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Trial registered on ANZCTR


Registration number
ACTRN12619000264189
Ethics application status
Approved
Date submitted
12/02/2019
Date registered
20/02/2019
Date last updated
11/06/2019
Date data sharing statement initially provided
20/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Understanding the role of tissue Fibrosis in Insulin Resistance associated with Polycystic Ovary Syndrome (PCOS) and the impact of Exercise: The FIREx study using a cohort and randomized control trial in women with and without PCOS.
Scientific title
Tissue fibrosis and exercise in Polycystic Ovary Syndrome: Linking Mechanisms to therapy
Secondary ID [1] 297411 0
Nil Known
Universal Trial Number (UTN)
U1111-1228-1587
Trial acronym
FIREx study
Linked study record
Follow-up study to:
ACTRN12615000242527 and ACTRN12618000155291

Health condition
Health condition(s) or problem(s) studied:
Polycystic Ovary Syndrome 311445 0
Obesity 311446 0
Insulin Resistance 311447 0
Condition category
Condition code
Metabolic and Endocrine 310087 310087 0 0
Diabetes
Physical Medicine / Rehabilitation 310088 310088 0 0
Other physical medicine / rehabilitation
Reproductive Health and Childbirth 310089 310089 0 0
Menstruation and menopause
Diet and Nutrition 310205 310205 0 0
Obesity
Renal and Urogenital 310206 310206 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The is a four group cohort study exploring the role of TGFß super family ligand signalling and tissue fibrosis in PCOS-specific insulin resistance and the role of obesity in reproductive aged women with and without PCOS. The cohort study is a cross-sectional comparison of baseline measures across the 4 groups. This is complimented with a randomised control trial sub-study, in the two groups of overweight women (one with and one without PCOS) that will explore the impact of High-intensity Intermittent Training (HIIT) on the TGFß super family ligand signalling and tissue fibrosis and PCOS-specific insulin resistance.
All participants, lean women with (n=36) and without PCOS (n=36) and overweight women with (n=46) and without PCOS (n=46) will under go a series of baseline assessments.

The two cohorts (n=92) of women meeting the classification of being overweight will progress, within 2 weeks to the sub-study randomized control trial after undertaking an evidence-based lifestyle coaching program (2 x 1 hour group tutorials on separate days usually 3-7 days apart) focusing on simple nutritional and exercise advice as per the current Australian guidelines for healthy eating and physical activity. The tutorials will be delivered in a group setting by an accredited exercise physiologist (AEP) at the University exercise clinics (Australian Catholic University [ACU] and Victoria University [VU]), coaching the participants on behavioural modification techniques, including goal setting, self-monitoring, social support, coping strategies, problem solving and relapse prevention. After completion of these tutorials the overweight women (with and without PCOS) will be randomised into either the 12-week HIIT or control interventions. The women randomized to the HIIT invention will commence the exercise training program within 7-10 days of completing the lifestyle coaching tutorials.
The HIIT intervention:
Twenty three non-PCOS and 23 PCOS overweight women will undertake the exercise intervention that requires 2 x 20 minute and 1 x 40 minute sessions per week that includes low volume (90-100% heart rate max [HRmax] ) and aerobic (85-95%HRmax) supervised HIIT sessions equating to 80 minutes of vigorous exercise per week.
All exercise activities for the HIIT group will be conducted on cycle ergometers in a group setting in the fitness centres at ACU and VU under the supervision of AEPs. The training program is personalised to starting fitness levels, is adjusted depending on progression. The HIIT intervention encompasses two feasible protocols:
• 2 sessions/week of low-volume HIIT cycling undertaking 8–12x 1min at 90-100% HRmax with 1 min recovery.
• 1 session/week of aerobic HIIT cycling undertaking 4–8x 4min at 85-94% HRmax with 1 min recovery.
All Exercise sessions include warm-up and cool-down protocols.

Adherence and compliance of women in HIIT treatment will be monitored via session attendance logs (adherence). Compliance will be assessed based on the percentage of achieved prescribed exercise for each of the 36 sessions.
Intervention code [1] 313584 0
Lifestyle
Intervention code [2] 313585 0
Treatment: Other
Comparator / control treatment
The twenty three women with and 23 without PCOS randomized to the control group will be have no formal intervention but encouraged to engage in lifestyle changes to meet national guidelines, and be contacted in weeks 3, 6, 9 and 12 via email/phone.
Control group
Active

Outcomes
Primary outcome [1] 318978 0
For the cohort (cross-sectional) study: Difference between groups in insulin sensitivity (Glucose infusion rate; GIR) as assessed by euglycaemic hyperinsulinaemic clamp.
For sub-study RCT: Difference between groups of changes in GIR for the euglycaemic hyperinsulinaemic clamp.
Timepoint [1] 318978 0
For cohort study (all women):
GIR measured at baseline.
For the sub-study RCT (overweight women):
Differences in GIR as measured at baseline and 3 days after last exercise training
session of the 12 week intervention ( or ~90-100 days after baseline clamp in control
group).



Primary outcome [2] 318979 0
For the cohort (cross-sectional) study: Difference between groups in circulating Transforming Growth Factor beta (TGFB) assessed by plasma assay.
For sub-study RCT: Difference between groups of changes in TGFB assessed by plasma assay.
Timepoint [2] 318979 0
For cohort study (all women):
TGFB measured at baseline.
For the sub-study RCT (overweight women):
Difference in changes in TGFB as measured at baseline and 3 days after last exercise
training session of the 12 week intervention ( or ~90-100 days after baseline clamp in
control group).
Primary outcome [3] 319094 0
For the cohort (cross-sectional) study: Difference between groups of muscle collagen content as measured by histology and immunoblotting.
For sub-study RCT: Difference between groups of changes in muscle collagen content as measured by histology and immunoblotting.
Timepoint [3] 319094 0
For cohort study (all women):
muscle collagen content measured at baseline.
For the sub-study RCT (overweight women):
Difference in changes in muscle collagen content as measured at baseline and 3 days
after last exercise training session of the 12 week intervention ( or ~90-100 days after
baseline clamp in
control group).
Secondary outcome [1] 366574 0
For the cohort (cross-sectional) study: Difference between groups of muscle insulin signalling as measured by immunoblotting.
For sub-study RCT: Difference between groups of changes in muscle insulin signalling as measured by immunoblotting.
Timepoint [1] 366574 0
For cohort study (all women):
muscle insulin signalling measured at baseline.
For the sub-study RCT (overweight women):
Difference in changes in muscle insulin signalling as measured at baseline
and 3 days after last exercise training session of the 12 week intervention ( or ~90-100
days after baseline clamp in controls)



Secondary outcome [2] 366575 0
For the cohort (cross-sectional) study: Difference between groups of fat insulin signalling as measured by immunoblotting.
For sub-study RCT: Difference between groups of changes in fat insulin signalling as measured by immunoblotting.
Timepoint [2] 366575 0
For cohort study (all women):
fat insulin signalling measured at baseline.
For the sub-study RCT (overweight women):
Difference in changes in fat insulin signalling as measured at baseline
and 3 days after last exercise training session of the 12 week intervention ( or ~90-100
days after baseline clamp in controls)
Secondary outcome [3] 366963 0
For the cohort (cross-sectional) study: Difference between groups in circulating testosterone assessed by serum assay.
For sub-study RCT: Difference between groups of changes in testosterone assessed by serum assay.
Timepoint [3] 366963 0
For cohort study (all women):
Testosterone measured at baseline.
For the sub-study RCT (overweight women):
Difference in changes in testosterone as measured at baseline and 3 days after last
exercise training session of the 12 week intervention ( or ~90-100 days after baseline
clamp in control group).
Secondary outcome [4] 366964 0
For the cohort (cross-sectional) study: Difference between groups in health related quality of life (HRQoL) assessed by SF-36 questionnaire.
For sub-study RCT: Difference between groups of changes in HRQoL) assessed by SF-36 questionnaire.
Timepoint [4] 366964 0
For cohort study (all women):
SF-36 score administered at baseline.
For the sub-study RCT (overweight women):
Difference in changes in SF-36 score as measured at baseline and 3 days after last
exercise training session of the 12 week intervention ( or ~90-100 days after baseline
clamp in control group).
Secondary outcome [5] 367121 0
For the cohort (cross-sectional) study: Difference between groups of muscle TGFB signalling as measured by immunoblotting.
For sub-study RCT: Difference between groups of changes in muscle TGFB signalling as measured by immunoblotting.
Timepoint [5] 367121 0
For cohort study (all women):
muscle TGFB signalling measured at baseline.
For the sub-study RCT (overweight women):
Difference in changes in muscle TGFB signalling as measured at baseline
and 3 days after last exercise training session of the 12 week intervention ( or ~90-100
days after baseline clamp in controls)

Secondary outcome [6] 367122 0
For the cohort (cross-sectional) study: Difference between groups of fat TGFB signalling as measured by immunoblotting.
For sub-study RCT: Difference between groups of changes in fat TGFB signalling as measured by immunoblotting.
Timepoint [6] 367122 0
For cohort study (all women):
fat TGFB signalling measured at baseline.
For the sub-study RCT (overweight women):
Difference in changes in fat TGFB signalling as measured at baseline
and 3 days after last exercise training session of the 12 week intervention ( or ~90-100
days after baseline clamp in controls)

Eligibility
Key inclusion criteria
Women with PCOS:
Premenopausal women aged between 18-45 with PCOS. PCOS will be diagnosed by Rotterdam Criteria which requires two of the following (after exclusion of other causes of hyperandrogenism):
1. Oligoovulation (irregular ovulation) or anovulation (lack of ovulation)
2. Clinical and/or signs of hyperandrogenism,
3. Polycystic ovaries on ultrasound and.

Women without PCOS (Control women):
Premenopausal women aged between 18-45 without PCOS, will be defined by having no Rotterdam features.
Minimum age
18 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Current Smoker
2. Pregnancy
3. Known cardiovascular or respiratory conditions (e.g. asthma, cardiac arrhythmias),
4. Hypertension (resting blood pressure >160/105)
5. Bleeding disorders
6. Eating disorders
7. Skin or anaesthetic allergies,
8. Musculoskeletal injuries that may be aggravated by exercise,
9. Type 1 or 2 diabetes
10. Currently taken medication including:
a. Antihypertensives
b. insulin sensitisers (metformin),
c. anti-obesity drugs
d. hormonal contraceptives (pill, subdermal)

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 study statistician not directly involved in the outcome measure collection or tissue analysis for this will prepare the randomisation schedule using block randomisation to maintain balance between treatment arms and PCOS status. Specific allocation will involve contacting the holder of the allocation schedule who is "off-site" (Monash University)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation to maintain balance between treatment arms and PCOS status.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
This study is a 4 group cohort (cross-sectional) study, with a randomized control trial sub-study. Participants will be numbered sequentially, but cannot be blinded to the intervention undertaken. Study staff involved in tissue and endpoint-data analysis will be blinded from intervention and PCOS status. Staff involved in tissue/data collection and exercise training will be blinded to PCOS status unless relevant for medical emergency management .
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
All endpoint data (physiological, clinical, biochemical, mental health and health related quality of life) will be assessed for skewness, and transformed if required. These endpoints from the cross-sectional and cell culture studies will be assessed using correlations and ANOVAs (with post hoc testing) as appropriate to establish associations and group differences respectively.
The exercise intervention endpoints (physiological, clinical, biochemical, mental health and health related quality of life) will be assessed using two-way repeated measures ANOVA to evaluate if the endpoints vary significantly over time among the different groups.
Mediation analysis with mixed modelling will be used to account for changes in adherence, diet or physical activity.
Bonferroni corrections will be applied to minimise type I error for multiple tests. Significance will be accepted when a<0.05.

Recruitment
Recruitment status
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)
VIC
Recruitment hospital [1] 13058 0
Western Hospital - Footscray - Footscray
Recruitment hospital [2] 13059 0
Sunshine Hospital - St Albans
Recruitment hospital [3] 13060 0
The Royal Women's Hospital - Parkville
Recruitment hospital [4] 13061 0
St Vincents & Mercy Private Hospital - Mercy campus - East Melbourne
Recruitment hospital [5] 13062 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [6] 13063 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [7] 13064 0
Monash IVF - Clayton - Clayton
Recruitment postcode(s) [1] 25569 0
3002 - East Melbourne
Recruitment postcode(s) [2] 25566 0
3011 - Footscray
Recruitment postcode(s) [3] 25567 0
3021 - St Albans
Recruitment postcode(s) [4] 25568 0
3052 - Parkville
Recruitment postcode(s) [5] 25570 0
3065 - Fitzroy
Recruitment postcode(s) [6] 25571 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 301897 0
Government body
Name [1] 301897 0
NHMRC Project Grant (APP1156329)
Address [1] 301897 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 301897 0
Australia
Primary sponsor type
Individual
Name
Nigel Stepto
Address
Institute for Health and Sport
Victoria University
Ballarat Road
Footscray
Victoria 3011
Postal:
PO Box 14428
Melbourne
Victoria 8001
Country
Australia
Secondary sponsor category [1] 301650 0
Individual
Name [1] 301650 0
John Hawley
Address [1] 301650 0
Mary McKillop Institute for Health Research
Australian Catholic University
Level 5, 215 Spring Street
Melbourne Vic 3000
Country [1] 301650 0
Australia
Other collaborator category [1] 280528 0
Individual
Name [1] 280528 0
Barabora de Courten
Address [1] 280528 0
Monash Centre for Health Research and Implementation
Level 1, 43-51 Kanooka Grove
Clayton
Victoria 3168
Country [1] 280528 0
Australia
Other collaborator category [2] 280529 0
Individual
Name [2] 280529 0
Raymond Rodgers
Address [2] 280529 0
Robinson Research Institute
The University of Adelaide,
Adelaide
South Australia 5005
Country [2] 280529 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302587 0
Victoria University Human Research Ethics Committee
Ethics committee address [1] 302587 0
Victoria University
PO Box 14428
Melbourne
Victoria 8001
Ethics committee country [1] 302587 0
Australia
Date submitted for ethics approval [1] 302587 0
06/02/2019
Approval date [1] 302587 0
14/03/2019
Ethics approval number [1] 302587 0
HRE19-012
Ethics committee name [2] 302588 0
Australian Catholic University Human Research Ethics Committee
Ethics committee address [2] 302588 0
Manager, Ethics and Integrity
c/o Office of the Deputy Vice Chancellor (Research)
Australian Catholic University
North Sydney Campus
PO Box 968
NORTH SYDNEY, NSW 2059
Ethics committee country [2] 302588 0
Australia
Date submitted for ethics approval [2] 302588 0
08/03/2019
Approval date [2] 302588 0
29/03/2019
Ethics approval number [2] 302588 0
2019-65R

Summary
Brief summary
Polycystic ovary syndrome (PCOS) is a major public health concern affecting young Australian women, with significant metabolic [diabetes] and reproductive [sub-fertility and menstrual disturbance] consequences that are underpinned by insulin resistance (IR). However, knowledge gaps remain in our understanding the mechanisms of IR in PCOS and if current exercise therapies can overcome these mechanisms. We hypothesis that transforming growth factor beta induced tissue fibrosis causes PCOS-specific IR and that high- intensity exercise will resolve PCOS-IR via its impact on tissue fibrosis. Using a four group cohort study in women with and without PCOS across the lean and overweight BMIs with measures of insulin sensitivity and advanced molecular techniques investigate tissue fibrosis as a mechanisms of IR in PCOS. In a sub-study randomized control trial in the of cohorts of overweight women with and without PCOS we will explore the impact of high-intensity intermittent training (HIIT) vs. no lifestyle coaching on this proposed mechanism of insulin resistance.
Trial website
https://www.vu.edu.au/about-vu/news-events/news/women-with-or-without-pcos-wanted-for-health-study
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90738 0
Prof Nigel Stepto
Address 90738 0
Institute for Health and Sport
Victoria University
PO box 14428
Melbourne
Victoria 8001
Country 90738 0
Australia
Phone 90738 0
+61 3 99195416
Fax 90738 0
Email 90738 0
Nigel.Stepto@vu.edu.au
Contact person for public queries
Name 90739 0
Prof Nigel Stepto
Address 90739 0
Institute for Health and Sport
Victoria University
PO box 14428
Melbourne
Victoria 8001
Country 90739 0
Australia
Phone 90739 0
+61 3 99195416
Fax 90739 0
Email 90739 0
Nigel.Stepto@vu.edu.au
Contact person for scientific queries
Name 90740 0
Prof Nigel Stepto
Address 90740 0
Institute for Health and Sport
Victoria University
PO box 14428
Melbourne
Victoria 8001
Country 90740 0
Australia
Phone 90740 0
+61 3 99195416
Fax 90740 0
Email 90740 0
Nigel.Stepto@vu.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?
Data released to participants:
Clinical characteristics (body composition, hormone profiles, lipid profiles, insulin sensitivity measures, cardio-respiratory fitness etc.) and any changes induced by the exercise interventions.
De-identfied but code data for research purposes:
participant's clinical characteristics (body composition, hormone profiles, lipid profiles, insulin sensitivity measures
When will data be available (start and end dates)?
Personal patient (clinical) data will be available to participants when the individual has completed the trial (July 2019), with data from batch analysed tissue and changes in clinical outcomes from intervention being available after June 2022.
De-identified data for research purposes will be available after the last participant completes the trial when databases have be checked and locked.
Available to whom?
Participants will have access to their own data and summary report.
Data for research purposes (de-identified but coded):
FIREx study team- data will be available at completion of trial data collection and clinical trial the database has been checked and locked, allowing outcome data analyses for dissemination.
Additional analysis by FIREx team or their collaborators (after Jan 2023)
Available for what types of analyses?
FIREx team will undertake granted funded tissue and data analysis needed to establish a mechanistic role of transforming growth factor beta and tissue fibrosis in PCOS specific insulin resistance, as wells as the impact of the exercise intervention on women with and without PCOS.
Additional analysis may include IPD meta-analyses, new hypothesis driven analysis of collected tissues.
How or where can data be obtained?
Data will be available to the FIREx study team via RedCap and VU repository databases (password protected and accessible via permission of Prof Stepto). Any additional analyses on data and tissues beyond the study design can be undertake after written permission has been sort from Prof Stepto and all relevant ethical and integrity requirements have been met.
What supporting documents are/will be available?
No other documents available
Summary results
No Results