Reprod Med Biol (2015) 14:185–193
DOI 10.1007/s12522-015-0211-y

ORIGINAL ARTICLE

A multi-center, randomized, open-label, parallel group studyof a natural micronized progesterone vaginal tablet as a luteal
support agent in Japanese women undergoing assisted
reproductive technology
Toshihiro Fujiwara1

Received: 16 February 2015 / Accepted: 20 May 2015 / Published online: 14 June 2015
Ó The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract
Purpose To verify sufficient progesterone supplementation during the luteal phase and to determine the efficacy
and safety of a natural micronized progesterone vaginal
tablet (FE 999913) in Japanese women undergoing in vitro
fertilization-embryo transfer or intracytoplasmic sperm
injection.
Methods In a multi-center, randomized, open-label, parallel group trial, 108 subjects were randomized to receive
FE 999913 vaginally twice daily (n = 54) or three times
daily (n = 54) for up to 10 weeks. Primary endpoints were
the proportion of subjects with serum progesterone concentration C10 ng/ml on day 5 and ongoing pregnancy rate
at week 5.
Results Ninety-four subjects completed the trial and 90
subjects underwent embryo transfer. The proportion ofsubjects with serum progesterone concentration C10 ng/ml
on day 5 was 98.9 % and the lower limit of 95 % CI of thedifference between the current trial and MEGASET trial
was -3.6 %, which was within the non-inferiority criterion. The ongoing pregnancy rate was 22.2 %, which issimilar to that in actual clinical settings in Japan. No safetyconcerns were observed.
Conclusions FE 999913 was useful in this trial from the
aspects of sufficient supplementation of progesterone,comparable pregnancy rate with that in clinical practice inJapan, and safety.

& Toshihiro Fujiwara
fujiwat@iuhw.ac.jp
1

Center for Human Reproduction and Gynecologic
Endoscopy, Sanno Hospital, International University of
Health and Welfare, 8-10-16 Akasaka, Minato-ku,
Tokyo 107-0052, Japan

Clinical trial registration
NCT01710514.

ClinicalTrials.gov identifier:

Keywords Assisted reproductive technology (ART)  FE
999913  Luteal support  Pregnancy rate  Vaginal insert

Introduction
Luteal support in assisted reproductive technology (ART)is important to maintain implantation after embryo transfer
and to improve pregnancy rates. Luteal phase deficiency(luteal dysfunction) may result from controlled ovarian
stimulation (COS) by hormonal management using gonadotropin-releasing hormone (GnRH) agonists or GnRH
antagonists in ART [1–3]. Therefore, hormone replacementwith exogenous progesterone or activation of the corpus
luteum by administration of human chorionic gonadotropin(hCG) is necessary for implantation after embryo transfer
and maintenance of pregnancy. Luteal activation or luteal
support with hCG improves pregnancy rates [4, 5], but may
result in the onset of ovarian hyperstimulation syndrome(OHSS) [6–9] and should therefore not be used by patientswith a high risk of OHSS. Exogenous progesterone, on theother hand, does not cause OHSS [10]. Administration ofexogenous progesterone is considered to be a useful
method of luteal support therapy in ART treatment in Japanand worldwide.
Approved progesterone preparations in Japan are limited
to injectable solutions and oral synthetic preparations
indicated for the treatment of amenorrhea, dysmenorrhea,
menometrorrhagia, infertility due to luteal phase defect,
threatened abortion/premature labor, and habitual abortion.
There are no approved vaginal progesterone preparations,nor approved progesterone preparations with the indication

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of luteal support in ART. Therefore, progesterone is used
off-label in Japan, mainly as progesterone intramuscular(IM) injections or oral synthetic progesterone preparations.
Treatment with IM progesterone injections involves dailyadministration, which imposes a temporal and physicalburden on patients. Daily injections are associated with arisk of injection site pain, nerve injury, and muscle contracture. The extent of the use of oral synthetic progesterone preparations in luteal support is unknown and forsome of these preparations there are concerns regarding
possible effects on the fetus [1]. Oral synthetic progesterone preparations are rarely used worldwide [11].
Foreign progesterone vaginal preparations are being
unofficially imported or dispensed by the in-house pharmacies at some medical institutions [12]. However, there
are concerns regarding not only the quality of these
preparations but also the development of adverse drug
reactions and compensation and relief if such reactions
develop. In the European Union and the US, vaginal progesterone preparations are used as a standard therapy forluteal support in infertility treatment [11, 12]. In Japan,
however, there is an unmet medical need for progesterone
supplementation during ART. Therefore, the Japan Societyof Fertilization and Implantation and the non-profit organization Fertility Information Network (Fine) filed arequest for ‘‘addition of a vaginal dosage form for luteal
supplementation during in vitro fertilization and embryotransfer (IVF-ET)’’ to the Ministry of Health, Labor, andWelfare, which subsequently recruited a corporation todevelop the requested vaginal preparation.
FE 999913 is a natural micronized progesterone effervescent vaginal tablet that contains 100 mg of progesterone
per tablet as its active ingredient. It can be reliably
administered by insertion vaginally using a dedicatedapplicator. As of October 2014, the FE 999913 vaginal
tablet has been approved in 37 countries and territories
worldwide including Japan, the US, and the UK, and isindicated for luteal support as part of an ART treatment
program for infertile women.
The present investigation is a phase III clinical trial
conducted to confirm the efficacy and safety of FE 999913
in an actual clinical setting in Japan.

Materials and methods
This trial was a multi-center, randomized, open-label,parallel group phase III trial performed in 108 Japanesewomen of reproductive age undergoing IVF-ET or intracytoplasmic sperm injection (ICSI).
The trial was designed to verify sufficient supplementation of progesterone during vaginal administration of123

Reprod Med Biol (2015) 14:185–193

100 mg FE 999913 (LUTINUS; Ferring Pharmaceuticals)
twice daily (BID) or three times daily (TID) and to determine the efficacy and safety of FE 999913.
The trial was conducted at six sites in Japan from
October 2012 to August 2013 and was conducted inaccordance with the Declaration of Helsinki and its
amendments in force at the initiation of the trial, incompliance with the approved protocol, international
conference on harmonization—good clinical practice,Japanese good clinical practice and applicable regulatory requirements. The trial was approved by an institutional review board at each site before the initiationof the trial.

Trial population
Enrolled trial subjects were Japanese women of reproductive age who met the following inclusion criteria; (1) earlyfollicular phase (day 2–4) follicle stimulating hormone
concentration B12 IU/l and estradiol concentration \100
pg/ml; (2) luteinizing hormone, prolactin, and thyroidstimulating hormone within the normal limits for theclinical laboratory, or considered not clinically significant
by the investigator within 6 months prior to screening; (3)a documented history of infertility [e.g., unable to conceive
for at least 1 year (or for 6 months for women C38 yearsof age) or bilateral tubal occlusion or absence]; (4)transvaginal ultrasound (TVU) at screening (or within
14 days prior to screening) consistent with findings adequate for ART with respect to uterus and adnexa (peripheral reproductive organs); (5) at least one cycle with nofertility medication prior to screening; (6) hysterosalpingography, hysteroscopy, sonohysterogram, or TVU documenting a normal uterine cavity; (7) consent tocontraception during the cycle in which pituitary down
regulation was performed (prior to start of COS); and (8)signed informed consent to fertility treatment using
FE 999913 after the subject and her husband had thoroughly understood the content.
Main exclusion criteria were the following: donor
oocyte or embryo recipients; women with a body massindex (BMI) of[34 kg/m2; women with a poor response togonadotropins; women with current or recent (within thepast 12 months) substance abuse; women currently breast
feeding, pregnant, or with a contraindication to pregnancy;
women who refused to or were unable to comply with thetrial procedures/conditions in the protocol; women who
had participated in any experimental drug trial within
60 days prior to screening; women with a history of C3
spontaneous miscarriages and women with severe hepatic
dysfunction or hepatic disease.

Reprod Med Biol (2015) 14:185–193

Treatment regimen
COS was performed using the long GnRH agonist protocol
or GnRH antagonist protocol according to the proceduresof the trial site. Subjects meeting all eligibility criteria at
screening were randomized to either the BID group or the
TID group on the day of oocyte retrieval and administration of FE 999913 was initiated on the day following
oocyte retrieval. Embryo transfer was performed on day 3
or day 5 after oocyte retrieval in accordance with thestandard procedures of the trial site. Treatment with
FE 999913 continued for up to 10 weeks if pregnancy wasconfirmed. A serum b-hCG pregnancy test was performed
at week 2 of treatment, and subjects were assessed forclinical pregnancy at week 4 of treatment and for ongoing
pregnancy at week 5 of treatment.
Trial endpoints
The primary endpoints were: (1) the proportion of subjects
with serum progesterone concentration C10 ng/ml on day 5of treatment and (2) the ongoing pregnancy rate (confirmation of fetal heart movements on TVU at week 5 oftreatment). Only a subset of the randomized subjects hadembryos available for transfer. The availability of embryos
for transfer was not related to FE 999913. Therefore theevaluation of the ongoing pregnancy rate was based on thesubjects who underwent embryo transfer. Secondary endpoints included the positive b-hCG rate at week 2 oftreatment, the clinical pregnancy rate (defined as presenceof a gestational sac on TVU at week 4 of treatment) and theserum progesterone concentration throughout the treatment.
The safety of FE 999913 was evaluated by frequency
and severity of adverse events, clinical laboratory tests(biochemistry, hematology, and urinalysis), 12-lead electrocardiogram, physical examinations and gynecologicalexaminations.

Sample size and statistical analysis
This trial was powered with respect to the first co-primary
endpoint, the proportion of subjects with serum progesterone
concentration C10 ng/ml on day 5 of treatment. The target
was to demonstrate non-inferiority against a historical control (the overseas MEGASET trial [13]), in which 631/632(99.8 %) women had a progesterone concentration C10 ng/
ml on day 5 of progesterone administration. The non-inferiority limit was set to -10.0 % (absolute). Assuming thatthe probability of having a progesterone concentration
C10 ng/ml is 98.5 % and using a non-inferiority margin of-10.0 % (absolute), a total sample size of 80 subjects yielded more than 80 % power for establishing non-inferiority

187

using a two-sided 95 % confidence interval (CI, corresponding to using a one-sided alpha of 2.5 %).
The efficacy was analyzed using the full analysis set(FAS). For quantitative variables, the number of subjects,
mean ± standard deviation (SD), and maximum and minimum are shown. For qualitative variables, the number ofsubjects and proportion of subjects in each category are
shown. The first co-primary endpoint was verified bycomparing the proportion of subjects with serum progesterone concentration C10 ng/ml on day 5 of treatment
observed in this trial to the proportion observed in the
MEGASET trial [13] using a non-inferiority argument
based on the two-sided 95 % CI. For the second co-primary
endpoint, the ongoing pregnancy rates at week 5 of treatment in the subjects with embryo transfer were calculated
for each treatment group, along with two-sided 95 % CIs.
The positive b-hCG rate and clinical pregnancy rate wereanalyzed in the same manner as the ongoing pregnancy
rate. The intention-to-treat (ITT) population was includedin the safety analysis. Safety parameters are summarizedusing descriptive statistics.

Results
Subject disposition
A total of 145 subjects were screened to participate in thetrial, 37 subjects of whom were screening failures. The
most common reason for screening failure was that inclusion/exclusion criteria were not met. Thus, 108 eligible
subjects were randomized to receive FE 999913.
A total of 94 subjects (87.0 %) completed the trial and
14 subjects (13.0 %) discontinued the trial. The mostcommon reason for discontinuation was an adverse event,with six subjects (11.1 %) in the BID group and sevensubjects (13.0 %) in the TID group. One subject in the BID
group discontinued due to withdrawn consent.
The ITT population included all 108 randomized subjects (54 in the BID group and 54 in the TID group). The
FAS, defined as all randomized and exposed subjects withat least one completed primary efficacy assessment after
treatment initiation, included 94 subjects (46 in the BID
group and 48 in the TID group). The FAS with embryotransfer population included 90 subjects (43 in the BID
group and 47 in the TID group).
Baseline characteristics
In the FAS with embryo transfer population, subjects wereJapanese women with a mean age of 34.7 years (range,
26–42 years), and the mean BMI was 21.3 kg/m2 (range,
16.0–28.0 kg/m2). The mean duration of infertility was

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42.8 months (range, 9–137 months), and the most common
cause of infertility was male factor (32 subjects, 35.6 %).
The mean number of embryos transferred was 1.1. A totalof 81 subjects (90.0 %) received one embryo and 83 subjects (92.2 %) underwent embryo transfer on day 3 after
oocyte retrieval. Forty subjects underwent IVF-ET and 50
subjects underwent ICSI. No differences were seen
between treatment groups in terms of baseline characteristics (Table 1).
In the FAS, the mean duration of treatment(mean ± SD) was 27 ± 21 days, with a range of
3–72 days.
Table 1 Baselinecharacteristics—FAS withembryo transfer

Serum progesterone concentration
The proportion of subjects in the FAS with a serum progesterone concentration C10 ng/ml on day 5 of treatment was
98.9 % (95 % CI 94.2; 100.0, 93/94 subjects) (Table 2). In the
MEGASET trial [13] this proportion was 99.8 % (95 % CI
99.1; 100.0, 631/632 subjects). The lower limit of the 95 % CIof the difference between the proportion of subjects withserum progesterone concentration C10 ng/ml on day 5 oftreatment in the current trial and the MEGASET trial was-3.6 %, which exceeded the non-inferiority criterion-10.0 % and therefore this primary objective was met.

Demographic data

FE 999913 BID

FE 999913 TID

Total

FAS with embryo transfer (N)

43

47

90

Mean ± SD

35 ± 3.5

34.5 ± 4.3

34.7 ± 3.9

Range

26–42

26–41

26–42

\35 years

16 (37.2 %)21 (44.7 %)37 (41.1 %)35–37 years

16 (37.2 %)

14 (29.8 %)

30 (33.3 %)38–40 years
41–42 years

10 (23.3 %)
1 (2.3 %)

7 (14.9 %)
5 (10.6 %)

17 (18.9 %)6 (6.7 %)Age (years)

Age group N (%)

BMI (kg/m2)
Mean ± SD

21.2 ± 2.8

21.3 ± 2.9

21.3 ± 2.9

Range

16–27.9

17.2–28

16–28

Mean ± SD

42.1 ± 27.4

43.3 ± 23.1

42.8 ± 25.1

Range

9–137

13–101

9–137

Unexplained

11 (25.6 %)

12 (25.5 %)

23 (25.6 %)Tubal factor

16 (37.2 %)

14 (29.8 %)

30 (33.3 %)Duration of infertility (months)

Primary cause for infertility N (%)

Male factor (mild)

2 (4.7 %)

6 (12.8 %)

8 (8.9 %)Male factor (moderate)

8 (18.6 %)

5 (10.6 %)

13 (14.4 %)Male factor (severe)

2 (4.7 %)

9 (19.1 %)

11 (12.2 %)WHO Group I anovulatory infertility

2 (4.7 %)WHO Group II anovulatory infertility
Other

1 (2.3 %)
1 (2.3 %)

2 (2.2 %)
1 (2.1 %)

1 (1.1 %)
2 (2.2 %)Day of transfer N (%)
Day 3 embryo transfer

38 (88.4 %)

45 (95.7 %)83 (92.2 %)Day 5 embryo transfer

5 (11.6 %)2 (4.3 %)

7 (7.8 %)1 embryo

39 (90.7 %)42 (89.4 %)81 (90.0 %)2 embryos

4 (9.3 %)

5 (10.6 %)

9 (10.0 %)Embryos transferred (mean ± SD)

1.09 ± 0.294

1.11 ± 0.312

1.1 ± 0.302

IVF

19 (44.2 %)21 (44.7 %)40 (44.4 %)ICSI

24 (55.8 %)

26 (55.3 %)

50 (55.6 %)Subjects with embryo transferred N (%)

Method of insemination N (%)

FAS full analysis set, BID bis in die/twice daily, TID ter in die/three times daily, SD standard deviation,
BMI body mass index, WHO World Health Organization, IVF in vitro fertilization, ICSI intracytoplasmic
sperm injection

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189

Table 2 Proportion of subjects with serum progesterone concentration C10 ng/ml on day 5 of treatment-FAS
FE 999913 (BID/TID)a

MEGASET trial progesterone preparationb

Differencec

Nd

Ne

Estimate (%)

95 % CIf

Nd

Ne

Estimate (%)

95 % CIf

Estimate (%)

95 % CIg

94

93

98.9

94.2; 100.0

632

631

99.8

99.1; 100.0-0.9-3.6;1.8

FAS full analysis set, BID bis in die/twice daily, TID ter in die/three times dailyabcData from the BID group and TID group were pooled
Historical control
Difference = the current trial - the MEGASET trialdTotal number of subjectseNumber of subjects with serum progesterone concentration C10 ng/ml on day 5 of treatmentf

95 % CI was calculated based on the exact Clopper–Pearson methodg

95 % CI was calculated based on asymptotic normal distribution with a continuity correction(ng/mL)
140

Serum progesterone concentration

Fig. 1 Serum progesterone
concentration profile(mean ± SD) in subjects who
were confirmed to be ongoing
pregnant at week 5. This figure
shows the mean serum
progesterone concentration
between day 5 and the end oftrial in the 20 subjects in whom
ongoing pregnancy wasconfirmed at week 5. In both
treatment groups (100 mg BID:
bis in die/twice daily, 100 mg
TID: ter in die/three times
daily), mean serum
progesterone concentration
sustained over 10 ng/ml
throughout the treatment and nomarked change was seen

100mg BID
100mg TID
Total

120

Mean± SD

100
80
60
40
20

10ng/mL

0100mg BID (n)100mg TID (n)Total (n)Baseline
6
14
20

The mean serum progesterone concentrations in the 20
subjects in whom ongoing pregnancy was confirmed at
week 5 of treatment were 78.2 (day 5), 55.9 (week 2), 64.2
(week 4), 57.1 (week 5), 49.8 (week 8), and 48.4 ng/ml(end of trial). The mean serum progesterone concentrations
sustained at the Japanese standard level during mid-luteal
phase (C10 ng/ml) throughout the 10 weeks, and nomarked changes were seen (Fig. 1).
Pregnancy rates
In the FAS with embryo transfer population, the second coprimary endpoint, the ongoing pregnancy rate at week 5 oftreatment was 22.2 % (95 % CI 14.1; 32.2, 20/90 subjects)(Table 3). The clinical pregnancy rate was the same as theongoing pregnancy rate; however, one pregnancy loss
occurred in the BID group between week 2 and week 4.
Stratified analysis of the ongoing pregnancy rate in the
FAS with embryo transfer was conducted using subgroups

Day 5
6
14
20

Week 26
14
20

Week 46
14
20

Week 56
14
20

Week 851217End of Trial
6
1420

based on the day of embryo transfer, the number ofembryos transferred, the primary cause for infertility, BMI,
age, protocol type, and method of insemination.
There was no difference (p = 1.000, Fisher’s exact test)in the ongoing pregnancy rate between the BID and TID
groups in subjects younger than 35 years of age; 18.8 % (3/
16 subjects) in the BID group and 14.3 % (3/21 subjects) in
the TID group, while the ongoing pregnancy rate in the
TID group was significantly higher in subjects 35 years ormore; 11.1 % (3/27 subjects) in the BID group and 42.3 %(11/26 subjects) in the TID group (p = 0.014, Fisher’s
exact test) (Table 4).
No distinct trends were observed in the ongoing pregnancy rates of the other subgroups.
SafetyThe overall incidence of adverse events was 35.2 % (38subjects, 51 events) in the 108 subjects in the safety

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Table 3 Ongoing pregnancy rates—FAS with embryo transferabN

Estimate (%)

95 % CI

BID

43

6

14.0

5.3; 27.9

TID

47

14

29.8

17.3; 44.9

Total

90

20

22.2

14.1; 32.2

Treatment group
N
Ongoing pregnancy ratec

The profile of adverse events that were seen relatively
frequently was similar between the BID group and the TID
group.
Also, there were no clinically significant trends either
within or between treatment groups with respect to clinicallaboratory tests, vital signs, ECG, physical examination,and gynecological examination.

FAS full analysis set, BID bis in die/twice daily, TID ter in die/threetimes dailyaTotal number of subjectsbNumber of subjects with confirmed ongoing pregnancy

Discussionc

95 % CI was calculated based on the exact Clopper–Pearson
methodThe current trial was the first randomized trial evaluating
the efficacy and safety of vaginal administration of progesterone in Japanese women undergoing IVF-ET or ICSI.

Table 4 Ongoing pregnancy rates by age—FAS with embryotransfer

Serum progesterone level with FE 999913

Treatment group

Na

Nb

Estimate (%)

p valuec

1.000

Ongoing pregnancy rate
\35 years
BID

16

3

18.8

TID

21

3

14.3

C35 years
BID

27

3

11.1

TID

26

11

42.3

0.014

FAS full analysis set, BID bis in die/twice daily, TID ter in die/threetimes dailyaTotal number of subjectsbNumber of subjects with confirmed ongoing pregnancyc

P value was calculated based on Fisher’s exact test

population. The incidence of serious adverse events (SAE)
was 0.9 % (one subject, one event), and the incidence ofadverse events that led to discontinuation was 8.3 % (ninesubjects, nine events). The incidence of adverse events forwhich a causal relationship to FE 999913 could not be
ruled out was 8.3 % (nine subjects, 12 events).
The most common adverse event in the safety population was OHSS at an incidence of 20.4 % (22 subjects). No
cases of OHSS were judged to be severe in intensity, andthe majority of cases were mild. A relationship to
FE 999913 was ruled out for all cases of OHSS that
occurred. Other common adverse events were abdominal
distension (3.7 %, four subjects) and vaginal bleeding(3.7 %, four subjects).
One adverse event led to hospitalization (subchorionichemorrhage), but was judged as not related to FE 999913
by the investigator.
The most common adverse events for which relationshipto FE 999913 could not be ruled out were headache,somnolence, vaginal bleeding (1.9 %, two subjects each).

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This trial demonstrated that the administration of
FE 999913 100 mg BID or TID could maintain serum
progesterone concentrations at C10 ng/ml, which is thelower reference level of the mid-luteal phase criterion in
Japanese women. FE 999913 also maintained a high serum
progesterone concentration (mean values *50 ng/ml)
throughout the treatment period in subjects who became
pregnant.
The proportion of subjects with a serum progesterone
concentration of C10 ng/ml on day 5 of treatment wascompared with the results from an overseas clinical trial(MEGASET trial [13]). The proportion of subjects withserum progesterone concentration C10 mg/ml on day 5 oftreatment in the current trial fulfilled the non-inferiority
criterion relative to the results of the MEGASET trial.
Furthermore, the daily dosage of progesterone used in thecurrent trial was 200 or 300 mg. Nonetheless, non-inferiority to the vaginal high-dose (600 mg) progesterone capsule that was used in the MEGASET trial(UTROGESTAN: not approved in Japan) was verified.
Pregnancy rate of FE 999913
The ongoing pregnancy rate per embryo transfer at week 5of treatment in this trial was 22.2 % (20/90 subjects; BID
group: 14.0 %, TID group: 29.8 %). This pregnancy rate iscomparable to the pregnancy rates in Japanese clinical
trials of the already approved ART drugs FOLLISTIM
injection and GANIREST subcutaneous injection (22.9 %;35/153 subjects and 25.6 %; 20/78 subjects, respectively)[14, 15].
The clinical pregnancy rate at week 4 of treatment(22.2 %, 20/90 subjects) was comparable to the pregnancy
rates listed in the ‘‘Report of the Registration and Survey
Subcommittee of the 2012 Ethics Committee’’ of the Japan
Society of Obstetrics and Gynecology (20.8 %; IVF-ET:

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22.6 %, ICSI—ejaculation sperm: 19.0 %, ICSI—testicular sperm extraction sperm: 15.3 %) [16].
Although the objective of this trial was not to compareand determine the efficacy of the two dose regimens, anumeric difference in the ongoing pregnancy rates wasobserved between the BID group (14.0 %, 6/43 subjects)
and the TID group (29.8 %, 14/47 subjects). There were nodifferences in demographic variables between the twotreatment groups. The ongoing pregnancy rate varied from10 to 57 % depending on the site, and some sites had
pregnant subjects only in the BID group or the TID group.
Thus, it appears that there was no essential difference in the
pregnancy rate between the BID and the TID groups, andthe numeric difference between two groups was incidental.
In addition, the ongoing pregnancy rate in subjects
35 years or more (42.3 %, 11/26 subjects) was higher thanthat in subjects younger than 35 years (14.3 %, 3/21 subjects) in the TID group. This numeric difference between
two strata was also considered as incidental. Thus, therelatively small number of subjects in the current trial
precludes drawing conclusions with regard to this observation. Further investigations are required to accumulate
and evaluate more data in the future.
In a previous US multi-center, randomized, open-label,parallel group trial for the progesterone vaginal tablet(ENDOMETRIN: trade name of FE 999913 in the US),ENDOMETRIN was compared to a progesterone gel(CRINONE 8 % gel) in women undergoing IVF-ET or
ICSI [17]. This trial included 1211 patients and concluded
that both ENDOMETRIN 100 mg BID and TID were noninferior to progesterone gel with respect to ongoing pregnancy rate. The ongoing pregnancy rates in this trial ranged
from 38.6 to 42.3 % in the three treatment groups, which isin line with the US registry data [18]. The different
ongoing pregnancy rates between the current Japanese trial
and the US trial may partly be due to differences in baseline characteristics. The mean number of embryos transferred was 1.1 in the Japanese trial and 2.4 in the US trial.
Only 8 % of the embryo transfers were performed on day 5in the Japanese trial as compared to 30 % or more in the
US trial.
Safety of FE 999913
Adverse events occurred in 38 of 108 subjects (35.2 %).
The most common adverse event was OHSS, which
occurred in 22/108 subjects (20.4 %). However, OHSS isan adverse event associated with COS and is not related to
FE 999913. The majority of adverse events were mild andtransient and no clinically important events were noted.
In this trial, no new safety issues of concern wereobserved that would affect the known safety profile of191

FE 999913. No major safety-related problems were identified, and FE 999913 was well tolerated.
Usefulness of vaginal administration
Preparations of vaginal progesterone include gel, suppositories, and micronized progesterone vaginal inserts. However, as described previously, no progesterone
preparations, including vaginal preparations, are approved
for the indication of luteal support in ART in Japan.
Therefore, injectable progesterone solutions, oral synthetic
progesterone preparations, or progesterone vaginal preparations, unofficially imported or dispensed by in-house
pharmacies, are currently used. Treatment with progesterone injections is time-consuming and requires daily
visits to the hospital. Additionally, daily injections areassociated with a risk of injection site pain, nerve injury,
and muscle contracture. In the case of imported progesterone vaginal preparations, there are concerns regarding
compensation and relief if adverse drug reactions should
occur.
Vaginally administered FE 999913 overcomes the disadvantages of progesterone IM injections and will likely
improve patient adherence. Additionally, the concerns
regarding the use of imported vaginal preparations are
addressed. Furthermore, while the vaginal administrationof FE 999913 does not yield high serum concentrations ofprogesterone as seen with IM progesterone injections,higher concentrations can be achieved in the endometrium
than with IM administration [19–21]. The mechanism
responsible is considered to be the direct delivery of progesterone from the vagina to the uterus (uterine first-passeffect) [22, 23]. As a result, a reduction in systemic adverse
drug reactions associated with high serum concentrations
was achieved [24–26].
Gel preparations accumulate a significant vaginal buildup that can be uncomfortable for patients and may induce
vaginal irritation [26]. Meanwhile, the dedicated applicator
enables the delivery of FE 999913 into the depth of thevaginal cavity. This shortens the distance to the target
organ (endometrium) and resolves the issues seen with thegel preparations such as discomfort with gel accumulation,
vaginal irritancy, and the necessity for frequent handwashing.
FE 999913 has been useful overseas as a luteal support
therapy in ART. Results of a nationwide survey of infertile
patients in US undergoing ART, such as IVF, revealed thatpatients prefer ENDOMETRINÒ vaginal inserts to progesterone-in-oil injections, and to all other vaginal progesterone supplements. The reasons cited most frequently
for their preference included easy, convenient, and painfree administration [27].

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Use of FE 999913 for frozen embryo transfer
In current clinical practice in Japan, frozen embryo transfer
using hormone replacement is frequently performed. The
2012 Ethics Committee Registration/Surveillance Subcommittee Report (Clinical data for IVF/ET etc. in 2012
and registered institutions as of July 2014) reported that theefficacy of frozen embryo transfer is higher than that for
fresh embryo transfer [16], with pregnancy rates of 33.7 %following frozen embryo transfer as compared to 20.8 %following fresh embryo transfer. In addition, according to
the Japanese nationwide registry data from 2008 to 2010[28], pregnancy rates after single embryo transfer are
19.0 % in fresh cleaved embryo transfer, 30.0 % in fresh
blastocyst transfer, 19.4 % in thawed cleaved embryotransfer, and 38.5 % in thawed blastocyst transfer.
FE 999913 is expected to be used in frozen embryotransfer cycle using hormone replacement, but further
investigations are needed to confirm the efficacy and safetyof FE 999913 in frozen embryo transfer cycles.

Conclusions
The administration of FE 999913 BID or TID up to
10 weeks in Japanese women undergoing fertility treatment with IVF-ET or ICSI could sufficiently supplement
and maintain progesterone concentrations throughout thetreatment period. Additionally, it was confirmed that the
pregnancy rate was similar to that of already approved
Japanese ART drug preparations, and similar to the pregnancy rate in actual clinical settings in Japan. The safety
results from the current trial were consistent with the
known safety profile of FE 999913 identified in previous
overseas clinical trials. Thus, treatment with FE 999913
was safe and well tolerated in Japanese women undergoing
IVF-ET or ICSI.
Finally, there is a significant need for the use of avaginal progesterone preparation with documented efficacy
and safety in Japanese clinical practice. The use of
FE 999913 in Japan is therefore expected to contribute
greatly to fertility treatment in Japan and to allow luteal
support with a safe, efficacious, and convenient therapy.
Indeed, once FE 999913 is launched with an indication of‘‘luteal support in ART’’ in Japan, it is expected that
FE 999913 will become the most useful agent for luteal
support in ART.
Acknowledgments The author wishes to thank all the principal
investigators (PI), sub-investigators, and other staff at the participating centers in Japan: (1) Sanno Hospital, Tokyo (PI: Takako Kurosawa); (2) Bashamichi Ladies’ Clinic, Yokohama (PI: Hideyuki
Ikenaga); (3) Sophia Ladies’ Clinic, Sagamihara (PI: Yoshiaki Sato);(4) Hanabusa Women’s Clinic, Kobe (PI: Masahide Shiotani); (5) IVF

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Reprod Med Biol (2015) 14:185–193
Namba Clinic, Osaka (PI: Keijiro Ito); and (6) Ebina Ladies’ Clinic,
Ebina (PI: Yoshihito Kondo). The author would also like to thankProfessor Osamu Ishihara, MD, PhD, Saitama Medical University fortrial coordination. This clinical trial was sponsored by Ferring Pharmaceuticals Co., Ltd.
Conflict of interest The author acts as a medical advisor of thisclinical trial and consultant for Ferring Pharmaceuticals. The author
also acts as a consultant for ASKA Pharmaceutical. The author
receives an unrestricted educational grant from Merck Serono andMochida Pharmaceutical.
Human rights statements and informed consent All procedures
followed were in accordance with the ethical standards of the
responsible committee on human experimentation (institutional andnational) and with the Helsinki Declaration of 1964 and its later
amendments. Informed consent was obtained from all patients forbeing included in the study.
Animal studies

This study did not include any animal experiments.

Open Access This article is distributed under the terms of theCreative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide alink to the Creative Commons license, and indicate if changes were
made.

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