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The Effect of Pre-treatment With GnRH Analogues Prior in Vitro Fertilization in Patients With Endometriosis (ENDOFIV)

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ClinicalTrials.gov Identifier: NCT01581359
Recruitment Status : Completed
First Posted : April 20, 2012
Last Update Posted : October 22, 2015
Sponsor:
Information provided by (Responsible Party):
Instituto de Investigacion Sanitaria La Fe

Brief Summary:
The purpose of this study is to determine whether the administration of an analogue of gonadotropin-releasing hormone (GnRH) during the three months prior to the performing of an IVF may improve the response to ovarian stimulation, implantation rate and clinical pregnancy rate in patients with endometriosis/ endometriomas.

Condition or disease Intervention/treatment Phase
Endometriosis Infertility Drug: Triptorelin acetate Phase 4

Detailed Description:

Endometriosis is defined as the presence of ectopic endometrial tissue which induces a local inflammatory reaction. Usually, this tissue is located at any level in the pelvic region, but extrapelvic locations have been described. It is a chronic disease whose cause is unknown, although a genetic predisposition has been proven. It is estimated that endometriosis affects 7-15% of women of fertile age, and up to 30-40% of women with endometriosis have infertility.

Assisted reproduction techniques (ART) are the treatment of many causes of infertility, including endometriosis. The results of assisted reproduction in women with endometriosis appear to be somewhat worse than those obtained from women without endometriosis. Some authors have proven a significant reduction in implantation and pregnancy rates in these patients.

The worst pregnancy rate and implantation is believed to be originated in a poor oocyte quality, which can lead to a lower rate of fertilization. This poor oocyte quality produce poorer quality embryos with a reduced capacity to implant, particularly in severe endometriosis.

On the other hand, endometrial receptivity does not appear to contribute to the reduction of results of ART in these women.

In an attempt to improve ART outcomes in women with endometriosis, different strategies have been proposed prior to the cycle realization, with different results.

Surgical resection of endometriomas (endometriosis cysts) before the cycle of IVF/ICSI may adversely affect the results. On the other hand, careful laparoscopic cystectomy appears not to affect the ovarian response to stimulation.

In addition to surgical approaches, have been tried different medical treatments to improve the results of IVF / intracytoplasmatic sperm injection (ICSI) in women with endometriosis. It has been suggested that treatment with Danazol prior to IVF may improve results. Similarly, prolonged treatment with GnRH analogues few months before IVF could improve the implantation and pregnancy rates. Unfortunately, many of these studies were not randomized and / or controlled so that the true value of therapy with GnRH analogues before IVF in women with endometriosis still needs to be valued. A recent meta-analysis showed that a 3-6 month treatment with GnRH analogues before IVF increased 4 times the odds of clinical pregnancy in women with endometriosis. Nevertheless, these results were concluded from 165 patients and 78 pregnancies, included in 3 clinical trials, which was not specifically to patients with endometriomas.

The lack of studies with proper design, suggests that there is insufficient evidence at present to establish firm recommendations in this regard. This study will contribute to increasing scientific evidence to recommend or not pretreatment with GnRH agonists before IVF en patients with endometriosis.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Comparative Study, Randomized, Blinded, About the Effect of Pre-treatment With GnRH Analogues Versus Placebo in Infertile Patients With Endometriosis Undergoing in Vitro Fertilization Treatment
Study Start Date : March 2012
Actual Primary Completion Date : March 2015
Actual Study Completion Date : May 2015

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: GnRHa
Triptorelin acetate 3,75 mg subcutaneous injection administered on days 1, 28 and 56 after menstrual cycle.
Drug: Triptorelin acetate
  • Triptorelin acetate Dosing regimen: 1 subcutaneous injection of 3,75 mg/28 days, total of 3 doses
  • Placebo Dosing regimen: subcutaneous injection of the same volume of physiological serum/28 days, total of 3 doses
Other Name: Gonapeptyl Depot 3,75
Placebo Comparator: Physiological serum
physiological serum subcutaneous injection with same delivery device and same volume that active comparator ) administered on days 1, 28 and 56 after menstrual cycle.
Drug: Triptorelin acetate
  • Triptorelin acetate Dosing regimen: 1 subcutaneous injection of 3,75 mg/28 days, total of 3 doses
  • Placebo Dosing regimen: subcutaneous injection of the same volume of physiological serum/28 days, total of 3 doses
Other Name: Gonapeptyl Depot 3,75



Primary Outcome Measures :
  1. Clinical pregnancy rate by started cycle [ Time Frame: 2 weeks after biochemical diagnosis of pregnancy ]
    Number of pregnancies with fetal hearth beat on ultrasound exam divided by total number of started cycle


Secondary Outcome Measures :
  1. Number of oocytes retrieved, total and metaphase II [ Time Frame: In the moment of oocyte retrieval ]
  2. Embryo quality [ Time Frame: Two-three days after oocyte recovery and IVF ]
    • A Class: high quality; 4 equal cells, <11% fragmentation, display no irregularities (vacuoles and multinucleation) and normal zona pellucida.
    • B Class: good quality; 2 or 5 cells and <26% fragmentation or 4 cells and 12-25% fragmentation, same or similar size (cells even number), display no irregularities and normal zona pellucida.
    • C Class: intermediate quality; no multinucleation , 3 or 6 cells with <36% fragmentation or 2, 4 and 5 cells with 25-35% fragmentation or inequal size blastomeres or absence/low vacuoles cells or anormal zona pellucida.

  3. Number and size of endometrioma(s) [ Time Frame: Day of the Basal ultrasound ]
    Total number in each ovary, uni or bilateral cysts and maximum diameter (mm) of the biggest endometrioma

  4. Rate of pregnancy to term in patients with endometriosis / endometriomas [ Time Frame: 37 weeks after cycle ]
    Number of deliveries at 37th to 41st weeks of pregnancy divided by total number of pregnancies

  5. Miscarriage rate [ Time Frame: 22nd week of pregnancy ]
    Number of pregnancy losses divided by total number clinical pregnancies

  6. Rate of healthy and live births [ Time Frame: 37th to 41st weeks of pregnancy ]
    Number of healthy and live births divided by total number of started cycle

  7. Fertilization rate [ Time Frame: Two days after oocyte recovery and IVF ]
    Number of cleavage embryos divided by total number of metaphase II oocytes

  8. Total dose of gonadotropins and days of treatment [ Time Frame: Day of the administration of human chorionic gonadotropin (hCG) ]
    Total dose of gonadotropins in IU, and total days on treatment

  9. Cancellation rate and causes [ Time Frame: Last day of gonadotropin treatment ]
    Number of cancelled cycles divided by total number or started cycles

  10. Ovarian Hyperstimulation Syndrome (OHSS) incidence [ Time Frame: One month after hCG ]
    Number of patients diagnosed of OHSS divided by ended cycles. Classification in mild, moderate and severe



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Infertile women with endometriosis diagnosed by surgery in the previous year to their inclusion in the study with signs of residual disease and/or by the existence of ovarian endometrioma in vaginal ecography who are susceptible to IVF treatment.
  • BMI < 28 Kg/m2
  • Age < 40 years old
  • Signed informed consent to perform IVF and participation in this study

Exclusion Criteria:

  • Follicle stimulating hormone (FSH) 2nd-5th cycle day > 12 IU/L
  • Liver disease (sALAT> 80 IU/L)
  • Kidney disease (creatinine > 130 nmol/L)
  • Other relevant disease that contraindicates a pregnancy

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): NCT01581359


Locations
Spain
Human Reproduction Unit of the La Fe University and Politechnic Hospital
Valencia, Spain, 46026
Sponsors and Collaborators
Instituto de Investigacion Sanitaria La Fe
Investigators
Principal Investigator: ANA Mª MONZÓ, MD, PhD La Fe University Hospital

Publications:

Responsible Party: Instituto de Investigacion Sanitaria La Fe
ClinicalTrials.gov Identifier: NCT01581359     History of Changes
Other Study ID Numbers: ENDOFIV-010
2010-022216-39 ( EudraCT Number )
First Posted: April 20, 2012    Key Record Dates
Last Update Posted: October 22, 2015
Last Verified: April 2014

Keywords provided by Instituto de Investigacion Sanitaria La Fe:
Endometriosis
GnRH treatment
Infertility
IVF

Additional relevant MeSH terms:
Infertility
Endometriosis
Genital Diseases, Male
Genital Diseases, Female
Triptorelin Pamoate
Luteolytic Agents
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents