Timepoint [1] 304950 0
Week 0 visit 1
Secondary outcome [1] 343687 0
Clinic blood pressure assessed by sphygmomanometry.
Timepoint [1] 343687 0
Week 0, visit 1.
Secondary outcome [2] 343689 0
Cerebral arterial compliance assessed by TCD ultrasound.
Timepoint [2] 343689 0
Week 0, visit 1.
Secondary outcome [3] 343690 0
Cerebrovascular responsiveness (CVR) to hypercapnia assessed by TCD ultrasound.
Timepoint [3] 343690 0
Week 0, visit 1.
Secondary outcome [4] 343692 0
Neurovascular coupling (cerebrovascular responsiveness to cognitive stimuli) assessed by TCD ultrasound
Timepoint [4] 343692 0
Week 0, visit 1.
Secondary outcome [5] 343693 0
Composite secondary outcome: Individual test performance. Performance on a neuropsychological test battery, assessing executive function, working memory, processing speed, memory and psychomotor speed of the cognitive domain using the Trail Making Task, the N-back task, Rey-Osterrieth complex figure, and the NIH Toolbox Battery of cognitive function.
Timepoint [5] 343693 0
Week 0, visit 1
Secondary outcome [6] 343695 0
Manual dexterity (psychomotor speed), measured using the NIH Toolbox 9-hole Pegboard Dexterity test.
Timepoint [6] 343695 0
Week 0, visit 2.
Secondary outcome [7] 343696 0
Central auditory processing function, assessed using iPad and headphones, using the "words-in-noise" test.
Timepoint [7] 343696 0
Week 0, visit 2
Secondary outcome [8] 343699 0
Composite secondary outcome: Mood assessed using the Profile of Mood States (POMS) Questionnaire and the Center for Epidemiological Studies Depression Scale (CES-D).
Timepoint [8] 343699 0
Week 0, visit 2.
Secondary outcome [9] 343700 0
Diabetes self-care, assessed using a 16-question questionnaire: the Diabetes Self-Management Questionnaire (DSMQ), designed to assess behaviours associated with metabolic control in common treatment regimes for T1D and T2D in adult patients.
Timepoint [9] 343700 0
Week 0, visit 2.
Secondary outcome [10] 343701 0
Cardiometabolic biomarkers (HbA1C; lipids; inflammatory biomarkers such as IL-1b, IL-6, IL-8, IL-10, IL-12A/B and TNF-a), assessed by plasma assay.
Timepoint [10] 343701 0
Week 0, visit 2.
Secondary outcome [11] 343702 0
S100ß (marker of blood-brain-barrier integrity), assessed by plasma assay.
Timepoint [11] 343702 0
Week 0, visit 2.

Eligibility
Key inclusion criteria
Inclusion criteria for T1D:
Age 30 – 80 years old
T1D diagnosed before 18 years of age
No advanced diabetes complications such as blindness or deafness
Not hospitalised for severe glycemic events in the last 3 months

Inclusion criteria for control group:
No T1D or T2D diagnosis and HbA1c <6.5%
Not taking medication for hypertension and cholesterol
Minimum age
30 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Not fluent in reading and writing in English
No detectable transcranial Doppler (TCD) ultrasound signal in the middle cerebral artery on either side.
Liver or kidney disease
Malignant cancer
Excessive alcohol intake (>15 drinks per week)
Pregnancy
Neurological conditions including stroke, TIA, major depression, multiple sclerosis, Parkinson’s disease or dementia or mild cognitive impairment.
Unwilling to provide a blood sample

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Independent t-tests will be used to compare group differences in each of the following: basal cerebral hemodynamics (PI, RI, CVRi and mean blood flow velocity), CVR to hypercapnia, CVR to the cognitive test battery (neurovascular coupling capacity), performance on each of the individual cognitive tests, auditory function and overall performance to the test battery. Associations between cerebrovascular function, cognitive function, auditory function participant characteristics and markers of diabetes including disease duration, metabolic profile, glycaemic fluctuations, self-care and inflammatory cytokines will be examined using correlation coefficient analyses and Bayesian analysis. Covariates such as age, gender and pre-test glucose levels will be included when appropriate. Adjustment for multiple comparisons will also be made.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 21888 0
2300 - Newcastle

Funding & Sponsors
Funding source category [1] 298809 0
Other Collaborative groups
Name [1] 298809 0
Hunter Medical Research Institute – Keith Tulloch Wines Project Grant
Address [1] 298809 0
Lot 1 Kookaburra Circuit, New Lambton Heights, NSW, 2305
Country [1] 298809 0
Australia
Primary sponsor type
University
Name
University of Newcastle
Address
University of Newcastle
Faculty of Health and Medicine
School of Biomedical Sciences & Pharmacy
Clinical Nutrition Research Centre
University Drive
Callaghan, New South Wales 2308
Country
Australia
Secondary sponsor category [1] 298007 0
None
Name [1] 298007 0
Address [1] 298007 0
Country [1] 298007 0
Other collaborator category [1] 279965 0
University
Name [1] 279965 0
Curtin University
Address [1] 279965 0
Curtin University
Curtin Health Innovation Research Institute
School of Public Health
Kent Street
Bentley WA 6102
Country [1] 279965 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299756 0
University of Newcastle Human Research Ethics Committee
Ethics committee address [1] 299756 0
Research & Innovation Services
Research Integrity Unit
The University of Newcastle
University Drive
Callaghan NSW 2308
Ethics committee country [1] 299756 0
Date submitted for ethics approval [1] 299756 0
02/02/2018
Approval date [1] 299756 0
30/04/2018
Ethics approval number [1] 299756 0
H-2018-0038

Summary
Brief summary
To date, almost all large neurocognitive studies of type 1 diabetes (T1D) have focused on paediatric groups, as compared to most type 2 diabetes (T2D) studies which focus on old age. Early onset diabetes has severe impacts on the neurocognitive development of children and adolescents with T1D, particularly in learning and memory skills. This deficit is accompanied by atrophic changes in the medial prefrontal regions that are known to be rapidly developing in children. While there is a plethora of literature linking T2D with greater risk of dementia, little is known about the role of metabolic and vascular factors on the ageing brain in adults with T1D. One retrospective study has shown that elderly adults with T1D are 83% more likely to get dementia compared to a 50% greater risk in T2D than in non-diabetic adults. However, the frequent presence of comorbidities in older diabetic adults further complicates the underlying mechanism of accelerated brain ageing in T1D.
A postulated underlying mechanism of T1D-related cognitive decline is endothelial dysfunction in the cerebral microvasculature caused by pro-inflammatory cytokines associated with the disease and advanced glycation end-products (AGE) due to hyperglycaemia.
We have shown significant cerebral arterial stiffness (20%) in elderly T2D adults compared to non-diabetics, which is linked to poorer perfusion and performance during cognitive testing. Structural and functional changes of the cerebral vasculature is already evident in young T1D adults (mean age of 32 years) where a significant 20% reduction in cerebral vasodilator responsiveness to a hypercapnic challenge was seen compared to non-diabetic controls. The authors also reported significant stiffening of the carotid arteries that is independent of the presence of hyperlipidaemia. It seems that despite the arduous therapy of multiple insulin injections daily, this does not prevent the occurrence of serious late-arising complications including kidney failure, blindness and widespread cardiovascular disease in T1D.
Given that diabetes is a systemic disease, it is plausible that multiple organs including the auditory system are also affected; yet little attention has been given to preserving auditory function in diabetes.
Age-related neurodegeneration of different cortical areas and/or cognitive impairment may also affect central auditory function. Central auditory dysfunction is hypothesised to occur before objective cognitive tests become abnormal. There is no study evaluating the link between cerebrovascular dysfunction and cognitive impairment and central auditory dysfunction in T1D. We hypothesise that T1D adults have cerebrovascular dysfunction and elevated inflammation, mediated by glycation of the endothelium, which will negatively impact their cognitive and auditory function.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81470 0
Dr Rachel Wong
Address 81470 0
University of Newcastle
Faculty of Health and Medicine
School of Biomedical Sciences & Pharmacy
Clinical Nutrition Research Centre
University Drive
Callaghan, New South Wales 2308
Country 81470 0
Australia
Phone 81470 0
+61 2 4921 6408
Fax 81470 0
Email 81470 0
Rachel.Wong@newcastle.edu.au
Contact person for public queries
Name 81471 0
Dr Rachel Wong
Address 81471 0
University of Newcastle
Faculty of Health and Medicine
School of Biomedical Sciences & Pharmacy
Clinical Nutrition Research Centre
University Ring Road
Callaghan, New South Wales 2308
Country 81471 0
Australia
Phone 81471 0
+61 2 4921 6408
Fax 81471 0
Email 81471 0
Rachel.Wong@newcastle.edu.au
Contact person for scientific queries
Name 81472 0
Dr Rachel Wong
Address 81472 0
University of Newcastle
Faculty of Health and Medicine
School of Biomedical Sciences & Pharmacy
Clinical Nutrition Research Centre
University Ring Road
Callaghan, New South Wales 2308
Country 81472 0
Australia
Phone 81472 0
+61 2 4921 6408
Fax 81472 0
Email 81472 0
Rachel.Wong@newcastle.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
Study is de-identified
What supporting documents are/will be available?
No other documents available
Summary results
No Results