Ignite Creation Date:
2024-05-06 @ 12:35 PM
Last Modification Date:
2024-10-26 @ 1:01 PM
Study NCT ID:
NCT03809221
Status:
UNKNOWN
Last Update Posted:
2019-01-18
First Post:
2019-01-15
Brief Title:
The Effectiveness and Safety of the Prolonged Down-regulation Protocol for Controlled Ovarian Hyperstimulation
Sponsor:
Peking University Peoples Hospital
Organization:
Peking University Peoples Hospital
Study Overview
Official Title:
The Effectiveness and Safety of the Early Follicular Phase Prolonged Down-regulation Protocol for Controlled Ovarian Hyperstimulation a Randomized Paralleled Controlled Multicenter Trial
Status:
UNKNOWN
Status Verified Date:
2019-01
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Since the first tube baby Louise Brown was born in the United Kingdom in 1978 many infertile couples have been benefitted from in vitro fertilization and embryo transfer IVF-ET and intracytoplasmic sperm injection ICSI Although a late starter China is developing rapidly in ART and playing a more and more important role in the area of reproductive medicine
In spite of the continuous development in ART so far the overall success rate of IVFICSI is still hovering around 25-40 There are many factors influencing the success rate of IVFICSI Among them an appropriate controlled ovarian hyperstimulation COH protocol is directly associated with the number of oocyte retrieved as well as the number and quality of embryos which exert an important influence on the success rate of IVFICSI The luteal phase pituitary down-regulation protocol is one of the most widely used COH protocols in clinical practice particularly in China Though effective it may lead to an increased incidence of ovarian hyperstimulation syndrome OHSS as well as a negative impact on endometrial receptivity The coping strategy is to freeze all the embryos and transfer in the next cycle Though avoiding the above mentioned adverse effects such strategy increases the time to pregnancy TTP and therefore results in certain psychological and economic burdens for infertile couples
In recent years some Chinese researches applied the early follicular full-dose down-regulation protocol that is always performed to women with endometriosis to a more general IVFICSI population and found a clinical pregnancy rate of 64 in the fresh embryo transfer cycle much higher than that of the luteal phase down-regulation protocol Furthermore since this protocol decrease the risk of progesterone elevation on hCG day it increases the fresh embryo transfer rate and shortens TTP
Given most studies regarding the effectiveness and safety of the early follicular phase full-dose down-regulation protocol are retrospective studies the results may be biased by several confounding factors Therefore we would like to conduct a multicenter randomized controlled trial to compare the pregnancy outcome and safety indicators between the early follicular phase full-dose down-regulation protocol and the luteal phase down-regulation protocol
In spite of the continuous development in ART so far the overall success rate of IVFICSI is still hovering around 25-40 There are many factors influencing the success rate of IVFICSI Among them an appropriate controlled ovarian hyperstimulation COH protocol is directly associated with the number of oocyte retrieved as well as the number and quality of embryos which exert an important influence on the success rate of IVFICSI The luteal phase pituitary down-regulation protocol is one of the most widely used COH protocols in clinical practice particularly in China Though effective it may lead to an increased incidence of ovarian hyperstimulation syndrome OHSS as well as a negative impact on endometrial receptivity The coping strategy is to freeze all the embryos and transfer in the next cycle Though avoiding the above mentioned adverse effects such strategy increases the time to pregnancy TTP and therefore results in certain psychological and economic burdens for infertile couples
In recent years some Chinese researches applied the early follicular full-dose down-regulation protocol that is always performed to women with endometriosis to a more general IVFICSI population and found a clinical pregnancy rate of 64 in the fresh embryo transfer cycle much higher than that of the luteal phase down-regulation protocol Furthermore since this protocol decrease the risk of progesterone elevation on hCG day it increases the fresh embryo transfer rate and shortens TTP
Given most studies regarding the effectiveness and safety of the early follicular phase full-dose down-regulation protocol are retrospective studies the results may be biased by several confounding factors Therefore we would like to conduct a multicenter randomized controlled trial to compare the pregnancy outcome and safety indicators between the early follicular phase full-dose down-regulation protocol and the luteal phase down-regulation protocol
Detailed Description:
Background
Since the first tube baby Louise Brown was born in the United Kingdom in 1978 many infertile couples have been benefitted from in vitro fertilization and embryo transfer IVF-ET and intracytoplasmic sperm injection ICSI It is reported that there are over 5 million babies born with the help of assisted reproductive technology ART According to the 2015 national data published by Human Fertility and Embryology Authority HFEA 48147 women received 61726 IVFICSI cycles and gave birth to 17041 newborns In the United States 169602 IVFICSI cycles were performed in 2014 and 68791 tubal babies were born China has a huge population base and therefore has a substantial number of infertile couples Although a late starter China is developing rapidly in ART and playing a more and more important role in the area of reproductive medicine
In spite of the continuous development in ART so far the overall success rate of IVFICSI is still hovering around 25-40 The live birth rate per stimulated cycle is 256 in the UK in 2015 fluctuating from 19 in women aged 45 and elder to 322 in women younger than 35 years old The IVFICSI success rate in 2014 in the US is similar In China according to the data submitted by 115 reproductive medicine centers on the ART data reporting system developed by Chinese Society of Reproductive Medicine the delivery rate is about 40 Hence there is much room for improvement regarding the live birth rate of IVFICSI which is of great significance to infertile couples
There are many factors influencing the success rate of IVFICSI eg the infertile couples age the controlled ovarian hyperstimulation COH protocol the quality and number of embryos for transferring the endometrium and luteal phase support protocol etc Among them an appropriate COH protocol is directly associated with the number of oocyte retrieved as well as the number and quality of embryos which exert an important influence on the success rate of IVFICSI The luteal phase pituitary down-regulation protocol is one of the most widely used COH protocols in clinical practice particularly in China In this protocol gonadotropin releasing hormone agonist GnRHa administered in the previous luteal phase induces a state of down regulation of the pituitary gland via competitive occupying and further exhausting the GnRH receptors in the pituitary which inhibits the endogenous luteinizing hormone LH peak and avoid spontaneous ovulation decreasing the cycle cancellation rate But the classic down-regulation protocol may lead to an increased incidence of ovarian hyperstimulation syndrome OHSS as well as a negative impact on endometrial receptivity due to the progesterone elevation after multiple oocytes development The coping strategy is to freeze all the embryos and transfer in the next cycle Though avoiding the above mentioned adverse effects such strategy increases the time to pregnancy TTP and therefore results in certain psychological and economic burdens for infertile couples
In recent years some Chinese researches applied the early follicular down-regulation protocol that is always performed to women with endometriosis to a more general IVFICSI population and found a clinical pregnancy rate of 64 in the fresh embryo transfer cycle much higher than that of the luteal phase down-regulation protocol The possible mechanism is that it may improve the down regulation of LH and the endometrial receptivity therefore having a better control of LH during COH increasing the endometrial thickness on hCG day as well as the embryo implantation rate and clinical pregnancy rate Furthermore since this protocol decrease the risk of progesterone elevation on hCG day it increases the fresh embryo transfer rate and shortens TTP
Objective
Given most studies regarding the effectiveness and safety of the early follicular phase down-regulation protocol are retrospective studies the results may be biased by several confounding factors Therefore we would like to conduct a multicenter randomized controlled trial to compare the pregnancy outcome and safety between the early follicular phase and luteal phase down-regulation protocols
Study design
1 Screening 1 Evaluation vital signs physical examination laboratory test routine tests AMH chromosome and ultrasound examination evaluating the ovarian reserve function 2 Screening to decide whether the women can be included in the study or not 3 Collection of basic information via electronic medical records and questionnaires demographic characteristics the history of infertility menstrual marriage and childbearing the past history and surgery history and the history of adverse environmental exposure
2 Inclusion and randomization After the evaluation patients met the eligible criteria will be informed and those who sign the consent form will be included in this study We will randomly assign women 11 to early follicular phase down-regulation group intervention group or luteal phase down-regulation group control group using a central randomization system with block sizes of 4 to 6 changing constantly and setting hospital as a stratification factor
3 Blinding The researchers physicians nurses and embryologists and patients are not blinded due to the nature of both interventions while the data analysts are blinded
4 Intervention and control The treatment period is from the down-regulation day to the day of oocyte retrieval and the participants receive one of the following treatments
1 Early follicular phase prolonged down-regulation group intervention group Patients have a injection of 375mg long-acting GnRHa Dipherelin IPSEN France on the 1st-4th day of menstrual cycle as pituitary down-regulation
2 Luteal phase long down-regulation group intervention group Patients have a injection of short-acting GnRHa Decapeptyl Ferring Germany 01mg per day 10-12 days before the menstruation as pituitary down-regulation
5 Embryo transfer and Luteal phase support Patients will receive luteal phase support with intramuscular progesterone 60mgday since the day of oocyte retrieval On day 3 after oocyte retrieval two top quality cleavage-stage embryos will be transferred via a catheter under transabdominal ultrasound guidance The patients will lie in bed for 15 minutes after the procedure Luteal phase support will be switched to 8 progesterone sustained-releasing vaginal gel Crinone Merck Switzerland 90mg and dydrogesterone Duphaston AbbottBiologicals Netherlands 20mg per day and continued for at least 2 weeks For those who get pregnancy luteal phase support will be continued to 10 weeks of gestation The dosage adjustment will be determined by physicians of each study site according to their personal experience
6 Pregnancy evaluation and follow up All the information will be recorded in our follow-up forms designed specifically for each follow-up visit
1 Biochemical determination 144 days after embryo transfer serum β-hCG will be tested to determine pregnancy
2 Clinical pregnancy determination 284 days after embryo transfer a transvaginal ultrasound scan will be performed to confirm the presence of fetal sac yolk sac and fetal heart
3 Ongoing pregnancy determination A transvaginal ultrasound scan will be performed at 10-12 weeks of gestation to confirm ongoing pregnancy The presence of first-trimester pregnancy complications eg OHSS ectopic pregnancy miscarriage etc will be registered according to the participants medical record and a telephone follow-up
4 28 weeks of gestation A telephone follow-up will be conducted to collect the information regarding the second trimester pregnancy complications
5 37 weeks of gestation A telephone follow-up will be conducted to collect the information regarding the third trimester pregnancy complications
6 Delivery information A telephone follow-up will be made to collect delivery information including gestational age delivery mode delivery complications and infant information such as birth weight any birth defect etc
7 Postpartum information Postpartum information includes complications of both the mother and the infant which will be collected 6 weeks after delivery
For those not receiving a fresh embryo transfer eg due to OHSS and those not achieving live birth and with surplus cryopreserved embryos the outcome of frozen-thawed embryo transfer cycles will be followed up and recorded as well
7 Outcome measures
1 Main outcome live birth rate effective indicator per stimulated cycle 2 Secondary outcomes include effective and safety indicators 8 Biostatistic analysis method and sample size calculation
1 Sample size will be calculated based on superiority test α005 1-β080 The reported live birth rate is about 30 while the live birth rate of the prolonged protocol is predicted to be around 40 based on previous retrospective studies We set the delta value as 6 and the ratio between groups will be 11 therefore the sample size of each group is 851 Taking into consideration a drop rate of 10 we expect to ultimately have a total of 1892 enrollees with 946 participants in each group
2 Statistical analysis method
1 Statistical description We will adopt descriptive statistical analysis to summarize the participants demographic characteristics physical examination laboratory tests other health information and the outcome indicators The continuous variables will be described with means and standard deviation or median and interquartile range while the categorical variable will be described with frequency and percentage The proportion of drop-off cases will be calculated and analyzed
2 Comparable analysis It will be used to compare the demographic and other baseline characteristics to make sure the comparability of the two groups If the continuous variables follow the normal distribution t test will be performed if not the rank sum test or a normal transformation will be performed For the categorical variables chi-square test or Fishers exact test will be performed
3 Statistical analysis for the outcome measures Between-group differences for categorical and continuous outcome variables will be assessed by logistic regression and linear regression respectively
4 Safety analysis Adverse events and reaction will be listed and analyzed using the chi-square test
5 The analysis for the primary outcome and important outcome measurements will be based on both the intention-to-treat analysis and per-protocol analysis The results of these two analyses will be compared in the final analysis
Since the first tube baby Louise Brown was born in the United Kingdom in 1978 many infertile couples have been benefitted from in vitro fertilization and embryo transfer IVF-ET and intracytoplasmic sperm injection ICSI It is reported that there are over 5 million babies born with the help of assisted reproductive technology ART According to the 2015 national data published by Human Fertility and Embryology Authority HFEA 48147 women received 61726 IVFICSI cycles and gave birth to 17041 newborns In the United States 169602 IVFICSI cycles were performed in 2014 and 68791 tubal babies were born China has a huge population base and therefore has a substantial number of infertile couples Although a late starter China is developing rapidly in ART and playing a more and more important role in the area of reproductive medicine
In spite of the continuous development in ART so far the overall success rate of IVFICSI is still hovering around 25-40 The live birth rate per stimulated cycle is 256 in the UK in 2015 fluctuating from 19 in women aged 45 and elder to 322 in women younger than 35 years old The IVFICSI success rate in 2014 in the US is similar In China according to the data submitted by 115 reproductive medicine centers on the ART data reporting system developed by Chinese Society of Reproductive Medicine the delivery rate is about 40 Hence there is much room for improvement regarding the live birth rate of IVFICSI which is of great significance to infertile couples
There are many factors influencing the success rate of IVFICSI eg the infertile couples age the controlled ovarian hyperstimulation COH protocol the quality and number of embryos for transferring the endometrium and luteal phase support protocol etc Among them an appropriate COH protocol is directly associated with the number of oocyte retrieved as well as the number and quality of embryos which exert an important influence on the success rate of IVFICSI The luteal phase pituitary down-regulation protocol is one of the most widely used COH protocols in clinical practice particularly in China In this protocol gonadotropin releasing hormone agonist GnRHa administered in the previous luteal phase induces a state of down regulation of the pituitary gland via competitive occupying and further exhausting the GnRH receptors in the pituitary which inhibits the endogenous luteinizing hormone LH peak and avoid spontaneous ovulation decreasing the cycle cancellation rate But the classic down-regulation protocol may lead to an increased incidence of ovarian hyperstimulation syndrome OHSS as well as a negative impact on endometrial receptivity due to the progesterone elevation after multiple oocytes development The coping strategy is to freeze all the embryos and transfer in the next cycle Though avoiding the above mentioned adverse effects such strategy increases the time to pregnancy TTP and therefore results in certain psychological and economic burdens for infertile couples
In recent years some Chinese researches applied the early follicular down-regulation protocol that is always performed to women with endometriosis to a more general IVFICSI population and found a clinical pregnancy rate of 64 in the fresh embryo transfer cycle much higher than that of the luteal phase down-regulation protocol The possible mechanism is that it may improve the down regulation of LH and the endometrial receptivity therefore having a better control of LH during COH increasing the endometrial thickness on hCG day as well as the embryo implantation rate and clinical pregnancy rate Furthermore since this protocol decrease the risk of progesterone elevation on hCG day it increases the fresh embryo transfer rate and shortens TTP
Objective
Given most studies regarding the effectiveness and safety of the early follicular phase down-regulation protocol are retrospective studies the results may be biased by several confounding factors Therefore we would like to conduct a multicenter randomized controlled trial to compare the pregnancy outcome and safety between the early follicular phase and luteal phase down-regulation protocols
Study design
1 Screening 1 Evaluation vital signs physical examination laboratory test routine tests AMH chromosome and ultrasound examination evaluating the ovarian reserve function 2 Screening to decide whether the women can be included in the study or not 3 Collection of basic information via electronic medical records and questionnaires demographic characteristics the history of infertility menstrual marriage and childbearing the past history and surgery history and the history of adverse environmental exposure
2 Inclusion and randomization After the evaluation patients met the eligible criteria will be informed and those who sign the consent form will be included in this study We will randomly assign women 11 to early follicular phase down-regulation group intervention group or luteal phase down-regulation group control group using a central randomization system with block sizes of 4 to 6 changing constantly and setting hospital as a stratification factor
3 Blinding The researchers physicians nurses and embryologists and patients are not blinded due to the nature of both interventions while the data analysts are blinded
4 Intervention and control The treatment period is from the down-regulation day to the day of oocyte retrieval and the participants receive one of the following treatments
1 Early follicular phase prolonged down-regulation group intervention group Patients have a injection of 375mg long-acting GnRHa Dipherelin IPSEN France on the 1st-4th day of menstrual cycle as pituitary down-regulation
2 Luteal phase long down-regulation group intervention group Patients have a injection of short-acting GnRHa Decapeptyl Ferring Germany 01mg per day 10-12 days before the menstruation as pituitary down-regulation
5 Embryo transfer and Luteal phase support Patients will receive luteal phase support with intramuscular progesterone 60mgday since the day of oocyte retrieval On day 3 after oocyte retrieval two top quality cleavage-stage embryos will be transferred via a catheter under transabdominal ultrasound guidance The patients will lie in bed for 15 minutes after the procedure Luteal phase support will be switched to 8 progesterone sustained-releasing vaginal gel Crinone Merck Switzerland 90mg and dydrogesterone Duphaston AbbottBiologicals Netherlands 20mg per day and continued for at least 2 weeks For those who get pregnancy luteal phase support will be continued to 10 weeks of gestation The dosage adjustment will be determined by physicians of each study site according to their personal experience
6 Pregnancy evaluation and follow up All the information will be recorded in our follow-up forms designed specifically for each follow-up visit
1 Biochemical determination 144 days after embryo transfer serum β-hCG will be tested to determine pregnancy
2 Clinical pregnancy determination 284 days after embryo transfer a transvaginal ultrasound scan will be performed to confirm the presence of fetal sac yolk sac and fetal heart
3 Ongoing pregnancy determination A transvaginal ultrasound scan will be performed at 10-12 weeks of gestation to confirm ongoing pregnancy The presence of first-trimester pregnancy complications eg OHSS ectopic pregnancy miscarriage etc will be registered according to the participants medical record and a telephone follow-up
4 28 weeks of gestation A telephone follow-up will be conducted to collect the information regarding the second trimester pregnancy complications
5 37 weeks of gestation A telephone follow-up will be conducted to collect the information regarding the third trimester pregnancy complications
6 Delivery information A telephone follow-up will be made to collect delivery information including gestational age delivery mode delivery complications and infant information such as birth weight any birth defect etc
7 Postpartum information Postpartum information includes complications of both the mother and the infant which will be collected 6 weeks after delivery
For those not receiving a fresh embryo transfer eg due to OHSS and those not achieving live birth and with surplus cryopreserved embryos the outcome of frozen-thawed embryo transfer cycles will be followed up and recorded as well
7 Outcome measures
1 Main outcome live birth rate effective indicator per stimulated cycle 2 Secondary outcomes include effective and safety indicators 8 Biostatistic analysis method and sample size calculation
1 Sample size will be calculated based on superiority test α005 1-β080 The reported live birth rate is about 30 while the live birth rate of the prolonged protocol is predicted to be around 40 based on previous retrospective studies We set the delta value as 6 and the ratio between groups will be 11 therefore the sample size of each group is 851 Taking into consideration a drop rate of 10 we expect to ultimately have a total of 1892 enrollees with 946 participants in each group
2 Statistical analysis method
1 Statistical description We will adopt descriptive statistical analysis to summarize the participants demographic characteristics physical examination laboratory tests other health information and the outcome indicators The continuous variables will be described with means and standard deviation or median and interquartile range while the categorical variable will be described with frequency and percentage The proportion of drop-off cases will be calculated and analyzed
2 Comparable analysis It will be used to compare the demographic and other baseline characteristics to make sure the comparability of the two groups If the continuous variables follow the normal distribution t test will be performed if not the rank sum test or a normal transformation will be performed For the categorical variables chi-square test or Fishers exact test will be performed
3 Statistical analysis for the outcome measures Between-group differences for categorical and continuous outcome variables will be assessed by logistic regression and linear regression respectively
4 Safety analysis Adverse events and reaction will be listed and analyzed using the chi-square test
5 The analysis for the primary outcome and important outcome measurements will be based on both the intention-to-treat analysis and per-protocol analysis The results of these two analyses will be compared in the final analysis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None