Impact of Estrogen + Estradiol Receptor Alpha Modulator Therapy on Oxidative Stress in Post-menopausal Women With and Without Sleep Apnea

Oxidative Stress Clinical Trial

— Alpha MenoX  

Official title:

Impact of Estrogen + Estradiol Receptor Alpha Modulator Therapy on Oxidative Stress in Post-menopausal Women With and Without Sleep Apnea

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03981341
• Other study ID #: IUCPQ220519
• Status: Recruiting
• Phase: Phase 3
• Start date: November 1, 2019
• Est. completion date: December 1, 2023

Study information

• Verified date: April 2022
• Source: Laval University
• Contact: Frederic Series
• Phone: 418 656 8711
• Email: frederic.series[@]med.ulaval.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

One of the most likely mechanisms explaining the sleep apnea (SA)-induced increase in metabolic syndrome is the oxidative stress (OS) induced by intermittent hypoxia (IH). There are clear-cut signs of OS in postmenopausal women that may be further enhanced by SA. In rats exposed to IH, an estradiol receptor alpha agonist decreases the level of OS markers. The aims of this study are to compare OS in apneic and non-apneic postmenopausal women and to demonstrate that OS will improve after 3 months of treatment with ER alpha agonists (Duavive) in apneic post-menopausal women.

Description:

Sleep apnoea (SA) is highly prevalent in general population. It is a sex-specific respiratory disease with a lower incidence in women than in men but it increases after menopause. SA and nocturnal intermittent hypoxia (IH) predict the risks of metabolic syndrome independently of obesity, and in patients without comorbidities, SA is associated with insulin resistance. One of the most likely mechanisms explaining the SA-induced increase in metabolic syndrome is the oxidative stress (OS) induced by IH. There are clear-cut signs of OS in postmenopausal women that may be further enhanced by SA resulting in an increased activity of the sympathetic system as well as damages in adipose tissue, blood vessels, and in the liver. Estradiol is a potent antioxidant hormone. Recent experiments conducted in Dr Joseph laboratory demonstrated that in ovariectomized female rats exposed to IH, an ER alpha agonist decreases the level of "Advanced Oxidation Protein Products", prevents excessive mitochondrial ROS production, and the increase of arterial blood pressure. Oestrogens combined with a tissue-specific estradiol receptor modulators (bazedoxifene) are approved and available in Canada (Duavive) for the treatment of vasomotor symptoms and prevention of osteoporosis associated with menopause. The aims of this study are to compare OS in apneic and non-apneic postmenopausal women and to demonstrate that OS will improve after 3 months of treatment with ER alpha agonists (Duavive) in apneic post-menopausal women. 18 newly diagnosed women with untreated severe SA and 18 without SA will be recruited from the sleep clinic. Eligible subjects will be post-menopausal non-smoking women aged 30 to 65 years with a BMI less/equal to 35 kg.m-2, apnoea + hypopnea index < 15/h (non SA group) or ≥ 30/h (SA group) on a polysomnographic recording. The study will be a prospective comparative trial. Following completion of baseline measurements, subjects will receive 1 tablet of Duavive (0.45 estrogens mg and 20 mg bazedoxifene) daily for 3 months. A follow-up phone call will be completed monthly, and side effects will be recorded. All measurements will be repeated after 3 months of Duavive. The main outcome is the levels of Advanced Oxidation Protein Products and malondialdehyde as a reflect of cellular oxidative damages. The investigators will also measure plasmatic activity of superoxide dismutase and serum nitrite + nitrate levels. Secondary outcomes are related to metabolic (anthropometric variables, biologic markers of glucose homeostasis, lipid profiles, orexin-A and liver function), cardiac health (arterial blood pressure, 24-h heart rate variability to measure cardiac autonomic function) and quality of life. Analysis: Differences between results obtained in each condition will be analysed using ANOVA. Statistical significance will be considered at p<0.05. Considering the changes in OS observed with hormonal therapy in post-menopausal women and those observed with SA treatment, the sample size was determined to be able to demonstrate a 30 % difference in OS between SA and non-apneic women following 3 month of treatment with Duavive with alpha =0.05, 80% power analysis and a 20% drop-out rate. New avenues in postmenauposal hormonal therapy may have a huge impact on morbidity/mortality and a drug therapy should be more easily accepted that CPAP to reach this goal. These results should open the door to an RCT aimed at quantifying benefits of such treatment on metabolic syndrome features.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: December 1, 2023
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 45 Years to 65 Years

Eligibility

Inclusion Criteria:

• post-menopausal women

• aged 45 to 65 years

• BMI less/equal 35 kg.m-2,

• apnoea + hypopnea index (AHI) < 15/h (non SA group) or = 30/h (SA group) on a polysomnographic recording,

• 90% of AHI associated with obstructive events,

• regular exercise, dietary and sleep habits

• free of sleep debt (insomnia, reported habitual sleep time > 6 h/night),

• stable medical condition.

Exclusion Criteria:

• clinically significant diurnal somnolence requiring immediate treatment in SA patients,

• nocturnal hypoventilation (% sleep time below 90% SaO2 > 10 %, PaCO2 > 45 mmHg),

• use of hormonal therapy,

• use of any medication with a respiratory depressant effect (narcotics),

• contraindication to the dug used in the protocol

Related Conditions & MeSH terms

• Apnea
• Oxidative Stress
• Post Menopausal
• Sleep Apnea
• Sleep Apnea Syndromes

Intervention

Drug:
• Duavive (0.45 estrogens mg and 20 mg bazedoxifene)
Drug given for 3 months in each participant

Locations

Country	Name	City	State
Canada	IUCPQ	Quebec

Sponsors (4)

Lead Sponsor	Collaborator
Laval University	C Minville, C Rheaume, V Joseph

Country where clinical trial is conducted

Canada, 

References & Publications (4)

Barrera J, Chambliss KL, Ahmed M, Tanigaki K, Thompson B, McDonald JG, Mineo C, Shaul PW. Bazedoxifene and conjugated estrogen prevent diet-induced obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the reproductive tract. Am J Physiol Endocrinol Metab. 2014 Aug 1;307(3):E345-54. doi: 10.1152/ajpendo.00653.2013. Epub 2014 Jun 17. — View Citation

de Lima AM, Franco CM, de Castro CM, Bezerra Ade A, Ataíde L Jr, Halpern A. Effects of nasal continuous positive airway pressure treatment on oxidative stress and adiponectin levels in obese patients with obstructive sleep apnea. Respiration. 2010;79(5):370-6. doi: 10.1159/000227800. Epub 2009 Jul 3. — View Citation

Laouafa S, Ribon-Demars A, Marcouiller F, Roussel D, Bairam A, Pialoux V, Joseph V. Estradiol Protects Against Cardiorespiratory Dysfunctions and Oxidative Stress in Intermittent Hypoxia. Sleep. 2017 Aug 1;40(8). doi: 10.1093/sleep/zsx104. Erratum in: Sleep. 2020 Jul 13;43(7):. — View Citation

Xue B, Zhao Y, Johnson AK, Hay M. Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species. Am J Physiol Heart Circ Physiol. 2008 Sep;295(3):H1025-H1032. doi: 10.1152/ajpheart.00021.2008. Epub 2008 Jul 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	oxidative stress	Advanced Oxidation Protein Products	Changes between baseline and after 3 months drug treatment
Secondary	glucose homeostasis	HOMA-IR	Changes between baseline and after 3 months drug treatment
Secondary	total cholesterol	serum cholesterol	Changes between baseline and after 3 months drug treatment
Secondary	triglycerides	serum triglycerides	Changes between baseline and after 3 months drug treatment
Secondary	aspartate aminotransferase (AST)	serum aspartate aminotransferase	Changes between baseline and after 3 months drug treatment
Secondary	gamma-glutamyl transferase (?-GT)	serum gamma-glutamyl transferase	Changes between baseline and after 3 months drug treatment
Secondary	Orexin-A	Orexin-A	Changes between baseline and after 3 months drug treatment
Secondary	C-reactive protein	serum C-reactive protein	Changes between baseline and after 3 months drug treatment
Secondary	arterial blood pressure	resting arterial blood pressure	Changes between baseline and after 3 months drug treatment
Secondary	heart rate variability	24-holter	Changes between baseline and after 3 months drug treatment