primary objective:To evaluate the effect of individualised FE 999049 treatment on ovarian response in a long GnRH agonist protocol versus a GnRH antagonist protocolSecondary objectives:* To evaluate the effect of individualised FE 999049 treatment…
ID
Source
Brief title
Condition
- Sexual function and fertility disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
Number of oocytes retrieved
Secondary outcome
Secondary endpoints:
Proportion of subjects with cycle cancellation due to poor ovarian response or
excessive ovarian response
Proportion of subjects with blastocyst transfer cancellation after oocyte
retrieval due to (risk of) ovarian hyperstimulation syndrome (OHSS)
Number and size of follicles on stimulation day 6 and end-of-stimulation
Proportion of subjects with <4, 4-7, 8-14, 15-19 and >=20 oocytes retrieved
Number of metaphase II oocytes (only applicable for those inseminated using
ICSI), fertilisation rate as well as number and quality of embryos on day 3 and
blastocysts on day 5 after oocyte retrieval
*
Circulating concentrations of FSH, luteinising hormone (LH), estradiol,
progesterone and inhibin B on stimulation day 6, end-of-stimulation and at
oocyte retrieval
Total gonadotropin dose and number of stimulation days
Positive βhCG rate (positive serum βhCG test 13-15 days after transfer)
Implantation rate (number of gestational sacs 5-6 weeks after transfer divided
by number of blastocysts transferred)
*
Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)
Vital pregnancy rate (at least one intrauterine gestational sac with fetal
heart beat 5-6 weeks after transfer)
*
Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks
after transfer
*
Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks
after transfer divided by number of blastocysts transferred)
*
Proportion of subjects with early OHSS (including OHSS of moderate/severe grade)
*
Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)
*
Frequency and intensity of adverse events
*
Technical malfunctions of the prefilled injection pen
Background summary
FE 999049 (follitropin delta) is a novel human recombinant follicle-stimulating
hormone (rFSH) under global development by Ferring Pharmaceuticals. FE 999049
is individually dosed based on the patient*s body weight and serum
anti-Müllerian hormone (AMH) level. In December 2016, Ferring received
Marketing Authorisation approval from the European Commission for FE 999049
under the trade name REKOVELLE. During 2017, FE 999049 was approved in
Australia, Brazil, Israel and Switzerland, and in 2018, also in Canada and
Mexico. The indication
is: *Controlled ovarian stimulation for the development of multiple follicles
in women undergoing assisted reproductive technologies (ART) such as an in
vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle.*
All clinical phase 2 and 3 trials conducted with FE 999049 have applied the
gonadotropinreleasing hormone (GnRH) antagonist protocol and the FE 999049
dosing algorithm has not yet been studied in a long GnRH agonist protocol.
Previous studies comparing the efficacy and safety of a GnRH antagonist
protocol with a long GnRH agonist protocol using rFSH derived from Chinese
hamster ovary (CHO) cell lines have consistently indicated that the cohort of
recruited follicles is slightly smaller in GnRH antagonist cycles. The
difference in the largest randomised controlled trial was -1.0 oocyte (95%
confidence interval [CI] -1.8; -0.2) which is in agreement with the estimated
difference of -1.07 oocyte (95% CI -1.52; -0.61) in a Cochrane review including
27 randomised controlled trials. The evidence available suggests that the long
GnRH agonist protocol compared to the GnRH antagonist protocol is generally
associated with
one more oocyte retrieved, one more day of stimulation, and consequently a
higher total dose of exogenous FSH equivalent to one more day of dosing. The
impact on ovarian response and efficacy when applying the long GnRH agonist
protocol instead of the GnRH antagonist protocol with FE 999049 is hypothesised
to be similar to those described in the literature for existing rFSH
preparations. In the pivotal phase 3 trial ESTHER-1,
the mean number of oocytes retrieved was 9.6± 5.8 in the FE 999049 group and
10.1 ± 6.6 in the GONAL-F group for all randomised subjects. For subjects with
triggering of final follicular maturation the mean number of oocytes retrieved
was 10.0 ± 5.6 in the FE 999049 group and
10.4 ± 6.5 in the GONAL-F group. When analysed by AMH, the mean number of
oocytes retrieved was 8.0 ± 4.3 in the FE 999049 group versus 7.0 ± 3.9 in the
GONAL-F group among patients with AMH <15 pmol/L, and 11.6 ± 5.9 in the FE
999049 group versus 13.3 ± 6.9 oocytes
in the GONAL-F group among patients with AMH >=15 pmol/L. This prospective,
comparative trial is designed to document the ovarian response following the
application of the individualised FE 999049 dosing regimen in a long GnRH
agonist protocol compared to a GnRH antagonist protocol. The trial will
describe the impact of the protocol on the mean number of oocytes retrieved,
the mean number of oocytes retrieved in patients with AMH <15 pmol/L and AMH
>=15 pmol/L as well as the distribution of the number of oocytes retrieved (<4,
4-7, 8-14, 15-19, >=20 oocytes).
Study objective
primary objective:
To evaluate the effect of individualised FE 999049 treatment on ovarian
response in a long GnRH agonist protocol versus a GnRH antagonist protocol
Secondary objectives:
*
To evaluate the effect of individualised FE 999049 treatment on other
pharmacodynamic
parameters in a long GnRH agonist protocol versus a GnRH antagonist protocol
To evaluate the effect of individualised FE 999049 treatment on pregnancy rates
in a long
GnRH agonist protocol versus a GnRH antagonist protocol
To evaluate the safety of individualised FE 999049 treatment in a long GnRH
agonist
protocol versus a GnRH antagonist protocol
Study design
This will be a randomised, controlled, open label, parallel group, multicentre
trial comparing the efficacy and safety of individualised FE 999049 dosing in
first cycle patients aged 18-40 years undergoing controlled ovarian stimulation
for IVF/ICSI following either a long GnRH agonist
protocol or a GnRH antagonist protocol.
Intervention
Subjects will be randomised in a 1:1 ratio to controlled ovarian stimulation
with FE 999049 in a long GnRH agonist protocol or to
controlled ovarian stimulation with FE 999049 in a GnRH antagonist protocol.
Study burden and risks
The physical examinations and assessment, the number of visits and the
psychological burden during this study will not differ compare the current
daily care for this indication. The investinational product is registered in
the Netherlands using the GnRH-antagonists protocol. This study will compare
the efficacy and safety of the use of the investigational product in the
GnRH-agonistprotocol versus the GnRH-antagonistprotocol. All other medicinal
product that are used in both protocol have been registered in the Netherlands
for the indication that is being studied.
Participation in this trial is not expected to have a negative influence on the
subject*s likelihood of conceiving compared to normal clinical practice.
Furthermore, participation does not imply extra risks for the subjects in
comparison to routine controlled ovarian stimulation.
For more information on the number of blood samples and physical examinations
and assessment please refer to E6 and J.
The number of visits to the site is dependent on the success of follicular
maturation. Minimum can therefore not be defined.
Maximum number of visits is:
- GnRH agonist arm: Maximum 20 visits
- GnRH antagonist arm: Maximum 25 visits
For the risk associated with the investigational product please refer to
questions E9
Kay Fiskers Plads 11
Copenhagen 2300
DK
Kay Fiskers Plads 11
Copenhagen 2300
DK
Listed location countries
Age
Inclusion criteria
1. Informed Consent Documents signed prior to screening evaluations., 2. In
good physical and mental health. , 3. The subjects must be at least 18 years
(including the 18th birthday) when they sign the informed consent and no more
than 40 years (up to the day before the 41st birthday) at the time of
randomisation., 4. Infertile women diagnosed with tubal infertility,
unexplained infertility, endometriosis stage I/II or with partners diagnosed
with male factor infertility, eligible for in vitro fertilisation (IVF) and/or
intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm
from male partner or sperm donor., 5. Infertility for at least one year before
randomisation for subjects < 38 years or for at least 6 months for subjects
>=38 years (not applicable in case of tubal or severe male factor infertility).
, 6. The trial cycle will be the subject*s first controlled ovarian stimulation
cycle for IVF/ICSI., 7. Regular menstrual cycles of 24-35 days (both
inclusive), presumed to be ovulatory. , 8. Hysterosalpingography,
hysteroscopy, saline infusion sonography, or transvaginal ultrasound
documenting a uterus consistent with expected normal function (e.g. no evidence
of clinically interfering uterine fibroids defined as submucous or intramural
fibroids larger than 3 cm in diameter, no polyps and no congenital structural
abnormalities which are associated with a reduced chance of pregnancy) within 1
year prior to randomisation. , 9. Transvaginal ultrasound documenting presence
and adequate visualisation of both ovaries, without evidence of significant
abnormality (e.g. no endometrioma greater than 2 cm or enlarged ovaries which
would contraindicate the use of gonadotropins) and normal adnexa (e.g. no
hydrosalpinx) within 1 year prior to randomisation. Both ovaries must be
accessible for oocyte retrieval., 10. Early follicular phase (cycle day 2-5)
serum levels of FSH between 1 and 15 IU/L at screening., 11. Negative serum
Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human
Immunodeficiency Virus (HIV) antibody tests within 1 year prior to
randomisation. , 12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both
inclusive) at screening. , 13. If < 38 years willing to accept single
blastocyst transfer. If >=38 years willing to accept transfer of a single
good-quality blastocyst (double blastocyst transfer may be performed if no
good-quality blastocyst is available).
Exclusion criteria
1. AMH >35 pmol/L at screening., 2. Strong preference of the subject for either
treatment protocol. , 3. Known endometriosis stage III-IV (defined by the
revised American Society for Reproductive Medicine [ASRM] classification,
1996)., 4. Known history of recurrent miscarriage (defined as three consecutive
losses after ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and
before week 24 of pregnancy). , 5. Known abnormal karyotype of subject or of
her partner / sperm donor, as applicable, depending on source of sperm used for
insemination in this trial. , 6. Any known clinically significant systemic
disease (e.g. insulin-dependent diabetes)., 7. Known inherited or acquired
thrombophilia disease., 8. Active arterial or venous thromboembolism or severe
thrombophlebitis, or a history of these events., 9. Known porphyria., 10. Any
known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver
or kidney) with the exception of controlled thyroid function disease., 11.
Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or
hypothalamus which would contraindicate the use of gonadotropins., 12. Known
moderate or severe impairment of renal or hepatic function., 13. Currently
breast-feeding., 14. Undiagnosed vaginal bleeding., 15. Known abnormal cervical
cytology of clinical significance observed within 3 years prior to
randomisation (unless the clinical significance has been resolved)., 16.
Findings at the gynaecological examination at screening which preclude
gonadotropin stimulation or are associated with a reduced chance of pregnancy,
e.g. congenital uterine abnormalities or retained intrauterine device., 17.
Pregnancy (negative pregnancy test must be documented at screening) or
contraindication to pregnancy., 18. Known current active pelvic inflammatory
disease., 19. Use of fertility modifiers during the last menstrual cycle before
randomisation, including dehydroepiandrosterone (DHEA), metformin or cycle
programming with oral contraceptives, progestogen or estrogen preparations.,
20. Use of hormonal preparations (except for thyroid medication) during the
last menstrual cycle before randomisation., 21. Known history of chemotherapy
(except for gestational conditions) or radiotherapy. , 22. Current or past (1
year prior to randomisation) abuse of alcohol or drugs and/or current (last
month) intake of more than 14 units of alcohol per week., 23. Current or past
(3 months prior to randomisation) smoking habit of more than 10 cigarettes per
day., 24. Hypersensitivity to any active ingredient or excipients in the
medicinal products used in the trial., 25. Previous participation in the trial,
26. Use of any non-registered investigational drugs during the last 3 months
prior to randomisation., See also Withdrawal Criteria in the study protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002783-40-NL |
| ClinicalTrials.gov | NCT03809429 |
| CCMO | NL67333.028.18 |