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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Primary Infertility, Secondary Infertility, Low Responders, Mild to Moderate Male Factor Infertility

Intervention / Treatment
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* Combination Product: INVOCell, Letrozole 2.5 mg, recFSH 75 IU
* Procedure: STEP-3: LH Suppression & Monitoring
* Procedure: STEP-4: HCG Timing
* Procedure: STEP-5: OPU, ET, Cancellation
* Procedure: INVOCell (Intravaginal Culturing)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 37 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Letrozole, recFSH, INVOCell, Monitoring<br>Infertile couple following MSP with INVO IVF | Combination Product: INVOCell, Letrozole 2.5 mg, recFSH 75 IU<br>* 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.<br>* Other names: Indomethacin 50 mg;Procedure: STEP-3: LH Suppression & Monitoring<br>* 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.<br>Procedure: STEP-4: HCG Timing<br>* 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<br>* Other names: IVF-C 5000 IU;Procedure: STEP-5: OPU, ET, Cancellation<br>* 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<br>* Other names: Ultrasound Guided;Procedure: INVOCell (Intravaginal Culturing)<br>* 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.<br>* Other names: Diaphragm (Retention Device);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Follicles >18 mm on the day of HCG; Number of Oocytes aspirated; Fertilisation Rate |  | Quarterly | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pregnancy Rate; Cost of Treatment |  | Every 6 months |