Minimal Stimulation Protocol Using Aromek(Letrozole) and Follitrope(recFSH) Combined With INVOCell-Low Cost IVF

Primary Infertility Clinical Trial

— MSP-INVO IVF  

Official title:

A Scientific & Clinical Review of Minimal Stimulation Protocol Using AROMEK (Letrozole) and Follitrope (Recombinant FSH)Combined With INVOCell(Intravaginal Culturing) - Effectiveness as Low Cost IVF

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01058252
• Other study ID #: GIVF-SRM 1001
• Status: Recruiting
• Start date: May 2021
• Est. completion date: March 2022

Study information

• Verified date: March 2021
• Source: Galaxy Pharma (Pvt) Limited
• Contact: Dr Gul Rana, MBBS
• Phone: +923353039246
• Email: gulrana8[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of this study to evaluate a low cost minimal stimulation protocol combined with Intravaginal Culturing, to make IVF affordable and available across the large infertile/subfertile population

Description:

In routine ART procedures for IVF, ovarian stimulation is performed using down regulation with GNRH Agonist combined with high daily FSH doses followed with ovulation induction with HCG 10000 IU, ovum pick-up 34-36 hours after HCG injection and embryo transfer on day 2, 3 or 5. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: March 2022
• Est. primary completion date: December 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 37 Years

Eligibility

Inclusion Criteria:

• Tubal factor without Hydrosalpinx
• 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:

• If previous IVF or INVO attempts resulted in failed fertilisation
• 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

Related Conditions & MeSH terms

• Infertility
• Low Responders
• Mild to Moderate Male Factor Infertility
• Primary Infertility
• Secondary Infertility

Intervention

Combination Product:
• 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.

Procedure:
• 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.

Locations

Country	Name	City	State
Pakistan	Ova IVF & Reproductive Health Clinics	Karachi	Sindh
Pakistan	Lady Wallington Hospital	Lahore	Punjab

Sponsors (2)

Lead Sponsor	Collaborator
Galaxy Pharma (Pvt) Limited	Ova IVF & Reproductive Health Clinics, Karachi

Country where clinical trial is conducted

Pakistan, 

References & Publications (23)

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. — View Citation

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. — View Citation

Bernabeu R, Roca M, Torres A, Ten J. Indomethacin effect on implantation rates in oocyte recipients. Hum Reprod. 2006 Feb;21(2):364-9. Epub 2005 Nov 10. — View Citation

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- — View Citation

Freude G, Artner B, Leodolter S. [Intravaginal culture--simplification of IVF]. Wien Med Wochenschr. 1990 Oct 31;140(20):498-501. German. — View Citation

García-Ferreyra J, Hilario R, Luna D, Villegas L, Romero R, Zavala P, Dueñas-Chacón 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 M — View Citation

Garcia-Velasco JA, Moreno L, Pacheco A, Guillén 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 — View Citation

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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. — View Citation

Hewitt J. Intravaginal culture: present and potential uses. Br J Hosp Med. 1990 Sep;44(3):182, 184-5, 188. Review. — View Citation

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. — View Citation

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. Epub 2006 May 4. — View Citation

Kadoch IJ, Al-Khaduri M, Phillips SJ, Lapensée 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. — View Citation

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. — View Citation

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. — View Citation

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 201 — View Citation

Ozmen B, Sönmezer 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. — View Citation

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. — View Citation

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. — View Citation

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 rando — View Citation

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. German. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Follicles >18 mm on the day of HCG; Number of Oocytes aspirated; Fertilisation Rate		Quarterly
Secondary	Pregnancy Rate; Cost of Treatment		Every 6 months

External Links

•   Real-world experience with intravaginal culture using INVOCELL: an alternative model for infertility treatment