Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial

Phase 3

Terminated

• Conditions: Infertility; Poor Ovarian Response
• Interventions: Drug: Testosterone gel; Drug: Placebo gel

• Registration Number: NCT02418572
• Lead Sponsor: Institut Universitari Dexeus

Brief Summary

Previous work indicates that 2 months androgen pre-treatment may equip preantral follicles with more FSH receptors and increase the cohort of follicles surviving to the recruitable antral stage. In this regard it may result in an increase in the oocyte yield and the reproductive outcome in women with poor ovarian response. These findings provide a strong rationale for a definitive large RCT. The TTRANSPORT study will include 400 women with poor ovarian response randomized to receive pre-treatment with transdermal testosterone gel or placebo in order to provide conclusive evidence regarding the superiority or not of transdermal testosterone pre-treatment for the management of poor ovarian responders fulfilling the Bologna criteria.

Detailed Description

Studies in primates showed that treatment with testosterone increased the number of growing follicles, lead to proliferation of granulosa and theca cells, while finally reduced the apoptosis of granulosa cells (Vendola et al., 1999; Weil et al., 1999). These studies further suggest that androgens may have a specific action in pre-antral and small antral follicles, prior to serving as substrate for estradiol synthesis in larger follicles and in this regard influence the responsiveness of the ovaries to gonadotropins and amplify the effects of FSH on the ovary.

Despite the available evidence, only 3 small RCTs evaluated the effect of transdermal testosterone on infertile patients with poor ovarian response to stimulation. A pooled analysis of these studies demonstrated a benefit in clinical and ongoing pregnancy rates for testosterone pre-treated patients (González-Comadran et al., 2012). However, two of these trials were considerably small, whereas all of them restricted testosterone administration between 5 and 21 days prior ovarian stimulation. Evidence from basic research and early trials suggest that androgens should be administered for at least 2 months before initiation of ovarian stimulation (Casson PR, 2000), in order affect preantral follicles and equip them with more FSH receptors in an attempt to have a larger cohort of follicles surviving to the recruitable antral stage.

Taking into account the promising results from recently conducted small RCTS, the investigators decided to perform a double blind placebo controlled randomized controlled trial, with adequate sample size, in order to test the effect of administration of transdermal testosterone in poor ovarian responders fulfilling the Bologna criteria, for 2 months prior ovarian stimulation in a long agonist protocol. The daily dose of transdermal testosterone gel (TTG) will be 0.55gr (5.5mg testosterone/day). The specific dose was selected based on previous pharmacokinetic studies in women according to which daily application of 5 mg of transdermal testosterone cream (Fooladi, 2014) or TTG (Singh et al. 2006, Nathorst-Böös et al., 2005) is likely to restore fT levels to the premenopausal reference range. Although no side effects had been described after pre-treatment with higher doses of 12.5mg TTG for 21 days in a previous randomized controlled trial (Kim et al., 2011), it is likely that higher doses will result in supraphysiological TT and fT levels. Therefore the dose of 0.55gr TTG (5.5mg testosterone/day) has been selected for the T-TRANSPORT trial since this will restore TT and fT levels to levels above and within the upper normal reference range.

Study Timeline

• Study Start: 2015-04
• Study First Submitted: 2015-04-13
• Study First Submitted QC: 2015-04-15
• Study First Posted: 2015-04-16
• Primary Completion: 2023-12
• Study Completion: 2024-02
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-21
• Last Update Posted: 2024-05-22

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Female
• Target Recruitment: 290

Inclusion Criteria

Patients participating in the TTRANSPORT study will be women who are considered poor ovarian responders according to the "Bologna criteria" (Ferraretti et al., 2011).

Subjects must fulfil the following criteria to be included in the study:

1. All subjects must sign the Informed consent documents prior to screening evaluations.
2. Age: between 18-43 years old.
3. One of the features below:

Infertile female <40 years old with i. ≤ 3 oocytes in a previous cycle and AFC <7 OR ii. ovarian surgery/chemotherapy and AFC<7 OR iii. ≤ 3 oocytes in at least 2 previous cycles with ≥300IU gonadotropins

Infertile female ≥40 years old with i. ≤ 3 oocytes in a previous cycle OR ii. AFC <7. Patients will be randomized according to different age groups (<36, 36-39 and ≥40 years old).

Exclusion Criteria

1. Perimenopausal women with amenorrhea not having a regular cycle
2. Basal FSH >20 IU/l
3. Uterine malformations
4. Recent history of any current untreated endocrine abnormality
5. Unilateral or bilateral hydrosalpinx (visible on USS, unless clipped)
6. Contraindications for the use of gonadotropins
7. Recent history of severe disease requiring regular treatment
8. Use of androgens during the last 3 months
9. Patients with SHBG values <20nmol/L or >160nmol/L
10. Azoospermia (sperm derived through FNA or TESE)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Transdermal testosterone gel	Testosterone gel	Patients will receive once daily application of 0.55 gr TTG (Testosterone gel 1%; Laboratories Besins International,Paris,France) with a 5.5 mg/d nominal delivery rate of testosterone starting from day 1 or 2 of the following menstrual cycle, for approximately 65 days. Pituitary down-regulation will be induced by daily injections of 0.1mg triptorelin started on day 21 of the next cycle following enrollment in the study, up to and including the day of hCG administration. After 2 weeks of down-regulation, daily SC injections of HP-hMG (Menopur®) (300 IU/day) will be administered up to the day of hCG administration. Ovulation triggering will be induced with 250μg rhCG (Ovidrelle®) followed by oocyte pick-up \~36 hours later and ICSI. A maximum of 2 embryos, following each center's national criteria of single embryo transfer, will be transferred 3 days later. Luteal phase support with be performed with progesterone tablets ( Utrogestan®) (200mg x3, intravaginally).
Placebo transdermal gel	Placebo gel	Patients will receive once daily application of 0.55 gr identical placebo gel starting from day 1 or 2 of the following menstrual cycle, for approximately 65 days. Pituitary down-regulation will be induced by daily injections of 0.1mg triptorelin started on day 21 of the next cycle following enrollment in the study, up to and including the day of hCG administration. After 2 weeks of down-regulation, daily SC injections of HP-hMG (Menopur®) (300 IU/day) will be administered up to the day of hCG administration. Ovulation triggering will be induced with 250μg rhCG (Ovidrelle®) followed by oocyte pick-up \~36 hours later and ICSI. A maximum of 2 embryos, following each center's national criteria of single embryo transfer, will be transferred 3 days later. Luteal phase support with be performed with progesterone tablets ( Utrogestan®) (200mg x3, intravaginally).

Primary Outcome Measures

Name	Time	Method
Clinical pregnancy	7 weeks of gestation	The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 7 weeks of gestation

Secondary Outcome Measures

Name	Time	Method
Ongoing pregnancy	9-10 weeks of gestation	The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 9-10 weeks of gestation.
Biochemical pregnancy	2 weeks after embryo transfer	Positive pregnancy test 2 weeks after embryo transfer
Number of oocytes retrieved	9 -20 days from initiation of ovarian stimulation	The outcome will be evaluated on the day of oocyte retrieval
Number of MII oocytes retrieved	9 -20 days from initiation of ovarian stimulation	The outcome will be evaluated on the day of oocyte retrieval
Cycle cancellation due to poor ovarian response	10 days after initiation of daily injections of HP-hMG	On stimulation day 10 (visit 8) the cycle will be cancelled in case of no follicular or monofollicular development
Number of cycles reaching the stage of embryo transfer	9 -20 days from initiation of ovarian stimulation	The outcome will be evaluated 3 days after oocyte retrieval
Number and quality of embryos	Day of embryo transfer (9 -20 days from initiation of ovarian stimulation)	The outcome will be evaluated 3 days after oocyte retrieval
Number of cycles with frozen supernumerary embryos	9 -20 days from initiation of ovarian stimulation	The outcome will be evaluated 5 days after oocyte retrieval or 2-6 days after embryo transfer in case of an embryo transfer

Trial Locations

Locations (10)

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

University Hospital Basel; 🇨🇭 Basel, Switzerland

Universitair Ziekenhuis Brussel; 🇧🇪 Brussels, Belgium

Hospital Universitario Quiron Dexeus; 🇪🇸 Barcelona, Spain

Hospìtal Universitario HM Puerta del Sur; 🇪🇸 Madrid, Spain

Fertility Clinic Rigshospitalet; 🇩🇰 Copenhagen, Denmark

The Fertility Clinic, Skive Regional Hospital, Skive, Denmark; 🇩🇰 Skive, Denmark

Hospital Universitario HM Monteprincipe; 🇪🇸 Madrid, Spain

Quiron Madrid Hospital; 🇪🇸 Madrid, Spain