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Trial registered on ANZCTR


Registration number
ACTRN12614000837628
Ethics application status
Approved
Date submitted
1/08/2014
Date registered
7/08/2014
Date last updated
19/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of intragastric administration of L-amino acids on gastric emptying, gut hormone release, blood glucose and energy intake in healthy, normal weight and overweight or obese type 2 diabetic patients.
Scientific title
Effects of intragastric administration of L-amino acids on gastric emptying, gut hormone release, blood glucose and energy intake in healthy, normal weight and overweight or obese type 2 diabetic patients.
Secondary ID [1] 285095 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 292641 0
Type 2 Diabetes 292642 0
Healthy Human Gastrointestinal Physiology 292643 0
Condition category
Condition code
Diet and Nutrition 292953 292953 0 0
Obesity
Oral and Gastrointestinal 292954 292954 0 0
Normal oral and gastrointestinal development and function
Metabolic and Endocrine 292955 292955 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is comprised of nine sub-studies. Eight of the sub-studies will investigate one L-amino acid as follows: i) L-isoleucine; ii) L-valine; iii) L-tyrosine; iv) L-methionine; v) L-lysine; vi) L-arginine; vii) L-cysteine; viii) L-phenylalanine. The ninth sub-study (ix) will investigate a comparison between L-isoleucine and L-leuine. Separate recruitment will be conducted for each sub-study.

Gastric emptying (measured by 2D ultrasound and breath testing), blood glucose, gut hormones release, insulin concentrations, appetite perceptions (measured by Visual Analogue Scales, VAS) and energy intake during a buffet meal, will be measured in each sub-study.

Subjects enrolled in each sub-study i) to viii) will receive, in randomized, double-blind fashion, an intragastric bolus infusion (200mls) of i) 5g L-amino acid; ii) 10g L-amino acid; iii) saline (control). Those enrolled in study ix) will receive in randomized, double-blind fashion, an intragastric bolus infusion (200mls) of i) 5g L-isoleucine; ii) 5g L-leucine; iii) saline (control). Subjects will receive one infusion per visit. Study visits will be separated by 3-7 days.

For each study visit a baseline blood sample, VAS, ultrasound, and breath sample will be taken (t = -20). At t = -17 min the infusion will be administered over 2 minutes using a feeding tube. At t = -2 min a further VAS and ultrasound will be taken. At t = -1 min, subjects will consume, within 1 minute, a mixed-nutrient drink (Ensure, 400 kcal, 300 ml) labeled with 150 mg of 13C-acetate for measurement of gastric emptying by breath sampling. Blood samples, VAS and ultrasound measurements will be taken every 15 minutes over the next hour (t = 0 to 60 min). Breath samples will be taken every 5 minutes from t = 0 to 60 min.

At t = 60 min, subjects will be presented with a cold, buffet-style meal. Subjects will be allowed 30 minutes to freely consume the buffet meal until comfortably full. At t = 90 min a final blood sample will be taken, and VAS administered.
Intervention code [1] 289941 0
Treatment: Other
Comparator / control treatment
Saline
Control group
Placebo

Outcomes
Primary outcome [1] 292813 0
Gastric Emptying (measurement of 13CO2 in breath samples, and 2D ultrasound of the antral area).
Timepoint [1] 292813 0
Breath samples will be collected at t = -20 min and every 5 minutes from t = 0 to 60 min. 2D ultrasound will be taken at t = -20 min, t = -2 min, and every 15 minutes from t = 0 to 60 min.
Primary outcome [2] 292814 0
Plasma concentrations of gastrointestinal hormones (e.g. CCK, GLP-1, PYY, GIP and ghrelin), insulin and glucose.
Timepoint [2] 292814 0
Gut hormone release will be assessed by Enzyme-linked Immunosorbent Assay (ELISA) or Radio Immnunosorbent Assay (RIA) from blood samples taken at t = -20 min, every 15 minutes from t = 0 to 60 min, and a final sample taken after a 1/2 hr lunch period immediately following each study visit (t = 90 min).
Secondary outcome [1] 309726 0
Appetite sensations using a Visual Analogue Scale (VAS) (satiety, hunger, fullness, thirst, desire to eat and amount of food desired to eat).
Timepoint [1] 309726 0
VAS questionnaires are taken at t = -20 min, t = -2 min, and every 15 minutes from t = 0 to 60 min. A final VAS is administered at the end of a 1/2 hr lunch period immediately following each study visit (t = 90 min).
Secondary outcome [2] 309727 0
Macronutrient and total energy intake at the buffet meal measured using the computer software program FoodWorks.
Timepoint [2] 309727 0
A buffet meal will be presented immediately following each study visit. The subject will be allowed to freely consume food until comfortably full for 30 minutes.

Eligibility
Key inclusion criteria
A total of 20 healthy, lean (BMI 19-25 kg/m2) and 20 obese T2DM (BMI 30-35 kg/m2) male and female Caucasian subjects, aged between 18 - 55 years, will be included in each sub-study i) - ix). T2DM diagnosis will be based on WHO criteria. HbA1c will be >=6.5 - <=7.9% at screening. Patients will be diet-controlled, with or without metformin (<2 g/d). All subjects will be required to be weight stable (ie <5% fluctuation) at study entry, which will be ascertained by a stable body weight in the preceeding 4 weeks. Subjects will be required to maintain their normal physical activity over the course of the study, which will be assessed using diaries.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
All subjects: Significant gastrointestinal symptoms, disease or surgery; use of prescribed or non-prescribed medications (including vitamins and herbal supplements) which may affect energy metabolism, gastrointestinal function, body weight or appetite (eg domperidone and cisapride, anticholinergic drugs (eg atropine), metoclopramide, erythromycin, hyoscine, orlistat, green tea extracts, Astragalus, St Johns Wort etc.); lactose intolerance/other food allergy(ies); current gallbladder or pancreatic disease; cardiovascular or respiratory diseases; individuals with low ferritin levels (females less than 15 ng/mL, males less than 30 ng/mL), or who have donated blood in the 12 weeks prior to taking part in the study; any other illnesses as assessed by the investigator (including chronic illnesses not explicitly listed above); high performance athletes; current intake of greater than 2 standard drinks on greater than 5 days per week; current smokers of cigarettes/cigars/marijuana; current intake of any illicit substance; vegetarians; inability to comprehend study protocol; unable to tolerate naso-gastric tube; in female subjects, pregnancy or lactation; phenylketonuria (only applies to the part involving L-phenylalanine).

Healthy subjects only: fasting glucose >6.9 mmol/l or HbA1c >=6.5%; restrained eaters (score >12 on the three factor eating questionnaire).

Obese T2DM subjects only: HbA1c <6.5% - >7.9%; metformin medication >2g/d; estimated glomerular filtration rate <45ml/min. The degree of eating restraint will be assessed, but not used as an exclusion criteria, as obese often have some degree of eating restraint.

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)
Volunteers are asked to visit the clinic for a 40-60 minute screening visit. A questionnaire is answered by the volunteer, and based on the inclusion/exclusion criteria, eligibility is determined. A signed informed consent is obtained and study dates are established. Eligible volunteers are assigned a subject number and randomised treatment for each study visit. Randomisation involves contacting the holder (study assistant) of the randomisation table to inform them of the next subjects details and study dates. The unblinded study assistant is therefore responsible for allocationg a random treatment to the subject and preparing the solution on each study day.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation is generated using a randomization plan generator available at www.randomization.com
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
Not Applicable
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
11/08/2014
Actual
29/08/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
320
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 289701 0
Hospital
Name [1] 289701 0
Royal Adelaide Hospital Project Grant 2014
Country [1] 289701 0
Australia
Funding source category [2] 289702 0
Other
Name [2] 289702 0
Diabetes Australia Research Trust (DART) Research Grant 2014.
Country [2] 289702 0
Australia
Primary sponsor type
Individual
Name
Christine Feinle-Bisset
Address
Discipline of Medicine
University of Adelaide
Level 3 Eleanor Harrald Building,
Frome Road,
Adelaide, SA 5000
Country
Australia
Secondary sponsor category [1] 288394 0
Individual
Name [1] 288394 0
Robert E Steinert
Address [1] 288394 0
Discipline of Medicine
University of Adelaide
Level 3 Eleanor Harrald Building,
Frome Road,
Adelaide, SA 5000
Country [1] 288394 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291440 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [1] 291440 0
Level 3, Hanson Institute
North Terrace
Adelaide SA, 5000
Ethics committee country [1] 291440 0
Australia
Date submitted for ethics approval [1] 291440 0
Approval date [1] 291440 0
30/06/2014
Ethics approval number [1] 291440 0
140626

Summary
Brief summary
Obesity has reached epidemic proportions globally and is associated with serious co-morbidities, including type 2 diabetes. Once adipose tissue has been accumulated, and food intake is limited by low calorie diets, counter-regulatory mechanisms induce an increase in appetite and a decrease in energy expenditure, which makes weight loss very difficult to maintain. To combat the global burden of obesity and its co-morbidities, a major challenge lies in the development of effective therapies that increase fullness and satiety, and result in good blood glucose control, while lacking adverse effects that are often associated with current therapies.

There is increasing evidence that nutrient stimuli in the gastrointestinal tract play a central role in the control of energy intake and blood glucose. Proteins, and their building blocks, amino acids, are of interest, since high-protein diets are very effective for weight loss, particularly loss of fat, rather than muscle mass, and for improving postprandial glycaemic control, in obese individuals with and without type 2 diabetes. There is some evidence that a number of amino acids (including those to be studied) may also have effects on energy intake, blood glucose and gut function in humans. Thus, they are of special interest in terms of potential therapeutic approaches for obesity and type 2 diabetes.

This study will investigate the dose-related effects of intragastric administration of specific L-amino acids on gastric emptying, gut hormone release, glycaemic control, appetite perceptions and energy intake in healthy, normal weight and overweight or obese type 2 diabetic patients.
Trial website
Trial related presentations / publications
Ullrich SS, Fitzgerald PCE, Schober G, Steinert RE, Horowitz M, Feinle-Bisset C. Intragastric administration of leucine or isoleucine lowers the blood glucose response to a mixed-nutrient drink by different mechanisms in healthy, lean volunteers. Am J Clin Nutr 2016; 104:1274–84
Public notes

Contacts
Principal investigator
Name 50382 0
Prof Professor Christine Feinle-Bisset
Address 50382 0
Discipline of Medicine, University of Adelaide Level 3 Eleanor Harrald Building, Frome Road, Adelaide, South Australia 5000
Country 50382 0
Australia
Phone 50382 0
+61 8 8222 5247
Fax 50382 0
Email 50382 0
[email protected]
Contact person for public queries
Name 50383 0
Prof Professor Christine Feinle-Bisset
Address 50383 0
Discipline of Medicine, University of Adelaide Level 3 Eleanor Harrald Building, Frome Road, Adelaide, South Australia 5000
Country 50383 0
Australia
Phone 50383 0
+61 8 8222 5247
Fax 50383 0
Email 50383 0
[email protected]
Contact person for scientific queries
Name 50384 0
Prof Professor Christine Feinle-Bisset
Address 50384 0
Discipline of Medicine, University of Adelaide Level 3 Eleanor Harrald Building, Frome Road, Adelaide, South Australia 5000
Country 50384 0
Australia
Phone 50384 0
+61 8 8222 5247
Fax 50384 0
Email 50384 0
[email protected]

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