Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001315505
Ethics application status
Approved
Date submitted
13/10/2015
Date registered
2/12/2015
Date last updated
4/11/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
The influence of preovulatory and postovulatory progesterone on the outcome of the in vitro fertilization (IVF)
Scientific title
Efficacy of frozen/thawed embryo transfer and 5th day embryo transfer in the blastocyst stage on positive implantation and clinical pregnancy rate in female patients with low fertility linked to high preovulatory and postovulatory progesterone
Secondary ID [1] 287646 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fertility problems among female patients and IVF outcome in terms of high preovulatory and postovulatory progesterone 296477 0
Condition category
Condition code
Reproductive Health and Childbirth 296730 296730 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a prospective cohort study. 400 stimulated patients in IVF treatment will be prospectively analyzed by determining progesterone (P4) and estradiol (E2) on the day of hCG administration. Patients with a normal preovulatory P4 (less than or equal to 4.77 nmol/l) will be in a control group (300 women), while patients with elevated P4 (>4.77 nmol/l) will represent a study group (100 women). The study group will be further divided into two subgroups; normal responder patients will be in the first subgroup (85 women), while the other subgroup (15 women) will be represented with high responder patients. All the patients will be paired according to their age, BMI, stimulation protocol, gonadotropin dosage and the number of retrieved oocytes and transferred embryos. Ovulation stimulation among patients will be conducted with GnRH analogues in the ovulation induction. Gonadotropin dosage and their selection (single drug or drug combination) as well as the overall duration of the intervention period for each participant will be adjusted according to patients' age, FSH, AFC (antral follicle counts), BMI and previous IVF procedure. Drugs that will be used in this research are Follitropine Alfa (Gonal F, MerckSerono, Germany), Follitropine Beta (Puregon, Organon, Netherland), Triptorelin (Decapeptyl SR, Ferring Pharmaceuticals, Switzerland), Cetrorelix acetate (Cetrotide, MerckSerono, Germany), Choriogonadotropin Alfa (Ovitrelle, MerckSerono, Germany), Menotropin (Menopur, Ferring Pharmaceuticals, Switzerland). Every drug will be administered as a subcutaneous injection. Follitropine Alfa can be used as a single drug or in combination with GnRH agonists. If we use Follitropine Alfa as a single drug, it will be used from the second day of the cycle till the 10th day of the cycle (9 days in total). The initial dose will be 225 IU (3 ampoules of 75 IU) for the first 3-4 days of the treatment of the patients and the later dose will be 150 IU (2 ampoules of 75 IU). Follitropine Beta will be used from the second day of the cycle till the 10th day of the cycle (9 days in total). The initial dose will be 200 IU (4 ampoules of 50 IU) for the first 3-4 days of the treatment of the patients and the later dose will be 150 IU (3 ampoules of 50 IU). On the 10th day, Choriogonadotrophin Alfa will be administered in a single dose of 250 micro g. If we use the combination of Follitropine Alfa and GnRH agonists, the treatment will start on the second day of the cycle (short protocol) with single daily dose of Triptorelin of 0,1mg and its duration will be till the 10th day of the cycle (9 days in total). Long protocol with Triptorelin can also be used with a single daily dose of 0,1mg from the 21st day of the previous cycle till the 10th day of the cycle (18 days in total). Cetrorelix acetate will be used in a daily dose of 0,25mg starting on the 6th or the 7th day of the cycle till the 10th day of the cycle (4-5 days in total). If we use the single dose of the Cetrorelix acetate, we will administer 3mg of Cetrorelix acetate on the 7th day of the cycle. Choriogonadotropin Alfa will be administered in a single dose of 250 micro g when more than 3 follicles in diameter of 17 mm and more are registered on the ovaries on the ultrasound examination. Menotropin will be administered for at least 5 days starting on the second day of the cycle and the duration of the treatment must not be more than 20 days. The daily dose of Menotropin will be 225 IU (3 ampoules of 75 IU). Folliculogenesis will be monitored by ultrasound examination and by determination of E2 serum levels. When more than 3 follicles in diameter of 17 mm and more are registered on the ovaries on the ultrasound examination, hCG will be given to the patients and 36 hours later transvaginal follicle aspiration will be performed. All patients will receive the luteal support in form of micronized vaginal P4 (Utrogestan, Besins Laboratories International, France), which will be used for 12 days in a dose of 600mg a day (3 doses of 200mg). Since all the patients will receive Utrogestan, micronized P4 will not affect the results of the study of preovulatory P4. Considering the possibility that different populations have different levels of P4 after the ovulation on the 5th day, the mean P4 on the 5th day will be determined in the control group. The obtained value of P4 on the 5th day of the control group would be the discriminatory border on which will the study patients be classified for the frozen/thawed embryo transfer (FET) or blastocyst embryo transfer (BET). In the study subgroup, among normal responders who have higher values of P4 on the 5th day as compared to the mean P4 value on the 5th day obtained in the control group, FET will be made, while at lower values of P4 as compared to the mean P4 value on the 5th day obtained in the control group, BET will be conducted. In high responders with elevated preovulatory and postovulatory P4 a randomized fresh or delayed blastocysts transfer is planned. The overall duration of the intervention period for each participant would be 28 days (single 28 day cycle). The duration of the study will be maximum 2 years.
Intervention code [1] 293044 0
Treatment: Other
Comparator / control treatment
Patients with a normal preovulatory progesterone (P4) (<4.77 nmol/l) will be in a control group (300 women).
Control group
Active

Outcomes
Primary outcome [1] 296509 0
To determine the impact of the preovulatory P4 after the ovarian stimulation during the IVF treatment on the pregnancy outcome through the implantation and clinical pregnancy rate in normal responders and high responders with the fresh or frozen/thawed blastocysts transfer. This outcome will be assessed through the serum hCG assay and an ultrasound examination.
Timepoint [1] 296509 0
2 weeks after the embryo transfer
Secondary outcome [1] 318223 0
To analyze the IVF outcome in patients with elevated preovulatory P4 (>4.77 mmol/l) as compared to patients without high preovulatory P4.
The secondary outcome will be assessed through the ultrasound examination.
Timepoint [1] 318223 0
6-8 weeks after the embryo transfer
Secondary outcome [2] 318224 0
To compare the IVF outcome in normal responders with elevated preovulatory P4 where the postovulatory level of P4 is lower than the mean P4 value on the 5th day of the cycle with fresh blastocyst transfer and the normal responders where the postovulatory P4 is higher than that determined value P4 with the frozen/thawed blastocyst transfer in the natural cycle.
The secondary outcome will be assessed through the ultrasound examination.
Timepoint [2] 318224 0
6-8 weeks after the embryo transfer
Secondary outcome [3] 318226 0
To compare the IVF outcome in high responders with elevated preovulatory P4 through randomized fresh blastocyst and frozen/thawed blastocyst transfer in a natural cycle.
The secondary outcome will be assessed through the ultrasound examination.
Timepoint [3] 318226 0
6-8 weeks after the embryo transfer

Eligibility
Key inclusion criteria
Patients undergoing IVF treatment, patients with normal P4 values on the 2nd, 3rd and 4th day of the cycle, patients older then 18 years and younger then 37 years, normal responder patients (E2<3000 pg/ml, the number of oocytes <20) and high responder patients (E2>3000 pg/ml, the number of oocytes>20) will be included in the study.
Minimum age
18 Years
Maximum age
37 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with elevated P4 on the 2nd, 3rd and 4th day of the cycle, women older than 37 years and poor responder patients (number of retrieved oocytes <4 on the day of hCG and E2 <500 pg/ml) will be excluded from the study since each of the above parameters adversely affects the IVF outcome.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint/s
Statistical methods / analysis
Statistical analysis will be conducted using the testing procedures in programs SPSS 21 (IBM Corp. Released 2012 IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.) and MedCalc Statistical Software version 13.1.2 (MedCalc Software BVBA, Ostend, Belgium; http://www.medcalc.org; 2014). An adjustedness and a roundness distribution less than 1 will be considered as a normal distribution of the continuous variables. Distribution regularity will be analyzed with the Kolmogorov-Smirnov test. Measures of central tendency and dispersion of continuous variables will be descriptively expressed with the median and range of age, or median and 25th and 75th percentiles for the variables that are different from the normal distribution. Measures of central tendency and dispersion of continuous variables that have normal distribution will be descriptively expressed with mean and standard deviation. Nominal indicators will be shown with the distribution of frequencies in groups and with share. To determine the difference between more than two independent samples with normal distribution, ANOVA analysis will be used, followed by post hoc analysis (usually Tukey). To determine the difference between the two independent samples of an uneven distribution, Kruskal-Wallis ANOVA test and Mann-Whitney U-test for post hoc nonparametric analysis will be used. To determine the difference among the proportions between more than two independent samples, Pearson's chi square test and chi square test for post hoc analysis will be used. To determine the sample relation, Kendall tau and Spearman's rho test for nonparametric analysis, the Pearson correlation coefficient for properly distributed continuous variables, and method of partial correlation analysis of the impact of certain variables on the association of others with control will be used. Predictive values of the continuous variables, the sensitivity and specificity of the test as well as the positive and negative likelihood ratios and predictive values will be conducted by the ROC analysis. The probability of the null hypothesis to obtain results equal or different from the observed will be set to the limit of 0.05.
Prior to this study, a pilot study was conducted in order to determine the number of participants required. Alpha level was appointed to 0,05, Beta level was appointed to 0,20 and the power was set at 80%. Due to these calculations, it has been concluded that 400 patients (300 in the control group and 100 in the study group) are required in this study.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
20/07/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
400
Accrual to date
Final
Recruitment outside Australia
Country [1] 7221 0
Croatia
State/province [1] 7221 0

Funding & Sponsors
Funding source category [1] 292211 0
Hospital
Name [1] 292211 0
University Hospital Centre Zagreb, Department of Obstetrics and Gynaecology
Country [1] 292211 0
Croatia
Primary sponsor type
Hospital
Name
University Hospital Centre Zagreb, Department of Obstetrics and Gynaecology
Address
Petrova 13, 10 000 Zagreb
Country
Croatia
Secondary sponsor category [1] 290884 0
None
Name [1] 290884 0
None
Address [1] 290884 0
Country [1] 290884 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293680 0
Ethics committee of the University Hospital Centre Zagreb, Department of Obstetrics and Gynaecology
Ethics committee address [1] 293680 0
Ethics committee country [1] 293680 0
Croatia
Date submitted for ethics approval [1] 293680 0
15/01/2015
Approval date [1] 293680 0
16/02/2015
Ethics approval number [1] 293680 0
021-1/20-2015

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 60934 0
Dr Emina Ejubovic
Address 60934 0
Cantonal Hospital Zenica
Crkvice 67, 72 000 Zenica,
Bosnia and Herzegovina
Country 60934 0
Bosnia and Herzegovina
Phone 60934 0
+38761824035
Fax 60934 0
+38732404714
Email 60934 0
[email protected]
Contact person for public queries
Name 60935 0
Emina Ejubovic
Address 60935 0
Cantonal Hospital Zenica
Crkvice 67, 72 000 Zenica,
Bosnia and Herzegovina
Country 60935 0
Bosnia and Herzegovina
Phone 60935 0
+38761824035
Fax 60935 0
+38732226576
Email 60935 0
[email protected]
Contact person for scientific queries
Name 60936 0
Emina Ejubovic
Address 60936 0
Cantonal Hospital Zenica
Crkvice 67, 72 000 Zenica,
Bosnia and Herzegovina
Country 60936 0
Bosnia and Herzegovina
Phone 60936 0
+38761824035
Fax 60936 0
+38732226576
Email 60936 0
[email protected]

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What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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