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出境医 / 临床实验 / Impact of Estrogen + Estradiol Receptor Alpha Modulator Therapy on Oxidative Stress in Post-menopausal Women With and Without Sleep Apnea (Alpha MenoX)

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

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
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated 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)
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 : November 1, 2019
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : October 1, 2021
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
Outcome Measures
Primary Outcome Measures :
  1. oxidative stress [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    Advanced Oxidation Protein Products


Secondary Outcome Measures :
  1. glucose homeostasis [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    HOMA-IR

  2. total cholesterol [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum cholesterol

  3. triglycerides [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum triglycerides

  4. aspartate aminotransferase (AST) [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum aspartate aminotransferase

  5. gamma-glutamyl transferase (∂-GT) [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum gamma-glutamyl transferase

  6. Orexin-A [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    Orexin-A

  7. C-reactive protein [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum C-reactive protein

  8. arterial blood pressure [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    resting arterial blood pressure

  9. heart rate variability [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    24-holter


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   45 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   post menopausal women
Accepts Healthy Volunteers:   No
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
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Frederic Series 418 656 8711 ext 5513 frederic.series@med.ulaval.ca

Locations
Layout table for location information
Canada
IUCPQ Recruiting
Quebec, Canada, G1V 4G5
Contact: Frederic Series, MD    418 656 8711 ext 5513    frederic.seriesd@med.ulaval.ca   
Principal Investigator: Frederic Series, MD         
Sponsors and Collaborators
Laval University
V Joseph
C Minville
C Rheaume
Tracking Information
First Submitted Date  ICMJE May 22, 2019
First Posted Date  ICMJE June 10, 2019
Last Update Posted Date November 13, 2019
Actual Study Start Date  ICMJE November 1, 2019
Estimated Primary Completion Date July 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 7, 2019) 		oxidative stress [ Time Frame: Changes between baseline and after 3 months drug treatment ]
Advanced Oxidation Protein Products
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 8, 2019)
  • glucose homeostasis [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    HOMA-IR
  • total cholesterol [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum cholesterol
  • triglycerides [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum triglycerides
  • aspartate aminotransferase (AST) [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum aspartate aminotransferase
  • gamma-glutamyl transferase (∂-GT) [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum gamma-glutamyl transferase
  • Orexin-A [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    Orexin-A
  • C-reactive protein [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum C-reactive protein
  • arterial blood pressure [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    resting arterial blood pressure
  • heart rate variability [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    24-holter
Original Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2019)
  • glucose homeostasis [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    HOMA-IR
  • total cholesterol [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum cholesterol
  • triglycerides [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum triglycerides
  • aspartate aminotransferase (AST) [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum aspartate aminotransferase
  • gamma-glutamyl transferase (∂-GT) [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum gamma-glutamyl transferase
  • C-reactive protein [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    serum C-reactive protein
  • arterial blood pressure [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    resting arterial blood pressure
  • heart rate variability [ Time Frame: Changes between baseline and after 3 months drug treatment ]
    24-holter
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact of Estrogen + Estradiol Receptor Alpha Modulator Therapy on Oxidative Stress in Post-menopausal Women With and Without Sleep Apnea
Official Title  ICMJE Impact of Estrogen + Estradiol Receptor Alpha Modulator Therapy on Oxidative Stress in Post-menopausal Women With and Without Sleep Apnea
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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)
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Sleep Apnea
  • Post Menopausal
  • Oxidative Stress
Intervention  ICMJE Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene)
Drug given for 3 months in each participant
Study Arms  ICMJE
  • Experimental: Post menopausal sleep apnea
    Post menopausal women with severe sleep apnea
    Intervention: Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene)
  • Experimental: Post menopausal non sleep apnea
    Post menopausal women without sleep apnea
    Intervention: Drug: Duavive (0.45 estrogens mg and 20 mg bazedoxifene)
Publications *
  • 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):.
  • 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.
  • 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.
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 7, 2019) 		36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2021
Estimated Primary Completion Date July 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: post menopausal women
Ages  ICMJE 45 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Frederic Series 418 656 8711 ext 5513 frederic.series@med.ulaval.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03981341
Other Study ID Numbers  ICMJE IUCPQ220519
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Frédéric Sériès, Laval University
Study Sponsor  ICMJE Laval University
Collaborators  ICMJE
  • V Joseph
  • C Minville
  • C Rheaume
Investigators  ICMJE Not Provided
PRS Account Laval University
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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