InfertilityPhase 3LEINCT01844453
Local Endometrial Injury in Fresh Embryo Transfer Cycles
A Phase 3 study testing Endometrial Biopsy in people with Infertility, run by McGill University at 1 site in Canada.
Trial summary
The application of in-vitro fertilization (IVF) has provided remarkable opportunities for infertile couple to conceive in the last four decades. Historically IVF was performed for patients with bilateral tubal obstruction, but its use is presently widespread. Read more about this study
- Who is it for?
- Ages 36 to 44 years, women only
- Conditions the study is for
- Infertility
- What is being tested?
- Endometrial Biopsy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 360 participants
- Where
- 1 siteCanada
- Study dates
- Aug 2013to Aug 2016
- Phase
- Phase 3
- 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 36 to 44 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Infertile patients age ≥36 years old.
- Patients who are planned to undergo a second fresh IVF cycle
- Patients who have previously had a fresh IVF-ET and ≥1 frozen - thawed ET in the past and did not achieve a clinical pregnancy [two or more failed embryo transfers].
- Ovarian stimulation with a "microdose flare" protocol
- Patients who are scheduled to undergo a single embryo transfer
- Consent in writing to participate in the study.
Who cannot join
- Age of <36 years old.
- Known or suspected intrauterine factor on ultrasound imaging (submucosal fibroid, endometrial polyp, intrauterine adhesions or intramural fibroids causing uterine distortion).
- Endometriosis (documented by laparoscopy or known endometriomas by ultrasound)
- Previous hysteroscopy (since the start of their 1st IVF cycle)
- Patients who does not speak English or French.
- Patients who will be transferred more than one embryo.
Trial locations and contacts
1 site in 1 country.
Canada1 site
McGill University Health Centre
Montreal, Quebec, H3A1A1
Dan Nayot, BSc, MSc, MD
Hananel Holzer, MD
About this study
Official title: Impact of Local Endometrial Injury on Implantation Rates in Fresh Embryo Transfer Cycles
The application of in-vitro fertilization (IVF) has provided remarkable opportunities for infertile couple to conceive in the last four decades. Historically IVF was performed for patients with bilateral tubal obstruction, but its use is presently widespread. Although the efficacy of assisted reproductive technology continues to improve, endometrial implantation remains the limiting step towards a successful pregnancy. Reduced endometrial receptivity and embryonic defects are the probable primary causes of implantation failure during IVF(1). Patients with repeated implantation failure despite transferring good-quality embryos continue to be a major dilemma for clinicians and are a topic of great research interest. Barash et al. unintentionally discovered and initially reported that an endometrial biopsy prior to IVF in women who have had one or more implantation failures was associated with an increased clinical pregnancy (66.7% vs 30.3%, p<0.01) and live birth rates 48.9% vs 22.5%, p=0.02) compared to a control group(2). The mechanism by which a local endometrial injury (LEI) may increase the pregnancy rate is still not fully clear. Possible etiologies include its role in promoting a beneficial local inflammatory response, inducing endometrial decidualization, or improving endometrial maturation synchrony (3-6).
Following Barash et al's publication, several randomized controlled studies confirmed their findings (7-11). However, there has been extensive heterogeneity among studies, including the number of biopsies, how the biopsy is performed and the selected patient population. On the other hand all the studies have in common that the endometrial biopsy was performed prior to the start of the IVF cycle.
The optimal timing of an endometrial biopsy with respect to an IVF cycle is unknown. There is reason to suspect that an endometrial biopsy during the follicular phase of an IVF stimulation cycle may improve pregnancy outcomes, although this has not been directly examined. We therefore propose a randomized controlled study to evaluate the impact of an endometrial biopsy on the implantation and pregnancy rate in both the luteal phase prior to the IVF cycle as well as the follicular phase of the concurrent IVF cycles.
Read the detailed description
HYPOTHESIS
- Local endometrial injury improves implantation and pregnancy rates
- Specifically, local endometrial injury during the follicular phase of an IVF cycle improves the implantation and pregnancy rates in comparison to that in the luteal phase prior to ovarian stimulation .
OBJECTIVES Primary objective
•To determine the impact of local endometrial injury on implantation rates in patients undergoing fresh IVF cycles.
Secondary objectives
- To determine the impact of local endometrial injury on pregnancy outcomes (biochemical pregnancy rate, clinical pregnancy rate, miscarriage rate and live birth rate) in patients undergoing fresh IVF cycles.
- To determine the optimal timing for local endometrial injury (mid-luteal phase prior to ovarian stimulation or early follicular phase during ovarian stimulation) to improve pregnancy outcomes.
- To determine if there is a correlation between endometrial biopsy pathology and IVF pregnancy outcomes among patients randomized to local endometrial injury.
STUDY DESIGN The study will be a randomized controlled study (RCT) and consists of patients undergoing fertility treatment with their second fresh IVF cycle, which includes ovarian stimulation with gonadotropin hormones ("microdose flare protocol"), an oocyte collection procedure and a single embryo transfer.
The patient population will be randomized using computer-generated random table into three arms:
- Luteal Phase Arm: LEI in mid-luteal phase (day 21-26) prior to the treatment cycle.
- Proliferative Phase Arm: LEI in early proliferative phase of current treatment cycle (day 2-3).
- Control Arm: No LEI will be performed. Patients will undergo a routine fresh IVF treatment cycle.
Other than the local endometrial injury, all patients will receive the same treatment and follow up care as per standard practice at our clinic.
All patients in this study will undergo a "microdose flare protocol" fresh IVF cycle. As part of this protocol patients are to take oral contraception pills for a month duration prior to the start of the IVF cycle. Therefore the possibility of an undocumented pregnancy at the time of the LEI in the luteal phase is minimized.
The LEI will be performed using the standard technique using a Pipelle sampling catheter in the outpatient department. After a speculum examination is performed and the cervix is well visualized, the Pipelle will be inserted gently through the cervical canal into the uterine cavity and advanced slowly until resistance is noted. At this point the internal piston is withdrawn to create negative suction and the Pipelle is gently maneuvered up and down alongside the uterine cavity wall. The Pipelle catheter is then withdrawn gently and any obtained specimen (uterine lining) will be sent for histopathological examination.
Both the embryologist who prepares the embryo and the physician who will transfer the embryo will not be directly aware of which study arm the patient was allocated to. However all procedures performed at our clinic, including a LEI, are documented on the patients chart and therefore are accessible.
As per routine practice at our clinic, pregnancy tests will be performed by quantitative serum beta-hCG level 12 days after embryo transfer. A clinical pregnancy will be confirmed by using a transvaginal ultrasound 2 weeks after a positive pregnancy test (serum BHCG).
- Conditions
- Infertility
- Being tested
- Endometrial Biopsy
- Keywords
- Subfertility, Recurrent Implantation Failure
- Medical subject headings
- Infertility
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Endometrial BiopsyProcedure or surgery
Also called Local Endometrial Injury
The Local Endometrial Injury will be performed using the standard technique using a Pipelle sampling catheter in the outpatient department. After a speculum examination is performed and the cervix is well visualized, the Pipelle will be inserted gently through the cervical canal into the uterine cavity and advanced slowly until resistance is noted. At this point the internal piston is withdrawn to create negative suction and the Pipelle is gently maneuvered up and down alongside the uterine cavity wall. The Pipelle catheter is then withdrawn gently and any obtained specimen (uterine lining) will be sent for histopathological examination.
| Study group | Role | What they receive |
|---|---|---|
| Luteal Phase Arm | Experimental | Local Endometrial Injury in mid-luteal phase (cycle day 21-26) prior to the treatment cycle. Receives: Procedure: Endometrial Biopsy |
| Proliferative Phase Arm | Experimental | Local Endometrial Injury in early proliferative phase of current treatment cycle (cycle day 2-3). Receives: Procedure: Endometrial Biopsy |
| Control Arm | No intervention | No Local Endometrial Injury will be performed. Patients will undergo a routine fresh IVF treatment cycle. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Implantation Rate
Implantation rate is defined as the number of intrauterine gestational sacs seen on transvaginal ultrasound (clinical pregnancy) divided by the number of embryos transferred [implantation rate = number of gestational sacs noted on the viability ultrasound / number of embryos transferred].
Measured: 4-5 weeks after embryo transfer
Secondary outcomes (4)
biochemical pregnancy rate
Blood test = BHCG
Measured: 2 weeks after embryo transfer
clinical pregnancy rate
A clinical pregnancy is defined as the presence of an intrauterine embryo with fetal heart rate seen on transvaginal ultrasound.
Measured: 4-6 weeks after embryo transfer
Live birth rate
A live birth is defined as having a delivery of a baby >20 weeks gestational age and birth weight >500grams.
Measured: within 1 year of embryo transfer
Miscarriage Rates
A clinical miscarriage (gestational age <20weeks or birthweight <500g)
Measured: Within 5 months of embryo transfer
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 May 2013 (estimated)
- Study startAug 2013
- Primary completionAug 2016 (estimated)
- Study completionAug 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- 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
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Care provider
- Enrolment
- 360 participants (estimated)
Sponsor and investigators
- Lead sponsor
- McGill University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Dan Nayot, McGill University
- Investigators
- Dan Nayot, BSc; MSc; MD, Study director, McGill University Health Centre/Research Institute of the McGill University Health CentreTogas Tulandi, MD, MHCM, Principal investigator, McGill University Health Centre/Research Institute of the McGill University Health CentreHananel Holzer, MD, Principal investigator, McGill University Health Centre/Research Institute of the McGill University Health Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01844453
- Sponsor's protocol ID
- 3216
- Acronym
- LEI
- Status last verified
- Apr 2013
- First submitted
- 29 Apr 2013
- Last updated
- 1 May 2013
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 May 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Local Endometrial Injury on Implantation Rates in Fresh Embryo Transfer Cycles
- ClinicalTrials.gov ID
- NCT01844453
- Acronym / sponsor ID
- LEI / 3216
- Conditions
- Infertility
- Keywords
- Subfertility, Recurrent Implantation Failure
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 360 participants (estimated)
- Lead sponsor
- McGill UniversityUniversity, hospital or other
- Study start
- Aug 2013
- Primary completion
- Aug 2016 (estimated)
- Study completion
- Aug 2016 (estimated)
- First posted
- 1 May 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.
The application of in-vitro fertilization (IVF) has provided remarkable opportunities for infertile couple to conceive in the last four decades. Historically IVF was performed for patients with bilateral tubal obstruction, but its use is presently widespread. Although the efficacy of assisted reproductive technology continues to improve, endometrial implantation remains the limiting step towards a successful pregnancy. Reduced endometrial receptivity and embryonic defects are the probable primary causes of implantation failure during IVF(1). Patients with repeated implantation failure despite transferring good-quality embryos continue to be a major dilemma for clinicians and are a topic of great research interest. Barash et al. unintentionally discovered and initially reported that an endometrial biopsy prior to IVF in women who have had one or more implantation failures was associated with an increased clinical pregnancy (66.7% vs 30.3%, p<0.01) and live birth rates 48.9% vs 22.5%, p=0.02) compared to a control group(2). The mechanism by which a local endometrial injury (LEI) may increase the pregnancy rate is still not fully clear. Possible etiologies include its role in promoting a beneficial local inflammatory response, inducing endometrial decidualization, or improving endometrial maturation synchrony (3-6).
Following Barash et al's publication, several randomized controlled studies confirmed their findings (7-11). However, there has been extensive heterogeneity among studies, including the number of biopsies, how the biopsy is performed and the selected patient population. On the other hand all the studies have in common that the endometrial biopsy was performed prior to the start of the IVF cycle.
The optimal timing of an endometrial biopsy with respect to an IVF cycle is unknown. There is reason to suspect that an endometrial biopsy during the follicular phase of an IVF stimulation cycle may improve pregnancy outcomes, although this has not been directly examined. We therefore propose a randomized controlled study to evaluate the impact of an endometrial biopsy on the implantation and pregnancy rate in both the luteal phase prior to the IVF cycle as well as the follicular phase of the concurrent IVF cycles.
Detailed description
HYPOTHESIS
- Local endometrial injury improves implantation and pregnancy rates
- Specifically, local endometrial injury during the follicular phase of an IVF cycle improves the implantation and pregnancy rates in comparison to that in the luteal phase prior to ovarian stimulation .
OBJECTIVES Primary objective
•To determine the impact of local endometrial injury on implantation rates in patients undergoing fresh IVF cycles.
Secondary objectives
- To determine the impact of local endometrial injury on pregnancy outcomes (biochemical pregnancy rate, clinical pregnancy rate, miscarriage rate and live birth rate) in patients undergoing fresh IVF cycles.
- To determine the optimal timing for local endometrial injury (mid-luteal phase prior to ovarian stimulation or early follicular phase during ovarian stimulation) to improve pregnancy outcomes.
- To determine if there is a correlation between endometrial biopsy pathology and IVF pregnancy outcomes among patients randomized to local endometrial injury.
STUDY DESIGN The study will be a randomized controlled study (RCT) and consists of patients undergoing fertility treatment with their second fresh IVF cycle, which includes ovarian stimulation with gonadotropin hormones ("microdose flare protocol"), an oocyte collection procedure and a single embryo transfer.
The patient population will be randomized using computer-generated random table into three arms:
- Luteal Phase Arm: LEI in mid-luteal phase (day 21-26) prior to the treatment cycle.
- Proliferative Phase Arm: LEI in early proliferative phase of current treatment cycle (day 2-3).
- Control Arm: No LEI will be performed. Patients will undergo a routine fresh IVF treatment cycle.
Other than the local endometrial injury, all patients will receive the same treatment and follow up care as per standard practice at our clinic.
All patients in this study will undergo a "microdose flare protocol" fresh IVF cycle. As part of this protocol patients are to take oral contraception pills for a month duration prior to the start of the IVF cycle. Therefore the possibility of an undocumented pregnancy at the time of the LEI in the luteal phase is minimized.
The LEI will be performed using the standard technique using a Pipelle sampling catheter in the outpatient department. After a speculum examination is performed and the cervix is well visualized, the Pipelle will be inserted gently through the cervical canal into the uterine cavity and advanced slowly until resistance is noted. At this point the internal piston is withdrawn to create negative suction and the Pipelle is gently maneuvered up and down alongside the uterine cavity wall. The Pipelle catheter is then withdrawn gently and any obtained specimen (uterine lining) will be sent for histopathological examination.
Both the embryologist who prepares the embryo and the physician who will transfer the embryo will not be directly aware of which study arm the patient was allocated to. However all procedures performed at our clinic, including a LEI, are documented on the patients chart and therefore are accessible.
As per routine practice at our clinic, pregnancy tests will be performed by quantitative serum beta-hCG level 12 days after embryo transfer. A clinical pregnancy will be confirmed by using a transvaginal ultrasound 2 weeks after a positive pregnancy test (serum BHCG).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (care provider)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Luteal Phase Arm | Experimental | Procedure: Endometrial BiopsyLocal Endometrial Injury in mid-luteal phase (cycle day 21-26) prior to the treatment cycle. |
| Proliferative Phase Arm | Experimental | Procedure: Endometrial BiopsyLocal Endometrial Injury in early proliferative phase of current treatment cycle (cycle day 2-3). |
| Control Arm | No intervention | –No Local Endometrial Injury will be performed. Patients will undergo a routine fresh IVF treatment cycle. |
Who may qualify
- Ages
- 36 to 44 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Infertile patients age ≥36 years old.
- Patients who are planned to undergo a second fresh IVF cycle
- Patients who have previously had a fresh IVF-ET and ≥1 frozen - thawed ET in the past and did not achieve a clinical pregnancy [two or more failed embryo transfers].
- Ovarian stimulation with a "microdose flare" protocol
- Patients who are scheduled to undergo a single embryo transfer
Key exclusion criteria (6 listed)
- Age of <36 years old.
- Known or suspected intrauterine factor on ultrasound imaging (submucosal fibroid, endometrial polyp, intrauterine adhesions or intramural fibroids causing uterine distortion).
- Endometriosis (documented by laparoscopy or known endometriomas by ultrasound)
- Previous hysteroscopy (since the start of their 1st IVF cycle)
- Patients who does not speak English or French.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Endometrial BiopsyAlso: Local Endometrial InjuryThe Local Endometrial Injury will be performed using the standard technique using a Pipelle sampling catheter in the outpatient department. After a speculum examination is performed and the cervix is well visualized, the Pipelle will be inserted gently through the cervical canal into the uterine cavity and advanced slowly until resistance is noted. At this point the internal piston is withdrawn to create negative suction and the Pipelle is gently maneuvered up and down alongside the uterine cavity wall. The Pipelle catheter is then withdrawn gently and any obtained specimen (uterine lining) will be sent for histopathological examination. | Procedure or surgery | Luteal Phase Arm, Proliferative Phase Arm |
Primary outcome
Implantation Rate
Time frame: 4-5 weeks after embryo transfer
Implantation rate is defined as the number of intrauterine gestational sacs seen on transvaginal ultrasound (clinical pregnancy) divided by the number of embryos transferred [implantation rate = number of gestational sacs noted on the viability ultrasound / number of embryos transferred].
4 secondary outcomes
biochemical pregnancy rate
Time frame: 2 weeks after embryo transfer
clinical pregnancy rate
Time frame: 4-6 weeks after embryo transfer
Live birth rate
Time frame: within 1 year of embryo transfer
Miscarriage Rates
Time frame: Within 5 months of embryo transfer
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 May 2013.
Related trials for Infertility
RecruitingObservational study
International Pilot Study for Dual Non-invasive Assesment of Embryo Development
Infertility
Active, not recruitingObservational study
Retrieval of Sperm From Men With Azoospermia Using Ultrasound-guided Rete Testis Aspiration
Azoospermia, Nonobstructive, Infertility, Male
Not yet recruiting
Spinery Basivertebral Nerve Ablation for Vertebrogenic Chronic Low Back Pain
Low Back Pain, Chronic Low Back Pain (CLBP)
RecruitingObservational study
Impact of Infertility on the Sexual Sphere in Couples Undergoing Assisted Reproduction
Sexual Health Quality of Life, Infertile Patients
RecruitingObservational study
Pilot Study of Discarded Blastocysts
Infertility (IVF Patients)
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.
Dan Nayot, BSc; MSc; MD study director
McGill University Health Centre/Research Institute of the McGill University Health Centre
Togas Tulandi, MD, MHCM principal investigator
McGill University Health Centre/Research Institute of the McGill University Health Centre
Hananel Holzer, MD principal investigator
McGill University Health Centre/Research Institute of the McGill University Health Centre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Endometrial Biopsy in people with Infertility, run by McGill University at 1 site in Canada.
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 6 inclusion and 6 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 1 May 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. 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.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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?
Contact Dan Nayot, MD (4166163334, dan.nayot@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Implantation Rate (time frame: 4-5 weeks after embryo transfer). 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 1 May 2013.