ANZCTR - Registration

Registration number

ACTRN12623000165684

Ethics application status

Approved

Date submitted

8/02/2023

Date registered

17/02/2023

Date last updated

17/02/2023

Date data sharing statement initially provided

17/02/2023

Type of registration

Prospectively registered

Titles & IDs

Public title

Evaluating Testosterone Therapy to Prevent Heart Failure in Women: The ETHEL study.

Scientific title

Evaluating Testosterone Therapy to Prevent Heart Failure in Women: The ETHEL study.

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

ETHEL

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Stage B heart failure with preserved ejection fraction

Condition category

Condition code

Reproductive Health and Childbirth

Menstruation and menopause

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a randomised double-blind placebo-controlled crossover study. Participants will receive either treatment or placebo for 4 months, then receive the alternative study drug for 4 months with a 4-week washout period in between each 4-month treatment cycle. The total duration of participation in this study is 9 months.

Application of active treatment, 1% testosterone cream, 0.5ml (10mg/ml), or placebo cream
applied transdermally daily to upper thigh or buttock by participant for 4 months.
Compliance will be assessed by collection and weighing of returned cream containers at end of treatment period.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo is unmedicated Androfeme 1 base formulation cream containing dl-8- tocopherol acetate (vitamin E), almond oil, butylated hydroxytoluene, carbomer 940, cetomacrogol 1000, cetostearyl alcohol, citric acid -anhydrous, triethanolamine, water purified and Phenonip® - a preservative containing hydroxybenzoates and phenoxyethanol.0.5ml daily applied transdermally to upper thigh or buttock for 4 months.

Control group

Placebo

Outcomes

Primary outcome [1]

The primary outcome will be any change in cardiorespiratory fitness, assessed by change in VO2peak during cardiopulmonary exercise testing (CPET) on a cycle ergometer.

Timepoint [1]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [1]

Any change in body-weight corrected power (W/kg) during a two leg countermovement jump measured via the Leonardo Mechanography Ground Reaction Force Platform.

Timepoint [1]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [2]

Any change in body-weight corrected power (W/kg) during a two leg countermovement jump measured via the Leonardo Mechanography Ground Reaction Force Platform.

Timepoint [2]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [3]

Any change in grip force measured via the Leonardo Mechanography Ground Reaction Force Platform.

Timepoint [3]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [4]

Any change in grip work (endurance) measured via the Leonardo Mechanography Ground Reaction Force Platform.

Timepoint [4]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [5]

Any change in measures of balance (standing with feet together eyes open/closed, tandem stance eyes open/closed, single leg stance eyes open/closed) measured via stabilometry on the Leonardo Mechanography Ground Reaction Force Platform.

Timepoint [5]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [6]

Any change in power during the heel rise test measured via the Leonardo Mechanography Ground Reaction Force Platform.

Timepoint [6]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [7]

Any change in ventricular structure or function assessed by echocardiogram.

Timepoint [7]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [8]

Any change in cardiac structure, function, mass, or ventricular remodelling assessed by cardiac magnetic resonance imaging.

Timepoint [8]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [9]

Any change in serum sex steroid levels (testosterone, estradiol, estrone, dehydroepiandrosterone, dihydrotestosterone).

Timepoint [9]

Change from baseline will be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [10]

Change in overall health status as measured via the short-form 36 questionnaire.

Timepoint [10]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [11]

Change in well-being as measured by the psychological general well-being index.

Timepoint [11]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Secondary outcome [12]

Change in physical activity and sedentary behaviours, measured over 7 days via a hip-worn accelerometer & activity log.

Timepoint [12]

Change will be measured at 4 months post randomisation (at the conclusion of first treatment phase). It will then be measured both before and after the second phase of treatment (i.e. at 5 and 9 months post randomisation).

Eligibility

Key inclusion criteria

- Evidence of Stage B heart failure with reduced functional capacity (<85% age-predicted VO2peak).
- Normal mammogram within the preceding 2 years

Minimum age

60 Years

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

No

Key exclusion criteria

- Heart failure, either documented or undiagnosed with an EF <40% or NTproBNP >400ng/L
- Other cardiac disease (myocardial infarction, angina; known coronary artery disease; valve disease more than moderate)
- Features incompatible with the study design (unlikely to be adherent to follow-up; <12 months life expectancy due to concomitant disease; participation in another clinical trial where blinded treatment would be unacceptable; unable to provide written informed consent)
- Inability to acquire interpretable echo images (uncommon)
- Unstable diabetes (HbA1C>7.5%)
- Estrogen-sensitive cancer
- Use of any drugs or dietary supplements that may affect testosterone effects including, but not limited to systemic antiandrogen therapy (spironolactone; cyproterone acetate; finasteride; minoxidil)
- Treatment with SGLT-2 inhibitors or GLP-1 agonists as indicated
- Recent use of androgen therapy
- Contraindication to exercise
- Inability to speak or understand English

Study design

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

6/03/2023

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

38

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

The Heart Foundation

Country [1]

Australia

Primary sponsor type

University

Name

Monash University

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash University Human Ethics Committee

Ethics committee address [1]

Research Support Services
Level 2, iBlock,
Monash Medical Centre
246 Clayton Road,
CLAYTON VIC 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

15/12/2022

Approval date [1]

11/01/2023

Ethics approval number [1]

36621

Summary

Brief summary

This proof-of-concept randomised double-blind placebo-controlled crossover study will determine the effects of transdermal testosterone supplementation in post-menopausal females with stage B heart failure with preserved ejection fraction (HFpEF) on attenuation of heart failure risk. We seek to do this based on the previously demonstrated efficacy of this approach in female patients with chronic HF as our epidemiological evidence that suggests low testosterone in females is associated with increased risk of major cardiovascular events and there is an urgent need to identify effective prevention and treatment strategies for the patients with HFpEF. 
Our hypothesis is that transdermal testosterone, versus placebo, will result in a clinically meaningful improvement in V02peak, which is a strong prognostic indicator for future HF risk in postmenopausal women with stage B HFpEF. The improvement will be due to improvements in central cardiac function and structure.
The study will provide high-quality evidence as to whether testosterone, as a novel intervention, will improve cardiorespiratory fitness in women at risk of  HFpEF, and therefore whether testosterone therapy has the potential and feasibility as a treatment for this condition, for which there is currently no known treatment.

Trial website

Public notes

Contacts

Principal investigator

Name

Prof Susan Davis

Address

The Women’s Health Research Program,
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Rd,
Melbourne, Victoria 3004

Country

Australia

Phone

+61 3 9903 0827

Email

[email protected]

Contact person for public queries

Name

Susan Davis

Address

The Women’s Health Research Program,
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Rd,
Melbourne, Victoria 3004

Country

Australia

Phone

+61 3 9903 0827

Email

[email protected]

Contact person for scientific queries

Name

Susan Davis

Address

The Women’s Health Research Program,
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Rd,
Melbourne, Victoria 3004

Country

Australia

Phone

+61 3 9903 0827

Email

[email protected]

Trial Review

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