Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial (T-TRANSPORT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Infertility; Poor Ovarian Response
• Intervention / Treatment: Drug: Testosterone gel; Drug: Placebo gel

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 Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Nikolaos P Polyzos, MD PhD; Phone Number: 0034932274700; Email: nikpol@dexeus.com

Study Locations

• Belgium
  • Antwerp, Belgium
    • Withdrawn
    • UZ Antwerp
  • Brussels, Belgium, 1090
    • Recruiting
    • Universitair Ziekenhuis Brussel
    • Contact: C P Blockeel
• Denmark
  • Copenhagen, Denmark
    • Not yet recruiting
    • Fertility Clinic Rigshospitalet
    • Contact: A Pinborg
  • Skive, Denmark
    • Recruiting
    • The Fertility Clinic, Skive Regional Hospital, Skive, Denmark
    • Contact: Peter Humaidan
• Spain
  • Barcelona, Spain
    • Recruiting
    • Hospital Universitario Quiron Dexeus
    • Contact: Pedro N Barri, MD PhD
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario 12 de octubre
    • Contact: L De La Fuente
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario La Paz
    • Contact: S Iniesta
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Hm Puerta Del Sur
    • Contact: I Bruna
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario HM Monteprincipe
    • Contact: I Bruna
  • Madrid, Spain
    • Recruiting
    • Quiron Madrid Hospital
    • Contact: Antonio Gosálvez Vega
• Switzerland
  • Basel, Switzerland
    • Recruiting
    • University Hospital Basel
    • Contact: Christian De Geyter, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 41 years (Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Biochemical pregnancy	Positive pregnancy test 2 weeks after embryo transfer	2 weeks after embryo transfer
Number of oocytes retrieved	The outcome will be evaluated on the day of oocyte retrieval	9 -20 days from initiation of ovarian stimulation
Number of MII oocytes retrieved	The outcome will be evaluated on the day of oocyte retrieval	9 -20 days from initiation of ovarian stimulation
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
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
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)
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: April 13, 2015
• First Submitted That Met QC Criteria: April 15, 2015
• First Posted (Estimate): April 16, 2015

Study Record Updates

• Last Update Posted (Actual): May 15, 2023
• Last Update Submitted That Met QC Criteria: May 12, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Androgens; Testosterone
• Other Study ID Numbers: 2014.TTRANSPORT; 2014-001835-35 (EudraCT Number)