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Trial registered on ANZCTR


Registration number
ACTRN12617000719336
Ethics application status
Approved
Date submitted
17/05/2017
Date registered
18/05/2017
Date last updated
25/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of small intestinal quinine (bitter agonist) on gut function and blood glucose in healthy, lean volunteers.
Scientific title
Effects of intraduodenal quinine (bitter agonist), on upper gastrointestinal (GI) functions, energy intake and blood glucose, in healthy, lean volunteers.
Secondary ID [1] 291843 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 303090 0
Type 2 Diabetes 303091 0
Healthy Human Gastrointestinal Physiology 303092 0
Condition category
Condition code
Diet and Nutrition 302548 302548 0 0
Obesity
Oral and Gastrointestinal 302549 302549 0 0
Normal oral and gastrointestinal development and function
Metabolic and Endocrine 302550 302550 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention in this study consists of the intraduodenal infusion of a quinine or control solution over a 60 minute period during which the measurement of gut motility, blood glucose, gut hormone concentration, insulin concentrations, appetite perceptions and energy intake during a buffet meal will be measured.

Subjects enrolled into the study will receive, in randomized, double-blind fashion
(i) 0.625mg/min quinine,
(ii) 1.25mg/min quinine,
(iii) 3.75mg/min quinine.
(iv) saline (control)
each occurring at separate visits. Each visit will last 3-6hrs in duration, and will be separated by 3-7 days. Visits will be carried out in the clinic room facility of the Discipline of Medicine, University of Adelaide by staff members trained in the required techniques, and will be conducted on an individual basis.

Subjects will be asked to consume a standardised dinner meal the night before each visit by no later than 6pm, After fasting for 14 hrs overnight and refraining from exercise and alcohol for 24 hrs, subjects will arrive at the laboratory at 8am . Upon arrival, subjects will be intubated with a 17-channel manometric catheter that will be inserted through an anaesthetised nostril and allowed to pass through the stomach and into the duodenum by peristalsis. The manometric catheter consists of 16 side holes spaced at 1.5 cm intervals, measuring pressures in the antrum, pylorus, and duodenum (APD pressures). An additional channel (with the side hole positioned approx 14 cm distal to the pylorus when the catheter is in position) is used for intraduodenal infusions. The correct positioning of the catheter will be maintained by continuous measurement of the transmucosal potential difference (TMPD) between the most distal antral channel and the most proximal duodenal channel. All manometric channels will be perfused with degassed, distilled water, except for the two TMPD channels, which will be perfused with degassed 0.9% saline, at 0.15 ml/min. An intravenous cannula will be placed into a right forearm vein for regular blood sampling to measure plasma hormone concentrations. Once the catheter has been positioned correctly, fasting motility will be monitored continuously, and immediately after the end of phase III activity of the fasting migrating motor complex (MMC), during a period of motor quiescence (t=-15 - 0 min), a 10 ml venous blood sample (baseline) will be taken, and the subject will complete a visual analogue scale questionnaire (VAS) to assess appetite-related perceptions (fullness, hunger, etc.) and gastrointestinal symptoms (nausea and bloating). At t = 0 min (during phase I of the MMC), the 60-min intraduodenal infusion (either (i), (ii), or (iii) as outlined above) will commence . APD pressures will be measured continually over the 60-min period. Blood samples will be collected and VASs completed every 15 min from t = 0 to 60 min. At t = 60 min, the manometric catheter will be removed and subjects will be presented with a cold, buffet-style meal. Subjects will be allowed 30 min to freely consume food until they are comfortably full. At t = 90 min, a final blood sample will be taken, and VAS administered. The intravenous cannula will then be removed and subjects will be allowed to leave the laboratory. A total of 70 ml of blood will be taken on each study day (280 ml over all study visits).

In addition, on one further occasion, oral detection thresholds for bitter taste will be assessed using 3-Alternative Forced Choice procedure, an established technique for the quantification of oral taste detection thresholds. Samples for the assessment of bitter taste will be prepared using quinine dissolved in deionised water. All samples will be presented at room temperature, under a red light to minimise visual cues. Participants will wear nose-clips to ensure detection of differences is not due to smell, and will be asked to rinse their mouths with water after each set of samples. There will be 1 min between presentations of sample sets. A set of samples will be presented as three trays of three samples, each tray containing one sample of the quinine concentration being tested and two samples of deionised water. The subject will taste the samples from left to right on each tray and choose the one sample that tastes ‘odd’ compared to the other two. If the subject does not choose the three samples containing quinine in that set, they will be presented with the next set of samples at a higher concentration. Once the subject selects the three correct samples containing quinine, this will be recorded as their detection threshold.
Intervention code [1] 297956 0
Treatment: Other
Comparator / control treatment
Saline
Control group
Placebo

Outcomes
Primary outcome [1] 301971 0
Energy intake at the buffet meal. The weight of the foods will be recorded before and after being offered to the subjects and energy intake and macronutrient composition calculated subsequently using commercially available software (Foodworks, Xyris Software, Highgate Hill, QLD, Australia).
Timepoint [1] 301971 0
A buffet meal will be presented immediately following each intraduodenal infusion (t = 60 - 90 min). The subject will be allowed to freely consume food until comfortably full for 30 minutes.
Primary outcome [2] 301972 0
Antropyloroduodenal motility (number of antral, duodenal and isolated pyloric pressure waves, and basal pyloric pressure) will be measured using a 17-channel manometric assembly (Dentsleeve, Mui Scientific).
Timepoint [2] 301972 0
Baseline (t = -15 - 0 min) and during intraduodenal infusion (t = 0 - 60 min).
Primary outcome [3] 301973 0
Plasma concentrations of gastrointestinal hormones (e.g. CCK, GLP-1, PYY, GIP and ghrelin), insulin and glucose will be assessed by Enzyme-linked Immunosorbent Assay (ELISA) or Radio Immnunosorbent Assay (RIA).

This intervention is of an exploratory nature to characterise the effects of varying doses of quinine. As such, it is unknown which plasma hormone concentrations may prove to be of importance. Hence these have been grouped into one composite primary outcome.
Timepoint [3] 301973 0
15 minute intervals from t=-15 - 60 min, and 90 min.
Secondary outcome [1] 334407 0
Appetite sensations (hunger, fullness, thirst, desire to eat, amount of food the subject thinks they could eat) and gastrointestinal symptoms (nausea, bloating) will be measured using a 100mm Visual Analogue Scale (VAS). This VAS has been extensively employed in published studies conducted by the investigator.

This intervention is of an exploratory nature to characterise the effects of varying doses of quinine. As such, it is unknown which appetite sensations or gastrointestinal symptoms may prove to be of importance. Hence these have been grouped into one composite secondary outcome.
Timepoint [1] 334407 0
15 minute intervals from t=-15 - 60 min, and 90 min.
Secondary outcome [2] 334420 0
Blood glucose will be assessed using a hospital grade portable glucmometer.
Timepoint [2] 334420 0
15 minute intervals from t=-15 - 60 min, and 90 min.
Secondary outcome [3] 334421 0
Oral bitter taste threshold will be assessed using 3-AFC technique.
Timepoint [3] 334421 0
To be conducted at a visit separate to the ID infusions.

Eligibility
Key inclusion criteria
A total of 12 healthy, lean (BMI 19-25 kg/m2) male subjects, aged between 18 - 55 years will be included. 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 preceding 4 weeks.
Minimum age
18 Years
Maximum age
55 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
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
Those with low ferritin levels (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
Restrained eaters (score >12 on the three factor eating questionnaire)

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 involves contacting the holder of the randomisation table (study assistant) to inform them of the next subjects details and study dates. The unblinded study assistant is therefore responsible for allocating a randomly generated treatment sequence to the subject and preparing the intraduodenal infusion 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
Pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/05/2017
Actual
18/05/2017
Date of last participant enrolment
Anticipated
Actual
15/01/2018
Date of last data collection
Anticipated
Actual
9/02/2018
Sample size
Target
12
Accrual to date
Final
14
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 296340 0
Government body
Name [1] 296340 0
National Health and Medical Research Council (NHMRC)
Country [1] 296340 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] 295270 0
Individual
Name [1] 295270 0
Tanya Little
Address [1] 295270 0
Level 5, Adelaide Health and Medical Sciences Building
Cnr North Terrace and George Street
Adelaide
South Australia 5005
Country [1] 295270 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297571 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [1] 297571 0
Ethics committee country [1] 297571 0
Australia
Date submitted for ethics approval [1] 297571 0
04/10/2016
Approval date [1] 297571 0
15/11/2016
Ethics approval number [1] 297571 0
RAH Protocol No. R20161005 HREC/16/RAH/410

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

Contacts
Principal investigator
Name 74478 0
Prof Christine Feinle-Bisset
Address 74478 0
Level 5, Adelaide Health and Medical Sciences Building
Cnr North Terrace and George Street
Adelaide
South Australia 5005
Country 74478 0
Australia
Phone 74478 0
+61 8 8313 6053
Fax 74478 0
Email 74478 0
[email protected]
Contact person for public queries
Name 74479 0
Christine Feinle-Bisset
Address 74479 0
Level 5, Adelaide Health and Medical Sciences Building
Cnr North Terrace and George Street
Adelaide
South Australia 5005
Country 74479 0
Australia
Phone 74479 0
+61 8 8313 6053
Fax 74479 0
Email 74479 0
[email protected]
Contact person for scientific queries
Name 74480 0
Christine Feinle-Bisset
Address 74480 0
Level 5, Adelaide Health and Medical Sciences Building
Cnr North Terrace and George Street
Adelaide
South Australia 5005
Country 74480 0
Australia
Phone 74480 0
+61 8 8313 6053
Fax 74480 0
Email 74480 0
[email protected]

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