Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000799651
Ethics application status
Approved
Date submitted
16/07/2014
Date registered
28/07/2014
Date last updated
11/11/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Glucagaon-like peptide (GLP-1) and Adipose Tissue Inflammation in Obesity Study
Scientific title
Effect of glucagon-like peptide infusion on systemic and adipose tissue inflammation in obese people.
Secondary ID [1] 284953 0
Nil
Universal Trial Number (UTN)
U1111-1151-3675
Trial acronym
GATIO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 292436 0
Condition category
Condition code
Metabolic and Endocrine 292747 292747 0 0
Diabetes
Inflammatory and Immune System 292787 292787 0 0
Other inflammatory or immune system disorders
Diet and Nutrition 292863 292863 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm1. Intravenous infusion of glucagon-like peptide (GLP-1) at a dose of 0.9 pmol/kg/min. The GLP-1 will be obtained from Bachem AG in sealed vials (Clinalfa). The GLP-1 will be infused for 240 min into fasted individuals in the early morning. Plasma concentrations of GLP-1 will be measured.
Arm2. Infusion of 0.9% saline as a control. There will be a 3 week washout period between treatments in an individual to prevent carryover from one treatment to the next.
Intervention code [1] 289780 0
Treatment: Drugs
Comparator / control treatment
An infusion of sterile, 0.9% saline at the same rate as the infusion of GLP-1 will serve as a control.
Control group
Placebo

Outcomes
Primary outcome [1] 292595 0
Adipose tissue mRNA levels of interleukin-6, tumor necrosis factor-a, and monocyte chemotactic protein-1. This is a composite primary outcome.
Timepoint [1] 292595 0
Measurements will be made at beginning and end of 240 min infusion. RT-PCR analysis on adipose tissue biopsy material will be used to measure mRNA levels of the cytokines and these levels will be normalized to amounts of 18S.
Primary outcome [2] 292596 0
Plasma concentrations of interleukin-6 (IL-6).
Timepoint [2] 292596 0
Plasma IL-6 will be measured at 0, 30, 60, 120, 240 min during infusions. Primary time-points for plasma IL-6 are changes in concentrations from baseline at 30min and 60 min during infusions. Variation in plasma cytokines during the 240 min infusions will also be assessed. Plasma IL-6 concentrations will be measured by ELISA.
Primary outcome [3] 292598 0
Adipose tissue content of IL-6, tumor necrosis factor-a, and monocyte chemotactic protein-1. This is a composite primary endpoint.
Timepoint [3] 292598 0
Measurements will be made at beginning and end of 240 min infusion.A Luminex assay of adipose tissue will be used to measure the cytokines in a digest of adipose tissue.
Secondary outcome [1] 309289 0
Adipose tissue mRNA levels of adipocyte differentiation markers.
Timepoint [1] 309289 0
Measurements will be made at beginning and after 240 min of infusion. RT-PCR analysis will be used to measure levels of mRNA.
Secondary outcome [2] 309290 0
Adipose tissue macrophage numbers.
Timepoint [2] 309290 0
Measurements will be made at beginning and after 240 min infusion. Flow Cytometric Analysis of a cell digest of adipose tissue biopsy sample will be used to assess macrophage numbers.
Secondary outcome [3] 318821 0
Circulating monocyte activation markers CD14/CD16 will be measured by FACS after separation of cells from plasma.
Timepoint [3] 318821 0
At baseline and after 240 min infusion.

Eligibility
Key inclusion criteria
Body mass index>30 kg/m2
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Diabetes, cigarette smoking, malignancies, cardiac and vascular diseases, uncontrolled hypertension, psychiatric disorders, previous significant abdominal surgery, medications which affect inflammation or glucose metabolism

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)
A person who is not involved with analysis of the trial data will randomize consented volunteers to an order of treatments (GLP-1 infusion first or second. The order of treatment will be placed in a sealed opaque envelope with the participant's ID and given to the study nurse who will administer the treatments.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization of participants to GLP-1 infusion as the first or second treatment they receive will be done using odd or even last digits in a series of random numbers with one unique number for each participant.
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
Crossover
Other design features
3 week washout period between treatments.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Power calculation: A previous study (Regulatory Peptides 2013; 183: 54-61) has reported that a significant 2h decrease of 0.5 ng/l (42%) in plasma IL-6 concentrations during a GLP-1 infusion in 6 obese, diabetic subjects. Using the SD (0.55 ng/l) for the 60 min change in plasma IL-6 concentration during oral glucose ingestion in our previous study (PLoS One 8(6): e66395. Doi:10.1371/journal.pone.006395.), we calculate (using interactive website Statistical Considerations for Clinical Trials and Scientific Experiments hedwig.mgh.harvard.edu/sample_size.html) that a difference of 0.5 ng/l in plasma IL-6 between GLP-1 and placebo treatments could be detected in 12 individuals in a crossover study at 80% power and P=0.05.
Statistical analysis: Change in outcome variables during the infusions will be dependent variables in linear mixed models analysis with fixed effects of treatment, order of treatments, period, baseline value (covariate) and gender and a random variable for participants. For plasma markers of inflammation measured at 0, 30, 60, 120, and 240 min, linear mixed models with treatment, order of treatments, period, time, treatment x time, baseline values and gender as fixed effects and a variable for participants as a random effect, will also be tested.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/08/2014
Actual
11/03/2015
Date of last participant enrolment
Anticipated
30/03/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment outside Australia
Country [1] 6208 0
New Zealand
State/province [1] 6208 0
Otago

Funding & Sponsors
Funding source category [1] 289574 0
University
Name [1] 289574 0
University of Otago Strategic Research Grant
Country [1] 289574 0
New Zealand
Primary sponsor type
Individual
Name
Associate Professor Patrick Manning
Address
Endocrinology Research Unit
Department of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 288257 0
Individual
Name [1] 288257 0
Dr Wayne Sutherland
Address [1] 288257 0
Endocrinology Research Unit
Department of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country [1] 288257 0
New Zealand
Secondary sponsor category [2] 288258 0
Individual
Name [2] 288258 0
Dr Rajesh G Katare
Address [2] 288258 0
Department of Physiology
University of Otago
PO Box 56
Dunedin 9054
Country [2] 288258 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291311 0
Southern Health and Disability Ethics Committees
Ethics committee address [1] 291311 0
C/- MEDSAFE
Level 6, Deloitte House
10 Brandon Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 291311 0
New Zealand
Date submitted for ethics approval [1] 291311 0
Approval date [1] 291311 0
30/06/2014
Ethics approval number [1] 291311 0
14/STH/60

Summary
Brief summary
One of the risk factors for developing diabetes and cardiovascular disease (heart attacks and stroke) is obesity. We think that one of the reasons that obesity increases this risk is because there is increased production of inflammatory molecules such as interleukin-6 (IL-6) and tumor necrosis factor-a, in fat (adipose) tissue. These inflammatory molecules may damage blood vessels and reduce the effectiveness of the body’s glucose regulating hormone called insulin. A hormone called glucogon-like peptide-1 (GLP-1) that is released from the gut early after intake of food, is thought to decrease inflammation. However, there is little known about the effect of GLP-1 on inflammation in adipose tissue. Our previous research has shown that levels of IL-6 in the blood decrease early after ingestion of food. This decrease in IL-6 levels might be due to an increase in GLP-1 levels in the blood after a meal. The aim of our study is to determine the effect of GLP-1 infusion on adipose tissue inflammation and plasma concentrations of IL-6 and other inflammatory molecules in obese people.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49818 0
A/Prof Patrick Manning
Address 49818 0
Endocrinology Research Unit
Department of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 49818 0
New Zealand
Phone 49818 0
+64 3 470 9911
Fax 49818 0
+64 3 470 9916
Email 49818 0
PatrickManning@healthotago.co.nz
Contact person for public queries
Name 49819 0
A/Prof Patrick Manning
Address 49819 0
Endocrinology Research Unit
Department of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 49819 0
New Zealand
Phone 49819 0
+64 3 470 9911
Fax 49819 0
+64 3 470 9916
Email 49819 0
PatrickManning@healthotago.co.nz
Contact person for scientific queries
Name 49820 0
Dr Wayne Sutherland
Address 49820 0
Endocrinology Research Unit
Department of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 49820 0
New Zealand
Phone 49820 0
+64 3 470 9911
Fax 49820 0
+64 3 470 9916
Email 49820 0
wayne.sutherland@otago.ac.nz

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