T-TRANSPORT: Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial

Sponsor

Institut Universitari Dexeus (Other)

Overall Status

Recruiting

CT.gov ID

NCT02418572

Collaborator

(none)

400

Enrollment

Locations

Arms

Duration (Months)

36.4

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Infertility Poor Ovarian Response	Drug: Testosterone gel Drug: Placebo gel	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Transdermal Testosterone Gel for Poor Ovarian Responders. A Multicenter Double-blind Placebo Controlled Randomized Trial

Study Start Date :

Apr 1, 2015

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Transdermal 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).	Drug: Testosterone gel Patients will receive once daily application of 0.55 gr testosterone gel-TTG (GROUP A) (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. The application will be administered in the morning by the patient onto clean dry healthy skin over external surface of the thighs. The gel will be simply spread on the skin gently as a thin layer. TTG will start on the day of enrollment and will continue until patients' menstruation (28-30 days). Daily administration of TTG or placebo will continue for 35 days (21days until the initial of downregulation with triptorelin and for 14 more days until the initiation of ovarian stimulation with HP-hMG). Ovarian stimulation will commence the day after last testosterone gel application. (GROUP A) Other Names: Androgel 1% 0.55 gr / day
Placebo Comparator: Placebo transdermal 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).	Drug: Placebo gel Patients will receive once daily application of 0.55 gr of placebo gel from day 1 or 2 of the following menstrual cycle, for approximately 65 days. The application will be administered in the morning by the patient onto clean dry healthy skin over external surface of the thighs. The gel will be simply spread on the skin gently as a thin layer. Placebo gel will start on the day of enrollment and will continue until patients' menstruation (28-30 days). Daily administration of placebo gel will continue for 35 days (21 days until the initial of downregulation with triptorelin and for 14 more days until the initiation of ovarian stimulation with HP-hMG

Arm

Intervention/Treatment

Experimental: Transdermal 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).

Drug: Testosterone gel

Patients will receive once daily application of 0.55 gr testosterone gel-TTG (GROUP A) (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. The application will be administered in the morning by the patient onto clean dry healthy skin over external surface of the thighs. The gel will be simply spread on the skin gently as a thin layer. TTG will start on the day of enrollment and will continue until patients' menstruation (28-30 days). Daily administration of TTG or placebo will continue for 35 days (21days until the initial of downregulation with triptorelin and for 14 more days until the initiation of ovarian stimulation with HP-hMG). Ovarian stimulation will commence the day after last testosterone gel application. (GROUP A)

Other Names:

Androgel 1% 0.55 gr / day

Placebo Comparator: Placebo transdermal 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).

Drug: Placebo gel

Patients will receive once daily application of 0.55 gr of placebo gel from day 1 or 2 of the following menstrual cycle, for approximately 65 days. The application will be administered in the morning by the patient onto clean dry healthy skin over external surface of the thighs. The gel will be simply spread on the skin gently as a thin layer. Placebo gel will start on the day of enrollment and will continue until patients' menstruation (28-30 days). Daily administration of placebo gel will continue for 35 days (21 days until the initial of downregulation with triptorelin and for 14 more days until the initiation of ovarian stimulation with HP-hMG

Outcome Measures

Primary Outcome Measures

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

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

Other Outcome Measures

Adverse events [Up to 70 days from treatment start date]
Any adverse event related with testosterone administration must be reported in Adverse Event Report Form

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 43 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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:

All subjects must sign the Informed consent documents prior to screening evaluations.
Age: between 18-43 years old.
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:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	UZ Antwerp	Antwerp	Belgium
2	Universitair Ziekenhuis Brussel	Brussels	Belgium	1090
3	Fertility Clinic Rigshospitalet	Copenhagen	Denmark
4	The Fertility Clinic, Skive Regional Hospital, Skive, Denmark	Skive	Denmark
5	Hospital Universitario Quiron Dexeus	Barcelona	Spain
6	Hospital Universitario 12 de Octubre	Madrid	Spain
7	Hospital Universitario HM Monteprincipe	Madrid	Spain
8	Hospital Universitario La Paz	Madrid	Spain
9	Hospìtal Universitario HM Puerta del Sur	Madrid	Spain
10	Quiron Madrid Hospital	Madrid	Spain
11	University Hospital Basel	Basel	Switzerland

Sponsors and Collaborators

Institut Universitari Dexeus

Investigators

Principal Investigator: Nikolaos P Polyzos, MD PhD, Institut Universitari Dexeus

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Nikolaos Polyzos, Principal Investigator, Institut Universitari Dexeus

ClinicalTrials.gov Identifier:

NCT02418572

Other Study ID Numbers:

2014.TTRANSPORT
2014-001835-35

First Posted:

Apr 16, 2015

Last Update Posted:

Oct 5, 2021

Last Verified:

Oct 1, 2021

Additional relevant MeSH terms:

Infertility

Testosterone

Study Results

No Results Posted as of Oct 5, 2021