Clinical trial NCT01219153: Extended High Dose Letrozole Regimen Versus Short Low Dose Letrozole Regimen as an Adjuvant to GnRH Antagonist Protocol in the Management of Poor Responders Undergoing IVF-ET
Official title: Extended High Dose Letrozole Regimen Versus Short Low Dose Letrozole Regimen as an Adjuvant to GnRH Antagonist Protocol in the Management of Patients With Poor Ovarian Response Undergoing IVF-ET, a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infertility
Keywords: Letrozole ,IVF, poor responders , GnRH antagonist
Lead sponsor: Cairo University
Sponsor class: OTHER
Collaborators: name: Ahmed Elgazzar Hospital
First posted: 2010-10-13
Enrollment: 136
Sex: FEMALE
Minimum age (years): 30
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this randomized controlled trial is to compare the efficacy of extended high dose letrozole regimen (5 mg /day for the first 5 days of cycle and 2.5 mg/day for the subsequent 3 days ) with short low dose letrozole regimen (2,5 mg/day from cycle day 3 to 7 ) as an adjuvant to GnRH antagonist protocol in the management of patients with poor ovarian response 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 compare the efficacy of extended high dose letrozole regimen (5 mg /day for the first 5 days of cycle and 2.5 mg/day for the subsequent 3 days ) with conventional short low dose letrozole regimen (2,5 mg/day from cycle day 3 to 7 ) as an adjuvant to GnRHant protocol in the management of patients with poor ovarian response undergoing IVF-ET.

Eligibility criteria: Inclusion Criteria:

* Patients who produced less than three mature follicles in response to standard GnRH agonist long protocol in their first IVF cycle

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

Primary outcomes:
measure: Clinical pregnancy rate per started cycle
timeFrame: 5 weeks after embryo transfer
Secondary outcomes:
measure: Ongoing Pregnancy Rate per started cycle
timeFrame: 18 weeks after embryo transfer
Other outcomes:
Locations:
city: Giza,
country: Egypt
facility: Ahmed Elgazzar hospital , Assisted conception unit
Study officials:
affiliation: Cairo University
name: Usama M Fouda, M.D, PhD
role: STUDY_CHAIR
affiliation: Cairo University
name: Ahmed M Sayed, M.D, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Yarali H, Esinler I, Polat M, Bozdag G, Tiras B. Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol. Fertil Steril. 2009 Jul;92(1):231-5. doi: 10.1016/j.fertnstert.2008.04.057. Epub 2008 Aug 3.
citation: Fouda UM, Sayed AM. Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET. Gynecol Endocrinol. 2011 Dec;27(12):1018-22. doi: 10.3109/09513590.2011.579661. Epub 2011 Jun 30.