Clinical trial NCT03741699: Recombinant LH Prior to Ovarian Stimulation in Poor Ovarian Responders (PRE-LH)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility, Female
Keywords: Poor ovarian response
Recombinant LH
Advanced maternal age
Oocyte retrieved
Lead sponsor: Instituto Valenciano de Infertilidad, IVI Alicante
Sponsor class: OTHER
Collaborators: name: Merck, S.L., Spain
name: Syntax for Science, S.L
name: Fundación IVI
First posted: 2018-11-15
Enrollment: 88
Sex: FEMALE
Minimum age (years): 35
Maximum age (years): 43
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: prospective, interventional, randomised, unblinded and controlled study with 2 parallel groups
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: number of oocytes retrieved
timeFrame: 37 days
Secondary outcomes:
measure: Number of follicles >17 mm on the previous day or the day of GnRH agonist injection (Decapeptyl)
timeFrame: from day 8-12 to day 33-37
measure: P 4 and E 2 levels on the previous day or the day of GnRH agonist injection
timeFrame: from day 8-12 to day 33-37
measure: Duration of stimulation and total gonadotropin dose during COS
timeFrame: from day 8-12 to day 33-37
measure: Serum hormonal profile before and after IMP treatment and after stimulation
timeFrame: from day 8-12 to day 33-37
measure: 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)
timeFrame: from day 8-12 to day 33-37
measure: Number of mature or metaphase II (MII) oocytes/number of oocytes retrieved per puncture
timeFrame: Day 37
measure: Number of retrieved oocytes/number of expected oocytes (follicles >15 mm on the day of GnRH agonist injection)
timeFrame: Day 37
measure: Fertilization rate
timeFrame: Day 38
measure: Hormonal profile in follicular fluid on the day of the puncture
timeFrame: Day 37
measure: Gene expression profile in granulosa cells
timeFrame: Day 37
measure: Apoptosis rate in granulosa cells
timeFrame: Day 37
measure: Morphological variables of embryonic quality
timeFrame: Day 38 to 43
measure: Blastocyst rate
timeFrame: Day 43
measure: Number of optimal embryos (type A or B, according to ASEBIR classification)
timeFrame: Day 43
measure: Number of euploid and aneuploid embryos
timeFrame: Day 50
measure: Stimulation cycle yield (number of frozen embryos).
timeFrame: Day 43
measure: Number of cycles with embryo transferred/ number of stimulation cycle started
timeFrame: Day 43
measure: Pregnancy rates (per stimulation cycle and embryo transfer)
timeFrame: Throughout the study, estimate 1 year
measure: Implantation rates
timeFrame: Throughout the study, estimate 1 year
measure: Ongoing pregnancy rates (per stimulation cycle and embryo transfer)
timeFrame: Throughout the study, estimate 1 year
measure: Clinical and biochemical miscarriages rates (per stimulation cycle and embryo transfer)
timeFrame: Throughout the study, estimate 1 year
measure: Ectopic pregnancy rates (per stimulation cycle and embryo transfer)
timeFrame: Throughout the study, estimate 1 year
measure: Live birth rates
timeFrame: Throughout the study, estimate 18 +/-3 months
measure: Assessment and recording of adverse events
timeFrame: Throughout the study, estimate 18 +/-3 months
Other outcomes:
Locations:
city: Alicante
country: Spain
facility: IVI Alicante
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: IVI Madrid
city: Murcia
country: Spain
facility: IVI Murcia
Study officials:
affiliation: Physician - Investigator
name: Manuel Muñoz, Dr.
role: PRINCIPAL_INVESTIGATOR
References: