Comparison of a Semi-automated Closed Vitrification System (Gavi®) With a Manual Open Vitrification Sytem (Cryotop®) (Gavi)

November 25, 2020 updated by: Prof. Dr. med. M.Sc. Georg Griesinger, University of Luebeck

Prospective, Multi-center, Randomized, Controlled, Open Non-inferiority Trial Comparing a Semi-automated Closed Vitrification System (Gavi®) With a Manual Open Vitrification Sytem (Cryotop®)

The GAVI® closed vitrification system is a CE labelled device licensed for use in human IVF. It has been developed to standardize the process of vitrification and to increase the safety of the procedure. It has been demonstrated that the novel semiautomated, closed vitrification system providing standardized equilibration prior to cryopreservation can produce similar results in terms of recovery rate and Embryo development up to the blastocyst stage as compared to the commonly used Manual Cryotop® open vitrifcation system when applied in a mouse model.

Furthermore, its application has resulted in first pregnancies after transfer of vitrifiedwarmed biopsied human blastocyts. Due to limitations of the preliminary studies (application in mouse model; absence of a larger clinical Trial assessing pregnancy and live birth rates in human model etc.) it is of paramount importance to compare the GAVI® vitrification method to the routinely used Cryotop® method in a human IVF setting employing randomization and a-priori sample size definitions.

The primary objective of this study is to demonstrate non-inferiority of vitrification using the semi-automated GAVI® closed system over the so-far routinely used manual Cryotop® open system in terms of post-thawing survival rate of 2PN oocytes.

The secondary objective of this trial is to study differences in embryo development, clinical pregnancy rate, ongoing pregnancy rate and live birth rate.

Furthermore, differences in procedure duration and convenience will be evaluated.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

One hundred and eighty (n=180) patients presenting more than 2 surplus 2 PNoocytes for vitrification or patients having all available 2PN oocytes electively vitrified will be randomly allocated (1:1) on day of fertilization check (day 1 after ovum pickup) to either procedure. In the study group, 2PN oocytes will be cryopreserved utilizing the semi-automated GAVI® open vitrification/warming technique.

In the control group, 2PN oocytes will be cryopreserved utilizing the manual Cryotop® open vitrification/warming technique.

The participation in this study will be limited to one cycle per patient. The study population consists of infertile couples undergoing IVF or ICSI treatment.

The study duration will be minimally 6 months per subject, e.g. the main study on the Primary outcome 2PN survival will be closed 6 months after randomization of the last patient.

Data from pregnancy and live birth outcome will be reported in addenda to the main clinical study report, as appropriate.

Before initiation of the study, all study sites will have investigators sufficiently trained.

The study will be performed in at least three sites within Germany. Patient recruitment will be competitive between study´centers.

The number of patients having oocyte pick-up during the time frame of the study conduct will consist of the population screened for inclusion.

In general, patients complying with the inclusion and exclusion criteria are eligible for inclusion and randomization.

There are no restrictions on the ovarian stimulation protocol and type or dose of ovulation induction agent (hCG or GnRH-agonist). Ovum pick-up is usually performed by transvaginal ultrasound-guided follicle aspiration 36±2 hours after hCG administration.

IVF or ICSI procedure is performed according to the investigator site´s standard operating procedure.

Fertilization check is performed on day 1 after ovum pick-up (OPU) 17±1 hours post insemination. The number of regularly fertilized oocytes, defined as oocyte presenting 2 pronuclei and 2 polar bodies, is assessed.

Patients presenting ≥ 2 surplus regularly fertilized oocytes for cryoperservation on day 1 and patients undergoing elective cryopreservation of all available 2 PN oocytes are are allocated to one of the two 2 procedures.

Randomization will be performed on day of fertilization check (day 1 after OPU) by lab staff by opening a numbered, opaque sealed envelopes. The random sequence will be software-generated and blocks will be used. All randomized patients will be logged in a paper- based randomization log with initials, DOB, study number, date, study group, name and signature of staff. Randomization will be stratified by Center and by indication (surplus 2PN oocyte cryopreservation vs. elective cryopreservation of all available 2PN oocytes).

All vitrification and warming procedures will be performed according to the manufacturer´s instructions.

In order to investigate the differences in vitrification procedure duration, the time span between starting with preparations needed for vitrification and transferring the vitrification device(s) into the liquid nitrogen tank for storage will be recorded.

Depending on the investigator site's cryo embryo transfer policy, in a subsequent natural or programmed cycle vitrified/warmed embryos will be replaced. Within site, all patients will undergo the same cryoprotocol for preparation of the endometrium.

There are no specifications on the protocol to be used. The number of 2 PN oocytes to be warmed will be decided by the investigator on a case by case basis. Embryo culture will be performed in all cases in individual microdroplets covered with culture oil up to the day of scheduled embryo transfer.

The day of embryo transfer and the number of embryos to be transferred will be decided by the investigator on a case by case basis.

In order to investigate survival rate, warmed 2PN-ooytes will be assessed immediately and 2 hours post warming procedure. Survival will be confirmed by the presence of an intact oolemma and regular cytoplasm 2 hours after the warming procedure and/or when embryonic cleavage is observed.

In order to investigate potential differences in development and quality of vitrified/warmed embryos cleavage and morphology will be assessed as followed:

day 2 (44±1 hours post insemination) : cell number, blastomere size, grade of fragmentation

day 3 (68±1 hours post insemination): cell number, blastomere size, grade of fragmentation

day 5 (116±1 hours post insemination): blastocyst stage (grade of expansion), ICM (inner cell mass) morphology, TE (trophectoderm) morphology

day 6 (140±1 hours post insemination): blastocyst stage (grade of expansion), ICM (inner cell mass) morphology, TE (trophectoderm) morphology

Patients who conceive will undergo ultrasound examination to confirm clinical pregnancy at 6-7 weeks of gestation. Follow-up data regarding the confirmation of ongoing pregnancy will be obtained by telephone. Live birth including related data will be obtained by a questonaire to be completed by the patient and returned to the investigator´s clinic.

The analyses will be done per-intention-to-treat (ITT) and per protocol (PP), as appropriate. The ITT population is the randomized patient population. The PP population is the population of patients undergoing an attempt of thawing.

Source data will be paper-based case report forms (CRF).

  • study ID number
  • date of birth (female patient)
  • age female (years)
  • age male (years)
  • type of stimulation protocol (Antagonist/Agonist protocol, short/long protocol)
  • type of gonadotropin used (uFSH, rFSH, HMG, mix, Elonva)
  • total dose of gonadotropins
  • type of oocyte insemination (IVF, ICSI)
  • Date and time of trigger
  • Type and dose of triggering medication
  • Date and time of ovum pick-up
  • Date of randomization
  • study group
  • date and time of IVF/ICSI
  • date and time of fertilization check (2PN assessment)
  • number of fertilized oocytes (2PN oocytes)
  • reason for vitrification (surplus vs. elective)
  • date and time of vitrification (start/end)
  • duration of vitrification procedure (minutes)
  • date and time of warming (start/end)
  • duration of warming procedure (minutes)
  • number of warmed 2PN-oocytes
  • number of vital 2PN-oocytes
  • number of top quality embryos on day 2, day 3, day 5 and day 6 (depending on day of embryo transfer)
  • number of transferred embryos
  • number of revitrified embryos
  • cycle outcome (no pregnancy, positive hCG test)
  • course of pregnancy (abortion, termination, vanishing twin, etc.)
  • Multiplicity (singleton, twin, triplet)
  • pregnancy outcome (clinical pregnancy, ongoing pregnancy, live birth)

Descriptive statistics will be performed by analysing median, mean, n, standard deviation, ranges and 95% confidence intervals (CI). The differences between arms will be summarized as absolute difference with 95% CI. For the primary outcome, a linear model will be constructed accounting for treatment group, study site and randomization stratum exclusively for the per-protocol population.

For secondary outcomes ITT and/or PP analyses will be performed. No correction for multiplicity is planned. Parametric and non-parametric tests will be used for normally distributed and non-normally distributed variables, respectively, to compare secondary outcomes between groups.

The patient data will be entered into a computer database in a pseudonymized way. Data management and analysis will be carried out by the Principal Investigator.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
149

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Kiel, Germany, 24105
        • Universitäres Kinderwunschzentrum Kiel
      • Lübeck, Germany, 23562
        • Universitäres Kinderwunschzentrum Lübeck
      • Ulm, Germany, 89077
        • Kinderwunsch-Zentrum Ulm

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • IVF or ICSI treatment
  • 2 or more surplus 2 PN oocytes OR elective cryopreservation of all 2 PN oocytes on day of fertilization check
  • willingness to participate (signed ICF)

Exclusion Criteria:

  • history of low response to controlled ovarian hyper stimulation in previous IVF or ICSI treatments (ESHRE Bologna criteria; Ferranetti et al., Hum Reprod 2011)
  • uterine pathology evident on transvaginal sonography, hysterosalpingography, hysteroscopy or laparoscopy
  • participation in a PGS or PGD program
  • previous participation in this study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Gavi®
surplus or all fertilized oocytes will be cryoperserved by utilizing the closed, semi-automated Gavi® vitrification system
Procedure: Gavi® Vitrification
A closed, semi-automated vitrification system
Active Comparator: Cryotop®
surplus or all fertilized oocytes will be cryoperserved by utilizing the open, manual Cryotop® vitrification system
Procedure: Cryotop® Vitrification
An open, manual vitrification system

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
post-thawing survival rate
Time Frame: 2 hours
confirmation of survival by presence of intact oolemma and regular cytoplasm 2 hours post warming procedure and by observation of embryonic cleavage on
2 hours

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of top quality embryos on day 2
Time Frame: 2 days
Number of top quality embryos on day 2 (according to the Istanbul Consensus on embryo assessment) divided by the number of vitrified- warmed 2PN-oocytes
2 days
Number of top quality embryos on day 3
Time Frame: 3 days
Number of top quality embryos on day 3 (according to the Istanbul Consensus on embryo assessment) divided by the number of vitrified- warmed 2PN-oocytes
3 days
Number of top quality embryos on day 5
Time Frame: 5 days
Number of top quality embryos on day 5 (according to the Istanbul Consensus on embryo assessment) divided by the number of vitrified- warmed 2PN-oocytes
5 days
Number of top quality embryos on day 6
Time Frame: 6 days
Number of top quality embryos on day 6 (according to the Istanbul Consensus on embryo assessment) divided by the number of vitrified- warmed 2PN-oocytes
6 days
Clinical pregnancy rate
Time Frame: 6 weeks
number of viable pregnancies at 6 weeks of gestation per ITT and PP
6 weeks
Ongoing pregnancy rate
Time Frame: 12 weeks
number of viable pregnancies at 12 weeks of gestation per ITT and PP
12 weeks
Live birth rate
Time Frame: 44 weeks
number of at least one live born infant per ITT and PP
44 weeks

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Procedure duration
Time Frame: 1 day
time span start - end of procedures in minutes:seconds, adjusted for number of 2 PN oocytes vitrified
1 day
Convenience
Time Frame: 1 day
questionaire to be completed by operating lab personnel after having performed at least 3 procedures with both methods
1 day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Luebeck

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Georg Griesinger, Prof Dr MSc, University of Luebeck

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 6, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 25, 2020

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 25, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 1, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 18, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 19, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 30, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 25, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 712225

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Fully anonymized data can be shared after primary publication upon reasonable request.

IPD Sharing Time Frame

from 12/2021 on

IPD Sharing Access Criteria

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0532-z

IPD Sharing Supporting Information Type

  • Study Protocol
  • Clinical Study Report (CSR)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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