Asthma Severity in Women: The Influence of Training and Menopause

Study Overview
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Brief Summary
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Introduction: Late-onset asthma in women is characterized by poor disease control and reduced quality of life despite intensive treatment with inhaled steroid and beta2-agonist. The condition is further worsened at menopause due to the loss of estrogen leading to increased asthma exacerbation frequency, increased airway inflammation and decreased lung function. Exercise training may increase disease control of asthma patients, but to what extent the same effect is seen in postmenopausal women with late-onset asthma is unknown. These asthma patients represent a phenotype that is characterized by low eosinophilic airway inflammation, severe symptoms, moderate obesity and poor response to conventional medicine. Thus, our hypothesis is that regular physical exercise is especially associated with an improvement in asthma control in this phenotype. The aim of this project is to test this hypothesis and to assess whether an improvement is associated with reduced local and systemic inflammation, change in heart function, lung function and/or body composition. Study design: 40 postmenopausal women with late-onset asthma are recruited via the outpatient clinic at the Respiratory Department at Bispebjerg Hospital and through advertisement. The participants are randomized 1:1 into two groups. One group performs supervised exercise training (spinning) three times per week for 12 weeks while the other group is a control group. Before and after the intervention asthma control, local and systemic inflammation, heart function and body composition is measured. Results: Analysis will be performed to detect changes within and between the groups before and after intervention. Primary outcome is change in ACQ (Asthma Control Questionnaire). Local and systemic inflammation is measured by changes in bronchial challenge to methacholine, sputum cell count and blood tests. Furthermore, secondary outcomes include change in heart function measured by stress-echocardiography and change in body composition measured by Dual-energy X-ray absorptiometry (DEXA). Conclusion: There are to date no prospective studies that can support recommendations containing asthma rehabilitation with supervised regular physical activity for postmenopausal women. Thus, this study will provide novel understanding of the importance of physical activity in a chronic disease such as asthma.

Detailed Description
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Overall study design The study is a single-blinded randomized controlled intervention study. Forty postmenopausal women with late-onset asthma (>16 years at debut) are recruited from the asthma outpatient-clinic at Bispebjerg Hospital or other hospital/practitioner in the region and/or by advertisement. The participants are block-randomized into two groups of 20, where one group is control and the other undergoes a period of regular exercise training. The investigators will be blinded and will not know whether the subjects have trained or not. Detailed study design Participants allocated to the exercise training group undergo a training intervention consisting of 45 minutes of intermittent high intensity aerobic spinning training three times per week for 12 weeks. Participants allocated to the control group will continue usual care without training. No changes to current treatment will be made by the investigators on any of the groups. The training will consist of short periods of high intensity intervals where subjects reach above 80% of maximal oxygen consumption. Spinning sessions will be fully supervised by trained instructors with a bachelor of sports and science or bachelor of medicine and conducted in the Department of Nutrition, Exercise and Sports, University of Copenhagen. Subjects will wear heart rate monitors to ensure adherence to the training protocol. Within two weeks, before and after the intervention, participants from both groups undergo 3 days of testing. To ensure equal compliance with asthma medication both groups will receive daily electronic reminders. Once a week, all participants will be asked about their compliance to their medication.

Official Title
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The ATOM Study: Asthma Severity in Women: The Influence of Training and Menopause

Conditions
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Late-Onset Asthma

Intervention / Treatment
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* Behavioral: Aerobic exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Late onset asthma (Debut ≥ 16 years of age) ACQ ≥ 1.25 Daily treatment for asthma (GINA 2 and above) Age 45 - 75 Postmenopausal defined as no menstruation for 6 months, Serum Follicle stimulating hormone >20 International Units per Liter and P-Estradiol nmol/L <0.09 BMI 25 - 35 Positive bronchial challenge to methacholine, mannitol or positive reversibility to beta2-agonist now or historically Untrained (no participation in vigorous exercise for more than 1 hour per week during the last 2 months) Capable of exercising on a bike Exclusion Criteria: Unable to speak and understand Danish or English. Current or former smokers (>6 months cessation) with >20 years of daily smoking with 20 cigarettes per day. Other respiratory disease of clinical significance Cardiovascular: Unstable ischemic heart disease, myocardial infarction within the last 12 months, symptomatic heart failure (EF <40%), symptomatic heart arrhythmia (documented with ECG), uncontrolled hypertension (>155/100) Any disorder that is not stable and in the opinion of the investigator could affect the safety of the subject throughout the study Subjects, who by investigators determination, will not be able to adhere to study protocol

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, outcome assessor blinded, controlled trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerobic exercise intervention<br>Aerobic exercise by high intensity interval training, 3 times per week for 12 weeks | Behavioral: Aerobic exercise<br>* High Intensity Interval Training (HIIT)<br>|
| No Intervention: Control group<br>No intervention for 12 weeks | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma control - Asthma Control Questionnaire (ACQ) | Changes in Asthma Control Questionnaire (ACQ) 7-point scale (0=no impairment, 6= maximum impairment for symptoms and rescue use) | -21 to 0 days before intervention and 0 to 14 days post intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart Rate Variability | Changes in: - Heart rate variability | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart rhytm | Changes in: - Heart rhythm | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart Rate | Changes in: - electrocardiography | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Strain | Measured by stress-echocardiography - Strain | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Ejection fraction | Measured by stress-echocardiography - Ejection fraction | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Tricuspid annular plane systolic excursion | Measured by stress-echocardiography - Tricuspid annular plane systolic excursion | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Right ventricular function | Measured by stress-echocardiography - Right ventricular function | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Pulmonary pressure | Measured by stress-echocardiography - Pulmonary pressure | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Lung covered cor | Measured by stress-echocardiography - Lung covered cor | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Blood pressure | Blood pressure | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Cardiac output | Cardiac output | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Stroke volume | Stroke volume | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Heart function - Total peripheral resistance | Total peripheral resistance | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Systemic inflammation - Leukocytes + differential cell count count | Changes in - Leukocytes + differential cell count count | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Systemic inflammation - Interleukin 6 | Changes in - Interleukin 6 | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Systemic inflammation - Interleukin 8 | Changes in - Interleukin 8 | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Systemic inflammation | Changes in - Other interleukins | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Systemic inflammation - Tumor Necrosis Factor alpha | Changes in - Tumor Necrosis Factor alpha | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Systemic inflammation - Total immunoglobulin E, Specific immunoglobulin E | Changes in Total immunoglobulin E Specific immunoglobulin E | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Systemic inflammation - high sensitivity c reactive protein | Changes in - high sensitivity c reactive protein | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Local airway inflammation - Sputum cell count | Changes in - Sputum cell count | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Local airway inflammation - Fraction of exhaled nitric oxide | Changes in - Fraction of exhaled nitric oxide | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Local airway inflammation - Hyperreactivity to inhaled methacholine | Changes in - Hyperreactivity to inhaled methacholine | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Body Composition | Changes in - Total body fat | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Body Composition | Changes in - Lean body mass | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Body Composition | Changes in - Muscle mass | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Body Composition | Changes in - Weight | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Microbiome | Changes in the microbiota in sputum, oral cavity and nasal cavity before and after the training intervention | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Compliance - Foster score | Change in - Foster score Answers describe last weeks medicine use. Answers range form 0/7 - 7/7 with low values being worse. | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Other asthma related questionnaires - Nijmegen questionnaire | Changes in - Nijmegen questionnaire Values range from 0-64 and values below 20 are considered normal. | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Other asthma related questionnaires - Mini Asthma Quality of Life Questionnaire (miniAQLQ) | Changes in - Mini Asthma Quality of Life Questionnaire (miniAQLQ) 7-point Likert scale (7 = not impaired at all - 1 = severely impaired). | -21 to 0 days before intervention and 0 to 14 days post intervention | 
| Other asthma related questionnaires - Hospital Anxiety and Depression Scale (HADS) 2 items with 7 questions regarding anxiety and depression. (0 = no sign of depression/anxiety, 21 = maximal signs of anxiety/depression) | Changes in - Hospital Anxiety and Depression Scale (HADS) | -21 to 0 days before intervention and 0 to 14 days post intervention |