AdenomyosisPhase 4ADENOFERTNCT05937490
Adenomyosis and ART
A Phase 4 study testing Enantone, Dienogest 2 MG (milligram) and long GnRH agonist or flexible GnRH antagonist protocol. in people with Adenomyosis, run by Azienda Ospedaliero-Universitaria di Modena at 1 site in Italy.
Trial summary
The goal of this clinical trial is to: Prospectively investigate the association of Adenomyosis with fertility outcomes in relation to COH protocols for ART (long or ultra- long protocol) with a preventive high-dose anti-inflammatory progestin such as DNG and to assess their association with pregnancy and neonatal… Read more about this study
- Who is it for?
- Ages 18 to 42 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Adenomyosis
- What is being tested?
- Enantone, Dienogest 2 MG (milligram) and long GnRH agonist or flexible GnRH antagonist protocol.
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 500 participants
- Where
- 1 siteItaly
- Study dates
- 27 Mar 2023to Mar 2025
- 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 42 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Adenomyosis of the uterus defined with at least one of the following features: (1) heterogeneous myometrium; (2) hypoechoic striation in the myometrium; (3) myometrial anechoic lacunae or cysts; (4) asymmetrical myometrial thickening of the uterine walls.
- Couples who are undergoing a cycle of IVF/ICSI, where a cycle is defined as egg collection following ovarian stimulation.
- First or second IVF or ICSI attempt.
- Absence of severe premature ovarian insufficiency defined by antral follicle count \< 8 and AMH (anti-mullerian hormone) \< 1ng/ml
- Meet the criteria from the Italian law to be included in a ART program.
- The female partner is ≥18 and \< 42 years of age.
- The female partner has a BMI \<30.
- Both partners are willing and able to provide written informed consent.
Who cannot join
- Concurrent and/or recent involvement in other research that is likely to interfere with the intervention within the previous 3 months of study enrolment.
- Other potential causes of implantation failure: in situ leiomyoma, hydrosalpinx, malformed uterus (unicornis, bicornis, septate, duplex), antiphospholipid syndrome
- Uterine fibroids (untreated FIGO, International Federation of Gynecology and Obstetrics, Type 0-I-II and type III-IV fibroids \> 3 cm)
- Use of GnRH analogues within previous 3 months.
- Extremely severe male factor infertility (sperm count \< 1x 10 6 /ml, use o surgically retrieved spermatozoa)
- Positive plasma viral load for human immunodeficiency virus(HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) for one (or both) in the couple during the year before inclusion
- Couples unable to give fully informed consent to the study.
Trial locations and contacts
1 site in 1 country.
Facchinetti Fabio, Medical Doctor (MD) contact
Italy1 site, 1 recruiting
- Recruiting
Azienda Ospedaliero-Universitaria di Modena
Modena, 41124
Facchinetti Fabio, Medical Doctor (MD), 0594222512/3335824079, facchi@unimore.it/fabio.facchinetti@unimore.it
About this study
Official title: Assisted Reproductive Technology (ART) and Pregnancy Outcomes in Women With Adenomyosis (Internal Endometriosis) According to Stimulation Protocol in Relation to Immunological and Endometrial Features: a Prospective, Randomized Study
The goal of this clinical trial is to:
- Prospectively investigate the association of Adenomyosis with fertility outcomes in relation to COH protocols for ART (long or ultra- long protocol) with a preventive high-dose anti-inflammatory progestin such as DNG and to assess their association with pregnancy and neonatal outcomes (preterm delivery,pre-eclampsia,Caesarean section,fetal malpresentation,small for gestational age,low birth weight and postpartum hemorrhage).
- Understand how the endometrial interface by studying the response of progesterone and DNG stimulated decidualization markers, correlating them with the success of ART protocol stimulation and to pregnancy specific outcomes
- Evaluate the immune changes during the implantation period and in the different trimesters of the pregnancies after ART conception.
Read the detailed description
Adenomyosis (internal endometriosis) may negatively influence fertility and perinatal outcomes. Inflammation, immune modulation, oxidative stress, extracellular matrix remodelling, aberrant angiogenesis have been implicated in altered oocyte development, uterine receptivity, implantation, successful maintenance of pregnancy. An improvement for infertile women could be a longer GnRH(gonadotropin-releasing hormone) agonist protocol with the addition of a preventive high-dose progestin treatment during controlled ovarian hyperstimulation (COH) Infertile women with transvaginal ultrasound (TV-US) based diagnosis of adenomyosis treated will be randomized into 3 different protocols of COH. Study group 1: Long COH, Study group 2: Long COH + high-dose dienogest (DNG), Study Group 3: Ultra-long COH. COH in controls without adenomyosis will be performed using a long GnRH agonist protocol as previous described or using a flexible GnRH antagonist protocol, according to clinical practice. Our aim is to include a total of n=250 women with adenomyosis and n=250 healthy women of a similar age and basal features at the first ART attempt. The primary outcome will be the number of live birth defined as delivery of one or more live-born infant at > 22 weeks of gestation. Many secondary outcomes will be evaluated as well.
Subsequent eventual ongoing pregnancies will be followed as in normal clinical practice, in particular for the risk of preterm delivery, pre-eclampsia, Caesarean section, fetal malpresentation,small for gestational age, low birth weight and postpartum hemorrhage. In a subgroup of randomized women, the role of endometrial decidualization and its mechanisms will be evaluated in endometrial cells in vitro looking at the response to progesterone and DNG stimulated decidualization markers (in particular osteopontin and prolactin). The different responses will be related to the outcome of ARt and pregnancy related outcomes (preterm delivery, pre-eclampsia, Caesarean section, fetal malpresentation, small for gestational age, low birth weight and postpartum hemorrhage).
Another in vitro study will evaluate the immune system contribution in the implantation period and its changes in the different trimesters of pregnancies after ART conception in women with and without adenomyosis. Blood samples will be obtained - Baseline: prior to ovarian stimulation - Post ovarian stimulation (day of HCG, human chorionic gonadotropin, administration) - Post implantation (2 weeks after embryo transfer, the day of first beta HCG measurement -Second (18-24 gestational weeks) and -Third trimester (28-32 gestational week) of eventual subsequent pregnancies).
The aim of this study will be to identify immunological markers such as cellular component and related cytokines in healthy women and women with adenomyosis that undergo ART. In particular the immune system cells population and relative cytokines, the frequency of immune system cells, the interleukins profile, T cells activity and of specific receptors of pregnancy hormone involved in T cell activity will be studied. These results will be linked with estradiol, progesterone and nitric oxide in vivo levels: this will be very important in order to prevent birth losses and to propose new therapies and targets to improve early stages of blastocyst implantation in women with adenomyosis. Forty women with adenomyosis vs. 40 healthy controls will be included in this last part of the study.
- Conditions
- Adenomyosis
- Being tested
- Enantone, Dienogest 2 MG (milligram), long GnRH agonist or flexible GnRH antagonist protocol.
- Keywords
- Adenomyosis, Assisted reproductive technology, ART
- Medical subject headings
- Adenomyosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EnantoneDrug
administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle.
Dienogest 2 MG (milligram)Drug
Also called Enantone
Before COH, patients will be treated with DNG at high dose (2 mg+2 mg/day) for 28 days, from the first day of previous menstrual cycle. COH will be performed using a long GnRH agonist protocol (administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle).
EnantoneDrug
COH will be performed using a ultra-long GnRH agonist protocol (administration of the first depot leuprorelin 3.75 mg on day 21 of menstrual cycle, repeated after 28 days for other two times).
long GnRH agonist or flexible GnRH antagonist protocol.Drug
During TV-US monitoring, when at least one follicle reached 14 mm in diameter, to achieve LH suppression avoiding spontaneous ovulation, GnRH antagonist 0.25 mg/day will be added subcutaneously until the day of HCG administration.
| Study group | Role | What they receive |
|---|---|---|
| Group 1 (Long) | Experimental | COH will be performed using a long GnRH agonist protocol(administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle). COH will be commenced when pituitary desensitization was achieved(~14 days after the initiation of GnRH agonists) as evidenced by the absence of ovarian follicles \>10 mm and endometrial thickness \<4 mm on TV-US examination. Receives: Drug: Enantone |
| Group 2 (Long + high dose DNG) | Experimental | Before COH, patients will be treated with DNG at high dose (2 mg+2 mg/day) for 28 days, from the first day of previous menstrual cycle. COH will be performed using a long GnRH agonist protocol (administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle). COH will be commenced when pituitary desensitization was achieved (~14 days after the initiation of GnRH agonists), as defined above. Receives: Drug: Dienogest 2 MG (milligram); Drug: Enantone |
| Group 3 (ultra-long): | Experimental | COH will be performed using a ultra-long GnRH agonist protocol (administration of the first depot leuprorelin 3.75 mg on day 21 of menstrual cycle, repeated after 28 days for other two times). COH will be commenced when pituitary desensitization was achieved (~14 days after the initiation of GnRH agonists), as described above. Receives: Drug: Enantone |
| Control group (without adenomyosis) | Other | COH will be performed by using a long GnRH agonist protocol as previous described or using a flexible GnRH antagonist protocol. During TV-US monitoring, when at least one follicle reached 14 mm in diameter, to achieve LH (luteinizing hormone) suppression avoiding spontaneous ovulation, GnRH antagonist 0.25 mg/day will be added subcutaneously until the day of HCG administration. Receives: Drug: long GnRH agonist or flexible GnRH antagonist protocol. |
What is being measured
The primary outcome is the main question the study is designed to answer.
live birth after ART
Primary Outcome:Number of live birth after ART attempt defined as delivery of one or more live-born infant at >22 weeks of gestation.
Measured: Through study completion, an average of 2 year
Secondary outcomes (11)
Other ART and pregnancy outcomes
Uterine volume reduction between TV-US measurements at baseline and at time of COH onset
Measured: Through study completion, an average of 2 year
Other ART and pregnancy outcomes
Occurrence of poor responders
Measured: Through study completion, an average of 2 year
Other ART and pregnancy outcomes
Implantation rate
Measured: Through study completion, an average of 2 year
Other ART and pregnancy outcomes
Number of participants with ongoing pregnancy
Measured: Through study completion, an average of 2 year
Other ART and pregnancy outcomes
Preterm delivery rate
Measured: Immediately after the childbirth
Other ART and pregnancy outcomes
Pre-eclampsia occurrence
Measured: Immediately after the childbirth
Other ART and pregnancy outcomes
Caesarean section rate
Measured: Immediately after the childbirth
Other ART and pregnancy outcomes
Fetal malpresentation rate
Measured: Immediately after the childbirth
Other ART and pregnancy outcomes
Small for gestational age rate
Measured: Immediately after the childbirth
Other ART and pregnancy outcomes
Low birth weight (<5 centile) rate
Measured: Immediately after the childbirth
Other ART and pregnancy outcomes
Postpartum hemorrhage(>500 ml) rate
Measured: Immediately after the childbirth
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jul 2023
- Study start27 Mar 2023
- Primary completionMar 2025 (estimated)
- Study completionMar 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (25)Papers the sponsor has linked to this study.
- Other trials for AdenomyosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- None (open label)
- Enrolment
- 500 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Azienda Ospedaliero-Universitaria di Modena
- Sponsor type
- University, hospital or other
- Collaborators
- University of Modena and Reggio Emilia, Ministero della Salute, Italy
- Responsible party
- Principal investigator, Fabio Facchinetti, Azienda Ospedaliero-Universitaria di Modena
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05937490
- Sponsor's protocol ID
- ENDO-2021-12371935
- Acronym
- ADENOFERT
- Status last verified
- Jul 2023
- First submitted
- 13 Jun 2023
- Last updated
- 10 Jul 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Abbott JA. Adenomyosis and Abnormal Uterine Bleeding (AUB-A)-Pathogenesis, diagnosis, and management. Best Pract Res Clin Obstet Gynaecol. 2017 Apr;40:68-81. doi: 10.1016/j.bpobgyn.2016.09.006. Epub 2016 Sep 30.
PubMed 27810281Chapron C, Vannuccini S, Santulli P, Abrao MS, Carmona F, Fraser IS, Gordts S, Guo SW, Just PA, Noel JC, Pistofidis G, Van den Bosch T, Petraglia F. Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update. 2020 Apr 15;26(3):392-411. doi: 10.1093/humupd/dmz049.
PubMed 32097456Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012 Sep;98(3):511-9. doi: 10.1016/j.fertnstert.2012.06.029. Epub 2012 Jul 20.
PubMed 22819144Lalani S, Choudhry AJ, Firth B, Bacal V, Walker M, Wen SW, Singh S, Amath A, Hodge M, Chen I. Endometriosis and adverse maternal, fetal and neonatal outcomes, a systematic review and meta-analysis. Hum Reprod. 2018 Oct 1;33(10):1854-1865. doi: 10.1093/humrep/dey269.
PubMed 30239732Koot YE, van Hooff SR, Boomsma CM, van Leenen D, Groot Koerkamp MJ, Goddijn M, Eijkemans MJ, Fauser BC, Holstege FC, Macklon NS. An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF. Sci Rep. 2016 Jan 22;6:19411. doi: 10.1038/srep19411.
PubMed 26797113Peng Y et al. Biol Reprod. 2021 Feb 2:ioab017.
Nirgianakis K, Kalaitzopoulos DR, Schwartz ASK, Spaanderman M, Kramer BW, Mueller MD, Mueller M. Fertility, pregnancy and neonatal outcomes of patients with adenomyosis: a systematic review and meta-analysis. Reprod Biomed Online. 2021 Jan;42(1):185-206. doi: 10.1016/j.rbmo.2020.09.023. Epub 2020 Oct 4.
PubMed 33191131Grandi G, Barra F, Ferrero S, Sileo FG, Bertucci E, Napolitano A, Facchinetti F. Hormonal contraception in women with endometriosis: a systematic review. Eur J Contracept Reprod Health Care. 2019 Feb;24(1):61-70. doi: 10.1080/13625187.2018.1550576. Epub 2019 Jan 21.
PubMed 30664383Grandi G, Mueller MD, Bersinger NA, Facchinetti F, McKinnon BD. The association between progestins, nuclear receptors expression and inflammation in endometrial stromal cells from women with endometriosis. Gynecol Endocrinol. 2017 Sep;33(9):712-715. doi: 10.1080/09513590.2017.1314458. Epub 2017 Apr 17.
PubMed 28412861Grandi G, Mueller M, Bersinger N, Papadia A, Nirgianakis K, Cagnacci A, McKinnon B. Progestin suppressed inflammation and cell viability of tumor necrosis factor-alpha-stimulated endometriotic stromal cells. Am J Reprod Immunol. 2016 Oct;76(4):292-8. doi: 10.1111/aji.12552. Epub 2016 Aug 12.
PubMed 27515307Grandi G, Mueller MD, Papadia A, Kocbek V, Bersinger NA, Petraglia F, Cagnacci A, McKinnon B. Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J Reprod Immunol. 2016 Sep;117:30-8. doi: 10.1016/j.jri.2016.06.004. Epub 2016 Jun 17.
PubMed 27371899Grandi G, Mueller M, Bersinger NA, Cagnacci A, Volpe A, McKinnon B. Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. Inflamm Res. 2016 Mar;65(3):183-92. doi: 10.1007/s00011-015-0909-7. Epub 2015 Dec 9.
PubMed 26650031Grandi G, Xholli A, Napolitano A, Palma F, Cagnacci A. Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study. Reprod Sci. 2015 May;22(5):626-32. doi: 10.1177/1933719114556488. Epub 2014 Nov 13.
PubMed 25394646Grandi G, Ferrari S, Xholli A, Cannoletta M, Palma F, Romani C, Volpe A, Cagnacci A. Prevalence of menstrual pain in young women: what is dysmenorrhea? J Pain Res. 2012;5:169-74. doi: 10.2147/JPR.S30602. Epub 2012 Jun 20.
PubMed 22792003Grandi G, Xholli A, Ferrari S, Cannoletta M, Volpe A, Cagnacci A. Intermenstrual pelvic pain, quality of life and mood. Gynecol Obstet Invest. 2013;75(2):97-100. doi: 10.1159/000343997. Epub 2012 Nov 23.
PubMed 23182853
Study at a glance
From the registry record, last updated by the sponsor on 10 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assisted Reproductive Technology (ART) and Pregnancy Outcomes in Women With Adenomyosis (Internal Endometriosis) According to Stimulation Protocol in Relation to Immunological and Endometrial Features: a Prospective, Randomized Study
- ClinicalTrials.gov ID
- NCT05937490
- Acronym / sponsor ID
- ADENOFERT / ENDO-2021-12371935
- Conditions
- Adenomyosis
- Keywords
- Adenomyosis, Assisted reproductive technology, ART
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 500 participants (estimated)
- Lead sponsor
- Azienda Ospedaliero-Universitaria di ModenaUniversity, hospital or other
- Collaborators
- University of Modena and Reggio Emilia, Ministero della Salute, Italy
- Study start
- 27 Mar 2023 (actual)
- Primary completion
- Mar 2025 (estimated)
- Study completion
- Mar 2025 (estimated)
- First posted
- 10 Jul 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this clinical trial is to:
- Prospectively investigate the association of Adenomyosis with fertility outcomes in relation to COH protocols for ART (long or ultra- long protocol) with a preventive high-dose anti-inflammatory progestin such as DNG and to assess their association with pregnancy and neonatal outcomes (preterm delivery,pre-eclampsia,Caesarean section,fetal malpresentation,small for gestational age,low birth weight and postpartum hemorrhage).
- Understand how the endometrial interface by studying the response of progesterone and DNG stimulated decidualization markers, correlating them with the success of ART protocol stimulation and to pregnancy specific outcomes
- Evaluate the immune changes during the implantation period and in the different trimesters of the pregnancies after ART conception.
Detailed description
Adenomyosis (internal endometriosis) may negatively influence fertility and perinatal outcomes. Inflammation, immune modulation, oxidative stress, extracellular matrix remodelling, aberrant angiogenesis have been implicated in altered oocyte development, uterine receptivity, implantation, successful maintenance of pregnancy. An improvement for infertile women could be a longer GnRH(gonadotropin-releasing hormone) agonist protocol with the addition of a preventive high-dose progestin treatment during controlled ovarian hyperstimulation (COH) Infertile women with transvaginal ultrasound (TV-US) based diagnosis of adenomyosis treated will be randomized into 3 different protocols of COH. Study group 1: Long COH, Study group 2: Long COH + high-dose dienogest (DNG), Study Group 3: Ultra-long COH. COH in controls without adenomyosis will be performed using a long GnRH agonist protocol as previous described or using a flexible GnRH antagonist protocol, according to clinical practice. Our aim is to include a total of n=250 women with adenomyosis and n=250 healthy women of a similar age and basal features at the first ART attempt. The primary outcome will be the number of live birth defined as delivery of one or more live-born infant at > 22 weeks of gestation. Many secondary outcomes will be evaluated as well.
Subsequent eventual ongoing pregnancies will be followed as in normal clinical practice, in particular for the risk of preterm delivery, pre-eclampsia, Caesarean section, fetal malpresentation,small for gestational age, low birth weight and postpartum hemorrhage. In a subgroup of randomized women, the role of endometrial decidualization and its mechanisms will be evaluated in endometrial cells in vitro looking at the response to progesterone and DNG stimulated decidualization markers (in particular osteopontin and prolactin). The different responses will be related to the outcome of ARt and pregnancy related outcomes (preterm delivery, pre-eclampsia, Caesarean section, fetal malpresentation, small for gestational age, low birth weight and postpartum hemorrhage).
Another in vitro study will evaluate the immune system contribution in the implantation period and its changes in the different trimesters of pregnancies after ART conception in women with and without adenomyosis. Blood samples will be obtained - Baseline: prior to ovarian stimulation - Post ovarian stimulation (day of HCG, human chorionic gonadotropin, administration) - Post implantation (2 weeks after embryo transfer, the day of first beta HCG measurement -Second (18-24 gestational weeks) and -Third trimester (28-32 gestational week) of eventual subsequent pregnancies).
The aim of this study will be to identify immunological markers such as cellular component and related cytokines in healthy women and women with adenomyosis that undergo ART. In particular the immune system cells population and relative cytokines, the frequency of immune system cells, the interleukins profile, T cells activity and of specific receptors of pregnancy hormone involved in T cell activity will be studied. These results will be linked with estradiol, progesterone and nitric oxide in vivo levels: this will be very important in order to prevent birth losses and to propose new therapies and targets to improve early stages of blastocyst implantation in women with adenomyosis. Forty women with adenomyosis vs. 40 healthy controls will be included in this last part of the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Group 1 (Long) | Experimental | Drug: EnantoneCOH will be performed using a long GnRH agonist protocol(administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle). COH will be commenced when pituitary desensitization was achieved(~14 days after the initiation of GnRH agonists) as evidenced by the absence of ovarian follicles \>10 mm and endometrial thickness \<4 mm on TV-US examination. |
| Group 2 (Long + high dose DNG) | Experimental | Drug: Dienogest 2 MG (milligram), Drug: EnantoneBefore COH, patients will be treated with DNG at high dose (2 mg+2 mg/day) for 28 days, from the first day of previous menstrual cycle. COH will be performed using a long GnRH agonist protocol (administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle). COH will be commenced when pituitary desensitization was achieved (~14 days after the initiation of GnRH agonists), as defined above. |
| Group 3 (ultra-long): | Experimental | Drug: EnantoneCOH will be performed using a ultra-long GnRH agonist protocol (administration of the first depot leuprorelin 3.75 mg on day 21 of menstrual cycle, repeated after 28 days for other two times). COH will be commenced when pituitary desensitization was achieved (~14 days after the initiation of GnRH agonists), as described above. |
| Control group (without adenomyosis) | Other | Drug: long GnRH agonist or flexible GnRH antagonist protocol.COH will be performed by using a long GnRH agonist protocol as previous described or using a flexible GnRH antagonist protocol. During TV-US monitoring, when at least one follicle reached 14 mm in diameter, to achieve LH (luteinizing hormone) suppression avoiding spontaneous ovulation, GnRH antagonist 0.25 mg/day will be added subcutaneously until the day of HCG administration. |
Who may qualify
- Ages
- 18 to 42 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Adenomyosis of the uterus defined with at least one of the following features: (1) heterogeneous myometrium; (2) hypoechoic striation in the myometrium; (3) myometrial anechoic lacunae or cysts; (4) asymmetrical myometrial thickening of the uterine walls.
- Couples who are undergoing a cycle of IVF/ICSI, where a cycle is defined as egg collection following ovarian stimulation.
- First or second IVF or ICSI attempt.
- Absence of severe premature ovarian insufficiency defined by antral follicle count \< 8 and AMH (anti-mullerian hormone) \< 1ng/ml
- Meet the criteria from the Italian law to be included in a ART program.
Key exclusion criteria (7 listed)
- Concurrent and/or recent involvement in other research that is likely to interfere with the intervention within the previous 3 months of study enrolment.
- Other potential causes of implantation failure: in situ leiomyoma, hydrosalpinx, malformed uterus (unicornis, bicornis, septate, duplex), antiphospholipid syndrome
- Uterine fibroids (untreated FIGO, International Federation of Gynecology and Obstetrics, Type 0-I-II and type III-IV fibroids \> 3 cm)
- Use of GnRH analogues within previous 3 months.
- Extremely severe male factor infertility (sperm count \< 1x 10 6 /ml, use o surgically retrieved spermatozoa)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Enantoneadministration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle. | Drug | Group 1 (Long) |
| Dienogest 2 MG (milligram)Also: EnantoneBefore COH, patients will be treated with DNG at high dose (2 mg+2 mg/day) for 28 days, from the first day of previous menstrual cycle. COH will be performed using a long GnRH agonist protocol (administration of depot leuprorelin 3.75 mg on day 21 of the previous luteal phase of the stimulation cycle). | Drug | Group 2 (Long + high dose DNG) |
| EnantoneCOH will be performed using a ultra-long GnRH agonist protocol (administration of the first depot leuprorelin 3.75 mg on day 21 of menstrual cycle, repeated after 28 days for other two times). | Drug | Group 2 (Long + high dose DNG), Group 3 (ultra-long): |
| long GnRH agonist or flexible GnRH antagonist protocol.During TV-US monitoring, when at least one follicle reached 14 mm in diameter, to achieve LH suppression avoiding spontaneous ovulation, GnRH antagonist 0.25 mg/day will be added subcutaneously until the day of HCG administration. | Drug | Control group (without adenomyosis) |
Primary outcome
live birth after ART
Time frame: Through study completion, an average of 2 year
Primary Outcome:Number of live birth after ART attempt defined as delivery of one or more live-born infant at >22 weeks of gestation.
11 secondary outcomes
Other ART and pregnancy outcomes
Time frame: Through study completion, an average of 2 year
Other ART and pregnancy outcomes
Time frame: Through study completion, an average of 2 year
Other ART and pregnancy outcomes
Time frame: Through study completion, an average of 2 year
Other ART and pregnancy outcomes
Time frame: Through study completion, an average of 2 year
Other ART and pregnancy outcomes
Time frame: Immediately after the childbirth
Other ART and pregnancy outcomes
Time frame: Immediately after the childbirth
Other ART and pregnancy outcomes
Time frame: Immediately after the childbirth
Other ART and pregnancy outcomes
Time frame: Immediately after the childbirth
Other ART and pregnancy outcomes
Time frame: Immediately after the childbirth
Other ART and pregnancy outcomes
Time frame: Immediately after the childbirth
Other ART and pregnancy outcomes
Time frame: Immediately after the childbirth
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2023.
- Background: PubMed 27810281Abbott JA. Adenomyosis and Abnormal Uterine Bleeding (AUB-A)-Pathogenesis, diagnosis, and management. Best Pract Res Clin Obstet Gynaecol. 2017 Apr;40:68-81. doi: 10.1016/j.bpobgyn.2016.09.006. Epub 2016 Sep 30.
- Background: PubMed 32097456Chapron C, Vannuccini S, Santulli P, Abrao MS, Carmona F, Fraser IS, Gordts S, Guo SW, Just PA, Noel JC, Pistofidis G, Van den Bosch T, Petraglia F. Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update. 2020 Apr 15;26(3):392-411. doi: 10.1093/humupd/dmz049.
- Background: PubMed 22819144Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012 Sep;98(3):511-9. doi: 10.1016/j.fertnstert.2012.06.029. Epub 2012 Jul 20.
- Background: PubMed 30239732Lalani S, Choudhry AJ, Firth B, Bacal V, Walker M, Wen SW, Singh S, Amath A, Hodge M, Chen I. Endometriosis and adverse maternal, fetal and neonatal outcomes, a systematic review and meta-analysis. Hum Reprod. 2018 Oct 1;33(10):1854-1865. doi: 10.1093/humrep/dey269.
- Background: PubMed 26797113Koot YE, van Hooff SR, Boomsma CM, van Leenen D, Groot Koerkamp MJ, Goddijn M, Eijkemans MJ, Fauser BC, Holstege FC, Macklon NS. An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF. Sci Rep. 2016 Jan 22;6:19411. doi: 10.1038/srep19411.
- BackgroundPeng Y et al. Biol Reprod. 2021 Feb 2:ioab017.
- Background: PubMed 33191131Nirgianakis K, Kalaitzopoulos DR, Schwartz ASK, Spaanderman M, Kramer BW, Mueller MD, Mueller M. Fertility, pregnancy and neonatal outcomes of patients with adenomyosis: a systematic review and meta-analysis. Reprod Biomed Online. 2021 Jan;42(1):185-206. doi: 10.1016/j.rbmo.2020.09.023. Epub 2020 Oct 4.
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- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Facchinetti Fabio, Medical Doctor (MD) contact
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Enantone, Dienogest 2 MG (milligram) and long GnRH agonist or flexible GnRH antagonist protocol. in people with Adenomyosis, run by Azienda Ospedaliero-Universitaria di Modena at 1 site in Italy.
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 8 inclusion and 7 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: status not confirmed, as of the sponsor's last update on 10 Jul 2023. 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 Italy. 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. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Facchinetti Fabio, Medical Doctor (MD) (0594222512/3335824079, facchi@unimore.it/fabio.facchinetti@unimore.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
live birth after ART (time frame: Through study completion, an average of 2 year). 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 NCT05937490, which also lists 25 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 10 Jul 2023; AzTrials last refreshed its copy on 27 Oct 2026.