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Trial registered on ANZCTR


Registration number
ACTRN12623001236684
Ethics application status
Approved
Date submitted
21/09/2023
Date registered
30/11/2023
Date last updated
30/11/2023
Date data sharing statement initially provided
30/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The Combination of Tirzepatide and Resistance EXercise (T-REX) for the Management of Body Composition
Scientific title
A parallel group superiority trial comparing the impacts of Tirzepatide, and the combination of Tirzepatide and Resistance Exercise training (T-REX), on body composition and cardiovascular variables, in community dwelling men and post-menopausal women with overweight and obesity
Secondary ID [1] 309540 0
None
Universal Trial Number (UTN)
Trial acronym
T-REX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 329825 0
Overweight 330714 0
Condition category
Condition code
Metabolic and Endocrine 326722 326722 0 0
Normal metabolism and endocrine development and function
Physical Medicine / Rehabilitation 328427 328427 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tirzepatide (background therapy, given to all participants):
Doses will be administered as once weekly subcutaneous injections by a research nurse or other qualified research personnel at the study centre. Tirzepatide will be initiated at a dose of 2.5 mg once weekly and increased by 2.5 mg every 4 weeks during the dose-escalation period aiming to reach a maintenance dose of 15 mg once weekly by week 20. Therapy at this dose will continue at either the maximum tolerated dose or at 15 mg for a further 20 weeks (40 weeks' intervention in total). This intervention period allows for attainment of metabolic benefit and provision of centre-based and supervised exercise interventions, described below.

Exercise intervention:
Participants randomised to the exercise groups will attend 3 x one-hour exercise sessions per week for 40 weeks. Participants will exercise in group sessions and the program will focus on increasing skeletal muscle mass and function. Exercise sessions will be undertaken in a dedicated research gym at the University of Western Australia, supervised by an Accredited Exercise Physiologist (AEP). The exercise training program will be in line with recommendations for the prescription and programming of resistance training, endorsed by Exercise and Sport Science Australia (ESSA). Exercise will commence with light-moderate intensity exercises and focus on developing correct technique, whilst the participants become accustomed to resistance training. Over the course of the 40-week training program, the intensity will gradually increase to moderate-vigorous exercise.
Each 1 hr session will consist of a general whole body warm up, followed by resistance-based exercises involving major muscle groups using a variety of apparatus, including bodyweight exercises, bands, cables, machines, and free-weights. Example exercises are squats, deadlifts, leg-press, lateral pulldowns, shoulder press and chest press. Each session will conclude with a 5 min cool down. Borg's Category Scale will be used to rate perceived exertion during session. A record of attendance will be kept.
Intervention code [1] 325967 0
Treatment: Drugs
Intervention code [2] 326676 0
Treatment: Other
Comparator / control treatment
The non-training (tirzepatide only) group will be required to attend one session per week across the 40 week intervention phase to obtain their weekly tirzepatide dose, and to perform strength testing at the same time points as the exercise training groups, This attendance will ensure compliance with the drug regimen and also provide a basis to account for the Hawthorne effect.
Control group
Active

Outcomes
Primary outcome [1] 334660 0
Change in lean mass will be assessed using dual energy X-ray absorptiometry (DXA)
Timepoint [1] 334660 0
Pre-intervention (week 0), during the intervention (at 8, 16, 24, 32 weeks post-baseline). Post-intervention (40 weeks post-baseline - primary timepoint) and follow-up (week 56 post-baseline).
Primary outcome [2] 336263 0
Change in fat mass will be assessed using dual energy X-ray absorptiometry (DXA)
Timepoint [2] 336263 0
Pre-intervention (week 0), during the intervention (at 8, 16, 24, 32 weeks post-baseline). Post-intervention (40 weeks post-baseline - primary timepoint) and follow-up (week 56 post-baseline)
Secondary outcome [1] 421594 0
Skeletal muscle function:
One repetition maximum (1RM) muscle strength testing.
Timepoint [1] 421594 0
Weeks 0, 8, 16, 24, 32 ,40 and 56 weeks post-baseline
Secondary outcome [2] 421596 0
Cardiopulmonary fitness: Graded exercise test VO2peak test
Cardiorespiratory fitness will be assessed via a graded exercise treadmill test with analysis of continuous expired air using a metabolic cart.
Timepoint [2] 421596 0
Weeks 0, 40 and 56 post-baseline
Secondary outcome [3] 421602 0
Endothelial function will be assessed in the brachial and femoral arteries using non-invasive, high resolution Duplex ultrasound. The flow-mediated dilation (FMD%) increase in artery dilation is an indicator of artery function and independently predicts CV events. Endothelium-independent dilation is examined using a single, 400 µg sublingual administration of glyceryl trinitrate. Carotid intima-media thickness will be measured using ultrasound.
Timepoint [3] 421602 0
Weeks 0, 40 and 56 post-baseline
Secondary outcome [4] 421614 0
Skin microvascular function will be measured using Optical Coherence Tomography (OCT) imaging (which is non-invasive).
Timepoint [4] 421614 0
Weeks 0, 40 and 56 post-baseline
Secondary outcome [5] 421615 0
Cardiac mechanics will be assessed via transthoracic echocardiography
Timepoint [5] 421615 0
Weeks 0, 40 and 56 post-baseline
Secondary outcome [6] 424406 0
Resting blood pressure will be measured using an automated dynamometer (Dinamap).
Timepoint [6] 424406 0
Weeks 0, 8, 16, 24, 32, 40 and 56 post-baseline
Secondary outcome [7] 424783 0
Body mass will be measured using electronic scales
Timepoint [7] 424783 0
Weeks 0,8,16,24,32,40,56 post-baseline
Secondary outcome [8] 424785 0
Physical activity will be recorded for a 7-day period, using a small, wearable accelerometer.
Timepoint [8] 424785 0
Weeks 0, 8, 24, 40 and 56 post-baseline
Secondary outcome [9] 424786 0
Full-blood count, from blood sample.
Timepoint [9] 424786 0
Weeks 0, 40 and 56 post-baseline
Secondary outcome [10] 427612 0
Waist girth will be measured using a constant-tension tape measure
Timepoint [10] 427612 0
Weeks 0,8,16,24,32,40,56 post-baseline
Secondary outcome [11] 427613 0
BMI will be calculated from measured weight (digital scales) and height (stadiometer).
Timepoint [11] 427613 0
Weeks 0,8,16,24,32,40,56 post-baseline
Secondary outcome [12] 428639 0
Urine samples of 2 mls will be collected and stored at -80 C for future research-related assays.
Timepoint [12] 428639 0
Weeks 0, 8, 16, 24, 32, 40 and 56 post-baseline
Secondary outcome [13] 428641 0
Urea/electrolytes, from blood sample.
Timepoint [13] 428641 0
Weeks 0, 8, 24, 40 and 56 post-baseline
Secondary outcome [14] 428642 0
Liver function, from blood sample.
Timepoint [14] 428642 0
Weeks 0, 8, 24, 40 and 56 post-baseline
Secondary outcome [15] 428643 0
Glycated haemoglobin (HbA1c) from blood sample.
Timepoint [15] 428643 0
Weeks 0, 40 and 56 post-baseline
Secondary outcome [16] 428644 0
Blood glucose, from blood sample
Timepoint [16] 428644 0
Weeks 0, 40 and 56 post-baseline
Secondary outcome [17] 428645 0
Lipid profile, from blood sample.
Timepoint [17] 428645 0
Weeks 0, 40 and 56 post-baseline
Secondary outcome [18] 428738 0
Hip girth will be measured using a constant-tension measuring tape
Timepoint [18] 428738 0
Weeks 0,8,16,24,32,40,56 post-baseline
Secondary outcome [19] 428746 0
Insulin, from blood sample
Timepoint [19] 428746 0
Weeks 0, 40 and 56 post-baseline

Eligibility
Key inclusion criteria
Men and women aged 50-70 years with body mass index (BMI) greater than or equal to 30 kg/m², or greater than or equal to 27 kg/m² with at least one weight-related comorbidity (e.g. hypertension, dyslipidaemia or obstructive sleep apnoea)
Minimum age
50 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known pregnancy, cardiovascular disease, diabetes, any history of pancreatitis; any history of multiple endocrine neoplasia (MEN) type 2 or medullary thyroid carcinoma; previous or planned bariatric surgery; any prior use of incretin-based therapies; use of non-incretin based anti-obesity or CV medications (e.g. statins, BP drugs) within 3 months of enrolment; and any other clinically significant illnesses (e.g. cancer, severe respiratory disease). Total cholesterol greater than 7.0 mmol/L, LDL greater than 4.0 mmol/L, eGFR less than 45 mL/min, HbA1c greater than 7.0% and/or evidence of significant liver disease. BP greater than 160/100 mmHg during the clinic visit.

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)
The allocation will be concealed via central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation will be used for participant allocation in order to ensure similar numbers and sex-matching of participants between groups. A bespoke ‘ralloc’ package will be used (Stata software, StataCorp, College Station, TX): blocks of 4 or 8 will be randomly selected and block randomisation will be stratified for gender.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Data will be analysed on an intention to treat basis, by a professional statistician who is independent of the study. Data will be included for any participant who has received at least one session/dose of the intervention. For each of the pre-specified outcomes linear mixed models will be used to investigate the relationship between variables, exercise and time, while accounting for age, sex and BMI. A random intercept will be included in each model to account for the repeated nature of the data. The linear mixed model (LMM) is the preferred statistical test for repeated measures data sets. We will also conduct a completers analysis. For all analyses, interactions and main effects will be calculated.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
8/01/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 313732 0
University
Name [1] 313732 0
The University of Western Australia
Country [1] 313732 0
Australia
Funding source category [2] 314876 0
Commercial sector/Industry
Name [2] 314876 0
Eli Lilly
Country [2] 314876 0
Australia
Primary sponsor type
University
Name
The University of Western Australia
Address
35 Stirling Highway Crawley, Western Australia 6009
Country
Australia
Secondary sponsor category [1] 316255 0
None
Name [1] 316255 0
Address [1] 316255 0
Country [1] 316255 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312904 0
The University of Western Australia Human Ethics Committee
Ethics committee address [1] 312904 0
35 Stirling HighwayPerth WA 6009 Australia
Ethics committee country [1] 312904 0
Australia
Date submitted for ethics approval [1] 312904 0
Approval date [1] 312904 0
21/02/2023
Ethics approval number [1] 312904 0
2022/ET000666

Summary
Brief summary
Obesity and physical inactivity are gateway conditions to prevalent and costly cardiovascular (CV) diseases including hypertension, type 2 diabetes, coronary artery disease, stroke and chronic kidney disease.

Previous randomised trials have shown promising impacts on weight loss with the use of a self-administered drug called tirzepatide by modifying hormones released from the gastrointestinal tract, as a strategy for the management of obesity. However, an important issue in this and similar studies relates to the type of weight that was lost. In addition to losing fat, participants treated with tirzepatide can lose lean mass, including skeletal muscle. Maintenance of skeletal muscle mass and function are crucial to avoiding frailty, which is linked to cardiovascular diseases and mortality. Resistance exercise training (involving weight lifting type exercises) is known to increase skeletal muscle mass and function in humans,

We hypothesise that:
-The combination of tirzepatide and a resistance exercise intervention (targeted at reducing fat and increasing skeletal muscle mass), will optimise changes in body composition in our enrolled population, who are at high risk of future cardiovascular diseases.
-Combining tirzepatide with exercise training will optimise vascular function and health in older men and women at high risk of future cardiovascular diseases.
-Combining tirzepatide with exercise training will optimise heart function in older men and women at high risk of future cardiovascular diseases
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126282 0
Prof Daniel Green
Address 126282 0
The University of Western AustraliaM408, 35 Stirling HighwayCrawleyWA 6009
Country 126282 0
Australia
Phone 126282 0
+61 8 6488 2361
Fax 126282 0
Email 126282 0
[email protected]
Contact person for public queries
Name 126283 0
Andy Haynes
Address 126283 0
The University of Western AustraliaM408, 35 Stirling HighwayCrawleyWA 6009
Country 126283 0
Australia
Phone 126283 0
+61 8 6488 5609
Fax 126283 0
Email 126283 0
[email protected]
Contact person for scientific queries
Name 126284 0
Daniel Green
Address 126284 0
The University of Western AustraliaM408, 35 Stirling HighwayCrawleyWA 6009
Country 126284 0
Australia
Phone 126284 0
+61 8 6488 2361
Fax 126284 0
Email 126284 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
IPD will not be shared, some aggregate data may be made available on reasonable request.


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.