Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial

Infertility Clinical Trial

— T-TRANSPORT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02418572
• Other study ID #: 2014.TTRANSPORT
• Secondary ID: 2014-001835-35
• Status: Recruiting
• Phase: Phase 3
• Start date: April 2015
• Est. completion date: June 2024

Study information

• Verified date: May 2023
• Source: Institut Universitari Dexeus
• Contact: Nikolaos P Polyzos, MD PhD
• Phone: 0034932274700
• Email: nikpol[@]dexeus.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: June 2024
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 43 Years

Eligibility

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)

Related Conditions & MeSH terms

• Infertility
• Poor Ovarian Response

Intervention

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)
• 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

Locations

Country	Name	City	State
Belgium	UZ Antwerp	Antwerp
Belgium	Universitair Ziekenhuis Brussel	Brussels
Denmark	Fertility Clinic Rigshospitalet	Copenhagen
Denmark	The Fertility Clinic, Skive Regional Hospital, Skive, Denmark	Skive
Spain	Hospital Universitario Quiron Dexeus	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario HM Monteprincipe	Madrid
Spain	Hospìtal Universitario HM Puerta del Sur	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Quiron Madrid Hospital	Madrid
Switzerland	University Hospital Basel	Basel

Sponsors (1)

Lead Sponsor	Collaborator
Institut Universitari Dexeus

Countries where clinical trial is conducted

Belgium,  Denmark,  Spain,  Switzerland, 

References & Publications (9)

Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod. 2000 Oct;15(10):2129-32. doi: 10.1093/humrep/15.10.2129. — View Citation

Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011 Jul;26(7):1616-24. doi: 10.1093/humrep/der092. Epub 2011 Apr 19. — View Citation

Fooladi E, Reuter SE, Bell RJ, Robinson PJ, Davis SR. Pharmacokinetics of a transdermal testosterone cream in healthy postmenopausal women. Menopause. 2015 Jan;22(1):44-9. doi: 10.1097/GME.0000000000000259. — View Citation

Gonzalez-Comadran M, Duran M, Sola I, Fabregues F, Carreras R, Checa MA. Effects of transdermal testosterone in poor responders undergoing IVF: systematic review and meta-analysis. Reprod Biomed Online. 2012 Nov;25(5):450-9. doi: 10.1016/j.rbmo.2012.07.011. Epub 2012 Jul 26. — View Citation

Kim CH, Howles CM, Lee HA. The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders. Fertil Steril. 2011 Feb;95(2):679-83. doi: 10.1016/j.fertnstert.2010.07.1077. — View Citation

Nathorst-Boos J, Jarkander-Rolff M, Carlstrom K, Floter A, von Schoultz B. Percutaneous administration of testosterone gel in postmenopausal women--a pharmacological study. Gynecol Endocrinol. 2005 May;20(5):243-8. doi: 10.1080/09513590500097283. — View Citation

Singh AB, Lee ML, Sinha-Hikim I, Kushnir M, Meikle W, Rockwood A, Afework S, Bhasin S. Pharmacokinetics of a testosterone gel in healthy postmenopausal women. J Clin Endocrinol Metab. 2006 Jan;91(1):136-44. doi: 10.1210/jc.2005-1640. Epub 2005 Nov 1. — View Citation

Vendola K, Zhou J, Wang J, Famuyiwa OA, Bievre M, Bondy CA. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod. 1999 Aug;61(2):353-7. doi: 10.1095/biolreprod61.2.353. — View Citation

Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab. 1999 Aug;84(8):2951-6. doi: 10.1210/jcem.84.8.5929. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse events	Any adverse event related with testosterone administration must be reported in Adverse Event Report Form	Up to 70 days from treatment start date
Primary	Clinical pregnancy	The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 7 weeks of gestation	7 weeks of gestation
Secondary	Ongoing pregnancy	The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 9-10 weeks of gestation.	9-10 weeks of gestation
Secondary	Biochemical pregnancy	Positive pregnancy test 2 weeks after embryo transfer	2 weeks after embryo transfer
Secondary	Number of oocytes retrieved	The outcome will be evaluated on the day of oocyte retrieval	9 -20 days from initiation of ovarian stimulation
Secondary	Number of MII oocytes retrieved	The outcome will be evaluated on the day of oocyte retrieval	9 -20 days from initiation of ovarian stimulation
Secondary	Cycle cancellation due to poor ovarian response	On stimulation day 10 (visit 8) the cycle will be cancelled in case of no follicular or monofollicular development	10 days after initiation of daily injections of HP-hMG
Secondary	Number of cycles reaching the stage of embryo transfer	The outcome will be evaluated 3 days after oocyte retrieval	9 -20 days from initiation of ovarian stimulation
Secondary	Number and quality of embryos	The outcome will be evaluated 3 days after oocyte retrieval	Day of embryo transfer (9 -20 days from initiation of ovarian stimulation)
Secondary	Number of cycles with frozen supernumerary embryos	The outcome will be evaluated 5 days after oocyte retrieval or 2-6 days after embryo transfer in case of an embryo transfer	9 -20 days from initiation of ovarian stimulation