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Preparing and Timing of the Endometrium in Modified Natural Cycle Frozen-thawed Embryo Transfers

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ClinicalTrials.gov Identifier: NCT03795220
Recruitment Status : Recruiting
First Posted : January 7, 2019
Last Update Posted : January 15, 2019
Sponsor:
Collaborators:
I. Fertility Clinic, Hvidovre Hospital, Copenhagen University Hospital
II. Kvindeafdelingen, Horsens og Institut for Klinisk Medicin, Århus Universitet
III. Fertility Clinic, Herlev Hospital, Copenhagen University Hospital
IV. Fertilitetsenheden og Center for Præimplantationsdiagnostik, Ålborg Universitetshospital
Information provided by (Responsible Party):
Anja Bisgaard Pinborg, Rigshospitalet, Denmark

Brief Summary:
The increasing use of FET emphasizes the importance of preparing and timing the endometrium in FET cycles, however there is no consensus on luteal phase progesterone supplementation in mNC-FET and the optimal day of blastocyst warming and transfer. The aim of this multicenter RCT is to assess the effect of progesterone supplementation in hCG-triggered mNC-FET and the effect of embryo thawing and transfer at hCG+6 or hCG+7 days, respectively. In total 604 patients will be included with n=151 in each of the four study arms. The primary outcome is live birth rate per transfer (LBR) and the goal is to show a 10% increase in LBR after progesterone supplementation and to assess whether warming+transfer 6 days after hCG is superior to 7 days after hCG in mNC-FET.

Condition or disease Intervention/treatment Phase
Infertility Drug: Lutinus + transfer day 6 Drug: Lutinus + transfer day 7 Drug: No Lutinus + transfer day 6 Drug: No Lutinus + transfer day 7 Phase 4

Detailed Description:
Single embryo transfer and freezing of surplus embryos has lowered twin birth rates after in vitro fertilization (IVF) to a level of less than 5% in Denmark. However, several treatments with repeated frozen embryo transfers (FET) before a viable pregnancy is confirmed are burdensome to the patients. New freezing techniques and blastocyst transfer has optimized the quality of the embryo transferred in FET cycles, but optimization of the endometrium in the luteal phase is still lacking behind. In a mNC-FET, which is the routine in many clinics, ovulation is induced with an hCG injection, when the leading follicle is ≥17 mm. The hCG trigger injection may support the corpus luteum, on the other hand, triggering an unhealthy follicle at an inappropriate time may cause luteal phase insufficiency and thus dysfunction of the endometrium. Danish public hospitals are not routinely using progesterone supplementation in mNC-FET, but there may be a rationale to do so, and some implantations may be rescued. In this study live birth rates in mNC-FET with and without progesterone supplementation in the luteal phase will be compared, and further the optimal timing of embryo transfer, day 6 or day 7 after hCG injection, will be explored. This is a superiority study with the aim to detect an increase in live birth rates of 10%. Hence, this adequately powered RCT may make a major contribution to knowledge on mNC-FET to the benefits of patients. 302 patients will be included 1:1 in each arm +/- progesterone and these will further be divided 1:1 in transfer +6 and +7 days after hCG injection, respectively. The primary endpoint is live birth rate per transfer.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 604 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, controlled multicenter trial with inclusion of 604 mNC-FET cycles; the Intervention group (n=302) receives exogeneous progesterone supplementation as vaginal tablets (Progesterone ~ Lutinus® 100 mg/dose) three times daily for 14 days until the hCG-test and if positive (hCG) pregnancy test then 30 days more. Progesterone will be administered from four days after ovulation-trigger with hCG 6500 IU, and the control group (n=302) receives only hCG trigger but no luteal phase support. Further, the study subjects in each of the two groups will be equally distributed to warming + FET 6 or 7 days after hCG administration according to the following randomization:
Masking: Single (Investigator)
Masking Description: This is a single blinded study, where the study medication will be blinded for the doctors, but not for the patients and study nurses. The participants will not take progesterone in the morning, when they come for embryo transfer but take the progesterone immediately after transfer. To avoid the doctors to see that progesterone has been taken. Patients will only be seen by a doctor at the day of blastocyst transfer and at the day of pregnancy scan. Patients will be instructed in not disclosing their study group to the doctor. Study participants will not take progesterone in the morning before the transfer but immediately thereafter.
Primary Purpose: Treatment
Official Title: Preparing and Timing of the Endometrium in Modified Natural Cycle Frozen-thawed Embryo Transfers (mNC-FET) - a Randomized Controlled Multicenter Trial
Actual Study Start Date : January 6, 2019
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023

Arm Intervention/treatment
Active Comparator: Vaginal progesterone + transfer 6. day
Lutinus + blastocyst warming and transfer 6 days after hCG trigger
Drug: Lutinus + transfer day 6
Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.
Other Name: Lutinus

Active Comparator: Vaginal progesterone + transfer 7. day
Lutinus + blastocyst warming and transfer 7 days after hCG trigger
Drug: Lutinus + transfer day 7
Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.
Other Name: Lutinus

Active Comparator: No progesterone + transfer 6. day
No Lutinus + blastocyst warming and transfer 6 days after hCG trigger
Drug: No Lutinus + transfer day 6
Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.

Active Comparator: No progesterone + transfer 7. day
No Lutinus + blastocyst warming and transfer 7 days after hCG trigger
Drug: No Lutinus + transfer day 7
Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.




Primary Outcome Measures :
  1. Live birth rates per transfer [ Time Frame: Registered at the one-year follow-up after a positive pregnancy test. ]
    Comparison of live birth rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.


Secondary Outcome Measures :
  1. Chemical pregnancy rates per transfer [ Time Frame: Measured 16 days after ovulation trigger (hCG+16). ]
    Comparison of chemical pregnancy rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  2. Clinical pregnancy rates per transfer [ Time Frame: Ultrasound performed at 7-8 weeks of gestation. ]
    Comparison of clinical pregnancy rates (ultrasound) between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or seven after hCG trigger.

  3. Abortion rates per transfer [ Time Frame: Registered at the one-year follow-up after a positive pregnancy test. ]
    Comparison of abortion rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  4. ASAT (U/L) [ Time Frame: Measured at baseline. ]
    ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.

  5. ALAT (U/L) [ Time Frame: Measured at baseline. ]
    ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.

  6. AMH (pol/L) [ Time Frame: Measured at baseline. ]
    Comparison of AMH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  7. Estradiole (mmol/L) [ Time Frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. ]
    Comparison of estradiole measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  8. FSH (IU/L) [ Time Frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. ]
    Comparison of FSH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  9. LH (IU/L) [ Time Frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. ]
    Comparison of LH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  10. Progesterone (nmol/L) [ Time Frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. ]
    Comparison of progesterone measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  11. OH-progesterone (nmol/L) [ Time Frame: Measured at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. ]
    Comparison OH-progesterone measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  12. beta-hCG [ Time Frame: Measured at transfer day (hCG+6/7), hCG+11 and hCG+16. ]
    Comparison of beta-hCG measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  13. TSH (*10^3 IU/L) [ Time Frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7), at hCG+11, at hCG+14 and at hCG+19. ]
    Comparison of TSH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  14. Thyroglobulin antibodies (arb.units/L) [ Time Frame: Measured at baseline. ]
    Comparison of thyroglobulin antibodies measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  15. Thyroid peroxidase anitbodies (arb.units/L) [ Time Frame: Measured at baseline. ]
    Comparison of thyroid peroxidase antibodies measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  16. Obstetric complication rates [ Time Frame: Registered at the one-year follow-up after a positive pregnancy test. ]
    Comparison of obstetric complication rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  17. Neonatal complication rates [ Time Frame: Registered at the one-year follow-up after a positive pregnancy test. ]
    Comparison of neonatal complication rates for children of patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Female age 18-40 years, regular menstrual cycle (23-35 days), vitrified blastocysts derived from 1.-3. IVF/ICSI cycle and undergoing single blastocyst transfer.

Exclusion Criteria:

  • Previous participation in the study, uterine malformations, intrauterine polyps or submucosal fibromyomas, breast feeding or if patients are not fulfilling the inclusion criteria. Further exclusion criteria are the following contraindications to progesterone; allergy to the study medication, undiagnosed vaginal bleeding, missed abortion or ectopic pregnancy, hepatic insufficiency or severe hepatic disease, genital or breast cancer, arterial or venous thromboembolism or thrombophlebitis, porphyria.

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): NCT03795220


Contacts
Contact: Anja B. Pinborg, Prof., DMSC 0045 35 45 64 30 anja.bisgaard.pinborg@regionh.dk
Contact: Marte Saupstad, MD marte.saupstad@regionh.dk

Locations
Denmark
Fertility Clinic, Rigshospitalet, Copenhagen University Hospital Recruiting
Copenhagen, Denmark, 2100
Contact: Anja B. Pinborg, Prof., DMSc    004535456430    anja.bisgaard.pinborg@regionh.dk   
Contact: Marte Saupstad, MD    004535455289    marte.saupstad@regionh.dk   
Sponsors and Collaborators
Anja Bisgaard Pinborg
I. Fertility Clinic, Hvidovre Hospital, Copenhagen University Hospital
II. Kvindeafdelingen, Horsens og Institut for Klinisk Medicin, Århus Universitet
III. Fertility Clinic, Herlev Hospital, Copenhagen University Hospital
IV. Fertilitetsenheden og Center for Præimplantationsdiagnostik, Ålborg Universitetshospital
Investigators
Principal Investigator: Anja B. Pinborg, Prof., DMSC Fertility Clinic Rigshospitalet

Responsible Party: Anja Bisgaard Pinborg, Professor, chief consultant, DMSC, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT03795220     History of Changes
Other Study ID Numbers: 63569
2018-002207-34 ( EudraCT Number )
First Posted: January 7, 2019    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Infertility
Genital Diseases, Male
Genital Diseases, Female
Progesterone
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs