Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000155291
Ethics application status
Approved
Date submitted
13/12/2017
Date registered
1/02/2018
Date last updated
13/05/2019
Date data sharing statement initially provided
13/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Role of Skeletal Muscle in the development of Insulin Resistance in Women with Polycystic Ovary Syndrome
Scientific title
Insulin Sensitivity and Transforming Growth Factor- beta (TGF-ß) Signalling in Women with Polycystic Ovary Syndrome
Secondary ID [1] 293426 0
None
Universal Trial Number (UTN)
U1111-1206-1846
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Polycystic Ovary Syndrome
305584 0
Insulin Resistance 305585 0
Tissue Fibrosis 305586 0
Obesity 305731 0
Condition category
Condition code
Metabolic and Endocrine 304813 304813 0 0
Metabolic disorders
Reproductive Health and Childbirth 304948 304948 0 0
Other reproductive health and childbirth disorders
Metabolic and Endocrine 305255 305255 0 0
Diabetes

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This trial will be conducted using a cross-sectional design to allow for a comparison of metabolic health and function in Pre-menopausal women with and without PCOS. Women who choose to participate in the study following screening and informed consent will complete a series of physiological testing visits to help identify mechanisms responsible for insulin resistance. The duration of the study will be approximately 4 weeks with 1 visit per week lasting between 2-4 hours.

Visit one will include a familiarisation session for incremental exercise test performed on cycle ergometer used to determine VO2peak and a Dual-energy X-ray absorptiometry (DEXA) scan to determine body composition.

Visit two will include the incremental exercise test performed on cycle ergometer used to determine VO2peak.

Visit three will include an insulin clamp, blood sampling, tissue sampling and an assessment of resting metabolic rate. Insulin clamp will be used to determine insulin sensitivity. The blood sampling blood sampling includes blood taken for insulin clamp, DNA methylation, inflammatory markers, reproductive profiling (Anti-Mullerian Hormone, steroid hormone profile and menstrual cycle) and other metabolic regulatory molecules. Tissue Biopsies will be used for the determination of gene specific and global methylation, gene expression and protein abundance of key tissue fibrosis molecules as well as key metabolic pathways proteins and genes. Furthermore the skeletal muscle biopsies will be used to establish human primary cell lines for mechanistic investigations. The assessment of resting metabolic rate allows whole body substrate utilisation to be assessed at rest and during the insulin clamp.

Visit four will include an oral glucose tolerance test and blood sampling to measure insulin sensitivity and glucose tolerance.

The exercise testing will be performed by a accredited exercise physiologists and the other testing components will be carried out by medical physician and clinical exercise scientist/physiologist.
Intervention code [1] 299668 0
Not applicable
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 304214 0
insulin sensitivity by hypersulinaemic-euglycaemic clamp technique modified to include a glucose tracer.
Timepoint [1] 304214 0
visit 3
Primary outcome [2] 304215 0
TGF-Beta signalling pathways using gene expression analysis (QPCR), and protein abundance analysis via immunoblotting and immunohistochemistry
Timepoint [2] 304215 0
visit 3
Primary outcome [3] 304227 0
Effect of TGF-beta ligands on skeletal muscle insulin resistance in vitro. primary myotube cultures will be treated with TGF-beta ligands. Then analysed for glucose uptake and TGFß and insulin signalling for gene expression of key genes and abundance of proteins and phospho-proteins using real-time qPCR and immunoblotting.
Timepoint [3] 304227 0
visit 3
Secondary outcome [1] 341313 0
Adipose tissue samples obtained from biopsy will be analysed for insulin signalling
Timepoint [1] 341313 0
visit 3
Secondary outcome [2] 341316 0
Body composition by anthropometry and dual x-ray absorptiometry
Timepoint [2] 341316 0
visit 1
Secondary outcome [3] 342316 0
Adipose tissue samples obtained from biopsy will be analysed for TGF-beta signalling
Timepoint [3] 342316 0
Visit 3
Secondary outcome [4] 342317 0
Resting metabolic rate measured via indirect calorimetry to assess whole body metabolism
Timepoint [4] 342317 0
Visit 4
Secondary outcome [5] 342318 0
Cardiorespiratory fitness (VO2peak) as assessed via graded exercise test
Timepoint [5] 342318 0
Visit 2
Secondary outcome [6] 342319 0
Glucose tolerance and insulin sensitivity measured via oral glucose tolerance test
Timepoint [6] 342319 0
Visit 4
Secondary outcome [7] 342320 0
Blood and tissue samples will be assessed for DNA methylation
Timepoint [7] 342320 0
Visit 3
Secondary outcome [8] 342321 0
Blood samples will be used to assess hormonal profile including Lutenizing hormone, Follicle-stimulating hormone, Total and Free Testosterone, Dehydroepiandrosterone sulfate and anti-mullerian hormone
Timepoint [8] 342321 0
visit 3

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

Premenopausal women aged between 18-45 without PCOS, Control women will be defined by having no Rotterdam features.

Not using hormonal contraceptive methods (pill, implantation)
Not taking insulin sensitisers or medications which may affect endpoint data.
Not taking vitamins or natural supplements or have undergone a washout period of 1 month prior to this study.
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion Criteria. menopause, Secondary causes of menstrual disturbance and hyperandrogenism, pregnancy, smoking, Type 1 diabetes, Type 2 diabetes mellitus, uncontrolled hypertension (>160/100mm/Hg), cardiac ischemia, established cardiovascular disease, renal impairment and malignancy, and use of medications that interfere with endpoints (e.g. contraception, metformin, anti-androgens, and progestins anti-hypertensives, and lipid-lowering agents).

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample sizes are based on our prior work (Stepto et al, 2013) showed that the mean glucose infusion rates were 161, 257, 269 and 337 mg/kg/m2 for overweight PCOS (OP), Overweight Controls(OC), lean PCOS(LP) and Lean Controls(LC), respectively with pooled standard deviations of 45 and 65 for lean and overweight groups. To detect similar between-group differences in glucose infusion rate comparing LP vs. LC, OWP vs. OWC, OWC vs. LC and OWP vs. LP 8, 8, 11 and 8 women per group will be needed, respectively (80% power; a=0.05). Thus, recruiting 15 women per group will provide adequate power, account for drop-out and facilitate myotube studies as per prior primary cell culture studies (Corbould et al, 2005; McAinch & Cameron-Smith (2008)). Premenopausal women with PCOS with a BMI >27kg/m2 (n=15), Premenopausal women with PCOS with a BMI <27kg/m2 (n=15), Premenopausal women without PCOS with a BMI >27kg/m2 (n=15), Premenopausal women without PCOS with a BMI <27kg/m2 (n=15).

Measures of insulin sensitivity, glucose disposal and other endpoint data will be log-transformed as necessary to avoid heteroscedasticity. The data will then be analysed for between group differences and correlations using the general linear mixed-model and linear regressions.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
12/03/2018
Actual
12/03/2018
Date of last participant enrolment
Anticipated
23/03/2020
Actual
Date of last data collection
Anticipated
23/04/2020
Actual
Sample size
Target
45
Accrual to date
23
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 9489 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 9490 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 18231 0
3011 - Footscray
Recruitment postcode(s) [2] 18230 0
3021 - St Albans
Recruitment postcode(s) [3] 18229 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 298054 0
Government body
Name [1] 298054 0
Diabetes Australia
Country [1] 298054 0
Australia
Funding source category [2] 298149 0
Government body
Name [2] 298149 0
NHMRC Centre for Research Excellence in Polycystic Ovary Syndrome
Country [2] 298149 0
Australia
Primary sponsor type
University
Name
Victoria University
Address
Victoria University,
Ballarat Road
PO Box 14428,
Melbourne VIC 8001
Country
Australia
Secondary sponsor category [1] 297239 0
None
Name [1] 297239 0
Address [1] 297239 0
Country [1] 297239 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299073 0
Victoria University Human Research Ethics Commitee
Ethics committee address [1] 299073 0
Victoria University
PO Box 14428
Melbourne Victoria
8001
Ethics committee country [1] 299073 0
Australia
Date submitted for ethics approval [1] 299073 0
27/11/2017
Approval date [1] 299073 0
26/02/2018
Ethics approval number [1] 299073 0
HRE17-232

Summary
Brief summary
Polycystic ovary syndrome (PCOS) is an ill-defined endocrine condition impacting metabolic, reproductive and mental health. The condition affects up to 18% of women of a reproductive age in Australia depending on the diagnostic criteria applied. The condition is associated with a number of morbidities including subfertility, pregnancy complications, insulin resistance, type 2 diabetes mellitus, psychological disorders (depression and anxiety), and increased risk of cardiovascular disease. The aetiology of PCOS remains unknown however there are a number of contributing factors and hypothesis from environmental factors, genetics and in utero developmental programming. Given the complex nature of PCOS attempts have been made to identify biomarkers to determine the severity and improve diagnosis.

Women with PCOS are 27% less insulin sensitive than matched controls and insulin resistance is present in ~85% of these women irrespective of obesity. demonstrated that PCOS aetiology is underpinned by insulin resistance and is independent of, but exacerbated by obesity. However, the mechanisms of insulin resistance in PCOS is ill-defined and contributes to its exclusion from diagnostic criteria. insulin resistance in PCOS is currently treated by lifestyle intervention (diet and exercise), and insulin-sensitising medications, but the evidence shows that the efficiency of these therapies in PCOS is ineffective.

This study aims to provide novel insights into the mechanisms of insulin resistance that will allow the design of therapies and interventions to treat PCOS. To yield human data to advance understanding of PCOS aetiology. This will be achieved by investigating the role of TGF-beta signalling and tissue fibrosis in insulin resistance in women with PCOS.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79202 0
A/Prof Nigel K. Stepto
Address 79202 0
Victoria University
PO Box 14428
Melbourne Victoria
8001
Country 79202 0
Australia
Phone 79202 0
+61 3 9919 5416
Fax 79202 0
Email 79202 0
nigel.stepto@vu.edu.au
Contact person for public queries
Name 79203 0
A/Prof Nigel K. Stepto
Address 79203 0
Victoria University
PO Box 14428
Melbourne Victoria
8001
Country 79203 0
Australia
Phone 79203 0
+61 3 9919 5416
Fax 79203 0
Email 79203 0
nigel.stepto@vu.edu.au
Contact person for scientific queries
Name 79204 0
A/Prof Nigel K. Stepto
Address 79204 0
Victoria University
PO Box 14428
Melbourne Victoria
8001
Country 79204 0
Australia
Phone 79204 0
+61 3 9919 5416
Fax 79204 0
Email 79204 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 (No end date determined). The data from batch analysed biological samples will be available being available after June 2021

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):
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.
Available for what types of analyses?
The research 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 in 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 research team via 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 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.