Clinical trial NCT03981341: Impact of Estrogen + Estradiol Receptor Alpha Modulator Therapy on Oxidative Stress in Post-menopausal Women With and Without Sleep Apnea
Official title: Impact of Estrogen + Estradiol Receptor Alpha Modulator Therapy on Oxidative Stress in Post-menopausal Women With and Without Sleep Apnea
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Sleep Apnea
Post Menopausal
Oxidative Stress
Keywords: sleep apnea
post menopausal
oxidative stress
Lead sponsor: Laval University
Sponsor class: OTHER
Collaborators: name: V Joseph
name: C Minville
name: C Rheaume
First posted: 2019-06-10
Enrollment: 36
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open label treatment for 3 months in two parallel groups (post menopausal women without and with sleep apnea)
Primary purpose: BASIC_SCIENCE

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: oxidative stress
timeFrame: Changes between baseline and after 3 months drug treatment
Secondary outcomes:
measure: glucose homeostasis
timeFrame: Changes between baseline and after 3 months drug treatment
measure: total cholesterol
timeFrame: Changes between baseline and after 3 months drug treatment
measure: triglycerides
timeFrame: Changes between baseline and after 3 months drug treatment
measure: aspartate aminotransferase (AST)
timeFrame: Changes between baseline and after 3 months drug treatment
measure: gamma-glutamyl transferase (∂-GT)
timeFrame: Changes between baseline and after 3 months drug treatment
measure: Orexin-A
timeFrame: Changes between baseline and after 3 months drug treatment
measure: C-reactive protein
timeFrame: Changes between baseline and after 3 months drug treatment
measure: arterial blood pressure
timeFrame: Changes between baseline and after 3 months drug treatment
measure: heart rate variability
timeFrame: Changes between baseline and after 3 months drug treatment
Other outcomes:
Locations:
city: Quebec
country: Canada
facility: IUCPQ
Study officials:
References:
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.
citation: 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.
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.
citation: de Lima AM, Franco CM, de Castro CM, Bezerra Ade A, Ataide 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.