Time-restricted Eating to Improve Metabolic Abnormalities in Polycystic Ovarian Syndrome

Study Overview
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Brief Summary
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Polycystic ovarian syndrome (PCOS) is associated with metabolic symptoms such as hyperinsulinemia. Time-restricted eating may reduce serum insulin and improve insulin resistance in patients with PCOS. Currently, there are few studies investigating time-restricted eating in patients with PCOS. The investigators plan to test the feasibility of time-restricted eating in the management of PCOS by means of a real-world clinical intervention. The investigators will determine if an 18:6 eating protocol reduces insulin levels by means of a randomised controlled crossover trial.

Detailed Description
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Background: Polycystic ovarian syndrome (PCOS) is the most common reproductive endocrinopathy in women of reproductive age with many associated metabolic symptoms, in particular hyperinsulinemia, insulin resistance and a high lifetime risk of type 2 diabetes mellitus. The effects of time-restricted eating on metabolic profiles have been investigated in many endocrinopathies, but there are minimal data in PCOS. Methods: This study will investigate the feasibility of time-restricted eating in the management of PCOS, and its effects on insulin levels and other metabolic parameters. To achieve this, the investigators will recruit 20 patients with PCOS (normal weight, overweight, obese). In a randomised cross-over design, participants will be observed for two consecutive 12 week periods (with a 4 weeks washout period in between) following either 'time-restricted eating' or 'usual eating', detailed below. 18:6 protocol: 18 hours of fasting and a 6-hours eating window, with no other specific dietary advice. Participants choose their own 6-hour period according to their lifestyle and preference. Usual eating: follow usual eating patterns, no time restriction, no other dietary advice When fasting, participants are permitted to consume plain water, unflavoured/unsweetened sparkling water, black breakfast tea and black coffee. Dietary intake will be determined at baseline, at midpoint of each study arm, and at the end of the study using Nutritics software. Participants will self-record dietary intake using the Nutritics 'app'. The primary endpoints will be serum insulin and feasibility of the intervention as well as safety, acceptability, and compliance with time-restricted eating. Secondary endpoints will be insulin resistance (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), androgens (testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, 17-Hydroxyprogesterone (17-OHP) and sex hormone binding globulin (SHBG)), appetite (10-point visual analogue scale), hunger/satiety (glucagon-like peptide 1 (GLP-1), grehlin, PYY and oxyntomodulin, fasting glucose, HbA1c, lipid profile, lipoprotein lipid A, apolipoprotein A1, apolipoprotein B, anthropometrics (weight, body mass index, hip and waist circumference), dietary intake (calorie and macronutrient intake; micronutrient intake including iron, calcium; dietary pattern including timing). Results: Safety and acceptability will be measured by adverse event reporting and measurement of adherence. Paired t-test will be used to assess between baseline and post intervention measurements. Results considered statistically significant if p<0.05. Discussion: Time-restricted eating has potential to aid in improvement of insulin resistance in patients with PCOS based on studies in other populations. There is no substantial literature on this subject to date in the PCOS patient cohort, with this being the first randomised study to date. The investigators will discuss the effects of time-restricted eating on insulin levels in the specific population of women with PCOS based on the results.

Official Title
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The Effect of Time-restricted Eating on Insulin Levels and Other Metabolic Abnormalities in Polycystic Ovarian Syndrome: A Randomised Feasibility Study of Real-world Clinical Advice

Conditions
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PCOS, Hyperinsulinemia, Insulin Resistance

Intervention / Treatment
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* Other: Time restricted eating
* Other: Normal ad libitum diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult women of reproductive age with confirmed diagnosis of PCOS (Rotterdam Criteria, including at least 2 of 3 characteristics: oligomenorrhea, clinical and/or biochemical hyperandrogenism and ultrasound criteria) No BMI restriction Able and willing to provide explicit, informed consent Exclusion Criteria: Type 1 diabetes, medication-controlled type 2 diabetes Pregnancy Currently participating in weight loss programme, or reported weight change in last 3 months (>5% of current body weight) Documented history of eating disorder Ovulation medication, such as clomiphene citrate Weight loss medication affecting weight or appetite in last 6 months, including weight loss medications, antipsychotic drugs or other medications as determine by the physician (eg. Semaglutide, liraglutide, orlistat, amphetamines, Qsymia (phentermine-topiramate), bupropion-naltrexone (Contrave)) Known liver, renal or thyroid dysfunction (not including non-alcoholic fatty liver disease with hypothyroidism on treatment or subclinical hypothyroidism seen in a large proportion of patients with PCOS) Unable to participate in follow-up for at least 24 weeks Unable or unwilling to provide explicit, informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Time restricted eating<br>Time-restricted eating using 18:6 protocol (12 weeks) Washout Period (4 weeks) Crossover to Normal ad libitum diet (12 weeks) | Other: Time restricted eating<br>* Following a 3 day baseline dietary assessment using the Nutritics 'app', patients will immediately commence time-restricted eating on a 18:6 basis (18 hours fasting, 6 hours eating window) for 12 weeks. Participants will consume all their meals within a daily 6-hour period of their choosing, and this may change according to patient's lifestyle and preference to reflect a real-world situation. Participants may eat ad libitum / according to appetite during the eating period. Participants will fast for 18 hours per day, consuming only plain water, unflavoured/unsweetened sparkling water, black breakfast tea or black coffee. Alcohol must not be consumed during fasting periods Dietary intake will again be measured using the Nutritics 'app' midpoint through the 12-week period (week 6 +/- 1 week) and in the last week of the intervention (week 11/12).<br>|
| Active Comparator: Normal ad libitum diet<br>Normal ad libitum dietary patterns without defined eating window, fasting or restrictions on types of food or drink consumed (12 weeks) Washout Period (4 weeks) Crossover to time-restricted eating using 18:6 protocol (12 weeks) | Other: Normal ad libitum diet<br>* Following a 3-day baseline dietary assessment using the Nutritics 'app', participants with be directed to continue with their usual dietary intake without any time-related restrictions for 12 weeks. There will be no defined eating window and fasting or restrictions regarding types of food or drink consumed. Dietary intake will again be measured using the Nutritics 'app' midpoint through the 12-week period (week 6 +/- 1 week) and in the last week of the intervention (week 11/12).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drop-out rate | Assessing intervention feasibility | 6 weeks | 
| Drop-out rate | Assessing intervention feasibility | 12 weeks | 
| Adverse outcomes as assessed by CTCAE v4.0 | Assessing intervention feasibility | 6 weeks | 
| Adverse outcomes as assessed by CTCAE v4.0 | Assessing intervention feasibility | 12 weeks | 
| Change in serum insulin | Measured with serum insulin levels to assess effects | 6 weeks | 
| Change in serum insulin | Measured with serum insulin levels to assess effects | 12 weeks | 
| Change in food diaries | Assessment of change of eating behaviours | 6 weeks | 
| Change in food diaries | Assessment of change of eating behaviours | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin resistance | Assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and other ratio calculations measuring insulin resistance | 6 weeks | 
| Change in insulin resistance | Assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and other ratio calculations measuring insulin resistance | 12 weeks | 
| Change in testosterone levels | Assessed by plasma testosterone | 6 weeks | 
| Change in testosterone levels | Assessed by plasma testosterone | 12 weeks | 
| Change in free testosterone levels | Assessed by plasma free testosterone | 6 weeks | 
| Change in free testosterone levels | Assessed by plasma free testosterone | 12 weeks | 
| Change in dehydroepiandrosterone sulfate (DHEA-S) levels | Assessed by plasma dehydroepiandrosterone sulfate (DHEA-S) | 6 weeks | 
| Change in dehydroepiandrosterone sulfate (DHEA-S) levels | Assessed by plasma dehydroepiandrosterone sulfate (DHEA-S) | 12 weeks | 
| Change in androstenedione levels | Assessed by plasma androstenedione | 6 weeks | 
| Change in androstenedione levels | Assessed by plasma androstenedione | 12 weeks | 
| Change in sex hormone binding globulin (SHBG) levels | Assessed by plasma sex hormone binding globulin (SHBG) | 6 weeks | 
| Change in sex hormone binding globulin (SHBG) levels | Assessed by plasma sex hormone binding globulin (SHBG)) | 12 weeks | 
| Change in 17-Hydroxyprogesterone (17-OHP) levels | Assessed by 17-Hydroxyprogesterone (17-OHP) | 6 weeks | 
| Change in 17-Hydroxyprogesterone (17-OHP) levels | Assessed by 17-Hydroxyprogesterone (17-OHP) | 12 weeks | 
| Change in appetite | Measured by a validated 10-point visual analogue scale on a scale of 1-10, 1 being not hungry at all and 10 being very hungry | 6 weeks | 
| Change in appetite | Measured by a validated 10-point visual analogue scale on a scale of 1-10, 1 being not hungry at all and 10 being very hungry | 12 weeks | 
| Change in markers of satiety | Assess by plasma GLP-1 | 6 weeks | 
| Change in markers of satiety | Assess by plasma GLP-1 | 12 weeks | 
| Change in markers of satiety | Assess by plasma PYY | 6 weeks | 
| Change in markers of satiety | Assess by plasma PYY | 12 weeks | 
| Change in markers of satiety | Assess by plasma oxyntomodulin | 6 weeks | 
| Change in markers of satiety | Assess by plasma oxyntomodulin | 12 weeks | 
| Change in markers of hunger | Assess by plasma ghrelin | 6 weeks | 
| Change in markers of hunger | Assess by plasma ghrelin | 12 weeks | 
| Change in fasting glucose | Assessed in serum glucose measurements | 6 weeks | 
| Change in fasting glucose | Assessed in serum glucose measurements | 12 weeks | 
| Change in HbA1c | Assessed in serum HbA1c measurements | 6 weeks | 
| Change in HbA1c | Assessed in serum HbA1c measurements | 12 weeks | 
| Change in lipids | Assessed by Lipid profile | 6 weeks | 
| Change in lipids | Assessed by Lipid profile | 12 weeks | 
| Change in lipids | Assessed by Lipoprotein lipid A levels | 6 weeks | 
| Change in lipids | Assessed by Lipoprotein lipid A levels | 12 weeks | 
| Change in lipids | Assessed by Apolipoprotein A1 levels | 6 weeks | 
| Change in lipids | Assessed by Apolipoprotein A1 levels | 12 weeks | 
| Change in lipids | Assessed by Apolipoprotein B levels | 6 weeks | 
| Change in lipids | Assessed by Apolipoprotein B levels | 12 weeks | 
| Change in body weight | Body weight (kg) | 6 weeks | 
| Change in body weight | Body weight (kg) | 12 weeks | 
| Change in body mass index | BMI (kg/m2) | 6 weeks | 
| Change in body mass index | BMI (kg/m2) | 12 weeks | 
| Change in anthropometric measurements (waist circumference) | Waist circumference (cm) | 6 weeks | 
| Change in anthropometric measurements (waist circumference) | Waist circumference (cm) | 12 weeks | 
| Change in anthropometric measurements (waist-hip ratio) | Waist-hip ratio | 6 weeks | 
| Change in anthropometric measurements (waist-hip ratio) | Waist-hip ratio | 12 weeks | 
| Change in dietary intake | Assessed using interval dietary assessments with Nutritics 'app' | 6 weeks | 
| Change in dietary intake | Assessed using interval dietary assessments with Nutritics 'app' | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCOS, Intermittent Fasting, Fasting, Hyperinsulinemia, Insulin Resistance