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Trial registered on ANZCTR


Registration number
ACTRN12615001115527p
Ethics application status
Submitted, not yet approved
Date submitted
28/09/2015
Date registered
22/10/2015
Date last updated
22/10/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomized, Placebo-Controlled Clinical Trial of Transdermal dihydrotestosterone Gel to Improve In Vitro Fertilization Outcomes In Women With Poor Ovarian Response
Scientific title
Randomized, Placebo-Controlled Clinical Trial of Transdermal DHT Gel to Improve IVF Outcomes In Women With Poor Ovarian Response
Secondary ID [1] 287428 0
nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Women with poor ovarian response undergoing IVF 296142 0
Condition category
Condition code
Reproductive Health and Childbirth 296411 296411 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
DHT gel 5mg daily transdermal application for 21 days prior to controlled ovarian stimulation: The DHT or placebo gel will be similar and packed into capped 1 ml tuberculin-type syringes without needles and labelled with study and participant IDs. Each syringe has sufficient gel for 5 daily doses. Participating women will be given a supply of 5 syringes at the enrollment visit.. They will return the syringes at the end of the DHT treatment period (Day 21 of this study).

Compliance:
Compliance will be determined by counting returned syringes on day 21.

In addition women will provide at least one finger prick dried blood sample (DBS) at home to evaluate serum DHT during treatment. This uses our established DBS technology using a finger prick, similar to home blood glucose motoring, at home. Using a standard lancet, whole blood is dropped or smeared onto Guthrie-type filter paper and air dried. The filter paper with DBS can be kept in a dry place (plastic bag) at home without any special handling procedures unlike serum from venepuncture (i.e. no requirement for blood clotting, separation or refrigeration). The filter papers are returned with the used syringes for subsequently measurement of serum DHT.
Intervention code [1] 292787 0
Treatment: Drugs
Comparator / control treatment
Placebo gel- Glycerin and purified water
Control group
Placebo

Outcomes
Primary outcome [1] 296048 0
Number of clinical pregnancies - review of medical records
Timepoint [1] 296048 0
End of IVF treatment cycle
Secondary outcome [1] 317354 0
Number of follicles on hCG day - review of medical records
Timepoint [1] 317354 0
End of IVF treatment cycle
Secondary outcome [2] 318058 0
Number of oocytes retrieved- Review of medical records
Timepoint [2] 318058 0
End of IVF treatment cycle
Secondary outcome [3] 318059 0
Proportion of oocytes fertilised- review of medical records
Timepoint [3] 318059 0
end of IVF treatment cycle
Secondary outcome [4] 318061 0
Total number of embryos- review of medical records
Timepoint [4] 318061 0
end of IVF treatment
Secondary outcome [5] 318063 0
Cycle cancellation rate - review of medical reocrds
Timepoint [5] 318063 0
end of IVF treatment
Secondary outcome [6] 318068 0
Total dose & duration of FSH - review of medical records
Timepoint [6] 318068 0
end of IVF treatment
Secondary outcome [7] 318076 0
Sexual function (modified FSFI scale) - review of the answers to the questionnaire
Timepoint [7] 318076 0
At the end of IVF treatment
Secondary outcome [8] 318077 0
Steroid profiles in the serum and follicular fluid and correlation of these with the standard IVF outcomes - review of medical notes
Timepoint [8] 318077 0
End of IVF treatment
Secondary outcome [9] 318078 0
evaluate mRNA expression for AR splice variants and noncoding RNA regulatory FSH receptor - review of medical records
Timepoint [9] 318078 0
End of IVF treatment
Secondary outcome [10] 318079 0
Miscarriage rate - review of medical notes
Timepoint [10] 318079 0
End of IVF treatment
Secondary outcome [11] 318087 0
Adverse effects - At the day 21 visit, participants will be asked to if they have experienced any unusual, unexpected or unwanted effects (symptoms, signs, conditions or an observation) since they started treatment. Any reports of undesirable or unwelcome effects will be documented as adverse events (AE). The investigators will also judge whether the AE is definitely, likely, possible or unrelated to the study medication.
Timepoint [11] 318087 0
End of IVF treatment cycle

Eligibility
Key inclusion criteria
*Age >18 years
*Modified Bologna criteria stratified by age
-For women >40 years, no additional inclusion criteria
-For women <40 years, at least one additional inclusion criterion either previous IVF cycle with POR (<3 oocytes with conventional stimulation) and/or impaired ovarian reserve (ultrasonic antral follicle count <7 follicles or serum AMH <1.1 ng/ml)
Minimum age
18 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
*Use of androgens or pro-androgens in previous 2 months
*Perimenopausal (no regular cycle, high serum FSH)
*Major uterine abnormalities
*History of untreated systemic medical disease or organ failure (eg impaired cardiac, respiratory, hepatic, or renal function)
*Extensive skin disease that would interfere with use of the transdermal gel
*Participation in other clinical trials of medical therapy

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)
Patients attending RPAH IVF clinics will be invited to participate subject to providing written informed consent and meeting eligibility criteria. Patient recruitment will be undertaken by the gynaecologist co-investigators Dr Marren and Associate Professor Bowman, together with their fellow clinicians and clinic nurses.

Eligible, consenting participants will receive a consecutive, unique study enrolment number which will be documented in the participant’s medical record and all study documents. The participants will be randomized at the enrolment visit according to their unique study ID number to receive either DHT or placebo gel. All study staff and participants will remain blinded to treatment throughout the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eligible, consenting participants will receive a consecutive, unique study enrolment number which will be documented in the participant’s medical record and all study documents. The participants will be randomized at the enrolment visit according to their unique study ID number to receive either DHT or placebo gel. All study staff and participants will remain blinded to treatment throughout the study.

Randomization is according to a computer-generated random list, prepared by a person not directly involved with the study participants. The randomisation allocations will be provided in sealed opaque envelopes marked with the study ID number on the outside to allow for concealed allocation in a 1:1 ratio to either the DHT or placebo treatment groups.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
This is an investigator-initiated, proof-of-concept study as a randomized, placebo-controlled, parallel group clinical trial of DHT (5mg vs placebo) gel used daily for 21 days immediately prior to an IVF hyperstimulation cycle with the goal of improving ovarian response in women with prior poor ovarian response to IVF.

Eligible, consenting participants will, on enrolment, receive a unique study number which will be documented in the participant’s case record forms and all study documents. Participants will be randomly assigned to treatment (DHT or placebo) in a 1:1 ratio by means of receiving an opaque envelope numbered with her study ID on the outside and containing on the inside the drug allocation code. The randomization is created by a computer-generated randomization list of drug allocation codes so as to assure concealment of allocation from study staff and participants.
Phase
Phase 0
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary and secondary endpoints will be analysed on an intention-to-treat basis for efficacy endpoints and for per protocol for safety endpoints using paired t-tests or mixed model analysis of variance to incorporate covariables based on known risk factors for poor IVF outcomes.

Sample size and power:
Power calculation (PASS software) assuming two-sided alpha=0.05, beta=0.2 (80% power) and a background pregnancy rate in women with POR of 15% indicates that 121 women/group are required to reliably detect a significant benefit of DHT pre-treatment as defined as a doubling of the pregnancy rates to 30%.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 4314 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 10469 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 292004 0
Hospital
Name [1] 292004 0
Sydney Local Health District, Royal Prince Alfred Hospital
Address [1] 292004 0
Royal Prince Alfred Hospital, Missenden Road
Camperdown
NSW 2050
Country [1] 292004 0
Australia
Primary sponsor type
Individual
Name
Prof.David Handelsman
Address
The ANZAC Research Institute
Concord Repatriation General Hospital
Gate 3, Hospital Road
Concord NSW 2139, Australia
Country
Australia
Secondary sponsor category [1] 290671 0
None
Name [1] 290671 0
Address [1] 290671 0
Country [1] 290671 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 293492 0
Sydney Local Health District - RPAH
Ethics committee address [1] 293492 0
Research Development Office
Royal Prince Alfred Hospital
Missenden road
Camperdown
NSW 2050
Ethics committee country [1] 293492 0
Date submitted for ethics approval [1] 293492 0
09/10/2015
Approval date [1] 293492 0
Ethics approval number [1] 293492 0

Summary
Brief summary
Despite the advances in assisted reproduction techniques, suboptimal In Vitro Fertilization(IVF) outcomes in women with Poor Ovarian Response(POR) still remains a challenge. Older women seeking IVF have suboptimal utcomes, at least partly due to inadequate number of eggs on conventional stimulation. This suboptimal response relates
mainly to inadequate ovarian response but there is often also reduced live birth rates, increased risk cycle cancellation and a need larger doses of gonadotrophins, which increases both cost and risk of ovarian hyperstimulation syndrome (OHSS) risk.

There is now growing evidence that androgens (or male hormones) may improve egg quality and numbers in women with POR. So far the androgens used in women with POR include testosterone and the pro-androgen hormone Dehydroepiandrosterone(DHEA) as well as aromatase inhibitor drugs, which increase the body’s own testosterone levels by blocking its conversion to estradiol. For each of these drugs, their multiple levels of action mean that it is not clear whether they produce any benefits by acting as an androgen (or male hormone). For this reason, this study is using dihydrotestosterone (DHT), the natural product of testosterone in the body of men and women, and which acts only as a pure androgen in the body. As a result, the study will determine for the first time whether these drugs do work as androgens or not and may refine and improve the treatment for POR. In this study we will temporarily increase the circulating levels of DHT during the time when oocyte (egg) development and maturation is occurring. This will be achieved by applying the DHT gel onto the skin once a day for 21 days prior to the start of IVF ovarian stimulation.

Aims:
To investigate the efficacy of DHT gel treatment applied onto the skin before an IVF stimulation cycle in women with poor ovarian response.

Research Hypothesis
DHT pre-treatment prior to an IVF cycle will improve the number of healthy, fertilisable eggs retrieved.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 60126 0
Prof David Handelsman
Address 60126 0
ANZAC Research Institute,
Gate 3, Concord Repatriation General Hospital, Hospital Road,
Concord NSW 2139
Country 60126 0
Australia
Phone 60126 0
+61 2 97679100
Fax 60126 0
Email 60126 0
djh@anzac.edu.au
Contact person for public queries
Name 60127 0
Dr Nandini Shankara Narayana
Address 60127 0
ANZAC Research Institute,
Gate 3, Concord Repatriation General Hospital, Hospital Road,
Concord NSW 2139
Country 60127 0
Australia
Phone 60127 0
+61 2 97676026
Fax 60127 0
Email 60127 0
nsha7690@uni.sydney.edu.au
Contact person for scientific queries
Name 60128 0
Dr Nandini Shankara Narayana
Address 60128 0
ANZAC Research Institute,
Gate 3, Concord Repatriation General Hospital, Hospital Road,
Concord NSW 2139
Country 60128 0
Australia
Phone 60128 0
+61 2 97676026
Fax 60128 0
Email 60128 0
nsha7690@uni.sydney.edu.au

No information has been provided regarding IPD availability
Summary results
No Results