Extended Letrozole Regimen Co-treatment With Gonadotropin Releasing Hormone Antagonist Protocol Versus Gonadotropin Releasing Hormone Antagonist Protocol in Poor Responders Undergoing IVF-ET

NCT ID: NCT04268927

Last Updated: 2020-02-13

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 106 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-01
• Study Completion Date: 2020-04-20

Brief Summary

The object of this study is to evaluate the efficacy of extended letrozole co-treatment with GnRH-antagonist protocol in ovarian stimulation of poor responder patients undergoing IVF-ET.

Detailed Description

Poor response to controlled ovarian stimulation (COH) is estimated to occur in 9-24 % of all IVF cycles. Although there is no consensus on the definition of poor response to COH, inability to produce adequate number of mature follicles( ≤ 2-5) or to recruit adequate number of oocytes ( ≤ 3 oocytes ) in response to standard stimulation protocols are the main criteria used for diagnosis of poor responders .

Patients with poor response to COH usually have higher cyclical cancelation rate , poor embryo quality and less number of embryos suitable for transfer or cryopreservation .

During the past decade gonadotropin releasing hormone antagonists (GnRHant) were widely used in the treatment of patients with poor response to standard gonadotropin releasing hormone agonist (GnRHa) protocols .In contrast to GnRHa, GnRHant is administered at the late follicular phase and therefore don't suppress the early follicular phase endogenous gonadotropins and has no suppressive effect on ovarian function at the stage of follicular recruitment.Several studies comparing GnRHant protocol with the standard GnRHa long protocol revealed a reduction in the duration of stimulation , dose of required gonadotropins , and the costs of IVF cycle with GnRHant as well as equivalent pregnancy rates .

In 2001, Mitwally and Casper introduced letrozole ( a third generation non steroidal aromatase inhibitor licensed for treatment of hormonally-responsive breast cancer after surgery ) as new ovulation induction agent in clomiphene citrate resistant patients with polycystic ovary syndrome (PCOS) . Subsequent studies confirmed the effectiveness of letrozole in induction of ovulation in women with PCOS and in superovulation (either alone or in combination with gonadotropins ) .

In patients with poor response undergoing IVF, several studies revealed that the combination of letrozole ( 2.5 mg or 5 mg/day for 5 consecutive days in early follicular phase ) with GnRHant protocol improved the ovarian response and reduced the gonadotrophin dose required. On the other hand , Schoolcraft et al reported that letrozole(2.5 mg/day from cycle day 3 to 7)/GnRHant protocol has no advantages over microdose flare GnRHa protocol.

The ideal dose and duration of letrozole administration for ovulation and superovulation is still not clear. Several studies comparing two doses of letrozole (2.5 mg or 5 mg) in superovulation suggested that the higher dose might be associated with more follicles developing.

In almost all studies to date , letrozole was administered for five consecutive days in early follicular phase . In only one study , letrozole (2.5 mg/day) was administered for ten consecutive days starting on day 1 of menstrual cycle . In that study , prolonged administration of letrozole produced more mature follicles and pregnancies than short letrozole therapy regimen in patients with clomiphene citrate resistant polycystic ovary syndrome .

The investigators designed this randomized controlled trial to evaluate the efficacy of extended letrozole co-treatment with GnRH-antagonist protocol in ovarian stimulation of poor responder patients undergoing IVF-ET

Conditions

Infertility

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

GnRH ant/letrozole

Letrozole (Femara; Novertis pharma AG, Basle, Switzerland) is administered starting on cycle day one for 8 consecutive days . The dose of letrozole is 5mg /day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days .

Highly purified urinary FSH (HP-uFSH) (Fostimon, IBSA) 300 IU/day is started on cycle day 5 and is continued until and including the day of HCG administration. Starting from cycle day 8 , the dose of HP-uFSH is adjusted individually according to ovarian response which is monitored using transvaginal ultrasound and serum estradiol.

GnRH antagonist (cetrorelix acetate)(Cetrotide®) 0.25 mg S.C once daily is started when the leading follicle is 14 mm in mean diameter and is continued until and including the day of HCG administration .

Group Type: EXPERIMENTAL

GnRH ant/letrozole

Intervention Type: DRUG

Letrozole (Femara; Novertis pharma AG, Basle, Switzerland) is administered starting on cycle day one for 8 consecutive days . The dose of letrozole is 5mg /day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days .

Highly purified urinary FSH (HP-uFSH) (Fostimon, IBSA) 300 IU/day is started on cycle day 5 and is continued until and including the day of HCG administration. Starting from cycle day 8 , the dose of HP-uFSH is adjusted individually according to ovarian response which is monitored using transvaginal ultrasound and serum estradiol.

GnRH antagonist (cetrorelix acetate)(Cetrotide®) 0.25 mg S.C once daily is started when the leading follicle is 14 mm in mean diameter and is continued until and including the day of HCG administration .

GnRH ant

Highly purified urinary FSH (HP-uFSH) (Fostimon, IBSA) 300 IU/day is started on cycle day 5 and is continued until and including the day of HCG administration. Starting from cycle day 8 , the dose of HP-uFSH is adjusted individually according to ovarian response which is monitored using transvaginal ultrasound and serum estradiol.

GnRH antagonist (cetrorelix acetate)(Cetrotide®) 0.25 mg S.C once daily is started when the leading follicle is 14 mm in mean diameter and is continued until and including the day of HCG administration .

Group Type: ACTIVE_COMPARATOR

GnRH ant

Intervention Type: DRUG

Highly purified urinary FSH (HP-uFSH) (Fostimon, IBSA) 300 IU/day is started on cycle day 5 and is continued until and including the day of HCG administration. Starting from cycle day 8 , the dose of HP-uFSH is adjusted individually according to ovarian response which is monitored using transvaginal ultrasound and serum estradiol.

GnRH antagonist (cetrorelix acetate)(Cetrotide®) 0.25 mg S.C once daily is started when the leading follicle is 14 mm in mean diameter and is continued until and including the day of HCG administration .

Interventions

GnRH ant/letrozole

Letrozole (Femara; Novertis pharma AG, Basle, Switzerland) is administered starting on cycle day one for 8 consecutive days . The dose of letrozole is 5mg /day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days .

Highly purified urinary FSH (HP-uFSH) (Fostimon, IBSA) 300 IU/day is started on cycle day 5 and is continued until and including the day of HCG administration. Starting from cycle day 8 , the dose of HP-uFSH is adjusted individually according to ovarian response which is monitored using transvaginal ultrasound and serum estradiol.

GnRH antagonist (cetrorelix acetate)(Cetrotide®) 0.25 mg S.C once daily is started when the leading follicle is 14 mm in mean diameter and is continued until and including the day of HCG administration .

Intervention Type: DRUG

GnRH ant

Highly purified urinary FSH (HP-uFSH) (Fostimon, IBSA) 300 IU/day is started on cycle day 5 and is continued until and including the day of HCG administration. Starting from cycle day 8 , the dose of HP-uFSH is adjusted individually according to ovarian response which is monitored using transvaginal ultrasound and serum estradiol.

GnRH antagonist (cetrorelix acetate)(Cetrotide®) 0.25 mg S.C once daily is started when the leading follicle is 14 mm in mean diameter and is continued until and including the day of HCG administration .

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Poor responders according to the ESHRE Bologna criteria

Exclusion Criteria

Age > 42 years FSH> 12 IU/L Irregular menstrual cycles Unilateral ovary Polycystic ovary syndrome Endometriosis Male factor of infertility requiring ICSI History of recurrent miscarriage Endocrinologic disorders Systemic disease contraindicating pregnancy

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 42 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Cairo University

OTHER

Sponsor Role: lead

Responsible Party

Usama M Fouda

Prof.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Usama M Fouda, Prof

Role: STUDY_CHAIR

Cairo University

Usama M Fouda, Prof

Role: STUDY_CHAIR

Riyadh Fertility and Reproductive Health center

Locations

Obstetrics &Gynecology Department , Faculty of medicine ,Cairo university

Cairo, , Egypt

Site Status: RECRUITING

Riyadh Fertility and Reproductive Health center

Giza, , Egypt

Site Status: RECRUITING

Countries

Egypt

Central Contacts

Usama M Fouda, Prof

Role: CONTACT

umfrfouda@yahoo.com

+201095401375

Facility Contacts

Usama M Fouda, M.D,PhD

Role: primary

umfrfouda@yahoo.com

01095401375

Usama M Fouda, Prof

Role: primary

umfrfouda@yahoo.com

+20123595106

References

Badawy A, Mosbah A, Tharwat A, Eid M. Extended letrozole therapy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a novel protocol. Fertil Steril. 2009 Jul;92(1):236-9. doi: 10.1016/j.fertnstert.2008.04.065. Epub 2008 Aug 15.

Reference Type: BACKGROUND

PMID: 18706549 (View on PubMed)

Other Identifiers

letrozole/ GnRH ant

Identifier Type: -

Identifier Source: org_study_id