Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001226695
Ethics application status
Approved
Date submitted
6/10/2023
Date registered
28/11/2023
Date last updated
28/11/2023
Date data sharing statement initially provided
28/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
GRETEL - GastRic EmpTying acceleration after fast and slow hypoglycaEmic cLamp
Scientific title
Does the rate of reduction in blood glucose impact the gastric counter-regulatory response during acute hypoglycaemia in adults with type 1 diabetes?
Secondary ID [1] 310745 0
None
Universal Trial Number (UTN)
Trial acronym
GRETEL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
type 1 diabetes 331695 0
delayed gastric emptying 331696 0
Condition category
Condition code
Metabolic and Endocrine 328435 328435 0 0
Diabetes
Metabolic and Endocrine 328436 328436 0 0
Normal metabolism and endocrine development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each participant will be evaluated on 3 separate occasions, separated by at least 3 days in a randomised single blind crossover design. On each study day, participants will be exposed to (1) euglycaemia (baseline blood glucose level (BGL)) – 6.0mmol/L, (2) acute hypoglycaemia (reducing BGL from 6.0 to 2.8mmol/L in 15 min), and (3) gradual hypoglycaemia – (reducing BGL from 6.0 to 2.8mmol/L in 2 hours).

Hypoglycaemic clamp:
- Glycaemic conditions will be achieved by co-administration of intra-venous glucose and insulin infusions, termed a "hypoglycaemic clamp". This method has been well described previously (Amiel SA, Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS. Rate of glucose fall does not affect counter-regulatory hormone responses to hypoglycemia in normal and diabetic humans. Diabetes. 1987; 36: 518-22.) and has been used extensively by our research group to achieve target glycaemic conditions.
- On euglycaemic clamp study days, participants will have their BGL titrated with the clamp to maintain a BGL of 6.0mmol/L for 3 hours (time point 0 - 180 minutes).
- On slow hypoglycaemic clamp study days, participants will have their BGL titrated with the clamp to induce hypoglycaemia (BGL 2.8mmol/L) over a period of 2 hours (time point 0 to 120 minutes), and then maintained at 2.8mmol/L for a further 1 hour (time points 120 minutes to 180 minutes).
- On fast hypoglycaemic clamp study days, participants will have their BGL maintained at 6.0mmol/L for 1 hour and 45 minutes (time point 0 to 105 minutes) and then acutely titrated to 2.8mmol/L (time point 105 minutes to 120 minutes), and then maintained at 2.8mmol/L for a further 1 hour (time point 120 minutes to 180 minutes).
Hypoglycaemia will only ever be maintained for a maximum duration of 60 minutes on any study days. A study meal at the end of the study day will restore euglycaemic conditions.

Glucose monitoring: Glycaemic conditions will be monitored in several ways for protocol adherence and to generate results.
- a YSI (2950D rapid biochemistry analyzer) will be used for near continuous BGL monitoring. The YSI will be used to retrieve BGL values every 5 minutes to allow titration of clamping conditions.
- blood samples will be obtained every 30 minutes to yield lab-based plasma glucose levels. This will confirm clamping conditions were achieved when reporting results.
- Many participants may have continuous glucose monitoring (CGM) devices as part of their standard care. These CGM devices will have their alarms paused on study days only (to maintain blinding), however their data recording will continue and be retrieved to correlate with YSI and plasma glucose levels. All CGM alarms will recommence at conclusion of study days.
- Hypoglycaemia awareness instruments will be administered during the study to monitoring for symptoms: participants will self-administer a visual analog scale instrument every 30 minutes, and research staff will administer a separate instrument at the onset of target hypoglycaemia (time point 120 minutes) and at the end of study days (time point 180 minutes)

Study meals:
- A standardised high-protein, low-carbohydrate 100g radio-labelled beef patty meal will be ingested by all participants.
- This meal will be administered at time point 120 minutes, to coincide with the onset of hypoglycaemia (2.8mmol/L) in both acute and slow hypoglycaemia arms, with the same time time point used in the euglycaemic control arm as a comparator.
- participants will ingest the meal within 5 minutes

Strategies to monitor adherence:
Appropriately qualified and experienced research staff will be available to ensure and monitor adherence to the study protocols. Senior research staff with extensive experience in hypoglycaemic clamp studies will carry out a supervisory role to ensure study procedures are carried out appropriately.
A case-report form will log 5-minute BGL on study days to monitor adherence to hypoglycaemic clamp protocols. This will also allow frequent titration of insulin-glucose infusions to achieve the desired clamping conditions.
A dedicated research staff member will administer the glucose-insulin infusion and perform titrations to achieve the necessary clamping conditions.
Separate staff will perform the other study activities, including blood sampling, administration of hypoglycaemia awareness tools, preparation and assistance with study meals, and performance of scintigraphy.
Intervention code [1] 327419 0
Early detection / Screening
Comparator / control treatment
The euglycaemia study day will be the baseline/ comparator arm.
Control group
Dose comparison

Outcomes
Primary outcome [1] 336275 0
Gastric emptying
Timepoint [1] 336275 0
Scintigraphy will commence at the onset of hypoglycaemia (2.8mmol/L) and will continue for up to 60 minutes after ingestion of a standardised meal labelled with a radiotracer. Scintigraphy will commence 2 hours after study commencement for the slow hypoglycaemia and euglycaemia arms, and 15 minutes after the fast hypoglycaemia arm.
Secondary outcome [1] 427640 0
Humoral response
Timepoint [1] 427640 0
Assays will be taken every 30 min leading up to the onset of hypoglycaemia (2.8mmol/L) and up until 60 minutes after the onset of hypoglycaemia . Sequence of time points for assays are indicated below:
Time-point 0:
Plasma glucose, growth hormone, cortisol
Noradrenaline, adrenaline
Glucagon
Pancreatic polypeptide
Time-point 30:
Plasma glucose
Time-point 60:
Plasma glucose, growth hormone, cortisol
Noradrenaline, adrenaline
Time-point 90:
Plasma glucose
Time-point 105:
Plasma glucose, growth hormone, cortisol
Noradrenaline, adrenaline
Glucagon
Pancreatic polypeptide
Time-point 120:
Plasma glucose, growth hormone, cortisol
Noradrenaline, adrenaline
Glucagon
Pancreatic polypeptide
Time-point 150:
Plasma glucose
Time-point 180:
Plasma glucose, growth hormone, cortisol
Noradrenaline, adrenaline

Eligibility
Key inclusion criteria
Men and women with type 1 diabetes
Aged 18 years and over
HbA 1c lesser than or equal to 9.5 %
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• History of type 2 diabetes
• HbA 1c greater than 9.5 %
• History of gastrointestinal disease, including known gastroparesis, peptic
ulcer disease, significant upper or lower gastrointestinal symptoms, or
previous gastrointestinal surgery (other than uncomplicated
appendicectomy or cholecystectomy) or a history of migraine or panic
attacks.
• Other significant illness, including epilepsy, cardiovascular or respiratory
disease.
• Chronic Kidney Disease (CKD) 4-5 (eGFR less than 30) or if iron stores or liver function tests are outside the
following normal ranges:
- Haemoglobin 130 – 180 g/L (Males)
- Haemoglobin 115 – 155 g/L (Females)
- Ferritin less than 30 µg/L (Males)
- Ferritin less than 15µg/L(Females)
• Requirement for medication known to influence gastrointestinal function,
(e.g. prokinetic drugs [metoclopramide, domperidone, erythromycin],
antiemetics [ondansetron], antidiarrhoeals [loperamide], H 2 receptor
antagonists [ranitidine], drugs with substantial anticholinergic effects
[amitriptyline, doxepin, dothiepin, mirtazapine, haloperidol,
chlorpromazine, risperidone, oxybutynin], opioids [morphine, oxycodone,
codeine], orlistat.
• Evidence of drug or alcohol abuse, or consumption of more than 20 g
alcohol or 10 cigarettes on a daily basis.
• Donation of blood within the previous 3 months
• Participation in any other research studies within the previous 3 months
• Previous exposure to radiation for research purposes in the preceding 12
months
• Inability to give informed consent
• Positive pregnancy status or lactating (breast-feeding) female
• Vegetarian or vegan

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer sequence generation randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/12/2023
Actual
Date of last participant enrolment
Anticipated
16/12/2024
Actual
Date of last data collection
Anticipated
31/01/2025
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 314976 0
Charities/Societies/Foundations
Name [1] 314976 0
Diabetes Australia
Country [1] 314976 0
Australia
Primary sponsor type
Government body
Name
Central Adelaide Health Network
Address
Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000
Country
Australia
Secondary sponsor category [1] 316981 0
University
Name [1] 316981 0
University of Adelaide
Address [1] 316981 0
Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, South Australia, 5000
Country [1] 316981 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313950 0
Central Adelaide Health Network Human Research Ethics Committee
Ethics committee address [1] 313950 0
Level 3, Roma Mitchell Building, 136 North Terrace, Adelaide, SA 5000
Ethics committee country [1] 313950 0
Australia
Date submitted for ethics approval [1] 313950 0
Approval date [1] 313950 0
08/03/2023
Ethics approval number [1] 313950 0

Summary
Brief summary
We hypothesize that gastric emptying is accelerated to a greater extent when blood sugar falls rapidly compared to slowly.

Hypoglycaemia triggers counter-regulatory mechanisms to restore blood sugar by accelerating gastric emptying. It is not known whether the rate of onset of hypoglycaemia impacts gastric emptying acceleration. Accordingly we will study type 1 diabetic patients, and induced either rapid or slow hypoglycaemia using insulin clamps. We will record gastric emptying after a standardised radiolabelled meal. This study may show that slow onset hypoglycaemia requires treatments that bypass the oral route.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129894 0
Dr Mahesh Umapathysivam
Address 129894 0
Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000
Country 129894 0
Australia
Phone 129894 0
+61 459 925 514
Fax 129894 0
Email 129894 0
[email protected]
Contact person for public queries
Name 129895 0
Dr Aniket Nadkarni
Address 129895 0
Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000
Country 129895 0
Australia
Phone 129895 0
+61 426 810 417
Fax 129895 0
Email 129895 0
[email protected]
Contact person for scientific queries
Name 129896 0
Dr Aniket Nadkarni
Address 129896 0
Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000
Country 129896 0
Australia
Phone 129896 0
+61 426 810 417
Fax 129896 0
Email 129896 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified data will be made available upon direct request to the primary investigator and reviewed case-by-case by the management committee. Individual participant data of primary and secondary outcomes will be considered for sharing.
When will data be available (start and end dates)?
Data will be made available from the time of publication up until 15 years post study commencement in keeping with data management outlined in the ethics application.
Available to whom?
Anyone will be eligible to apply.
Available for what types of analyses?
Scientific analyses
How or where can data be obtained?
Data will not be placed in a public repository but will be directly sent to approved individuals or institutions after consideration of their application to PI Dr Mahesh Umapathysivam ([email protected]).


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
No additional documents have been identified.