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

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Brief Title

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

Official Title

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

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.
    

Detailed Description

      Objectives:

      The primary objective is to determine whether modified downregulation before embryo transfer
      improves the chance of clinical pregnancy after embryo transfer in women with moderate/severe
      adenomyosis of the uterus. A secondary objective is to evaluate the impact of IVF on
      adenomyosis-related symptom presence, severity and progression.

      Type of trial:

      A randomised, controlled, multi-site trial in women with moderate/severe adenomyosis of the
      uterus undergoing frozen-thawed embryo transfer.

      Trial design and methods:

      This will be a prospective, randomised controlled study of patients undergoing assisted
      conception.

      Prior to assisted conception all patients are referred for a diagnostic scan. The scan is
      done in a systematic fashion starting from the uterus in longitudinal plane and measurement
      of the endometrial thickness. The probe is then rotated to the transverse plane and the
      uterus scanned from the cervix to the fundus with any uterine pathologies noted and measured
      in 3 orthogonal planes. A 3D ultrasound volume is then be obtained and saved starting with
      the uterus in longitudinal view making sure to include all uterine tissue in the 3D volume
      sweep. Any congenital or acquired uterine anomalies are diagnosed according to published
      diagnostic criteria. Adenomyosis is diagnosed according to the diagnostic criteria outlined
      by Exacoustos et al and Naftalin et al and graded for severity according to the number of
      adenomyosis features present (assign a score of 1 for each of: i) asymmetrical myometrial
      thickening, ii) parallel shadowing, iii) myometrial cysts, iv) disrupted endometrial
      myometrial junction, v) endometrial striae, vi) endometrial islands, vii) adenomyoma).

      The operator then sweeps to the adnexae, starting from the left, identifies and measures the
      ovaries in 3 orthogonal planes and documents the antral follicle count. Each ovary is
      examined for the presence of cysts as well as for mobility and tenderness by gentle pressure
      with the ultrasound probe. Once the ovaries have been assessed the operator examines the
      pouch of Douglas for the presence of free fluid as well as any evidence of endometriosis such
      as obliteration and/or endometriotic nodules as previously described by Holland et al.
      Videosonography for a period of 5 mins will be performed. Once the ultrasound scan is
      concluded all information is added to the clinical database.

      Patients found to have moderate or severe adenomyosis (4 or more features of adenomyosis as
      defined by Mavrelos et al) on this scan will be approached by a member of the research team.
      The researcher will describe the project and provide a copy of the patient information
      leaflet. Patients will then be invited to return to the unit at a designated time for a scan
      by a member of the research team. On return to the unit the researcher will repeat the scan
      to confirm eligibility.

      After the scan and once eligibility is confirmed patients will be asked to confirm if they
      want to participate in the trial. If they agree they will be asked to sign a consent form.

      Participating patients will then be followed through the process of assisted conception.

      Consenting patients will be randomized to one of two protocols (A vs. B) for frozen thawed
      embryo transfer.

      Protocol A (standard) - start Norethisterone on day 14 of downregulation cycle and continue
      for 11 days. Start Buserelin 0.5ml 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 Progynova 2mg TDS PO. Serial
      scanning from day 10 until endometrial thickness more than 8mm. Once endometrial thickness
      more than 8mm start cyclogest 400mg BD PV/PR and lubion 25mg BD and proceed to embryo
      transfer on appropriate day for embryo age.

      Protocol B (modified) - Baseline scan on day 1-5 of bleed and administer Triptorelin acetate
      3.75 mg. 28 days later administer 1.875 mg Triptorelin acetate and 21 days later start
      Progynova 2 mg TDS PO. Serial scanning from day 10 of Progynova until endometrial thickness
      more than 8mm. Once endometrial thickness more than 8mm start Cyclogest 400mg BD PV/PR and
      Lubion 25mg BD and proceed to embryo transfer on appropriate day for embryo age.

      Patients 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.

      Trial duration per participant:

      8-12 weeks

      Estimated total duration:

      3 years.

      Planned trial sites:

      Multi-site.

      Total number of participants planned:

      162.

      Sample size estimation:

      The investigators recently reported that the clinical pregnancy rate in women with moderate
      to severe adenomyosis is 22.9% vs. 42.7% in women with mild disease. They speculate that the
      modified protocol will improve the chance of clinical pregnancy to be equivalent to those
      with mild disease.

      162 patients are required to have an 80% chance of detecting an increase in the clinical
      pregnancy rate from 22.9% in the control group to 42.7% in the experimental group, as
      significant at the 5% level (α = 0.05, β = 0.20). The trial is powered at 80%.

      Statistical methodology and analysis:

      The investigators will first perform univariate analysis to explore significant differences
      in the demographic characteristics (age, duration of subfertility), and clinical factors
      known to impact the outcome of assisted conception (number of oocytes retrieved, number and
      quality of embryos transferred) between women randomized to standard and modified FTET
      protocol.

      In the second stage analysis the investigators will perform univariate analysis to compare
      the primary outcome (clinical pregnancy rate after FTET) between woman randomized to the
      standard and modified clinical protocol. The investigators will perform univariate analysis
      to compare secondary outcomes (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). They will perform a sub-analysis for women with co-existing endometriosis. All
      models will be estimated in the Stat 12 statistical software.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Clinical pregnancy rate

Secondary Outcome

 Livebirth

Condition

Adenomyosis

Intervention

GnRH analogue downregulation

Study Arms / Comparison Groups

 Standard downregulation with GnRH analogue
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

162

Start Date

August 17, 2020

Completion Date

May 17, 2024

Primary Completion Date

August 17, 2023

Eligibility Criteria

        Inclusion Criteria:

          1. Couples who are undergoing a cycle of IVF/ICSI, where a cycle is defined as egg
             collection following ovarian stimulation.

          2. The female partner is ≥18 and < 42 years of age.

          3. The female partner has a BMI <30.

          4. Two out of three of the following criteria are met: AMH >5.4, FSH <8.9, antral
             follicle count >4.

          5. Moderate or severe adenomyosis of the uterus diagnosed on ultrasound scan.

          6. Both partners are 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 the previous 3 months of study enrolment.

          2. Previous open or laparoscopic myomectomy

          3. Uterine fibroids (untreated FIGO Type 0-I-II and type III-IV fibroids > 3 cm)

          4. Use of GnRH analogues within previous 3 months.

          5. Severe male factor infertility (sperm count < 2 x 106/ml, use of surgically retrieved
             spermatozoa)

          6. 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.
      

Gender

Female

Ages

18 Years - 42 Years

Accepts Healthy Volunteers

No

Contacts

, 02034476550, [email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT03946722

Organization ID

18/0458


Responsible Party

Sponsor

Study Sponsor

University College, London


Study Sponsor

, , 


Verification Date

February 2021