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

Primary Purpose

Infertility, Poor Ovarian Response

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Testosterone gel
Placebo gel
Sponsored by
Institut Universitari Dexeus
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infertility

Eligibility Criteria

18 Years - 43 Years (Adult)FemaleDoes not accept healthy volunteers

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)

Sites / Locations

  • UZ Antwerp
  • Universitair Ziekenhuis BrusselRecruiting
  • Fertility Clinic Rigshospitalet
  • The Fertility Clinic, Skive Regional Hospital, Skive, DenmarkRecruiting
  • Hospital Universitario Quiron DexeusRecruiting
  • Hospital Universitario 12 de OctubreRecruiting
  • Hospital Universitario HM MonteprincipeRecruiting
  • Hospital Universitario La PazRecruiting
  • Hospìtal Universitario HM Puerta del SurRecruiting
  • Quiron Madrid HospitalRecruiting
  • University Hospital BaselRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Transdermal testosterone gel

Placebo transdermal gel

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

Clinical pregnancy
The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 7 weeks of gestation

Secondary Outcome Measures

Ongoing pregnancy
The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 9-10 weeks of gestation.
Biochemical pregnancy
Positive pregnancy test 2 weeks after embryo transfer
Number of oocytes retrieved
The outcome will be evaluated on the day of oocyte retrieval
Number of MII oocytes retrieved
The outcome will be evaluated on the day of oocyte retrieval
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
Number of cycles reaching the stage of embryo transfer
The outcome will be evaluated 3 days after oocyte retrieval
Number and quality of embryos
The outcome will be evaluated 3 days after oocyte retrieval
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

Full Information

First Posted
April 13, 2015
Last Updated
May 12, 2023
Sponsor
Institut Universitari Dexeus
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1. Study Identification

Unique Protocol Identification Number
NCT02418572
Brief Title
Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial
Acronym
T-TRANSPORT
Official Title
Transdermal Testosterone Gel for Poor Ovarian Responders. A Multicenter Double-blind Placebo Controlled Randomized Trial
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 2015 (undefined)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Institut Universitari Dexeus

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility, Poor Ovarian Response

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Transdermal testosterone gel
Arm Type
Experimental
Arm Description
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).
Arm Title
Placebo transdermal gel
Arm Type
Placebo Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Testosterone gel
Other Intervention Name(s)
Androgel 1% 0.55 gr / day
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Placebo gel
Intervention Description
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
Primary Outcome Measure Information:
Title
Clinical pregnancy
Description
The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 7 weeks of gestation
Time Frame
7 weeks of gestation
Secondary Outcome Measure Information:
Title
Ongoing pregnancy
Description
The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 9-10 weeks of gestation.
Time Frame
9-10 weeks of gestation
Title
Biochemical pregnancy
Description
Positive pregnancy test 2 weeks after embryo transfer
Time Frame
2 weeks after embryo transfer
Title
Number of oocytes retrieved
Description
The outcome will be evaluated on the day of oocyte retrieval
Time Frame
9 -20 days from initiation of ovarian stimulation
Title
Number of MII oocytes retrieved
Description
The outcome will be evaluated on the day of oocyte retrieval
Time Frame
9 -20 days from initiation of ovarian stimulation
Title
Cycle cancellation due to poor ovarian response
Description
On stimulation day 10 (visit 8) the cycle will be cancelled in case of no follicular or monofollicular development
Time Frame
10 days after initiation of daily injections of HP-hMG
Title
Number of cycles reaching the stage of embryo transfer
Description
The outcome will be evaluated 3 days after oocyte retrieval
Time Frame
9 -20 days from initiation of ovarian stimulation
Title
Number and quality of embryos
Description
The outcome will be evaluated 3 days after oocyte retrieval
Time Frame
Day of embryo transfer (9 -20 days from initiation of ovarian stimulation)
Title
Number of cycles with frozen supernumerary embryos
Description
The outcome will be evaluated 5 days after oocyte retrieval or 2-6 days after embryo transfer in case of an embryo transfer
Time Frame
9 -20 days from initiation of ovarian stimulation
Other Pre-specified Outcome Measures:
Title
Adverse events
Description
Any adverse event related with testosterone administration must be reported in Adverse Event Report Form
Time Frame
Up to 70 days from treatment start date

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
43 Years
Accepts Healthy Volunteers
No
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: 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). Exclusion Criteria: 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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nikolaos P Polyzos, MD PhD
Phone
0034932274700
Email
nikpol@dexeus.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nikolaos P Polyzos, MD PhD
Organizational Affiliation
Institut Universitari Dexeus
Official's Role
Principal Investigator
Facility Information:
Facility Name
UZ Antwerp
City
Antwerp
Country
Belgium
Individual Site Status
Withdrawn
Facility Name
Universitair Ziekenhuis Brussel
City
Brussels
ZIP/Postal Code
1090
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
C P Blockeel
Facility Name
Fertility Clinic Rigshospitalet
City
Copenhagen
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A Pinborg
Facility Name
The Fertility Clinic, Skive Regional Hospital, Skive, Denmark
City
Skive
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Humaidan
Facility Name
Hospital Universitario Quiron Dexeus
City
Barcelona
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pedro N Barri, MD PhD
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
L De La Fuente
Facility Name
Hospital Universitario HM Monteprincipe
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
I Bruna
Facility Name
Hospital Universitario La Paz
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
S Iniesta
Facility Name
Hospìtal Universitario HM Puerta del Sur
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
I Bruna
Facility Name
Quiron Madrid Hospital
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Antonio Gosálvez Vega
Facility Name
University Hospital Basel
City
Basel
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christian De Geyter, MD PhD

12. IPD Sharing Statement

Citations:
PubMed Identifier
11006185
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.
Results Reference
background
PubMed Identifier
22999555
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.
Results Reference
background
PubMed Identifier
10411511
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.
Results Reference
background
PubMed Identifier
10443703
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.
Results Reference
background
PubMed Identifier
20801436
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.
Results Reference
background
PubMed Identifier
16263817
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.
Results Reference
background
PubMed Identifier
16019368
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.
Results Reference
background
PubMed Identifier
24845394
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.
Results Reference
background
PubMed Identifier
21505041
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.
Results Reference
background

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Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial

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