Letrozole Versus Gonadotropins in Clomiphene Citrate Resistance

• ClinicalTrials.gov Identifier: NCT04834791
• Recruitment Status: Completed
• First Posted: April 8, 2021
• Last Update Posted: April 8, 2021
• Sponsor: Tanta University
• Information provided by (Responsible Party): Ayman S Dawood, MD, Tanta University

Study Description

Brief Summary:

Clomiphene citrate resistance (CCR) occur in 15-40% in women with PCOS. Several studies have shown that letrozole is superior to CC regarding side effects, ovulation, and pregnancy rates. Letrozole or gonadotropins use for ovulation induction in CCR is not well established which is superior and most safe.

Condition or disease	Intervention/treatment	Phase
Clomiphene Citrate Resistance; Ovulation Induction; Letrozole; Gonadotropins	Drug: Letrozole 2.5mg; Drug: Gonadotropin	Phase 4

Detailed Description:

This study included 70 patients enrolled according inclusion and exclusion criteria. The inclusion criteria were (a) Infertility lasting one year or more in presence of regular intercourse, (b) Patients' age between 20-35years (c) Normal semen analysis according to WHO 2010 (d) Patent fallopian tubes (e) Normal prolactin and TSH. (e) Anovulatory cycles confirmed by mid-luteal progesterone ≤ 3 ng/ml and (f) Clomiphene citrate resistance for 3 cycles of 150mg. Exclusion Criteria were (a) Any hormonal disturbances eg. hyperprolactinemia, (b) Immunological causes of infertility, (c) Coital errors, (d) Metabolic disorders and (e) Poor patient compliance.

Sample size calculation: The minimum sample size calculated using Epi info program version 7 for unmatched case control study; 80% power and 95% Confidence interval was 22 for each group. For better accuracy and validity of results the sample size was increased by 10%=3 in each group. The total number of cases was 50 and 25 for each group.

Randomization and allocation: It was a prospective quesi-randomization. Based on the attendance order, patients with odd numbers were considered group I (Letrozole group) and those with even numbers were considered group II (Gonadotropin group). Allocation was equal 1:1.

Intervention:

Group I (Letrozole Group n=25): These patients were treated with letrozole (Femara®, Novartis New York, NY, USA) in a dose 2.5 mg (one tablet daily) orally began on the 3rd day to the 7th day of the cycle. If ovulation is not achieved dose is increased by 2.5 mg in next cycle till 3 cycles. If hyperstimulation occurred, the cycle was cancelled and the patients were excluded from the study.

Group II (Gonadotropin Group n=25) These patients were given urofollitropin (fostimon ®, IBSA, Lugano, Switzerland) in a dose of 75 IU/mL I.M from day 3rd to day 7th of the cycle beginning by one ampoule per day and the dose had been modulated according to response. If hyperstimulation occurred, the cycle was cancelled and the patients were excluded from the study.

Methods:

Proper history taking including age, gravidity, parity, infertility duration, history of laparoscopic surgery, previous induction of ovulation in the last 6 months. Examination was done to assess weight, height (BMI), signs of androgen excess, thyroid gland and breast examination.

Serum FSH, LH, testosterone level, prolactin level and thyroid stimulating hormone on day 3 of spontaneous menstrual cycle were done. Serum Progesterone (P4) was done on day 22 (midluteal) to confirm ovulation if ≥ 10ng/ml.

Basal transvaginal U/S on day3 of the cycle to detect criteria of PCOS and count number of antral follicles in both ovaries and to exclude of any basal ovarian cyst. Transvaginal ultrasound was also used to follow follicular growth and endometrial thickness starting on day 8 and then every other day till assuming good ovulatory response when one or more follicles is ≥ 18mm and endometrial thickness ≥ 6mm.

Human Chorionic Gonadotropin (choriomon®, IBSA, Lugano, Switzerland) 10.000IU/I.M was administered when good ovulatory response was assumed. The intercourse was advised on the day of HCG injection and every other day for 4 days after injection HCG.

Number and size of Dominant follicles, endometrial thickness were recorded. Clinical pregnancy was detected by serum pregnancy test and by presence of intrauterine gestational sac with fetal pulsation.

Outcome measures: Primary outcomes was ovulation rate. Secondary outcomes were pregnancy rate.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Letrozole Versus Gonadotropins for Ovulation Induction in Clomiphene Citrate Resistance: A Randomized Controlled Study
• Actual Study Start Date: March 1, 2019
• Actual Primary Completion Date: October 31, 2019
• Actual Study Completion Date: October 31, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Letrozole; These patients were treated with letrozole (Femara®, Novartis New York, NY, USA) in a dose 2.5 mg (one tablet daily) orally began on the 3rd day to the 7th day of the cycle. If ovulation is not achieved dose is increased by 2.5 mg in next cycle till 3 cycles.	Drug: Letrozole 2.5mg; These patients were treated with letrozole (Femara®, Novartis New York, NY, USA) in a dose 2.5 mg (one tablet daily) orally began on the 3rd day to the 7th day of the cycle. If ovulation is not achieved dose is increased by 2.5 mg in next cycle till 3 cycles
Active Comparator: Gonadotropins; These patients were given urofollitropin (fostimon ®, IBSA, Lugano, Switzerland) in a dose of 75 IU/mL I.M from day 3rd to day 7th of the cycle beginning by one ampoule per day and the dose had been modulated according to response.	Drug: Gonadotropin; These patients were given urofollitropin (fostimon ®, IBSA, Lugano, Switzerland) in a dose of 75 IU/mL I.M from day 3rd to day 7th of the cycle beginning by one ampoule per day and the dose had been modulated according to response.

Outcome Measures

Primary Outcome Measures :

1. Ovulation rate [ Time Frame: 6 months ]
   Number of mature follicles in each ovary>18mm

Secondary Outcome Measures :

1. Pregnancy rate [ Time Frame: 6 months ]
   Number of pregnant women evidenced by serum HCG and gestational sac inside the uterus

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 35 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Infertility lasting one year or more in presence of regular intercourse,
• Patients' age between 20-35years
• Normal semen analysis according to WHO 2010
• Patent fallopian tubes (e) Normal prolactin and TSH.
• Anovulatory cycles confirmed by mid-luteal progesterone ≤ 3 ng/ml and
• Clomiphene citrate resistance for 3 cycles of 150mg.

Exclusion Criteria:

• Any hormonal disturbances eg. hyperprolactinemia,
• Immunological causes of infertility,
• Coital errors,
• Metabolic disorders and
• Poor patient compliance.

Contacts and Locations

Locations

Egypt

Ayman Shehata Dawood

Tanta, Gharbia, Egypt, 31111

Sponsors and Collaborators

Tanta University

Investigators

• Principal Investigator: Ayman Dawood, MD; Assistant professor

More Information

• Responsible Party: Ayman S Dawood, MD, Assistant professor, Tanta University
• ClinicalTrials.gov Identifier: NCT04834791
• Other Study ID Numbers: CCR
• First Posted: April 8, 2021
• Last Update Posted: April 8, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: on request
• Supporting Materials: Study Protocol
• Time Frame: 3 months

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Letrozole; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs