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

Primary Purpose

Infertility

Status
Recruiting
Phase
Phase 4
Locations
Denmark
Study Type
Interventional
Intervention
Lutinus + transfer day 6
Lutinus + transfer day 7
No Lutinus + transfer day 6
No Lutinus + transfer day 7
Sponsored by
Anja Bisgaard Pinborg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infertility

Eligibility Criteria

18 Years - 41 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Female age 18-41 years, regular menstrual cycle (23-35 days), vitrified blastocysts derived from 1.-3. IVF/ICSI cycle in a public hospital and undergoing single blastocyst transfer.

Exclusion Criteria:

- Previous participation in the study, uterine malformations, intrauterine polyps or submucosal myomas, breast feeding, oocyte donation, preimplantation genetic testing, blastocyst conceived with sperm from testicular sperm aspiration, HIV (woman), hepatitis B and C (woman), known luteal phase insufficiency 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, current missed abortion or ectopic pregnancy, hepatic insufficiency or severe hepatic disease, genital or breast cancer, arterial or venous thromboembolism, thrombophlebitis or porphyria. For patients participating in the sub-study, thyroid disease is an exclusion criterion.

Sites / Locations

  • Fertility Clinic, Rigshospitalet, Copenhagen University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Vaginal progesterone + transfer 6. day

Vaginal progesterone + transfer 7. day

No progesterone + transfer 6. day

No progesterone + transfer 7. day

Arm Description

Lutinus + blastocyst warming and transfer 6 days after hCG trigger

Lutinus + blastocyst warming and transfer 7 days after hCG trigger

No Lutinus + blastocyst warming and transfer 6 days after hCG trigger

No Lutinus + blastocyst warming and transfer 7 days after hCG trigger

Outcomes

Primary Outcome Measures

Live birth rates per transfer
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

Chemical pregnancy rates per transfer
Comparison of chemical pregnancy rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Clinical pregnancy rates per transfer
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.
Abortion rates per transfer
Comparison of abortion rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
ASAT (U/L)
ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.
ALAT (U/L)
ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.
AMH (pol/L)
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.
Estradiole (mmol/L)
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.
FSH (IU/L)
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.
LH (IU/L)
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.
Progesterone (nmol/L)
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.
OH-progesterone (nmol/L)
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.
beta-hCG
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.
TSH (*10^3 IU/L)
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.
Thyroglobulin antibodies (arb.units/L)
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.
Thyroid peroxidase anitbodies (arb.units/L)
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.
Obstetric complication rates
Comparison of obstetric complication rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Neonatal complication rates
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.

Full Information

First Posted
December 4, 2018
Last Updated
April 3, 2023
Sponsor
Anja Bisgaard Pinborg
Collaborators
Copenhagen University Hospital, Hvidovre, Regionshospitalet Horsens, Copenhagen University Hospital at Herlev, Aalborg University Hospital, Hillerod Hospital, Denmark, Zealand University Hospital, Regionshospitalet Viborg, Skive
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1. Study Identification

Unique Protocol Identification Number
NCT03795220
Brief Title
Preparing and Timing of the Endometrium in Modified Natural Cycle Frozen-thawed Embryo Transfers
Official Title
Preparing and Timing of the Endometrium in Modified Natural Cycle Frozen-thawed Embryo Transfers (mNC-FET) - a Randomized Controlled Multicenter Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 6, 2019 (Actual)
Primary Completion Date
January 1, 2024 (Anticipated)
Study Completion Date
January 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Anja Bisgaard Pinborg
Collaborators
Copenhagen University Hospital, Hvidovre, Regionshospitalet Horsens, Copenhagen University Hospital at Herlev, Aalborg University Hospital, Hillerod Hospital, Denmark, Zealand University Hospital, Regionshospitalet Viborg, Skive

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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 blastocyst warming+transfer 6 days after hCG trigger is superior to 7 days after hCG trigger in mNC-FET.
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 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 is important for controlling the time of ovulation, but triggering an unhealthy follicle at an inappropriate time may cause luteal phase insufficiency and thus suboptimal function of the endometrium. Danish public fertility clinics 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 we will compare live birth rates in mNC-FET with and without progesterone supplementation in the luteal phase, and further we will explore the optimal timing of blastocyst warming and transfer by comparing embryo transfer at hCG trigger +6 days versus +7 days. 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. We will include 604 patients divided 1:1 (302:302) in each arm +/- progesterone and these will further be divided 1:1 in blastocyst warming and transfer +6 and +7 days after hCG injection. The primary endpoint is live birth rate per transfer.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Randomized, controlled multicenter trial with inclusion of 604 mNC-FET cycles. We will include 604 patients divided 1:1 (302:302) in each arm +/- progesterone supplementation and these will further be divided 1:1 in blastocyst warming and transfer +6 and +7 days after hCG injection. Patients randomised to progesterone supplementation will start administering medicine four days after the ovulation trigger up til the day of the pregnancy test. If the pregnancy test is positive, medication will continue for 30 days more.
Masking
Investigator
Masking Description
The study is a single blinded study; therefore, the study medication will be blinded for the treating doctors, but not for the patients, the non-treating doctors or the study nurses. Patients will only be seen by a treating doctor at the day of blastocyst transfer and at the day of the pregnancy scan. The participants will not take progesterone the morning of the blastocyst transfer, but immediately after to keep the treating doctors blinded. Patients will be instructed in not disclosing their study group to the treating doctor.
Allocation
Randomized
Enrollment
604 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Vaginal progesterone + transfer 6. day
Arm Type
Active Comparator
Arm Description
Lutinus + blastocyst warming and transfer 6 days after hCG trigger
Arm Title
Vaginal progesterone + transfer 7. day
Arm Type
Active Comparator
Arm Description
Lutinus + blastocyst warming and transfer 7 days after hCG trigger
Arm Title
No progesterone + transfer 6. day
Arm Type
Active Comparator
Arm Description
No Lutinus + blastocyst warming and transfer 6 days after hCG trigger
Arm Title
No progesterone + transfer 7. day
Arm Type
Active Comparator
Arm Description
No Lutinus + blastocyst warming and transfer 7 days after hCG trigger
Intervention Type
Drug
Intervention Name(s)
Lutinus + transfer day 6
Other Intervention Name(s)
Lutinus
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Lutinus + transfer day 7
Other Intervention Name(s)
Lutinus
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
No Lutinus + transfer day 6
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
No Lutinus + transfer day 7
Intervention Description
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 Measure Information:
Title
Live birth rates per transfer
Description
Comparison of live birth rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time Frame
Registered at the one-year follow-up after a positive pregnancy test.
Secondary Outcome Measure Information:
Title
Chemical pregnancy rates per transfer
Description
Comparison of chemical pregnancy rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time Frame
Measured 16 days after ovulation trigger (hCG+16).
Title
Clinical pregnancy rates per transfer
Description
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.
Time Frame
Ultrasound performed at 7-8 weeks of gestation.
Title
Abortion rates per transfer
Description
Comparison of abortion rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time Frame
Registered at the one-year follow-up after a positive pregnancy test.
Title
ASAT (U/L)
Description
ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.
Time Frame
Measured at baseline.
Title
ALAT (U/L)
Description
ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.
Time Frame
Measured at baseline.
Title
AMH (pol/L)
Description
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.
Time Frame
Measured at baseline.
Title
Estradiole (mmol/L)
Description
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.
Time Frame
Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
Title
FSH (IU/L)
Description
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.
Time Frame
Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
Title
LH (IU/L)
Description
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.
Time Frame
Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
Title
Progesterone (nmol/L)
Description
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.
Time Frame
Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
Title
OH-progesterone (nmol/L)
Description
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.
Time Frame
Measured at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
Title
beta-hCG
Description
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.
Time Frame
Measured at transfer day (hCG+6/7), hCG+11 and hCG+16.
Title
TSH (*10^3 IU/L)
Description
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.
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.
Title
Thyroglobulin antibodies (arb.units/L)
Description
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.
Time Frame
Measured at baseline.
Title
Thyroid peroxidase anitbodies (arb.units/L)
Description
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.
Time Frame
Measured at baseline.
Title
Obstetric complication rates
Description
Comparison of obstetric complication rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time Frame
Registered at the one-year follow-up after a positive pregnancy test.
Title
Neonatal complication rates
Description
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.
Time Frame
Registered at the one-year follow-up after a positive pregnancy test.

10. Eligibility

Sex
Female
Gender Based
Yes
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
41 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Female age 18-41 years, regular menstrual cycle (23-35 days), vitrified blastocysts derived from 1.-3. IVF/ICSI cycle in a public hospital and undergoing single blastocyst transfer. Exclusion Criteria: - Previous participation in the study, uterine malformations, intrauterine polyps or submucosal myomas, breast feeding, oocyte donation, preimplantation genetic testing, blastocyst conceived with sperm from testicular sperm aspiration, HIV (woman), hepatitis B and C (woman), known luteal phase insufficiency 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, current missed abortion or ectopic pregnancy, hepatic insufficiency or severe hepatic disease, genital or breast cancer, arterial or venous thromboembolism, thrombophlebitis or porphyria. For patients participating in the sub-study, thyroid disease is an exclusion criterion.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Anja B. Pinborg, Prof., DMSC
Phone
0045 35 45 64 30
Email
anja.bisgaard.pinborg@regionh.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Marte Saupstad, MD
Email
marte.saupstad@regionh.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anja B. Pinborg, Prof., DMSC
Organizational Affiliation
Fertility Clinic Rigshospitalet
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fertility Clinic, Rigshospitalet, Copenhagen University Hospital
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anja B. Pinborg, Prof., DMSc
Phone
004535456430
Email
anja.bisgaard.pinborg@regionh.dk
First Name & Middle Initial & Last Name & Degree
Marte Saupstad, MD
Phone
004535455289
Email
marte.saupstad@regionh.dk

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
On request the study protocol and deidentified individual study data collected during the trial, including stored biobank samples, can be shared with research groups with relevant aims and a methodologically sound proposal. Approvals by necessary ethic committees and the Danish Data Protection Agency will be needed before sharing of data. All costs for data sharing will be covered by the party requesting the data. Data cannot be shared with groups working on research projects with the same aims, secondary aims or purposes. Further no data can be shared until 3 months after publication of first papers on the primary and secondary outcomes in this study. Biobank samples cannot be shared with research groups outside Denmark. Proposals of data sharing should be directed to anja.bisgaard.pinborg@regionh.dk. To gain access, data requestors will need to sign a data sharing agreement.
IPD Sharing Time Frame
Data will be available from 3 months after publication of first papers on the primary and secondary outcomes in this study.
IPD Sharing Access Criteria
Approvals by necessary relevant ethic committees and the Danish Data Protection Agency will be needed before sharing of data. All costs for data sharing will be covered by the party requesting the data. Data cannot be shared with groups working on research projects with the same aims, secondary aims or purposes. Biobank samples cannot be shared with research groups outside Denmark.
Citations:
PubMed Identifier
31843833
Citation
Saupstad M, Freiesleben NC, Skouby SO, Andersen LF, Knudsen UB, Petersen KB, Husth M, Egeberg A, Petersen MR, Ziebe S, Andersen AN, Lossl K, Pinborg A. Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial. BMJ Open. 2019 Dec 15;9(12):e031811. doi: 10.1136/bmjopen-2019-031811.
Results Reference
derived

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

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