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Trial registered on ANZCTR


Registration number
ACTRN12618001370291
Ethics application status
Approved
Date submitted
8/08/2018
Date registered
15/08/2018
Date last updated
1/05/2019
Date data sharing statement initially provided
1/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The effects of nerve dysfunction upon blood vessels in diabetes.
Scientific title
The relationship between diabetic neuropathy and the response to a single exposure of remote ischaemic conditioning
Secondary ID [1] 291089 0
None
Universal Trial Number (UTN)
Trial acronym
DINERIC study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes 301894 0
Diabetic neuropathy 301895 0
Peripheral Arterial Disease 301896 0
Condition category
Condition code
Metabolic and Endocrine 301564 301564 0 0
Diabetes
Neurological 301565 301565 0 0
Other neurological disorders
Cardiovascular 301566 301566 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is remote ischaemic conditioning (RIC): a single session of 4 repeated cycles of 5 minute blood pressure cuff inflation to 200mmHg followed by 5 minutes of cuff deflation on the non-dominant upper arm. The RIC exposure will be applied by a general practitioner member of the research team with >10 years of clinical experience, or a suitably trained researcher, at either the Sport UNE Exercise Physiology laboratory at the University of New England (UNE), or the University Medical Centre at the UNE. The RIC involves the use of a standard pneumatic blood pressure cuff and sphygmomanometer. The researcher will be present throughout the intervention. Ischaemia will be confirmed by absence of the radial pulse and pulse oximetry on the cuffed arm during each cuff inflation. Participants will be asked to avoid alcohol, caffeine and minimise physical exercise for 24 hours prior to the study until study completion.
Intervention code [1] 297074 0
Treatment: Other
Comparator / control treatment
The control group will receive a sham RIC procedure. This will be an identical protocol to the intervention, but involve a blood pressure cuff inflation to a lower pressure. The researcher will verify the absence of ischaemia by pulse oximetry and confirmation that radial pulse is present on examination of the cuffed arm during the control treatment with each cuff inflation.
Control group
Placebo

Outcomes
Primary outcome [1] 300974 0
Change in plasma levels of vascular endothelial growth factor in peripheral venous blood (ELISA assay)
Timepoint [1] 300974 0
Measured at baseline immediately prior to intervention, then 15 and 60 minutes (primary endpoint) after intervention.
Primary outcome [2] 307083 0
Change in serum levels of apolipoprotein A-1 in peripheral venous blood.
Timepoint [2] 307083 0
Measured at baseline immediately prior to intervention, then 15 (primary endpoint) and 60 minutes after intervention.
Primary outcome [3] 307084 0
Change in plasma levels of calcitonin gene-related peptide in peripheral venous blood (ELISA assay)
Timepoint [3] 307084 0
Measured at baseline immediately prior to intervention, then 15 (primary endpoint) and 60 minutes after intervention.
Secondary outcome [1] 331306 0
Change in serum C reactive protein in peripheral venous blood
Timepoint [1] 331306 0
Measured at baseline immediately prior to intervention, then 15 and 60 minutes after intervention,
Secondary outcome [2] 331307 0
Changes in heart rate variability assessed with use of an ambulatory Holter monitor
Timepoint [2] 331307 0
Measured immediately prior to, during and 24 hours after the intervention, with continuous ambulatory monitoring.
Secondary outcome [3] 350622 0
Changes in arterial blood pressure (mmHg) using non-invasive continuous blood pressure monitoring of the dominant arm, measured by Finometer® Midi Model-2 (Finapres Medical Systems B.V., Amsterdam, The Netherlands)
Timepoint [3] 350622 0
Measured continuously from 10 minutes prior to intervention until 10 minutes after final cuff deflation.
Secondary outcome [4] 350634 0
Change in serum glucose in peripheral venous blood
Timepoint [4] 350634 0
Measured at baseline immediately prior to intervention, then 15 and 60 minutes after intervention. This is a possible confounding variable that might be part of secondary analysis to identify confounding factors.

Eligibility
Key inclusion criteria
Type 2 diabetic participants, with or without diabetic neuropathy
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Inability to provide informed consent
Pregnancy, breastfeeding
Proliferative diabetic retinopathy (or no eye examination within preceding 12 months)
Hypocalcaemia
Smoker within previous 12 months
Chronic atrial flutter or fibrillation
Bleeding disorders, warfarin (or equivalent) therapy
Anti-VEGF therapy
Lymphoedema or known vascular abnormality in upper limbs
Previous or current DVT
Severe systolic hypertension (>180mmHg)
Haematological malignancy
Recent severe acute illness

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 by contacting the holder of the allocation schedule at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation, stratifying for factors of glycaemic control (HbA1c), age, statin use and presence of peripheral sensor neuropathy. Computer generated random number sequence to determine RIC or sham group allocation. Block analysis every 10 participants to stratify.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Changes in peripheral blood markers of ischaemic response / neovascularisation and inflammation from baseline to 15 min and 60 min post-RIC will be correlated with variables. These are likely to include presence and/or severity of peripheral arterial disease and diabetic neuropathy, HbA1c, blood glucose levels, and medication use. Multiple regression analysis, partial correlation and multivariate analysis or variants will be used. Factor analysis will be utilised to determine intercorrelations of the variables.

Most data collected will be quantitative. T tests will be used with quantitative data for the purpose of comparing pre and post- RIC outcome measures. Similar statistical analyses will be performed with secondary outcome measures.

There are no existing studies or data with respect to the listed outcome measures in the use of RIC in Type 2 diabetes vs sham control. As this is the first study of its kind known to the research team, and a pilot study, the number of participants were based on estimation of 60 participants, allowing for a small drop out rate and also allowing enough participants to control for several variables that are important in diabetic patients.

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] 16584 0
2350 - Armidale
Recruitment postcode(s) [2] 16585 0
2358 - Uralla
Recruitment postcode(s) [3] 16586 0
2365 - Guyra
Recruitment postcode(s) [4] 16587 0
2354 - Walcha
Recruitment postcode(s) [5] 16588 0
2370 - Glen Innes

Funding & Sponsors
Funding source category [1] 295523 0
University
Name [1] 295523 0
University of New England
Address [1] 295523 0
Trevenna Road
Armidale
University of New England
NSW 2351
Country [1] 295523 0
Australia
Primary sponsor type
University
Name
University of New England
Address
Trevenna Road
Armidale
University of New England
NSW 2351
Country
Australia
Secondary sponsor category [1] 294346 0
None
Name [1] 294346 0
Address [1] 294346 0
Country [1] 294346 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296848 0
University of New England Human Research Ethics Committee
Ethics committee address [1] 296848 0
Ethics Office
Research Development & Integrity
Research Division
University of New England
Armidale NSW 2351
Ethics committee country [1] 296848 0
Australia
Date submitted for ethics approval [1] 296848 0
04/11/2016
Approval date [1] 296848 0
07/12/2016
Ethics approval number [1] 296848 0
HE16-276

Summary
Brief summary
This randomised controlled trial aims to establish if there is a correlation between diabetic neuropathy (nerve pathways affected by diabetes) and markers of blood vessel health in response to remote ischaemic conditioning (RIC). Via activation of nerves and beneficial compounds within the blood, RIC is known to protect areas at a distance from damage caused by a more prolonged and serious lack of oxygen-rich arterial blood flow in some patients.

Methodology
60 randomly recruited adult participants residing in the Armidale region with type 2 diabetes will have a baseline diabetic history taken, detailed physical examination and measurements collected.

Non-invasive cardiovascular physiological measurements will be obtained prior to, during and up to 24 hours after the intervention.

The RIC intervention consists of 5 mins upper arm ischaemia (brief cessation of oxygen-rich blood flow), with blood pressure cuff inflation to 200mmHg, followed by 5 mins of complete cuff deflation. This cycle will be repeated 3 times without delay between cycles. In the control group, the intervention will be the same, except cuff pressures inflated to a lower pressure.

Venous blood samples will be collected immediately before intervention, then 15 and 60 minutes after RIC. Changes in markers of blood vessel health will be the primary outcome measure. Secondary outcome measures will include changes in blood levels of markers of inflammation and physiological changes of the heart and circulation

Results will be correlated with variables. Blood samples will also be tested for blood sugar levels, full blood count, HbA1c (measure of diabetes control), and lipids.

Aims of the study
The study aims to provide a clearer insight into the mechanisms of RIC, assist in
predicting which diabetic patients are most likely to benefit from RIC, and potentially guide the development of new therapeutic strategies for the vascular complications of diabetes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72214 0
Prof Neil Smart
Address 72214 0
Exercise Physiology and Sports Science
School of Science and Technology
University of New England
Armidale NSW 2351
Country 72214 0
Australia
Phone 72214 0
+61 (0)2 6773 4076
Fax 72214 0
Email 72214 0
nsmart2@une.edu.au
Contact person for public queries
Name 72215 0
Dr Jacqueline Epps
Address 72215 0
Exercise Physiology and Sports Science
School of Science and Technology
University of New England
Armidale NSW 2351
Country 72215 0
Australia
Phone 72215 0
+61 (0)2 6773 5823
Fax 72215 0
Email 72215 0
jepps2@myune.edu.au
Contact person for scientific queries
Name 72216 0
Dr Jacqueline Epps
Address 72216 0
Exercise Physiology and Sports Science
School of Science and Technology
University of New England
Armidale NSW 2351
Country 72216 0
Australia
Phone 72216 0
+61 (0)2 6773 5823
Fax 72216 0
Email 72216 0
jepps2@myune.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
As per ethics approval
What supporting documents are/will be available?
No other documents available
Summary results
No Results