Body Fat as Determinant of Female Gonadal Dysfunction

NCT03841981 | Recruiting

• 1 other identifier: PI18/01122
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Reproduction requires from women enough energy depots to warrant an adequate nutritional supply to the fetus. Hence, adipose tissue is able to communicate with female hypothalamic-pituitary-ovary axis. The hypothesis of the project is that abnormalities in the quantity (absolute and relative to lean body mass), distribution and/or function of adipose tissue are associated with functional forms of female gonadal dysfunction in predisposed women, in a spectrum of anomalies that go from hypothalamic amenorrhea to the polycystic ovary syndrome (PCOS). To challenge this hypothesis, the investigators will study 5 groups of 10 women each: women with exercise-associated hypothalamic amenorrhea, women without ovulatory dysfunction that exercise equally, non-hyperandrogenic patients with PCOS, hyperandrogenic patients with PCOS, and healthy control women comparable to those with PCOS. The aims of the study will be: Primary objective: To identify novel signalling factors originating from adipose tissue and muscle using targeted and nontargeted evaluation of the proteome and of gene expression of superficial subcutaneous fat, deep subcutaneous fat (which mimics visceral adipose tissue) and skeletal muscle. Secondary objectives:

1. 1.To study the serum adipokine profile - including those identified by the primary objective - and circulating gut hormones during fasting and after a glucose load in the 5 groups of women, and their associations with sexual hormones and body fat distribution.
2. 2.To study body composition and body fat distribution in these women and their relationships with:

Conditions

Polycystic Ovary Syndrome; Hypothalamic Amenorrhea

Keywords

Exercise; Sex steroids; Hyperandrogenism; Adipose tissue; Muscle; Proteome; Gene expression; Adipokine; Cardiovascular risk; Microbiome

Outcome Measures

Primary Outcomes (1)

• Adipokine and myokine signaling identification

  Up to 5 years

Secondary Outcomes (14)

• Circulating adipokine profile

  Up to 5 years

• Appetite regulation hormonal profile

  Up to 5 years

• Association between body mass index and sex steroids

  Up to 5 years

• Association between percentage of fat mass with respect to total body weight and sex steroids

  Up to 5 years

• Association between percentage of lean mass with respect to total body weight and sex steroids

  Up to 5 years

Study Arms (5)

I- Hypothalamic amenorrhea

10 women with exercise-associated hypothalamic amenorrhea

Diagnostic Test: Anthropometric and physical examination; Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall; Diagnostic Test: Biochemical, hormonal and metabolic phenotyping; Diagnostic Test: Sonographic studies; Diagnostic Test: 24-hour Ambulatory blood pressure monitoring; Procedure: Percutaneous biopsy; Diagnostic Test: Cardiovascular autonomic function studies; Diagnostic Test: Oral smear and feces specimen

II- Hyperandrogenic polycystic ovary syndrome

5 lean women with hyperandrogenic polycystic ovary syndrome. 5 women with weight excess and hyperandrogenic polycystic ovary syndrome.

Diagnostic Test: Anthropometric and physical examination; Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall; Diagnostic Test: Biochemical, hormonal and metabolic phenotyping; Diagnostic Test: Sonographic studies; Diagnostic Test: 24-hour Ambulatory blood pressure monitoring; Procedure: Percutaneous biopsy; Diagnostic Test: Cardiovascular autonomic function studies; Diagnostic Test: Oral smear and feces specimen

III- Non-hyperandrogenic polycystic ovary syndrome

5 lean women with non-hyperandrogenic polycystic ovary syndrome 5 women with weight excess and non-hyperandrogenic polycystic ovary syndrome

Diagnostic Test: Anthropometric and physical examination; Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall; Diagnostic Test: Biochemical, hormonal and metabolic phenotyping; Diagnostic Test: Sonographic studies; Diagnostic Test: 24-hour Ambulatory blood pressure monitoring; Procedure: Percutaneous biopsy; Diagnostic Test: Cardiovascular autonomic function studies; Diagnostic Test: Oral smear and feces specimen

IV- Trained women without ovulatory dysfunction

10 women who exercise as intensively as women with exercise-associated hypothalamic amenorrhea but with normal ovulatory cycles.

Diagnostic Test: Anthropometric and physical examination; Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall; Diagnostic Test: Biochemical, hormonal and metabolic phenotyping; Diagnostic Test: Sonographic studies; Diagnostic Test: 24-hour Ambulatory blood pressure monitoring; Procedure: Percutaneous biopsy; Diagnostic Test: Cardiovascular autonomic function studies; Diagnostic Test: Oral smear and feces specimen

V- Non-hyperandrogenic healthy women

10 women matched by age and body mass index with women with polycystic ovary syndrome who do not perform physical activity on a regular basis

Diagnostic Test: Anthropometric and physical examination; Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall; Diagnostic Test: Biochemical, hormonal and metabolic phenotyping; Diagnostic Test: Sonographic studies; Diagnostic Test: 24-hour Ambulatory blood pressure monitoring; Procedure: Percutaneous biopsy; Diagnostic Test: Cardiovascular autonomic function studies; Diagnostic Test: Oral smear and feces specimen

Interventions

Anthropometric and physical examination DIAGNOSTIC_TEST

* Weight and height. * Waist-to-hip ratio. * Body composition: Bioelectrical impedance and \[Dual energy X-ray absorptiometry (DEXA)\].

I- Hypothalamic amenorrhea; II- Hyperandrogenic polycystic ovary syndrome; III- Non-hyperandrogenic polycystic ovary syndrome; IV- Trained women without ovulatory dysfunction; V- Non-hyperandrogenic healthy women

Indirect calorimetry, accelerometer and seven-day dietary recall DIAGNOSTIC_TEST

Energy availability assessment.

I- Hypothalamic amenorrhea; II- Hyperandrogenic polycystic ovary syndrome; III- Non-hyperandrogenic polycystic ovary syndrome; IV- Trained women without ovulatory dysfunction; V- Non-hyperandrogenic healthy women

Biochemical, hormonal and metabolic phenotyping DIAGNOSTIC_TEST

* Lipid profile. * Oral glucose tolerance test: plasma glucose and insulin, insulin sensitivity indices, gastrointestinal hormones, adipokines, oxidative stress markers. * Sex steroid profile. * Hypothalamic-pituitary-adrenal axis study. * Ferrokinetic study. * Subclinical chronic inflammatory markers.

I- Hypothalamic amenorrhea; II- Hyperandrogenic polycystic ovary syndrome; III- Non-hyperandrogenic polycystic ovary syndrome; IV- Trained women without ovulatory dysfunction; V- Non-hyperandrogenic healthy women

Sonographic studies DIAGNOSTIC_TEST

* Polycystic ovarian morphology. * Carotid intima-media thickness. * Eco-FAT: Ultrasound measurements of adipose tissue depots including sc, preperitoneal, intraperitoneal (ip), mesenteric, and perirenal fat thickness.

I- Hypothalamic amenorrhea; II- Hyperandrogenic polycystic ovary syndrome; III- Non-hyperandrogenic polycystic ovary syndrome; IV- Trained women without ovulatory dysfunction; V- Non-hyperandrogenic healthy women

24-hour Ambulatory blood pressure monitoring DIAGNOSTIC_TEST

A\&D TM2430EX oscillometric devices (A\&D Company Limited, Tokyo, Japan).

I- Hypothalamic amenorrhea; II- Hyperandrogenic polycystic ovary syndrome; III- Non-hyperandrogenic polycystic ovary syndrome; IV- Trained women without ovulatory dysfunction; V- Non-hyperandrogenic healthy women

Percutaneous biopsy PROCEDURE

Subcutaneous fat tissue and muscle tissue for proteomics an gene expression studies.

I- Hypothalamic amenorrhea; II- Hyperandrogenic polycystic ovary syndrome; III- Non-hyperandrogenic polycystic ovary syndrome; IV- Trained women without ovulatory dysfunction; V- Non-hyperandrogenic healthy women

Cardiovascular autonomic function studies DIAGNOSTIC_TEST

Parasympathetic and sympathetic responses to deep breathing, Valsalva's maneuver and orthostatism.

I- Hypothalamic amenorrhea; II- Hyperandrogenic polycystic ovary syndrome; III- Non-hyperandrogenic polycystic ovary syndrome; IV- Trained women without ovulatory dysfunction; V- Non-hyperandrogenic healthy women

Oral smear and feces specimen DIAGNOSTIC_TEST

Microbiome studies.

I- Hypothalamic amenorrhea; II- Hyperandrogenic polycystic ovary syndrome; III- Non-hyperandrogenic polycystic ovary syndrome; IV- Trained women without ovulatory dysfunction; V- Non-hyperandrogenic healthy women

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Patients with exercise-associated functional amenorrhea and polycystic ovary syndrome will be consecutively recruited from our Reproductive Endocrinolgy clinic. Those premenopausal adult women are referred to clinic because of symptoms of functional androgen excess such as hirsutism or menstrual dysfunction. The control group (Groups IV and V) will include healthy female volunteers recruited - contemporarily with the recruitment of patients - from the hospital's staff and overweight or obese women seeking medical attention in our department.

You may qualify if:

• Group I
• Body mass index between 18.5 and 25.0 kg/m2.
• Group 1 ovulatory dysfunction \[World Health Organization (WHO) classification\].
• Normal/low gonadotrophin levels \[follicle-stimulating hormone (FSH) and luteinizing (LH) \< 10 IU/l\] and low estradiol (\< 50 pg/ml).
• Moderate-vigorous intensity physical activity (\> 5 hours per week) plus low energy availability (\< 30 kcal/per kg of lean mass).
• Informed consent signed.
• Group II:
• Polycystic ovary syndrome phenotype I, II and III \[National Institute of Health (NIH)-2012\] with hyperandrogenemia (http://prevention.nih.gov/workshops/2012/resources.aspx).
• Body mass index between 18.5 and 40.0 kg/m2.
• Informed consent signed.
• Group III:
• Polycystic ovary syndrome phenotype IV (NIH-2012) (http://prevention.nih.gov/workshops/2012/resources.aspx).
• Body mass index between 18.5 and 40.0 kg/m2.
• Informed consent signed.
• Group IV:

You may not qualify if:

• Asherman's syndrome or outflow tract disorders.
• Current smoking or alcohol intake \> 40 g per day.
• Previous diagnosis of glucose intolerance, hypertension, dyslipidemia, known heart or lung diseases, kidney disease, liver disease, celiac disease or any other malabsorptive condition, chronic inflammatory disease or malignancy.

Sponsors & Collaborators

• Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal: lead
• Instituto de Salud Carlos III: collaborator
• University of Alcala: collaborator

Study Sites (1)

Endocrinology and Nutrition

Madrid, Madrid, 28034, Spain

RECRUITING

Related Publications (27)

• Ortiz-Flores AE, Luque-Ramirez M, Fernandez-Duran E, Alvarez-Blasco F, Escobar-Morreale HF. Diagnosis of disorders of glucose tolerance in women with polycystic ovary syndrome (PCOS) at a tertiary care center: fasting plasma glucose or oral glucose tolerance test? Metabolism. 2019 Apr;93:86-92. doi: 10.1016/j.metabol.2019.01.015. Epub 2019 Jan 30.

  PMID: 30710572 BACKGROUND

• Luque-Ramirez M, Jimenez-Mendiguchia L, Garcia-Cano A, Fernandez-Duran E, de Dios Rosa V, Nattero-Chavez L, Ortiz-Flores AE, Escobar-Morreale HF. Certified testosterone immunoassays for hyperandrogenaemia. Eur J Clin Invest. 2018 Dec;48(12):e13029. doi: 10.1111/eci.13029. Epub 2018 Oct 8.

  PMID: 30229887 BACKGROUND

• Insenser M, Murri M, Del Campo R, Martinez-Garcia MA, Fernandez-Duran E, Escobar-Morreale HF. Gut Microbiota and the Polycystic Ovary Syndrome: Influence of Sex, Sex Hormones, and Obesity. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2552-2562. doi: 10.1210/jc.2017-02799.

  PMID: 29897462 BACKGROUND

• Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018 May;14(5):270-284. doi: 10.1038/nrendo.2018.24. Epub 2018 Mar 23.

  PMID: 29569621 BACKGROUND

• Escobar-Morreale HF. The Role of Androgen Excess in Metabolic Dysfunction in Women : Androgen Excess and Female Metabolic Dysfunction. Adv Exp Med Biol. 2017;1043:597-608. doi: 10.1007/978-3-319-70178-3_26.

  PMID: 29224112 BACKGROUND

• Montes-Nieto R, Insenser M, Murri M, Fernandez-Duran E, Ojeda-Ojeda M, Martinez-Garcia MA, Luque-Ramirez M, Escobar-Morreale HF. Plasma thiobarbituric acid reactive substances (TBARS) in young adults: Obesity increases fasting levels only in men whereas glucose ingestion, and not protein or lipid intake, increases postprandial concentrations regardless of sex and obesity. Mol Nutr Food Res. 2017 Nov;61(11). doi: 10.1002/mnfr.201700425. Epub 2017 Aug 29.

  PMID: 28722287 BACKGROUND

• Escobar-Morreale HF, Martinez-Garcia MA, Montes-Nieto R, Fernandez-Duran E, Temprano-Carazo S, Luque-Ramirez M. Effects of glucose ingestion on circulating inflammatory mediators: Influence of sex and weight excess. Clin Nutr. 2017 Apr;36(2):522-529. doi: 10.1016/j.clnu.2016.01.015. Epub 2016 Jan 29.

  PMID: 26874912 BACKGROUND

• Insenser M, Montes-Nieto R, Martinez-Garcia MA, Escobar-Morreale HF. A nontargeted study of muscle proteome in severely obese women with androgen excess compared with severely obese men and nonhyperandrogenic women. Eur J Endocrinol. 2016 Mar;174(3):389-98. doi: 10.1530/EJE-15-0912. Epub 2015 Dec 15.

  PMID: 26671973 BACKGROUND

• Borruel S, Molto JF, Alpanes M, Fernandez-Duran E, Alvarez-Blasco F, Luque-Ramirez M, Escobar-Morreale HF. Surrogate markers of visceral adiposity in young adults: waist circumference and body mass index are more accurate than waist hip ratio, model of adipose distribution and visceral adiposity index. PLoS One. 2014 Dec 5;9(12):e114112. doi: 10.1371/journal.pone.0114112. eCollection 2014.

  PMID: 25479351 BACKGROUND

• Luque-Ramirez M, Escobar-Morreale HF. Polycystic ovary syndrome as a paradigm for prehypertension, prediabetes, and preobesity. Curr Hypertens Rep. 2014 Dec;16(12):500. doi: 10.1007/s11906-014-0500-6.

  PMID: 25304109 BACKGROUND

• Escobar-Morreale HF, Alvarez-Blasco F, Botella-Carretero JI, Luque-Ramirez M. The striking similarities in the metabolic associations of female androgen excess and male androgen deficiency. Hum Reprod. 2014 Oct 10;29(10):2083-91. doi: 10.1093/humrep/deu198. Epub 2014 Aug 7.

  PMID: 25104855 BACKGROUND

• Murri M, Insenser M, Luque M, Tinahones FJ, Escobar-Morreale HF. Proteomic analysis of adipose tissue: informing diabetes research. Expert Rev Proteomics. 2014 Aug;11(4):491-502. doi: 10.1586/14789450.2014.903158. Epub 2014 Mar 31.

  PMID: 24684164 BACKGROUND

• Murri M, Insenser M, Escobar-Morreale HF. Metabolomics in polycystic ovary syndrome. Clin Chim Acta. 2014 Feb 15;429:181-8. doi: 10.1016/j.cca.2013.12.018. Epub 2013 Dec 22.

  PMID: 24368231 BACKGROUND

• Luque-Ramirez M, Marti D, Fernandez-Duran E, Alpanes M, Alvarez-Blasco F, Escobar-Morreale HF. Office blood pressure, ambulatory blood pressure monitoring, and echocardiographic abnormalities in women with polycystic ovary syndrome: role of obesity and androgen excess. Hypertension. 2014 Mar;63(3):624-9. doi: 10.1161/HYPERTENSIONAHA.113.02468. Epub 2013 Dec 9.

  PMID: 24324038 BACKGROUND

• Escobar-Morreale HF. Reproductive endocrinology: Menstrual dysfunction--a proxy for insulin resistance in PCOS? Nat Rev Endocrinol. 2014 Jan;10(1):10-1. doi: 10.1038/nrendo.2013.232. Epub 2013 Nov 26. No abstract available.

  PMID: 24275746 BACKGROUND

• Insenser M, Escobar-Morreale HF. Proteomics and polycystic ovary syndrome. Expert Rev Proteomics. 2013 Oct;10(5):435-47. doi: 10.1586/14789450.2013.837665. Epub 2013 Oct 3.

  PMID: 24087928 BACKGROUND

• Murri M, Insenser M, Bernal-Lopez MR, Perez-Martinez P, Escobar-Morreale HF, Tinahones FJ. Proteomic analysis of visceral adipose tissue in pre-obese patients with type 2 diabetes. Mol Cell Endocrinol. 2013 Aug 25;376(1-2):99-106. doi: 10.1016/j.mce.2013.06.010. Epub 2013 Jun 18.

  PMID: 23791845 BACKGROUND

• Luque-Ramirez M, Martinez-Garcia MA, Montes-Nieto R, Fernandez-Duran E, Insenser M, Alpanes M, Escobar-Morreale HF. Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge. Hum Reprod. 2013 Jul;28(7):1908-18. doi: 10.1093/humrep/det097. Epub 2013 Apr 4.

  PMID: 23559188 BACKGROUND

• Insenser M, Montes-Nieto R, Murri M, Escobar-Morreale HF. Proteomic and metabolomic approaches to the study of polycystic ovary syndrome. Mol Cell Endocrinol. 2013 May 6;370(1-2):65-77. doi: 10.1016/j.mce.2013.02.009. Epub 2013 Feb 17.

  PMID: 23422073 BACKGROUND

• Borruel S, Fernandez-Duran E, Alpanes M, Marti D, Alvarez-Blasco F, Luque-Ramirez M, Escobar-Morreale HF. Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab. 2013 Mar;98(3):1254-63. doi: 10.1210/jc.2012-3698. Epub 2013 Feb 5.

  PMID: 23386652 BACKGROUND

• Montes-Nieto R, Insenser M, Martinez-Garcia MA, Escobar-Morreale HF. A nontargeted proteomic study of the influence of androgen excess on human visceral and subcutaneous adipose tissue proteomes. J Clin Endocrinol Metab. 2013 Mar;98(3):E576-85. doi: 10.1210/jc.2012-3438. Epub 2013 Jan 24.

  PMID: 23348399 BACKGROUND

• Alvarez-Blasco F, Luque-Ramirez M, Escobar-Morreale HF. Diet composition and physical activity in overweight and obese premenopausal women with or without polycystic ovary syndrome. Gynecol Endocrinol. 2011 Dec;27(12):978-81. doi: 10.3109/09513590.2011.579658. Epub 2011 May 24.

  PMID: 21609197 BACKGROUND

• Insenser M, Escobar-Morreale HF. Application of proteomics to the study of polycystic ovary syndrome. J Endocrinol Invest. 2011 Dec;34(11):869-75. doi: 10.3275/8108. Epub 2011 Nov 21.

  PMID: 22104628 BACKGROUND

• Escobar-Morreale HF, Samino S, Insenser M, Vinaixa M, Luque-Ramirez M, Lasuncion MA, Correig X. Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: plasma metabolomic approach using GC-MS. Clin Chem. 2012 Jun;58(6):999-1009. doi: 10.1373/clinchem.2011.176396. Epub 2012 Mar 16.

  PMID: 22427353 BACKGROUND

• Insenser M, Montes-Nieto R, Vilarrasa N, Lecube A, Simo R, Vendrell J, Escobar-Morreale HF. A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity. Mol Cell Endocrinol. 2012 Nov 5;363(1-2):10-9. doi: 10.1016/j.mce.2012.07.001. Epub 2012 Jul 14.

  PMID: 22796336 BACKGROUND

• Murri M, Luque-Ramirez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update. 2013 May-Jun;19(3):268-88. doi: 10.1093/humupd/dms059. Epub 2013 Jan 9.

  PMID: 23303572 BACKGROUND

• Martinez-Garcia MA, Montes-Nieto R, Fernandez-Duran E, Insenser M, Luque-Ramirez M, Escobar-Morreale HF. Evidence for masculinization of adipokine gene expression in visceral and subcutaneous adipose tissue of obese women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab. 2013 Feb;98(2):E388-96. doi: 10.1210/jc.2012-3414. Epub 2013 Jan 21.

  PMID: 23337724 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Serum Plasma Whole blood samples Subcutaneous adipose tissue by percutaneous biopsy Muscle tissue by percutaneous biopsy Feces Oral smear

MeSH Terms

Conditions

Polycystic Ovary Syndrome; Motor Activity; Hyperandrogenism

Interventions

Physical Examination; Blood Pressure Monitoring, Ambulatory

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Behavior; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Diagnostic Techniques and Procedures; Diagnosis; Blood Pressure Determination; Diagnostic Techniques, Cardiovascular; Monitoring, Ambulatory; Monitoring, Physiologic

Study Officials

• Héctor F Escobar-Morreale, PhD, MD

  Diabetes, Obesity and Human Reproduction Research Group (CIBERDEM), Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

  PRINCIPAL INVESTIGATOR

• Manuel Luque-Ramírez, PhD, MD

  Diabetes, Obesity and Human Reproduction Research Group (CIBERDEM), Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alejandra Quintero Tobar

CONTACT

34913369029; mariaalejandra.quintero@salud.madrid.org

Sara de Lope Quiñones

CONTACT

34913369029; sara.lope@salud.madrid.org

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2019
• First Posted: February 15, 2019
• Study Start: January 31, 2020
• Primary Completion: June 30, 2025
• Study Completion: December 31, 2025
• Last Updated: August 12, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Data will become available at the time of the first manuscript submission.
• Access Criteria: Public access

Locations

ES (1)