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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Insulin Resistance; Hyperinsulinemia; PCOS
• Intervention / Treatment: Other: Time restricted eating; Other: Normal ad libitum diet

Detailed Description

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.

1. 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.
2. 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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ruairí Floyd, BSc BMBS; Phone Number: (01) 414 2000; Email: floydr@tcd.ie

Study Locations

• Ireland
  • Leinster
    • Dublin, Leinster, Ireland, D24 NR0A
      • Recruiting
      • Robert Graves Institute of Endocrinology, Tallaght University Hospital
      • Contact: Ruairí Floyd, BSc BMBS; Email: floydr@tcd.ie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 42 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Time restricted eating; 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; 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).
Active Comparator: Normal ad libitum diet; 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; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ruairí Floyd
• Collaborators: Tallaght University Hospital
• Investigators: Principal Investigator: Lucy-Ann Behan, MD, Robert Graves Institute of Endocrinology, Tallaght University Hospital; Study Director: Sinead Duggan, R.D. PhD, University of Dublin, Trinity College

Publications and helpful links

General Publications

• Anton SD, Moehl K, Donahoo WT, Marosi K, Lee SA, Mainous AG 3rd, Leeuwenburgh C, Mattson MP. Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting. Obesity (Silver Spring). 2018 Feb;26(2):254-268. doi: 10.1002/oby.22065. Epub 2017 Oct 31.
• de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med. 2019 Dec 26;381(26):2541-2551. doi: 10.1056/NEJMra1905136. No abstract available. Erratum In: N Engl J Med. 2020 Jan 16;382(3):298. N Engl J Med. 2020 Mar 5;382(10):978.
• Asemi Z, Samimi M, Taghizadeh M, Esmaillzadeh A. Effects of Ramadan Fasting on Glucose Homeostasis, Lipid Profiles, Inflammation and Oxidative Stress in Women with Polycystic Ovary Syndrome in Kashan, Iran. Arch Iran Med. 2015 Dec;18(12):806-10.
• Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018 Aug;110(3):364-379. doi: 10.1016/j.fertnstert.2018.05.004. Epub 2018 Jul 19.
• Li C, Xing C, Zhang J, Zhao H, Shi W, He B. Eight-hour time-restricted feeding improves endocrine and metabolic profiles in women with anovulatory polycystic ovary syndrome. J Transl Med. 2021 Apr 13;19(1):148. doi: 10.1186/s12967-021-02817-2.
• Albosta M, Bakke J. Intermittent fasting: is there a role in the treatment of diabetes? A review of the literature and guide for primary care physicians. Clin Diabetes Endocrinol. 2021 Feb 3;7(1):3. doi: 10.1186/s40842-020-00116-1.
• Zangeneh F, Salman Yazdi R, Naghizadeh MM, Abedinia N. Effect of Ramadan Fasting on Stress Neurohormones in Women with Polycystic Ovary Syndrome. J Family Reprod Health. 2015 Jun;9(2):51-7.
• Pellegrini M, Cioffi I, Evangelista A, Ponzo V, Goitre I, Ciccone G, Ghigo E, Bo S. Effects of time-restricted feeding on body weight and metabolism. A systematic review and meta-analysis. Rev Endocr Metab Disord. 2020 Mar;21(1):17-33. doi: 10.1007/s11154-019-09524-w. Erratum In: Rev Endocr Metab Disord. 2020 Feb 18;:

Helpful Links

• The Irish Nutrition and Dietetic Institute - Polycystic Ovary Syndrome (PCOS)
• BDA The Association of UK Dieticians - Polycystic Ovary Syndrome (PCOS) Food Fact Sheet

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2021
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): January 31, 2023

Study Registration Dates

• First Submitted: October 28, 2021
• First Submitted That Met QC Criteria: November 16, 2021
• First Posted (Actual): November 18, 2021

Study Record Updates

• Last Update Posted (Actual): September 19, 2022
• Last Update Submitted That Met QC Criteria: September 15, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Insulin Resistance; PCOS; Fasting; Intermittent Fasting; Hyperinsulinemia
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Neoplasms; Endocrine System Diseases; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Insulin Resistance; Hyperinsulinism
• Other Study ID Numbers: TimeMAP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No