Comparison of luteal first dual stimulation (Luteal DUO-STIM) protocol with conventional follicular first dual stimulation (DUO-STIM) protocol in women undergoing IVF/ICSI cycles: A pilot randomised controlled trial

TITLE: Comparison of luteal first dual stimulation (Luteal DUO-STIM) protocol with conventional follicular first dual stimulation(DUO-STIM) protocol in women undergoing IVF/ICSI cycles: A pilot randomised controlled trial

AIM: To evaluate and compare IVF outcomes between luteal first  DuoStim (Luteal DUO-STIM) protocol and the conventional follicular-first DuoStim (DUO-STIM) protocol in women undergoing IVF/ICSI cycles

PRIMARY OBJECTIVES: To compare the efficacy of luteal-first dual stimulation (Luteal DUO-STIM) protocol with conventional follicular-first dual stimulation (DUO-STIM) protoocl in terms of total oocyte yield in women undergoing IVF/ICSI cycles.

SECONDARY OBJECTIVES:

1. To compare the luteal- first dual stimulation (Luteal DUO-STIM) protocol with conventional follicular-first dual stimulation (DUO-STIM) protocol in women undergoing IVF/ICSI cycles in terms of-

• Total dose of gonadotropins required
• Duration of controlled ovarian stimulation of individual Luteal Phase Stimulation (LPS) and Follicular Phase Stimulation (FPS) as well as of complete Luteal DUOSTIM and conventional DUOSTIM
• FORT (Follicular Output Rate)
• FOI(Follicle to Oocyte Index)
• Fertilization Rate
• Cleavage Rate
• Number of good quality embryos
• Clinical pregnancy rate
• Ongoing pregnancy rate
• Time to conception
• Cycle cancellation rate

2. To assess and compare the feasibility of fresh embryo transfer in both the groups

MATERIALS AND METHODS:

STUDY DESIGN: Prospective, Randomized Open Label Pilot Study

DURATION OF STUDY: From date of ethical clearance to july 2027

PLACE OF STUDY: Assisted Reproductive Technology (ART) Facility, Department of Obstetrics and Gynaecology, AIIMS, New Delhi.

STUDY POPULATION: Women less than 40 years of age with AMH  less than or equal to 3 ng/ml recruited for IVF/ICSI cycles

STUDY and CONTROL GROUPS:

• Study Group: Luteal DUOSTIM Protocol
• Control Group: Conventional DUOSTIM protocol

METHOD OF RANDOMIZATION : Block Randomization

SAMPLE SIZE: 50 patients (25 patients in each group)

SAMPLE SIZE CALCULATION: This is a pilot randomized controlled trial enrolling 50 patients with 25 patients allocated to each arm.

INCLUSION CRITERIA:

1. Infertile women less than 40 years of age undergoing IVF/ICSI
2. AMH less than or equal to 3 ng/ml
3. willing to participate in study

EXCLUSION CRITERIA:

1. Grade 3 or higher endometriosis
2. Uterine anomalies distorting endometrial cavity
3. Uncontrolled thyroid or prolactin disorders
4. Donoe recipient IVF cycles
5. Severe male factor infertility
6. BMI less than 19kg/m2 or more than 35 kg/m2
7. Unwilling to participate in the study

METHODOLOGY

RECRUITMENT: Infertile women attending the out-patient department and IVF Clinic will be recruited according to inclusion criteria.

RANDOMIZATION: Eligible candidates will be randomized into control and study group using mixed block randomization method.

INTERVENTION:

STUDY GROUP (Luteal DUOSTIM): LUTEAL PHASE STIMULATION (LPS): Baseline TVS and hormonal profile, is done on day 21 of menstrual cycle to ensure ovulation, to rule out any ovarian cyst formation, and to note the number of antral follicles of 2-8 mm in each ovary. Those with two or more follicles in each ovary, with signs of ovulation and no ovarian cyst will be subjected to ovarian stimulation with injection Human Menopausal Gonadotrophin, the dosage of which would be individualized based on the patient’s profile. Monitoring of the ovarian stimulation will be based on serial TVS for follicular growth and hormone assays, including serum estradiol (E2), luteinizing hormone (LH) and progesterone(P4) on day six of stimulation and thereafter will be done as deemed necessary. GnRH Antagonist will be added once the leading follicle has reached atleast 12 mm and will be continued upto and including the day of trigger. Final oocyte maturation will be triggered with injection leuprolide 2 mg subcutaneously when atleast 3 follicles have reached atleast 17mm size. Oocyte retrieval will be performed 34-36 hours after the trigger under transvaginal USG guidance. After first OR, Day3 embryos or blastocysts obtained will be cryopreserved. FOLLICULAR PHASE STIMULATION (FPS): After first oocyte retrieval (OR) subsequently, stimulation will be initiated with injection hMG on the second day of menstrual bleeding or 3-5 days of initial OR if bleeding has occured in previous stimulation, after baseline TVS and hormonal profile. Monitoring of ovarian response will be done by TVS and hormonal profile starting from day 5 of stimulation and thereafter will be done every 2-3 days as deemed necessary. GnRH Antagonist  will be administered daily once the leading follicle has reached atleast 12 mm and will be continued upto and including the day of trigger. Final oocyte maturation will be triggered with injection leuprolide 1mg and recombinant hCG 250 mcg given subcutaneously when atleast 3 follicles have reached atleast 17mm size. Oocyte retrieval will be performed 34-36 hours after the trigger under USG guidance. All follicles measuring above 12mm will be aspirated during the OR in all cases. The decision for fresh embryo transfer will be taken if endometrial growth is appropriate and ovarian -endometrial synchrony is documented. Fresh embryo transfer will be performed under ultrasound guidance. Luteal phase support in the form of injection micronized progesterone 25mg subcutaneously daily and/or micronized progesterone vaginal pessary 400mg twice daily starting from the day of oocyte retrieval. CONTROL GROUP (DUOSTIM): FOLLICULAR PHASE STIMULATION: All patients would receive luteal priming with Tab estradiol valerate 4 mg from day 18 of the previous cycle until the beginning of menses. Baseline TVS and hormonal profile  would be carried out on day 1 or 2 of menses to ensure downregulation, rule out ovarian cyst and to see number of antral follicles in both the ovaries. Ovarian stimulation will be done with injection Human Menopausal Gonadotrophin, the dosage of which would be individualized based on the patient’s profile. Monitoring of the ovarian stimulation will be based on serial transvaginal scans for follicular growth and hormone assays on day five and subsequently based on the response to ovarian stimulation. GnRH Antagonist will be administered daily once the leading follicle has reached atleast 12 mm and will be continued upto and including the day of trigger. Final oocyte maturation will be triggered with injection leuprolide 2 mg  subcutaneously when atleast 3 follicles have reached atleast 17mm size. Oocyte retrieval will be performed 34-36 hours after the trigger under USG guidance. Routine IVF or ICSI will be performed as per discretion of the embryologist. All day 3 or day 5 embryos will be vitrified. LUTEAL PHASE STIMULATION: 3-5 days after the first OPU, TVS and hormonal profile (E2/LH/P4) will be done followed by ovarian stimulation using same protocol as in FPS with injection HMG. Dose of HMG will be adjusted as per ovarian response to stimulation. Final oocyte maturation will be triggered with injection leuprolide 1mg and recombinant HCG 250 mcg given subcutaneously when atleast 3 follicles have reached atleast 17mm size. Oocyte retrieval will be performed 34-36 hours after the trigger under USG guidance. Decision for fresh or frozen embryo transfer will be individualized based on ovarian-endometrial synchrony and endometrial growth.

FOLLOW UP: Beta hCG and urine pregnancy test will be performed on day 14 after fresh embryo tranfer and progesterone will be continued up to 12 weeks of gestation in a normal intrauterine pregnancy and discontinued in case of a biochemical pregnancy or no pregnancy.

PRIMARY OUTCOME: Total oocyte yield

SECONDARY OUTCOMES:

1. Total dose of gonadotropins required
2. Duration of controlled ovarian stimulation of individual Luteal Phase Stimulation (LPS) and Follicular Phase Stimulation (FPS) as well as of complete Luteal DUOSTIM and conventional DUOSTIM
3. FORT (Follicular Output Rate)
4. FOI (Follicle to Oocyte Index)
5. Fertilization rate
6. Cleavage rate
7. Number of good quality embryos
8. Clinical pregnancy rate
9. Ongoing pregnancy rate
10. Time to conception
11. Cycle cancellation rate
12. Fresh embryo transfer rate