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Optimal Length of Progesterone Supplementation Before the Transfer of Cryopreserved(Frozen)-Thawed Embryos in an Artificial Cycle With Exogenous Estrogen and Progesterone. (PROFETA-5)

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ClinicalTrials.gov Identifier: NCT02032797
Recruitment Status : Completed
First Posted : January 10, 2014
Last Update Posted : September 27, 2019
Sponsor:
Information provided by (Responsible Party):
Arne van de Vijver, Universitair Ziekenhuis Brussel

Brief Summary:
The aim of the study is to determine whether 5 or 7 days of progesterone supplementation before transfer of a day 5 cryopreserved thawed embryos in an artificial cycle results in a significant higher pregnancy rate.

Condition or disease Intervention/treatment Phase
Cryopreservation Embryo Implantation Progesteron Drug: Progesterone Phase 4

Detailed Description:

Cryopreserved-thawed embryos are often replaced in an artificial cycle, in which the endometrium is prepared by exogenous estrogen and progesterone with or without the use of GnRH agonist downregulation. The correct duration for exposure to progesterone is still not well established. To date, there are no prospective randomized trials available, comparing different durations of progesterone supplementation before the date of transfer, with regard to treatment outcome (Nawroth).

The purpose is to transfer the embryo during the 'window of implantation', what is defined as the period during which the uterus is receptive for implantation of the free-lying blastocyst. This has been a subject of debate since many years (Bourgain et al, 2007).

Succesful implantation requires a co-ordinated series of events allowing a timely dialogue between a receptive endometrium and the intrusive blastocyst (Tabibzadeh, 1998). The period of receptivity is thought to be 3 days in human (Rogers et al, 1989; Yoshinaga, 1988; Psychoyos, 1993; Harper, 1992). It is suggested that blastocyst apposition begins about day LH+6 and is completed by day LH+10 (Lessey, 2000).

A number of structural and functional endometrial changes have been suggested to play a role in the implantation process: the formation of luminal epithelial pinopodes (Enders et al, 1973), expression of adhesion molecules and growth factors and cytokines (Lessey, 2000). Most of them are related directly or indirectly to progesterone secretion and influence on the endometrium.

In the Centre of Reproductive Medicine of the Brussels University Hospital, we start progesterone supplementation 7 days before the transfer of a day 5 embryo. In order to mimic the natural cycle, since progesterone starts to rise 2 to 3 days before ovulation, due to the LH-stimulated production by the peripheral granulosa cells (Speroff). In fresh IVF-cycles, progesterone is started from the day of oocyte retrieval. HCG administration in fresh cycles will lead to an increase in progesterone levels and therefore, endometrium will progress quickly, compared with frozen-thawed cycles which are hormone supplemented (Nawroth).

Our approach in artificial FrET cycles results in a pregnancy rate of 26%.

In other centres, progesterone supplementation is generally started 5 days before the embryo transfer. Recent studies show pregnancy rates up to 40.5% (Givens CR et al, 2009), using this approach.

In this trial, we want to determine the optimal duration of progesterone supplementation.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Optimal Length of Progesterone Supplementation Before the Transfer of Cryopreserved(Frozen)-Thawed Embryos in an Artificial Cycle With Exogenous Estrogen and Progesterone.
Study Start Date : November 2012
Actual Primary Completion Date : September 2019
Actual Study Completion Date : September 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: A: 7 days of progesterone

Transvaginal ultrasound (US) and hormone analysis for FSH, LH, E2 and P on day 2 of the cycle will be performed. The artificial preparation of the endometrium consists of 7 days oestradiol valerate (Progynova®, Bayer-Schering Pharma AG, Berlin, Germany) 2 mg bid (bi-daily), followed by 6 days oestradiol valerate 2 mg tid (thrice daily). On day 13, the endometrium is measured. If endometrial thickness is more than 7 mm, patients are randomly assigned to group A or B.

Group A receives 7 days of micronized progesterone vaginally (Utrogestan® ((Utrogestan, Besins International), 3x200mg daily), group B receives 5 days of micronized progesterone vaginally. On the 7th (group A) or 5th (group B) day of progesterone supplementation, the cryopreserved-thawed day 5 embryo is transferred.

Drug: Progesterone
Placebo Comparator: B: 5 days of progesterone

Transvaginal ultrasound (US) and hormone analysis for FSH, LH, E2 and P on day 2 of the cycle will be performed. The artificial preparation of the endometrium consists of 7 days oestradiol valerate (Progynova®, Bayer-Schering Pharma AG, Berlin, Germany) 2 mg bid (bi-daily), followed by 6 days oestradiol valerate 2 mg tid (thrice daily). On day 13, the endometrium is measured. If endometrial thickness is more than 7 mm, patients are randomly assigned to group A or B.

Group A receives 7 days of micronized progesterone vaginally (Utrogestan® ((Utrogestan, Besins International), 3x200mg daily), group B receives 5 days of micronized progesterone vaginally. On the 7th (group A) or 5th (group B) day of progesterone supplementation, the cryopreserved-thawed day 5 embryo is transferred.

Drug: Progesterone



Primary Outcome Measures :
  1. clinical pregnancy rate [ Time Frame: 7 weeks of pregnancy ]

Secondary Outcome Measures :
  1. live birth rate [ Time Frame: 40 weeks of pregnancy ]


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Ages Eligible for Study:   18 Years to 39 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Artificial cycles, in which a frozen-thawed day 5 embryo is replaced.
  • Signed informed consent.
  • Normal transvaginal ultrasound at screening, without evidence of clinically significant abnormality consistent with finding adequate for ART with respect to uterus and adnexa.
  • Embryos must be frozen by vitrification technique (cfr supra).
  • Single or dual embryo transfer.
  • Recipients of oocyte donation cycles may be included.

Exclusion Criteria:

  • Known allergic reactions to progesterone products.
  • Intake of experimental drug within 30 days prior to study start.
  • Contraindication for pregnancy.
  • Embryos of women above 39 years of age at the time of embryo freezing.

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): NCT02032797


Locations
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Belgium
Centre of Reproductive Medicine CRG
Jette, Brussels, Belgium, 1090
Sponsors and Collaborators
Universitair Ziekenhuis Brussel

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Responsible Party: Arne van de Vijver, Medical Doctor, Universitair Ziekenhuis Brussel
ClinicalTrials.gov Identifier: NCT02032797     History of Changes
Other Study ID Numbers: PROFETA-5
First Posted: January 10, 2014    Key Record Dates
Last Update Posted: September 27, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Progesterone
Estrogens
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs