PregnancyPIF-SET1NCT01803893
Prognostic Value of PIF Detection in Embryo Culture Media Correlation With Pregnancy Outcome
An observational study of Pregnancy and Fertility, run by BioIncept LLC at 5 sites in 3 countries.
Trial summary
PIF: biomarker of successful implantation To overcome the poor reproductive potential of embryos generated during in vitro fertilization cycles and the lack of markers enabling the identification of the most competent ones, it is common to transfer multiple embryos. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- How many people
- 500 participants
- Where
- 5 sitesin 3 countries
- Study dates
- Sep 2012to Aug 2014
- 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 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Study population: Infertile women attending IVF center who undergo in vitro fertilization in order to achieve pregnancy.
Who may be able to join
- All women included in our centers for classical IVF or ICSI, who will sign the written consent to participate in the study. PIF level evaluation in culture media (M) and pregnancy prognosis (S1 and S2) will be done only for women with SET.
- Exclusion criteria Women who will refuse to participate in the program.
Who cannot join
None listed.
Trial locations and contacts
5 sites in 3 countries.
5 sites in 3 countries
France3 sites
Lab Clement - Seine St. Denis Hospital, Le Blanc Mesnil
Paris, 93150
Poissy St Germain Hospital
Poissy, Cedex, 78303
Versailles St. Quentin University
Poissy, 2493
United States1 site
Yale Women and Children's Center for Blood Disorders & Yale Fertility Center
New Haven, Connecticut, 06511
About this study
Official title: Preimplantation Factor (PIF): Prognostic Value of a Non-invasive Embryo Viability Biomarker Detection in Culture Media Followed by Single Embryo Transfer - Correlation With Live Birth.
PIF: biomarker of successful implantation To overcome the poor reproductive potential of embryos generated during in vitro fertilization cycles and the lack of markers enabling the identification of the most competent ones, it is common to transfer multiple embryos. However this practice is associated with the risks of multi-fetal pregnancies and high morbidity/mortality. Ideally, the availability of a marker specifically produced by viable embryos would permit the transfer of a single embryo (SET) without affecting the chances of pregnancy and, most importantly, capable to drastically reduce multiple pregnancies after IVF. In preliminary work, we demonstrated that no pregnancy resulted following the transfer of embryos where PIF was undetectable in culture media.(Keramitsoglou, T et al. ASRI Meeting, Hamburg, 2012) Using a non-invasive method of detection of PIF in the media surrounding the embryo will be correlated to live birth following single embryo transfer. By selecting only viable embryos, it will reduce the need for multiple IVF cycles, increase the rate of pregnancy outcome associated with SET, and will minimize multi-fetal pregnancy that has very high medical and societal costs both in pregnancy and after delivery.
Read the detailed description
The aim of the proposed project is to investigate a non invasive biomarker, PIF (PreImplantation Factor), a 15amino acid peptide (MVRIKPGSANKPSDD) secreted only by viable embryos and placenta (Stamakin et al. RBE 2011).
PIF positive embryos will be able to grow to blastocyst stage and PIF levels could be a marker of progressive pregnancy. We will measure PIF levels in IVF culture media before embryo transfer to correlate IVF pregnancy with PIF levels. Our objective will be to define PIF as a biomarker for viable embryos in order to increase IVF success rates following SET. PIF levels will be retrospectively evaluated after 500 SET.
Our four reproductive centres perform about 200 SET per year and more than 500 in vitro fertilizations.
For women selected for a SET, PIF levels will be evaluated in all embryo culture media, and later at one and two weeks after each transfer of fresh or thawed frozen embryos in maternal serum. Embryo transfers will be done blinded to PIF results. SET or MET will be based on clinical evaluation and conventional embryo criteria. For these women, PIF will be also evaluated and compared with βhCG level on maternal serum.
PIF assessment will be performed using specific antibody marked with a fluorescent dye, in Luminex reader.
Specific Aim One will allow us to evaluate:
- PIF predictive value on implantation rate
- PIF predictive value on pregnancy Methodology All women will be fully informed and a written consent to participate in the study will be duly obtained.
In vitro procedure Oocytes were retrieved after natural cycle or after ovarian hyperstimulation which will be performed using the modified long protocol. Collected oocytes will be fertilized by classic IVF or ICSI. Fertilization will be confirmed by the observation of 2 pronuclei and two polar bodies, after 16-18 hours. Fertilized oocytes will be cultured in 60μl of culture media under oil. Embryo transfer will be performed 72 hours after IVF or ICSI procedure (at day D3) without PIF result. Before transfer, embryo quality will be scored according to number of cells, kinetic of cleavage and fragmentation rate. For women who will have a SET, according to clinical criteria (Age, FSH level, etc…) remaining good quality embryos will be frozen and thawed after uterine preparation in further attempts. All remaining culture supernatants (50-60μl) will be collected, transferred to 8-strip 0.2ml tubes and stored to -80C until they will test for PIF (M) Maternal serum retrieval
Maternal serum will be collected:
- before oocytes retrieval in course of a serum control of ovarian hyperstimulation (S0)
- one week after transfer (S1)
- two week after transfer during serial human β-chorionic gonadotrophin measurements (S2) PIF level evaluation PIF levels in culture supernatants and in maternal serum will be measured retrospectively, using a bead-based competitive assay for use in the Luminex 200 IS system. Results presented as median fluorescence intensity (MFI). PIF levels were derived from standard curve using a 5-parameter logistics curve. The threshold of detection was established by measuring the background from culture media or maternal serum alone, using mean+2SD as a cut off (18.7ng/ml).
Analysis Correlate PIF detection in embryo serum with embryo viability. Results of PIF detection in embryo supernatants will be correlated with pregnancy outcome.
Comparison with embryo selection by PIF+ vs PIF- embryos, using morphology alone, and by morphology combined with PIF presence.
Comparisons between groups will be performed using chi-square analysis and p<0.05 will be considered as statistically significant.
Inclusion/exclusion criteria
Inclusion criteria:
All women included in our centers for classical IVF or ICSI, who will sign the written consent to participate in the study. PIF level evaluation in culture media (M) and pregnancy prognosis (S1 and S2) will be done only for women with SET.
Exclusion criteria Women who will refuse to participate in the program. Planned assessments (time and events table) The overall project is planned to be carried out through five steps work plan in which we will investigate the use of PIF as a biomarker for better embryo selection (only women with SET will be included) and as a early pregnancy marker in maternal serum.
- Keywords
- In vitro fertilization, implantation, miscarriage, live birth
- Medical subject headings
- Abortion, Spontaneous
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 |
|---|---|---|
| Embryo culture media | measurement using immunoassay | |
| maternal serum | measurement by immunoassay |
What is being measured
The primary outcome is the main question the study is designed to answer.
Detection of PIF in early pregnancy maternal serum
Following PIF positive single embryo transfer, patients' pregnancy will be monitored by standard methods. This includes: blood tests and ultrasound until pregnancy viability has been established. The number of patients that fail to implant or end up in implantation failure (ie chemical pregnancy), miscarriage, gestational sac will be recorded.
Measured: end of pregnancy
Secondary outcomes (2)
Correlation between PIF positive and negative embryos and early pregnancy events
SET embryo transfers will be performed blinded, unrelated to PIF results. Subsequent to SET, the embryo culture media will be tested for presence/absence of PIF and documented. Following transfer, patients' pregnancy will be monitored by standard methods. This includes: blood tests and ultrasound to determine embryo viability.
Measured: end of pregnancy
Correlation between PIF positive and negative embryos and late pregnancy events
SET embryo transfers will be performed blinded, unrelated to PIF results. Subsequent to SET, the embryo culture media will be tested for presence/absence of PIF and documented. Following transfer, patients' pregnancy will be monitored by standard methods. Once viability is established by standard methods, patients will be followed throughout pregnancy until eventual delivery. Premature delivery, high risk pregnancy events will be recorded.
Measured: end of pregnancy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Mar 2013 (estimated)
- Study startSep 2012
- Primary completionAug 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PregnancyStudies 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
- 500 participants (estimated)
Sponsor and investigators
- Lead sponsor
- BioIncept LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Responsible party
- Sponsor
- Investigators
- Eytan R Barnea, MD, FACOG, Study chair, BioIncept LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01803893
- Sponsor's protocol ID
- BioIncept LLC-1
- Other IDs
- GFI Merck Serono 2012
- Acronym
- PIF-SET1
- Status last verified
- Mar 2013
- First submitted
- 28 Feb 2013
- Last updated
- 4 Mar 2013
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Preimplantation Factor (PIF): Prognostic Value of a Non-invasive Embryo Viability Biomarker Detection in Culture Media Followed by Single Embryo Transfer - Correlation With Live Birth.
- ClinicalTrials.gov ID
- NCT01803893
- Acronym / sponsor ID
- PIF-SET1 / BioIncept LLC-1
- Keywords
- In vitro fertilization, implantation, miscarriage, live birth
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 500 participants (estimated)
- Lead sponsor
- BioIncept LLCIndustry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Study start
- Sep 2012
- Primary completion
- Aug 2014 (estimated)
- First posted
- 4 Mar 2013 (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.
PIF: biomarker of successful implantation To overcome the poor reproductive potential of embryos generated during in vitro fertilization cycles and the lack of markers enabling the identification of the most competent ones, it is common to transfer multiple embryos. However this practice is associated with the risks of multi-fetal pregnancies and high morbidity/mortality. Ideally, the availability of a marker specifically produced by viable embryos would permit the transfer of a single embryo (SET) without affecting the chances of pregnancy and, most importantly, capable to drastically reduce multiple pregnancies after IVF. In preliminary work, we demonstrated that no pregnancy resulted following the transfer of embryos where PIF was undetectable in culture media.(Keramitsoglou, T et al. ASRI Meeting, Hamburg, 2012) Using a non-invasive method of detection of PIF in the media surrounding the embryo will be correlated to live birth following single embryo transfer. By selecting only viable embryos, it will reduce the need for multiple IVF cycles, increase the rate of pregnancy outcome associated with SET, and will minimize multi-fetal pregnancy that has very high medical and societal costs both in pregnancy and after delivery.
Detailed description
The aim of the proposed project is to investigate a non invasive biomarker, PIF (PreImplantation Factor), a 15amino acid peptide (MVRIKPGSANKPSDD) secreted only by viable embryos and placenta (Stamakin et al. RBE 2011).
PIF positive embryos will be able to grow to blastocyst stage and PIF levels could be a marker of progressive pregnancy. We will measure PIF levels in IVF culture media before embryo transfer to correlate IVF pregnancy with PIF levels. Our objective will be to define PIF as a biomarker for viable embryos in order to increase IVF success rates following SET. PIF levels will be retrospectively evaluated after 500 SET.
Our four reproductive centres perform about 200 SET per year and more than 500 in vitro fertilizations.
For women selected for a SET, PIF levels will be evaluated in all embryo culture media, and later at one and two weeks after each transfer of fresh or thawed frozen embryos in maternal serum. Embryo transfers will be done blinded to PIF results. SET or MET will be based on clinical evaluation and conventional embryo criteria. For these women, PIF will be also evaluated and compared with βhCG level on maternal serum.
PIF assessment will be performed using specific antibody marked with a fluorescent dye, in Luminex reader.
Specific Aim One will allow us to evaluate:
- PIF predictive value on implantation rate
- PIF predictive value on pregnancy Methodology All women will be fully informed and a written consent to participate in the study will be duly obtained.
In vitro procedure Oocytes were retrieved after natural cycle or after ovarian hyperstimulation which will be performed using the modified long protocol. Collected oocytes will be fertilized by classic IVF or ICSI. Fertilization will be confirmed by the observation of 2 pronuclei and two polar bodies, after 16-18 hours. Fertilized oocytes will be cultured in 60μl of culture media under oil. Embryo transfer will be performed 72 hours after IVF or ICSI procedure (at day D3) without PIF result. Before transfer, embryo quality will be scored according to number of cells, kinetic of cleavage and fragmentation rate. For women who will have a SET, according to clinical criteria (Age, FSH level, etc…) remaining good quality embryos will be frozen and thawed after uterine preparation in further attempts. All remaining culture supernatants (50-60μl) will be collected, transferred to 8-strip 0.2ml tubes and stored to -80C until they will test for PIF (M) Maternal serum retrieval
Maternal serum will be collected:
- before oocytes retrieval in course of a serum control of ovarian hyperstimulation (S0)
- one week after transfer (S1)
- two week after transfer during serial human β-chorionic gonadotrophin measurements (S2) PIF level evaluation PIF levels in culture supernatants and in maternal serum will be measured retrospectively, using a bead-based competitive assay for use in the Luminex 200 IS system. Results presented as median fluorescence intensity (MFI). PIF levels were derived from standard curve using a 5-parameter logistics curve. The threshold of detection was established by measuring the background from culture media or maternal serum alone, using mean+2SD as a cut off (18.7ng/ml).
Analysis Correlate PIF detection in embryo serum with embryo viability. Results of PIF detection in embryo supernatants will be correlated with pregnancy outcome.
Comparison with embryo selection by PIF+ vs PIF- embryos, using morphology alone, and by morphology combined with PIF presence.
Comparisons between groups will be performed using chi-square analysis and p<0.05 will be considered as statistically significant.
Inclusion/exclusion criteria
Inclusion criteria:
All women included in our centers for classical IVF or ICSI, who will sign the written consent to participate in the study. PIF level evaluation in culture media (M) and pregnancy prognosis (S1 and S2) will be done only for women with SET.
Exclusion criteria Women who will refuse to participate in the program. Planned assessments (time and events table) The overall project is planned to be carried out through five steps work plan in which we will investigate the use of PIF as a biomarker for better embryo selection (only women with SET will be included) and as a early pregnancy marker in maternal serum.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Embryo culture media | – | –measurement using immunoassay |
| maternal serum | – | –measurement by immunoassay |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Infertile women attending IVF center who undergo in vitro fertilization in order to achieve pregnancy.
Key inclusion criteria (2 listed)
- All women included in our centers for classical IVF or ICSI, who will sign the written consent to participate in the study. PIF level evaluation in culture media (M) and pregnancy prognosis (S1 and S2) will be done only for women with SET.
- Exclusion criteria Women who will refuse to participate in the program.
Key exclusion criteria (0 listed)
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
Detection of PIF in early pregnancy maternal serum
Time frame: end of pregnancy
Following PIF positive single embryo transfer, patients' pregnancy will be monitored by standard methods. This includes: blood tests and ultrasound until pregnancy viability has been established. The number of patients that fail to implant or end up in implantation failure (ie chemical pregnancy), miscarriage, gestational sac will be recorded.
2 secondary outcomes
Correlation between PIF positive and negative embryos and early pregnancy events
Time frame: end of pregnancy
Correlation between PIF positive and negative embryos and late pregnancy events
Time frame: end of pregnancy
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2013.
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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.
Eytan R Barnea, MD, FACOG study chair
BioIncept LLC
5 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pregnancy and Fertility, run by BioIncept LLC at 5 sites in 3 countries.
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 2 inclusion and 0 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: status not confirmed, as of the sponsor's last update on 4 Mar 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in France, United States, Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
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?
Results are not available in the source record.
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?
Detection of PIF in early pregnancy maternal serum (time frame: end of pregnancy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 4 Mar 2013.