Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000899741
Ethics application status
Approved
Date submitted
23/07/2013
Date registered
13/08/2013
Date last updated
9/01/2019
Date data sharing statement initially provided
9/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of L-leucine (alone or in combination with L-tryptophan or lauric acid) on gut functions, gastric emptying, gut hormone release and blood glucose control in healthy, and obese humans with type 2 diabetes
Scientific title
Effects of L-leucine (alone or in combination with L-tryptophan or lauric acid) on antropyloroduodenal motility, gastric emptying, gut hormone release, blood glucose control and energy intake in healthy, and obese humans with type 2 diabetes
Secondary ID [1] 282867 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 289680 0
Type 2 diabetes 289824 0
Healthy Human Gastrointestinal Physiology 289825 0
Condition category
Condition code
Diet and Nutrition 289997 289997 0 0
Obesity
Oral and Gastrointestinal 289998 289998 0 0
Normal oral and gastrointestinal development and function
Metabolic and Endocrine 290180 290180 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is comprised of nine sub-studies, with separate recruitment conducted for each sub-study.

Gut motility (measured by a manometric tube, study A, F-H), gastric emptying (measured by 2D ultrasound and breath testing, studies B-E, I), 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.

Study A, F-H: Subjects enrolled in each sub-study will receive, in randomized, double-blind fashion, each of the intraduodenal infusions described for that study. All intraduodenal infusions are administered over a 90-min period. All visits within a sub-study are separated by 3-7 days.
Study A (i) 0.15 kcal/min L-leucine, (ii) 0.45 kcal/min L-leucine, or (iii) saline (control).
Study F (i) 0.45 kcal/min L-leucine, (ii) 0.15 kcal/min L-tryptophan, (iii) combination of (i) and (ii), (iv) saline (control).
Study G (i) 0.45 kcal/min L-leucine, (ii) 0.4 kcal/min Lauric Acid, (iii) combination of (i) and (ii), (iv) saline (control).
Study H (i) 0.1 kcal/min L-tryptophan, (ii) 0.3 kcal/min lauric acid, (iii) combination of (i) and (ii), (iv) saline (control).
Blood samples will be collected and VAS completed every 15 min from t = -15 to 90 min. At t = 90 min, the manometric assembly will be removed and subjects will be presented with a cold, buffet-style meal.

Studies B-E, I: Subjects enrolled in each sub-study will receive, in randomized, double-blind fashion, each of the intragastric bolus infusions described for that study. Infusions will be administered over 3 minutes using a feeding tube. Study visits will be separated by 3-7 days.
Study B (i) 5g L-leucine, (ii) 10g L-leucine, or (iii) saline (control)
Study C (i) 3g L-tryptophan, (ii) 1.5g L-tryptophan, or (iii) saline (control)
Study D (i) 10g L-leucine, (ii) 3g L-tryptophan, (iii) combination of (i) and (ii), (iv) saline (control)
Study E (i) 10g L-leucine, (ii) 6g lauric acid, (iii) combination of (i) and (ii), (iv) saline (control).
Study I (i) 3g L-tryptophan, (ii) 6g lauric acid, (iii) combination of (i) and (ii), (iv) saline (control)
For each study visit, a mixed nutrient drink (Ensure, 400 kcal, 300ml) will be administered 15 min after the infusion (t=0). Blood samples will be collected and VAS completed every 15 min from t = -15 to 60 min. Gastric emptying measurements will be taken at t= -15 and every 5 min from t = 0 to 60 min. At t = 60 min, subjects will be presented with a cold, buffet-style meal.

For all studies, subjects will be allowed 30 min to freely consume the buffet meal until comfortably full. At t = 120 min (study A, F-H) or t = 90 min (studies B-E, I), a final blood sample will be taken, and VAS administered
Intervention code [1] 287564 0
Treatment: Other
Comparator / control treatment
Saline
Control group
Placebo

Outcomes
Primary outcome [1] 318611 0
All studies: Energy intake at the buffet meal measured using the computer software program FoodWorks.
Timepoint [1] 318611 0
All studies: 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.
Secondary outcome [1] 303833 0
All studies: Appetite sensations using a Visual Analogue Scale (VAS) (satiety, hunger, fullness, thirst, desire to eat and amount of food desired to eat)
Timepoint [1] 303833 0
All studies: VAS questionnaires are taken every 15 minutes from t=-15 for the duration of each study, and a final VAS administered at the end of a 1/2 hr lunch period immediately following each study visit.
Secondary outcome [2] 365524 0
Study A, F-H: Antropyloroduodenal motility (number of antral, duodenal and isolated pyloric pressure waves, and basal pyloric pressure)
Timepoint [2] 365524 0
Study A, F-H: Using a manometric assembly and catheter, antropyloroduodenal pressures will be continuously monitored from intubation until t=90 (end of infusion) for each intraduodenal infusion visit.
Secondary outcome [3] 365525 0
Studies B-E, I: Gastric Emptying (measurement of 13CO2 in breath samples, and 2D ultrasound of the antral area
Timepoint [3] 365525 0
Studies B-E, I: Breath samples will be collected, and 2D ultrasound carried out, at baseline (t=0) and every 5 minutes for the following 60 minutes for each intragastric infusion visit
Secondary outcome [4] 365526 0
All studies: Plasma concentrations of gastrointestinal hormones (e.g. CCK, GLP-1, PYY, GIP and ghrelin), insulin and glucose
Timepoint [4] 365526 0
All studies: Gut hormone release will be assessed by Enzyme-linked Immunosorbent Assay (ELISA) or Radio Immnunosorbent Assay (RIA) from blood samples taken every 15 minutes from t=-15 for the duration of each study, and a final sample taken after a 1/2 hr lunch period immediately following each study visit.

Eligibility
Key inclusion criteria
A total of 16 healthy, lean (BMI 19-25 kg/m2) and 16 obese T2DM (BMI 30-35 kg/m2) male and female Caucasian subjects, aged between 18 - 55 years, will be included in each Study A-I. 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
Healthy 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; in female subjects, pregnancy or lactation; restrained eaters (score >12 on the three factor eating questionnaire); fasting glucose >6.9 mmol/l or HbA1c >=6.5%.

Obese T2DM subjects: As for healthy subjects, except, 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 30 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, using a randomised table which was created on an excel spread sheet. Randomisation involved 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 table was generated using Microsoft Office Excel.
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
1/09/2013
Actual
4/10/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
288
Accrual to date
92
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 287645 0
Hospital
Name [1] 287645 0
Gum Bequest Grant, Royal Adelaide Hospital Endocrine Unit (2012-2013)
Country [1] 287645 0
Australia
Funding source category [2] 287672 0
Hospital
Name [2] 287672 0
Royal Adelaide Hospital Grant (2013-2015)
Country [2] 287672 0
Australia
Funding source category [3] 290891 0
Government body
Name [3] 290891 0
NHMRC
Country [3] 290891 0
Australia
Primary sponsor type
Individual
Name
Christine Feinle-Bisset
Address
Level 5, Adelaide Health and Medical Sciences Building
Cnr North Terrace and George Street
Adelaide
South Australia 5005
Country
Australia
Secondary sponsor category [1] 286386 0
Individual
Name [1] 286386 0
Robert E Steinert
Address [1] 286386 0
Level 5, Adelaide Health and Medical Sciences Building
Cnr North Terrace and George Street
Adelaide
South Australia 5005
Country [1] 286386 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289614 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 289614 0
Ethics committee country [1] 289614 0
Australia
Date submitted for ethics approval [1] 289614 0
Approval date [1] 289614 0
28/06/2013
Ethics approval number [1] 289614 0
130611

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 41574 0
Prof Professor Christine Feinle-Bisset
Address 41574 0
Level 5, Adelaide Health and Medical Sciences Building
Cnr North terrace and George Street
Adelaide
South Australia 5005
Country 41574 0
Australia
Phone 41574 0
+61 8 8313 6053
Fax 41574 0
Email 41574 0
[email protected]
Contact person for public queries
Name 41575 0
Professor Christine Feinle-Bisset
Address 41575 0
Level 5, Adelaide Health and Medical Sciences Building
Cnr North terrace and George Street
Adelaide
South Australia 5005
Country 41575 0
Australia
Phone 41575 0
+61 8 8313 6053
Fax 41575 0
Email 41575 0
[email protected]
Contact person for scientific queries
Name 41576 0
Professor Christine Feinle-Bisset
Address 41576 0
Level 5, Adelaide Health and Medical Sciences Building
Cnr North terrace and George Street
Adelaide
South Australia 5005
Country 41576 0
Australia
Phone 41576 0
+61 8 8313 6053
Fax 41576 0
Email 41576 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
To align with intellectual property agreement


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
SourceTitleYear of PublicationDOI
EmbaseEffects of intraduodenal infusion of the branched-chain amino acid leucine on ad libitum eating, gut motor and hormone functions, and glycemia in healthy men.2015https://dx.doi.org/10.3945/ajcn.115.114488
EmbaseIntragastric administration of leucine or isoleucine lowers the blood glucose response to a mixed-nutrient drink by different mechanisms in healthy, lean volunteers.2016https://dx.doi.org/10.3945/ajcn.116.140640
Dimensions AIComparative effects of intraduodenal amino acid infusions on food intake and gut hormone release in healthy males2017https://doi.org/10.14814/phy2.13492
EmbaseEffects of duodenal infusion of lauric acid and l-tryptophan, alone and combined, on fasting glucose, insulin and glucagon in healthy men.2019https://dx.doi.org/10.3390/nu11112697
EmbaseEffects of intraduodenal administration of lauric acid and L-tryptophan, alone and combined, on gut hormones, pyloric pressures, and energy intake in healthy men.2019https://dx.doi.org/10.1093/ajcn/nqz020
EmbaseEffects of intraduodenal coadministration of lauric acid and leucine on gut motility, plasma cholecystokinin, and energy intake in healthy men.2020https://dx.doi.org/10.1152/AJPREGU.00352.2019
EmbaseEffects of intragastric administration of L-tryptophan on the glycaemic response to a nutrient drink in men with type 2 diabetes - impacts on gastric emptying, glucoregulatory hormones and glucose absorption.2021https://dx.doi.org/10.1038/s41387-020-00146-9
N.B. These documents automatically identified may not have been verified by the study sponsor.