Women With Leiomyoma After at Least One Unsuccessful IVF Treatment Clinical Trial
Official title:
IVF Outcome Following Treatment With Ulipristal Acetate for Myomatous Uterus After at Least One IVF Failure
Hypothesis:
After reviewing the relevant medical data the investigators assume that treating a woman
with intramural fibroid not distorting the uterine cavity or mostly intramural with less
than 50% submucosal component with Ulipristal Acetate (UPA) for a 13 weeks course would
reduce the fibroid size and improve her chance for conceiving by IVF treatment.
Materials & Methods:
Study design: A proof of concept prospective not randomized study. The patients: About 20
women treated in the fertility and IVF unit after at least one IVF failure, with mostly
intramural (IM) fibroid [class 2-5 by FIGO (International Federation of Gynecology and
Obstetrics) classification system] in the size of >4 cm confirmed by Transvaginal ultrasound
(TVUS) and diagnostic hysteroscopy.
After US examination and diagnostic hysteroscopy to ascertain suitability for this study,
the investigators will offer a course of 13 weeks treatment with UPA 5 mg per day.
One month after cessation of treatment the investigators will perform another TVUS
examination & diagnostic hysteroscopy plus endometrial biopsy in order to assess the
endometrial & uterine status and will conduct an additional IVF cycle, using the same
stimulation protocol undertaken during the immediate cycle previous to the UPA treatment
course.
Ulipristal Acetate - Study design
Introduction:
Leiomyomas are well established factors to affect fertility. The key factor for fertility
disturbance is the fibroid location and not its size. The presence of submucosal fibroids
has long been known to reduce fertility as opposed to subserosal fibroids which do not alter
fertility. The effect of intramural fibroids on fertility is still a mystery.
These findings were best described in a meta-analysis of 23 studies:
- With no respect to location, women with fibroids have a lower chance for ongoing
pregnancy or live birth (RR 0.7, 95% CI 0.59-0.83) and a greater chance for spontaneous
abortion (RR 1.68, 95% CI 1.37-2.05).
- Women with fibroids that were submucosal or intramural with an intracavitary component
were less likely to become pregnant (RR 0.36, 95% CI 0.18-0.74) and more likely to have
a spontaneous abortion (RR 1.7, 95% CI 1.4-2.1).
- The picture is less clear for women with intramural fibroids. Overall, studies of women
with fibroids that did not distort the uterine cavity were less likely to become
pregnant (RR 0.81, 95% CI 0.70-0.94), less likely to have an ongoing pregnancy or to
deliver a live newborn (RR 0.7, 95% CI 0.58-0.85) and more likely to have a spontaneous
abortion (RR 1.7, 95% CI 1.2-2.5).
- In addition to these findings, women with cavity-distorting fibroids who undergone
myomectomy had a significant increase in conception rate (RR 2.03, 95% CI 1.08-3.83).
- There were no significant differences between women who had myomectomy for intramural
fibroids and those who did not go through surgical treatment, although the data for
this issue is quite lame.
Another strong evidence for the relevance of intramural fibroids for fertility can be found
in a meta-analysis that evaluated the association between non-cavity-distorting intramural
fibroids and IVF outcome, this study shows a significant decrease in the live birth (RR
0.79, 95% CI 0.70 -0.88) and clinical pregnancy rate (RR 0.85, 95% CI 0.77 - 0.94) in women
with non-cavity-distorting intramural fibroids compared with those without fibroids,
following IVF treatment.
Ulipristal:
Ulipristal acetate (UPA) is a selective progesterone receptor modulator (SPRM) prescribed
for women with symptomatic leiomyomas. Few phase 3 studies were conducted in order to prove
its clinical use and efficacy in treating women suffering from fibroids.
- PEARL (PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomas)
I was a randomized, double-blind, placebo controlled trial (48 patients in the placebo
arm, 95 treated with daily dosage of 5 mg & 94 with 10 mg of UPA) proving that
treatment with UPA 5 mg or 10 mg once daily for a 13 weeks course is efficient in
controlling uterine bleeding (91% & 92% respectively) in comparison to placebo (19%),
P<0.001 for each dose. The rates of amenorrhea were 73%, 82% and 6% respectively. The
median change in total fibroid volume was -22%, -12% & +3% (p=0.002 for the 5 mg group
& 0.006 for the 10 mg group in comparison to the placebo group).
- PEARL II was a double blind non-inferiority trial comparing UPA (5 mg or 10 mg once
daily) treatment for 3 months to once-monthly IM Leuprolide acetate 3.75 mg (97
patients in the 5 mg arm, 103 in the 10 mg arm & 101 treated by Leuprolide acetate).
The rates of uterine bleeding were comparable between the three groups - 90%, 98%, 89%.
Median times to amenorrhea were 7 days, 5 days, 21 days - respectively. Adverse effects
in the matter of moderate to severe hot flashes were much more common for women treated
with Leuprolide acetate - 40% in comparison to those treated with UPA (11% for the 5 mg
group & 10% for the 10 mg group, p<0.001 for both groups).
In November 2014 Luyckx et al. published a retrospective analysis of a series of 52 patients
from one medical center (participants in PEARL II or PEARL III) - of these patients, 21
wished to conceive upon treatment completion - 15 of them (71%) succeeded for a total of 18
pregnancies.
- Median time to conceive was 10 months after completion of therapy.
- Two women who did not need myomectomy after completion of the UPA treatment achieved 3
of the pregnancies.
- 15 pregnancies were after myomectomy (8 by laparoscopy, 7 by laparotomy).
- 6 of the pregnancies (6 of 18, 33%) resulted in early missed abortion while 12 of the
pregnancies ended in the live births of 13 babies. The relative high ratio of
miscarriage can be related to the age of the women (median 36.4 years) and to high
proportion of IVF (3/6 miscarriages).
- Only one of the deliveries was a vaginal delivery, 7 had elective cesarean delivery and
4 had emergent cesarean section.
- There was no significant fibroid regrowth during pregnancy.
- There was only one fetal anomaly in this cohort - in a patient who was treated by a new
UPA course while she was already pregnant (unexpectedly) - a fetus showing ectopic
right kidney on the inferior pole of the left kidney. A review of pregnancies after
exposure to mifepristone to induce abortion or UPA given as emergency contraception
shows no additional risk for congenital anomalies.
Selective progesterone receptor modulators as UPA are well known to induce endometrial
modification known as PAEC (Progesterone receptor modulators Associated Endometrial Changes)
- these changes are benign, non-proliferative & non-physiological. This histological pattern
is apparent in a large proportion of women after 13 weeks UPA treatment course (in PEARL I -
74.2% of the patients in the 5 mg group & 70.4% in the 10 mg group; in PEARL II 65.1% in the
5 mg group & 69.8% among the treated with 10 mg UPA). Endometrial biopsies taken six months
after treatment cessation showed return to normal histological endometrial appearance. In
both RCT's all endometrial biopsy examinations taken after week 13 showed only benign
changes except: (a) one patient after 5 mg UPA treatment whose specimen showed simple
hyperplasia and (b) one patient in the placebo group with complex atypical hyperplasia.
Hypothesis:
After reviewing the relevant medical data the investigators assume that treating a woman
with intramural fibroid not distorting the uterine cavity or mostly intramural with less
than 50% submucosal component with UPA for a 13 weeks course would reduce the fibroid size
and improve her chance for conceiving by IVF treatment.
Materials & Methods:
Study design: A proof of concept prospective not randomized study. The patients: About 20
women treated in our fertility and IVF unit after at least one IVF failure, with mostly
intramural fibroid [class 2-5 by FIGO classification system] in the size of >4 cm confirmed
by TVUS and diagnostic hysteroscopy.
After US examination and diagnostic hysteroscopy to ascertain suitability for our study, we
will offer a course of 13 weeks treatment with UPA 5 mg per day.
One month after cessation of treatment the investigators will perform another TVUS
examination & diagnostic hysteroscopy plus endometrial biopsy in order to assess the
endometrial & uterine status and will conduct an additional IVF cycle, using the same
stimulation protocol undertaken during the immediate cycle previous to the UPA treatment
course.
The data:
Demographic data - Age, BMI. Obstetrical data - Gravida, para. Gynecological data - Hormonal
profile, uterus size, fibroids features (location, size), infertility features (duration,
cause), past stimulation and IVF treatment variables.
;
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment