Efficacy Study of Granulocyte-macrophage Colony Stimulating Factor (GM-CSF) for Use in Human IVF

Study Overview
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Brief Summary
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This study is to assess whether addition of 2 ng/ml GM-CSF into a specific culture medium will increase the chance of a pregnancy after in vitro fertilisation.

Detailed Description
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Throughout its development, the embryo is naturally exposed to a large number of cytokines and growth factors that are present in the woman's reproductive organs. A growing body of evidence indicates that these factors play a physiological role in the regulation of normal development of the pre-implanted embryo and that these factors therefore help to increase the implantation of the embryo and subsequently ensure optimal development of both foetus and placenta. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be present in the female reproductive organs during early pregnancy in mice, sheep, cows and humans. 2 ng/ml GM-CSF has been proven safe in a previous study presented at the European Society of Human Reproduction and Embrylogy (ESHRE) congress 2007 (A. Loft et al. 2007). The present investigation (DK001) is to our knowledge the first large prospective randomised in vivo study in humans. Previous publications counting one Korean pilotstudy of 154 women prospectively randomised between culture medium with and without GM-CSF 2 ng/ml (Kim et al., 2001), showing a significant effect of GM-CSF on embryo implantation rate. Based on this knowledge we hypothesize that culture of human embryos in the presence of GM-CSF will significantly increase the implantation rate also in a larger population. This hypothesis is being tested by conducting a multicentre, randomised, parallel group, double-blind, placebo-controlled study with adaptive design, performed at 14 study centres. Each patient will participate in the study from retrieval of oocytes following standard hormonal treatment and until the 12th gestational week. Further a follow-up will be performed on pregnancies and children born. The test group will include a standard culture medium with 2 ng/ml GM-CSF added from the time of insemination, and the control group will be the exact same medium but without any additions. All procedures are according to standards of the clinic, with applied standard media except for the patient randomised study medium which is used for oocyte insemination, embryo culture and transfer. Embryo transfer will be performed Day 3. An interim analysis has been performed for final sample size calculation.

Official Title
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The Effect of Granulocyte-macrophage Colony Stimulating Factor (GM-CSF) During in Vitro Culture of Human Embryos on Subsequent Implantation Rates.

Conditions
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Infertility

Intervention / Treatment
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* Device: Test culture
* Device: Control culture


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The couple or single woman has signed an informed consent form before any trial-related activities. In Vitro Fertilization (IVF) or IntraCytoplasmic Sperm Injection (ICSI) treatment indicated 25-39 years of age (both inclusive) Regular menstrual cycle: 21-35 days (both inclusive) Women treated with a standard Gonadotropin-Releasing Hormone (GnRH) agonist or antagonist protocol and a Follicle Stimulating Hormone (FSH) / human Menopausal Gonadotropin (hMG) starting dose between 100 and 300 IU daily. human Chorionic Gonadotropin (hCG) administration when the leading follicle has a calculated diameter of minimum 17 mm, or the day after. At least 3 follicles with a calculated diameter of ≥ 14 mm at the day of hCG. Exclusion Criteria: The woman has previously participated in the DK001 study. Use of assisted hatching. Indication for Testicular Sperm Aspiration (TESA) or Percutaneous Epididymal Sperm Aspiration (PESA) Any medical conditions or genetic disorders prohibiting IVF/ICSI or interfering with the interpretation of results of the study (including pre-implantation genetic diagnostics). Use of any investigational drug within 30 days before oocyte retrieval Any severe chronic disease of relevance for reproductive function. Oocyte donation patients (donor or recipient).

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test culture<br>Culture with GM-CSF | Device: Test culture<br>* A standard culture medium with added GM-CSF (ready-to-use)<br>* Other names: EmbryoGen;|
| Placebo Comparator: Control culture<br>Culture without GM-CSF | Device: Control culture<br>* The same standard culture medium, but without any additions (ready-to-use)<br>* Other names: EmbryoAssist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing Implantation Rate Week 7 | Defined as number of gestational sacs with fetal heart beat, shown by ultrasound in gestational week 7 in percentage of number of embryo transferred. | Approximately 5 weeks from oocyte pick-up (corresponding to 7 weeks from ovulation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Top Quality Embryos (TQE´s) | Number of 4-5 cell embryo at 44 hours,at least 7 cell embryo at 68 hours, maximum 20% fragmentation, equally large blastomeres (less than 25% difference in size),No signs of multinucleation. Calculated in percentage of number of 2 pronuclei (2PN) oocytes. | 3 days from oocyte pick-up | 
| Live Birth | Subject having at least one live birth. Including a foetus which breathes or shows any other evidence of life after expulsion/extraction from its mother. The definition is independent of the duration of the pregnancy (ICMART/WHO criteria). | Until 7 days after birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GM-CSF, infertility