Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614001084673
Ethics application status
Approved
Date submitted
25/09/2014
Date registered
10/10/2014
Date last updated
22/10/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of plant extracts on appetite, energy intake and the glycemic response to a carbohydrate meal
Scientific title
Activation of the ileal brake- A nutritional intervention study to assess the efficacy of a starch breakdown inhibitor and a glucose uptake inhibitor present in natural plant extracts, on the oral delivery of carbohydrates, in modulating postprandial glucose, appetite and food intake in healthy and non-obese males.
Secondary ID [1] 285402 0
None
Universal Trial Number (UTN)
U1111-1160-3911
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postprandial glucose metabolism 293148 0
Appetite regulation 293181 0
Food (energy) intake 293182 0
Condition category
Condition code
Diet and Nutrition 293413 293413 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a randomised, placebo controlled, double-blind, 5-condition cross-over single day study with a 2 MJ high carbohydrate (CHO) breakfast meal, comprised of 185 g of white toast bread, followed 3 hours later by a lunch meal which is consumed ad libitum until the participant is comfortably full. The 5 intervention arms are:
1. 2MJ carbohydrate breakfast + Placebo in acid –resistant capsule given 60 minutes prior to breakfast (negative control)
2. 2MJ carbohydrate breakfast + Acarbose, 50 mg, in acid –resistant capsule given 60 minutes prior to breakfast (positive control)
3. 2MJ carbohydrate breakfast + grape seed extract (1500 mg, in acid –resistant capsule given 60 minutes prior to breakfast)
4. 2MJ carbohydrate breakfast + onion skin extract (1500 mg, in acid –resistant capsule given 60 minutes prior to breakfast)
5. 2MJ carbohydrate breakfast + grape seed extract (750 mg)/onion skin extract (750 mg) synergy in acid –resistant capsule given 60 minutes prior to breakfast
Participants will arrive at Plant and Food Research Ltd in the fasted state at 0800h. Treatments will be provided at 0830h in acid-resistant capsules to ensure delivery of extracts to the small intestine avoiding any potential loss of activity in the stomach. Participants will be provided a 2MJ carbohydrate breakfast at 0930h which they must consume in 15 minutes. Capillary blood glucose concentrations will be monitored via finger prick at 0830h (t= -60), 0930h (t=0) and at 30 minute intervals for the following 3 hours (1000h, 1030h, 1100h, 1130h, 1200h and 1230h) and 60 minute intervals for the following 2 hours (1330h and 1430h). Throughout the day participants will rate hunger, fullness and other appetite-related sensations, including satisfaction, current thoughts of food (TOF), energy level, thirst and nausea using visual analogue scales (VAS). An ad libitum lunch will be served at 1230h (t=180). For the measurement of energy and macronutrient intake, foods will be weighed before and after each meal. The study day finishes at 1500h. There will be a minimum washout period of 3 days in between treatments.
Intervention code [1] 290320 0
Treatment: Other
Comparator / control treatment
1. 2MJ carbohydrate breakfast + Placebo in acid –resistant capsule given 60 minutes prior to breakfast (negative control)
2. 2MJ CHO breakfast + Acarbose, 50 mg, in acid –resistant capsule given 60 minutes prior to breakfast (positive control)
Control group
Placebo

Outcomes
Primary outcome [1] 293242 0
Energy and macronutrient intake from the ad libitum lunch meal will be measured. For the measurement of energy and macronutrient intake, foods will be weighed before and after the lunch meal.
Timepoint [1] 293242 0
Assessed at an ad libitum lunch served at 1230h (t=180)
Primary outcome [2] 293277 0
VAS-assessed subjective appetite ratings will be measured throughout the study.
Timepoint [2] 293277 0
*0830h (t=-60): Capillary finger prick glucose. Encapsulated placebo, Acarbose or test plant extract (GSE, OSE and GSE+OSE) is given
*0930h (t=0): Finger prick glucose (baseline). Participant given the standard 2 MJ breakfast
*0945h (t=15): Post-breakfast appetite VAS + palatability VAS
*1000h (t=30): Appetite VAS
*1015h (t=45): Appetite VAS
*1030h (t=60): Appetite VAS
*1100h (t=90): Appetite VAS
*1130h (t=120): Appetite VAS
*1200h (t=150): Appetite VAS
*1230h (t=180): Appetite VAS, immediately prior to ad libitum lunch meal
*1300h (t=210): Appetite VAS, immediately post ad libitum lunch meal + palatability VAS
*1330h (t=240): Appetite VAS
*1400h (t=270): Appetite VAS
*1500h (t=330): Appetite VAS (Final)
Secondary outcome [1] 310661 0
Monitoring the blood glucose responses is a way of testing the efficacy of the test plant extracts, since we hypothesise that the rate of CHO digestion and subsequent absorption of glucose will be inhibited by the extracts. Capillary glucose concentrations will be measured using finger prick assessment methods.
Timepoint [1] 310661 0
Assessed at 0830h (t= -60), 0930h (t=0, baseline) and at 30 minute intervals for the following 3 hours at 1000h, 1030h, 1100h, 1130h, 1200h (pre-ad lib lunch meal) and 1300h (immediately post-lunch meal) ) and 60 minute intervals for the following 2 hours (1400h and 1500h). False

Eligibility
Key inclusion criteria
Inclusion Criteria
-Male
-Age 18-65 years
-Non-obese, as defined by BMI 18-29kg/m2
-Healthy, as ascertained by self-report
Minimum age
18 Years
Maximum age
65 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion Criteria
-Obese (BMI > 29kg/m2)
-Any medical conditions or medications known to affect appetite -related parameters, including depression
-Participation in an active diet program and/or loss/gain of >10% body weight within the last 6 months
-Smoker or ex-smoker who quit within the last 6 months
-Hypersensitivities or allergies to any foods or ingredients included in the study
-Dislike and/or unwilling to consume items listed as study foods
-Unwilling/unable to comply with study protocol
-Participating in another clinical intervention trial

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)
Allocation is not concealed.
Participants interested in the study will contact the research staff via phone or email for further information. The Participant Information Sheet (PIS) will be emailed or posted to the participants. On the screening day, the PIS will be provided, the study explanation will be given and written consent will be obtained. Subjects are screened for eligibility. Then, demographics (age, ethnicity) and anthropometry (height, body weight, BMI) will be obtained and the participant completes medical history.
The intervention arms will be randomised for the participants according to a Latin Square Design. All participants will attend a sensory facility at Plant and Food Ltd on 5 separate occasions where they are randomly allocated to one of the 5 intervention arms.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The intervention arms will be randomised for the participants according to a Latin Square Design.
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
Efficacy
Statistical methods / analysis
Data on demographic and anthropometric characteristics will be summarized using descriptive statistics. Efficacy endpoints of VAS and EI will be presented as mean, standard error of the mean (mean, SEM). VAS data assessing feelings of hunger, fullness and other satiety indicators throughout the study days as well as VAS data assessing the palatability of the breakfast and lunch meals will be analysed using repeated measures Linear Mixed Model ANOVA (SAS: PROC MIXED, SAS version 9.2, SAS Institute Inc, Cary, NC, USA, 2002– 2008). The energy and macronutrient intake data from the outcome meal (ad libitum lunch) following each of the 5 treatments will also be analysed using ANOVA. The treatment, participant and study day are included in the procedure, in addition to the treatment/time interaction which address whether the trajectory over time during the study period differed between the breakfast treatments (diet*time). Where the repeated measures Linear Mixed Model ANOVA is significant, Tukey's post hoc analysis will be used for comparisons between treatments. Statistical significance is set at P less than 0.05.
20 male participants will complete all 5 interventions. Energy intake at the ad lib lunch meal is the primary end point outcome variable in this trial. A power analysis was performed to provide estimates of variance components using data from a previous test meal experiment performed at the Human Nutrition Unit which investigated the effect of a test breakfast on satiety and energy intake (EI) at an ad libitum lunch meal in a similar group of 18 lean men. Energy intake at the ad lib lunch meal was the primary outcome, and the calculations have used the assumptions of outcome differences of 500kJ, equivalent to a change of 5 percent in an individual consuming a typical daily intake of 10MJ/day. In order to inform as to the within-person standard deviation, numbers corresponding to the smallest and largest standard deviation from the previous trial were used (686kJ, 990kJ):
Paired data (cross-over) – continuous outcome (EI)
Anticipated standardised effect is [anticipated difference in outcome250kJ or 500kJ]/ [sd of difference of outcome variable measured on two occasions estimated from previous studies]. In order to detect an outcome difference of 5% (500kJ) as significant at P<0.05
(i)difference is 500/686 and is equal to 0.73 80% are 17 subjects and 90% are 22 subjects
(ii)difference is 500/990 and is equal to 0.51 80% are 33 subjects and 90% are 42 subjects
The model based upon an estimated error variance taken from the previous study could be larger (or smaller) than previously observed & hence the actual probability of detecting the effect is uncertain. Using the upper 80% confidence interval (worst case scenario) the number of subjects required falls between 17-33 subjects.
Machin, D. et al. Sample Size Tables for Clinical Studies, 3rd Edition, 2008.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
13/10/2014
Actual
13/10/2014
Date of last participant enrolment
Anticipated
28/11/2014
Actual
1/12/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
20
Recruitment outside Australia
Country [1] 6376 0
New Zealand
State/province [1] 6376 0
Auckland

Funding & Sponsors
Funding source category [1] 290009 0
Government body
Name [1] 290009 0
Ministry of Business, Innovation, and Employment (MBIE)
Country [1] 290009 0
New Zealand
Primary sponsor type
Government body
Name
Plant and Food Research Institute Ltd
Address
120 Mt Albert Road
Sandringham
Auckland 1025
Country
New Zealand
Secondary sponsor category [1] 288693 0
University
Name [1] 288693 0
The Human Nutrition Unit at the University of Auckland in New Zealand
Address [1] 288693 0
18 Carrick Place, Mt Eden
Auckland 1024
Country [1] 288693 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291717 0
The Northern A Health and Disability Ethics Committee
Ethics committee address [1] 291717 0
Health and Disability Ethics Committees
Ministry of Health
Ministry of Health
No 1 The Terrace
PO Box 5013
Wellington 6145
Ethics committee country [1] 291717 0
New Zealand
Date submitted for ethics approval [1] 291717 0
10/09/2014
Approval date [1] 291717 0
23/09/2014
Ethics approval number [1] 291717 0
14/NTA/144

Summary
Brief summary
The gastrointestinal (GI) tract and specifically the most distal part of the small intestine (SI), the ileum, has become a renewed focus of interest for mechanisms targeting appetite suppression. The ‘ileal brake’ is stimulated when energy-containing nutrients are delivered beyond the duodenum
and jejunum and into the ileum, and is named for the feedback loop which slows or ‘brakes’ gastric emptying and duodenojejunal motility. More recently it has been hypothesised that the ileal brake also promotes secretion of satiety-enhancing GI peptides and suppresses hunger, and
hence in turn places a ’brake’ on food intake. Postprandial delivery of macronutrients to the ileum, other than unavailable carbohydrates (CHO) which bypass absorption in the small intestine en route to fermentation in the large bowel, is an uncommon event and hence this brake mechanism is
rarely activated following a meal. Evidence linking the ileal brake to enhanced satiety can be found from a number of studies that have delivered nutrients to the ileum enterally.
Early nasoileal (NI) tube feeding studies where lipid emulsions were infused directly into the ileum significantly decreased appetite and food intake (Welch et al., 1985; Welch et al., 1988b; Welch et al., 1988c; Maljaars et al., 2008, 20009, 2010, 2011, 2012; see review by Shin et al., 2013). There is some preliminary evidence that commercial lipid formulations designed to resist digestion and absorption in the proximal
small intestine are transported to the ileum and suppress food intake (Burns et al., 2000, 2001, 2002; Diepvens et al., 2007), although findings from these feeding studies remain mixed (Smit et al., 2011; Chan et al., 2012).
Our research group has recently shown that hunger and food intake can be altered acutely by infusion of glucose in to the ileum using an NI tube (Shin et al., unpublished data) suggesting that carbohydrates can also activate the ileal brake mechanism. However, no corresponding evidence
exists for ileal brake activation following the ingestion of carbohydrate containing foods. This is likely to be due to the very efficient digestion and absorption of carbohydrates by the proximal SI resulting in minimal glucose availability in the ileum.
In order to ensure arrival of CHOs into the distal small intestine (ileum) it is necessary to induce a degree of carbohydrate malabsorption in the proximal small intestine (duodenum and jejunum). This approach has previously been demonstrated using a carbohydrate meal and pharmacological interventions such as the a-glucosidase inhibitor migitol (Lee et al., 2002; Kaku et al., 2012) or a novel glucose transport inhibitor
LX4211 (Zambrowicz et al., 2013) where enhanced ratings of satiety and postprandial GLP-1 and PYY concentrations beyond 2 h have been demonstrated, indicating ileal brake activation.
A number of natural occurring plant phytochemicals have been
demonstrated to posses similar carbohydrate malabsorption potential (Lakshimi et al., 2012), although their ability to trigger ileal brake activation has not as yet been demonstrated in vivo. We have recently identified in vitro, a commercially available grape seed extract (Oxifend, Registerd Trademark, grape seed extract, New Zealand Extracts Ltd) and food-grade onion skin extract OSE produced on a pilot scale in collaboration with the Food Processing Engineering Lab in Tamaki Campus, University of Auckland, using a proprietary freeze-drying method, possessing the ability to inhibit the activity of starch digestive enzymes and the absorption of glucose by the gut mucosa, respectively. By combining these extracts with a starch based meal we hope to induce enough glucose malabsorption in the proximal SI to activate the ileal brake. However, efficacy of these blockers singularly or in combination has not yet been assessed in a human study population.
Trial website
Trial related presentations / publications
We have not presented data of the trial as yet. However, a manuscript of the trial for publication is being prepared.
Public notes

Contacts
Principal investigator
Name 51726 0
Dr John Ingram
Address 51726 0
Plant and Food Research Ltd
120 Mt Albert Rd. Mt Albert,
Auckland 1142
Country 51726 0
New Zealand
Phone 51726 0
+64 9 925 7119
Fax 51726 0
Email 51726 0
[email protected]
Contact person for public queries
Name 51727 0
Dr Hyun Sang shin
Address 51727 0
Human Nutrition Unit, University of Auckland 18 Carrick Place Mt Eden, Auckland 1024
Country 51727 0
New Zealand
Phone 51727 0
+64 9 630 3744
Fax 51727 0
Email 51727 0
[email protected]
Contact person for scientific queries
Name 51728 0
Dr Hyun Sang shin
Address 51728 0
Human Nutrition Unit, University of Auckland 18 Carrick Place Mt Eden, Auckland 1024
Country 51728 0
New Zealand
Phone 51728 0
+64 9 630 3744
Fax 51728 0
Email 51728 0
[email protected]

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