Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001060134
Ethics application status
Approved
Date submitted
27/06/2019
Date registered
30/07/2019
Date last updated
4/12/2019
Date data sharing statement initially provided
30/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of acute and sub-acute treatment with metformin on cardiovascular responses to a glucose challenge in type 2 diabetes
Scientific title
Effects of acute and sub-acute treatment with metformin on cardiovascular responses to a glucose challenge in type 2 diabetes
Secondary ID [1] 298614 0
MYIP10953
Universal Trial Number (UTN)
U1111-1236-0540
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
type 2 diabetes 313473 0
Condition category
Condition code
Metabolic and Endocrine 311903 311903 0 0
Diabetes
Cardiovascular 311904 311904 0 0
Normal development and function of the cardiovascular system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised double-blind cross-over placebo-controlled trial evaluating 2 treatment periods with a 2 week wash-out, with a total study duration of 4 weeks.: i) acute effects following 1 dose of metformin (850 mg) and ii) chronic effects following 1 week of treatment with metformin 850 mg twice daily. As for our previous work, randomisation will be undertaken using a random number generator and conducted through the RAH Pharmacy Department, who will also provide a placebo for metformin. Metformin and matching placebo will be capsules. The 24-hour ABP monitor consists of a cuff which fits around the upper arm and is the same cuff that is usually used to measure blood pressure. The cuff is attached to a monitor, which is about the size of a large smart phone which records the readings. The participant will be asked to record the time of meals, exercise and sleep while wearing the monitor. The ambulatory blood monitor may be associated with slight discomfort as blood pressure readings are taken every 15-30 minutes during the 24 hour period (but only hourly overnight). Following screening and consent (visit 1), patients will present to our institution on 7 occasions over 3 weeks for a total of 8 visits. Week 1 (metformin or placebo) will require a visit to be fitted for the baseline ambulatory blood pressure (ABP) monitor (visit 2) and subsequently baseline gastric emptying/cardiovascular response post glucose load (visit 3) with return of the 24-hour ABP monitor and stool sample. Visit 4 will include fitting of the ABP monitor and visit 5 chronic gastric emptying/cardiovascular response post glucose load on day 7 and return of the ABP monitor and stool sample. This will be followed by 2-week washout. Final week as per week 1 with the alternative treatment - visit 6 for acute gastric emptying study, visit 7 for fitting of ABP monitor and visit 8 for return of ABP monitor and stool sample and final gastric emptying study. Faecal sample collection tubes/instructions will be given at the same time as ABP fitting and returned at the same time of return of ABP. Adherence will be monitored by return of pre-filled Webster packs at the conclusion of the study.
Intervention code [1] 314874 0
Treatment: Drugs
Comparator / control treatment
Placebo controlled - participants will act as their own control in this cross-over study. Placebo capsules will consist of microcrystalline cellulose powder.
Control group
Placebo

Outcomes
Primary outcome [1] 320568 0
The primary outcome will be the difference in maximum fall in systolic blood pressure between treatment periods. BP will be measured with an automated oscillometric BP monitor (DINAMAP ProCare 100, GE Medical Systems, Milwaukee, WI, USA).
Timepoint [1] 320568 0
Blood pressure will be taken 5 minutely during the gastric emptying studies: i) acute after 24 hours treatment with metformin and ii) after 1 week treatment with metformin.
Secondary outcome [1] 372064 0
Blood pressure area under the curve (AUC) will be calculated using the trapezoidal rule. Blood pressure will be ascertained as above.
Timepoint [1] 372064 0
Blood pressure will be taken 5 minutely during the gastric emptying studies: i) acute after 24 hours treatment with metformin and ii) after 1 week treatment with metformin.
Secondary outcome [2] 372065 0
Radioisotope data will be acquired for 240 minutes after consumption of the test drink. Data will be corrected for participant movement, radionuclide decay and x-ray attenuation as per our published technique. Gastric emptying curves will be derived, and the time for 50% of liquid to empty (T50) will be calculated using standardised techniques.
Timepoint [2] 372065 0
Gastric emptying will be determined as above following acute (24 hours treatment with metformin) and ii) after 1 week treatment with metformin.
Secondary outcome [3] 372066 0
Plasma GLP-1 concentrations - incremental area under the curve (iAUC). GLP-1 measured using ELISA.
Timepoint [3] 372066 0
GLP-1 concentrations will be measured at regular intervals 0, 15, 30, 45, 60, 90, 120, 150, 180 and 240 minutes during the gastric emptying study and these values used to determine the iAUC. These measurements will be taken following i) acute (24 hours treatment with metformin) and ii) 1 week treatment with metformin.
Secondary outcome [4] 372067 0
Plasma insulin iAUC (ELISA).
Timepoint [4] 372067 0
Plasma insulin concentrations will be measured at regular intervals 0, 15, 30, 45, 60, 90, 120, 150, 180 and 240 minutes during the gastric emptying study and these values used to determine the iAUC. These measurements will be taken following i) acute (24 hours treatment with metformin) and ii) 1 week treatment with metformin.
Secondary outcome [5] 372068 0
Glucose absorption (3-OMG) (liquid chromatography and mass spectrometry).
Timepoint [5] 372068 0
3-OMG concentrations will be measured at regular intervals 0, 15, 30, 45, 60, 90, 120, 150, 180 and 240 minutes during the gastric emptying study and these values used to determine glucose absorption using standardised techniques. These measurements will be taken following i) acute (24 hours treatment with metformin) and ii) 1 week treatment with metformin.
Secondary outcome [6] 372069 0
Gut microbiome (16SRNA) - specimen will be stool sample.
Timepoint [6] 372069 0
Stool samples will be taken at baseline, following acute treatment with metformin (24 hours treatment with metformin) or placebo and following 7 days treatment with metformin or placebo.
Secondary outcome [7] 372641 0
Glucose iAUC. Glucose measured using hexokinase technique.
Timepoint [7] 372641 0
Glucose concentrations will be measured at regular intervals 0, 15, 30, 45, 60, 90, 120, 150, 180 and 240 minutes during the gastric emptying study and these values used to determine the iAUC. These measurements will be taken following i) acute (24 hours treatment with metformin) and ii) 1 week treatment with metformin.

Eligibility
Key inclusion criteria
Type 2 diabetes (World Health Organisation (WHO) criteria), managed by diet only
Body mass index (BMI) 25 - 35 kg/m2
Males and females, aged 40-80 years
Glycated haemoglobin (HbA1c) 6- 8.5%
Haemoglobin above the lower limit of the normal range (ie. >135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (ie. >30ng/mL for men and >20mg/mL for women)
Patients on stable doses of antihypertensives will be included.
Minimum age
40 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Use of any medication that may influence gastrointestinal motor function, body weight or appetite (opiates, anticholinergics, levodopa, clonidine, nitrates, tricyclic antidepressants, selective serotonin re-uptake inhibitors, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, prucalopride, or erythromycin)
Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes on a daily basis
History of gastrointestinal disease, including significant upper or lower gastrointestinal symptoms, pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy)
Other significant illness, including epilepsy, cardiovascular or respiratory disease
Impaired renal or liver function (as assessed by calculated creatinine clearance < 60 mL/min or abnormal liver function tests (> 2 times upper limit of normal range))
Donation of blood within the previous 3 months
Participation in any other research studies within the previous 3 months
Inability to give informed consent
Female participants who are not on long acting contraception
Previously unable to tolerate metformin or treatment with metformin within the past week.

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)
Central randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation 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
Crossover
Other design features
Phase
Phase 4
Type of endpoint/s
Pharmacodynamics
Statistical methods / analysis
Sample size requirements have been based on power calculations at alpha=0.05 and 1-beta = 0.8, performed with systolic BP as the primary outcome variable based on our previous data. Sixteen patients with T2DM are required to detect a 6mmHg reduction in the maximum fall in systolic BP during the gastric emptying measurement after administration of metformin compared to placebo for the two primary endpoints at day 1 (acute) and day 7 (subacute). We have estimated an overall ‘dropout rate’ of ~10% and have, therefore, budgeted for 18 subjects. Data will be analysed by repeated measures ANOVA with adjustment for period effects and Bonferroni adjusted post-hoc comparisons where ANOVAs reveal significance. All outcomes are quantitative. Data will be analysed in consultation with a professional biostatistician employed by our CRE.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2019
Actual
2/12/2019
Date of last participant enrolment
Anticipated
1/06/2021
Actual
Date of last data collection
Anticipated
2/07/2021
Actual
Sample size
Target
18
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 14115 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 26916 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 303156 0
Hospital
Name [1] 303156 0
Royal Adelaide Hospital
Country [1] 303156 0
Australia
Primary sponsor type
Hospital
Name
Royal Adelaide Hospital
Address
Port Road
Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 303157 0
None
Name [1] 303157 0
Address [1] 303157 0
Country [1] 303157 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303715 0
CALHN HREC
Ethics committee address [1] 303715 0
Royal Adelaide Hospital
Port Road
Adelaide South Australia 5000
Australia
Ethics committee country [1] 303715 0
Australia
Date submitted for ethics approval [1] 303715 0
18/02/2019
Approval date [1] 303715 0
27/05/2019
Ethics approval number [1] 303715 0
HREC/19/CALHN/96

Summary
Brief summary
Patients with type 2 diabetes are at high risk of cardiovascular disease. Treatments targeted at lowering glucose may reduce the risk of cardiovascular disease, however other approaches are needed as patients remain at an elevated residual risk of cardiovascular events. There is evidence that fluctuation in blood pressure (blood pressure variability) is an important risk factor for cardiovascular disease, such that substantial changes over time are detrimental and lead to an increased risk of cardiovascular disease. Metformin is a drug that has been used for diabetes for many years, though the mechanism of action remains incompletely understood. Early studies with this drug suggested that this particular agent was effective at reducing cardiovascular events and there is some evidence that metformin can modify both blood pressure, and gut responses following a meal. We are interested in looking to see whether metformin could reduce blood pressure fluctuations induced throughout the day, and in particular following meals. Information from this study will help guide further research into mechanisms behind and potential novel approaches to cardiovascular disease and blood pressure in diabetes. Given recent interest in the bacteria in the gut and how this influences health and blood sugar control, we will also look at the effect of metformin on bugs in the gut (microbiome).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94554 0
Dr Liza Phillips
Address 94554 0
Level 5 Adelaide Health and Medical Sciences (AHMS) Building
Corner George St and North Terrace
Adelaide, SA 5000
Country 94554 0
Australia
Phone 94554 0
+61 407764422
Fax 94554 0
Email 94554 0
[email protected]
Contact person for public queries
Name 94555 0
Dr Liza Phillips
Address 94555 0
Level 5 Adelaide Health and Medical Sciences (AHMS) Building
Corner George St and North Terrace
Adelaide, SA 5000
Country 94555 0
Australia
Phone 94555 0
+61 407764422
Fax 94555 0
Email 94555 0
[email protected]
Contact person for scientific queries
Name 94556 0
Dr Liza Phillips
Address 94556 0
Level 5 Adelaide Health and Medical Sciences (AHMS) Building
Corner George St and North Terrace
Adelaide, SA 5000
Country 94556 0
Australia
Phone 94556 0
+61 407764422
Fax 94556 0
Email 94556 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
Small numbers with potential for reidentification.


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.