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Trial registered on ANZCTR


Registration number
ACTRN12623001018606
Ethics application status
Approved
Date submitted
8/08/2023
Date registered
20/09/2023
Date last updated
20/09/2023
Date data sharing statement initially provided
20/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Changes in gut bacteria and inflammation after performing exercise in Non-Alcoholic Fatty Liver Disease (NAFLD) patients
Scientific title
The effects of a combined exercise intervention on gut microbiomes and systemic inflammatory biomarkers in NAFLD patients
Secondary ID [1] 310066 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-alcoholic fatty liver disease 330607 0
Gut microbiome diversity 330608 0
Overweight 330609 0
Obesity 330610 0
Health related quality of life 330611 0
Chronic inflammation 331205 0
Condition category
Condition code
Metabolic and Endocrine 327446 327446 0 0
Metabolic disorders
Oral and Gastrointestinal 327915 327915 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Physical Medicine / Rehabilitation 327916 327916 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Initial phase (baseline assessment):
Participants recruited will undergo baseline measurements for cross-sectional analysis of all outcome measures.
-Liver fibrosis and steatosis
-Body composition
-General blood biochemistry
-Inflammatory cytokine levels
-Quality of life questionnaire
-Gut microbiome richness (stool samples)
-Cardiovascualr fitness
-Muscular strength
-Dietary intake
All initial testing will be completed over 2-3 days (over one or two weeks) at no more than 2.5 hours per session. Interventional phase will start the following week straight after the initial assessments are completed.

Intervention phase:
Same participants from the initial phase will then participate in an exercise intervention
12 weeks of combined aerobic and resistance training for NAFLD patients
- Supervised by a qualified Accredited exercise physiologist
- Sessions will be in a group format 3-6 participants per group
- Aerobic and resistance training will be at a moderate intensity measured through heart rate reserve with BORG RPE and % one rep maximum, respectively
- Sessions will be conducted 3 days per week (12 weeks total), 30-35min aerobic training and ~30min resistance training (includes warm ups and cool down time) per session.
- Session attendance and progression of fitness (increased workload when fitness improved) will be monitored and recorded

The same outcome measeurements from baseline measurements will be collected after week 6 and week 12 of the exercise intervention.
Intervention code [1] 326474 0
Treatment: Other
Comparator / control treatment
Self controlled clinical trial
- Particpants will act as their own controls through baseline measurements and with additional measurements taken after 6 weeks of intervention (interim assessment) and after 12 weeks of intervention (post intervention assessment). Providing three data collection points total with the mid and end points being compared to baseline (control) measurements.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335305 0
NAFLD disease severity
- A FibroScan measurement device will be used to classify NAFLD disease severity
- Fibrosis/scarring of the liver is measured through vibration controleld transient elastography (F0-F4)
Timepoint [1] 335305 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)
Primary outcome [2] 335306 0
Gut microbiome diversity
- Measured through collection of stool samples (200mg)
- Samples will be processed usinga QIAamp PowerFecal Pro DNA kit
- Bacterial type, quantity and diversity will be determined using shotgun metagenomics
- Shannon Index and Richness will be used as outcome measures
Timepoint [2] 335306 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)
Primary outcome [3] 335307 0
Inflammatory cytokines
- Fasted blood samples (2x6mL tubes) will be collected and processed into serum and plasma
- Inflammatory cytokines (TNF alpha, IL1-beta, IL4, IL6, IL8 and IL10) will be analysed using a Millipore Human High Sensitivity T Cell Mag 6-plx through a MAGPIX instrument.
Timepoint [3] 335307 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)
Secondary outcome [1] 423856 0
Body composition (composite secondary outcome)
- Fat mass (overweight, obesity) through Dual X-ray absorptiometry
- Fat free mass (lack of muscles mass - sarcopenia) through Dual X-ray absorptiometry
Timepoint [1] 423856 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)
Secondary outcome [2] 423857 0
Cardiovascular fitness
- VO2max test will be used to assess cardiovascular fitness using a modified Bruce Protocol on a treadmill
Timepoint [2] 423857 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)
Secondary outcome [3] 423858 0
Muscular strength (Composite secondary outcome)
- Percentage one repetition maximum (%1RM) will be used on major muscle groups to determine strength
- Leg press, chest press, Lat pull down, and weighted row
Timepoint [3] 423858 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)
Secondary outcome [4] 423859 0
Blood biochemistry (composite secondary outcome) through venous blood sample
-Total cholesterol
-High density lipoprotein
-Low density lipoprotein
-Blood glucose
-C-reactive protein
-Gamma glutamyl transferase
-Aspartate transferase
-Alanine transaminase
-Triglycerides
-Ferritin
Timepoint [4] 423859 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)
Secondary outcome [5] 423860 0
Health related quality of life
- The SF36 health related quality of life questionnaire will be used
Timepoint [5] 423860 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)
Secondary outcome [6] 425824 0
NAFLD disease severity (primary outcome)
- Steatosis/liver fat content is measured through controlled attenuation parameter (S0-S3)
Timepoint [6] 425824 0
Baseline (pre exercise intervention/0 weeks), 6 weeks (mid intervention), 12 weeks (post intervention)

Eligibility
Key inclusion criteria
(i) A diagnosis of NAFLD
(ii) No other liver disease or cancer present
(iii) Other well-managed comorbidities, e.g. Type 2 Diabetes Mellitus (T2DM), and hypertension, are approved for the study
(iv) No recent or current exercise performed
(v) Commit to the cross-sectional study and assess for the longitudinal study
(vi) Complete consent form
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(i) Younger than 18 years of age
(ii) Serious cardiovascular, respiratory, or neurological diseases and cancers
(iii) Poorly controlled hypertension, glucose regulation or other serious chronic diseases
(iv) A disability that could prevent the completion of exercises
(v) High-risk participants with contraindications to exercise
(vi) Currently exercising more than 60 minutes per week
(vii) Participation in conflicting studies
(viii) Participants with internal artefacts that may obscure DXA readings
(ix) Participants who are pregnant, attempting to conceive or lactating.
(x) Participants exposed to radiation levels deemed unsafe in the DXA pre-testing preparation checklist.
(xi) Participants who cannot complete the 1RM and VO2max protocols.
(xii) Medications that could alter outcome measures

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Multivariate linear regression

Linear mixed effects model

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
29/09/2023
Actual
Date of last participant enrolment
Anticipated
30/09/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
46
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 25349 0
Sunshine Coast University Hospital - Birtinya
Recruitment postcode(s) [1] 41058 0
4575 - Birtinya

Funding & Sponsors
Funding source category [1] 314234 0
Hospital
Name [1] 314234 0
Sunshine Coast University Hospital
Country [1] 314234 0
Australia
Funding source category [2] 314235 0
University
Name [2] 314235 0
University of the Sunshine Coast
Country [2] 314235 0
Australia
Primary sponsor type
Individual
Name
Mr Christiaan Hattingh
Address
University of the Sushine Coast - School of Health90 Sippy Downs Drive, Sippy Downs 4556, Queenland
Country
Australia
Secondary sponsor category [1] 316167 0
Hospital
Name [1] 316167 0
Dr James O'Beirne (Sunshine Coast University Hospital)
Address [1] 316167 0
6 Doherty St, Birtinya Qld 4575
Country [1] 316167 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313354 0
Gold Coast Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 313354 0
Gold Coast University HospitalLevel 2, E Block (PED Building)1 Hospital BlvdSouthport Qld 4215
Ethics committee country [1] 313354 0
Australia
Date submitted for ethics approval [1] 313354 0
18/08/2022
Approval date [1] 313354 0
17/02/2023
Ethics approval number [1] 313354 0
HREC/2022/QGC/88548

Summary
Brief summary
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide; progression and severity are influenced by systemic inflammation, lifestyle factors and body composition. With no pharmacological treatments available, exercise and diet are first-line treatments. The mechanisms by which lifestyle interventions influence NAFLD severity are unknown but may be related to inflammation and gut microbiome composition. We aim to examine whether gut microbiome composition and inflammation are related to NAFLD severity; and whether 12-weeks of exercise impacts gut microbiome , inflammation and NAFLD severity. This research will provide basis for identifying novel treatments for NAFLD by targeting the microbiome.

This research will develop our understanding of how exercise improves NAFLD through modulation of gut microbiome diversity and inflammation. This will contribute to identifying effective exercise prescriptions that target underpinning mechanisms to improve health outcomes for patients with NAFLD and prevent disease progression. This in turn will contribute to better diagnosis/treatment when considering disease severity and outcomes for those with NAFLD. Additionally, assessment of potential changes in HRQoL of NAFLD patients in response to exercise training will verify real world efficacy, considering the gut microbiome and inflammation in NAFLD progression/severity.

There is evidence showing that exercise-mediated changes to the gut microbiome influence biological variables known to be related to NAFLD severity and progression. However, research is yet to examine correlations between gut microbiome alpha diversity, key inflammatory markers, and body composition with NAFLD severity. Additionally, research is yet to examine the effects of a combined exercise program on gut microbiome composition in NAFLD. Research aimed at filling these gaps could inform the development of evidence-based recommendations for diagnostic, exercise, and treatment-related outcomes in patients with NAFLD and place SCUH Hepatology/Gastroenterology as a leading department in novel research and treatment in this field. SCUH has the expertise to undertake clinical data collection, as well as access to a large patient group and access to excellent laboratory facilities, however, the department does not have the expertise required to run clinical exercise interventions or assess inflammation or gut microbiome diversity.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127854 0
Mr Christiaan Hattingh
Address 127854 0
University of the Sunshine Coast90 Sippy Downs Drive, Sippy Downs 4556, Queenland
Country 127854 0
Australia
Phone 127854 0
+61432905604
Fax 127854 0
Email 127854 0
cdh012@student.usc.edu.au
Contact person for public queries
Name 127855 0
Prof James O'Beirne
Address 127855 0
Sunshine Coast University Hospital6 Doherty St, Birtinya Qld 4575
Country 127855 0
Australia
Phone 127855 0
+61752021012
Fax 127855 0
Email 127855 0
james.obeirne@health.qld.gov.au
Contact person for scientific queries
Name 127856 0
Prof James O'Beirne
Address 127856 0
Sunshine Coast University Hospital6 Doherty St, Birtinya Qld 4575
Country 127856 0
Australia
Phone 127856 0
+61752021012
Fax 127856 0
Email 127856 0
james.obeirne@health.qld.gov.au

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


What supporting documents are/will be available?




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.