In Vitro Maturation of OocytesCAPA-IVM-SibNCT04285892
Embryo Developmental Potential in a Novel 2-step IVM System
A study testing CAPA-IVM in people with In Vitro Maturation of Oocytes, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
Trial summary
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. 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?
- CAPA-IVM
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 1 siteBelgium
- Study dates
- 16 Jul 2020to 31 Dec 2023
- Phase
- Interventional
- 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
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.
About this study
Official title: Trial Investigating the Developmental Potential of Embryos Obtained After Biphasic in Vitro Oocyte Maturation (IVM) of Oocytes Including a Pre Maturation Culture Step ('capacitation Step') Compared with Standard IVM.
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. To further enhance embryo quality after IVM, it was hypothesized to keep the connection and communication between oocyte and cumulus cells intact for a prolonged pre-maturation culture before IVM was initiated. This has been investigated and established using a meiotic blocker C-type Natriuretic peptide (CNP).
The CNP peptide is present in high concentrations in the growing follicle, is produced by the mural granulosa cell compartment and binds to the Natriuretic peptide receptor 2 (NRP2) present in the cumulus cells. Binding of CNP on NRP2 leads to intracellular cGMP increase in cumulus cells, which travels through the transzonal projections to the oocyte. In the oocyte, cGMP will block the resumption of meiosis.
Using CNP as natural inhibitor of meiosis, a new medium was designed to allow oocyte and surrounding cumulus cells to communicate and hence gain in competence for an additional culture period: the pre-maturation phase or Capacitation phase (CAPA). This system was devel-oped in mouse, tested in human in UZ Brussel on research material (toelating federaal EC: CFE-FCE ADV_073_ZUBrussel, toelating lokaal EC: 2016/411 BUN 143201630723) and used in a clinical setting in Vietnam.
Read the detailed description
The current IVM system in use in the clinic has a single step approach and seems to be less efficient compared to research and literature findings using a biphasic CAPA-IVM system in terms of maturation.
To ascertain the efficiency of the biphasic CAPA-IVM system, both standard IVM and CAPA-IVM will be performed on sibling oocytes: maturation in standard IVM in the investigator's center is on average 47.5%, where CAPA-IVM reaches 62% maturation in literature.
The investigators aim to prove superiority of the CAPA-IVM system in terms of maturation. Also fertilization and embryo development will be compared.
The participants admitted to the study will be receiving both the standard IVM treatment for part of the participant's oocytes and the biphasic CAPA IVM system for the second part of the participant's oocytes.
In one ovary a regular oocyte pick up (OPU) will take place with oocytes assigned to the standard IVM treatment, in the other ovary the CAPA IVM system will be applied. This means oocytes that are liberated from the follicular environment need to be exposed immediately to the inhibiting CNP peptide and herefore the tubes to collect the follicle fluid from the punctured follicles are prefilled with CNP supplemented medium. The OPU procedure is identical for both ovaries and according to our standard OPU IVM procedure with the sole difference of empty or prefilled tubes to collect follicle fluid.
Oocytes from the 2 ovaries are separately processed in the lab according to attributed protocol.
After IVM of oocytes, mature oocytes are subjected to ICSI with partner's sperm or donor sperm. Partner's sperm sample will be frozen at the latest the day of egg retrieval and will be thawed the day of intracytoplasmic sperm injection (ICSI): due to the use of 2 different IVM protocols with 2 different time lines (30 hours maturation versus 24 hours+30 hours maturation), ICSI will take place on two consecutive days with a freshly thawed straw of sperm cells for each day.
Embryo development is followed until day 3 (cleavage stage) after ICSI. All embryos of sufficient quality will be vitrified for a deferred embryo transfer in a hormone replacement therapy (HRT) cycle. One embryo will be selected for embryo transfer based on the morphological quality assessment parameters, with the better quality as first choice for transfer, regardless the preceding IVM method. Frozen single embryo transfer cycles are repeated until pregnancy.
- Conditions
- In Vitro Maturation of Oocytes
- Being tested
- CAPA-IVM
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CAPA-IVMDevice
CAPA medium keeps oocytes in meiotic arrest for 22-24 hours. IVM medium allows oocytes to resume meiosis.
CAPA medium: 10% human serum albumin (HSA) + 10nM estradiol (E2) + 25nM CNP + 5ng/ml Insulin + 1mIU/ml follicle stimulating hormone (FSH) IVM medium: 10% HSA + 10nM E2 + 5ng/ml Insulin + 101mIU/ml FSH + 100ng/ml AREG CNP: peptide naturally occurring in follicles to maintain meiotic arrest, E2: estrogen, enhances effects of CNP, Insulin: basic growth factor used in cell cultures and component of commercially available LAG medium of the standard IVM system, AREG: downstream effector of the LHCG receptor which helps meiotic resumption. HSA, FSH and hCG are CE labeled. CAPA IVM medium is currently not yet available as CE marked commercially available medium and needs to be prepared in house.
| Study group | Role | What they receive |
|---|---|---|
| CAPA IVM | Experimental | CAPA IVM is a 2-step In vitro Maturation system in which an additional culture step, in which the oocytes are kept in meiotic arrest by the presence of the C-type Natriuretic peptide (CNP) for 22-24 hours, is preceding the in vitro maturation step in which maturation medium is supplemented with amphiregulin (AREG). The 'IVM System' of Medicult-Origio is used as a base medium. Receives: Device: CAPA-IVM |
| Standard IVM | No intervention | The IVM is performed as a single step protocol in which oocytes are immediately exposed to in vitro maturation medium for 30 hours. This is the current standard procedure in the clinical practice using the commercially available 'IVM System' of Medicult-Origio. Standard IVM medium: 10% HSA + 75mIU/ml FSH + 100mIU/ml hCG |
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 in the standard IVM protocol and after 54 hours after CAPA IVM
Secondary outcomes (4)
Fertilization rate
the ability of the oocyte to be 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 the 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
embryo cryotolerance
the damage brought by the vitrification and warming process on cell survival within the embryo and the capacity of the vitrified/warmed embryo to resume cleavage divisions
Measured: First warming is done within one month after OPU in a new HRT cycle and repeated untill pregnancy up to 1 year after egg retrieval.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2020
- Study start16 Jul 2020
- Primary completion30 May 2021
- Study completion31 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for In Vitro Maturation of OocytesStudies 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 N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- prospective randomized control trial
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 23 participants (actual)
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, VUB- UZ Brussel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04285892
- Sponsor's protocol ID
- 2020-CAPA-IVM-Sibling
- Acronym
- CAPA-IVM-Sib
- Status last verified
- Nov 2024
- First submitted
- 14 Feb 2020
- Last updated
- 25 Nov 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Saenz-de-Juano MD, Ivanova E, Romero S, Lolicato F, Sanchez F, Van Ranst H, Krueger F, Segonds-Pichon A, De Vos M, Andrews S, Smitz J, Kelsey G, Anckaert E. DNA methylation and mRNA expression of imprinted genes in blastocysts derived from an improved in vitro maturation method for oocytes from small antral follicles in polycystic ovary syndrome patients. Hum Reprod. 2019 Sep 29;34(9):1640-1649. doi: 10.1093/humrep/dez121.
PubMed 31398248Sanchez F, Le AH, Ho VNA, Romero S, Van Ranst H, De Vos M, Gilchrist RB, Ho TM, Vuong LN, Smitz J. Biphasic in vitro maturation (CAPA-IVM) specifically improves the developmental capacity of oocytes from small antral follicles. J Assist Reprod Genet. 2019 Oct;36(10):2135-2144. doi: 10.1007/s10815-019-01551-5. Epub 2019 Aug 9.
PubMed 31399916Vuong LN, Le AH, Ho VNA, Pham TD, Sanchez F, Romero S, De Vos M, Ho TM, Gilchrist RB, Smitz J. Live births after oocyte in vitro maturation with a prematuration step in women with polycystic ovary syndrome. J Assist Reprod Genet. 2020 Feb;37(2):347-357. doi: 10.1007/s10815-019-01677-6. Epub 2020 Jan 4.
PubMed 31902102Romero S, Sanchez F, Lolicato F, Van Ranst H, Smitz J. Immature Oocytes from Unprimed Juvenile Mice Become a Valuable Source for Embryo Production When Using C-Type Natriuretic Peptide as Essential Component of Culture Medium. Biol Reprod. 2016 Sep;95(3):64. doi: 10.1095/biolreprod.116.139808. Epub 2016 Aug 3.
PubMed 27488026Sanchez F, Lolicato F, Romero S, De Vos M, Van Ranst H, Verheyen G, Anckaert E, Smitz JEJ. An improved IVM method for cumulus-oocyte complexes from small follicles in polycystic ovary syndrome patients enhances oocyte competence and embryo yield. Hum Reprod. 2017 Oct 1;32(10):2056-2068. doi: 10.1093/humrep/dex262.
PubMed 28938744
Study at a glance
From the registry record, last updated by the sponsor on 25 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Trial Investigating the Developmental Potential of Embryos Obtained After Biphasic in Vitro Oocyte Maturation (IVM) of Oocytes Including a Pre Maturation Culture Step ('capacitation Step') Compared with Standard IVM.
- ClinicalTrials.gov ID
- NCT04285892
- Acronym / sponsor ID
- CAPA-IVM-Sib / 2020-CAPA-IVM-Sibling
- Conditions
- In Vitro Maturation of Oocytes
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Universitair Ziekenhuis BrusselUniversity, hospital or other
- Study start
- 16 Jul 2020 (actual)
- Primary completion
- 30 May 2021 (actual)
- Study completion
- 31 Dec 2023 (actual)
- First posted
- 26 Feb 2020 (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.
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. To further enhance embryo quality after IVM, it was hypothesized to keep the connection and communication between oocyte and cumulus cells intact for a prolonged pre-maturation culture before IVM was initiated. This has been investigated and established using a meiotic blocker C-type Natriuretic peptide (CNP).
The CNP peptide is present in high concentrations in the growing follicle, is produced by the mural granulosa cell compartment and binds to the Natriuretic peptide receptor 2 (NRP2) present in the cumulus cells. Binding of CNP on NRP2 leads to intracellular cGMP increase in cumulus cells, which travels through the transzonal projections to the oocyte. In the oocyte, cGMP will block the resumption of meiosis.
Using CNP as natural inhibitor of meiosis, a new medium was designed to allow oocyte and surrounding cumulus cells to communicate and hence gain in competence for an additional culture period: the pre-maturation phase or Capacitation phase (CAPA). This system was devel-oped in mouse, tested in human in UZ Brussel on research material (toelating federaal EC: CFE-FCE ADV_073_ZUBrussel, toelating lokaal EC: 2016/411 BUN 143201630723) and used in a clinical setting in Vietnam.
Detailed description
The current IVM system in use in the clinic has a single step approach and seems to be less efficient compared to research and literature findings using a biphasic CAPA-IVM system in terms of maturation.
To ascertain the efficiency of the biphasic CAPA-IVM system, both standard IVM and CAPA-IVM will be performed on sibling oocytes: maturation in standard IVM in the investigator's center is on average 47.5%, where CAPA-IVM reaches 62% maturation in literature.
The investigators aim to prove superiority of the CAPA-IVM system in terms of maturation. Also fertilization and embryo development will be compared.
The participants admitted to the study will be receiving both the standard IVM treatment for part of the participant's oocytes and the biphasic CAPA IVM system for the second part of the participant's oocytes.
In one ovary a regular oocyte pick up (OPU) will take place with oocytes assigned to the standard IVM treatment, in the other ovary the CAPA IVM system will be applied. This means oocytes that are liberated from the follicular environment need to be exposed immediately to the inhibiting CNP peptide and herefore the tubes to collect the follicle fluid from the punctured follicles are prefilled with CNP supplemented medium. The OPU procedure is identical for both ovaries and according to our standard OPU IVM procedure with the sole difference of empty or prefilled tubes to collect follicle fluid.
Oocytes from the 2 ovaries are separately processed in the lab according to attributed protocol.
After IVM of oocytes, mature oocytes are subjected to ICSI with partner's sperm or donor sperm. Partner's sperm sample will be frozen at the latest the day of egg retrieval and will be thawed the day of intracytoplasmic sperm injection (ICSI): due to the use of 2 different IVM protocols with 2 different time lines (30 hours maturation versus 24 hours+30 hours maturation), ICSI will take place on two consecutive days with a freshly thawed straw of sperm cells for each day.
Embryo development is followed until day 3 (cleavage stage) after ICSI. All embryos of sufficient quality will be vitrified for a deferred embryo transfer in a hormone replacement therapy (HRT) cycle. One embryo will be selected for embryo transfer based on the morphological quality assessment parameters, with the better quality as first choice for transfer, regardless the preceding IVM method. Frozen single embryo transfer cycles are repeated until pregnancy.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- prospective randomized control trial
| Arm | Type | Receives |
|---|---|---|
| CAPA IVM | Experimental | Device: CAPA-IVMCAPA IVM is a 2-step In vitro Maturation system in which an additional culture step, in which the oocytes are kept in meiotic arrest by the presence of the C-type Natriuretic peptide (CNP) for 22-24 hours, is preceding the in vitro maturation step in which maturation medium is supplemented with amphiregulin (AREG). The 'IVM System' of Medicult-Origio is used as a base medium. |
| Standard IVM | No intervention | –The IVM is performed as a single step protocol in which oocytes are immediately exposed to in vitro maturation medium for 30 hours. This is the current standard procedure in the clinical practice using the commercially available 'IVM System' of Medicult-Origio. Standard IVM medium: 10% HSA + 75mIU/ml FSH + 100mIU/ml hCG |
Who may qualify
- Ages
- 18 to 36 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
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 |
|---|---|---|
| CAPA-IVMCAPA medium keeps oocytes in meiotic arrest for 22-24 hours. IVM medium allows oocytes to resume meiosis. CAPA medium: 10% human serum albumin (HSA) + 10nM estradiol (E2) + 25nM CNP + 5ng/ml Insulin + 1mIU/ml follicle stimulating hormone (FSH) IVM medium: 10% HSA + 10nM E2 + 5ng/ml Insulin + 101mIU/ml FSH + 100ng/ml AREG CNP: peptide naturally occurring in follicles to maintain meiotic arrest, E2: estrogen, enhances effects of CNP, Insulin: basic growth factor used in cell cultures and component of commercially available LAG medium of the standard IVM system, AREG: downstream effector of the LHCG receptor which helps meiotic resumption. HSA, FSH and hCG are CE labeled. CAPA IVM medium is currently not yet available as CE marked commercially available medium and needs to be prepared in house. | Device | CAPA IVM |
Primary outcome
oocyte maturation
Time frame: oocyte maturation is assessed after 30 hours in the standard IVM protocol and after 54 hours after CAPA IVM
the ability of the oocyte to extrude the first polar body
4 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
embryo cryotolerance
Time frame: First warming is done within one month after OPU in a new HRT cycle and repeated untill pregnancy up to 1 year after egg retrieval.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Nov 2024.
- Background: PubMed 31398248Saenz-de-Juano MD, Ivanova E, Romero S, Lolicato F, Sanchez F, Van Ranst H, Krueger F, Segonds-Pichon A, De Vos M, Andrews S, Smitz J, Kelsey G, Anckaert E. DNA methylation and mRNA expression of imprinted genes in blastocysts derived from an improved in vitro maturation method for oocytes from small antral follicles in polycystic ovary syndrome patients. Hum Reprod. 2019 Sep 29;34(9):1640-1649. doi: 10.1093/humrep/dez121.
- Background: PubMed 31399916Sanchez F, Le AH, Ho VNA, Romero S, Van Ranst H, De Vos M, Gilchrist RB, Ho TM, Vuong LN, Smitz J. Biphasic in vitro maturation (CAPA-IVM) specifically improves the developmental capacity of oocytes from small antral follicles. J Assist Reprod Genet. 2019 Oct;36(10):2135-2144. doi: 10.1007/s10815-019-01551-5. Epub 2019 Aug 9.
- Background: PubMed 31902102Vuong LN, Le AH, Ho VNA, Pham TD, Sanchez F, Romero S, De Vos M, Ho TM, Gilchrist RB, Smitz J. Live births after oocyte in vitro maturation with a prematuration step in women with polycystic ovary syndrome. J Assist Reprod Genet. 2020 Feb;37(2):347-357. doi: 10.1007/s10815-019-01677-6. Epub 2020 Jan 4.
- Background: PubMed 27488026Romero S, Sanchez F, Lolicato F, Van Ranst H, Smitz J. Immature Oocytes from Unprimed Juvenile Mice Become a Valuable Source for Embryo Production When Using C-Type Natriuretic Peptide as Essential Component of Culture Medium. Biol Reprod. 2016 Sep;95(3):64. doi: 10.1095/biolreprod.116.139808. Epub 2016 Aug 3.
- Background: PubMed 28938744Sanchez F, Lolicato F, Romero S, De Vos M, Van Ranst H, Verheyen G, Anckaert E, Smitz JEJ. An improved IVM method for cumulus-oocyte complexes from small follicles in polycystic ovary syndrome patients enhances oocyte competence and embryo yield. Hum Reprod. 2017 Oct 1;32(10):2056-2068. doi: 10.1093/humrep/dex262.
- 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
VUB- UZ Brussel
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing CAPA-IVM in people with 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: finished, as of the sponsor's last update on 25 Nov 2024. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
oocyte maturation (time frame: oocyte maturation is assessed after 30 hours in the standard IVM protocol and after 54 hours after CAPA IVM). 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 NCT04285892, which also lists 5 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 25 Nov 2024.