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Recombinant LH Prior to Ovarian Stimulation in Poor Ovarian Responders (PRE-LH) (PRE-LH)

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ClinicalTrials.gov Identifier: NCT03741699
Recruitment Status : Recruiting
First Posted : November 15, 2018
Last Update Posted : March 12, 2019
Sponsor:
Collaborators:
Merck, S.L., Spain
Syntax for Science, S.L
Fundación IVI
Information provided by (Responsible Party):
Instituto Valenciano de Infertilidad, IVI Alicante

Brief Summary:

Controlled ovarian stimulation (COS) is one of the first stages of assisted reproductive treatment. The goal is to mimic the ovarian cycle while stimulating the ovaries to overproduce eggs capable of being fertilized, thus maximizing the chances of reproductive success. The stimulation phase involves the use of different hormonal medications but requires tests to check the development of follicles, and hormonal adjustment to get the optimal ovarian response to stimulation.

However, between 9 to 24% of patients fail to respond adequately to standard stimulation protocols, resulting in Poor Ovarian Response (POR). In addition to the low oocyte production, POR results in a restricted number of good quality embryos with appropriate implantation potential, suggesting a compromised oocyte quality.

POR is one of the most challenging problems in reproductive medicine. Poor responders are difficult to treat since their response to stimulation tend to be deficient even when using different drugs or protocols. In recent years, different therapeutic alternatives have been proposed for these patients. However, to date, the optimal stimulation protocol has not yet been described and oocyte donation is often offered as their only option to achieve pregnancy.

Recently, evidence has emerged that supplementation with a specific hormone, luteinizing hormone (LH), during or prior to COS could lead to improved reproductive outcomes in poor responders by increasing the number of oocytes retrieved and improving their quality.

The present study aims to evaluate the effect of the treatment with LH prior to COS on the ovarian response in patients with POR and advanced maternal age, the worst prognosis but more frequent group of poor responders attending fertility clinics. We will assess whether LH treatment prior to COS increases the number and quality of oocytes retrieved in those patients and, finally, analyse the impact in their chances of getting pregnant and having a baby.


Condition or disease Intervention/treatment Phase
Infertility, Female Drug: Pre-treatment with rLH (Luveris 75 IU), Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: prospective, interventional, randomised, unblinded and controlled study with 2 parallel groups
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Multicentre, Randomized, Unblinded Clinical Trial to Test the Effect of Treatment With Recombinant LH Prior to Controlled Ovarian Stimulation in Poor Ovarian Responder Women With an Advanced Maternal Age
Actual Study Start Date : February 18, 2019
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm 1 - experimental group
Treatment with 150 IU/day rLH, administered subcutaneously for 4 consecutive days prior to COS (with a starting dose of 225 IU/day rFSH and 75 IU/day rLH for 18 days maximum in a short antagonist protocol).
Drug: Pre-treatment with rLH (Luveris 75 IU),
Treatment with 150 IU/day rLH (Luveris 75 IU), administered subcutaneously for 4 consecutive days prior to COS (Controlled ovarian stimulation)

No Intervention: Arm 2 - control (no pre-treatment) group
The subjects assigned to this group will not receive any treatment in the four days prior to COS (with a starting dose of 225 IU/day rFSH and 75 IU/day rLH for 18 days maximum in a short antagonist protocol).



Primary Outcome Measures :
  1. number of oocytes retrieved [ Time Frame: 37 days ]
    number of oocytes retrieved


Secondary Outcome Measures :
  1. Number of follicles >17 mm on the previous day or the day of GnRH agonist injection (Decapeptyl) [ Time Frame: from day 8-12 to day 33-37 ]
  2. P 4 and E 2 levels on the previous day or the day of GnRH agonist injection [ Time Frame: from day 8-12 to day 33-37 ]
  3. Duration of stimulation and total gonadotropin dose during COS [ Time Frame: from day 8-12 to day 33-37 ]
  4. Serum hormonal profile before and after IMP treatment and after stimulation [ Time Frame: from day 8-12 to day 33-37 ]
  5. Cycle cancellation rates (stimulation cycle cancelled prior to oocyte retrieval if there is no follicular response after 10 days of stimulation or due to premature ovulation at any time before oocyte retrieval) [ Time Frame: from day 8-12 to day 33-37 ]
  6. Number of mature or metaphase II (MII) oocytes/number of oocytes retrieved per puncture [ Time Frame: Day 37 ]
  7. Number of retrieved oocytes/number of expected oocytes (follicles >15 mm on the day of GnRH agonist injection) [ Time Frame: Day 37 ]
  8. Fertilization rate [ Time Frame: Day 38 ]
  9. Hormonal profile in follicular fluid on the day of the puncture [ Time Frame: Day 37 ]
  10. Gene expression profile in granulosa cells [ Time Frame: Day 37 ]
  11. Apoptosis rate in granulosa cells [ Time Frame: Day 37 ]
  12. Morphological variables of embryonic quality [ Time Frame: Day 38 to 43 ]
  13. Blastocyst rate [ Time Frame: Day 43 ]
  14. Number of optimal embryos (type A or B, according to ASEBIR classification) [ Time Frame: Day 43 ]
  15. Number of euploid and aneuploid embryos [ Time Frame: Day 50 ]
  16. Stimulation cycle yield (number of frozen embryos). [ Time Frame: Day 43 ]
  17. Number of cycles with embryo transferred/ number of stimulation cycle started [ Time Frame: Day 43 ]
  18. Pregnancy rates (per stimulation cycle and embryo transfer) [ Time Frame: Throughout the study, estimate 1 year ]
  19. Implantation rates [ Time Frame: Throughout the study, estimate 1 year ]
  20. Ongoing pregnancy rates (per stimulation cycle and embryo transfer) [ Time Frame: Throughout the study, estimate 1 year ]
  21. Clinical and biochemical miscarriages rates (per stimulation cycle and embryo transfer) [ Time Frame: Throughout the study, estimate 1 year ]
  22. Ectopic pregnancy rates (per stimulation cycle and embryo transfer) [ Time Frame: Throughout the study, estimate 1 year ]
  23. Live birth rates [ Time Frame: Throughout the study, estimate 18 +/-3 months ]
  24. Assessment and recording of adverse events [ Time Frame: Throughout the study, estimate 18 +/-3 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   35 Years to 43 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Only females
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. -Patients with POR according to specific criteria that are in line with the criteria defined by the ESHRE (Bologna Criteria), according to which a patient is classified as a poor ovarian responder when she meets two of the three of the following criteria: I.- Previous episode of POR (≤3 oocytes) with conventional stimulation protocol II.- Abnormal ovarian reserve test with an antral follicle count (AFC) <5-7 and/or anti-mullerian hormone values (AMH) <0.5-1.1 ng/mL.

    III.- Women ≥40 years old and/or who have any other risk factor for POR. In addition, two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ovarian reserve test.

  2. - Women ≥35 to ≤43 years for COS and assisted reproduction techniques (ART).
  3. - Couple or single woman, accepting preimplantation genetic diagnosis (PGS) after blastocyst biopsy and delayed transfer for selection of euploid embryos.
  4. - Body Mass Index (BMI) between18 and 30 kg/m 2 , inclusive.
  5. - Ejaculatory sperm with concentration ≥ 5 mill spermatozoa/mL and ≥ 5 mill total spermatozoa progressive motility. Bank and cryopreserved semen allowed.
  6. - Informed consent completed, signed and dated.

Exclusion Criteria:

  1. - Cases of recurrent spontaneous miscarriage (≥2 clinical miscarriages) or implantation failure (after transfer of 6 good D3 embryos or 4 good blastocysts) will be excluded.
  2. - Use of testicular or epididymal spermatozoa as well as ejaculate with concentration < 5 mill spermatozoa/mL and < 5 mill total spermatozoa progressive motility.
  3. - Primary ovarian failure, PCOS (in accordance with the Rotterdam criteria) or ovary/s inaccessible for oocyte retrieval.
  4. - Anatomical uterine abnormalities and any endometrium or myometrium pathology (adenomyosis, polyps, myoma, etc.) that may interfere with implantation or pregnancy. Patients with previous polypectomy, myomectomy or surgery for septate/subseptate/arcuatus uterus should not be excluded.
  5. - Presence of unilateral or bilateral hydrosalpinx that has not been surgically removed or ligated.
  6. - Presence of level III-IV endometriosis.
  7. - History of tumours in the hypothalamus or pituitary gland, or ovarian, uterine or breast cancer.
  8. - Abnormal bleeding of undetermined origin.
  9. - Known infection with human immunodeficiency virus, active hepatitis B or C virus in the woman or her partner.
  10. - Known allergy or hypersensitivity to the drugs administered during the trial.
  11. - Concurrent significant medical pathologies that would endanger the patient's safety (uncontrolled thyroid or adrenal dysfunction, severe hepatic or renal impairment, etc.) or interfere with the test evaluations or the clinical outcomes (i.e. confirmed thrombophilia).
  12. - Use of concomitant medication or any other circumstances that, in the opinion of the investigator, interferes with the development of the trial or does not ensure the safety and efficacy of the data.
  13. - Simultaneous participation in another clinical trial or previous participation in this study.
  14. - Participation in another clinical study two months before inclusion in the present study that could affect its objectives.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03741699


Contacts
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Contact: Manuel Muñoz, Dr. +34 966 01 24 90 Manuel.munoz@ivirma.com

Locations
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Spain
IVI Alicante Recruiting
Alicante, Comunidad Valenciana, Spain, 03015
Contact: Manuel Muñoz Cantero, Dr.         
Principal Investigator: Manuel Muñoz         
IVI Madrid Recruiting
Madrid, Spain, 28023
Contact: Juan Antonio García Velasco, Dr.         
Principal Investigator: Juan Antonio García Velasco         
IVI Murcia Recruiting
Murcia, Spain, 30007
Contact: Jose Landeras Gutiérrez, Dr.         
Principal Investigator: Jose Landeras Gutiérrez         
Sponsors and Collaborators
Instituto Valenciano de Infertilidad, IVI Alicante
Merck, S.L., Spain
Syntax for Science, S.L
Fundación IVI
Investigators
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Principal Investigator: Manuel Muñoz, Dr. Physician - Investigator

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Responsible Party: Instituto Valenciano de Infertilidad, IVI Alicante
ClinicalTrials.gov Identifier: NCT03741699     History of Changes
Other Study ID Numbers: 1601-ALC-002-MM
2017-004298-15 ( EudraCT Number )
First Posted: November 15, 2018    Key Record Dates
Last Update Posted: March 12, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Instituto Valenciano de Infertilidad, IVI Alicante:
Poor ovarian response
Recombinant LH
Advanced maternal age
Oocyte retrieved

Additional relevant MeSH terms:
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Infertility
Infertility, Female
Genital Diseases, Male
Genital Diseases, Female