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PRORAILS

Predicting ovarian response in artificial insemination with low stimulation

Go to the PRORAILS website.

Objective
This large prospective multi-center cohort study aims to identify patientís characteristics that significantly influence ovarian response to mild stimulation with a fixed dose of 75 IU recombinant FSH.

Study design
A multi-center, open-label, prospective cohorts study.
Patients with a regular indication for COH/IUI (controlled ovarian stimulation/ intra uterine insemination) will be asked to participate. Patientís characteristics will be documented including age, weight, BMI, smoking status, cycle day 2 or 3 FSH /Estradiol levels, antral follicle count, and AMH. AMH and FSH/Estradiol will be determined centrally after completion of inclusion of all patients in the study. All patients will receive a fixed 75 IU recFSH per day stimulation protocol starting from cycle day 3, 4 or 5 after exclusion of ovarian cysts by ultrasound. Ovarian response will be documented by ultrasound only. Once the dominant follicle(s) reaches a mean diameter of 16-18 mm, hCG (5000IU or 250 mcg) will be applied and insemination will be scheduled 36-42 hours later. Cancellation criteria will be defined according to the national guidelines provided by the NVOG.

Study population
Subfertile couples presenting at fertility clinics with an indication for IUI in stimulated cycles: couples with unexplained or mild male subfertility and a spontaneous chance of conception below 30% (Hunault score). Unexplained subfertility including minimal to mild endometriosis (AFS grade 1 or 2) is defined as the failure to conceive after at least one year of unprotected intercourse whereas the standard fertility work-up was unable to detect any factors that might influence fertility negatively. Thus semen analysis should be normal according to the WHO guidelines, ovulation should be documented (by BBT charts, ovulation detection by ultrasound or normal luteal progesterone values), tubal patency should be confirmed (negative CAT or HSG, laparoscopy or fertiloscopy) and when a postcoital test was performed a cervical factor should have been excluded. Mild male subfertility is defined as abnormal semen parameters according to the WHO but an average total motile sperm account before processing of at least 10 million.

Exclusion criteria are:
- Hunault score > 30%
- Endometriosis AFS grade 3 or 4
- Contra-indications for the use of gonadotrophins (cysts larger than 2 cm, allergy for gonadotrophins)
- Total motile sperm count after sperm processing below 1 million
- Women aged younger than eighteen years or older than 45 years.
- Previous treatment with COH/IUI for treating current subfertility
- Unable to speak or read the Dutch language


Intervention
All patients will receive a fixed dose of 75 IU recFSH per day, stimulation protocol starting from cycle day 3, 4 or 5. Once the dominant follicle(s) reaches a mean diameter of 16-18 mm, hCG (5000IU or 250 mcg) will be applied and insemination will be scheduled 36-42 hours later.

Outcome measures
Primary endpoint:
- To assess the relationship between AMH serum levels and ovarian response (defined by the number of dominant follicles >15mm) in IUI cycles stimulated with a fixed dose of 75 IU recFSH. All follicles > 11 mm will be documented.
Secondary endpoints:
- To assess the relationship between age, weight, BMI, smoking, AFC, FSH/E2 on CD3 and ovarian response (defined by the number of dominant follicles >15mm) in IUI cycles stimulated with a fixed dose of 75 IU recFSH.
- Pregnancy rate per started cycle.
- Multiple pregnancy rate per started cycle.
- Miscarriage rate per started cycle.
- Cancellation rate per stimulated cycle.

Power/data analysis
Per protocol analysis showed us that we will need 510 couples to provide reliable answers to our questions. In the power analysis for the primary endpoint, ovarian response, a relatively low correlation between AMH levels and ovarian response of 0.15 was assumed, increasing the likelihood of having a large enough sample to assess other endpoints (such as pregnancy) in a robust way. The other values used were a false-positive chance of 5% (¶Ń = 0.05) and a power to detect a relationship of 80% (1-¶¬ = 0.80). Linear regression analysis with a single predictor was used for the sample size calculation. Resulting in a sample size of 459. Assuming a drop-out of 10% in this study with a very low burden for the patient, the final sample size for the primary end point would be 510 couples.

Time schedule

First subject in: 01.10.2012
Last subject in: 01.05.2017
Last subject last dose: 01.07.2017
Last subject last visit: 01.09.2017
Trial report date: 01.03.2018


Projectleaders

Isala klinieken, Zwolle Dr. B. Cohlen
AMC, Amsterdam Prof. Dr. J.P.W. van der Veen
UMCU, Utrecht Prof. Dr. F. J. Broekmans
OLVG, Amsterdam E.M. Kaaij
St Elizabeth Ziekenhuis, Tilburg Dr. J. Smeenk
VUMC, Amsterdam Dr. P. Hompes
Catharina Ziekenhuis, Eindhoven Dr. M. van Rumste


Subsidy
Merck Serono B.V.

Contact (researcher)
Drs A.G.H. Rutten
Isala Clinics Zwolle
Dr van Heesweg 2
PO Box 10400
8000 GK Zwolle
email: a.g.h.rutten@isala.nl