Endometriosis Clinical Trial
Official title:
Effect of Granulocyte Colony-stimulating Factor on Clinical Pregnancy Rate in Patients With Endometriosis Undergoing In-vitro Fertilization After Recurrent Implantation Failure
The aim of this study is to evaluate the effect of granulocyte colony-stimulating factor on clinical pregnancy rate in patients with endometriosis undergoing in-vitro fertilization after recurrent implantation failure.
- Type of Study: A randomized double-blind controlled trial.
- Study Setting: IVF unit in Maternity Hospital of Ain Shams University.
- Study Population: A total of 88 women with endometriosis will be enrolled in the study
divided into two groups:
- Group A (N=44): women will receive intrauterine infusion of G-CSF on the day of
ovum-pick up during IVF cycle.
- Group B (N=44): women will receive placebo intrauterine infusion of saline on the
day of ovum-pick up during IVF cycle.
- Allocation and Concealment: Eighty eight envelopes will be numbered serially and in each
envelope the corresponding letter which denotes the allocated group will be put
according to randomization table. When the first patient arrives, the first envelope
will be opened and the patient will be allocated according to the letter inside
- Randomization Table:
SN Group SN Group SN Group SN Group SN Group SN Group SN Group SN Group
1. A 12 A 23 B 34 B 45 A 56 A 67 B 78 B
2. B 13 A 24 A 35 B 46 A 57 A 68 B 79 A
3. B 14 A 25 B 36 A 47 B 58 B 69 B 80 A
4. B 15 A 26 A 37 A 48 B 59 B 70 A 81 B
5. A 16 A 27 B 38 B 49 B 60 B 71 B 82 A
6. A 17 A 28 A 39 B 50 B 61 A 72 B 83 B
7. A 18 B 29 B 40 B 51 A 62 B 73 A 84 B
8. B 19 B 30 A 41 A 52 A 63 A 74 B 85 B
9. A 20 A 31 A 42 B 53 A 64 B 75 A 86 B
10. A 21 B 32 A 43 A 54 B 65 B 76 B 87 A
11. A 22 B 33 B 44 A 55 A 66 B 77 A 88 A
- Sample Size: 88 patients, 44 in group A (the cases) and 44 in group B (the
controls).
- Sample Justification:
The required sample size was calculated using the G*Power Software (Universitӓt Düsseldorf,
Germany).
The primary outcome measure is the clinical pregnancy rate. Currently, there is no adequate
information regarding the effect of granulocyte colony-stimulating factor on clinical
pregnancy rate in patients with endometriosis undergoing in-vitro fertilization; therefore,
the present exploratory study would target an effect size that could be clinically relevant.
So, it is estimated that the inclusion of 44 patients in each of the 2 study groups (total,
88 patients) would achieve a power of 80% (type II error, 0.2) to detect a statistically
significant difference between the 2 groups as regards the clinical pregnancy rate for a
medium effect size corresponding to a w coefficient of 0.3 using a two-sided chi-squared test
with 1 degree of freedom and the targeted test confidence set at a level of 95% (type I
error. 0.05). The effect size (w) is calculated as follows:
w = , where is the chi-squared statistic and N is the total sample size (Chow et al., 2003).
The targeted effect size of w = 0.3 has been selected as it could be regarded as a clinically
relevant difference to seek in this exploratory study.
- Ethical Considerations: A written informed consent will be obtained from all
participants prior to screening and enrollment. Participants will participate
voluntarily in the research and their confidentiality will be respected. Benefits from
participation in the research will be explained to all participants. Participation in
the research will cause no harm to participants after approval of research ethical
committee.
- Study Procedures:
All participants will be subjected to the following:
A) Detailed medical history including:
- Personal history
- Menstrual history
- Past and obstetric history
B) Physical examination:
After history taking and fulfillment of both inclusion and exclusion criteria, clinical
examination will be done including: general abdominal and pelvic examination.
C) Laboratory investigations:
Routine investigations including: fasting and postprandial blood sugar and complete blood
count.
D) Induction of ovulation:
- On day 3 of spontaneous cycles, all patients will have basal hormonal profile (FSH, LH,
E2, TSH and prolactin).
- Transvaginal (TV) ultrasound (U/S) on day 3 of non-stimulated cycles will be done by
transvaginal probe of 5-9 MHZ. Any patient found to have uterine abnormalities will be
excluded.
- Ovarian hyper stimulation protocol will be held according to a long GnRH agonist
protocol starting from midluteal phase by daily subcutaneous injection of triptoreline
acetate (Decapeptyl 0.05 mg, Ferring Pharmaceutical, Kid, Germany). Then on day 3 of
next cycle ovarian hyper stimulation will be started by daily injection of HMG (Menogon
75 lU/amp "Ferring Pharmceutical, Kid, Germany "or Merional 75 IU/amp" IBSA,
Switzerland"). The starting dose of gonadotropines will be prescribed according to the
age and body weight of the subjects, then the dose will be adjusted according to the
ovarian response that will be assessed by transvaginal folliculometry which will be done
on cycle day six.
- According to the ovarian response, every other day TV U/S will be performed and at the
moment when the leading follicle reaches 16mm, daily TV U/S will be performed till the
largest follicle reach a diameter of >18mm. The maximum duration of HMG will not be
allowed to exceed day 16.
- HCG (Choriomon 10,000 lU/amp. "IBSA, Switzerland") will be administered for triggering
ovulation.
E) Sonography:
Transvaginal sonography will be performed in the day of HCG administration to measure
endometrial thickness and pattern.
The endometrium pattern will be classified as:
- Proliferative when echogenicity is hypo echoic in relation to the myometrium.
- Peri-ovulatory when it is trilaminar.
- Secretory when it is hyperechoic.
F) Ovum pick up:
- 36 hours after HCG injection, the transducer will be connected to the ultrasound system.
The direction of the guide beam will be checked. The puncturing needle will be connected
to an aspiration apparatus attached by a fixation ring to the front and rear ends of the
vaginal transducer, thereby defining the direction of puncture corresponding to the
guide beam on the ultrasound image.
- The aspiration will be checked using test tubes. The uterus, both ovaries and iliac
vessels will be identified by the visualization in both planes. The distance between the
upper pole of the vagina and the ovary will be closely evaluated (care will be taken to
avoid intestinal or vascular interposition).
- Depth localization of the closest accessible follicle (distance from the upper vaginal
pole to the center of the follicle) will be done. Needle will be pushed forcefully to
the center of the follicle (Aspiration pressure 90-100mmHg).
G) IVF- ICSI:
- Intracytoplasmic sperm injection will be performed on metaphase II oocytes using the direct
penetration technique, fertilization results will be assessed 16 to 19 hours after ICSI.
Fertilization will be considered normal by the presence of two pronuclei. Oocyte degeneration
will be identified by collapse of cytoplasmic contents and separation from the zona. Failed
fertilization will be defined by the absence of the pronuclei.
H) Embryo transfer:
- Embryo transfer will be done on day 5 using cook catheter under ultrasound guide at a
distance about 1-1.5 cm from the fundus by the same gynecologist.
- Number of embryos transferred 2-3 embryos.
I) Finally:
A serum βhCG will be performed 12 days after embryo transfer and repeated after 48h. followed
by US 6 weeks after embryo transfer.
- Study Interventions: In G-CSF group at the day of oocyte retrieval, after oocytes
collection, 30 mU (300 mcg/0.5 ml) of G-CSF (NeupogenTM, Filgastrim, Amgen Inc.,
Thousand Oaks, CA, USA) was administered by slow transcervical intrauterine infusion
with IUI catheter (AINSEGREY, RIMOS, Italy). In controls, normal saline was used for
intrauterine infusion instead of G-CSF.
- Statistical Analysis: Data will be analyzed using IBM© SPSS© Statistics version 22 (IBM©
Corp., Armonk, NY). Normally distributed numerical data will be presented as mean and
SD, and skewed data as median and interquartile range. Qualitative data will be number
and percentage. Comparison of normally distributed numerical data will be done using the
unpaired t test. Skewed data will be compared using the Mann-whitney test. Categorical
data will be compared using the Pearson chi-squared test or fisher's exact test, if
appropriate. A two-sided p-value ˂0.05 will be considered statistically significant.
;
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