Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000187943
Ethics application status
Approved
Date submitted
22/01/2020
Date registered
19/02/2020
Date last updated
19/02/2020
Date data sharing statement initially provided
19/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating how oxidative stress and antioxidant treatment regulate blood sugar levels.
Scientific title
Determining the effects of intravenous glutathione infusion on insulin sensitivity following acute exercise and lipid infusion: A randomised controlled trial in healthy participants.
Secondary ID [1] 300341 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metabolic and Endocrine 315952 0
Condition category
Condition code
Metabolic and Endocrine 314219 314219 0 0
Normal metabolism and endocrine development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible participants will undergo body composition analysis and resting blood pressure and heart rate will be measured. Participants will then perform a graded exercise test to volitional exhaustion to determine their maximal aerobic capacity and peak power output (Wmax) which will be supervised by an experienced exercise physiologist.

After screening, participants will undergo four main testing sessions (exercise, lipid infusion, with and without antioxidant treatment) in a randomised cross-over fashion, with a minimum one-week washout period between sessions. The total intervention (all four testing sessions) is expected to be completed over a period of 4-6 weeks.

Upon arrival, a baseline blood sample and resting muscle biopsy sample will be taken and the infusion of the saline or glutathione solution will commence. Concomitant to this infusion (within 15 minutes) participants will undergo either 1 hour of high-intensity interval exercise (including 5 hours of recovery) or 6 hours of intravenous lipid infusion. Participants will remain rested on the hospital bed during the 5-hour post-exercise recovery period and for the duration of the 6-hour lipid infusion session. Insulin action will be measured by a 3-hour euglycaemic hyperinsulinemic clamp conducted during the final 3 hours of lipid infusion and post-exercise recovery period. Venous blood samples will be collected throughout and thigh muscle samples collected at baseline, 1 hour after exercise and lipid infusion, and at the end of the 3-hour insulin clamp. Adherence to the four sessions of the intervention will be monitored by a checklist signed off by the supervising researcher.

Exercise protocol.
The 1-hour exercise sessions will include a 2-minute warm-up at 50% of maximum estimated sustainable cycling workload (Wmax), followed by 10, 4-minute cycling intervals at 85% Wmax, interspersed with two-minute active recovery periods at 50% Wmax. The exercise will be supervised by an experienced exercise physiologist

Lipid and heparin infusion protocol.
The lipid infusion session will involve infusion of a commercially available fat emulsion (Intralipid 20%) at a rate of 1.5 mL/min for 6 hours, simultaneously with heparin at 0.4 U/min/kg body weight.

Antioxidant infusion protocol.
The antioxidant infusion session will involve infusion of L-Glutathione (reduced glutathione) at a rate of 15 mg/min, over 6 hours (5,400mg in total).

Placebo infusion protocol.
Saline solution (0.9%), which is an inert salty solution, will be infused at a rate of 0.4 ml/min (the same rate as the lipid infusion rate) as a placebo solution in the non-antioxidant control trials and exercise trial.

3-hour euglycaemic hyperinsulinemic clamp protocol.
Insulin sensitivity in the main four testing sessions will be measured via a 3-hour euglycaemic hyperinsulinemic euglycaemic insulin clamp. Insulin will be infused at a rate of 40 mU/m2/min. Concurrently, a glucose solution (20% glucose) will be infused at a variable rate to maintain blood glucose concentrations at normal levels (the target is 5 mmol.L-1). This technique is supervised by a medical practitioner and experienced research staff. During the clamp one hand will be warmed to arterialise the blood samples (a safe and easy method for measuring arterial blood). Blood samples (1 ml) will be taken every 5 minutes to monitor glucose which is used to adjust the glucose infusion rate.
Intervention code [1] 316617 0
Treatment: Other
Comparator / control treatment
All participants will repeat the trial with saline infusion (as opposed to antioxidant infusion), which will then act as the control group
Control group
Placebo

Outcomes
Primary outcome [1] 322604 0
Primary outcome is change in insulin sensitivity as measured via a 3-hour euglycaemic hyperinsulinemic clamp.
Timepoint [1] 322604 0
Insulin sensitivity will be measured in the final 3-hours of lipid infusion and post-exercise recovery period (both with and without antioxidant infusion).
Secondary outcome [1] 379025 0
Change in F2-isoprostanes measured in blood.
Timepoint [1] 379025 0
F2-isoprostanes will be measured at baseline (prior to exercise and lipid infusion), 30 minutes during exercise and lipid infusion, immediately after the 1 hour exercise session and 1 hour of lipid infusion, and at 30 minute intervals throughout the 5 hour post-exercise recovery period and lipid infusion session.

Eligibility
Key inclusion criteria
Inclusion Criteria.
1. Aged 18–40 years old
2. Normal weight (BMI 18-27 kg/m2).
3. Normotensive (seated brachial blood pressure <140/90 mmHg).
4. Have given signed informed consent to participate in the study.
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion Criteria.
1. Age <18 years or >40 years.
2. Underweight, Overweight or Obese with a BMI <18 kg/m2 or >30 kg/m2.
3. Known allergy to eggs.
4. Cardiometabolic diseases including diabetes, cardiovascular disease, or metabolic syndrome.
5. History of myocardial infarction or stroke.
6. Exercise capacity limited by a factor other than claudication, for example:
a. Coronary artery disease (angina pectoris)
b. Pulmonary disease
c. Arthritis or other musculoskeletal complication
7. Critical limb ischaemia including peripheral artery disease or previous revascularisation or other surgical treatment for peripheral artery disease.
8. Self-reported history of microvascular disease (retinopathy, nephropathy or neuropathy).
9. History of malignancy within past 5 years (except for non-melanoma skin cancers).
10. Identification of any medical condition requiring immediate therapeutic intervention.
11. Uncontrolled hypertension (resting brachial blood pressure =160/100 mmHg).
12. Current smoker or previous smoker (within the last 12 months).
13. History of severe liver disease.
14. Elective major surgery during the course of the study.
15. Pregnancy/lactation.

Study design
Purpose of the study
Educational / counselling / training
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block allocation - First 8 sealed opaque envolopes will all contain different combinations of order, this will then be repeated for the following 8 sealed opaque envelopes.
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
Statistical methods / analysis
Data will be checked for normality and analysed using Predictive Analytics Software (PASW v20, SPSS Inc.). Comparison of insulin action between “protocol” (lipid infusion and exercise, with and without antioxidant treatment) will be conducted using repeated measures ANOVA. Comparison of multiple means will be analysed using a two-factor repeated measures ANOVA with “time” (timepoint during the protocol) and “protocol” as the within-subject factors. Significant main effects and interactions will be analysed Post Hoc with Bonferroni correction.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/03/2020
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 304766 0
University
Name [1] 304766 0
Deakin University
Country [1] 304766 0
Australia
Primary sponsor type
University
Name
Deakin University
Address
221 Burwood Highway, Burwood, VIC, 3125
Country
Australia
Secondary sponsor category [1] 305080 0
None
Name [1] 305080 0
Address [1] 305080 0
Country [1] 305080 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305183 0
Deakin University Human Research Ethics Committee
Ethics committee address [1] 305183 0
221 Burwood Highway, Burwood, VIC, 3125
Ethics committee country [1] 305183 0
Australia
Date submitted for ethics approval [1] 305183 0
Approval date [1] 305183 0
08/07/2019
Ethics approval number [1] 305183 0
2019-202

Summary
Brief summary
Oxidative stress occurs within a cell when there is an imbalance between highly reactive molecules and neutralising antioxidants. Oxidative stress can cause damage to healthy cells that lead to the development of numerous conditions including cancer, type 2 diabetes, neurodegenerative and cardiovascular disease, and contributes to the age-associated loss in tissue and organ function. On the other hand, oxidative stress plays a beneficial role in maintaining and improving cell function and overall human health. Research has yet to elucidate the mechanisms behind how the same reactive molecules can lead to completely opposing health outcomes. We will explore how oxidative stress, antioxidant treatment, and cell signalling can lead to opposing health outcomes by transiently eliciting both favourable and unfavourable oxidative stress and antioxidant treatment conditions in humans.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99522 0
Dr Lewan Parker
Address 99522 0
Deakin University
Institute for Physical Activity and Nutrition (IPAN)
221 Burwood Highway, Burwood, VIC, 3125
Country 99522 0
Australia
Phone 99522 0
+61 3 9246 8740
Fax 99522 0
Email 99522 0
[email protected]
Contact person for public queries
Name 99523 0
Dr Lewan Parker
Address 99523 0
Deakin University
Institute for Physical Activity and Nutrition (IPAN)
221 Burwood Highway, Burwood, VIC, 3125
Country 99523 0
Australia
Phone 99523 0
+61 3 9246 8740
Fax 99523 0
Email 99523 0
[email protected]
Contact person for scientific queries
Name 99524 0
Dr Lewan Parker
Address 99524 0
Deakin University
Institute for Physical Activity and Nutrition (IPAN)
221 Burwood Highway, Burwood, VIC, 3125
Country 99524 0
Australia
Phone 99524 0
+61 3 9246 8740
Fax 99524 0
Email 99524 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.