Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12621001656820
Ethics application status
Approved
Date submitted
29/10/2021
Date registered
1/12/2021
Date last updated
15/04/2024
Date data sharing statement initially provided
1/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Exploring the Impact of Sex Hormones and Obesity on Asthma Outcomes in Women with Asthma
Scientific title
Exploring the Impact of Sex Hormones and Obesity on Asthma Outcomes in Women with Asthma
Secondary ID [1] 305694 0
None
Universal Trial Number (UTN)
Trial acronym
SHE-Asthma: Sex Hormone Effects on Asthma Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 324168 0
Condition category
Condition code
Respiratory 321641 321641 0 0
Asthma
Diet and Nutrition 330245 330245 0 0
Obesity

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Study Groups:
Group 1: Pre-menopause not using the oral contraceptive pill (OCP), non-obese
Group 2: Pre-menopause not using the OCP, obese
Group 3: Pre-menopause using the OCP, non-obese
Group 4: Pre-menopause using the OCP, obese
Group 5: Post-menopause, non-obese
Group 6: Post-menopause, obese

Assessment Schedule:
Groups 1 and 2 will attend THREE study visits as follows:
Each visit will be completed at the same time of day for each participant and the timing will be based on the results of ovulation test strips used from day 10 of the menstrual cycle. Day 1 is defined as the first day of menstruation.
- Visit E: Estrogen surge (approximately Day 10-14 of menstrual cycle).
- Visit P: Progesterone surge (approximately Day 19-23 of the menstrual cycle; 5-9 days after ovulation).
- Visit L: Low estrogen/progesterone: Visit L will be completed between 12-16 days post-ovulation (up to and including Day 2 of the following menstrual cycle).

Groups 3 and 4 will attend ONE study visit between Day 21-28 of their menstrual cycle (during WEEK THREE of their active pill). Day 1 is defined as the first day of taking the placebo pill. Women who are taking the OCP continuously (without the placebo pills) can complete their visit at any point.

Group 5 and 6 will attend ONE study visit.

Screening Visit: The screening visit is anticipated to take 1.5 hours. Participants will be screened for study eligibility. This visit will include medical history, medication usage, height, weight, lung function, asthma control and blood pressure. It will also include a mannitol challenge and/or measurement of bronchodilator response (post-bronchodilator FEV1 15 minutes following administration of 400µg salbutamol), if required to confirm variable airflow obstruction (VAO).

Pre-menopausal participants not using the OCP will be provided with a peak flow meter to take home and a link to complete an online patient diary. This diary will begin on day 1 of the menstrual cycle (first day of menstruation). Participants will also be provided with 10 Ovulation Test Strips.

Study Visit: The study visit is anticipated to take 2 hours. Participants will be instructed to withhold their asthma medications for 6-24 hours and antihistamine medications for 3 days. Participants will have their weight checked, a venous blood sample collected, and spirometry will be performed. Sputum induction will be performed using mannitol. Body composition and bone density will be measured by dual-energy x-ray absorptiometry (DXA). Asthma, menstrual, dietary and physical activity questionnaires will be completed.

Additional Study Visits (Groups 1 and 2 only; Visit E and P): The additional study visits are anticipated to take 2 hours each. At these visits, participants will perform all procedures as outlined above, except for DXA which will not be performed (i.e. for groups 1 and 2, DXA will only be performed at Visit L).
Intervention code [1] 322083 0
Not applicable
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 329414 0
Asthma Control Questionnaire score (ACQ7)
Timepoint [1] 329414 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [1] 402513 0
Sputum cell counts
Timepoint [1] 402513 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [2] 402514 0
Asthma medication use using a study-specific questionnaire.
Timepoint [2] 402514 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [3] 402515 0
Lung function (FEV1, FVC) measured by spirometry.
Timepoint [3] 402515 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [4] 402516 0
Plasma interleukin-6
Timepoint [4] 402516 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [5] 402517 0
Plasma TNF-alpha
Timepoint [5] 402517 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [6] 402518 0
Plasma C-reactive protein
Timepoint [6] 402518 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [7] 402519 0
PBMC gene expression of IL-5
Timepoint [7] 402519 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [8] 402520 0
PBMC gene expression of GLUT1
Timepoint [8] 402520 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [9] 402521 0
Peripheral blood immune cell counts
Timepoint [9] 402521 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [10] 403389 0
PBMC expression of IL-13
Timepoint [10] 403389 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [11] 403390 0
Sputum cell gene expression of IL-5
Timepoint [11] 403390 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [12] 403391 0
Sputum cell gene expression of IL-13
Timepoint [12] 403391 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [13] 403392 0
PBMC gene expression of HK
Timepoint [13] 403392 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [14] 403393 0
PBMC gene expression of PKM1
Timepoint [14] 403393 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [15] 403394 0
PBMC gene expression of PKM2
Timepoint [15] 403394 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [16] 403395 0
Sputum cell gene expression of GLUT1
Timepoint [16] 403395 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [17] 403396 0
Sputum cell gene expression of HK
Timepoint [17] 403396 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [18] 403397 0
Sputum cell gene expression of PKM1
Timepoint [18] 403397 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [19] 403398 0
Sputum cell gene expression of PKM2
Timepoint [19] 403398 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [20] 403402 0
Body composition (regional and total fat mass and fat free mass) measured using dual-energy x-ray absorptiometry (DXA)
Timepoint [20] 403402 0
Baseline
Secondary outcome [21] 403404 0
Waist circumference, measured using an inelastic tape measure.
Timepoint [21] 403404 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [22] 403405 0
Dietary intake measured by 24 hour dietary intake recall
Timepoint [22] 403405 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [23] 403406 0
Food cravings using the Food Cravings Questionnaire - State (FCQ-S)
Timepoint [23] 403406 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [24] 403407 0
Physical activity, measured using the International Physical Activity Questionnaire (IPAQ)
Timepoint [24] 403407 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [25] 403408 0
Asthma-related quality of life, using the Juniper asthma-related quality of life questionnaire (AQLQ)
Timepoint [25] 403408 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [26] 403409 0
Lung function, measured using a peak flow meter
Timepoint [26] 403409 0
Daily for an entire menstrual cycle (groups 1 and 2 only)
Secondary outcome [27] 403410 0
Menstrual symptom diary, using a study-specific diary
Timepoint [27] 403410 0
Daily for an entire menstrual cycle (groups 1 and 2 only)
Secondary outcome [28] 403411 0
Asthma symptoms, using the Asthma Control Diary
Timepoint [28] 403411 0
Daily for an entire menstrual cycle (groups 1 and 2 only)
Secondary outcome [29] 434049 0
Lung function (R5, R20, X5, AX), measured by the forced oscillation technique (FOT)
Timepoint [29] 434049 0
Secondary outcome [30] 434050 0
Lung function (R5, R20, X5, AX), measured by the forced oscillation technique (FOT)
Timepoint [30] 434050 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [31] 434051 0
Fractional exhaled nitric oxide (FeNO) concentration using a FeNO machine (a mouthpiece with a tube attached to a measurement device)
Timepoint [31] 434051 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)
Secondary outcome [32] 434052 0
Fractional exhaled nitric oxide (FeNO) concentration using a FeNO machine (a mouthpiece with a tube attached to a measurement device)
Timepoint [32] 434052 0
Baseline (and change at visit E vs visit P vs visit L for groups 1 and 2)

Eligibility
Key inclusion criteria
1. Physician diagnosed asthma
2. Female >=18 years of age
3. Confirmed variable airflow obstruction at screening visit or documented within the past 10 years:
• Bronchodilator response >200mL OR >12% (post-bronchodilator FEV1 following administration of 400µg salbutamol, pMDI with spacer; after 10 minutes, or following administration of nebulised Ventolin)
• Airway hyperresponsiveness (in response to any standard challenge agent)
• Peak flow variability >12% when monitored over at least one week
• FEV1 variability >12% (between two FEV1 values measured within two months of each other)
If not observed at screening visit or documented in file, then provide peak flow meter for two weeks monitoring, if required.
4. Using a combined monophasic oral contraceptive pill (Groups 3 and 4 only).
5. Stable disease with no respiratory infection, asthma exacerbation, corticosteroid burst (>10mg/day) or use of antibiotics to treat an asthma exacerbation, or change in asthma therapy in the four weeks preceding visit 1.
6. Able to provide written informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Asthma is not the primary respiratory diagnosis
2. Treatment with oral corticosteroids in the preceding four weeks (unless a low dose is being taken on a long-term basis: >=10mg for >3 months)
3. Current smoker, or smoked in the last six months
4. Perimenopausal (menstrual cycle less frequent or irregular with symptoms of estrogen insufficiency)
5. Pregnancy or breastfeeding
6. Endocrine disorder resulting in amenorrhoea (e.g. thyroid disease, hyper-prolactinoma or known pituitary disorder)
7. Irregular menstrual cycle (variability >15 days between shortest and longest cycle over 12 months or cycle length outside the range of 26-34 days)
8. Hormonal contraceptive use (other than the combined monophasic oral contraceptive pill for Groups 3 and 4)
9. Current lung cancer or other blood, lymphatic or solid organ malignancy
10. NSAID burst within 48 hours of study visit
11. Participant has a clinically important medical illness (including serious psychological disorders) likely to interfere with management or participation in the study

Study design
Purpose
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Aim 1: The sample will consist of pre-menopausal and post-menopausal women (i.e. all 6 groups). Linear models will be used to examine the association between hormone levels and the primary outcome (asthma control), adjusted for menopausal status, asthma severity, OCP use and body mass index (BMI). The modifying effect of obesity will be assessed by an interaction term with each hormone.

Aim 2: The sample will consist of pre-menopausal women not using OCP (measurements taken at all 3 visits). A linear mixed model with a random effect for menstrual phase will be used to examine the association of hormone levels and asthma control over the menstrual cycle, adjusted for asthma severity and BMI.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
17/01/2022
Actual
5/03/2024
Date of last participant enrolment
Anticipated
31/12/2025
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
150
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20999 0
Hunter Medical Research Institute - New Lambton Heights
Recruitment postcode(s) [1] 35830 0
2305 - New Lambton Heights

Funding & Sponsors
Funding source category [1] 310053 0
Charities/Societies/Foundations
Name [1] 310053 0
Thoracic Society of Australia and New Zealand
Country [1] 310053 0
Australia
Funding source category [2] 310055 0
Charities/Societies/Foundations
Name [2] 310055 0
John Hunter Hospital Charitable Trust
Country [2] 310055 0
Australia
Primary sponsor type
University
Name
The University of Newcastle
Address
University Drive, University of Newcastle, Callaghan, NSW, 2308
Country
Australia
Secondary sponsor category [1] 311105 0
Individual
Name [1] 311105 0
Prof Lisa Wood
Address [1] 311105 0
Room 606, Medical Sciences Building,
The University of Newcastle, University Drive,
Callaghan, NSW, 2308
Country [1] 311105 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309747 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 309747 0
Level 3, POD, HMRI, Lot 1 Kookaburra Circuit, New Lambton, NSW, 2305
Ethics committee country [1] 309747 0
Australia
Date submitted for ethics approval [1] 309747 0
21/06/2021
Approval date [1] 309747 0
06/09/2021
Ethics approval number [1] 309747 0
2021/ETH01221

Summary
Brief summary
Purpose of Study
In Australia, asthma affects >10% of adults and costs $28 billion per year. The highest burden occurs in obese, older women, with non-Type 2 (T2), non-eosinophilic severe asthma, which is resistant to corticosteroids. Severe, steroid-resistant disease is the biggest unmet need in asthma therapy, as patients have greatly reduced quality of life, with poor asthma control, frequent exacerbations and side effects from high-dose steroids. Severe asthma also disproportionately contributes to the economic burden of the disease, accounting for >50% of asthma costs. There are no effective therapies for non-T2 obesity-associated asthma, as the underlying mechanisms are largely unknown.

We have pilot data showing that the oral contraceptive pill (OCP) may be more effective than corticosteroids in controlling asthma in women, via effects on inflammation and metabolism (immunometabolism). We will extend upon these findings by examining the relationships between sex hormones, immunometabolism and asthma control in a well-defined clinical population of women with and without obesity.

Hypothesis
Female sex hormones play a major role in asthma control and asthma severity in women with comorbid asthma and obesity.

Aims
Aim 1 – Observational cross-sectional study:
To characterise the association between female sex hormone levels, inflammatory and metabolic markers, and asthma control in women with and without obesity.

Aim 2 – Observational longitudinal study:
To examine the effect of hormonal fluctuations on asthma control in pre-menopausal women with and without obesity.
Trial website
www.hmri.org.au/shestudy
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 115250 0
Prof Lisa Wood
Address 115250 0
Room 606, Medical Sciences Building,
The University of Newcastle, University Drive,
Callaghan, NSW, 2308
Country 115250 0
Australia
Phone 115250 0
+61 2 4921 7485
Fax 115250 0
Email 115250 0
[email protected]
Contact person for public queries
Name 115251 0
Dr Hayley Scott
Address 115251 0
Priority Research Centre for Healthy Lungs, The University of Newcastle
Level 2 West, HMRI Building
Lot 1 Kookaburra Circuit,
New Lambton Heights NSW 2305
Country 115251 0
Australia
Phone 115251 0
+61 2 4042 0113
Fax 115251 0
Email 115251 0
[email protected]
Contact person for scientific queries
Name 115252 0
Dr Hayley Scott
Address 115252 0
Priority Research Centre for Healthy Lungs, The University of Newcastle
Level 2 West, HMRI Building
Lot 1 Kookaburra Circuit,
New Lambton Heights NSW 2305
Country 115252 0
Australia
Phone 115252 0
+61 2 4042 0113
Fax 115252 0
Email 115252 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.