Ignite Creation Date:
2024-07-17 @ 11:06 AM
Last Modification Date:
2024-10-26 @ 3:33 PM
Study NCT ID:
NCT06481696
Status:
RECRUITING
Last Update Posted:
2024-07-01
First Post:
2024-06-21
Brief Title:
Possible Action of Resveratrol in Improving the Outcomes of IVFICSI in Couples With Unexplained Infertility
Sponsor:
Andros Day Surgery Clinic
Organization:
Andros Day Surgery Clinic
Study Overview
Official Title:
Randomized Placebo-controlled Double-blind Single-center Trial to Evaluate the Possible Action of Resveratrol in Improving the Outcomes of Controlled Ovarian Stimulation During the IVFICSI Cycles in Couples With Unexplained Infertility
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
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:
RECOS
Brief Summary:
Based on available evidence and given the potential beneficial effects of resveratrol in folliculogenesis and in oocyte development the investigators designed a randomized controlled double-blind single-center trial whose objective will be the comparison of biological and clinical outcomes of resveratrol supplement in women undergoing IVFICSI cycles for unexplained infertility
To the knowledge of the investigators no study has been published on the potential effect of resveratrol on IVFICSI outcomes considering couples with this infertility diagnosis which may be the natural target of this integrative treatment because the process of folliculogenesis and oocyte maturation cannot be routinely investigated An alteration of these biological mechanisms could be the unrecognized cause of part of the unexplained infertility and treatment with resveratrol could result in significant clinical improvement for the patients enrolled in the study
In more details the main objective of this randomized placebo-controlled double-blind single-center trial will be the evaluation of the possible effect of resveratrol in determining a better follicle development in patients with unexplained infertility undergoing controlled ovarian stimulation COS for IVFICSI
Infertile female patients with normal ovarian reserve will be treated according to clinical practice and the difference between expected through AFC and retrieved oocytes will be assessed in relation to use of resveratrol
To the knowledge of the investigators no study has been published on the potential effect of resveratrol on IVFICSI outcomes considering couples with this infertility diagnosis which may be the natural target of this integrative treatment because the process of folliculogenesis and oocyte maturation cannot be routinely investigated An alteration of these biological mechanisms could be the unrecognized cause of part of the unexplained infertility and treatment with resveratrol could result in significant clinical improvement for the patients enrolled in the study
In more details the main objective of this randomized placebo-controlled double-blind single-center trial will be the evaluation of the possible effect of resveratrol in determining a better follicle development in patients with unexplained infertility undergoing controlled ovarian stimulation COS for IVFICSI
Infertile female patients with normal ovarian reserve will be treated according to clinical practice and the difference between expected through AFC and retrieved oocytes will be assessed in relation to use of resveratrol
Detailed Description:
On the basis of the last estimates the global lifetime prevalence of infertility is 175 which means that approximately one in six people have experienced infertility at some stage in their lives
Despite an improvement in conventional diagnostic investigations still today around 25 of the causes of couple infertility remain unexplained
In fact several crucial moments of the human reproductive process cannot be studied and therefore specific reproductive alterations remain undiagnosed Just thinking of the process of ovarian folliculogenesis oocyte development embryonic implantation all ones real biological mysteries
Among these different biological aspects it is known that the oocyte quality is the main predictor of clinical pregnancy after IVFICSI Indeed oocyte maturation process influences the embryo development and consequently the embryo viability Although the mechanisms that determine a good quality oocyte are not known nevertheless energy-dependent processes are supposed to play a major role in oocyte development These processes are mediated by mitochondria whose concentration in oocytes is the highest among the other cells of human body The oocyte nuclear and cytoplasmic maturation is strictly connected with the growth of granulosa cells GCs These cells surround the oocyte and establish a functional bidirectional cross-talk with the oocyte itself through gap junctions and paracrine factors During folliculogenesis GCs increase the consumption of glucose and metabolize glucose into pyruvate which passes to the oocyte All this determines an increase in the energy supply to the oocyte itself demonstrated by the increase in ATP production which allows the latter cell to prepare for fertilization and the first stages of embryonic development which as known is totally oocyte dependent
Resveratrol seems to be able to fit into this area of cellular functioning It is a natural polyphenol widespread in foods plants drinks and it seems to induce GCs proliferation through an anti-apoptotic effect in a SIRT1-dependent manner Furthermore in GCs resveratrol reduces the oxidative stress increases the mitochondria biogenesis and the intracellular ATP levels determining a high energy availability which favours the oocyte growth Resveratrol seems to reduce in rat granulosa cells the expression of Vascular Endothelial Growth Factor VEGF implicated in angiogenesis and vascular permeability potentially showing a protective effect on the risk of Ovarian Hyperstimulation Syndrome OHSS a life-threatening condition associated with ovarian stimulation whose VEGF is the main mediator
A recent clinical randomized trial showed that a pre-treatment of 3 months with resveratrol in women affected by couple infertility and undergoing ICSI was associated with a higher number of retrieved and mature oocytes a higher fertilization rate a higher number of blastocysts per patient and a higher number of surplus cryopreserved embryos per patient even if no significant effect was observed in clinical pregnancies and live birth rates
Based on this last evidence and given the potential beneficial effects of resveratrol in folliculogenesis and in oocyte development the investigators designed a randomized controlled double-blind single-center trial whose objective will be the comparison of biological and clinical outcomes of resveratrol supplement in women undergoing IVFICSI cycles for unexplained infertility
To the knowledge of the investigators no study has been published on the potential effect of resveratrol on IVFICSI outcomes considering couples with this infertility diagnosis which may be the natural target of this integrative treatment because the process of folliculogenesis and oocyte maturation cannot be routinely investigated An alteration of these biological mechanisms could be the unrecognized cause of part of the unexplained infertility and treatment with resveratrol could result in significant clinical improvement for the patients enrolled in the study
In more details the main objective of this randomized placebo-controlled double-blind single-center trial will be the evaluation of the possible effect of resveratrol in determining a better follicle development in patients with unexplained infertility undergoing controlled ovarian stimulation COS for IVFICSI
Infertile female patients with normal ovarian reserve will be treated according to clinical practice and the difference between expected through AFC and retrieved oocytes will be assessed in relation to use of resveratrol
DESIGN AND METHODOLOGY
Couples affected by unexplained infertility will be enrolled The definition of unexplained infertility is the following infertility in couples with apparently normal ovarian function fallopian tubes uterus cervix and pelvis age 40 years and with adequate coital frequency and apparently normal testicular function genito-urinary anatomy and a normal ejaculate
All patients will be randomized for no treatment placebo Group - only folic acid and for treatment of resveratrol Study group with a 11 ratio The randomization list generated by a software will be managed by a nurse not directly involved in the study and will give the patients the drugs for all duration of treatment Neither the physiciansembryologists neither the patients will be aware of the content of the boxes of drugs folic acid or resveratrol Double blind design
The duration of treatment will be at least 65 days before the starting of stimulation from the stage of pre-antral follicles and until the day of oocyte pick up
All the AFC determinations will be performed by the same two physicians from 2nd to 6th day of the cycle in one of the last three months before the starting of stimulation All the follicles ranging from 2 to 10 mm will be recorded distinguishing between the follicles ranging from 2 to 5 mm and those ranging from 6 to 10 mm
COS will be carried out by daily injections of rFSH Gonal F Merck Serono Italy and will be started on the 2nd3rd day of the cycle and continued until the day of induction of oocyte maturation The pituitary suppression will be obtained by the administration of the GnRH antagonist ganirelix 025 mg per day Fyremadel Ferring SpA which will be started from the 6th day of the ovarian stimulation until the day of induction of oocyte maturation
Follicular development will be monitored after 5 days of treatment and thereafter at least every 2 days Monitoring will consist of a transvaginal ultrasound scan to evaluate the number and maximum diameter of ovarian follicles and the endometrial thickness b the dosage of 17β-oestradiol LH and progesterone only on the day of induction of oocyte maturation The transvaginal ultrasound for monitoring will be performed by the same two physicians
Highly purified urinary hCG Gonasi HP IBSA Farmaceutici Italy 10000 IU subcutaneously or intramuscularly will be used to induce final oocyte maturation when two or more follicles of 16 mm in diameter will be observed and will be administered 355-36 h before planned oocyte retrieval In case of OHSS risk the final oocyte maturation will be obtained by using a GnRH agonist Triptorelin Decapeptyl 01 mg Ipsen SpA Italy 03 mg subcutaneously and the oocyte retrieval will be planned with the same modalities described above in this case all the embryos obtained will be cryopreserved
No difference in the number of oocytes retrieved was shown comparing these two different modalities of triggering the final oocyte maturation Haahr et al 2017
The trigger of oocyte maturation will not be achieved in case of inability to reach at least 2 follicles 16 mm
The oocyte pick ups will be performed by the two physicians with the highest level of expertise
Fresh transfer of embryos will be performed on the second third or fifth day after retrieving the oocytes
In case of OHSS risk andor in case of progesterone rise on the day of hCG administration 15 ngml all the embryos will be cryopreserved The couples with all frozen embryos will be considered for the analysis of the endpoints
SAMPLE SIZE CALCULATION
To pursuit the aims of the present study protocol a priori sample size calculation was conducted to determine the minimal number of participants required Data available in the literature indicate in average a difference of 15 in the no of pre-ovulatory follicles 16mm between the group treated with resveratrol and the control group with an average increase of 15 in favour of the study group Thus considering a conservative difference of 10 which is equivalent to a large effect size of d080 a power 1- β of 95 an alpha of 005 a two-tails t-test and a ratio of 11 between the two groups a total of 90 subjects 45 for each group would be needed to verify a significant difference in primary outcome between the two groups
Despite an improvement in conventional diagnostic investigations still today around 25 of the causes of couple infertility remain unexplained
In fact several crucial moments of the human reproductive process cannot be studied and therefore specific reproductive alterations remain undiagnosed Just thinking of the process of ovarian folliculogenesis oocyte development embryonic implantation all ones real biological mysteries
Among these different biological aspects it is known that the oocyte quality is the main predictor of clinical pregnancy after IVFICSI Indeed oocyte maturation process influences the embryo development and consequently the embryo viability Although the mechanisms that determine a good quality oocyte are not known nevertheless energy-dependent processes are supposed to play a major role in oocyte development These processes are mediated by mitochondria whose concentration in oocytes is the highest among the other cells of human body The oocyte nuclear and cytoplasmic maturation is strictly connected with the growth of granulosa cells GCs These cells surround the oocyte and establish a functional bidirectional cross-talk with the oocyte itself through gap junctions and paracrine factors During folliculogenesis GCs increase the consumption of glucose and metabolize glucose into pyruvate which passes to the oocyte All this determines an increase in the energy supply to the oocyte itself demonstrated by the increase in ATP production which allows the latter cell to prepare for fertilization and the first stages of embryonic development which as known is totally oocyte dependent
Resveratrol seems to be able to fit into this area of cellular functioning It is a natural polyphenol widespread in foods plants drinks and it seems to induce GCs proliferation through an anti-apoptotic effect in a SIRT1-dependent manner Furthermore in GCs resveratrol reduces the oxidative stress increases the mitochondria biogenesis and the intracellular ATP levels determining a high energy availability which favours the oocyte growth Resveratrol seems to reduce in rat granulosa cells the expression of Vascular Endothelial Growth Factor VEGF implicated in angiogenesis and vascular permeability potentially showing a protective effect on the risk of Ovarian Hyperstimulation Syndrome OHSS a life-threatening condition associated with ovarian stimulation whose VEGF is the main mediator
A recent clinical randomized trial showed that a pre-treatment of 3 months with resveratrol in women affected by couple infertility and undergoing ICSI was associated with a higher number of retrieved and mature oocytes a higher fertilization rate a higher number of blastocysts per patient and a higher number of surplus cryopreserved embryos per patient even if no significant effect was observed in clinical pregnancies and live birth rates
Based on this last evidence and given the potential beneficial effects of resveratrol in folliculogenesis and in oocyte development the investigators designed a randomized controlled double-blind single-center trial whose objective will be the comparison of biological and clinical outcomes of resveratrol supplement in women undergoing IVFICSI cycles for unexplained infertility
To the knowledge of the investigators no study has been published on the potential effect of resveratrol on IVFICSI outcomes considering couples with this infertility diagnosis which may be the natural target of this integrative treatment because the process of folliculogenesis and oocyte maturation cannot be routinely investigated An alteration of these biological mechanisms could be the unrecognized cause of part of the unexplained infertility and treatment with resveratrol could result in significant clinical improvement for the patients enrolled in the study
In more details the main objective of this randomized placebo-controlled double-blind single-center trial will be the evaluation of the possible effect of resveratrol in determining a better follicle development in patients with unexplained infertility undergoing controlled ovarian stimulation COS for IVFICSI
Infertile female patients with normal ovarian reserve will be treated according to clinical practice and the difference between expected through AFC and retrieved oocytes will be assessed in relation to use of resveratrol
DESIGN AND METHODOLOGY
Couples affected by unexplained infertility will be enrolled The definition of unexplained infertility is the following infertility in couples with apparently normal ovarian function fallopian tubes uterus cervix and pelvis age 40 years and with adequate coital frequency and apparently normal testicular function genito-urinary anatomy and a normal ejaculate
All patients will be randomized for no treatment placebo Group - only folic acid and for treatment of resveratrol Study group with a 11 ratio The randomization list generated by a software will be managed by a nurse not directly involved in the study and will give the patients the drugs for all duration of treatment Neither the physiciansembryologists neither the patients will be aware of the content of the boxes of drugs folic acid or resveratrol Double blind design
The duration of treatment will be at least 65 days before the starting of stimulation from the stage of pre-antral follicles and until the day of oocyte pick up
All the AFC determinations will be performed by the same two physicians from 2nd to 6th day of the cycle in one of the last three months before the starting of stimulation All the follicles ranging from 2 to 10 mm will be recorded distinguishing between the follicles ranging from 2 to 5 mm and those ranging from 6 to 10 mm
COS will be carried out by daily injections of rFSH Gonal F Merck Serono Italy and will be started on the 2nd3rd day of the cycle and continued until the day of induction of oocyte maturation The pituitary suppression will be obtained by the administration of the GnRH antagonist ganirelix 025 mg per day Fyremadel Ferring SpA which will be started from the 6th day of the ovarian stimulation until the day of induction of oocyte maturation
Follicular development will be monitored after 5 days of treatment and thereafter at least every 2 days Monitoring will consist of a transvaginal ultrasound scan to evaluate the number and maximum diameter of ovarian follicles and the endometrial thickness b the dosage of 17β-oestradiol LH and progesterone only on the day of induction of oocyte maturation The transvaginal ultrasound for monitoring will be performed by the same two physicians
Highly purified urinary hCG Gonasi HP IBSA Farmaceutici Italy 10000 IU subcutaneously or intramuscularly will be used to induce final oocyte maturation when two or more follicles of 16 mm in diameter will be observed and will be administered 355-36 h before planned oocyte retrieval In case of OHSS risk the final oocyte maturation will be obtained by using a GnRH agonist Triptorelin Decapeptyl 01 mg Ipsen SpA Italy 03 mg subcutaneously and the oocyte retrieval will be planned with the same modalities described above in this case all the embryos obtained will be cryopreserved
No difference in the number of oocytes retrieved was shown comparing these two different modalities of triggering the final oocyte maturation Haahr et al 2017
The trigger of oocyte maturation will not be achieved in case of inability to reach at least 2 follicles 16 mm
The oocyte pick ups will be performed by the two physicians with the highest level of expertise
Fresh transfer of embryos will be performed on the second third or fifth day after retrieving the oocytes
In case of OHSS risk andor in case of progesterone rise on the day of hCG administration 15 ngml all the embryos will be cryopreserved The couples with all frozen embryos will be considered for the analysis of the endpoints
SAMPLE SIZE CALCULATION
To pursuit the aims of the present study protocol a priori sample size calculation was conducted to determine the minimal number of participants required Data available in the literature indicate in average a difference of 15 in the no of pre-ovulatory follicles 16mm between the group treated with resveratrol and the control group with an average increase of 15 in favour of the study group Thus considering a conservative difference of 10 which is equivalent to a large effect size of d080 a power 1- β of 95 an alpha of 005 a two-tails t-test and a ratio of 11 between the two groups a total of 90 subjects 45 for each group would be needed to verify a significant difference in primary outcome between the two groups
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