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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]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Obesity

Type 2 diabetes

Healthy Human Gastrointestinal Physiology

Condition category

Condition code

Diet and Nutrition

Obesity

Oral and Gastrointestinal

Normal oral and gastrointestinal development and function

Metabolic and Endocrine

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]

Treatment: Other

Comparator / control treatment

Saline

Control group

Placebo

Outcomes

Primary outcome [1]

All studies: Energy intake at the buffet meal measured using the computer software program FoodWorks.

Timepoint [1]

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]

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]

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]

Study A, F-H: Antropyloroduodenal motility (number of antral, duodenal and isolated pyloric pressure waves, and basal pyloric pressure)

Timepoint [2]

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]

Studies B-E, I: Gastric Emptying (measurement of 13CO2 in breath samples, and 2D ultrasound of the antral area

Timepoint [3]

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]

All studies: Plasma concentrations of gastrointestinal hormones (e.g. CCK, GLP-1, PYY, GIP and ghrelin), insulin and glucose

Timepoint [4]

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

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Gum Bequest Grant, Royal Adelaide Hospital Endocrine Unit (2012-2013)

Address [1]

Royal Adelaide Hospital
North Terrace,
Adelaide, SA 5000

Country [1]

Australia

Funding source category [2]

Hospital

Name [2]

Royal Adelaide Hospital Grant (2013-2015)

Address [2]

North Terrace
Adelaide, SA 5000

Country [2]

Australia

Funding source category [3]

Government body

Name [3]

NHMRC

Address [3]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [3]

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]

Individual

Name [1]

Robert E Steinert

Address [1]

Level 5, Adelaide Health and Medical Sciences Building
Cnr North Terrace and George Street
Adelaide
South Australia 5005

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Adelaide Local Health Network Human Research Ethics Committee

Ethics committee address [1]

Level 3, Roma Mitchell House, North Terrace, Adelaide SA 5000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

28/06/2013

Ethics approval number [1]

130611

Summary

Brief summary

There is increasing evidence that nutrient stimuli in the gut, especially in the small intestine, induce changes in gut motor and hormonal functions that play a central role in the control of energy intake and blood glucose. Previous research by our group has shown individual amino acids (L-tryptophan) and free fatty acids (lauric acid) to markedly reduce energy intake at a subsequent meal when administered intraduodenally or orally, respectively. This study aims to investigate the effects of the amino acids L-leucine, alone or in combination with L-tryptophan or lauric acid, on gut motility, gut hormone release, blood glucose control and energy intake in healthy lean individuals and obese patients with T2DM. We hypothesise that L-leucine, administered in combination with L-tryptophan or lauric acid, will take advantage of the several pathways activated by these two classes of nutrients enhancing their potency and thus, resulting in a marked improvement in the beneficial effects on gut functions and energy intake regulation previously associated with these nutrients alone.

Trial website

Trial related presentations / publications

Ullrich SS, Fitzgerald PCE, Giesbertz P, Steinert RE, Horowitz M, Feinle-Bisset C. Effects of Intragastric Administration of Tryptophan on the Blood Glucose Response to a Nutrient Drink and Energy Intake, in Lean and Obese Men. Nutrients 2018, 10, 463; doi:10.3390/nu10040463

Public notes

Contacts

Principal investigator

Name

Prof Professor Christine Feinle-Bisset

Address

Level 5, Adelaide Health and Medical Sciences Building
Cnr North terrace and George Street
Adelaide
South Australia 5005

Country

Australia

Phone

+61 8 8313 6053

Fax

christine.feinle@adelaide.edu.au

Contact person for public queries

Name

Professor Christine Feinle-Bisset

Address

Level 5, Adelaide Health and Medical Sciences Building
Cnr North terrace and George Street
Adelaide
South Australia 5005

Country

Australia

Phone

+61 8 8313 6053

Fax

christine.feinle@adelaide.edu.au

Contact person for scientific queries

Name

Professor Christine Feinle-Bisset

Address

Level 5, Adelaide Health and Medical Sciences Building
Cnr North terrace and George Street
Adelaide
South Australia 5005

Country

Australia

Phone

+61 8 8313 6053

Fax

christine.feinle@adelaide.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

Source	Title	Year of Publication	DOI
Embase	Effects of intraduodenal infusion of the branched-chain amino acid leucine on ad libitum eating, gut motor and hormone functions, and glycemia in healthy men.	2015	https://dx.doi.org/10.3945/ajcn.115.114488
Embase	Intragastric administration of leucine or isoleucine lowers the blood glucose response to a mixed-nutrient drink by different mechanisms in healthy, lean volunteers.	2016	https://dx.doi.org/10.3945/ajcn.116.140640
Dimensions AI	Comparative effects of intraduodenal amino acid infusions on food intake and gut hormone release in healthy males	2017	https://doi.org/10.14814/phy2.13492
Embase	Effects of duodenal infusion of lauric acid and l-tryptophan, alone and combined, on fasting glucose, insulin and glucagon in healthy men.	2019	https://dx.doi.org/10.3390/nu11112697
Embase	Effects of intraduodenal administration of lauric acid and L-tryptophan, alone and combined, on gut hormones, pyloric pressures, and energy intake in healthy men.	2019	https://dx.doi.org/10.1093/ajcn/nqz020
Embase	Effects of intraduodenal coadministration of lauric acid and leucine on gut motility, plasma cholecystokinin, and energy intake in healthy men.	2020	https://dx.doi.org/10.1152/AJPREGU.00352.2019
Embase	Effects 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.	2021	https://dx.doi.org/10.1038/s41387-020-00146-9

N.B. These documents automatically identified may not have been verified by the study sponsor.

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