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Trial registered on ANZCTR


Registration number
ACTRN12620000201976
Ethics application status
Approved
Date submitted
22/01/2020
Date registered
20/02/2020
Date last updated
20/02/2020
Date data sharing statement initially provided
20/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Glucagon-like peptide 1 (GLP-1) for lowering plasma glucose in type 2-diabetic patients: A systematic comparison of intravenous and subcutaneous routes.
Scientific title
GLP-1 for lowering plasma glucose in type 2-diabetic patients: A systematic comparison of intravenous and subcutaneous routes.
Secondary ID [1] 300338 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes mellitus 315947 0
Condition category
Condition code
Metabolic and Endocrine 314215 314215 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following enrolment, each participant will be studied on two occasions, separated by 5-21 days, in a double blind randomised controlled design. They will withhold their usual long acting insulin (glargine) on the day before the study, and any premixed or prandial insulin from 1500h on that day. Any oral agents will be continued. On the evening preceding the study day (~1900h), participants will be given a standardised evening meal (2472kJ) and a piece of fruit to consume with water. Following this meal, participants will be asked to fast from solids and liquids (other than water) until the following morning, when they will attend the study site at 0800h. On each study day one SC needle and two IV cannulae (in opposite arms) will be inserted. An infusion of GLP-1 (GMP grade, sterile and pyrogen-free) in normal saline with 1% albumin to prevent adhesion of peptide to tubing will commence via an infusion pump into either the SC needle or an IV cannula, with saline and albumin alone into the alternate site, and the sites reversed on the second study visit. Each infusion will be marked only with the subject code, intended route (SC or IV), and visit number to maintain allocation concealment; the appearance of the solutions will be identical. The rate of infusion will be adjusted every 2 h, commencing at a “physiological” rate (comparable to circulating postprandial concentrations) and progressing to pharmacological concentrations, for a total 8 h infusion period on each day (t = 0 to 480 min) as follows:
- 0.3, 0.6, 1.2 and 2.4 pmol/kg/min GLP-1 on the IV day, and
- 1.2, 2.4, 4.8, and 9.6 pmol/kg/min GLP-1 on the SC day
Blood will be sampled from the IV cannula in the arm opposite the IV infusion at baseline and then every 30min , i.e. t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min, for subsequent measurement of plasma glucose, insulin, C-peptide, glucagon, and intact and total GLP-1 concentrations. Blood glucose will also be monitored using a bedside glucometer every 30 min. The total amount of blood drawn during the study will be approx. 370 mL.
GI symptoms including nausea and appetite ratings will be scored using validated 100mm visual analog scales at the same intervals as blood sampling; the infusions will be terminated if nausea scores reach =50mm or vomiting occurs. Heart rate and blood pressure will be monitored every 15 min using an automated sphygmomanometer. Subjects will remain fasting throughout the infusion period, but at t=480 min will be offered a buffet meal, from which they will be given 30 min to eat until they feel comfortably full. All food items will be weighed before and after the meal to quantify energy intake. At the conclusion of the meal, the cannulae will be removed and subjects allowed to leave the facility, with instructions to resume their usual insulin therapy.
Intervention code [1] 316615 0
Treatment: Drugs
Comparator / control treatment
Participants will reiceive GLP-1 either subcutaneously (SC) or intravenously (IV). Saline is used for the other route on each study day (e.g. GLP-1 through SC route -> Saline through IV route).
Control group
Active

Outcomes
Primary outcome [1] 322602 0
Number of subjects achieving a plasma glucose < 6.1 mmol/l (< 110 mg/dl)
Timepoint [1] 322602 0
During entire infusion period (0-480 min) with blood sampling at following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Primary outcome [2] 322603 0
Number of subjects with more than negligible nausea, assessmed by visual analogue scale (VAS).
Timepoint [2] 322603 0
During entire infusion period (0-480 min) as measured at the following time points:
t = -15, 0, 90, 120, 210, 240, 330, 360, 450, 480 min.
Primary outcome [3] 322719 0
Number of subjects with vomiting as assessed by clinical observation
Timepoint [3] 322719 0
During entire infusion period (0-480 min), any event.
Secondary outcome [1] 379022 0
Changes in energy intake determined by consumption of food items on buffet menu after study. All food items will be weighed before and after the meal to quantify energy intake.
Timepoint [1] 379022 0
Of buffet menu after study
Secondary outcome [2] 379409 0
Changes of insulin concentrations
Timepoint [2] 379409 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [3] 379410 0
Changes of glucagon concentrations
Timepoint [3] 379410 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [4] 379411 0
Changes of intact GLP-1 concentrations
Timepoint [4] 379411 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [5] 379412 0
Changes of total GLP-1 concentrations
Timepoint [5] 379412 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [6] 379413 0
Changes of heart rate as assessed by combined heart rate / blood pressure monitor (electronic sphygmometer)
Timepoint [6] 379413 0
During entire infusion period (0-480 min) with measurements every 15 min during that period. Start at t = -15 min, end at t = 480 min.
Secondary outcome [7] 379414 0
Changes of blood pressure as assessed by combined heart rate / blood pressure monitor (electronic sphygmometer)
Timepoint [7] 379414 0
During entire infusion period (0-480 min) with measurements every 15 min during that period. Start at t = -15 min, end at t = 480 min.
Secondary outcome [8] 379415 0
Relationship between plasma active GLP-1 concentrations and plasma glucose concentration
Timepoint [8] 379415 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [9] 379416 0
Relationship between plasma active GLP-1 concentrations and insulin concentration
Timepoint [9] 379416 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [10] 379417 0
Relationship between plasma active GLP-1 concentrations and C-peptide concentration
Timepoint [10] 379417 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [11] 379418 0
Relationship between plasma active GLP-1 concentrations and glucagon concentration
Timepoint [11] 379418 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [12] 379419 0
Relationship between plasma active GLP-1 concentrations and GI symptoms as assessed by visual analogue scale (VAS)
Timepoint [12] 379419 0
During entire infusion period (0-480 min) as measured at the following time points:
t = -15, 0, 90, 120, 210, 240, 330, 360, 450, 480 min.
Secondary outcome [13] 379420 0
Relationship between plasma active GLP-1 concentrations and food intake. Changes in energy intake are determined by consumption of food items on buffet menu after study. All food items will be weighed before and after the meal to quantify energy intake.
Timepoint [13] 379420 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [14] 379421 0
Relationship between plasma total GLP-1 concentrations and plasma glucose concentration
Timepoint [14] 379421 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [15] 379422 0
Relationship between plasma total GLP-1 concentrations and insulin concentration
Timepoint [15] 379422 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [16] 379423 0
Relationship between plasma total GLP-1 concentrations and C-peptide concentration
Timepoint [16] 379423 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [17] 379425 0
Relationship between plasma total GLP-1 concentrations and glucagon concentration
Timepoint [17] 379425 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.
Secondary outcome [18] 379426 0
Relationship between plasma total GLP-1 concentrations and GI symptoms as assessed by visual analogue scale (VAS)
Timepoint [18] 379426 0
During entire infusion period (0-480 min) as measured at the following time points:
t = -15, 0, 90, 120, 210, 240, 330, 360, 450, 480 min.
Secondary outcome [19] 379427 0
Relationship between plasma total GLP-1 concentrations and food intake. Changes in energy intake are determined by consumption of food items on buffet menu after study. All food items will be weighed before and after the meal to quantify energy intake.
Timepoint [19] 379427 0
During entire infusion period (0-480 min) with blood sampling at the following time points:
t = -15, 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, and 480 min.

Eligibility
Key inclusion criteria
- Male and females aged 18 to 75 years (both included)
- Diagnosis of T2DM by ADA criteria
- Diabetes treatment for greater or equal to 3 months with:
* Basal insulin (glargine) or premixed insulin (e.g. Mixtard or Novomix),
* together with any combination of diet, metformin, sulfonylurea, thiazolidinedione, SGLT2 inhibitor, alpha-glucosidase inhibitor, or prandial insulin.
- Body mass index (BMI) 20 to 35 kg/m² (both included)
- Weight-stable ( less than or equal to 3% change in last 3 months)
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Use of insulin degludec (due to its very long half-life)
- Use of a DPP-4 inhibitor or GLP-1RA
- Patients with diagnosis of T1DM (based on islet autoantibodies)
- Patients with possible diabetes mellitus caused by diseases of the exocrine pancreas T3cDM (based on a history of alcohol intake greater or equal to 3 units daily, pancreatic disease, or steatorrhea)
-Impaired renal (eGFR less than 60mL/min as calculated by CKP-EPI formula) or liver function (transaminases more than or equal to 2 x ULN), iron deficiency (serum ferritin less than 20 µg/l) or anaemia (ie. haemoglobin less than 135g/L for men and less than 115g/L for women)
- Patients with contraindications to bilateral IV cannulation: history of mastectomy, axillary node clearance, axillary node radiotherapy, upper limb lymphedema and upper limb arteriovenous fistula for haemodialysis.
- Symptomatic ischaemic heart disease
- Pregnancy (pre-menopausal females will be using adequate contraception and record a negative pregnancy test on each study day)
- Patients with significant gastrointestinal (GI) symptoms (any upper GI symptom “moderate” or worse on the PAGI- SYM questionnaire)
- Previous GI surgery (other than appendicectomy or cholecystectomy)
- HbA1c less than 7.0%
- Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes daily
- Other significant illness, including epilepsy, cardiovascular or respiratory disease
- Donation of blood within the previous 12 weeks
- Participation in any other research studies within the previous 3 months
- Inability to give informed consent
- Vegetarians

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 304763 0
University
Name [1] 304763 0
The University of Adelaide
Address [1] 304763 0
Adelaide Medical School, The University of Adelaide, Level 5 AHMS Building, North Terrace, Adelaide, SA,5000
Country [1] 304763 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
Adelaide Medical School, The University of Adelaide, Level 5 AHMS Building, North Terrace, Adelaide, SA,5000
Country
Australia
Secondary sponsor category [1] 305077 0
None
Name [1] 305077 0
Address [1] 305077 0
Country [1] 305077 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305179 0
Central Adelaide Local Health Network Human Reseach Ethics Committe (CALHN HREC)
Ethics committee address [1] 305179 0
L3, Roma Mitchell House, North Terrace, Adelaide – Postal Details: RAH Clinical Trial Centre, Wayfinder 3D460.02, Level 3, Royal Adelaide Hospital, Port Road, ADELAIDE SA 5000
Ethics committee country [1] 305179 0
Australia
Date submitted for ethics approval [1] 305179 0
06/11/2019
Approval date [1] 305179 0
20/01/2020
Ethics approval number [1] 305179 0
R20191007

Summary
Brief summary
Certain gut hormones, like Glucagon like peptide 1 (GLP-1), have been proven to play a major role in the control of blood glucose. GLP-1 Receptor Agonists (GLP-1RAs) have been developed to treat type 2 diabetes mellitus (T2DM). So far, all GLP-1RAs that are marketed in Australia must be applied subcutaneously (SC). GLP-1RAs can cause gastrointestinal (GI) side-effects. In early studies on GLP-1 action through intravenous (IV) application, GI side-effects were less common or even absent. We want to compare the SC and the IV administration of GLP-1 regarding the potency of lowering BG and GI side-effects.
20 patients with T2DM managed by long-acting insulin will be studied. The study involves 2 study visits. Patients will be asked to withhold their long-acting insulin on the day before each visit. Patients will then, in a double-blind manner, receive continuous GLP-1 infusion. GLP-1 will be applied SC or IV on each study day. Infusion rate will be raised every 2 hours (max. 4 x per study day). Blood glucose and GI symptoms will be monitored closely. This experimental setup will allow to clarify the impact of the application route of GLP-1 on blood glucose and provocation of GI side-effects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99510 0
Prof Chris Rayner
Address 99510 0
Adelaide Medical School, The University of Adelaide, Level 5 AHMS Building, North Terrace, Adelaide, SA,5000
Country 99510 0
Australia
Phone 99510 0
+61 883136693
Fax 99510 0
Email 99510 0
chris.rayner@adelaide.edu.au
Contact person for public queries
Name 99511 0
Prof Chris Rayner
Address 99511 0
Adelaide Medical School, The University of Adelaide, Level 5 AHMS Building, North Terrace, Adelaide, SA,5000
Country 99511 0
Australia
Phone 99511 0
+61 883136693
Fax 99511 0
Email 99511 0
chris.rayner@adelaide.edu.au
Contact person for scientific queries
Name 99512 0
Prof Chris Rayner
Address 99512 0
Adelaide Medical School, The University of Adelaide, Level 5 AHMS Building, North Terrace, Adelaide, SA,5000
Country 99512 0
Australia
Phone 99512 0
+61 883136693
Fax 99512 0
Email 99512 0
chris.rayner@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification.
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following main results publication.
Available to whom?
Case-by-case basis at the discretion of Primary Investigator
Available for what types of analyses?
For IPD meta-analyses
How or where can data be obtained?
access subject to approvals by Principal Investigator Prof Chris Rayner (chris.rayner@adelaide.edu.au)
What supporting documents are/will be available?
No other documents available
Summary results
No Results