InfertilityPhase 4NCT03701750
Effect of LMWH on Pregnancy Outcome in Women With Multiple Failures of IVF-ET
A Phase 4 study testing Low Molecular Weight Heparin (enoxaparin sodium) in people with Infertility, run by Shenzhen Zhongshan Urology Hospital at 3 sites in China.
Trial summary
Low-Molecular-Weight-Heparin (LMWH) has been used empirically in patients undergoing in-vitro fertilization embryo transfer (IVF-ET) with the purpose to aid in improving pregnancy outcomes. Read more about this study
- Who is it for?
- Ages 20 to 38 years, women only
- Conditions the study is for
- Infertility
- What is being tested?
- Low Molecular Weight Heparin (enoxaparin sodium)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 240 participants
- Where
- 3 sitesChina
- Study dates
- 1 Nov 2018to 31 Oct 2022
- Phase
- Phase 4
- 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 20 to 38 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- ≥2 consecutive IVF/ICSI-ET without clinical pregnancy
- ≥2 oocytes retrieval cycles
- 19<BMI≤25
- Normal ovarian reserve ( AMH> 1, FSH <10 )
- Willing and able to sign the informed consent.
Who cannot join
- Uterine abnormalities confirmed by hysterosalpingography or hysteroscopy
- Parental chromosomal abnormalities
- PCOS
- Anti-phospholipid Syndrome
- Endocrine disorder
- Endometriosis
Show all 12Show fewer
- Hydrosalpinx
- Chronic disease (liver, renal, thyroid, and thrombocytopenia)
- Regular anticoagulation or antiplatelet treatment
- Patients who had contraindication for unfractionated heparin therapy
- History of tuberculosis, HIV, HBV, HCV or tests indicating carriage of HBV or HCV, or positive interferon-gamma release assay in any of the couple
- Enrollment in another clinical trial
Trial locations and contacts
3 sites in 1 country.
China3 sites, 3 recruiting
- Not yet recruiting
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Nanjing, Jiangsu, 210008
Lijun Ding, Ph.D., +86-25-83106666
Jie Mei, Ph.D., +86-25-83106666
- Recruiting
Clinical Research Center for Reproductive Medicine, Fertility Center, Shenzhen Zhongshan Urology Hospital
Shenzhen, Guangdong, 518045
Lianghui Diao, Ph.D., +86-755-88361001 ext. 9723
Songchen Cai, M.Phil, +86-755-88361001 ext. 9726
- Not yet recruiting
Renmin Hospital of Wuhan University
Wuhan, Hubei, 430060
Jie Li, MD/PhD, +86-27-88042292
About this study
Official title: Effect of Low-Molecular-Weight-Heparin (LMWH) on Pregnancy Outcome in Women With Multiple Failures of IVF-ET
Low-Molecular-Weight-Heparin (LMWH) has been used empirically in patients undergoing in-vitro fertilization embryo transfer (IVF-ET) with the purpose to aid in improving pregnancy outcomes. The potential mechanism is that LMWH could exert its anticoagulant effect by inhibiting factor Xa, reducing the risk of insufficiency blood supply in the very early stage of pregnancy. Moreover, LMWH is supposed to play a role in manipulating blastocyst supposition, adhesion, and implantation, as well as trophoblast differentiation and invasion. However, limited high-quality clinical trials focus on the effectivity of LMWH in IVF-ET, and the published evidence is not consensus, leading to considerable controversy in the clinical application of LMWH in IVF-ET patients. Here, investigators try to evaluate the effect of LMWH on pregnancy outcome in women with multiple failures of IVF-ET via a multi-center randomized controlled trial.
Read the detailed description
Implantation failure seems to be inevitable in some couples undergoing IVF-ET treatment, despite transferred with high-quality embryos. There are several factors, including coagulation, are supposed to contribute to the implantation failure. Several groups reported that inherited and acquired coagulation is highly prevalent in women with recurrent implantation failure (RIF). Besides, women undergoing assisted reproduction are more likely to expose to thrombotic risks because high-dose exogenous gonadotrophins are given to harvest more oocytes for the fertilization. Given the risk of thrombosis, patients are often recommended to receive thromboprophylaxis with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in many clinics empirically.
LMWH is generated by depolymerization from UFH. Compared with UFH, LWMH exerts its anticoagulant effect mainly by inhibiting factor Xa rather than factor IIa. LMWH has a more predictable antithrombotic response and allows the administration to patients themselves without the laboratory monitoring. Also, it substantially reduces the risk of heparin-induced thrombocytopenia (HIT).
Beyond its anticoagulant effects, heparin is supposed to improve pregnancy outcomes by modulating blastocyst supposition, adhesion and implantation and as well as trophoblast differentiation and invasion through interactions with several adhesion molecules, growth factors, cytokines, and enzymes. Also, complement activation induced by aPL antibodies in mice is inhibited, and pregnancy complications are attenuated when treated with heparin.
Unfortunately, the use of LMWH in IVF/ET seems based on biological plausibility rather than evidence of efficacy. The high-quality studies (randomized controlled trials or prospective controlled trials) are limited, and the results are controversial. A meta-analysis (including 2 RCT and 1 quasi-RCT) reported that there is no difference in implantation rate in women with ≥3 recurrent implantation failure when treated with LMWH. Although live birth rate (LBR) and miscarriage rates are improved, investigators are still concerned because limited studies and patients were included in this analysis. Even in the non-RIF patients with or without thrombophilia defects, no consensus results could be achieved.
Given the burden of daily injection, skin irritation at injection site and other potential side-effects, the effectivity of LMWH in IVF/ET should be carefully examined even though LMWH is regarded as safe thromboprophylaxis. Hence, investigators propose a multi-center randomized study to evaluate the efficacy of Heparin in IVF-ET.
- Conditions
- Infertility
- Being tested
- Low Molecular Weight Heparin (enoxaparin sodium)
- Keywords
- IVF, pregnancy, LMWH, Low Molecular Weight Heparin, Assisted Reproductive Technology, Implantation
- Medical subject headings
- Infertility
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low Molecular Weight Heparin (enoxaparin sodium)Drug
enoxaparin sodium 40mg/day subcutaneously after oocyte collection, and routine luteal phase support after embryo transfer until clinical pregnancy confirmed by ultrasound
| Study group | Role | What they receive |
|---|---|---|
| Experimental Arm | Experimental | Low Molecular Weight Heparin (enoxaparin sodium) + routine luteal phase support Receives: Drug: Low Molecular Weight Heparin (enoxaparin sodium) |
| Control Arm | No intervention | routine luteal phase support |
What is being measured
The primary outcome is the main question the study is designed to answer.
Live birth rate
Birth of liveborn
Measured: Time of delivery up to 42 weeks gestation
Secondary outcomes (4)
Embryo implantation rate
Gestational sacs are seen by ultrasound
Measured: 4 weeks
Clinical pregnancy rate
Fetal heartbeat is seen by ultrasound
Measured: 7-8 weeks
Miscarriage rate
After clinical pregnancy confirmed, before 28 weeks
Measured: Up to 28 weeks
Ovarian hyperstimulation syndrome (OHSS) rate
Ovarian hyperstimulations syndrome after COH
Measured: Up to 3 weeks after COH
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Oct 2018
- Study start1 Nov 2018
- Primary completion31 Oct 2021 (estimated)
- Study completion31 Oct 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)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
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 240 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Shenzhen Zhongshan Urology Hospital
- Sponsor type
- Other government
- Collaborators
- The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Renmin Hospital of Wuhan University
- Responsible party
- Principal investigator, Yong Zeng, Shenzhen Zhongshan Urology Hospital
- Investigators
- Haixiang Sun, M.D. Ph.D, Principal investigator, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical SchoolJing Yang, M.D. Ph.D, Principal investigator, Renmin Hospital of Wuhan UniversityRuochun Lian, M.D. Ph.D, Principal investigator, Shenzhen Zhongshan Urology Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03701750
- Sponsor's protocol ID
- szuh-2018-CT001
- Status last verified
- Jul 2020
- First submitted
- 7 Oct 2018
- Last updated
- 29 Jul 2020
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Urman B, Ata B, Yakin K, Alatas C, Aksoy S, Mercan R, Balaban B. Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labeled pilot trial. Hum Reprod. 2009 Jul;24(7):1640-7. doi: 10.1093/humrep/dep086. Epub 2009 Apr 8.
PubMed 19357135Noci I, Milanini MN, Ruggiero M, Papini F, Fuzzi B, Artini PG. Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study. Reprod Biomed Online. 2011 Jun;22(6):615-20. doi: 10.1016/j.rbmo.2011.03.016. Epub 2011 Mar 22.
PubMed 21498125Stern C, Chamley L, Norris H, Hale L, Baker HW. A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies. Fertil Steril. 2003 Aug;80(2):376-83. doi: 10.1016/s0015-0282(03)00610-1.
PubMed 12909502
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Low-Molecular-Weight-Heparin (LMWH) on Pregnancy Outcome in Women With Multiple Failures of IVF-ET
- ClinicalTrials.gov ID
- NCT03701750
- Acronym / sponsor ID
- szuh-2018-CT001
- Conditions
- Infertility
- Keywords
- IVF, pregnancy, LMWH, Low Molecular Weight Heparin, Assisted Reproductive Technology, Implantation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 240 participants (estimated)
- Lead sponsor
- Shenzhen Zhongshan Urology HospitalOther government
- Collaborators
- The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Renmin Hospital of Wuhan University
- Study start
- 1 Nov 2018 (actual)
- Primary completion
- 31 Oct 2021 (estimated)
- Study completion
- 31 Oct 2022 (estimated)
- First posted
- 10 Oct 2018 (actual)
- 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.
Low-Molecular-Weight-Heparin (LMWH) has been used empirically in patients undergoing in-vitro fertilization embryo transfer (IVF-ET) with the purpose to aid in improving pregnancy outcomes. The potential mechanism is that LMWH could exert its anticoagulant effect by inhibiting factor Xa, reducing the risk of insufficiency blood supply in the very early stage of pregnancy. Moreover, LMWH is supposed to play a role in manipulating blastocyst supposition, adhesion, and implantation, as well as trophoblast differentiation and invasion. However, limited high-quality clinical trials focus on the effectivity of LMWH in IVF-ET, and the published evidence is not consensus, leading to considerable controversy in the clinical application of LMWH in IVF-ET patients. Here, investigators try to evaluate the effect of LMWH on pregnancy outcome in women with multiple failures of IVF-ET via a multi-center randomized controlled trial.
Detailed description
Implantation failure seems to be inevitable in some couples undergoing IVF-ET treatment, despite transferred with high-quality embryos. There are several factors, including coagulation, are supposed to contribute to the implantation failure. Several groups reported that inherited and acquired coagulation is highly prevalent in women with recurrent implantation failure (RIF). Besides, women undergoing assisted reproduction are more likely to expose to thrombotic risks because high-dose exogenous gonadotrophins are given to harvest more oocytes for the fertilization. Given the risk of thrombosis, patients are often recommended to receive thromboprophylaxis with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in many clinics empirically.
LMWH is generated by depolymerization from UFH. Compared with UFH, LWMH exerts its anticoagulant effect mainly by inhibiting factor Xa rather than factor IIa. LMWH has a more predictable antithrombotic response and allows the administration to patients themselves without the laboratory monitoring. Also, it substantially reduces the risk of heparin-induced thrombocytopenia (HIT).
Beyond its anticoagulant effects, heparin is supposed to improve pregnancy outcomes by modulating blastocyst supposition, adhesion and implantation and as well as trophoblast differentiation and invasion through interactions with several adhesion molecules, growth factors, cytokines, and enzymes. Also, complement activation induced by aPL antibodies in mice is inhibited, and pregnancy complications are attenuated when treated with heparin.
Unfortunately, the use of LMWH in IVF/ET seems based on biological plausibility rather than evidence of efficacy. The high-quality studies (randomized controlled trials or prospective controlled trials) are limited, and the results are controversial. A meta-analysis (including 2 RCT and 1 quasi-RCT) reported that there is no difference in implantation rate in women with ≥3 recurrent implantation failure when treated with LMWH. Although live birth rate (LBR) and miscarriage rates are improved, investigators are still concerned because limited studies and patients were included in this analysis. Even in the non-RIF patients with or without thrombophilia defects, no consensus results could be achieved.
Given the burden of daily injection, skin irritation at injection site and other potential side-effects, the effectivity of LMWH in IVF/ET should be carefully examined even though LMWH is regarded as safe thromboprophylaxis. Hence, investigators propose a multi-center randomized study to evaluate the efficacy of Heparin in IVF-ET.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experimental Arm | Experimental | Drug: Low Molecular Weight Heparin (enoxaparin sodium)Low Molecular Weight Heparin (enoxaparin sodium) + routine luteal phase support |
| Control Arm | No intervention | –routine luteal phase support |
Who may qualify
- Ages
- 20 to 38 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- ≥2 consecutive IVF/ICSI-ET without clinical pregnancy
- ≥2 oocytes retrieval cycles
- 19<BMI≤25
- Normal ovarian reserve ( AMH> 1, FSH <10 )
- Willing and able to sign the informed consent.
Key exclusion criteria (12 listed)
- Uterine abnormalities confirmed by hysterosalpingography or hysteroscopy
- Parental chromosomal abnormalities
- PCOS
- Anti-phospholipid Syndrome
- Endocrine disorder
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 |
|---|---|---|
| Low Molecular Weight Heparin (enoxaparin sodium)enoxaparin sodium 40mg/day subcutaneously after oocyte collection, and routine luteal phase support after embryo transfer until clinical pregnancy confirmed by ultrasound | Drug | Experimental Arm |
Primary outcome
Live birth rate
Time frame: Time of delivery up to 42 weeks gestation
Birth of liveborn
4 secondary outcomes
Embryo implantation rate
Time frame: 4 weeks
Clinical pregnancy rate
Time frame: 7-8 weeks
Miscarriage rate
Time frame: Up to 28 weeks
Ovarian hyperstimulation syndrome (OHSS) rate
Time frame: Up to 3 weeks after COH
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2020.
- Background: PubMed 19357135Urman B, Ata B, Yakin K, Alatas C, Aksoy S, Mercan R, Balaban B. Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labeled pilot trial. Hum Reprod. 2009 Jul;24(7):1640-7. doi: 10.1093/humrep/dep086. Epub 2009 Apr 8.
- Background: PubMed 21498125Noci I, Milanini MN, Ruggiero M, Papini F, Fuzzi B, Artini PG. Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study. Reprod Biomed Online. 2011 Jun;22(6):615-20. doi: 10.1016/j.rbmo.2011.03.016. Epub 2011 Mar 22.
- Background: PubMed 12909502Stern C, Chamley L, Norris H, Hale L, Baker HW. A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies. Fertil Steril. 2003 Aug;80(2):376-83. doi: 10.1016/s0015-0282(03)00610-1.
- Individual participant dataSharing planned: Undecided
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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.
Haixiang Sun, M.D. Ph.D principal investigator
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Jing Yang, M.D. Ph.D principal investigator
Renmin Hospital of Wuhan University
Ruochun Lian, M.D. Ph.D principal investigator
Shenzhen Zhongshan Urology Hospital
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Low Molecular Weight Heparin (enoxaparin sodium) in people with Infertility, run by Shenzhen Zhongshan Urology Hospital at 3 sites in China.
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 5 inclusion and 12 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 29 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in China. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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 Lianghui Diao, Ph.D. (+86-755-88361001 ext. 9723, diaolianghui@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Live birth rate (time frame: Time of delivery up to 42 weeks gestation). 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 NCT03701750, which also lists 3 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 29 Jul 2020.