Clinical trial NCT02418572: Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial
Official title: Transdermal Testosterone Gel for Poor Ovarian Responders. A Multicenter Double-blind Placebo Controlled Randomized Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Infertility
Poor Ovarian Response
Lead sponsor: Fundacion Dexeus
Sponsor class: OTHER
First posted: 2015-04-16
Enrollment: 290
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 43
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Clinical pregnancy
timeFrame: 7 weeks of gestation
Secondary outcomes:
measure: Ongoing pregnancy
timeFrame: 9-10 weeks of gestation
measure: Biochemical pregnancy
timeFrame: 2 weeks after embryo transfer
measure: Number of oocytes retrieved
timeFrame: 9 -20 days from initiation of ovarian stimulation
measure: Number of MII oocytes retrieved
timeFrame: 9 -20 days from initiation of ovarian stimulation
measure: Cycle cancellation due to poor ovarian response
timeFrame: 10 days after initiation of daily injections of HP-hMG
measure: Number of cycles reaching the stage of embryo transfer
timeFrame: 9 -20 days from initiation of ovarian stimulation
measure: Number and quality of embryos
timeFrame: Day of embryo transfer (9 -20 days from initiation of ovarian stimulation)
measure: Number of cycles with frozen supernumerary embryos
timeFrame: 9 -20 days from initiation of ovarian stimulation
Other outcomes:
measure: Adverse events
timeFrame: Up to 70 days from treatment start date
Locations:
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Copenhagen
country: Denmark
facility: Fertility Clinic Rigshospitalet
city: Skive
country: Denmark
facility: The Fertility Clinic, Skive Regional Hospital, Skive, Denmark
city: Barcelona
country: Spain
facility: Hospital Universitario Quiron Dexeus
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario HM Monteprincipe
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospìtal Universitario HM Puerta del Sur
city: Madrid
country: Spain
facility: Quiron Madrid Hospital
city: Basel
country: Switzerland
facility: University Hospital Basel
Study officials:
affiliation: Fundacion Dexeus
name: Nikolaos P Polyzos, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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.
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.
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.
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.
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.
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.
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.