Minimal Stimulation Protocol Using Aromek(Letrozole) and Follitrope(recFSH) Combined With INVOCell-Low Cost IVF
NCT ID: NCT01058252
Last Updated: 2021-03-24
Study Results
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Basic Information
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UNKNOWN
30 participants
OBSERVATIONAL
2021-05-31
2022-03-31
Brief Summary
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Detailed Description
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In routine ART procedure for IVF, embryology is done in very high tech lab, contamination free environment, which also exclude VOC, high quality CO2 Incubators, laminar flow with heated table top, high magnification stereo microscope along with equipments for maintaining quality control, with a highly trained embryologist. The primary reason is we need to create a womb like environment in the embryology lab as eggs, and mainly fertilised embryos are going to spend minimum 2 or 3 and in case blastocyst 5 days in this lab.
In recent years, various studies have been published identifying various minimal stimulation protocols for IVF, and also another variation of IVF where rather than using CO2 Incubator for culturing, vaginal cavity of the female partner is used for incubation using a specially designed capsule which have walls permeable to vaginal pCO2 and O2. Oocytes are retrieved by the physician and handed over to basic embryologist to identify and grade oocytes and washed sperms are placed in a embryo toxic tested, sterile, individual single use capsule (INVOCell) and placed in vaginal cavity using diaphragm, patient goes back to home with some instructions for care, on day 2 patient comes back to the IVF Clinic and physician gets the capsule out and hands over to the basic embryologist trained on INVOCell to identify embryos and grade them, further loading of embryos on ET Catheter.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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Letrozole, recFSH, INVOCell, Monitoring
Infertile couple following MSP with INVO IVF
INVOCell, Letrozole 2.5 mg, recFSH 75 IU
OVARIAN STIMULATION:
In previous cycles, cycle length and ovulatory status must be assessed and documented.
STEP 1: ANOVULATION by ORAL CONTRACEPTION
* Place patients on monophasic low dose of oral contraceptive pills (OCP) such as Marvelon (Organon, 0.03 mg) continuously for 21 days, 22 days but no more.
* Before stopping the oral contraceptive pills, perform an ultrasound to check for the absence of cysts (no cyst \> 10 mm).
* Give estradiol (2mg, 3 times a day) for 3 days from D21 or D22 and wait for bleeding.
STEP 2: STIMULATION and MONITORING Day one of the cycle equals the first day of bleeding (not spotting).
* On Day 3 (D3), start letrozol 2.5mg (AROMEK) for 5 days (D7). LetrozolE can be pushed for 2 more days.
* Start hMG or FSH (75 IU a day) on Day 3 like LetrozolE and continue for 5 to 7 days without increasing the dose. The dose of hMG OR FSH can be increased to 150 IU a day if low responder.
STEP-3: LH Suppression & Monitoring
Baseline Day-2 Ultrasound to estimate antral follicles; Follow-up TVS scans on Day- 5,6,7,8 and 9 of the stimulated cycle. Ideally the lead follicle should be 18 mm on or around day 10 of the cycle.
• When the leading follicle reaches 14 to15 mm (D8 or D9), give Indomethacine (50 mg, 3 times a day) until the evening preceding the egg retrieval. The Indomethacine will prevent a premature ovulation.
The endometrium should be minimum 8 mm on the day of HCG (IVF-C 5000 IU x 2)
No need of LH testing, or E2 testsing during the stimulated cycle.
STEP-4: HCG Timing
IVF-C (HCG 10000 IU) shall be injected to trigger the ovulation, when any of the following occur:
* E2 level is over 150 pg/ml/per mature follicle (\> 15 mm)
* Domminent follicle is greater than 18 mm in mean diameter
* LH Remains as Baseline, OR
* The day when Urinary LH Surge is positive
STEP-5: OPU, ET, Cancellation
Ultrasound guided Ovum Pick-Up is performed 34-36 hours after IVF-C (HCG 10000 IU) injection.
Embryo Transfer is performed after 48-72 hours of incubation at 4-8 cell stage.
Maximum of 2 embryos are transferred, using ultrasound guided transfer.
Cancellation Criteria:
* Poor patient compliance
* Premature Ovulation
* Premature LH Surge
* Endometrium \< 7 mm
* Poor Follicular Development
* E2 Level \> 2,500 pg/ml
INVOCell (Intravaginal Culturing)
Sperm preparation through Swim-Up or Gradient is performed 1 hour prior to the oocyte retrieval; Fill the device without air bubble. Only 100000 motile spermatozoa are added into the device; After follicle aspiration, oocyte(s) are identified in the follicular fluid and immediately placed into the device; The device is closed, placed into a protective outer rigid shell and then positioned into the vaginal cavity for 2 to 3 days; No activity restriction is required for the patient, except baths. After 2 or 3 days of incubation, the retention system and the device are removed from the vagina in sterile environment. The device is opened and the contents are observed in a sterile environment under microscope to find the embryos. The two best quality embryos are loaded into embryo transfer catheter and transferred immediately unto the uterine cavity using aseptic techniques.
Interventions
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INVOCell, Letrozole 2.5 mg, recFSH 75 IU
OVARIAN STIMULATION:
In previous cycles, cycle length and ovulatory status must be assessed and documented.
STEP 1: ANOVULATION by ORAL CONTRACEPTION
* Place patients on monophasic low dose of oral contraceptive pills (OCP) such as Marvelon (Organon, 0.03 mg) continuously for 21 days, 22 days but no more.
* Before stopping the oral contraceptive pills, perform an ultrasound to check for the absence of cysts (no cyst \> 10 mm).
* Give estradiol (2mg, 3 times a day) for 3 days from D21 or D22 and wait for bleeding.
STEP 2: STIMULATION and MONITORING Day one of the cycle equals the first day of bleeding (not spotting).
* On Day 3 (D3), start letrozol 2.5mg (AROMEK) for 5 days (D7). LetrozolE can be pushed for 2 more days.
* Start hMG or FSH (75 IU a day) on Day 3 like LetrozolE and continue for 5 to 7 days without increasing the dose. The dose of hMG OR FSH can be increased to 150 IU a day if low responder.
STEP-3: LH Suppression & Monitoring
Baseline Day-2 Ultrasound to estimate antral follicles; Follow-up TVS scans on Day- 5,6,7,8 and 9 of the stimulated cycle. Ideally the lead follicle should be 18 mm on or around day 10 of the cycle.
• When the leading follicle reaches 14 to15 mm (D8 or D9), give Indomethacine (50 mg, 3 times a day) until the evening preceding the egg retrieval. The Indomethacine will prevent a premature ovulation.
The endometrium should be minimum 8 mm on the day of HCG (IVF-C 5000 IU x 2)
No need of LH testing, or E2 testsing during the stimulated cycle.
STEP-4: HCG Timing
IVF-C (HCG 10000 IU) shall be injected to trigger the ovulation, when any of the following occur:
* E2 level is over 150 pg/ml/per mature follicle (\> 15 mm)
* Domminent follicle is greater than 18 mm in mean diameter
* LH Remains as Baseline, OR
* The day when Urinary LH Surge is positive
STEP-5: OPU, ET, Cancellation
Ultrasound guided Ovum Pick-Up is performed 34-36 hours after IVF-C (HCG 10000 IU) injection.
Embryo Transfer is performed after 48-72 hours of incubation at 4-8 cell stage.
Maximum of 2 embryos are transferred, using ultrasound guided transfer.
Cancellation Criteria:
* Poor patient compliance
* Premature Ovulation
* Premature LH Surge
* Endometrium \< 7 mm
* Poor Follicular Development
* E2 Level \> 2,500 pg/ml
INVOCell (Intravaginal Culturing)
Sperm preparation through Swim-Up or Gradient is performed 1 hour prior to the oocyte retrieval; Fill the device without air bubble. Only 100000 motile spermatozoa are added into the device; After follicle aspiration, oocyte(s) are identified in the follicular fluid and immediately placed into the device; The device is closed, placed into a protective outer rigid shell and then positioned into the vaginal cavity for 2 to 3 days; No activity restriction is required for the patient, except baths. After 2 or 3 days of incubation, the retention system and the device are removed from the vagina in sterile environment. The device is opened and the contents are observed in a sterile environment under microscope to find the embryos. The two best quality embryos are loaded into embryo transfer catheter and transferred immediately unto the uterine cavity using aseptic techniques.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Unexplained infertility with unsuccessful attempts in achieving pregnancy through timed intercourse or IUI
* Boarder line male factor infertility
* Sperm DNA Fragmentation \< 30%
* Normal Uterine Cavity
* Normal baseline ultrasound with adequate number of primary follicles present
* Normal FSH and E2 on Day 3
* Age of the female is \< 35 years old
Exclusion Criteria
* Male partner who has difficulty in producing semen sample
* Very low sperm count, very low percentage of sperm motility and morphology
* Sperm DNA Fragmentation \> 30%
* Age of female patient \> 37 years
* Borderline or elevated E2 or FSH on day 3 or failed CCCT or low blood inhibin levels
* Poor ovarian response
* Hydrosalpinx
* Anatomic difficulties in reaching ovaries for oocyte retrieval
* Cervical stenosis, making embryo transfer difficult
* Uterine abnormalities or deformities
* Obesity
20 Years
37 Years
ALL
Yes
Sponsors
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Ova IVF & Reproductive Health Clinics, Karachi
UNKNOWN
Galaxy Pharma (Pvt) Limited
INDUSTRY
Responsible Party
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Principal Investigators
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Dr Gul Rana, MBBS
Role: STUDY_DIRECTOR
Ova IVF & Reproductive Health Clinics
Locations
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Lady Wallington Hospital
Lahore, Punjab Province, Pakistan
Ova IVF & Reproductive Health Clinics
Karachi, Sindh, Pakistan
Countries
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Central Contacts
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Facility Contacts
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Prof. Ayesha Malik
Role: primary
References
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Hewitt J. Intravaginal culture: present and potential uses. Br J Hosp Med. 1990 Sep;44(3):182, 184-5, 188.
Ranoux C, Poirot C, Foulot H, Aubriot FX, Dubuisson JB, Chevallier O. [Intravaginal culture and embryo transfer]. Rev Fr Gynecol Obstet. 1988 Oct;83(10):637-8. French.
Ranoux C, Aubriot FX, Dubuisson JB, Cardone V, Foulot H, Poirot C, Chevallier O. A new in vitro fertilization technique: intravaginal culture. Fertil Steril. 1988 Apr;49(4):654-7. doi: 10.1016/s0015-0282(16)59835-5.
Sterzik K, Rosenbusch B, Sasse V, Wolf A, Beier HM, Lauritzen C. A new variation of in-vitro fertilization: intravaginal culture of human oocytes and cleavage stages. Hum Reprod. 1989 Nov;4(8 Suppl):83-6. doi: 10.1093/humrep/4.suppl_1.83.
Freude G, Artner B, Leodolter S. [Intravaginal culture--simplification of IVF]. Wien Med Wochenschr. 1990 Oct 31;140(20):498-501. German.
Sterzik K, Rosenbusch B, Sasse V, Terinde R, Wolf A, Beier HM, Lauritzen C. [Experiences and successes with intravaginal fertilization and culture of human oocytes]. Geburtshilfe Frauenheilkd. 1988 Dec;48(12):850-3. doi: 10.1055/s-2008-1026639. German.
Sh Tehrani Nejad E, Abediasl Z, Rashidi BH, Azimi Nekoo E, Shariat M, Amirchaghmaghi E. Comparison of the efficacy of the aromatase inhibitor letrozole and clomiphen citrate gonadotropins in controlled ovarian hyperstimulation: a prospective, simply randomized, clinical trial. J Assist Reprod Genet. 2008 May;25(5):187-90. doi: 10.1007/s10815-008-9209-2. Epub 2008 Apr 19.
Grabia A, Papier S, Pesce R, Mlayes L, Kopelman S, Sueldo C. Preliminary experience with a low-cost stimulation protocol that includes letrozole and human menopausal gonadotropins in normal responders for assisted reproductive technologies. Fertil Steril. 2006 Oct;86(4):1026-8. doi: 10.1016/j.fertnstert.2006.03.034. Epub 2006 Aug 28.
Baysoy A, Serdaroglu H, Jamal H, Karatekeli E, Ozornek H, Attar E. Letrozole versus human menopausal gonadotrophin in women undergoing intrauterine insemination. Reprod Biomed Online. 2006 Aug;13(2):208-12. doi: 10.1016/s1472-6483(10)60617-7.
Jee BC, Ku SY, Suh CS, Kim KC, Lee WD, Kim SH. Use of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemination cycles: a pilot study. Fertil Steril. 2006 Jun;85(6):1774-7. doi: 10.1016/j.fertnstert.2006.02.070. Epub 2006 May 4.
Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena A, Pellicer A. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril. 2005 Jul;84(1):82-7. doi: 10.1016/j.fertnstert.2005.01.117.
Verpoest WM, Kolibianakis E, Papanikolaou E, Smitz J, Van Steirteghem A, Devroey P. Aromatase inhibitors in ovarian stimulation for IVF/ICSI: a pilot study. Reprod Biomed Online. 2006 Aug;13(2):166-72. doi: 10.1016/s1472-6483(10)60611-6.
Ozmen B, Sonmezer M, Atabekoglu CS, Olmus H. Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocols. Reprod Biomed Online. 2009 Oct;19(4):478-85. doi: 10.1016/j.rbmo.2009.05.007.
Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, Chakravarty BN, Kabir SN. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod. 2004 Sep;19(9):2031-5. doi: 10.1093/humrep/deh359. Epub 2004 Jun 24.
Kadoch IJ, Al-Khaduri M, Phillips SJ, Lapensee L, Couturier B, Hemmings R, Bissonnette F. Spontaneous ovulation rate before oocyte retrieval in modified natural cycle IVF with and without indomethacin. Reprod Biomed Online. 2008 Feb;16(2):245-9. doi: 10.1016/s1472-6483(10)60581-0.
Janssens RM, Lambalk CB, Vermeiden JP, Schats R, Schoemaker J. In-vitro fertilization in a spontaneous cycle: easy, cheap and realistic. Hum Reprod. 2000 Feb;15(2):314-8. doi: 10.1093/humrep/15.2.314.
Bernabeu R, Roca M, Torres A, Ten J. Indomethacin effect on implantation rates in oocyte recipients. Hum Reprod. 2006 Feb;21(2):364-9. doi: 10.1093/humrep/dei343. Epub 2005 Nov 10.
Khan M, Zafar S, Syed S. Successful intravaginal culture of human embryos for the first time in Pakistan--an experience at the Sindh Institute of Reproductive Medicine, Karachi. J Pak Med Assoc. 2013 May;63(5):630-2.
Lucena E, Saa AM, Navarro DE, Pulido C, Lombana O, Moran A. INVO procedure: minimally invasive IVF as an alternative treatment option for infertile couples. ScientificWorldJournal. 2012;2012:571596. doi: 10.1100/2012/571596. Epub 2012 May 2.
Doody KJ, Broome EJ, Doody KM. Comparing blastocyst quality and live birth rates of intravaginal culture using INVOcell to traditional in vitro incubation in a randomized open-label prospective controlled trial. J Assist Reprod Genet. 2016 Apr;33(4):495-500. doi: 10.1007/s10815-016-0661-0. Epub 2016 Feb 3.
Babcock Gilbert S, Polotsky AJ. Vaginal culture for IVF allows two mothers to carry the same pregnancy: Is more always better? Case Rep Womens Health. 2019 Jan 26;21:e00099. doi: 10.1016/j.crwh.2019.e00099. eCollection 2019 Jan.
Garcia-Ferreyra J, Hilario R, Luna D, Villegas L, Romero R, Zavala P, Duenas-Chacon J. In Vivo Culture System Using the INVOcell Device Shows Similar Pregnancy and Implantation Rates to Those Obtained from In Vivo Culture System in ICSI Procedures. Clin Med Insights Reprod Health. 2015 Jun 10;9:7-11. doi: 10.4137/CMRH.S25494. eCollection 2015.
Mitri F, Esfandiari N, Coogan-Prewer J, Chang P, Bentov Y, McNaught J, Klement AH, Casper RF. A pilot study to evaluate a device for the intravaginal culture of embryos. Reprod Biomed Online. 2015 Dec;31(6):732-8. doi: 10.1016/j.rbmo.2015.09.005. Epub 2015 Sep 18.
Other Identifiers
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GIVF-SRM 1001
Identifier Type: -
Identifier Source: org_study_id
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