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Comparison of letrozole and clomiphen in mild protocol among infertile poor responders

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History
# Registration date Revision Id
4 2021-08-30, 1400/06/08 196777
3 2021-03-16, 1399/12/26 175742
2 2021-03-04, 1399/12/14 174236
1 2011-08-10, 1390/05/19 6861
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  • General information

    184
    200
    2011-01-01, 1389/10/11
    2011-05-30, 1390/03/09

  • Ethics committees

    #1
    1990-12-01, 1369/09/10
    2010-12-01, 1389/09/10
    13/1389
    IR.SSU13/1389

Protocol summary

Study aim
The aim of present study was to compare the efficacy of letrozole and clomiphene citrate for mild ovarian stimulation on ART outcomes in poor responder women.
Design
phase 2 of clinical trial. a computer-generated list of random numbers was used for patient classification
Settings and conduct
It is a randomized clinical trial, No blinding. Yazd Infertility Research Center was conducted.
Participants/Inclusion and exclusion criteria
women included in this study who had one or more previous failed ART cycle in which three or fewer oocytes were been retrieved and had serum E2 levels ≤500 pg/ml on the day of hCG administration. The exclusion criteria were: ٔBMI> 30 kg/m2 ,Endocrine or metabolic disorders,History of ovarian surgery ,Severe endometriosis,Azoospermia in male partner ,FSH >15 m IU/ml
Intervention groups
All women received oral contraceptive for 21 days which started on the first day of previous cycle. In group I, stimulation was started by administration of clomiphene citrate 100 mg daily from day 3 of menstruation cycle until day 7 of the cycle. Patients in group II received letrozole from day 3 of the cycle 5mg /day for 5 days. In both groups, gonadotropins stimulation with hMG 225-300 IU daily was started from day 5 of cycle. Patient was monitored by serial vaginal ultrasonography and measurement of serum E2 levels.As the dominant follicle reached to 14mm in mean diameter, 0.25 mg/day GnRH antagonist . When at least two follicles with a mean diameter of 18 mm were observed, 10000 IU hCG (Pregnyl, Organon, Netherlands) was administrated.
Main outcome variables
Chemical pregnancy was defined by positive β-hCG, 12 days after embryos transfer. Clinical pregnancy was identified as observation of fetal heart activity by transvaginal ultrasonography.

General information

Reason for update
Updating the trial according to the last changes in methods and adding results
Acronym
IRCT registration information
IRCT registration number: IRCT201107146420N3
Registration date: 2011-08-10, 1390/05/19
Registration timing: retrospective

Last update: 2021-03-18, 1399/12/28
Update count: 3
Registration date
2011-08-10, 1390/05/19
Registrant information
Name
Maryam Eftekhar
Name of organization / entity
Yazd Research and Clinical Center for Infertility
Country
Iran (Islamic Republic of)
Phone
+98 35182470856
Email address
eftekhar@ssu.ac.ir
Recruitment status
Recruitment complete
Funding source
Research and Clinical Center for infertility, Shahid Sadoughi University of Medical Sciences
Expected recruitment start date
2009-01-01, 1387/10/12
Expected recruitment end date
2011-08-01, 1390/05/10
Actual recruitment start date
2009-03-01, 1387/12/11
Actual recruitment end date
2011-05-30, 1390/03/09
Trial completion date
2011-10-30, 1390/08/08
Scientific title
Comparison of letrozole and clomiphen in mild protocol among infertile poor responders
Public title
Comparison of letrozole and clomiphen in mild protocol among infertile poor responders
Purpose
Treatment
Inclusion/Exclusion criteria
Inclusion criteria:
three or fewer oocytes were been retrieved in previous failed ART cycle; serum E2 levels ≤ 500 pg/ml on the day of hCG administration.
Exclusion criteria:
BMI >30 mg/m2; endocrine or metabolic disorders; history of ovarian surgery; severe endometriosis; azoospermia in male partner. FSH >15 m IU/ml
Age
From 20 years old to 45 years old
Gender
Female
Phase
2
Groups that have been masked
No information
Sample size
Target sample size: 200
Actual sample size reached: 184
Randomization (investigator's opinion)
Randomized
Randomization description
Randomization by table of random numbers
Blinding (investigator's opinion)
Not blinded
Blinding description
Placebo
Not used
Assignment
Parallel
Other design features

Secondary Ids

empty

Ethics committees

1

Ethics committee
Name of ethics committee
Ethics committee of Yazd Research and Clinical Center for infertility, Shahid Sadoughi University of
Street address
Bouali Ave, Safaeiyeh
City
Yazd
Province
Yazd
Postal code
8916877391
Approval date
2010-12-01, 1389/09/10
Ethics committee reference number
IR.SSU13/1389

Health conditions studied

1

Description of health condition studied
Infertility
ICD-10 code
N70-N77
ICD-10 code description
Inflammatory diseases of female pelvic organs

Primary outcomes

1

Description
chemical pregnancy
Timepoint
12 day after embryo transfer
Method of measurement
beta hCG blood test

2

Description
clinical pregnancy
Timepoint
3 weeks after chemical pregnancy
Method of measurement
observation of fetal heart activity by transvaginal ultrasonography

3

Description
implantation rate
Timepoint
3 weeks after chemical pregnancy
Method of measurement
the ratio of the number of embryonic sacs diagnosed by sonography to the total number of the embryos transferred

Secondary outcomes

empty

Intervention groups

1

Description
group I: clomiphen citrate 50 mg twice a day from 3th day of menstruation cycle until 7th day of the cycle.
Category
Treatment - Drugs

2

Description
group II: letrozole 2.5 mg twice a day from 3th of the cycle until 8th day.
Category
Treatment - Drugs

Recruitment centers

1

Recruitment center
Name of recruitment center
Research and Clinical Center for Infertility
Full name of responsible person
Maryam Eftekhar
Street address
Bouali Ave
City
Yazd
Province
Yazd
Postal code
8916977443
Phone
+98 35 3824 7085
Email
eftekhar@ssu.ac.ir

Sponsors / Funding sources

1

Sponsor
Name of organization / entity
shahid sadoughi university of medical science
Full name of responsible person
masood mirzaee
Street address
bahonar Ave
City
Yazd
Province
Yazd
Postal code
8916978477
Phone
+98 35 3726 3733
Email
masoud_mirzaei@hotmail.com
Grant name
Grant code / Reference number
Is the source of funding the same sponsor organization/entity?
Yes
Title of funding source
shahid sadoughi university of medical science
Proportion provided by this source
100
Public or private sector
Public
Domestic or foreign origin
Domestic
Category of foreign source of funding
empty
Country of origin
Type of organization providing the funding
Academic

Person responsible for general inquiries

Contact
Name of organization / entity
Research and Clinical Center for Infertility
Full name of responsible person
Maryam Eftekhar
Position
Reserch faculty member
Latest degree
Medical doctor
Other areas of specialty/work
Gynecology and Obstetrics
Street address
Safaeiyeh, Bouali Ave
City
Yazd
Province
Yazd
Postal code
8916977443
Phone
+98 35 1824 7085
Fax
Email
eftekhar@ssu.ac.ir
Web page address

Person responsible for scientific inquiries

Contact
Name of organization / entity
Research and Clinical Center for Infertility
Full name of responsible person
Maryam Eftekhar
Position
Gynecologist/MD
Latest degree
Medical doctor
Other areas of specialty/work
Gynecology and Obstetrics
Street address
Safaeiyeh, Bouali Ave
City
Yazd
Province
Yazd
Postal code
8916877391
Phone
+98 35 1824 7085
Fax
Email
eftekhar@ssu.ac.ir
Web page address

Person responsible for updating data

Contact
Name of organization / entity
Yazd University of Medical Sciences
Full name of responsible person
Maryam eftekhar
Position
Professor
Latest degree
Medical doctor
Other areas of specialty/work
Gynecology and Obstetrics
Street address
Yazd Yazd Infertility Research Center, Bouali Street
City
Yazd
Province
Yazd
Postal code
8916977443
Phone
+98 35 3824 7085
Email
eftekhar@ssu.ac.ir

Sharing plan

Deidentified Individual Participant Data Set (IPD)
Yes - There is a plan to make this available
Study Protocol
Yes - There is a plan to make this available
Statistical Analysis Plan
Yes - There is a plan to make this available
Informed Consent Form
Yes - There is a plan to make this available
Clinical Study Report
Yes - There is a plan to make this available
Analytic Code
Yes - There is a plan to make this available
Data Dictionary
Yes - There is a plan to make this available
Title and more details about the data/document
All participant data sets are to be shared
When the data will become available and for how long
2 months after the result publication
To whom data/document is available
A journal in which the results are published
Under which criteria data/document could be used
Submission of an official application via the agent that is legally in charge
From where data/document is obtainable
Yazd Reproductive Sciences Institute, Bouali Ave, Yazd, Iran
What processes are involved for a request to access data/document
Request from the Research Deputy, submitted to the Research Council of the Center if the request accepts its referral to the security and after completion of the relevant forms, the request is referred to the research experts and then get the data.
Comments

Trial results

Please tick if results have been published
Yes
Summary result posting date
2021-03-07, 1399/12/17
Table of baseline comparison

Baseline characteristics of the patients in both groups

Variable Clomiphene group (n=80) Letrozole group (n=87) p-values
Mean age (years) 37.37 ± 4.36 37.22 ± 3.95 0.807
BMI (kg/m2) 24.56 ± 2.53 25.2 ± 2.34 0.099
Infertility duration (years) 9.17 ± 6.53 7.93 ± 4.70 0.169
Basal FSH level (mIU/mL) 8.95 ± 4.08 8.70 ±4.20 0.705
Number of previous failed failing IVF/ICSI cycles 2.53 ± 1.12 2.16 ±0.44 0.431
Duration of hormonal stimulation (days) 11.22 ± 1.39 11.35 ± 1.23 0.520
Total number of hMG ampoules (IU) 29.60 ± 9.07 29.27 ± 9.78 0.825
E2 level on the day of hCG (pg/mL) 978.46 ± 614.99 1131.83 ± 677.73 0.216
Endometrial thickness (mm) 8.39 ± 0.38 9.16 ± 1.24 0.000
Number of oocyte retrieved 3.97 ± 3.18 4.25 ± 2.84 0.553
Number of embryo obtained 2.50 ± 2.04 2.31 ± 1.10 0.452
Number of embryo transferred 2.01 ± 0.92 2.00 ± 0.83 0.927

Participant flow diagram
Table of variable outcomes' results

Outcome of IVF/ICSI-ET treatment cycles in both groups

Variable Clomiphene group (n=80) Letrozole group (n=87) p-value
Fertilization rate (%) 58.74% 62.6% 0.482
Implantation rate (%) 6.6% 7.2% 0.024
Chemical pregnancy rate a n, (%) 10.87 (11.5%) 11.80 (13.8%) 0.816
Clinical pregnancy rate b n, (%) 7 (8%) 9 (11.3%) 0.601
Miscarriage rate c n, (%) (30%) (27.3%) 1.00

chi-square test was use.

P ≤0.05 was considered statistically significant

a: Chemical pregnancy per cycle b: Clinical pregnancy per cycle c: Miscarriage rate per pregnancy

Table of adverse events
First publication date
2014-11-15, 1393/08/24
Abstract of published paper
Abstract Background: Poor ovarian response to controlled ovarian stimulation is one of the most important interest points in assisted reproduction. Mild ovarian stimulation seems to be preferable to high dose of FSH regimens in women with a history of poor ovarian response in previous protocol. Clomiphene citrate and letrozole alone or in combination with FSH have been used in mild ovarian stimulation protocol. Objective: To compare the efficacy of letrozole and clomiphene citrate for mild ovarian stimulation on assisted reproductive technology outcomes in poor responders. Materials and Methods: In a randomized control study, 184 women aged between 20 and 45 years with the history of poor response to ovarian stimulation who were candidate for ART were randomly subdivided into two groups: group I (n= 80), women who underwent the clomiphene/gonadotropin/antagonist protocol; and group II (n= 87), patients who underwent the letrozole/gonadotropin/antagonist protocol. Groups were compared regarding implantation, chemical and clinical pregnancy rates. Results: There was a significant difference in the mean endometrial thickness between two groups (9.16±1.2 mm vs. 8.3±0.3 mm). The implantation rate was significantly higher in letrozole group compare to clomiphene group (7.2 vs. 6.6%, p=0.024 respectively). No significant differences were found in chemical and clinical pregnancy rate between two groups. Conclusion: In mild ovarian stimulation protocol, letrozole and clomiphene have similar value for the poor responder. The optimal treatment strategy for these patients remains debated.
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