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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Infertility, Female

Intervention / Treatment
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* Drug: GROUP 1: Long testosterone
* Drug: GROUP 2: Short testosterone
* Drug: GROUP 3: Control


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GROUP 1: Long testosterone<br>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. | Drug: GROUP 1: Long testosterone<br>* 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<br>|
| Active Comparator: GROUP 2: Short testosterone<br>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. | Drug: GROUP 2: Short testosterone<br>* 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.<br>|
| Active Comparator: GROUP 3: Control<br>The COS starts directly on the second day of the cycle without prior medication. | Drug: GROUP 3: Control<br>* The COS starts directly on the second day of the cycle without prior medication.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of obtained embryos |  | 6 days after ovarian puncture. | 
| 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) | 
| 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) | 
| Number of days of stimulation duration |  | Time P (time of follicular puncture): 36 hours after the induction | 
| Number of total follicles and greater than 16 mm |  | Time I (Day of induction): 10-12 days after controlled ovarian stimulation | 
| Total dose of gonadotrophins used |  | Time I (Day of induction): 10-12 days after controlled ovarian stimulation | 
| Cancellation rate due to lack of ovarian response |  | Time C: 10-12 days after controlled ovarian stimulation | 
| Number of cumulus-oocyte complexes recovered on day of follicular puncture |  | Time P (time of follicular puncture): 36 hours after the induction | 
| Fertilization rate |  | 24 hours after the puncture | 
| Rate of cycles that achieve embryo transfer |  | Time ET ( day of embryo transfer): 4-5 days after the stimulation | 
| Number of good quality embryos available |  | 48-72 hours after puncture | 
| Number of embryos transferred |  | Time ET (day of embryo transfer): 4-5 days after the stimulation | 
| Number of cycles with supernumerary embryos to freeze |  | 6 days after embryo transfer | 
| Ongoing pregnancy rate per cycle started and per transfer |  | 70-75 days after embryo transfer | 
| Clinical pregnancy rate per cycle started and per transfer |  | 30-35 days after embryo transfer | 
| Miscarriage rate |  | At 11-13 weeks of pregnancy, if there is no previous news of the patient (Trial completion time) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Poor Ovarian Response