Split Cohort Trial Comparing IVF Outcomes After the Use of Testicular vs. Ejaculated Sperm for ICSI

Study Overview
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Brief Summary
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The primary objective of this study is to determine if there is a difference in in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) outcomes when using testicular sperm versus ejaculated sperm in couples with elevated sperm DNA fragmentation after a failed in vitro fertilization (IVF) cycle

Detailed Description
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The experimental design for this study is as follows: Couples with male partners who will be undergoing a TESA procedure secondary to elevated DNA fragmentation (>25% DFI) as part of their routine IVF treatment will be contacted for possible study participation. Informed consent will be obtained The primary investigator will be notified of the couple's participation. The male partner will cryopreserve an ejaculated semen sample if there is no cryopreserved ejaculated specimen in inventory. The male partner will undergo a surgical sperm retrieval (TESA) and the specimen will be frozen per routine. Serum will be collected from the male partner and preserved for future analysis. The cryopreserved pre-TESA ejaculate and TESA specimen will be thawed on the day of oocyte retrieval per protocol. After oocyte retrieval, oocytes will be analyzed per routine and assessed for maturity. The oocytes will be divided into two groups per embryologist discretion. One group will be labeled 'A' and the other will be labeled B.' A random letter generator will create a list of 'A' and 'B's which will be placed in sequentially numbered, sealed envelopes. The envelopes will be opened in sequence according to patient enrollment. The first envelope opened by the embryologist will reveal the letter of the oocyte group that will be inseminated with testicular sperm. The other group will be inseminated with the frozen/ thawed ejaculated sperm. Therefore, half of the oocytes will be inseminated using intracytoplasmic sperm injection (ICSI) with testicular sperm and the other half will be inseminated via ICSI with ejaculated sperm. If there are an odd number of oocytes, the extra oocyte will always belong to group A for simplicity. If fertilized, the group of zygotes created using testicular sperm will take the group letter that corresponded to the testicular sperm. This will also be true of the zygotes using ejaculated sperm. Both groups of zygotes will be cultured to the blastocyst stage with culture conditions per standard laboratory procedures. Fertilization and blastulation rates of the two groups will be recorded for each patient. Each blastocyst will be biopsied for comprehensive chromosome screening (CCS) in routine fashion. Once comprehensive chromosomal screening results are available, if at least one euploid embryo is available, patients will undergo a single embryo transfer in a subsequent menstrual cycle. Frozen embryo transfer cycles will be performed using either a programmed cycle (exogenous estradiol with subsequent progesterone) or a natural cycle to prepare the endometrium for embryo transfer. If at least one euploid embryo is available from each group, a second randomization will occur at the time of embryo selection. The embryologist selecting the embryo for transfer will open a second sealed envelope, which contains the letter of the group from which the embryo for transfer should reside. The best quality embryo (per embryologist discretion) from the group corresponding to the letter in this envelope will be selected for transfer. The embryologist selecting the embryo will be blinded as to which group of embryos was created with ejaculated versus testicular sperm. The group from which the embryo selected for transfer was derived will be recorded. Both the patient and the physician performing the embryo transfer will be blinded with regard to the group from which the embryo selected for transfer derived. Pregnancy testing and follow up will proceed as per routine. Approximately 8 weeks post-transfer, each participant will be assigned a cycle outcome (i.e., no pregnancy, miscarriage, ongoing pregnancy). At that time, the study participants can be notified of whether the sperm utilized for ICSI was derived from testicular sperm or ejaculated sperm. This information could be shared via telephone or in-person.

Official Title
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Prospective Split Cohort Trial Comparing in Vitro Fertilization (IVF) Outcomes After the Use of Testicular Versus Ejaculated Sperm for ICSI in Med With Elevated DNA Fragmentation After a Failed IVF Cycle

Conditions
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Infertility

Intervention / Treatment
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* Other: ICSI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to comply with all study procedures and be available for the duration of the study Failed at least one IVF cycle (i.e., no live birth) Elevated DNA fragmentation noted in ejaculated sperm (>25% DFI according to the American Society of Reproductive Medicine guidelines) Couple electing single embryo transfer Couples electing comprehensive chromosome screening (CCS) of embryos At least 4 oocytes retrieved in IVF cycle in order to randomize Exclusion Criteria: Anything that would place the individual at increased risk or preclude the individual's full compliance with or completion of the study. Contraindication to IVF Clinical indication for preimplantation genetic diagnosis (PGD) (i.e., screening for single gene disorder, chromosomal translocation, or any other disorders requiring detailed embryo genetic analysis) Male partner with azoospermia (<100,000 motile spermatozoa) Male partner with Y-chromosome microdeletion Male partner with any Karyotype other than 46,XY(normal male karyotype) Female partner history of hydrosalpinges or adnexal mass Female partner history of endometrial insufficiency (max endometrial thickness < 7mm) Female partner BMI < 35

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| elevated sperm DNA fragmentation<br>Couples with male partners who will be undergoing a TESA procedure secondary to elevated DNA fragmentation (>25% DFI) as part of their routine IVF treatment will have half of the women's eggs inseminated with ejaculated sperm and the other half with surgically obtained sperm via the ICSI procedure | Other: ICSI<br>* The cryopreserved pre-TESA ejaculate and TESA specimen will be thawed on the day of oocyte retrieval per protocol for ICSI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blastulation Rate of testicular vs. ejaculated sperm after ICSI | # blast per 2 pronuclei in each group | 1 week post ICSI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fertilization Rate | # fertilized per M2 in each group | 24 hrs post ICSI | 
| Aneuploidy Rate | # abnormal embryos per useable blast in each group | approximately 2 weeks post trophectoderm biopsy | 
| Clinical Pregnancy Rate | defined by presence of gestational sac and yolk sac in uterus on ultrasound | approximately 2 weeks post pregnancy test |