Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial

NCT02418572 | Terminated Phase 3 DMC

• 2 other identifiers: 2014.TTRANSPORT2014-001835-35
• Study Type: interventional
• Target: 290
• Locations: 4 countries
• Sites: 10

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.

Conditions

Infertility; Poor Ovarian Response

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Ongoing pregnancy

  9-10 weeks of gestation

• Biochemical pregnancy

  2 weeks after embryo transfer

• Number of oocytes retrieved

  9 -20 days from initiation of ovarian stimulation

• Number of MII oocytes retrieved

  9 -20 days from initiation of ovarian stimulation

• Cycle cancellation due to poor ovarian response

  10 days after initiation of daily injections of HP-hMG

Other Outcomes (1)

• Adverse events

  Up to 70 days from treatment start date

Study Arms (2)

Transdermal testosterone gel

EXPERIMENTAL

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

Placebo transdermal gel

PLACEBO COMPARATOR

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

Interventions

Testosterone gel DRUG

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)

Also known as: Androgel 1% 0.55 gr / day

Transdermal testosterone gel

Placebo gel DRUG

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

Placebo transdermal gel

Eligibility Criteria

• Age: 18 Years - 43 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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)

Sponsors & Collaborators

• Fundacion Dexeus: lead

Study Sites (10)

Universitair Ziekenhuis Brussel

Brussels, 1090, Belgium

Location

Fertility Clinic Rigshospitalet

Copenhagen, Denmark

Location

The Fertility Clinic, Skive Regional Hospital, Skive, Denmark

Skive, Denmark

Location

Hospital Universitario Quiron Dexeus

Barcelona, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario HM Monteprincipe

Madrid, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

Hospìtal Universitario HM Puerta del Sur

Madrid, Spain

Location

Quiron Madrid Hospital

Madrid, Spain

Location

University Hospital Basel

Basel, Switzerland

Location

Related Publications (10)

• 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.

  PMID: 11006185 BACKGROUND

• 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.

  PMID: 22999555 BACKGROUND

• 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.

  PMID: 10411511 BACKGROUND

• 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.

  PMID: 10443703 BACKGROUND

• 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.

  PMID: 20801436 BACKGROUND

• 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.

  PMID: 16263817 BACKGROUND

• 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.

  PMID: 16019368 BACKGROUND

• 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.

  PMID: 24845394 BACKGROUND

• 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.

  PMID: 21505041 BACKGROUND

• Leathersich SJ, Davis SR, Garcia Martinez S, Blockeel C, Martinez F, Gosalvez A, Humaidan P, de la Fuente L, Fabregues F, Pinborg A, Stoop D, Polyzos NP. The impact of transdermal testosterone treatment on quality of life in women with diminished ovarian reserve: secondary analysis of a randomized controlled trial. Hum Reprod. 2025 Dec 29:deaf233. doi: 10.1093/humrep/deaf233. Online ahead of print.

  PMID: 41461161 DERIVED

MeSH Terms

Conditions

Infertility

Interventions

Testosterone

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Androstenols; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Testosterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Nikolaos P Polyzos, MD PhD

  Fundacion Dexeus

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 13, 2015
• First Posted: April 16, 2015
• Study Start: April 1, 2015
• Primary Completion: December 1, 2023
• Study Completion: February 1, 2024
• Last Updated: May 22, 2024

Record last verified: 2024-05

Locations

DK (2); BE (1); CH (1); ES (6)