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Trial registered on ANZCTR


Registration number
ACTRN12621001100886
Ethics application status
Approved
Date submitted
21/06/2021
Date registered
18/08/2021
Date last updated
22/08/2022
Date data sharing statement initially provided
18/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the effect of topical testosterone cream on bone loss and sexual function in women with premature ovarian insufficiency and early menopause: a randomized, double blind, placebo-controlled trial..
Scientific title
Investigating the effect of topical testosterone cream on bone loss and sexual function in women with premature ovarian insufficiency (POI) and early menopause (EM): a randomized, double blind, placebo-controlled trial.
Secondary ID [1] 304522 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoporosis 322388 0
Sexual dysfunction 322389 0
Primary Ovarian Insufficiency 322430 0
Early menopause 327423 0
Condition category
Condition code
Musculoskeletal 320048 320048 0 0
Osteoporosis
Reproductive Health and Childbirth 320050 320050 0 0
Other reproductive health and childbirth disorders
Reproductive Health and Childbirth 320575 320575 0 0
Menstruation and menopause

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Application of active treatment, 1% testosterone cream, 0.5ml (10mg/ml), or placebo cream
applied transdermally daily to upper thigh or lower torso by participant for 12 months.

Dosing may be modified by an appointed independent Study Safety Monitor (a clinician experienced in T therapy for women) who will have access to the randomisation code and will review each participant’s 12 and 26-week T level (measured locally). For any woman with a T level 1.5 times the upper limit of the premenopausal range for each site’s T assay, the Safety Monitor will request both the participant with high T, as well as a randomly selected participant from the same study site on placebo with a recent blood draw, decrease the amount of T cream applied (by 25%) and both to have repeat blood levels after 3 weeks. This ensures dose adjustment without unblinding.
Compliance will be assessed by collection and weighing of returned cream containers at week 12, week 26 and week 52 after commencement of treatment.
Intervention code [1] 320880 0
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 lower torso for 12 months
Control group
Placebo

Outcomes
Primary outcome [1] 327922 0
Total hip bone mineral density (BMD) as measured by dual energy X-ray absorptiometry (DXA) after 12 months of transdermal testosterone (T) cream or placebo in women with premature ovarian insufficiency and early menopause (POi/EM) on standard estrogen replacement therapy (ERT).
Timepoint [1] 327922 0
52 weeks post intervention commencement.
Secondary outcome [1] 397014 0
The effects of transdermal T versus placebo therapy on a measure of musculoskeletal health: BMD at the lumbar spine and radius measured by dual-energy X-ray absorptiometry (DXA)
Timepoint [1] 397014 0
52 weeks post intervention commencement
Secondary outcome [2] 398001 0
The effects of transdermal T versus placebo therapy on a measure of musculoskeletal health: serum biochemical markers of bone turnover
Timepoint [2] 398001 0
52 weeks post intervention commencement
Secondary outcome [3] 398002 0
The effects of transdermal T versus placebo therapy on a measure of musculoskeletal health: trabecular bone score (TBS) using high resolution- peripheral quantitative computed tomography (HR-pQCT).
Timepoint [3] 398002 0
52 weeks post intervention commencement
Secondary outcome [4] 398003 0
The effects of transdermal T versus placebo therapy on a measure of musculoskeletal health: lean muscle and fat mass measured by whole body DXA scans. This is a composite secondary outcome
Timepoint [4] 398003 0
52 weeks post intervention commencement
Secondary outcome [5] 398004 0
The effects of transdermal T versus placebo therapy on sexual wellbeing using a validated questionnaire: sexual desire, arousal, orgasm, pleasure, concerns, responsiveness, and self-image measured by the Profile of Female Sexual Function
Timepoint [5] 398004 0
12, 26 and 52 weeks post intervention commencement
Secondary outcome [6] 398005 0
The effects of transdermal T versus placebo therapy on sexually associated personal distress assessed by the Female Sexual Distress Scale
Timepoint [6] 398005 0
12, 26 and 52 weeks post intervention commencement
Secondary outcome [7] 398006 0
The effects of transdermal T versus placebo therapy on cardio-metabolic health as assessed by fat distribution measured by whole body DXA scan, body mass index (BMI-height measured with stadiometer, weight measured with digital scales) , waist: hip ratio measured in cm.
This is a composite secondary outcome.
.
Timepoint [7] 398006 0
12, 26 and 52 weeks post intervention commencement
Secondary outcome [8] 398007 0
The effects of transdermal T versus placebo therapy on
serum lipid profiles
Timepoint [8] 398007 0
12, 26 and 52 weeks post intervention commencement
Secondary outcome [9] 398008 0
The effects of transdermal T versus placebo therapy on a measure of musculoskeletal health: hand grip as measured by dynamometer
Timepoint [9] 398008 0
52 weeks post intervention commencement
Secondary outcome [10] 398902 0
The effects of transdermal T versus placebo therapy on a measure of musculoskeletal health: bone microarchitecture using high resolution- peripheral quantitative computed tomography (HR-pQCT).
Timepoint [10] 398902 0
52 weeks post intervention commencement
Secondary outcome [11] 398903 0
The effects of transdermal T versus placebo therapy on
estimated insulin resistance from fasting blood glucose and insulin
Timepoint [11] 398903 0
12, 26 and 52 weeks post intervention commencement
Secondary outcome [12] 398904 0
The effects of transdermal T versus placebo therapy on a measure of musculoskeletal health: knee extension strength as assessed by dynamometer
Timepoint [12] 398904 0
52 weeks post intervention commencement

Eligibility
Key inclusion criteria
We will include women who:
1. have an established diagnosis of POI/EM as diagnosed by 4/12 amenorrhea and follicle stimulating hormone (FSH) levels in menopausal range on 2 occasions > 6/52 apart before 45 years of age, or women who have had a bilateral oophorectomy before 45 years of age
2. are aged between 18 and less than 45 years at the screening visit.
3. have been on a stable dose of estrogen replacement therapy (ERT) for at least 3 months with a dose equivalent to at least any of a 50mcg transdermal estradiol (E2) patch, daily 1mg transdermal E2 gel, daily 0.625mg/day of oral conjugated estrogen, daily 2mg/day of oral E2, a current E2 implant, or taking an E2-containing oral contraceptive pill (OCP)
4. have a negative pregnancy test at screening (not required for hysterectomised /oophorectomised women)
5. have a clinically acceptable cervical cancer screening test, if the cervix is present within the time frame of usual screening
6. are available for the entire study period and willing to adhere to participate in the study by providing written informed consent
Minimum age
18 Years
Maximum age
44 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Women will be excluded if they are found on screening to have:
1. other known metabolic bone disease or a condition associated with osteoporosis such as rheumatoid arthritis, malabsorption, or anti-estrogen therapy
2. taken, or be taking, any drug known to affect bone metabolism such as bisphosphonates, denosumab, systemic corticosteroids, antineoplastic drugs, thiazide diuretics, anti-epileptic drugs, heparin
3. a body mass index <18 or >38 kg/metre2
4. a Beck Depression Inventory -II (BDI-II) score on screening > 28 i.e., severe depression
5. developed POI post-chemotherapy / an estrogen sensitive cancer
6. used recent androgen therapy (T implant <16 weeks, transdermal T cream <8 weeks, tibolone
7. <12 weeks, oral T <4 weeks, injected T <6 weeks, oral dehydroepiandrosterone (DHEA) < 4 weeks)
8. taken an OCP containing ethinylestradiol/ other synthetic estrogen in the prior 3 months
9. a pre-randomisation sex hormone binding globulin (SHBG) level 2 x the upper limit of
normal for the local laboratory as an elevated SHBG interferes with the efficacy of T therapy
10. any major illness requiring hospitalization within the prior 6 months.
11. undiagnosed vaginal bleeding
12. moderate to severe acne or hirsutism, have used antiandrogen therapy for acne or hirsutism in the preceding 5 years, have androgenic alopecia
13. taken any drugs or dietary supplements that, in the Investigator’s opinion, may affect the participant’s sexual desire including, but not limited to, flibanserin, bremelanotide, bupropion, buspirone, mirtazapine, phosphodiesterase type 5 inhibitors, testosterone, dehydroepiandrosterone, ginkgo biloba, maca root, stimulants, cocaine, cannabis, or other drugs of abuse, serotonin-norepinephrine reuptake inhibitors. systemic antiandrogen therapy (spironolactone, cyproterone acetate, finasteride, minoxidil).
14. alcohol consumption > 3 standard drinks per day
15. an abnormal thyroid function (abnormal thyroid stimulating hormone (TSH) value confirmed by a free thyroxine (T4) outside laboratory
range)
16. been considered by the Clinical Investigator (CI) to be unsuitable for participation in the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is concealed by central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization codes will be computer generated and participants will be randomly allocated to treatment with T or identical placebo in a 1:1 ratio. There will be 3 collaborating centres with approximately 38 women recruited per centre. Two separate randomisation schedules will be generated for each centre, one for women on oral estrogen and the other for women using transdermal ERT as these two modes of estrogen administration have different effects on the protein binding of T.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The analysis will be by intention-to-treat with all women who were randomised and received at least one dose of study medication included. For women who do not complete the study, data collected at 6 months or at their exit visit will be used (last observation carried forward). The primary outcome variable (% change in BMD adjusted for baseline differences) will be analysed appropriately depending on the normality of the distribution of the data, using either astudent’s t-test for independent means or the Wilcoxon rank sum test. Other outcome variables will be analysed as change in the relevant parameter +/- adjustment for baseline differences between groups, with biochemical data likely to be transformed prior to analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/09/2021
Actual
16/02/2022
Date of last participant enrolment
Anticipated
30/09/2024
Actual
Date of last data collection
Anticipated
30/09/2025
Actual
Sample size
Target
116
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
WA,VIC
Recruitment hospital [1] 19778 0
Monash University Public Health and Preventive Medicine - Melbourne
Recruitment hospital [2] 19779 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 19780 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 34422 0
3004 - Melbourne
Recruitment postcode(s) [2] 34423 0
3168 - Clayton
Recruitment postcode(s) [3] 34424 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 308887 0
Government body
Name [1] 308887 0
Australian Federal Department of Health
Country [1] 308887 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Road
Clayton
Victoria 3800
Country
Australia
Secondary sponsor category [1] 309809 0
None
Name [1] 309809 0
Address [1] 309809 0
Country [1] 309809 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308790 0
Monash University Human Research Ethics Committee
Ethics committee address [1] 308790 0
Monash Research Office,
26 Sports Walk,
Monash University,
Wellington Road,
Clayton VIC 3800.
Ethics committee country [1] 308790 0
Australia
Date submitted for ethics approval [1] 308790 0
14/06/2021
Approval date [1] 308790 0
16/07/2021
Ethics approval number [1] 308790 0
Ethics committee name [2] 309252 0
Monash Health Human Research Ethics Committee
Ethics committee address [2] 309252 0
Research Support Services
Level 2, iBlock,
Monash Medical Centre
246 Clayton Road,
CLAYTON VIC 316
Ethics committee country [2] 309252 0
Australia
Date submitted for ethics approval [2] 309252 0
20/08/2021
Approval date [2] 309252 0
Ethics approval number [2] 309252 0

Summary
Brief summary
The purpose of this research is to determine whether the use of a topical testosterone cream prevents bone loss and improves sexual function in women with premature ovarian insufficiency (POI) and early menopause who are taking a standard dose of estrogen.
We hypothesize that 0.5ml of testosterone cream, versus placebo, applied daily for 12 months will result in a clinical improvement in total hip bone mineral density in these women, and other markers of musculoskeletal health, as well as improvements in sexual function and reduced sexually associated personal distress.


The purpose of this research is to determine whether the use of transdermal testosterone therapy, in a dose shown restores testosterone levels to those of premenopausal women, prevents bone loss and improves sexual function in women with POI who are taking the standard dose of estrogen.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111894 0
Prof Susan Davis
Address 111894 0
The Women’s Health Research Program,
Chronic Disease and Ageing
Monash University
553 St Kilda Rd,
Melbourne, Victoria 3004
Country 111894 0
Australia
Phone 111894 0
+61 3 9903 0827
Fax 111894 0
+61 3 9903 0828
Email 111894 0
[email protected]
Contact person for public queries
Name 111895 0
Prof Susan Davis
Address 111895 0
The Women’s Health Research Program,
Chronic Disease and Ageing
Monash University
553 St Kilda Rd,
Melbourne, Victoria 3004
Country 111895 0
Australia
Phone 111895 0
+61 3 9903 0827
Fax 111895 0
+61 3 9903 0828
Email 111895 0
[email protected]
Contact person for scientific queries
Name 111896 0
Prof Susan Davis
Address 111896 0
The Women’s Health Research Program,
Chronic Disease and Ageing
Monash University
553 St Kilda Rd,
Melbourne, Victoria 3004
Country 111896 0
Australia
Phone 111896 0
+61 3 9903 0827
Fax 111896 0
+61 3 9903 0828
Email 111896 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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
12161Study protocol  [email protected]



Results publications and other study-related documents

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