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

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ClinicalTrials.gov Identifier: NCT03946722
Recruitment Status : Not yet recruiting
First Posted : May 13, 2019
Last Update Posted : May 15, 2019
Sponsor:
Information provided by (Responsible Party):
University College, London

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). The investigators will take uterine flushings from consenting women for laboratory analysis to examine whether there is suppression of the endometrial inflammatory reaction with prolonged downregulation. 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 will be miscarriage, gestational age at delivery, birthweight at delivery.


Condition or disease Intervention/treatment Phase
Adenomyosis Drug: GnRH analogue downregulation Procedure: Uterine flushing Other: Patient questionnaire Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 162 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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 two week period of downregulation. Downregulation will be extended by four 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.
Masking: None (Open Label)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Modified Downregulation for Women With Adenomyosis of the Uterus Prior to Frozen-thawed Embryo Transfer.
Estimated Study Start Date : October 1, 2019
Estimated Primary Completion Date : July 1, 2023
Estimated Study Completion Date : July 1, 2023

Arm Intervention/treatment
Standard downregulation with GnRH analogue

Participants in this arm will be assigned to the routine IVF protocol currently being used in the investigators' IVF unit, as outlined below, with two weeks 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

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 2 weeks 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.


Procedure: Uterine flushing

Consenting participants will undergo a uterine flushing procedure. In patients randomised to the standard downregulation arm this will be performed on D6-13 prior to starting downregulation.

In patients randomised to modified downregulation this will be performed on D6-13 prior to starting downregulation and also on D21 following the second dose of GnRH analogue.


Other: Patient questionnaire
Patients will be offered the opportunity to complete an adenomyosis symptom assessment questionnaire at the start of their treatment, and again three months after completion of treatment.

Experimental: Prolonged downregulation with GnRH analogue

Participants in this arm will be exposed to an additional four 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 (Triptorelin acetate 3.75 mg subcutaneously single injection). 28 days later administer second dose of GnRH analogue (Triptorelin 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

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 2 weeks 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.


Procedure: Uterine flushing

Consenting participants will undergo a uterine flushing procedure. In patients randomised to the standard downregulation arm this will be performed on D6-13 prior to starting downregulation.

In patients randomised to modified downregulation this will be performed on D6-13 prior to starting downregulation and also on D21 following the second dose of GnRH analogue.


Other: Patient questionnaire
Patients will be offered the opportunity to complete an adenomyosis symptom assessment questionnaire at the start of their treatment, and again three months after completion of treatment.




Primary Outcome Measures :
  1. Clinical pregnancy rate [ Time Frame: 6 weeks after embryo transfer ]
    Clinical pregnacy is defined as an intrauterine pregnancy with a visible heart beat older than 6 weeks gestation.


Secondary Outcome Measures :
  1. Miscarriage rate [ Time Frame: 6 weeks after embryo transfer ]
    MIscarriage is defined as an intrauterine pregnancy with no visible heart beat older than 6 weeks gestation

  2. Gestational age at delivery [ Time Frame: 9 months after embryo transfer ]
    Number of completed weeks of gestation at time of delivery

  3. Birthweight at delivery [ Time Frame: 9 months after embryo transfer ]
    Weight of baby at time of delivery

  4. Presence and severity of adenmyosis-related symptoms [ Time Frame: 3 months after embryo transfer ]
    Menorrhagia, dysmenorrhoea



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Ages Eligible for Study:   20 Years to 42 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Adenomyosis of the uterus is a condition which affects women only.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Moderate/severe adenomyosis of the uterus diagnosed on baseline ultrasound scan as part of IVF treatment.
  2. Willing and able to provide written informed consent.

Exclusion Criteria:

  1. Concurrent and/or recent involvement in other research that is likely to interfere with the intervention within last 3 months of study enrolment.
  2. Previous surgery to the uterus, as this may alter ultrasound image acquisition.
  3. Uterine fibroids, as this may confound the effect of adenomyosis.
  4. Use of GnRH analogues within last 3 months.
  5. Women 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.

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): NCT03946722


Contacts
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Contact: Dimitrios Mavrelos, MRCOG MD 02034476550 dimitrios.mavrelos@nhs.net
Contact: Sania Latif, MRCOG sanialatif@nhs.net

Locations
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United Kingdom
University College London Hospital
London, United Kingdom, NW1 2BU
Contact: Dimitrios Mavrelos, MRCOG MD       dimitrios.mavrelos@nhs.net   
Contact: Sania Latif, MRCOG       sanialatif@nhs.net   
Sponsors and Collaborators
University College, London

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03946722    
Other Study ID Numbers: 18/0458
First Posted: May 13, 2019    Key Record Dates
Last Update Posted: May 15, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data will not be shared outside of the research group.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University College, London:
In vitro fertilisation
Assisted conception
Randomised controlled trial
Down-regulation
Additional relevant MeSH terms:
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Adenomyosis
Uterine Diseases
Genital Diseases, Female
Prolactin Release-Inhibiting Factors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs