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EndometriosisPhase 4ENDOFIVNCT01581359

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

A Phase 4 study testing Triptorelin acetate in people with Endometriosis and Infertility, run by Instituto de Investigacion Sanitaria La Fe at 1 site in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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/… Read more about this study

Who is it for?
Ages 18 to 40 years, women only
Conditions the study is for
Endometriosis, Infertility
What is being tested?
Triptorelin acetate
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
200 participants
Where
1 siteSpain
Study dates
Mar 2012to May 2015
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 40 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

Spain1 site
  • Human Reproduction Unit of the La Fe University and Politechnic Hospital

    Valencia, Valencia, 46026

Other trials in Spain

About this study

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

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.

Read the 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.

Being tested
Triptorelin acetate
Keywords
Endometriosis, GnRH treatment, Infertility, IVF
Medical subject headings
Endometriosis, Infertility

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Triptorelin acetateDrug

    Also called Gonapeptyl Depot 3,75

    • 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
Study groups in NCT01581359
Study groupRoleWhat they receive
GnRHaActive comparatorTriptorelin acetate 3,75 mg subcutaneous injection administered on days 1, 28 and 56 after menstrual cycle.
Receives: Drug: Triptorelin acetate
Physiological serumPlacebo comparatorphysiological serum subcutaneous injection with same delivery device and same volume that active comparator ) administered on days 1, 28 and 56 after menstrual cycle.
Receives: Drug: Triptorelin acetate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinical pregnancy rate by started cycle

    Number of pregnancies with fetal hearth beat on ultrasound exam divided by total number of started cycle

    Measured: 2 weeks after biochemical diagnosis of pregnancy

Secondary outcomes (10)
  1. Number of oocytes retrieved, total and metaphase II

    Measured: In the moment of oocyte retrieval

  2. Embryo quality

    • 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.

    Measured: Two-three days after oocyte recovery and IVF

  3. Number and size of endometrioma(s)

    Total number in each ovary, uni or bilateral cysts and maximum diameter (mm) of the biggest endometrioma

    Measured: Day of the Basal ultrasound

  4. Rate of pregnancy to term in patients with endometriosis / endometriomas

    Number of deliveries at 37th to 41st weeks of pregnancy divided by total number of pregnancies

    Measured: 37 weeks after cycle

  5. Miscarriage rate

    Number of pregnancy losses divided by total number clinical pregnancies

    Measured: 22nd week of pregnancy

  6. Rate of healthy and live births

    Number of healthy and live births divided by total number of started cycle

    Measured: 37th to 41st weeks of pregnancy

  7. Fertilization rate

    Number of cleavage embryos divided by total number of metaphase II oocytes

    Measured: Two days after oocyte recovery and IVF

  8. Total dose of gonadotropins and days of treatment

    Total dose of gonadotropins in IU, and total days on treatment

    Measured: Day of the administration of human chorionic gonadotropin (hCG)

  9. Cancellation rate and causes

    Number of cancelled cycles divided by total number or started cycles

    Measured: Last day of gonadotropin treatment

  10. Ovarian Hyperstimulation Syndrome (OHSS) incidence

    Number of patients diagnosed of OHSS divided by ended cycles. Classification in mild, moderate and severe

    Measured: One month after hCG

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Apr 2012 (estimated)
  2. Study startMar 2012
  3. Primary completionMar 2015
  4. Study completionMay 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
200 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01581359
Sponsor's protocol ID
ENDOFIV-010
Other IDs
2010-022216-39
Acronym
ENDOFIV
Status last verified
Apr 2014
First submitted
20 Mar 2012
Last updated
22 Oct 2015
Results posted
No
Data monitoring committee
Yes

Publications

  • Matson PL, Yovich JL. The treatment of infertility associated with endometriosis by in vitro fertilization. Fertil Steril. 1986 Sep;46(3):432-4. doi: 10.1016/s0015-0282(16)49581-6.

    PubMed 3091408
  • Simon C, Gutierrez A, Vidal A, de los Santos MJ, Tarin JJ, Remohi J, Pellicer A. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod. 1994 Apr;9(4):725-9. doi: 10.1093/oxfordjournals.humrep.a138578.

    PubMed 8046030
  • Arici A, Oral E, Bukulmez O, Duleba A, Olive DL, Jones EE. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo transfer program. Fertil Steril. 1996 Mar;65(3):603-7. doi: 10.1016/s0015-0282(16)58162-x.

    PubMed 8774295
  • Cahill DJ, Wardle PG, Maile LA, Harlow CR, Hull MG. Ovarian dysfunction in endometriosis-associated and unexplained infertility. J Assist Reprod Genet. 1997 Nov;14(10):554-7. doi: 10.1023/a:1022568331845.

    PubMed 9447453
  • Inoue M, Kobayashi Y, Honda I, Awaji H, Fujii A. The impact of endometriosis on the reproductive outcome of infertile patients. Am J Obstet Gynecol. 1992 Jul;167(1):278-82. doi: 10.1016/s0002-9378(11)91675-5.

    PubMed 1442943
  • Dmowski WP, Rana N, Michalowska J, Friberg J, Papierniak C, el-Roeiy A. The effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates. Fertil Steril. 1995 Mar;63(3):555-62. doi: 10.1016/s0015-0282(16)57425-1.

    PubMed 7851586
  • Olivennes F, Feldberg D, Liu HC, Cohen J, Moy F, Rosenwaks Z. Endometriosis: a stage by stage analysis--the role of in vitro fertilization. Fertil Steril. 1995 Aug;64(2):392-8. doi: 10.1016/s0015-0282(16)57740-1.

    PubMed 7615119
  • Tanbo T, Omland A, Dale PO, Abyholm T. In vitro fertilization/embryo transfer in unexplained infertility and minimal peritoneal endometriosis. Acta Obstet Gynecol Scand. 1995 Aug;74(7):539-43. doi: 10.3109/00016349509024386.

    PubMed 7618453
  • Huang HY, Lee CL, Lai YM, Chang MY, Chang SY, Soong YK. The outcome of in vitro fertilization and embryo transfer therapy in women with endometriosis failing to conceive after laparoscopic conservative surgery. J Am Assoc Gynecol Laparosc. 1997 May;4(3):299-303. doi: 10.1016/s1074-3804(05)80219-1.

    PubMed 9154777
  • Hickman TN. Impact of endometriosis on implantation. Data from the Wilford Hall Medical Center IVF-ET Program. J Reprod Med. 2002 Oct;47(10):801-8.

    PubMed 12418061
  • Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002 Jun;77(6):1148-55. doi: 10.1016/s0015-0282(02)03112-6.

    PubMed 12057720
  • Wardle PG, Mitchell JD, McLaughlin EA, Ray BD, McDermott A, Hull MG. Endometriosis and ovulatory disorder: reduced fertilisation in vitro compared with tubal and unexplained infertility. Lancet. 1985 Aug 3;2(8449):236-9. doi: 10.1016/s0140-6736(85)90289-2.

    PubMed 2862417
  • Hull MG, Williams JA, Ray B, McLaughlin EA, Akande VA, Ford WC. The contribution of subtle oocyte or sperm dysfunction affecting fertilization in endometriosis-associated or unexplained infertility: a controlled comparison with tubal infertility and use of donor spermatozoa. Hum Reprod. 1998 Jul;13(7):1825-30. doi: 10.1093/humrep/13.7.1825.

    PubMed 9740433
  • Bergendal A, Naffah S, Nagy C, Bergqvist A, Sjoblom P, Hillensjo T. Outcome of IVF in patients with endometriosis in comparison with tubal-factor infertility. J Assist Reprod Genet. 1998 Oct;15(9):530-4. doi: 10.1023/a:1022526002421.

    PubMed 9822979
  • Pal L, Shifren JL, Isaacson KB, Chang Y, Leykin L, Toth TL. Impact of varying stages of endometriosis on the outcome of in vitro fertilization-embryo transfer. J Assist Reprod Genet. 1998 Jan;15(1):27-31. doi: 10.1023/a:1022574221115.

    PubMed 9493063

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Triptorelin acetate in people with Endometriosis and Infertility, run by Instituto de Investigacion Sanitaria La Fe at 1 site in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinical pregnancy rate by started cycle (time frame: 2 weeks after biochemical diagnosis of pregnancy). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01581359, which also lists 53 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2015.

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