Modified Downregulation for Women With Adenomyosis of the Uterus Prior to Frozen-thawed Embryo Transfer.

NCT03946722 | Unknown Phase 4 DMC

• 1 other identifier: 18/0458
• Study Type: interventional
• Target: 162
• Locations: 1 country
• Sites: 1

Brief Summary

1 in 7 couples experience difficulty in conceiving. Many will require in vitro fertilization (IVF). IVF involves an initial period of downregulation to suppress the ovaries and prevent premature ovulation. Hormone injections are then used to stimulate a woman's ovaries to produce eggs which are removed by a minor operation. The harvested eggs are mixed with sperm to create embryos in the laboratory. These embryos are replaced in the womb a few days after they are created (fresh embryo transfer). Any remaining embryos are frozen such that they can be thawed and transferred at a later date (frozen thawed embryo transfer, FTET). The investigators have previously shown that the presence of moderate or severe adenomyosis significantly reduces the chance of clinical pregnancy after embryo transfer. The purpose of this study is to examine whether it is possible to improve the chance of clinical pregnancy in these women by modifying the IVF protocol they undergo for FTET. The hypothesis is that a prolonged downregulation regimen for women with adenomyosis would reduce the inflammatory reaction in the endometrium of these women and thus improve the chance of implantation after embryo transfer. Consenting patients will be offered FTET. Those proceeding will be randomized to one of two protocols (A - standard protocol vs. B - prolonged downregulation protocol). Women will also be offered a questionnaire before and after IVF treatment to assess their adenomyosis symptoms . The primary outcome of the study is clinical pregnancy defined as an intrauterine pregnancy with a visible heart beat older than 6 weeks gestation. Secondary outcomes include livebirth, pregnancy loss (biochemical pregnancy, miscarriage, ectopic pregnancy, stillbirth, termination of pregnancy), gestational age at delivery, birth weight, neonatal mortality, major congenital anomaly, serious medication reaction, number of frozen embryos available for transfer, number of days to achieve optimal endometrial thickness.

Conditions

Adenomyosis

Keywords

In vitro fertilisation; Assisted conception; Randomised controlled trial; Down-regulation

Outcome Measures

Primary Outcomes (1)

• Clinical pregnancy rate

  Clinical pregnancy is defined as an intrauterine pregnancy with a visible heart beat older than 6 weeks gestation.

  6 weeks after embryo transfer

Secondary Outcomes (10)

• Livebirth

  9 months after embryo transfer

• Pregnancy loss

  9 months after embryo transfer

• Gestational age at delivery

  9 months after embryo transfer

• Birthweight at delivery

  9 months after embryo transfer

• Neonatal mortality

  9 months after embryo transfer

Study Arms (2)

Standard downregulation with GnRH analogue

OTHER

Participants in this arm will be assigned to the routine IVF protocol currently being used in the investigators' IVF unit, as outlined below, with one week of downregulation. Downregulation is the suppression of the ovaries during an IVF cycle in order to perform controlled ovarian stimulation and prevent premature ovulation. Start progesterone (Norethisterone 5mg twice daily orally) on day 14 of downregulation cycle and continue for 11 days. Start GnRH analogue (Buserelin 0.5ml subcutaneously once daily) on day 21 of downregulation cycle and reduce to 0.2ml on day 1 of bleed. Baseline scan on day 1 - 5 of bleed and start oestrogen (Progynova 2mg three times daily orally). Serial scanning from day 10 until endometrial thickness more than 8mm. Once endometrial thickness more than 8mm start progesterone (Cyclogest 400mg twice daily vaginally/rectally and Lubion 25mg twice daily subcutaneously) and proceed to embryo transfer on appropriate day for embryo age.

Drug: GnRH analogue downregulation; Other: Participant questionnaire

Prolonged downregulation with GnRH analogue

EXPERIMENTAL

Participants in this arm will be exposed to an additional five weeks of downregulation using a GnRH analogue. Downregulation is the suppression of the ovaries during an IVF cycle in order to perform controlled ovarian stimulation and prevent premature ovulation. Baseline scan on day 1-5 of bleed and administer GnRH analogue (Leuprorelin acetate 3.75 mg subcutaneously single injection). 28 days later administer second dose of GnRH analogue (Leuprorelin acetate 1.875 mg subcutaneously), and 21 days later start oestrogen (Progynova 2 mg three times daily orally). Serial scanning from day 10 of oestrogen until endometrial thickness more than 8mm. Once endometrial thickness more than 8mm start progesterone (Cyclogest 400mg twice daily vaginally/rectally and Lubion 25mg twice daily subcutaneously) and proceed to embryo transfer on appropriate day for embryo age.

Drug: GnRH analogue downregulation; Other: Participant questionnaire

Interventions

GnRH analogue downregulation DRUG

Downregulation is the suppression of the ovaries during an IVF cycle in order to perform controlled ovarian stimulation and prevent premature ovulation. Participants will be exposed to one week of downregulation using a GnRH analogue in the standard downregulation arm and 6 weeks of downregulation using a GnRH analogue in the modified downregulation arm.

Prolonged downregulation with GnRH analogue; Standard downregulation with GnRH analogue

Participant questionnaire OTHER

Participant will be offered the opportunity to complete an adenomyosis symptom assessment questionnaire at the start of their treatment, and again two months after completion of treatment.

Prolonged downregulation with GnRH analogue; Standard downregulation with GnRH analogue

Eligibility Criteria

• Age: 18 Years - 42 Years
• Gender Eligibility Details: Adenomyosis of the uterus is a condition which affects women only.
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Couples who are undergoing a cycle of IVF/ICSI, where a cycle is defined as egg collection following ovarian stimulation.
• The female partner is ≥18 and \< 42 years of age.
• The female partner has a BMI \<30.
• Two out of three of the following criteria are met: AMH \>5.4, FSH \<8.9, antral follicle count \>4.
• Moderate or severe adenomyosis of the uterus diagnosed on ultrasound scan.
• Both partners are willing and able to provide written informed consent.

You may not qualify if:

• Concurrent and/or recent involvement in other research that is likely to interfere with the intervention within the previous 3 months of study enrolment.
• Previous open or laparoscopic myomectomy
• Uterine fibroids (untreated FIGO Type 0-I-II and type III-IV fibroids \> 3 cm)
• Use of GnRH analogues within previous 3 months.
• Severe male factor infertility (sperm count \< 2 x 106/ml, use of surgically retrieved spermatozoa)
• Couples who in the opinion of the researcher by virtue of language or learning impairment would be unable to give fully informed consent to the study.

Sponsors & Collaborators

• University College, London: lead

Study Sites (1)

University College London Hospital

London, NW1 2BU, United Kingdom

RECRUITING

Related Publications (1)

• Latif S, Wattar BHA, Balachandren N, Lukaszewski T, Saridogan E, Yasmin E, Serhal P, Mavrelos D. Effectiveness of modified downregulation for women with moderate and severe adenomyosis of the uterus prior to frozen thawed embryo transfer (MODA) study protocol: a pragmatic randomised-controlled trial. BMJ Open. 2021 Oct 29;11(10):e050248. doi: 10.1136/bmjopen-2021-050248.

  PMID: 34716161 DERIVED

MeSH Terms

Conditions

Adenomyosis

Condition Hierarchy (Ancestors)

Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Central Study Contacts

Dimitrios Mavrelos, MRCOG MD

CONTACT

02034476550; dimitrios.mavrelos@nhs.net

Sania Latif, MRCOG

CONTACT

sanialatif@nhs.net

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: It will not be possible to perform blinding due to the difference in frequency of administration of medication between the two protocols, therefore an open label method will be used.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a prospective, randomised controlled trial with two parallel arms. Frozen thawed embryo transfer takes approximately 6 weeks in a standard protocol, including a one week period of downregulation. Downregulation will be extended by five weeks in the modified protocol compared to the standard protocol. Participants will be followed up until the pregnancy outcome is determined, maximum 9 months after embryo transfer.

Study Record Dates

• First Submitted: May 7, 2019
• First Posted: May 13, 2019
• Study Start: August 17, 2020
• Primary Completion: August 17, 2023
• Study Completion: May 17, 2024
• Last Updated: February 16, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)