DuoStim in Cases of PGT: Comparison of Embryo Quantity and Embryonic Quality Using MitoScore

Infertility, Female Clinical Trial

Official title:

Double Ovarian Stimulation in Cases of Preimplantation Genetic Testing: Comparison of Embryo Quantity and Embryonic Quality Using MitoScore

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03291821
• Other study ID #: 1702-MAD-014-MC
• Status: Completed
• Phase: N/A
• Start date: December 1, 2017
• Est. completion date: June 1, 2020

Study information

• Verified date: December 2020
• Source: IVI Madrid
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Since preimplantation genetic testing (PGT) is being more frequently requested from patients as women pursue infertility treatments at an advanced age with a poorer prognosis, sometimes physicians are compelled to perform several stimulation cycles to obtain more eggs and, consequently, a greater number of biopsied embryos. Hence, the idea of carrying out this study arises as an attempt to optimize each menstrual cycle to the maximum. It is believed that the double stimulation (DuoStim) protocol could be an alternative for this group of patients, allowing to obtain a larger number of oocytes in a shorter period, thus, increasing the number of biopsied embryos and possibly decreasing the interval to achieve a successful pregnancy. The investigators aim to evaluate the potential usefulness of the DuoStim protocol for patients desiring to obtain oocytes as soon as possible. Using PGT, the investigators will compare the rate of euploid embryos per cycle in patients undergoing DuoStim protocol versus patients undergoing two conventional controlled ovarian hyperstimulation in consecutive cycles. Patients will include women with advanced age and poor response. This is a unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV clinical study. The investigators hypothesize that the rate of euploid embryos per cycle is similar in the DuoStim group compared to the group undergoing two conventional controlled ovarian hyperstimulation in consecutive cycles. Furthermore the investigators will evaluate if there are differences regarding the number of total oocytes obtained, the number of mature oocytes, the number of biopsied blastocysts and the MitoScore index of the available euploid embryos.

Description:

Classically, the follicular development was thought to occur only during the follicular phase of the menstrual cycle. However, new data demonstrated several waves of cyclic development of the antral follicles within the same menstrual cycle. Some authors insist that follicles formed during the luteal phase may have a similar ovulation potential of those formed in the follicular phase, thus offering new possibilities for ovarian stimulation. Due to the use of vitrification technique and the appearance of the gonadotropins, physicians have been allowed to innovate the protocols applied to controlled ovarian hyperstimulation and have been able to obtain more oocytes in a shorter period for patients requiring rapid intervention, such as oncologic patients. Because of the accumulated experience with these new approaches, some investigators have recently proposed a double stimulation (DuoStim) protocol. Evidence of the competence of oocytes obtained from the luteal phase have been recently defined and published. Also, it has not been related with an increased risk for congenital anomalies. The DuoStim is a protocol consisting of two stimulations within the same menstrual cycle, one in the follicular phase starting in day 2 of the cycle and the other in the luteal phase starting 5 days after the first ovarian puncture. Trigger is always performed with GnRH agonist. Additionally, patients demanding infertility treatments are increasingly older and the use of preimplantation genetic testing (PGT) allows for a finer embryo selection along with better reproductive outcomes. Currently, most of PGTs are carried out at the blastocysts stage, which improve the prognosis but, on the contrary, also oblige to frozen those embryos and perform a deferred transfer, lengthening the procedure. Another innovative tool for a more accurate embryo selection which has been recently described is the MitoScore. The MitoScore is a mitochondrial biomarker index developed by Igenomix aiming to indicate the energetic status of the embryo. It intends to select those embryos with best implantation potential and, therefore, more likely to result in an ongoing pregnancy after an IVF treatment. It is calculated dividing the number of mitochondrial DNA copies by the amount of nuclear DNA. Although still controversial, it has been proved by some authors to increase success rates of implantation and ongoing pregnancies in IVF cycles and to diminish the number of multiple gestations. Since PGT is being more frequently requested from patients as women pursue infertility treatments at an advanced age with a poorer prognosis, sometimes physicians are compelled to perform several stimulation cycles to obtain more eggs and, consequently, a greater number of biopsied embryos. Hence, the idea of carrying out this study arises as an attempt to optimize each menstrual cycle to the maximum. It is believed that the DuoStim protocol could be an alternative for this group of patients, allowing to obtain a larger number of oocytes in a shorter period, thus, increasing the number of biopsied embryos and possibly decreasing the interval to achieve a successful pregnancy. The investigators aim to evaluate the potential usefulness of the DuoStim protocol for patients desiring to obtain oocytes as soon as possible. Also, using PGT, the investigators will compare the rate of euploid embryos per cycle in patients undergoing DuoStim protocol versus patients undergoing two conventional controlled ovarian hyperstimulation in consecutive cycles. Patients will include women with advanced age and poor response. This is a unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV clinical study. The investigators hypothesize that the rate of euploid embryos per cycle is similar in the DuoStim group compared to the group undergoing two conventional controlled ovarian hyperstimulation in consecutive cycles. Furthermore the investigators will evaluate if there are differences regarding the number of total oocytes obtained, the number of mature oocytes, the number of biopsied blastocysts and the MitoScore index of the available euploid embryos. These variables will be assessed and compared depending on whether the oocytes were obtained in the follicular phase or the luteal phase for the DuoStim group. Resulting data will be compared with those obtained from the conventional stimulation group. The period elapsed from the beginning of the ovarian stimulation until the embryo transfer will also be addressed. Patients will call the clinic at the Cycle Programing Department to arrange a treatment. After a short period taking contraceptive pills, patients will be referred to a medical appointment. At the time of the first consultation the attending physician will randomize patients desiring to participate and meeting inclusion criteria, using a random allocation software commissioned by the department of informatics. There will be no blinding since this study is an open trial. Participants have the right to withdraw from the study at any time and for any reason without any inconvenience for their future medical care. Withdrawal means that the subject does not want to receive any further treatment nor does the patient wish to continue participating in the study. Reasons for withdrawal from the study: patient desire, lack of collaboration, toxicity or adverse event affecting patient's safety, decision of the principal investigator whenever the interruption is in favor of the patient's interests, death, and violation or breach of the study protocol. The trial will be terminated when all participants have completed an adequate follow-up period. It might also be interrupted before completion date due to security reasons, failure to meet expected recruitment deadlines or even if there are any risks concerning patient's safety or health. All participants discontinued from the trial will remain in the follow-up phase, except for those who withdraw their informed consent or die. Entries made in the Clinical Research Data Capture Profile (CRD) must be in accordance with those contained in the source documents. Data will be exported from the institutional repository software platform which withholds patient´s medical records. Integrity and accuracy will be checked by at least one investigator assuring that both extracted information and all the required regulatory documents are appropriate. Study files and all source documents will be stored for the time needed. Considering an euploid embryo rate per cycle of 20% for conventional stimulation and a difference between means of 10% (Conventional X DuoStim group), a sample size of 136 patients (68 per arm) was estimated to obtain a power of 80% with an alfa error of 5%. A loss rate of 5% was also considered to calculate the sample size. Categorical variables will be assessed by the number of subjects as well as absolute and relative frequencies. Continuous variables will be assessed by the means, medians, standard deviations, 25th and 75th percentiles, minimum and maximum. For both categorical and continuous variables, a confidence interval of 95% will be considered. The exploratory analysis of data will allow to determine quality of the data and to detect any abnormality. The means and proportions of the descriptive variables will be compared to verify if the randomization was correctly performed. Whenever the variables are normally distributed, it will be applied a parametric test such as chi-square test for categorical variables and a T-student test or ANOVA for continuous variables. If the distribution is not normal a non-parametric test such as a Mann-Whitney U or Wilcoxon test will be applied according to the characteristics of the variable. If the investigators find statically significant differences for descriptive variables between the two groups, those variables will be included in a regression model to control their interference. Additionally, linear or logistic regression models will be defined, depending on whether the outcome variable is quantitative or categorical, respectively. It will allow to adjust possible confounding factors that may potentially influence the results.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 136
• Est. completion date: June 1, 2020
• Est. primary completion date: December 1, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 35 Years to 42 Years

Eligibility

Inclusion Criteria:

• Signed informed consent;
• 35-42 years of age;
• Patients from the IVI Madrid undergoing controlled ovarian hyperstimulation cycle including PGT analysis for infertility treatment;
• BMI 18-30 kg/m2;
• Suspicion of suboptimal or poor response:

AMH < 1.5 ng/mL; AFC < 8; FSH > 10; Poor response in a previous cycle (defined as < 6 oocytes).

Exclusion Criteria:

• Simultaneous participation in another clinical trial or in any other study that could result in a confounding factor.

Related Conditions & MeSH terms

• Infertility
• Infertility, Female

Intervention

Drug:
• human menopausal gonadotropin
human menopausal gonadotropin subcutaneously
• GnRH antagonist
GnRH antagonist subcutaneously
• GnRH analog
GnRH analog subcutaneously

Procedure:
• Trophectoderm biopsy
Trophectoderm biopsy is the process of removing few cells from an in vitro fertilization embryo.

Diagnostic Test:
• MitoScore
The cells removed from an in vitro fertilization embryo during the trophectoderm biopsy will be used to assess the mitochondrial DNA content as a viability indicator in the euploid embryos.

Procedure:
• Intracytoplasmic sperm injection
ICSI is an in vitro fertilization procedure in which a single sperm is injected directly into an oocyte.
• Ovarian puncture
Egg retrieval is a simple procedure. It is performed in an operating room for safety reasons. It is performed vaginally and involves aspirating the follicular fluid through a thin needle. Embryologists then retrieve from this fluid the eggs that have matured during stimulation. It lasts for 5 to 15 minutes, and a mild sedative is administered to prevent any kind of pain during the procedure.

Diagnostic Test:
• Preimplantation genetic test
The cells removed from an in vitro fertilization embryo during the trophectoderm biopsy will be tested for chromosomal normalcy before transferring the embryo to the uterus.

Procedure:
• Embryo transfer
Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus

Diagnostic Test:
• Pregnancy test
A pregnancy test is used to determine whether a woman is pregnant.

Procedure:
• Embryo freezing
Embryo freezing is a method for cryopreserving embryos.
• Embryo thawing
Embryo thawing is the procedure to recover previously frozen embryos prior to an embryo transfer.

Locations

Country	Name	City	State
Spain	IVI Madrid	Madrid

Sponsors (1)

Lead Sponsor	Collaborator
IVI Madrid

Country where clinical trial is conducted

Spain, 

References & Publications (12)

Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003 Jul;80(1):116-22. — View Citation

Bedoschi GM, de Albuquerque FO, Ferriani RA, Navarro PA. Ovarian stimulation during the luteal phase for fertility preservation of cancer patients: case reports and review of the literature. J Assist Reprod Genet. 2010 Aug;27(8):491-4. doi: 10.1007/s10815-010-9429-0. Epub 2010 May 9. Review. — View Citation

Bentov Y, Esfandiari N, Gokturk A, Burstein E, Fainaru O, Casper RF. An ongoing pregnancy from two waves of follicles developing during a long follicular phase of the same cycle. Fertil Steril. 2010 Jun;94(1):350.e8-11. doi: 10.1016/j.fertnstert.2009.12.033. — View Citation

Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril. 2013 Dec;100(6):1673-80. doi: 10.1016/j.fertnstert.2013.07.1992. Epub 2013 Aug 26. — View Citation

Cakmak H, Rosen MP. Random-start ovarian stimulation in patients with cancer. Curr Opin Obstet Gynecol. 2015 Jun;27(3):215-21. doi: 10.1097/GCO.0000000000000180. Review. — View Citation

Chen H, Wang Y, Lyu Q, Ai A, Fu Y, Tian H, Cai R, Hong Q, Chen Q, Shoham Z, Kuang Y. Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles. Fertil Steril. 2015 May;103(5):1194-1201.e2. doi: 10.1016/j.fertnstert.2015.02.020. Epub 2015 Mar 23. — View Citation

Diez-Juan A, Rubio C, Marin C, Martinez S, Al-Asmar N, Riboldi M, Díaz-Gimeno P, Valbuena D, Simón C. Mitochondrial DNA content as a viability score in human euploid embryos: less is better. Fertil Steril. 2015 Sep;104(3):534-41.e1. doi: 10.1016/j.fertnstert.2015.05.022. Epub 2015 Jun 11. — View Citation

Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014 Dec;29(6):684-91. doi: 10.1016/j.rbmo.2014.08.009. Epub 2014 Sep 6. — View Citation

Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, Shoham Z. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril. 2014 Jan;101(1):105-11. doi: 10.1016/j.fertnstert.2013.09.007. Epub 2013 Oct 23. — View Citation

Sönmezer M, Türkçüoglu I, Coskun U, Oktay K. Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles. Fertil Steril. 2011 May;95(6):2125.e9-11. doi: 10.1016/j.fertnstert.2011.01.030. Epub 2011 Feb 3. — View Citation

Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, Trabucco E, Venturella R, Vajta G, Rienzi L. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. 2016 Jun;105(6):1488-1495.e1. doi: 10.1016/j.fertnstert.2016.03.002. Epub 2016 Mar 25. — View Citation

von Wolff M, Thaler CJ, Frambach T, Zeeb C, Lawrenz B, Popovici RM, Strowitzki T. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril. 2009 Oct;92(4):1360-1365. doi: 10.1016/j.fertnstert.2008.08.011. Epub 2008 Oct 18. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of euploid embryos per cycle	Rate of chromosomally normal embryos per cycle in the DuoStim group compared to the group undergoing two controlled ovarian hyperstimulation in consecutives cycles.	up to 9 months
Secondary	Number of oocytes obtained	Total number of oocytes obtained in both arms after ovarian puncture	up to 9 months
Secondary	Number of fertilized oocytes	Number of fertilized oocytes in both arms after FIV/ICSI procedure	up to 9 months
Secondary	Number of biopsied blastocysts	Number of biopsied blastocysts in both arms	up to 9 months
Secondary	MitoScore index of the euploid embryos	Analysis of the MitoScore index of the euploid embryos obtained in both arms	up to 9 months
Secondary	Implantation rate	Implantation rate of euploid embryos in both arms after single or double embryo transfer	up to 9 months
Secondary	Pregnancy rate	Pregnancy rate of euploid embryos in both arms after single or double embryo transfer	up to 9 months
Secondary	Abortion rate	Abortion rate presented by each arm after single or double embryo transfer	up to 9 months
Secondary	Time until embryo transfer	Period elapsed from the beginning of the ovarian stimulation until the embryo transfer	up to 9 months