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CAPA-IVM Versus STANDARD IVM

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ClinicalTrials.gov Identifier: NCT03921710
Recruitment Status : Completed
First Posted : April 19, 2019
Last Update Posted : April 23, 2019
Sponsor:
Information provided by (Responsible Party):
Mỹ Đức Hospital

Tracking Information
First Submitted Date  ICMJE April 15, 2019
First Posted Date  ICMJE April 19, 2019
Last Update Posted Date April 23, 2019
Actual Study Start Date  ICMJE April 29, 2017
Actual Primary Completion Date October 10, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
Live birth rate [ Time Frame: At least 24 weeks of gestation up to the time of delivery ]
Live birth is defined as the birth of at least one newborn after 24 weeks' gestation that exhibits any sign of life (twin will be a single count). For the timing of this occur, ongoing pregnancy will be used, i.e. ongoing pregnancy at 12 weeks will be used in calculations, conditional on the fact that this ongoing pregnancy results in live birth.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03921710 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
  • Ongoing pregnancy rate [ Time Frame: At a minimum of 12 weeks from the beginning of the last menstrual cycle ]
    Pregnancy with detectable heart rate at 12 weeks' gestation
  • Clinical pregnancy rate [ Time Frame: At a minimum of 12 weeks from the beginning of the last menstrual cycle ]
    Pregnancy with detectable gestational sac at 7 weeks' gestation
  • Number of oocytes retrieved [ Time Frame: Maximum at 30 minutes after oocyte retrieval procedure ]
    The number of oocyte identified after oocyte retrieval
  • Oocyte maturation rate [ Time Frame: After at least 30 hours of maturation culture ]
    Rate of mature oocytes on culture oocytes
  • Number of fertilized oocytes [ Time Frame: 16-18 hours after intra-cytoplasmic sperm injection ]
    Number of fertilized oocyte after sperm insemination
  • Number of embryos [ Time Frame: At least 3 days after intra-cytoplasmic sperm injection ]
    Number of cleavage embryos obtained
  • Number of good quality embryos [ Time Frame: At least 3 days after intra-cytoplasmic sperm injection ]
    Number of good cleavage embryos obtained
  • Number of embryos frozen [ Time Frame: At least 3 days after intra-cytoplasmic sperm injection ]
    Number of cleavage embryos frozen
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE CAPA-IVM Versus STANDARD IVM
Official Title  ICMJE Research Study to Evaluate Capacitation Culture (CAPA) Followed by in Vitro Maturation (IVM) of Human Oocytes: A Randomized Pilot Study
Brief Summary The aim of this study is to evaluate the effectiveness and safety of CAPA-IVM versus standard IVM in women with polycystic ovarian morphology (PCOM) or polycystic ovary syndrome (PCOS) .
Detailed Description

Patients preparation

Patients with PCOM are allowed to enroll in the study: (1) women with normal menstrual cycle lengths (≤35 days), and (2) women with oligomenorrhea (menstruation occurring at intervals >35 days with 4-9 periods/year) or total amenorrhea. Patients were followed up until the end of pregnancy.

Patients have their first clinic visit on day 2 of the menstrual cycle. At this visit a blood sample was taken for assessment of FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone), estradiol and progesterone, and they have their gonadotropin injection 150 IU (international unit) once a day in the afternoon. All patients return in the morning of the next day (cycle day 3) for ultrasound and and the final dose of gonadotropin was given in the afternoon (2pm). When all follicles were <8 mm in diameter, another dose of gonadotropin was given, and patients returned the next day for ultrasound, blood tests and have their final dose of gonadotropin that afternoon (2pm). The maximum number of gonadotropin injections are three, and oocyte retrieval is scheduled at 42-46 hours after the last gonadotropin injection in all patients. Ultrasound and blood tests to determine FSH, LH, estradiol and progesterone levels are performed on the day of OPU (Oocyte Pick-up). During OPU, follicle size is measured before puncture. Larger follicles (≥6 mm) are punctured first, then the needle flushes, then smaller follicles (<6 mm) are punctured. Therefore, each tube contains COCs (Cumulus-Oocyte Complex) of a specific size (<6 or ≥6 mm).

Oocyte culture

Oocytes from patients in the CAPA-IVM group are collected and processed in the presence of CNP (C-type Natriuretic Peptide) as meiotic inhibitor. In the CAPA-IVM group, COCs are plated into a 4-well dish (Nunc, Denmark) at 10 COCs/well using CAPA medium (Medicult IVM medium; Origio, Denmark) supplemented with 1 mIU/mL rFSH, 5 ng/mL insulin, 10 nM estradiol, 10 mg/mL human serum albumin [SAGE, Denmark] and 25 nM (nanoMol) CNP under oil for 24 hours at 37°C, 6% carbon dioxide in air). After 24 hours, COCs are washed and transferred into IVM medium (Origio, Denmark) containing 5 ng/mL insulin, 10 nM estradiol, 100 ng/mL human recombinant amphiregulin and 100 mIU/mL rFSH (recombinant Follicle Stimulating Hormone), and incubated under oil for 30 h at 37°C, 6% carbon dioxide in air.

In the standard IVM group (control), COCs were plated into a 4-well dish at 10 COCs/well using IVM medium supplemented with 75 mIU/mL recombinant FSH (Merck, Switzerland), 100 mIU/mL hCG (MSD, USA), 0.01 mg/mL growth hormone (Merck, Switzerland) and 10 mg/mL human serum albumin (SAGE, Denmark). COCs are incubated for 30 hours using the same physical and atmospheric conditions as the CAPA-IVM group.

Fertilization and embryo culture

After IVM, matured oocytes are fertilized using intracytoplasmic sperm injection (ICSI) and cultured in an incubator at 37°C, 5% carbon dioxide, 5% oxygen. Fertilization check is performed at 16-18 hours after ICSI. Embryos are cultured to day 3 in Global Total LP (Life Global, Canada) in groups of 2-3 embryos per 30 µL microdroplet. Embryos that fulfill the freezing criteria were vitrified (Cryotech, Japan) as cleaving day 3 embryos. Embryos of extremely poor quality (Istanbul consensus on embryo quality assessment) defined as fragmentation >30%, <6 cells, and multi nucleation are not frozen.

Endometrial priming and embryo transfer

No fresh embryo transfers is performed. Patients receive oral estradiol 2 mg 4 times daily from day 2 of their menstrual cycle. After an estradiol treatment period of at least 10 days and when endometrial thickness was ≥8 mm, progesterone 200 mg is administered intra-vaginally 4 times daily. Embryo transfer is scheduled 3 days after starting progesterone. Serum beta hCG is tested 14 days after embryo transfer. If a woman become pregnant, beta human chorionic gonadotropin (hCG) >5 mIU/mL, progesterone administration is maintained at the same dose until at least 11 weeks of pregnancy. An ultrasound scan to determine the viability of pregnancy is performed at 7 weeks' gestation.

Safety of the ART (Assisted Reproductive Technology) procedure in PCOS

Safety is monitored at each clinic visit or, if any side effects occurred, by questioning and examining the patient, with adverse events and serious adverse events recorded on case report forms. Adverse events are defined as any unexpected medical occurrence (symptoms or signs, abnormal laboratory findings or diseases) that emerge or worsen during the trial, relative to the initial trial visit. Possible adverse events including ectopic pregnancy, miscarriage, medication-related reactions such as overdose, sensitivity and toxicity, and any adverse outcomes related to egg collection. Serious adverse events are defined as any unexpected medical occurrence that resulted in death, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, or resulted in persistent or significant disability or incapacitation. Congenital anomaly or birth defect are considered to be serious adverse events.

Statistical analysis

A key goal of this study is to determine feasibility, acceptability, and outcome variability to aid in planning a larger, adequately-powered efficacy trial. The planned sample size is 80 patients (40 per group), which should allow relatively precise conclusions regarding feasibility outcomes. Given that this is the first time that CAPA-IVM has been used clinically at our center, the objective of this pilot study is to estimate the live birth rate and associated 95% confidence intervals (CI) for the new intervention in clinical practice. Nonparametric statistical methods such as Wilcoxon rank sum is applied to continuous or ordinal outcomes. To estimate 95% confidence intervals (CI) for the difference between two medians, bootstrapping and related resampling methods is applied. The incidence of outcomes is estimated for each treatment group, and the difference between groups was analyzed using relative risk (RR), 95% CI of RR and Fisher exact test. A subgroup analysis is performed based on follicular size (<6 versus ≥6 mm). Data are presented as mean values with standard deviation (SD), medians and interquartile ranges (IQRs), or proportions. All analyses are performed using R (Version 3.0.1; R Foundation for Statistical Computing, Vienna, Austria). Statistical significance is defined as p<0.05.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomized Clinical Trial

Patients are randomized to either CAPA-IVM or STANDARD-IVM using block randomization by an independent study coordinator using a computer-generated random list (block size 4) on the second day of their periods.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Infertility, Female
Intervention  ICMJE
  • Drug: CAPA-IVM
    Immature oocytes were plated into a 4-well dish (Nunc, Denmark) at 10 COCs/well using CAPA medium (Medicult IVM medium; Origio, Denmark supplemented with 1 mIU/mL rFSH, 5 ng/mL insulin, 10 nM estradiol, 10 mg/mL human serum albumin [SAGE, Denmark] and 25 nM CNP under oil for 24 h at 37°C, 6% carbon dioxide in air). After 24 hours, COCs were washed and transferred into IVM medium (Origio, Denmark) containing 5 ng/mL insulin, 10 nM estradiol, 100 ng/mL human recombinant amphiregulin and 100 mIU/mL rFSH, and incubated under oil for 30 h at 37°C, 6% carbon dioxide in air.
  • Drug: Standard-IVM
    Immature oocytes are plated into a 4-well dish at 10 COCs/well using IVM medium supplemented with 75 mIU/mL recombinant FSH (Merck, Switzerland), 100 mIU/mL hCG (MSD, USA), 0.01 mg/mL growth hormone (Merck, Switzerland) and 10 mg/mL human serum albumin (SAGE, Denmark). COCs were incubated for 30 hours at 37°C, 6% carbon dioxide in air.
Study Arms  ICMJE
  • Active Comparator: CAPA-IVM
    Immature oocytes are culture in the new capacitation-IVM system.
    Intervention: Drug: CAPA-IVM
  • Active Comparator: Standard-IVM
    Immature oocytes are cultured in the standard IVM system.
    Intervention: Drug: Standard-IVM
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 17, 2019)
80
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 10, 2018
Actual Primary Completion Date October 10, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • < 38 years
  • PCOS patients with polycystic ovarian morphology: at least 25 follicles (2-9 mm) throughout the whole ovary and/or increased ovarian volume (>10ml) (it is sufficient that 1 ovary fits these criteria)
  • No major uterine or ovarian abnormalities

Exclusion criteria:

  • High (>grade 2) grade endometriosis
  • Cases with extremely poor sperm (OAT) such as azoospermia or cryptozoospermia
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Wives in infertile couples
Ages  ICMJE up to 37 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03921710
Other Study ID Numbers  ICMJE 17-2017/QD-CGRH-NCKH&DT
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mỹ Đức Hospital
Study Sponsor  ICMJE Mỹ Đức Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Tuong M Ho, MD HOPE Research Center
PRS Account Mỹ Đức Hospital
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP