ANZCTR - Registration

Registration number

ACTRN12624000534583

Ethics application status

Approved

Date submitted

19/03/2024

Date registered

30/04/2024

Date last updated

30/04/2024

Date data sharing statement initially provided

30/04/2024

Type of registration

Retrospectively registered

Titles & IDs

Public title

Evaluating the effects of the gut hormone, glucose-dependent insulinotropic polypeptide (GIP) on stomach emptying, blood pressure, gut blood flow and blood sugar levels in healthy older subjects

Scientific title

Effects of exogenous and endogenous glucose-dependent insulinotropic polypeptide on gastric emptying, blood pressure, splanchnic blood flow and glycaemia in healthy older subjects

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

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

postprandial hypotension

Condition category

Condition code

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Each participant will be studied on 3 separate occasions, separated by an intervals of at least 7 days. Participants will be given an intravenous (iv) injection of GIP (1.5 pmol/kg/min), GIP antagonist (800 pmol/kg/min) or 0.9% saline (placebo) at approximately 9.00am (t = -30 min). Thirty minutes after the iv dose, the participant will be given a drink (t = 0 min) comprising 75g glucose and 5g 3-Ortho-Methyl-glucose labelled with 20 MBq 99mTc-calcium phytate, made up to 300ml water. 3-OMG is a non-metabolisable glucose analogue and plasma levels can be used to assess glucose absorption. Gastric emptying, plasma glucose, plasma insulin, blood pressure (BP), heart rate (HR), superior mesenteric artery (SMA) flow and appetite will be monitored for 180 minutes after ingestion of the drink. At t = 180 min, the participants will be presented with a cold, buffet-style meal and be allowed 30 minutes to freely consume food until they are comfortably full. The weight of the food will be recorded before and after it is offered to the subjects and energy intake and macronutrient composition calculated subsequently using commercially available software.

At least one member of the research team will be present at all times to monitor participants and to ensure adherence to the intervention.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Intravenous infusion of 0.9% saline

Control group

Placebo

Outcomes

Primary outcome [1]

To evaluate the effect of the change in systolic blood pressure (BP) after placebo compared to the GIP antagonist and GIP in healthy older people

Timepoint [1]

On study days, BP will be measured immediately prior to administration of the study drug (GIP, GIP antagonist or placebo) (t = -33 minutes) and at 3 minute intervals until just prior to ingestion of the drink (ie t = -3 minutes) and then at 5 minute intervals from t = 0 - 180 minutes, using an automated BP device. Measurements will also be taken at -39, -36, -33 minutes prior to administration of study drug (or saline) and the average taken to represent ‘baseline’.

Secondary outcome [1]

Area under the systolic BP curve 0-120 min between placebo and the GIP antagonist and GIP

Timepoint [1]

On study days, BP will be measured immediately prior to administration of the study drug (GIP, GIP antagonist or placebo) (t = -33 minutes) and at 3 minute intervals until just prior to ingestion of the drink (ie t = -3 minutes) and then at 5 minute intervals from t = 0 - 180 minutes, using an automated BP device. Measurements will also be taken at -39, -36, -33 minutes prior to administration of study drug (or saline) and the average taken to represent ‘baseline’.

Secondary outcome [2]

Area under the diastolic BP curve 0-120 min between placebo and the GIP antagonist and GIP

Timepoint [2]

On study days, BP and HR will be measured immediately prior to administration of the study drug (GIP, GIP antagonist or placebo) (t = -33 minutes) and at 3 minute intervals until just prior to ingestion of the drink (ie t = -3 minutes) and then at 5 minute intervals from t = 0 - 180 minutes, using an automated BP device. Measurements will also be taken at -39, -36, -33 minutes prior to administration of study drug (or saline) and the average taken to represent ‘baseline’.

Secondary outcome [3]

Area under the HR curve 0-120 min between placebo and the GIP antagonist and GIP

Timepoint [3]

On study days, HR will be measured immediately prior to administration of the study drug (GIP, GIP antagonist or placebo) (t = -33 minutes) and at 3 minute intervals until just prior to ingestion of the drink (ie t = -3 minutes) and then at 5 minute intervals from t = 0 - 180 minutes, using an automated BP device. Measurements will also be taken at -39, -36, -33 minutes prior to administration of study drug (or saline) and the average taken to represent ‘baseline’.

Secondary outcome [4]

Area under the gastric emptying curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [4]

Gastric emptying will be assessed immediately after drink ingestion (t=0 minutes) in dynamic mode i.e. in 1 min frames for the first 60 minutes and in 3-minute frames thereafter until t=180 minutes.

Secondary outcome [5]

Area under the blood glucose curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [5]

Blood samples (12 ml) will be obtained prior to administration of study drug (t = -33 minutes), 15 minutes into the administration of the study drug (t = -15 minutes), just prior to the ingestion of the drink (ie t = -3 minutes) and then at t = 0, 5, 15, 30, 45, 60, 90, 120, 150 and 180 minutes for measurement of plasma glucose.

Secondary outcome [6]

Area under the oral glucose absorption curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [6]

Blood samples (5 ml) will be collected at t = 5, 15, 30, 60, 90, 120, 150 and 180 minutes for measurement of serum 3-OMG as a measure of oral glucose absorption.

Secondary outcome [7]

Area under the SMA blood flow curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [7]

SMA blood flow will be assessed using a Logiq-9 GE ultrasound system.. SMA blood flow will be measured immediately prior to injection of GIP, GIP antagonist or placebo (t = -33 minutes) and ingestion of the drink (t = -3 minutes) then every 15 minutes until t = 180 minutes.

Secondary outcome [8]

Area under the plasma c-peptide curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [8]

Blood samples (12 ml) will be obtained prior to administration of study drug (t = -33 minutes), 15 minutes into the administration of the study drug (t = -15 minutes), just prior to the ingestion of the drink (ie t = -3 minutes) and then at t = 0, 5, 15, 30, 45, 60, 90, 120, 150 and 180 minutes for measurement of c-peptide.

Secondary outcome [9]

Area under the plasma insulin curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [9]

Blood samples (12 ml) will be obtained prior to administration of study drug (t = -33 minutes), 15 minutes into the administration of the study drug (t = -15 minutes), just prior to the ingestion of the drink (ie t = -3 minutes) and then at t = 0, 5, 15, 30, 45, 60, 90, 120, 150 and 180 minutes for measurement of plasma insulin.

Secondary outcome [10]

Area under the plasma GLP-1 curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [10]

Blood samples (12 ml) will be obtained prior to administration of study drug (t = -33 minutes), 15 minutes into the administration of the study drug (t = -15 minutes), just prior to the ingestion of the drink (ie t = -3 minutes) and then at t = 0, 5, 15, 30, 45, 60, 90, 120, 150 and 180 minutes for measurement of plasma GLP-1.

Secondary outcome [11]

Area under the plasma glucagon curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [11]

Blood samples (12 ml) will be obtained prior to administration of study drug (t = -33 minutes), 15 minutes into the administration of the study drug (t = -15 minutes), just prior to the ingestion of the drink (ie t = -3 minutes) and then at t = 0, 5, 15, 30, 45, 60, 90, 120, 150 and 180 minutes for measurement of plasma glucagon.

Secondary outcome [12]

Area under the plasma GIP curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [12]

Blood samples (12 ml) will be obtained prior to administration of study drug (t = -33 minutes), 15 minutes into the administration of the study drug (t = -15 minutes), just prior to the ingestion of the drink (ie t = -3 minutes) and then at t = 0, 5, 15, 30, 45, 60, 90, 120, 150 and 180 minutes for measurement of plasma GIP.

Secondary outcome [13]

Area under the Hunger curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [13]

Sensations of hunger will be evaluated using a visual analogue scale immediately prior injection of GIP, GIP antagonist or placebo (t = -33 minutes) and ingestion of the drink (t = -3 minutes) then every 15 minutes until t = 180 minutes. A final visual analogue questionnaire will be administered at t=210 min after the buffet meal.

Secondary outcome [14]

Area under the Fullness curve 0-180 min between placebo and the GIP antagonist and GIP

Timepoint [14]

Sensations of fullness will be evaluated using a visual analogue scale immediately prior injection of GIP, GIP antagonist or placebo (t = -33 minutes) and ingestion of the drink (t = -3 minutes) then every 15 minutes until t = 180 minutes. A final visual analogue questionnaire will be administered at t=210 min after the buffet meal.

Secondary outcome [15]

Subsequent food intake at the buffet meal between placebo and the GIP antagonist and GIP

Timepoint [15]

Food intake during the period t=180-210 min will be assessed.

Eligibility

Key inclusion criteria

• Male or female healthy participants
• Body Mass Index (BMI) 19 - 35 kg/m²

Minimum age

65 Years

Maximum age

80 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

• Participants with diabetes, a history of severe respiratory, cardiovascular, hepatic and/or renal disease (severe in that the social or physical manifestation of the disease, or living with the condition, impact negatively and significantly on the individuals’ ability to lead a normal day to day life), chronic alcohol abuse or epilepsy (excluded by history) or if iron status, or liver function tests are outside the following ranges:
• Alanine aminotransferase (ALT) 0 - 55 U/L
• Alkaline phosphatase 30 - 110 U/L
• Aspartate transaminase 0 - 45 U/L
• Amylase and/or lipase >3 x ULN
• Bilirubin 6 - 24 mmol/L
• Ferritin 15 – 200 ng/mL (Females)
30 – 300 ng/mL (Males)
• Haemoglobin 115 - 155 g/L (Females)
135 – 172 g/L (Males)

• Participants with a creatinine clearance cut-off of < 50 ml/min
Calculated creatinine clearance will be determined as follows (29):
Cr clearance = [140 - age (years) x weight (kg)] / [0.814 x serum creatinine (µmol/L)]
(For female subjects, multiply Cr clearance x 0.85)
• Participants requiring medication likely to influence BP or gastrointestinal function
• Participants with a past history of gastrointestinal disease, including known gastroparesis, significant upper gastrointestinal symptoms and previous gastric surgery
• Participants with a history of unexplained pancreatitis, chronic pancreatitis, pancreatectomy,
• Participants with a current or prior history of c-cell carcinoma
• Smoking > 10 cigarettes/day
• Alcohol consumption > 20 g/day
• Participants who have donated blood in the previous 12 weeks

Study design

Statistical methods / analysis

Twenty healthy participants aged 65 - 80 years will be recruited (to allow for dropouts, which based on our experience approximates 10%). Eighteen participants are required to detect a 7mmHg decrease in the maximum fall in systolic BP after placebo compared to GIP(3-30)NH2, allowing for all possible post hoc tests between the 3 visits (power 80%, significance 5%). Data will be analysed using standardised, non-parametric or parametric statistical methods where appropriate (e.g. repeated measures Analysis of Variance (ANOVA)

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

13/02/2020

Date of last participant enrolment

Anticipated

Actual

24/11/2023

Date of last data collection

Anticipated

Actual

22/12/2023

Sample size

Target

18

Accrual to date

Final

18

Recruitment in Australia

Recruitment state(s)

SA

Recruitment hospital [1]

The Royal Adelaide Hospital - Adelaide

Recruitment postcode(s) [1]

5000 - Adelaide

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Royal Adelaide Hospital

Country [1]

Australia

Primary sponsor type

University

Name

University of Adelaide

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Adelaide Local Health Network HREC

Ethics committee address [1]

https://www.rah.sa.gov.au/research/for-researchers/central-adelaide-local-health-network-human-research-ethics-committee

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

15/05/2018

Approval date [1]

14/02/2019

Ethics approval number [1]

HREC/18/CALHN/320

Summary

Brief summary

Some people over the age of 65 years experience a substantial fall in BP after eating, so-called, postprandial hypotension. Recent, compelling, evidence indicates that the gut hormones, GLP-1 and GIP, modulate  BP after a meal. Unlike GLP-1, GIP does not slow stomach emptying and may accelerate it. While the role of endogenous GIP in the regulation of postprandial blood glucose and BP remains uncertain, due to the lack of a specific GIP antagonist, our recent studies strongly support the concept that GIP regulates BP and gut blood flow.  Colleagues in Copenhagen have recently developed  an effective GIP antagonist in humans. We will use the GIP antagonist to define the roles of GIP, in the blood glucose, BP, gut blood flow flow and stomach emptying responses to a glucose drink in healthy older people..

Trial website

Public notes

Contacts

Principal investigator

Name

Prof Karen Jones

Address

Adelaide Medical School, The University of Adelaide, Level 5, AHMS Building, North Tce, Adelaide, SA, 5000

Country

Australia

Phone

+61 8 83137821

Email

[email protected]

Contact person for public queries

Name

Prof Karen Jones

Address

Adelaide Medical School, The University of Adelaide, Level 5, AHMS Building, North Tce, Adelaide, SA, 5000

Country

Australia

Phone

+61 8 83137821

Email

[email protected]

Contact person for scientific queries

Name

Prof Karen Jones

Address

Adelaide Medical School, The University of Adelaide, Level 5, AHMS Building, North Tce, Adelaide, SA, 5000

Country

Australia

Phone

+61 8 83137821

Email

[email protected]

Trial Review

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