In Vitro Maturation of OocytesIVM-FSHhCGNCT05370794
Is in Vitro Maturation of Oocytes Influenced by the Origin of Gonadotropins Used in Maturation Medium: is There a Difference in Efficiency When Using Urinary Versus Recombinant Produced Follicle Stimulating Hormone and Human Chorionic Gonadotropin
An observational study of In Vitro Maturation of Oocytes, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
Trial summary
Standard IVM currently contains urinary purified hormones which might contain contaminants possibly affecting maturation of embryo development. The investigators will test if the efficiency in terms of oocyte maturation after IVM of recombinant (without contaminants) is equivalent to urinary gonadotropins. Read more about this study
- Who is it for?
- Ages 18 to 36 years, women only
- Conditions the study is for
- In Vitro Maturation of Oocytes
- What is being tested?
- rhCG= Ovitrelle®, 250g/0.5ml = 26000IU/ml, Merck-Serono and rFSH = Gonal F®, 300IU/0.5ml, Merck-Serono
- How many people
- 35 participants
- Where
- 1 siteBelgium
- Study dates
- 19 Apr 2022to 30 Jun 2023
- How long will I take part?
- 18 Months
- 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 to 36 years
- Women only
- No healthy volunteers
- Adult
Study population: infertility patients
Who may be able to join
- PCO(S) patients
- Anti-Mullerian Hormone ≥ 3.6 ng/mL
- Basal Antral Follicle Count ≥ 20
- All ranks of trial
Who cannot join
- Surgically obtained semen sample
- Grade 3 or 4 endometriosis, minor or major uterine abnormalities
- Preimplantation Genetic Testing
- Priming with Letrozole
Trial locations and contacts
1 site in 1 country.
Belgium1 site, 1 recruiting
- Recruiting
UZ Brussel
Brussels, 1090
Ingrid Segers, PhD, +3224749020, ingrid.segers@uzbrussel.be
About this study
Standard IVM currently contains urinary purified hormones which might contain contaminants possibly affecting maturation of embryo development. The investigators will test if the efficiency in terms of oocyte maturation after IVM of recombinant (without contaminants) is equivalent to urinary gonadotropins. Urinary and recombinant FSH and hCG will be used in equivalent bioactivity as measured in IU/ml and specified by the manufacturer. Sibling oocytes of the patient will be subjected to IVM medium containing urinary or recombinant gonadotropins. Oocyte maturation is the primary outcome, however, fertilization rate and preimplantation embryo development will be investigated.
Read the detailed description
In vitro maturation is a valid option for PCO(S) patients in the daily ART clinic, however maturation and embryologic development are not yet matching the efficiency levels obtained by standard COS treatment (Ho et al. 2019). To further enhance embryo quality after IVM, media and supplements should be efficient, safe and pure. It has been described that a threshold of FSH activity is necessary for maturation in human IVM (Cadenas et al. 2021), but hCG might be redundant (Ge et al 2008).
Until now, the investigators have been using highly purified urinary derived gonadotropins to supplement IVM media. However in the last decades more recombinant products are available and thoroughly characterized. In ART, both urinary derived and recombinant produced hormones are used to induce multiple follicle growth and ovulation in an ovarian stimulation cycle. Due to the fear of transmis-sion of pathogens (though not yet documented) and of intolerance caused by contaminants, recombinant products are often preferred in the clinic, with no indications of differences in effectiveness and safety (Nahuis 2009). In an in vitro bioassay, contaminating proteins may alter biological re-sponses with undesired effects. uFSH is documented to contain e.g. Insulin-like growth factor binding protein 1 (IGFBP7), that may inhibit oestrogen production, and Eosinophil Derived Neurotoxin (EDN), with known inhibitory effects on mouse oocyte maturation (Bassett 2009). Hence it is important in an in vitro system to use products with the highest purity available.
Moreover the oligosaccharide sialylation is different depending on the production method, altering the acidity and hereby the half-life in the body, but more importantly for an in vitro system, also the receptor binding potency (Bassett 2009, Riccetti 2017).
Hence, before changing our standard system for a theoretically better alternative, The investigators need to test the efficiency of recombinant hormones compared to the routinely used urinary hormones in terms of oocyte maturation efficiency in the in vitro maturation system.
PCOS patients eligible for an IVM cycle to treat infertility will be included. Patients will receive a mild ovarian stimulation protocol, identical to our standard IVM care program.
The investigators will conduct a non-inferiority study for oocyte maturation efficiency with a limit of 10%, significance level of 5% and power of 80%, leading to a sample size of 618 oocytes. The investigators estimate this will be obtained if 35 patients are included in the study.
After OR follicle fluids containing COC are filtered over a 70µm mesh filter to eliminate contaminating blood cells and hereby visualizing the COC. The first detected COC will be transferred into a wash droplet of a 4-well dish, the second COC will be kept in the second wash droplet of the 4-well dish, … According to the randomization list, the COC in the first droplet of the 4-well dish will be allocated to the standard or experimental IVM. The randomization list is generated with www.sealedenvelope.com.
Mature oocytes will be ferilized by Intracytoplasmic Sperm Injection (ICSI) and fertilization and embryological development will be recorded. Embryos of sufficient quality on day 3 will be vitrified for a deferred vitrified/warmed embryo transfer.
- Conditions
- In Vitro Maturation of Oocytes
- Being tested
- rhCG= Ovitrelle®, 250g/0.5ml = 26000IU/ml, Merck-Serono, rFSH = Gonal F®, 300IU/0.5ml, Merck-Serono
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
rhCG= Ovitrelle®, 250g/0.5ml = 26000IU/ml, Merck-SeronoDrug
recombinant hCG
rFSH = Gonal F®, 300IU/0.5ml, Merck-SeronoDrug
recombinant FSH
| Study group | Role | What they receive |
|---|---|---|
| standard IVM: urinary purified gonadotropins (uFSH and uhCG) | uhCG = Pregnyl®, 5000IU/ vial, Organon-Merck: final concentration 100mIU/ml + uFSH = Menopur® 75mIU/ml, Ferring: final concentration 75mIU/ml. Administered during 30h of in vitro maturation culture | |
| Experimental IVM: recombinant gonadotropins (rFSH and rhCG) | rhCG= Ovitrelle®, 250g/0.5ml = 26000IU/ml, Merck-Serono : final concentration 100mIU/ml + rFSH = Gonal F®, 300IU/0.5ml, Merck-Serono: final concentration 75mIU/ml.
Administered during 30h of in vitro maturation culture Receives: Drug: rhCG= Ovitrelle®, 250g/0.5ml = 26000IU/ml, Merck-Serono; Drug: rFSH = Gonal F®, 300IU/0.5ml, Merck-Serono |
What is being measured
The primary outcome is the main question the study is designed to answer.
oocyte maturation
the ability of the oocyte to extrude the first polar body
Measured: oocyte maturation is assessed after 30 hours of in vitro maturation
Secondary outcomes (3)
Fertilization rate
the ability of the oocyte to ba activated and form pronuclei
Measured: the presence of 2 pronuclei is assessed between 18-20 hours after ICSI
morphologic parameters describing embryo quality per fertilized oocyte
embryo developmental potential as estimated by morphological characteristics: embryos with 6 cells or more, less than 20% fragmentation, cell size according to division pattern and the absence of multinucleated blastomeres are considered as good quality embryos. As secondary parameters, the presence of vacuoles or granulation in the majority of blastomeres will exclude the embryo from the 'good quality' group regardless of the earlier mentioned parameters.
Measured: embryo developmental assessment is performed 3 days after ICSI
utilization rate
the embryos of sufficient quality to be vitrified for a deferred embryo transfer
Measured: utilization rate will be established 3 days after ICSI
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 May 2022
- Study start19 Apr 2022
- Primary completion30 Jun 2023 (estimated)
- Study completion30 Jun 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for In Vitro Maturation of OocytesStudies of the same condition, open and under way.
- More trials run by Universitair Ziekenhuis BrusselThe sponsor's other registered studies.
- 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
- Cohort
- Time perspective
- Prospective
- Enrolment
- 35 participants (estimated)
- Target duration
- 18 Months
Sponsor and investigators
- Lead sponsor
- Universitair Ziekenhuis Brussel
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Michel De Vos, MD,PhD, Principal investigator, Universitair Ziekenhuis Brussel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05370794
- Sponsor's protocol ID
- 2021-IVM-FSHhCG
- Acronym
- IVM-FSHhCG
- Status last verified
- May 2022
- First submitted
- 4 Apr 2022
- Last updated
- 7 Nov 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ho VNA, Braam SC, Pham TD, Mol BW, Vuong LN. The effectiveness and safety of in vitro maturation of oocytes versus in vitro fertilization in women with a high antral follicle count. Hum Reprod. 2019 Jun 4;34(6):1055-1064. doi: 10.1093/humrep/dez060.
PubMed 31111879Cadenas J, Nikiforov D, Pors SE, Zuniga LA, Wakimoto Y, Ghezelayagh Z, Mamsen LS, Kristensen SG, Andersen CY. A threshold concentration of FSH is needed during IVM of ex vivo collected human oocytes. J Assist Reprod Genet. 2021 Jun;38(6):1341-1348. doi: 10.1007/s10815-021-02244-8. Epub 2021 May 28.
PubMed 34050448Ge HS, Huang XF, Zhang W, Zhao JZ, Lin JJ, Zhou W. Exposure to human chorionic gonadotropin during in vitro maturation does not improve the maturation rate and developmental potential of immature oocytes from patients with polycystic ovary syndrome. Fertil Steril. 2008 Jan;89(1):98-103. doi: 10.1016/j.fertnstert.2007.02.021. Epub 2007 May 24.
PubMed 17524398Nahuis M, van der Veen F, Oosterhuis J, Mol BW, Hompes P, van Wely M. Review of the safety, efficacy, costs and patient acceptability of recombinant follicle-stimulating hormone for injection in assisting ovulation induction in infertile women. Int J Womens Health. 2010 Aug 9;1:205-11. doi: 10.2147/ijwh.s4729.
PubMed 21072289Bassett R, Lispi M, Ceccarelli D, Grimaldi L, Mancinelli M, Martelli F, Van Dorsselaer A. Analytical identification of additional impurities in urinary-derived gonadotrophins. Reprod Biomed Online. 2009 Sep;19(3):300-13. doi: 10.1016/s1472-6483(10)60163-0.
PubMed 19778474Riccetti L, Klett D, Ayoub MA, Boulo T, Pignatti E, Tagliavini S, Varani M, Trenti T, Nicoli A, Capodanno F, La Sala GB, Reiter E, Simoni M, Casarini L. Heterogeneous hCG and hMG commercial preparations result in different intracellular signalling but induce a similar long-term progesterone response in vitro. Mol Hum Reprod. 2017 Oct 1;23(10):685-697. doi: 10.1093/molehr/gax047.
PubMed 29044421
Study at a glance
From the registry record, last updated by the sponsor on 7 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Is in Vitro Maturation of Oocytes Influenced by the Origin of Gonadotropins Used in Maturation Medium: is There a Difference in Efficiency When Using Urinary Versus Recombinant Produced Follicle Stimulating Hormone and Human Chorionic Gonadotropin
- ClinicalTrials.gov ID
- NCT05370794
- Acronym / sponsor ID
- IVM-FSHhCG / 2021-IVM-FSHhCG
- Conditions
- In Vitro Maturation of Oocytes
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 35 participants (estimated)
- Lead sponsor
- Universitair Ziekenhuis BrusselUniversity, hospital or other
- Study start
- 19 Apr 2022 (actual)
- Primary completion
- 30 Jun 2023 (estimated)
- Study completion
- 30 Jun 2023 (estimated)
- First posted
- 12 May 2022 (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.
Standard IVM currently contains urinary purified hormones which might contain contaminants possibly affecting maturation of embryo development. The investigators will test if the efficiency in terms of oocyte maturation after IVM of recombinant (without contaminants) is equivalent to urinary gonadotropins. Urinary and recombinant FSH and hCG will be used in equivalent bioactivity as measured in IU/ml and specified by the manufacturer. Sibling oocytes of the patient will be subjected to IVM medium containing urinary or recombinant gonadotropins. Oocyte maturation is the primary outcome, however, fertilization rate and preimplantation embryo development will be investigated.
Detailed description
In vitro maturation is a valid option for PCO(S) patients in the daily ART clinic, however maturation and embryologic development are not yet matching the efficiency levels obtained by standard COS treatment (Ho et al. 2019). To further enhance embryo quality after IVM, media and supplements should be efficient, safe and pure. It has been described that a threshold of FSH activity is necessary for maturation in human IVM (Cadenas et al. 2021), but hCG might be redundant (Ge et al 2008).
Until now, the investigators have been using highly purified urinary derived gonadotropins to supplement IVM media. However in the last decades more recombinant products are available and thoroughly characterized. In ART, both urinary derived and recombinant produced hormones are used to induce multiple follicle growth and ovulation in an ovarian stimulation cycle. Due to the fear of transmis-sion of pathogens (though not yet documented) and of intolerance caused by contaminants, recombinant products are often preferred in the clinic, with no indications of differences in effectiveness and safety (Nahuis 2009). In an in vitro bioassay, contaminating proteins may alter biological re-sponses with undesired effects. uFSH is documented to contain e.g. Insulin-like growth factor binding protein 1 (IGFBP7), that may inhibit oestrogen production, and Eosinophil Derived Neurotoxin (EDN), with known inhibitory effects on mouse oocyte maturation (Bassett 2009). Hence it is important in an in vitro system to use products with the highest purity available.
Moreover the oligosaccharide sialylation is different depending on the production method, altering the acidity and hereby the half-life in the body, but more importantly for an in vitro system, also the receptor binding potency (Bassett 2009, Riccetti 2017).
Hence, before changing our standard system for a theoretically better alternative, The investigators need to test the efficiency of recombinant hormones compared to the routinely used urinary hormones in terms of oocyte maturation efficiency in the in vitro maturation system.
PCOS patients eligible for an IVM cycle to treat infertility will be included. Patients will receive a mild ovarian stimulation protocol, identical to our standard IVM care program.
The investigators will conduct a non-inferiority study for oocyte maturation efficiency with a limit of 10%, significance level of 5% and power of 80%, leading to a sample size of 618 oocytes. The investigators estimate this will be obtained if 35 patients are included in the study.
After OR follicle fluids containing COC are filtered over a 70µm mesh filter to eliminate contaminating blood cells and hereby visualizing the COC. The first detected COC will be transferred into a wash droplet of a 4-well dish, the second COC will be kept in the second wash droplet of the 4-well dish, … According to the randomization list, the COC in the first droplet of the 4-well dish will be allocated to the standard or experimental IVM. The randomization list is generated with www.sealedenvelope.com.
Mature oocytes will be ferilized by Intracytoplasmic Sperm Injection (ICSI) and fertilization and embryological development will be recorded. Embryos of sufficient quality on day 3 will be vitrified for a deferred vitrified/warmed embryo transfer.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 18 Months
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| standard IVM: urinary purified gonadotropins (uFSH and uhCG) | – | –uhCG = Pregnyl®, 5000IU/ vial, Organon-Merck: final concentration 100mIU/ml + uFSH = Menopur® 75mIU/ml, Ferring: final concentration 75mIU/ml. Administered during 30h of in vitro maturation culture |
| Experimental IVM: recombinant gonadotropins (rFSH and rhCG) | – | Drug: rhCG= Ovitrelle®, 250g/0.5ml = 26000IU/ml, Merck-Serono, Drug: rFSH = Gonal F®, 300IU/0.5ml, Merck-SeronorhCG= Ovitrelle®, 250g/0.5ml = 26000IU/ml, Merck-Serono : final concentration 100mIU/ml + rFSH = Gonal F®, 300IU/0.5ml, Merck-Serono: final concentration 75mIU/ml. Administered during 30h of in vitro maturation culture |
Who may qualify
- Ages
- 18 to 36 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
- Study population
- infertility patients
Key inclusion criteria (4 listed)
- PCO(S) patients
- Anti-Mullerian Hormone ≥ 3.6 ng/mL
- Basal Antral Follicle Count ≥ 20
- All ranks of trial
Key exclusion criteria (4 listed)
- Surgically obtained semen sample
- Grade 3 or 4 endometriosis, minor or major uterine abnormalities
- Preimplantation Genetic Testing
- Priming with Letrozole
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 |
|---|---|---|
| rhCG= Ovitrelle®, 250g/0.5ml = 26000IU/ml, Merck-Seronorecombinant hCG | Drug | Experimental IVM: recombinant gonadotropins (rFSH and rhCG) |
| rFSH = Gonal F®, 300IU/0.5ml, Merck-Seronorecombinant FSH | Drug | Experimental IVM: recombinant gonadotropins (rFSH and rhCG) |
Primary outcome
oocyte maturation
Time frame: oocyte maturation is assessed after 30 hours of in vitro maturation
the ability of the oocyte to extrude the first polar body
3 secondary outcomes
Fertilization rate
Time frame: the presence of 2 pronuclei is assessed between 18-20 hours after ICSI
morphologic parameters describing embryo quality per fertilized oocyte
Time frame: embryo developmental assessment is performed 3 days after ICSI
utilization rate
Time frame: utilization rate will be established 3 days after ICSI
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Nov 2022.
- Background: PubMed 31111879Ho VNA, Braam SC, Pham TD, Mol BW, Vuong LN. The effectiveness and safety of in vitro maturation of oocytes versus in vitro fertilization in women with a high antral follicle count. Hum Reprod. 2019 Jun 4;34(6):1055-1064. doi: 10.1093/humrep/dez060.
- Background: PubMed 34050448Cadenas J, Nikiforov D, Pors SE, Zuniga LA, Wakimoto Y, Ghezelayagh Z, Mamsen LS, Kristensen SG, Andersen CY. A threshold concentration of FSH is needed during IVM of ex vivo collected human oocytes. J Assist Reprod Genet. 2021 Jun;38(6):1341-1348. doi: 10.1007/s10815-021-02244-8. Epub 2021 May 28.
- Background: PubMed 17524398Ge HS, Huang XF, Zhang W, Zhao JZ, Lin JJ, Zhou W. Exposure to human chorionic gonadotropin during in vitro maturation does not improve the maturation rate and developmental potential of immature oocytes from patients with polycystic ovary syndrome. Fertil Steril. 2008 Jan;89(1):98-103. doi: 10.1016/j.fertnstert.2007.02.021. Epub 2007 May 24.
- Background: PubMed 21072289Nahuis M, van der Veen F, Oosterhuis J, Mol BW, Hompes P, van Wely M. Review of the safety, efficacy, costs and patient acceptability of recombinant follicle-stimulating hormone for injection in assisting ovulation induction in infertile women. Int J Womens Health. 2010 Aug 9;1:205-11. doi: 10.2147/ijwh.s4729.
- Background: PubMed 19778474Bassett R, Lispi M, Ceccarelli D, Grimaldi L, Mancinelli M, Martelli F, Van Dorsselaer A. Analytical identification of additional impurities in urinary-derived gonadotrophins. Reprod Biomed Online. 2009 Sep;19(3):300-13. doi: 10.1016/s1472-6483(10)60163-0.
- Background: PubMed 29044421Riccetti L, Klett D, Ayoub MA, Boulo T, Pignatti E, Tagliavini S, Varani M, Trenti T, Nicoli A, Capodanno F, La Sala GB, Reiter E, Simoni M, Casarini L. Heterogeneous hCG and hMG commercial preparations result in different intracellular signalling but induce a similar long-term progesterone response in vitro. Mol Hum Reprod. 2017 Oct 1;23(10):685-697. doi: 10.1093/molehr/gax047.
- 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.
Michel De Vos, MD,PhD principal investigator
Universitair Ziekenhuis Brussel
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of In Vitro Maturation of Oocytes, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
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 4 inclusion and 4 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 7 Nov 2022. 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 Belgium. 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?
Contact Ingrid Segers, PhD (+3224776690, ingrid.segers@uzbrussel.be), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
oocyte maturation (time frame: oocyte maturation is assessed after 30 hours of in vitro maturation). 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 NCT05370794, which also lists 6 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 7 Nov 2022.