InfertilityNCT02386384
TNFα and MFG-E8: Novel Biomarkers to Predict Implantation Failure
An observational study of Infertility and Recurrent Pregnancy Loss, run by Eastern Virginia Medical School.
Trial summary
Question: Can implantation failure (IF) be predicted prior to in vitro fertilization (IVF)? A pilot, non-interventional, clinical study Prospective, controlled, cohort study Read more about this study
- Who is it for?
- Ages 21 to 35 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Infertility, Recurrent Pregnancy Loss
- How many people
- 15 participants
- Where
- No sites listed yet
- Study dates
- Mar 2015to Jul 2017
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 35 years
- Women only
- Healthy volunteers accepted
- Adult
Study population: women 21-35 years old attending an infertility clinic in an academic center
Who may be able to join
- women 21-35y
- with no contraindication to pregnancy
- on no hormonal contraception
- normal uterine cavity
- absence of hydrosalpinges
- normal ovarian reserve (FSH<13 mIU/.ml or AMH>1 ng/ml or normal antral follicular count>10 total follicles <10 mm in diameter, American Society for Reproductive Medicine-ASRM 2012).
- Three groups of patients will be enrolled: 10 fertile controls (C1-10: women who are participating in the donor egg program as egg donors), 10 with unexplained implantation failure (IF1-10: patients who have failed IVF cycles -failure of implantation following 2 or more cycles with transfer of embryos of good quality-at least 2 cleaving embryos with 6-8 cells, grades 1- 3 (scale 1-highest and 5-poorest morphology score), and normal uterus, and 10 with recurrent unexplained first trimester miscarriages (RM1-10: 2 consecutive miscarriages under 10 weeks, after spontaneous or IVF conceptions).
Who cannot join
- contraindication to pregnancy
- use of hormonal contraception
- abnormal uterine cavity
- hydrosalpinges
- abnormal karyotype.
- women who are pregnant or planning to get pregnant in the cycle in which they are participating in this study
- women who have had a hysterectomy (previous removal of your uterus)
- have a current medical condition, which, in the opinion of the investigator, would result in hazards to the subject, should she participate in the study or have a current medical condition which would potentially confound the study results.
About this study
Official title: TNFα (Tumor Necrosis Factor Alpha) and MFG-E8 (Milk Fat Globule-Epidermal Growth Factor 8): Novel Biomarkers to Predict Implantation Failure
Question: Can implantation failure (IF) be predicted prior to in vitro fertilization (IVF)? A pilot, non-interventional, clinical study Prospective, controlled, cohort study
Read the detailed description
The investigators hypothesize that TNFα and MFG-E8 cooperatively maintain the integrity of the normal endometrium, and that in patients with IF or with recurrent pregnancy loss (RPL) of unexplained origin, excessive TNFα increases the maternal shedding of MFG-E8, disrupting the normal protective effect of this protein, resulting in damage of the endometrial epithelium and impairing trophoblast invasion. The investigators propose that these molecules can be measured in local tissue (endometrium) as well as in serum as a reflection of increased inflammation and can therefore be used as markers of implantation and its failure. The investigators hypothesis is that TNFα is up-regulated in serum of women with implantation defects (IF and RM of unexplained origin) and this causes perturbation of MFG-E8 secretion. These results will provide first evidence demonstrating endometrial dysfunctions resulting from over-expression of pro-inflammatory molecules. The release of significant quantities of these molecules into serum broadens the maternal-fetal interface beyond the uterus and into the maternal circulation. The characterization of these molecules is essential to better understand, not only their biological effects, but also their potential as prognostic and diagnostic biomarkers for detection of IF. More importantly, these molecules could be potential therapeutic targets (perhaps intrauterine infusion of MFG-E8 for tissue repair, and/or oral administration of TNFα antagonists) to improve implantation outcomes. Two recent studies have reported the successful therapeutic use of recombinant human MFG-E8 (rhMFG-E8) in animals: one was used to decrease intestinal injury after whole body radiation (Ajakaiye et al, 2012), and the other was to mitigate inflammation and tissue injury after hemorrhagic stroke (Wang et al, 2012). Also, TNFα inhibitors have been shown to significantly increase IVF outcome in infertile patients (Winger et al, 2009 and 2008). In summary, these two pivotal studies show promising clinical uses of rhMFG-E8 in tissue repair/remodeling by decreasing apoptosis, and provide basis for their use as candidates for further clinical development in reproductive health.
Objectives: Here, the investigators seek to delineate novel diagnostic methods with the ultimate long term goal of designing directed therapies to improve embryo implantation competence.
- The specific aim is to quantify and correlate MFG-E8 and TNFα in serum and in endometrial biopsies of women in 3 groups: controls, IF and RM.
- The ultimate goal of this study is to provide data leading to a simple and quick test to measure soluble serum markers of IF/RM in order to discriminate prospectively between these groups of patients.
- To translate these findings into the use of modulators of these inflammatory molecules to improve pregnancy rates in patients with predicted implantation defects. It is widely known that "classic" markers of endometrial receptivity such as those provided by an invasive endometrial biopsy (with Hematoxilin-Eosin staining, or immuhistochemistry, or even with microarray technology) are not reliable to establish clear-cut diagnosis due to cycle-to-cycle variations and overlap of results.
- Conditions
- Infertility, Recurrent Pregnancy Loss
- Keywords
- pregnancy failure
- Medical subject headings
- Infertility
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Control | Normal fertile | |
| Implantation Failure | Failure to conceive | |
| Recurrent Pregnancy Loss | 2 or more unexplained miscarriages |
What is being measured
The primary outcome is the main question the study is designed to answer.
concentration of MFG-E8 and TNFα in serum and in endometrial biopsies controls, IF and RM.
Measured: 1 menstrual cycle
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Mar 2015 (estimated)
- Study startMar 2015
- Primary completionJul 2017
- Study completionJul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for InfertilityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Eastern Virginia Medical School
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Silvina Bocca, Eastern Virginia Medical School
- Investigators
- Silvina M Bocca, MD, PhD, Principal investigator, Eastern Virginia Medical School
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02386384
- Sponsor's protocol ID
- 15-01-FB-0004
- Status last verified
- Jul 2017
- First submitted
- 6 Mar 2015
- Last updated
- 27 Jul 2017
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Yu L, Anderson S, Oehninger S, Bocca S. Tumor necrosis factor alpha up-regulates endometrial milk fat globule-epidermal growth factor 8 protein production via nuclear factor kappaB activation, resulting in cell migration of epithelial cells. Fertil Steril. 2014 Feb;101(2):552-9. doi: 10.1016/j.fertnstert.2013.10.032. Epub 2013 Nov 18.
PubMed 24262600Schmitz C, Yu L, Bocca S, Anderson S, Cunha-Filho JS, Rhavi BS, Oehninger S. Role for the endometrial epithelial protein MFG-E8 and its receptor integrin alphavbeta3 in human implantation: results of an in vitro trophoblast attachment study using established human cell lines. Fertil Steril. 2014 Mar;101(3):874-82. doi: 10.1016/j.fertnstert.2013.12.015. Epub 2014 Jan 11.
PubMed 24424369Sarhan et al, MFG-E8 (milk fat globule EGF factor 8 protein) is a novel endometrial epithelial glycoprotein regulated by human chorionic gonadotropin (hCG) and secreted via microparticles. J Cell Signaling and Trafficking 2013
Bocca SM, Anderson S, Amaker B, Swanson RJ, Franchi A, Lattanzio F, Oehninger S. Milk fat globule epidermal growth factor 8 (MFG-E8): a novel protein in the mammalian endometrium with putative roles in implantation and placentation. Placenta. 2012 Oct;33(10):795-802. doi: 10.1016/j.placenta.2012.06.015. Epub 2012 Jul 5.
PubMed 22770563Riggs RM, Bocca S, Anderson S, Franchi A, Rhavi BS, Oehninger S. Epithelial cell protein milk fat globule-epidermal growth factor 8 and human chorionic gonadotropin regulate stromal cell apoptosis in the human endometrium. Fertil Steril. 2012 Dec;98(6):1549-56.e3. doi: 10.1016/j.fertnstert.2012.07.1127. Epub 2012 Aug 24.
PubMed 22921913Franchi A, Bocca S, Anderson S, Riggs R, Oehninger S. Expression of milk fat globule EGF-factor 8 (MFG-E8) mRNA and protein in the human endometrium and its regulation by prolactin. Mol Hum Reprod. 2011 Jun;17(6):360-71. doi: 10.1093/molehr/gaq102. Epub 2010 Dec 21.
PubMed 21177637Bocca et al. Milk fat globule epithelial growth factor 8 (MFG-E8) regulates human endometrial endothelial cell adhesion and proliferation. Fertil Steril 2010, P423.
Franchi A, Zaret J, Zhang X, Bocca S, Oehninger S. Expression of immunomodulatory genes, their protein products and specific ligands/receptors during the window of implantation in the human endometrium. Mol Hum Reprod. 2008 Jul;14(7):413-21. doi: 10.1093/molehr/gan029. Epub 2008 Jun 4.
PubMed 18524812Mirkin S, Arslan M, Churikov D, Corica A, Diaz JI, Williams S, Bocca S, Oehninger S. In search of candidate genes critically expressed in the human endometrium during the window of implantation. Hum Reprod. 2005 Aug;20(8):2104-17. doi: 10.1093/humrep/dei051. Epub 2005 May 5.
PubMed 15878921Mirkin S, Nikas G, Hsiu JG, Diaz J, Oehninger S. Gene expression profiles and structural/functional features of the peri-implantation endometrium in natural and gonadotropin-stimulated cycles. J Clin Endocrinol Metab. 2004 Nov;89(11):5742-52. doi: 10.1210/jc.2004-0605.
PubMed 15531538
Study at a glance
From the registry record, last updated by the sponsor on 27 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- TNFα (Tumor Necrosis Factor Alpha) and MFG-E8 (Milk Fat Globule-Epidermal Growth Factor 8): Novel Biomarkers to Predict Implantation Failure
- ClinicalTrials.gov ID
- NCT02386384
- Acronym / sponsor ID
- 15-01-FB-0004
- Conditions
- Infertility, Recurrent Pregnancy Loss
- Keywords
- pregnancy failure
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Eastern Virginia Medical SchoolUniversity, hospital or other
- Study start
- Mar 2015 (actual)
- Primary completion
- Jul 2017 (actual)
- Study completion
- Jul 2017 (actual)
- First posted
- 11 Mar 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Question: Can implantation failure (IF) be predicted prior to in vitro fertilization (IVF)? A pilot, non-interventional, clinical study Prospective, controlled, cohort study
Detailed description
The investigators hypothesize that TNFα and MFG-E8 cooperatively maintain the integrity of the normal endometrium, and that in patients with IF or with recurrent pregnancy loss (RPL) of unexplained origin, excessive TNFα increases the maternal shedding of MFG-E8, disrupting the normal protective effect of this protein, resulting in damage of the endometrial epithelium and impairing trophoblast invasion. The investigators propose that these molecules can be measured in local tissue (endometrium) as well as in serum as a reflection of increased inflammation and can therefore be used as markers of implantation and its failure. The investigators hypothesis is that TNFα is up-regulated in serum of women with implantation defects (IF and RM of unexplained origin) and this causes perturbation of MFG-E8 secretion. These results will provide first evidence demonstrating endometrial dysfunctions resulting from over-expression of pro-inflammatory molecules. The release of significant quantities of these molecules into serum broadens the maternal-fetal interface beyond the uterus and into the maternal circulation. The characterization of these molecules is essential to better understand, not only their biological effects, but also their potential as prognostic and diagnostic biomarkers for detection of IF. More importantly, these molecules could be potential therapeutic targets (perhaps intrauterine infusion of MFG-E8 for tissue repair, and/or oral administration of TNFα antagonists) to improve implantation outcomes. Two recent studies have reported the successful therapeutic use of recombinant human MFG-E8 (rhMFG-E8) in animals: one was used to decrease intestinal injury after whole body radiation (Ajakaiye et al, 2012), and the other was to mitigate inflammation and tissue injury after hemorrhagic stroke (Wang et al, 2012). Also, TNFα inhibitors have been shown to significantly increase IVF outcome in infertile patients (Winger et al, 2009 and 2008). In summary, these two pivotal studies show promising clinical uses of rhMFG-E8 in tissue repair/remodeling by decreasing apoptosis, and provide basis for their use as candidates for further clinical development in reproductive health.
Objectives: Here, the investigators seek to delineate novel diagnostic methods with the ultimate long term goal of designing directed therapies to improve embryo implantation competence.
- The specific aim is to quantify and correlate MFG-E8 and TNFα in serum and in endometrial biopsies of women in 3 groups: controls, IF and RM.
- The ultimate goal of this study is to provide data leading to a simple and quick test to measure soluble serum markers of IF/RM in order to discriminate prospectively between these groups of patients.
- To translate these findings into the use of modulators of these inflammatory molecules to improve pregnancy rates in patients with predicted implantation defects. It is widely known that "classic" markers of endometrial receptivity such as those provided by an invasive endometrial biopsy (with Hematoxilin-Eosin staining, or immuhistochemistry, or even with microarray technology) are not reliable to establish clear-cut diagnosis due to cycle-to-cycle variations and overlap of results.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Control | – | –Normal fertile |
| Implantation Failure | – | –Failure to conceive |
| Recurrent Pregnancy Loss | – | –2 or more unexplained miscarriages |
Who may qualify
- Ages
- 21 to 35 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
- Study population
- women 21-35 years old attending an infertility clinic in an academic center
Key inclusion criteria (7 listed)
- women 21-35y
- with no contraindication to pregnancy
- on no hormonal contraception
- normal uterine cavity
- absence of hydrosalpinges
Key exclusion criteria (8 listed)
- contraindication to pregnancy
- use of hormonal contraception
- abnormal uterine cavity
- hydrosalpinges
- abnormal karyotype.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
concentration of MFG-E8 and TNFα in serum and in endometrial biopsies controls, IF and RM.
Time frame: 1 menstrual cycle
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jul 2017.
- Background: PubMed 24262600Yu L, Anderson S, Oehninger S, Bocca S. Tumor necrosis factor alpha up-regulates endometrial milk fat globule-epidermal growth factor 8 protein production via nuclear factor kappaB activation, resulting in cell migration of epithelial cells. Fertil Steril. 2014 Feb;101(2):552-9. doi: 10.1016/j.fertnstert.2013.10.032. Epub 2013 Nov 18.
- Background: PubMed 24424369Schmitz C, Yu L, Bocca S, Anderson S, Cunha-Filho JS, Rhavi BS, Oehninger S. Role for the endometrial epithelial protein MFG-E8 and its receptor integrin alphavbeta3 in human implantation: results of an in vitro trophoblast attachment study using established human cell lines. Fertil Steril. 2014 Mar;101(3):874-82. doi: 10.1016/j.fertnstert.2013.12.015. Epub 2014 Jan 11.
- BackgroundSarhan et al, MFG-E8 (milk fat globule EGF factor 8 protein) is a novel endometrial epithelial glycoprotein regulated by human chorionic gonadotropin (hCG) and secreted via microparticles. J Cell Signaling and Trafficking 2013
- Background: PubMed 22770563Bocca SM, Anderson S, Amaker B, Swanson RJ, Franchi A, Lattanzio F, Oehninger S. Milk fat globule epidermal growth factor 8 (MFG-E8): a novel protein in the mammalian endometrium with putative roles in implantation and placentation. Placenta. 2012 Oct;33(10):795-802. doi: 10.1016/j.placenta.2012.06.015. Epub 2012 Jul 5.
- Background: PubMed 22921913Riggs RM, Bocca S, Anderson S, Franchi A, Rhavi BS, Oehninger S. Epithelial cell protein milk fat globule-epidermal growth factor 8 and human chorionic gonadotropin regulate stromal cell apoptosis in the human endometrium. Fertil Steril. 2012 Dec;98(6):1549-56.e3. doi: 10.1016/j.fertnstert.2012.07.1127. Epub 2012 Aug 24.
- Background: PubMed 21177637Franchi A, Bocca S, Anderson S, Riggs R, Oehninger S. Expression of milk fat globule EGF-factor 8 (MFG-E8) mRNA and protein in the human endometrium and its regulation by prolactin. Mol Hum Reprod. 2011 Jun;17(6):360-71. doi: 10.1093/molehr/gaq102. Epub 2010 Dec 21.
- BackgroundBocca et al. Milk fat globule epithelial growth factor 8 (MFG-E8) regulates human endometrial endothelial cell adhesion and proliferation. Fertil Steril 2010, P423.
- Background: PubMed 18524812Franchi A, Zaret J, Zhang X, Bocca S, Oehninger S. Expression of immunomodulatory genes, their protein products and specific ligands/receptors during the window of implantation in the human endometrium. Mol Hum Reprod. 2008 Jul;14(7):413-21. doi: 10.1093/molehr/gan029. Epub 2008 Jun 4.
- Background: PubMed 15878921Mirkin S, Arslan M, Churikov D, Corica A, Diaz JI, Williams S, Bocca S, Oehninger S. In search of candidate genes critically expressed in the human endometrium during the window of implantation. Hum Reprod. 2005 Aug;20(8):2104-17. doi: 10.1093/humrep/dei051. Epub 2005 May 5.
- Background: PubMed 15531538Mirkin S, Nikas G, Hsiu JG, Diaz J, Oehninger S. Gene expression profiles and structural/functional features of the peri-implantation endometrium in natural and gonadotropin-stimulated cycles. J Clin Endocrinol Metab. 2004 Nov;89(11):5742-52. doi: 10.1210/jc.2004-0605.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Silvina M Bocca, MD, PhD principal investigator
Eastern Virginia Medical School
Questions about this trial
What is this clinical trial studying?
An observational study of Infertility and Recurrent Pregnancy Loss, run by Eastern Virginia Medical School.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
concentration of MFG-E8 and TNFα in serum and in endometrial biopsies controls, IF and RM. (time frame: 1 menstrual cycle). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02386384, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jul 2017.