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

Sponsor

Laval University (Other)

Overall Status

Recruiting

CT.gov ID

NCT03981341

Collaborator

V Joseph (Other), C Minville (Other), C Rheaume (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sleep Apnea Post Menopausal Oxidative Stress	Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene)	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open label treatment for 3 months in two parallel groups (post menopausal women without and with sleep apnea)Open label treatment for 3 months in two parallel groups (post menopausal women without and with sleep apnea)

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Nov 1, 2019

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Post menopausal sleep apnea Post menopausal women with severe sleep apnea	Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene) Drug given for 3 months in each participant
Experimental: Post menopausal non sleep apnea Post menopausal women without sleep apnea	Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene) Drug given for 3 months in each participant

Arm

Intervention/Treatment

Experimental: Post menopausal sleep apnea

Post menopausal women with severe sleep apnea

Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene)

Drug given for 3 months in each participant

Experimental: Post menopausal non sleep apnea

Post menopausal women without sleep apnea

Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene)

Drug given for 3 months in each participant

Outcome Measures

Primary Outcome Measures

oxidative stress [Changes between baseline and after 3 months drug treatment]
Advanced Oxidation Protein Products

Secondary Outcome Measures

glucose homeostasis [Changes between baseline and after 3 months drug treatment]
HOMA-IR
total cholesterol [Changes between baseline and after 3 months drug treatment]
serum cholesterol
triglycerides [Changes between baseline and after 3 months drug treatment]
serum triglycerides
aspartate aminotransferase (AST) [Changes between baseline and after 3 months drug treatment]
serum aspartate aminotransferase
gamma-glutamyl transferase (∂-GT) [Changes between baseline and after 3 months drug treatment]
serum gamma-glutamyl transferase
Orexin-A [Changes between baseline and after 3 months drug treatment]
Orexin-A
C-reactive protein [Changes between baseline and after 3 months drug treatment]
serum C-reactive protein
arterial blood pressure [Changes between baseline and after 3 months drug treatment]
resting arterial blood pressure
heart rate variability [Changes between baseline and after 3 months drug treatment]
24-holter

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 65 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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