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Trial registered on ANZCTR


Registration number
ACTRN12615000242527
Ethics application status
Approved
Date submitted
19/02/2015
Date registered
17/03/2015
Date last updated
19/02/2019
Date data sharing statement initially provided
19/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The (i)mpact of (H)igh (I)ntensity intermittent (T)raining on health and mechanisms of insulin resistance in women with (P)oly(c)ystic (O)vary (S)yndrome: The iHIT-PCOS randomised control trial.
Scientific title
A randomized control trial comparing the impacts of high intensity intermittent exercise to current physical activity guideline recommendations and standard care on reproductive health, health related quality of life and mechanisms of insulin resistance in overweight women with Polycystic Ovary Syndrome
Secondary ID [1] 286204 0
NIL
Universal Trial Number (UTN)
U1111-1167-3442
Trial acronym
iHIT-PCOS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Polycystic Ovary Syndrome
294239 0
Insulin Resistance 294240 0
Obesity 294241 0
Menstrual disturbances and ovulation
294242 0
Depression 294243 0
Polycystic Ovary Syndrome Health related quality of life 294244 0
Barriers and facilitators to physical activity 294245 0
Condition category
Condition code
Metabolic and Endocrine 294556 294556 0 0
Other metabolic disorders
Diet and Nutrition 294557 294557 0 0
Obesity
Reproductive Health and Childbirth 294558 294558 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Women will be randomized into the control and 2 exercise intervention groups. Three weeks prior to the exercise intervention phase women in all groups will undertake a behavioural lifestyle intervention: an adapted, evidence based lifestyle behavioural intervention will be provided to all participants to i) ensure exercise is provided in context of combined behavioural and dietary intervention and ii) to optimise retention, engagement, motivation and sustainability of exercise. This program includes provision of healthy eating advice and health promotion behaviour change principles resulting in improved retention (~10% attrition rates in 3 large prior RCT’s compared to standard ~30% dropout rates). This involves 3 x 1 hour group sessions (1 session per week over 3 weeks) focused on diet information and behavioural modification techniques based on social cognitive theory including goal setting, self-monitoring, social support, coping strategies, problem solving and relapse prevention . Non-prescriptive and non-individualised dietary advice is provided consistent with the Australian Dietary and Healthy Eating Guidelines with a focus on healthy food choices, reducing intake of energy-dense and non-core foods and increasing intake of low energy-dense foods. These sessions encourage physical activity (low intensity exercise for 150 minutes/week) but do not include structured exercise. Lifestyle sessions will be provided by trained accredited exercise physiologists (AEPs).
Exercise treatments: Exercise will be conducted in group setting on stationary bikes or treadmills according to the participant’s preference; and exercise intensities prescribed and monitored using heart rates. Sessions will be conducted at the university fitness centre/ exercise clinic under the supervision of AEPs,
Volume matching and training progression: The supervised standard exercise recommendation (SSE) and High intensity intermittent training (HIIT) intervention arms will be matched for training volume (MET.min/week) and progressed weekly by manipulating session time and intensity. Both SSE and HIIT will progress from 312 MET.min/week in week 1 to 530 MET.min/week in weeks 8-12, meeting exercise guideline minimums. Exercise sessions include warm-up and cool down protocols, and are adjusted to individual capabilities and training adaptations. In addition to lifestyle intervention and wearable technology, details of the three exercise treatment arms are:
i) Control Group: Exercise advice but without structured exercise as per standard care.
ii) SSE Group: Supervised standard exercise recommendations at minimum exercise/ physical activity recommendations (150 min per week) in three supervised sessions/week of continuous low to moderate intensity exercise sessions (building up to 50 min sessions of cycling/walking at 3.3 METs or 50-60% HRR).
iii) HIIT Group: Vigorous exercise at minimum exercise/physical activity recommendations (~75 min per week) in three supervised sessions/week of HIIT exercise (cycling/running). Based on existing literature and patient consultation, we will use a practical training program encompassing two successful HIIT protocols:
* two sessions/week of short constant load cycling of 8–12 x 1 min at ~9METs (or 90-95% HRR) with 1 minute passive recovery
* one session/week of cycling/jogging/running 4–8 x 4 min at 8 METS (or 70-85%HRR) with 1 minute passive recovery.
These HIIT sessions have proven feasible, enjoyable, and are safe in populations with significant metabolic disease and in the pilot study in overweight PCOS women, and is best tolerated with progressive weekly increases, as per best-practice exercise prescription principles.
Intervention code [1] 291224 0
Lifestyle
Intervention code [2] 291225 0
Behaviour
Intervention code [3] 291226 0
Treatment: Other
Comparator / control treatment
The control group will receive current standard care for women with Polycystic Ovary Syndrome which includes general dietary and exercise advise and undertake the behavioural lifestyle intervention described above Whilst the program has successfully prevented weight gain and has been sustainable, improvements in exercise engagement have been limited. Hence, we do not expect our control group to engage in significant exercise.
Control group
Active

Outcomes
Primary outcome [1] 294351 0
Cardio-metabolic health as assessed as insulin sensitivity by hypersulinaemic-euglycaemic clamp technique modified to include a glucose tracer.
Timepoint [1] 294351 0
Baseline and 36 hrs post last exercise training session of the 12 week intervention
Primary outcome [2] 294352 0
Reproductive health as assessed as a composite outcome includidng analysis of:
1) Ovulation status by Antimullarian Hormone (AMH) and menstrual diaries.
2) Steriod hormone profiles including testosterone, dihydrotestosterone, 3alpha and 3beta androstanediols, estradiol, estrone, DHEA, androstenedione and progesterone determined by LC-MS mass spectrometry
Timepoint [2] 294352 0
AMH and steroid hormone profiles will be measured where possible in the early follicular phase at baseline and 36 hrs after the last exercise session of the 12 week interventions.
Menstrual diaries will be maintained from baseline to end of study.
Primary outcome [3] 294353 0
Primary Molecular outcome 1: Extra-cellular matrix remodeling pathways using gene expression analysis (QPCR), and protein abundance analysis via immunoblotting and immunohistochemistry
Timepoint [3] 294353 0
These analyses will occur on samples obtained at baseline and 36hrs after the last exercise bout in the 12 week intervention.
Secondary outcome [1] 313085 0
Psychosocial status (Depression, Anxiety, Polycystic Ovary Syndrome specific Quality of Life) assessed as composite measure using validated questionnaires which include:
1) Polycystic Ovary Syndrome Quality of Life Questionaire
2) Depression Anxiety Stress Scale
Timepoint [1] 313085 0
Baseline, after the 12 week intervention and at 6 and 12 months post intervention.
Secondary outcome [2] 313086 0
Physical activity engagement monitored remotely using active minutes and step counts from Fitbits and the associated web-platform.
Timepoint [2] 313086 0
Physical activity will be monitored remotely for 1 month before intervention to the end of the 12 month follow up. Which is achieved via participants wearing the Fitbits continuously throughout the study during waking hours.
Secondary outcome [3] 313341 0
Physical activity behaviours which is a composite outcome determined via questionaires:
1) International Physical activity Questionaire
2) Intrinsic Motivation Inventory
3) Behaviour Regulation in exercise questionaire
4) Feeling Scale
Timepoint [3] 313341 0
Baseline, after the 12 week intervention and at 6 and 12 months post intervention.
Secondary outcome [4] 313343 0
Primary molecular outcome 2: Muscle lipid accumulation by lipidomic analysis using ionspray mass spectrometry and immunohistochemistry techniques.
Timepoint [4] 313343 0
These analyses will occur on samples obtained at baseline and 36hrs after the last exercise bout in the 12 week intervention.
Secondary outcome [5] 313344 0
Primary Molecular outcome 3:
Epigenetic signatures including DNA methylation and histone positioning in skeletal muscle.
Timepoint [5] 313344 0
These analyses will occur on samples obtained at baseline and 36hrs after the last exercise bout in the 12 week intervention.
Secondary outcome [6] 313345 0
Body composition by antropometry and dual x-ray absorbtiometry.
Timepoint [6] 313345 0
Before and immediately after the 12 week interventions (36hrs post last exercise session)
Secondary outcome [7] 313500 0
Secondary measure of cardio-metabolic health by assessing maximal aerobic fitness by graded exercise testing.
Timepoint [7] 313500 0
This analysis will occur at baseline and within 1 week after the the completion of the last exercise bout in the 12 week intervention.
Secondary outcome [8] 313501 0
A further secondary measure of cardio-metabolic health will be assessing blood pathology including HbA1C and blood lipid profiles.
Timepoint [8] 313501 0
This measure will occur on blood samples obtained at baseline and 36hrs after the last exercise bout in the 12 week intervention.

Eligibility
Key inclusion criteria
Must be diagnosed with Polycystic Ovary Syndrome by Rotterdam criteria as recommended criteria by both the NHMRC approved guideline for managing and treating PCOS and a recent NIH workshop with exclusion of other causes of hyperandrogenism (thyroid and prolactin disorders and non-classical congenital adrenal hyperplasia). The diagnostic criteria Polycystic Ovary syndrome include two of (i) irregular menstrual cycles (<21 or >35 days), (ii) clinical (hirsutism, acne) or biochemical (elevation of at least one circulating ovarian androgen) hyperandrogenism and (iii) Polycystic ovaries on ultrasound.Must have a BMI>25 m/kg2
Minimum age
18 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Secondary causes of menstrual disturbance and hyperandrogenism, pregnancy (pregnancy test at baseline), smoking, diabetes, uncontrolled hypertension (>160/100), established CVD, renal impairment and malignancy, clinical depression, those on medications that interfere with end-points (e.g. anti-hypertensives, lipid-lowering agents) or >75min/week exercise as this is 50% of minimum recommended physical activity.

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)
Participants will be responding to advertisements placed in local media publications,notice boards, web pages. Once the participant has responded to the advertisement they will be screened via telephone to establish eligibility. Once meeting the criteria they will be sent an study information pack and informed consent forms, and invited to attend a medical screening session to confirm PCOS diagnosis and check health status. Once eligibility is confirmed by a clinician and informed consent provided the participant. The participants will be stratified by age, body mass index (BMI) and race and then be block randomized into either control standard exercise or high intensity intermittent training groups. This process will be consealed and undertaken by a trial coordinator using central randomisation by computer at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation procedures used will be a simple randomisation procedure using table created by computer software (i.e. computerised sequence generation). But Participants will be stratified by age, BMI and race
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
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Statistical approach:
Measures of insulin sensitivity and other endpoint data will be log-transformed, as appropraite, to avoid the problem of heteroscedasticity. The effects of the treatments will be estimated using linear mixed-model procedures with inclusion of covariates as appropriate to estimate effects of moderators and mediators. Data analysis will be completed by the in-house biostatistician who has engaged in study design/sample size estimation.
Samples size:
The primary endpoint is insulin sensitivity with the smallest worthwhile between groups change in insulin sensitivity in the RCT is expected to be a change in glucose infusion rate (GIR) of 20 mg.min-1.m-2 (an effect size of 0.35) in response to training with a sample size of 20 per group (n=60) we are powered at 99% with a=0.05, allowing for a conservative 30% attrition 42 participants will be powered at 82% (a=0.05). These power calculations apply to mechanistic endpoints based on gene expression data with the lowest power for any measurement being 80% with a=0.05 and 30% attrition. We will therefore aim to recruit a sample size of 60 participants for this RCT.

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] 3482 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 3483 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 9249 0
3021 - St Albans
Recruitment postcode(s) [2] 9250 0
3000 - Melbourne
Recruitment postcode(s) [3] 9251 0
3011 - Footscray
Recruitment postcode(s) [4] 9324 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 290784 0
Self funded/Unfunded
Name [1] 290784 0
Address [1] 290784 0
Country [1] 290784 0
Primary sponsor type
University
Name
Victoria University
Address
Victoria University, PO Box 14428, Melbourne VIC 8001
OR
Cnr Ballarat and Geelong Roads, Footscray VIC 3011
Country
Australia
Secondary sponsor category [1] 289468 0
University
Name [1] 289468 0
Monash University
Address [1] 289468 0
Wellington Road
Clayton
Vic 3008
Country [1] 289468 0
Australia
Other collaborator category [1] 278357 0
University
Name [1] 278357 0
Adelaide University
Address [1] 278357 0
The University of Adelaide
Adelaide, South Australia
5005
Country [1] 278357 0
Australia
Other collaborator category [2] 278358 0
University
Name [2] 278358 0
Deakin University
Address [2] 278358 0
75 Pigdons Road, Waurn Ponds VIC 3216
Country [2] 278358 0
Australia
Other collaborator category [3] 278359 0
Other Collaborative groups
Name [3] 278359 0
BakerIDI
Address [3] 278359 0
75 Commercial Road, Melbourne VIC 3004
Country [3] 278359 0
Australia
Other collaborator category [4] 278360 0
Charities/Societies/Foundations
Name [4] 278360 0
NovoNordisk Foundation for Basic Metabolic Research
Address [4] 278360 0
Integrative Physiology Research Section
Blegdamsvej 3B, building 6.6
DK-2200 Copenhagen N
Country [4] 278360 0
Denmark

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292416 0
Victoria University Human Research Ethics Commitee
Ethics committee address [1] 292416 0
Victoria University
PO Box 14428
Melbourne Victoria
8001
Ethics committee country [1] 292416 0
Australia
Date submitted for ethics approval [1] 292416 0
25/11/2015
Approval date [1] 292416 0
01/03/2016
Ethics approval number [1] 292416 0
HRE15-298

Summary
Brief summary
Polycystic ovary syndrome (PCOS) is a major public health concern affecting one in five young Australian women and costs the country $800 million/y. It has significant metabolic [diabetes (T2DM) and adverse cardiovascular risk factors (CVRF)] and reproductive [sub-fertility and menstrual disturbance] consequences that are underpinned by insulin resistance (IR) and exacerbated by obesity. Despite the successful work of our group and others, gaps remain in
understanding the mechanisms of IR in PCOS and in determining optimal therapies – including exercise interventions. We will advance understanding of the biological origins of PCOS, and of optimal therapies. Using gold-standard measures of insulin sensitivity and advanced molecular techniques we will significantly advance knowledge on mechanisms of IR in PCOS including ectopic lipid accumulation, tissue fibrosis, and epigenetics and the impact of exercise in a randomised control trial. We will recruit 60 over weight women with PCOS and compare the benefits and impact of high-intensity intermittent training (HIIT), with standard exercise recommendations or lifestyle advice. The impact of HIIT on these mechanisms will be elucidated, clarifying its value as an effective lifestyle intervention. This work will reveal mechanisms of IR and impact of exercise in PCOS, uncover potential therapeutic targets for IR in PCOS and obesity and inform optimal exercise prescription for lifestyle therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 55054 0
Prof Nigel Stepto
Address 55054 0
Institute for Health and Sport (IHES), Victoria University, PO Box 14428, Melbourne, VIC, 8001
Country 55054 0
Australia
Phone 55054 0
+61399195416
Fax 55054 0
Email 55054 0
Nigel.Stepto@vu.edu.au
Contact person for public queries
Name 55055 0
Prof Nigel Stepto
Address 55055 0
Institute for Health and Sport (IHES), Victoria University, PO Box 14428, Melbourne, VIC, 8001
Country 55055 0
Australia
Phone 55055 0
+61399195416
Fax 55055 0
Email 55055 0
Nigel.Stepto@vu.edu.au
Contact person for scientific queries
Name 55056 0
Prof Nigel Stepto
Address 55056 0
Institute for Health and Sport (IHES), Victoria University, PO Box 14428, Melbourne, VIC, 8001
Country 55056 0
Australia
Phone 55056 0
+61399195416
Fax 55056 0
Email 55056 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 (Sept 2016), with data from batch analysed tissue and changes in clinical outcomes from intervention being available after June 2020.
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):
iHITPCOS 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 iHITPCOS team or their collaborators (after Dec 2020)
Available for what types of analyses?
IHITPCOS team will undertake self funded tissue and data analysis needed to establish the impact of different exercise interventions on insulin sensitivity, muscle tissue ECM remodelling and reproductive health markers (AMH) in PCOS .
Additional analysis may include IPD meta-analyses, new hypothesis driven analysis of collected tissues.
By what mechanism will data be made available?
Data will be available to the iHITPCOS study 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 other documents available
Summary results
No Results