Clinical Trial to Assess the Effect of Testosterone in Patients With Poor Ovarian Response (TESTOPRIM)

Infertility, Female Clinical Trial

— TESTOPRIM  

Official title:

Clinical Effect of Follicular Preparation With Testosterone in Poor Ovarian Response: a Randomized Controlled Clinical Trial (TESTOPRIM)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03378713
• Other study ID #: TESTOPRIM
• Status: Completed
• Phase: Phase 3
• Start date: August 7, 2017
• Est. completion date: February 11, 2019

Study information

• Verified date: February 2019
• Source: Instituto de Investigacion Sanitaria La Fe
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Trial to determine the absolute and relative efficacy of two follicular preparation regimens with transdermal testosterone during the cycle (s) prior to the initiation of COS (controlled ovarian stimulation) in patients diagnosed with POR (poor ovarian response) for the increase in the number of mature oocytes recovered.

Description:

POR is a challenge for reproductive medicine because of its impact on treatment outcomes and the lack of sufficiently proven therapeutic tools. According to recent publications based on retrospective studies of large registries, there is a correlation between the number of oocytes and LBR (live birth rate), so the investigators consider that variable mature oocytes are a reasonable compromise and a solid substitute for other outcome variables such as LBR or CPR (clinical pregnancy rate).

Regarding the duration of treatment, the investigators decided to include two groups of testosterone treatment (compared to the control group) with different duration. One will explore the role of testosterone in prolonged treatments (two full menstrual cycles). The other will test the pattern most commonly used in most studies, that is, testosterone in luteal phase of the previous cycle (about 10 days in short protocol with GnRH antagonist). In this way the investigators will establish an absolute comparison with the control group and relative between both treatment groups (long testosterone vs. short testosterone) to determine if / which of the two regimen (the two, only one or none) improves the number of mature oocytes recovered.

The product under investigation is testosterone gel, transdermal administration, 50 mg / single dose (Testim®, Ferring, Madrid, Spain). Regarding the dose, the investigators decided to keep the most used in the rest of studies (12.5 mg / day).

This study population will include only patients diagnosed with POR based on ESHRE Bologna criteria, in order to homogenize the population and allow comparisons with other studies in the future.

Regarding the dose, the investigators decided to keep the most used in the rest of studies (12.5 mg/day) which so far has been the only one proven effective. It is clearly possible that lower and more physiological doses are equally effective, but this yet has to be proven in well-designed studies. The gel is self-administered by the patients who are adequately instructed by a research nurse.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: February 11, 2019
• Est. primary completion date: February 11, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed Informed consent prior to the completion of any procedure related to the clinical trial.

• Female older than 18 years old at the time of randomization.

• Prior diagnosis of poor ovarian response (POR) according to ESHRE Bologna criteria. Patients must meet at least 2 of the following:

• Advanced maternal age (40 years or more) or any other risk factor for POR.

• A previous POR (3 oocytes or less) with a conventional ovarian stimulation protocol.

• Abnormal ovarian reserve test (RFA <5-7 or AMH 3.3-7.9 pmol / l).

Exclusion Criteria:

• Presence of uterine malformations, corrected or not.

• Presence of uterine pathology defined as submucous myomas or endometrial polyps, documented by transvaginal ultrasound.

• Couples with severe male factor defined as REM <1 or azoospermia.

• Hydrosalpinx unilateral or bilateral uncorrected.

• Perimenopausal patients with irregular menstrual cycles.

• Concurrent untreated endocrine disorders.

• Patients who have participated in a clinical trial in a period of less than one month.

• Known allergy to the drug.

• Patients who have received androgen treatment within 3 months prior to inclusion in the study.

• BMI> 35 kg / m2

Related Conditions & MeSH terms

• Infertility
• Infertility, Female

Intervention

Drug:
• GROUP 1: Long testosterone
Application of testosterone in transdermal gel during the 2 cycles prior to initiation of controlled ovarian stimulation and until the onset of second menstruation (approximately 56 days). The COS begins the day after the last testosterone application
• GROUP 2: Short testosterone
Application of testosterone in transdermal gel begins on day 21 of menstrual cycle, from the luteal phase of the cycle prior to initiation of controlled ovarian stimulation and until menstruation (approximately 10 days). The COS begins the day after the last testosterone application.
• GROUP 3: Control
The COS starts directly on the second day of the cycle without prior medication.

Locations

Country	Name	City	State
Spain	Hospital Universitario y Politécnico La Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Instituto de Investigacion Sanitaria La Fe

Country where clinical trial is conducted

Spain, 

References & Publications (27)

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Balasch J, Fábregues F, Peñarrubia J, Carmona F, Casamitjana R, Creus M, Manau D, Casals G, Vanrell JA. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum Reprod. 2006 Jul;21(7):1884-93. Epub 2006 Mar 3. — View Citation

Bastu E, Buyru F, Ozsurmeli M, Demiral I, Dogan M, Yeh J. A randomized, single-blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. Eur J Obstet Gynecol Reprod Biol. 2016 Aug;203:30-4. doi: 10.1016/j.ejogrb.2016.05.027. Epub 2016 May 24. — View Citation

Bosdou JK, Venetis CA, Dafopoulos K, Zepiridis L, Chatzimeletiou K, Anifandis G, Mitsoli A, Makedos A, Messinis IE, Tarlatzis BC, Kolibianakis EM. Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial. Hum Reprod. 2016 May;31(5):977-85. doi: 10.1093/humrep/dew028. Epub 2016 Mar 7. — View Citation

Bosdou JK, Venetis CA, Kolibianakis EM, Toulis KA, Goulis DG, Zepiridis L, Tarlatzis BC. The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update. 2012 Mar-Apr;18(2):127-45. doi: 10.1093/humupd/dmr051. Epub 2012 Feb 3. Review. — View Citation

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Escriva AM, Diaz-Garcia C, Monterde M, Rubio JM, Pellicer A. Antral Follicle Priming Before Intracytoplasmic Sperm Injection in Previously Diagnosed Low Responders: A Randomized Controlled Trial (FOLLPRIM). J Clin Endocrinol Metab. 2015 Jul;100(7):2597-605. doi: 10.1210/jc.2015-1194. Epub 2015 May 8. — View Citation

Fábregues F, Peñarrubia J, Creus M, Manau D, Casals G, Carmona F, Balasch J. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial. Hum Reprod. 2009 Feb;24(2):349-59. doi: 10.1093/humrep/den428. Epub 2008 Dec 3. — View Citation

Fanchin R, Cunha-Filho JS, Schonäuer LM, Kadoch IJ, Cohen-Bacri P, Frydman R. Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens. Fertil Steril. 2003 Feb;79(2):316-21. — 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

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Jeve YB, Bhandari HM. Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis. J Hum Reprod Sci. 2016 Apr-Jun;9(2):70-81. doi: 10.4103/0974-1208.183515. Review. — View Citation

Kim CH, Ahn JW, Moon JW, Kim SH, Chae HD, Kang BM. Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders. Dev Reprod. 2014 Sep;18(3):145-52. doi: 10.12717/DR.2014.18.3.145. — 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

Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J, Tarlatzis BC. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril. 2009 Mar;91(3):749-66. doi: 10.1016/j.fertnstert.2007.12.077. Epub 2008 Jul 21. Review. — View Citation

Massin N, Cedrin-Durnerin I, Coussieu C, Galey-Fontaine J, Wolf JP, Hugues JN. Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique--a prospective, randomized, double-blind study. Hum Reprod. 2006 May;21(5):1204-11. Epub 2006 Feb 13. — View Citation

National Collaborating Centre for Women’s and Children’s Health (UK). Fertility: Assessment and Treatment for People with Fertility Problems. London: Royal College of Obstetricians & Gynaecologists; 2013 Feb. — View Citation

Nielsen ME, Rasmussen IA, Kristensen SG, Christensen ST, Møllgård K, Wreford Andersen E, Byskov AG, Yding Andersen C. In human granulosa cells from small antral follicles, androgen receptor mRNA and androgen levels in follicular fluid correlate with FSH receptor mRNA. Mol Hum Reprod. 2011 Jan;17(1):63-70. doi: 10.1093/molehr/gaq073. Epub 2010 Sep 14. — View Citation

Pandian Z, McTavish AR, Aucott L, Hamilton MP, Bhattacharya S. Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev. 2010 Jan 20;(1):CD004379. doi: 10.1002/14651858.CD004379.pub3. Review. — View Citation

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Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011 Jul;26(7):1768-74. doi: 10.1093/humrep/der106. Epub 2011 May 10. — View Citation

Tarlatzis BC, Zepiridis L, Grimbizis G, Bontis J. Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update. 2003 Jan-Feb;9(1):61-76. Review. — View Citation

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* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total number of mature oocytes obtained at follicular puncture.	Determining whether a Follicular preparation with transdermal testosterone increases the number of mature oocytes retrieved in patients diagnosed with Poor Ovarian Response and which testosterone administration regimen is more effective for this purpose.	36 hours after induction of ovulation with recombinant HCG.
Secondary	Number of obtained embryos		6 days after ovarian puncture.
Secondary	Number of antral follicles at the start of stimulation		Time E: prior to controlled ovarian stimulation (at the beginning of the third cycle after inclusion and randomization, approximately 56 days after Day 0)
Secondary	Initiation rate	Quotient between the number of patients initiating COS and the total number of patients, overall and in each group	Time E: prior to controlled ovarian stimulation (at the beginning of the third cycle after inclusion and randomization, approximately 56 days after Day 0)
Secondary	Number of days of stimulation duration		Time P (time of follicular puncture): 36 hours after the induction
Secondary	Number of total follicles and greater than 16 mm		Time I (Day of induction): 10-12 days after controlled ovarian stimulation
Secondary	Total dose of gonadotrophins used		Time I (Day of induction): 10-12 days after controlled ovarian stimulation
Secondary	Cancellation rate due to lack of ovarian response		Time C: 10-12 days after controlled ovarian stimulation
Secondary	Number of cumulus-oocyte complexes recovered on day of follicular puncture		Time P (time of follicular puncture): 36 hours after the induction
Secondary	Fertilization rate		24 hours after the puncture
Secondary	Rate of cycles that achieve embryo transfer		Time ET ( day of embryo transfer): 4-5 days after the stimulation
Secondary	Number of good quality embryos available		48-72 hours after puncture
Secondary	Number of embryos transferred		Time ET (day of embryo transfer): 4-5 days after the stimulation
Secondary	Number of cycles with supernumerary embryos to freeze		6 days after embryo transfer
Secondary	Ongoing pregnancy rate per cycle started and per transfer		70-75 days after embryo transfer
Secondary	Clinical pregnancy rate per cycle started and per transfer		30-35 days after embryo transfer
Secondary	Miscarriage rate		At 11-13 weeks of pregnancy, if there is no previous news of the patient (Trial completion time)
Secondary	Serum hormone levels	Serum hormone levels of FSH, LH, E2, progesterone, testosterone, androstenedione, DHEA, SHBG and FAI	Day 0; Time I (day of induction): 10-12 days after controlled ovarian stimulation; and Time E (prior to controlled ovarian stimulation: at the beginning of the third cycle after inclusion and randomization, approximately 56 days after Day 0)