Primary objectiveThe primary objective of this trial is to identify the optimal effective dose of AS900672-Enriched to induce ovulation in oligo-anovulatory infertile women.Secondary objectives* To demonstrate that the clinical pregnancy rate of the…
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Source
Brief title
Condition
- Sexual function and fertility disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the ovulation rate.
Secondary outcome
The main secondary endpoint is the clinical pregnancy rate. Safety endpoints
include the stimulation cycle cancellation rates for risk of OHSS and multiple
pregnancy, the nature, incidence and severity of adverse events (AEs) and of
injection site reactions, changes from baseline in vital signs and in clinical
laboratory parameters, incidence and severity of OHSS, and incidence of
multiple pregnancy.
Background summary
AS900672-Enriched has the same mechanism of action as recombinant human
folliclestimulating hormone (r-hFSH) and endogenous FSH. FSH is produced by the
pituitary and stimulates ovarian follicular growth and maturation during the
follicular phase of the menstrual cycle. It acts on the granulosa cells of the
ovarian follicles by promoting cell differentiation, LH receptor expression,
stimulation of steroidogenesis, and aromatase activity. This contributes to the
production of a single dominant follicle that is ovulated at mid-cycle and
released into the fallopian tube, where it can be fertilised.
Clomiphene citrate (CC), an oral anti-oestrogen, is the first-line treatment.
It restores ovulation in 60-85% of subjects and results in pregnancy in around
30-40% of them. Laparoscopic ovarian drilling, a surgical procedure by which
the ovaries are punctured, is an alternative that is particularly effective in
thin patients with high LH levels. Gonadotropins are the most common
second-line therapy in patients who did not achieve pregnancy with CC. Among
several available treatment protocols, the chronic low dose step-up protocol is
widely used. Usually, the treatment duration is of 12 to 14 days. With this
protocol, stimulation is started with a low FSH dose, which may be increased
very slowly (but not before the first 14 days and then at intervals of not less
than 7 days), by small amounts (usually 37.5 IU/day), up to a maximum of 225
IU/day. With a starting dose of 75 IU/day, a 70% mono-ovulation rate, 40%
pregnancy rate, and 6% multiple pregnancy rate have been reported.
Merck Serono*s market research has shown that patients suffer from a high level
of anxiety as they attempt to administer all of their medication correctly.
Moreover, ease of drug delivery is a key driver in the choice of gonadotropin
product. AS900672-Enriched is intended as a longacting FSH. It has a longer
half-life than currently available FSH products and is therefore expected to
decrease the total number of injections. This treatment simplification should
increase patient convenience and decrease the risk of dosing errors. Based on
the available data, a single AS900672-Enriched injection is expected to support
ovarian stimulation for the first 6 to 7 days of the stimulation cycle and may
then be followed by daily r-hFSH injections to achieve optimal follicular
development.
Study objective
Primary objective
The primary objective of this trial is to identify the optimal effective dose
of AS900672-Enriched to induce ovulation in oligo-anovulatory infertile women.
Secondary objectives
* To demonstrate that the clinical pregnancy rate of the optimal effective dose
of
AS900672-Enriched is within the range of the clinical pregnancy rate obtained
with
follitropin alfa daily dosing, and
* To evaluate safety and tolerability of AS900672-Enriched in oligo-anovulatory
infertile
women undergoing OI.
Study design
This is a phase II, multicentre, randomised, assessor-blinded,
active-comparator, parallelgroup dose finding trial to evaluate
AS900672-Enriched versus follitropin alfa (GONAL-f®) in oligo-anovulatory
infertile women undergoing ovulation induction (OI). The trial will be
conducted in three stages: i) an initial stage to define effective doses among
the four tested doses of AS900672-Enriched, ii) a second stage to identify the
optimal effective dose(s) of AS900672-Enriched, and iii) a final stage to gain
additional pregnancy data for the selected optimal dose(s) of
AS900672-Enriched. A Data Monitoring Committee (DMC) will review the results
after the each of the first two stages and make recommendations on the dose(s)
of AS900672-Enriched to be tested in the subsequent stage.
The AS900672-Enriched doses to be evaluated are 10, 20, 30 and 40 mcg,
administered as a single injection, and, depending upon each subject*s ovarian
response, followed by supplemental follitropin alfa 75 IU daily injections,
which may begin on stimulation day 7. Subjects enrolled in the comparator arm
will receive daily injections of follitropin alfa (GONAL-f®) 75 IU.
Oligo-anovulatory infertile women who are candidates for OI will be
prospectively screened for enrolment. Each subject will be allowed one
treatment cycle. Treatment will begin on stimulation day 1 (S1), corresponding
to day 3 or 4 of an induced
menstrual cycle, at which time the subject will be randomised to receive either
one of four doses of AS900672-Enriched or follitropin alfa (GONAL-f®) 75 IU
daily injections.Subjects will return to clinic for monitoring of ovarian
response on stimulation day 5 (S5), stimulation day 7 (S7), as well as when
deemed necessary by the Investigator (Sn). Beginning on S7, and depending upon
each subject*s ovarian response, subjects randomised to AS900672-Enriched may
receive supplemental r-hFSH, given as follitropin alfa 75 IU daily injections.
Ovarian stimulation treatment will continue in all treatment arms until
criteria for hCG administration are met or to a maximum of 14 days (S14),
unless ovarian response is imminent (i.e. a clinically relevant rise in
oestradiol (E2) above baseline), in which case stimulation treatment can
continue for 1 or 2 additional days, as judged by the Investigator.
Recombinant hCG (r-hCG) will be administered when the ovarian ultrasound scan
shows <= 3 follicles with a mean diameter of >= 14 mm and of these 1 or 2 have
a mean diameter of >= 17 mm. A single injection of r-hCG 250 mcg will be given
to induce ovulation. Insemination will take place via intercourse and/or
intrauterine insemination (IUI) within 48
hours following r-hCG administration. No luteal support will be given. Blood
sampling for progesterone (P4) levels will be performed 5 to 7 days and, again,
8 to10 days, post-hCG administration, with 3 days between samplings.
All subjects will return to the trial centre for a post-treatment follow-up
visit on day 15 to 20 post-hCG. Subjects with a positive pregnancy test
(beta-hCG > 10 IU/L) will undergo an ultrasound 35 to 42 days post-hCG to
confirm clinical pregnancy.
Throughout the treatment period, samples will also be collected from all
subjects for a population pharmacokinetic (PK) and pharmacodynamic (PD)
analysis.
Intervention
This trial will be conducted in tree stages. During the first stage (define
effetive doses) there are 5 groups: one group will inject the comparator
GONAL-f® daily, the other 4 groups will be injected with respectively a single
dose of 10, 20, 30 or 40 microgram AS900672-Enriched (followed by supplemental
GONAL-f® injections). In the second stage the most ineffective dose(s) of
AS900672-Enriched will be dropped out to continue to compare GONAL-f® with the
other doses of AS900672-Enriched to identify the optimal effective dose. In the
third stage additional pregnancy data will be gained with again the remaining
doses after the second stage.
Study burden and risks
Based on the results of the phase I trial, AS900672-Enriched appears to be well
tolerated. Based upon the results of non-clinical testing, a teratogenic
potential exists. Therefore, tests will be performed to exclude pregnancy prior
to initiating therapy with AS900672-Enriched. No anti-AS900672-Enriched
antibodies were detected in the phase I trial. It may, however, be that when
exposing a higher number of subjects to the compound, as will be done in this
phase II trial, an immune response could be revealed, although this is highly
unlikely after exposure to a single injection. Furthermore, the compound*s
longer elimination half-life may lead to an increased incidence of OHSS or, in
order to prevent hyperstimulation, to a higher incidence of cycle cancellation,
compared to follitropin alfa treatment. Given the early stage of development of
AS900672-Enriched, it is unknown whether subjects can expect any clinical
benefit from taking part in this trial, compared to the standard care of
therapy and in terms of pregnancy rate. Based on the phase I results,
AS900672-Enriched is able to stimulate multiple follicular development. However
it remains to be demonstrated whether AS900672-Enriched treatment will induce
ovulation in oligo-anovulatory women, given the high variability of ovarian
response in this population, and whether the obtained pregnancy rate is
clinically acceptable.
9, Chemin des mines
CH-1202 Geneve
Zwitserland
9, Chemin des mines
CH-1202 Geneve
Zwitserland
Listed location countries
Age
Inclusion criteria
1. Oligo-anovulation defined by a menstrual period duration of 35 days to 6 months,
2. Spontaneous menses or a positive response to progestin or clomiphene citrate
withdrawal within the prior 6 months,
3. Aged between 18 and 36 years, inclusive, at time of informed consent signature,
4. Body mass index 18 to 30 kg/m2, inclusive,
5. Early follicular phase serum TSH, DHEA-S, prolactin, and FSH within the normal
range for the central laboratory,
Exception: Subjects with low TSH level who receive replacement therapy can be
enrolled at the discretion of the investigator if local laboratory results (T4)
demonstrate satisfactory thyroid function,
6. Fasting glucose and fasting insulin within the normal range for the central laboratory,
7. Normal uterine cavity and presence of at least one ovary with ipsilateral patent
fallopian tube, as determined by means of HSG and/or laparoscopy-hysteroscopy
within the prior 3 years,
8. PAP smear test without clinically significant abnormalities within 6 months prior to
randomisation,
9. Negative pregnancy test prior to randomisation,
10. Male partner with semen analysis demonstrating adequacy for insemination via
intercourse and/or IUI within 6 months prior to randomisation,
Note: Use of donor sperm is not allowed,
11. Willing and able to comply with the protocol,
12. Voluntary provision of written informed consent, prior to any trial-related procedure that was not part of normal medical care, with the understanding that the subject can withdraw consent at any time without prejudice to her future medical care, including willingness to provide follow-up information on babies born as part of this trial.
Exclusion criteria
1. History of >= 2 consecutive gonadotrophin stimulation cycles that did not lead to
ovulation,
2. History of clomiphene citrate stimulation cycles of which none led to ovulation,
3. Prior excessive response to gonadotrophin stimulation, defined as the development of L4 mature follicles (>17 mm) or cancellation of the OI cycle due to excessive follicular response after treatment with FSH at a dose of <= 75 IU/day,
4. Previous severe ovarian hyperstimulation syndrome (OHSS),
5. Administration of any gonadotrophin, clomiphene citrate, GnRH analogue, tamoxifen or aromatase inhibitors within the prior 30 days,
6. Laparoscopic ovarian drilling and/or ovarian cauterisation within the prior 6 months,
7. Any contraindication to pregnancy and/or to carrying pregnancy to term,
8. A clinical pregnancy that ended in a miscarriage within the prior 3 months,
9. History of >= 3 consecutive miscarriages, due to any cause,
10. Abnormal gynaecological bleeding of undetermined origin,
11. Clinically significant abnormal findings of the uterine cavity evident on a transvaginal pelvic ultrasound performed during screening,
12. Presence of endometriosis grade III * IV,
13. Ovarian cyst with a mean diameter of >25 mm and E2 > 80 pg/mL on the day of
randomisation,
14. History of ovarian, uterine or mammary cancer,
15. Adrenal congenital hyperplasia, partial or complete enzymatic block,
16. Use of metformin related to infertility within the prior 2 months,
17. Known allergy or hypersensitivity to human gonadotrophin preparations or to
compounds that are structurally similar to any of the other medications administered
during the trial,
18. Any contra-indication to gonadotrophin therapy,
19. Known infection with human immunodeficiency virus (HIV), or positive hepatitis B
surface antigen (HBsAg) or anti-hepatitis C antibodies in the trial subject or her male partner,
20. Any active substance abuse or history of drug, medication or alcohol abuse within the prior 5 years,
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 | EUCTR2007-002823-34-NL |
| CCMO | NL19546.029.07 |