Pregnancy Clinical Trial
Official title:
Investigation of Ibuprofen in the Delay of Ovulation in NC-IVF (Natural Cycle in Vitro Fertilisation) Therapy With the Objective of Reducing Premature Ovulation and Thus Improving Effectivity (Off Label Use)
During natural cycle in vitro fertilisation, no gonadotropin stimulation is used to stimulate
oocyte production. Ovulation is induced with HCG (human chorionic gonadotropin) and the
follicle is retrieved 36 hours later.
In this study the patient in the intervention group will receive Ibuprofen as a study
intervention beginning at the same time as the HCG injection. The treatment dose will either
be 400mg every 8 to 12 hours or 800mg every 8 to 12 hours until the follicle retrieval,
totalling 5 tablets. Instead of the usual time period of 36 hours, the follicular punction
will occur after 42 hours. Should the oocyte still be accessible after this time period, then
it is proven that Ibuprofen delays ovulation. In this case the patient will continue the
regular NC-IVF treatment cycle.
The study design is a admissible two-stage design. During stage 1, 8 cycles in 8 patients
will be examined. Should it be the case that after these 8 patients have completed a cycle, 4
or more show a positive treatment effect from the Ibuprofen intake, then the study will
continue to stage 2 with 17 more more patients, totalling 25.
Should it be the case however, that after 8 patients, 3 or less show an effect of the
Ibuprofen intake, then the study will be stopped prematurely for futility. The study
intervention will be increased to 800mg of Ibuprofen and the study will recommence with 8
more patients.
A control group will consist of women undergoing intrauterine insemination (IUI) or timed
sexual intercourse (TSI). 42 hours after Beta-HCG injection, an ultrasound examination will
be performed in order to determine the number of remaining follicles in the ovary. This
examination is to verify and control the proposed time limit of 42 hours.
Background
In vitro fertilisation can be performed without the use of gonadotropin-stimulating
medication, = Natural Cycle-IVF or NC-IVF for short. The effectivity of NC-IVF is limited as
pro treatment cycle only one follicle develops, which can ovulate prematurely. If this is the
case, a follicle aspiration is no longer possible and the next cycle must be awaited. One
possibility of preventing premature ovulation is the prescription of NSAID, which is common
practice in many centres, even though up until now, the effectivity has not been proven.
To test the meaningfulness of the worldwide implementation of NSAIDs in NC-IVF, a proof of
concept is needed. An exactly defined study outline will explore the use Ibuprofen in a
dosage of 3x400mg/24h or 3x800mg/24h. At the lower dose, Ibuprofen did not show increased
side effects in randomised placebo-controlled studies.
The primary purpose of the study is therefore to determine whether or not NSAIDs in the form
of Ibuprofen can successfully delay ovulation in such a way that it would be useful for
everyday application in NC-IVF. Secondary purposes are to measure the effect of Ibuprofen on
the Prostaglandin-E2 levels in the fluid of the extracted follicles and also whether the
number of oocytes obtained in the extracted follicles differs from regular IVF-treatment.
The study design is a prospective, non-randomised, single-arm, no-treatment controlled,
proof-of-concept trial. The intervention to be studied is a dose of either 400mg Brufen® or a
dose of 800mg Brufen® (Drug class: Ibuprofen), taken every 8h (at night up to 12 hours)
equalling a daily dose of 1200mg/24h or 2400mg/24h. The intervention will continue for 42h,
totalling 5 tablets. Patients recruited will enter the study and take part for the duration
of one NC-IVF treatment cycle, roughly for 2 months. Each patient can take part once, for one
treatment cycle. The control group will consist of females undergoing either IUI or TSI
treatment. One ultrasound examination will be performed, to measure the number of naturally
occuring delayed ovulation, 42h after HCG injection. Patients recruited can take part once,
for one treatment cycle.
The study population will include females between the ages of 18-42, with an indication for
NC-IVF, IUI or TSI. They must wish for this treatment and fulfil all the necessary
requirements, such as a regular menstruation every 26-32 days and the accessibility of both
ovaries for the transvaginal follicular puncture.
The study intervention is planned with 25 completed cycles in 25 individual patients and two
interim analyses which allows stopping of the trial for futility potentially after the first
8 completed cycles (two-stage design). The study control is planned with 25 treatment cycles
in 25 individual patients. Blinding will not occur, as no placebo or non-historical test
group will be used, thus it is an open trial.
No randomisation or stratified sampling will occur. Patients who qualify will be recruited in
the NC-IVF, IUI or TSI consultations in our own Clinic.
The total study for the intervention group will span 5 consultations:
- Consult 1: Recruitment of patients, description of study and hand out of patient
information informed consent documentation.
- Consult 2: Day 8-14 of the Patients' menstrual cycle. Collection of informed consent
documentation and definitive enrollment in study. The patients undergo a sonographic
examination of the follicle size as well as determination of E2 and LH serum levels.
Following the consultation, the patients will self-inject the HCG and at the same time
commence the study intervention of 400mg Brufen® every 8 hours until Consult 3.
- Consult 3: Exactly 42h after the HCG injection, the patients undergo a sonographic check
of the follicle and if it remains unovulated, then it will be retrieved via vaginal
access. Along with the OPU, the second study intervention in form of a 5ml venous blood
sample will take place, in order to determine the serum levels of Ibuprofen.
- Consult 4: If a follicle was retrieved and successfully fertilised, 2-3 days later it
will be transferred in the patients' uterus-
- Consult 5: 14-18 days after the embryo transfer, the patients will perform a pregnancy
test.
Should after 8 completed cycles the dose of 400mg Brufen® not be able to show the effect of
delaying ovulation in >3 of the 8 study participants, then the treatment dose will be raised
to 800mg Brufen® and the study recommences.
The total study for the control group IUI will span 5 consultations:
- Consult 1: Recruitment of patients, description of study and hand out of patient
information informed consent documentation.
- Consult 2: Day 8-14 of the Patients' menstrual cycle. Collection of informed consent
documentation and definitive enrollment in study. The patients undergo a sonographic
examination of the follicle size as well as determination of E2 and LH serum levels.
Following the consultation, the patients will self-inject the HCG.
- Consult 3: Exactly 36h after the HCG injection, the patients undergo intrauterine
insemination.
- Consult 4: Exactly 42h after the HCG injection, the patients undergo a sonographic check
of the follicle, to see if it remains unovulated.
- Consult 5: 14-18 days after the embryo transfer, the patients will perform a pregnancy
test.
The total study for the control group TSI will span 4 consultations:
- Consult 1: Recruitment of patients, description of study and hand out of patient
information informed consent documentation.
- Consult 2: Day 8-14 of the Patients' menstrual cycle. Collection of informed consent
documentation and definitive enrollment in study. The patients undergo a sonographic
examination of the follicle size as well as determination of E2 and LH serum levels.
Following the consultation, the patients will self-inject the HCG. 24-48h after HCG
injection, the patients have sexual intercourse.
- Consult 3: Exactly 42h after the HCG injection, the patients undergo a sonographic check
of the follicle, to see if it remains unovulated.
- Consult 4: 14-18 days after the embryo transfer, the patients will perform a pregnancy
test.
Justification of the study design:
Large studies including one prospective randomised study using NSAIDs versus no medication
have been performed to test the efficacy of NSAIDs. However, the study designs have been
proven not to be useful to test the hypothesis that NSAIDs delay the ovulation.
Therefore the only design which will prove this hypothesis is the ovulation induction
followed by a follicle aspiration so late that the follicle will definitely have been
ovulated. If patients take Ibuprofen and the follicle has still not ovulated 42 hours after
ovulation induction, the hypothesis will be confirmed. The time limit of 42h shall be
verified by a control group, consisting of a similar patient collective as the intervention
group.
Objective
- Overall Objective The purpose of this study is to evaluate whether Ibuprofen delays
ovulation in such a manner that it can be used effectively in patients undergoing NC-IVF
treatment and aims to describe an efficacy and safety profile for Ibuprofen in this
context.
- Primary Objective The study seeks primarily to determine whether Ibuprofen can delay
ovulation, in order to reduce the rate of premature ovulations in NC-IVF.
- Secondary Objectives A secondary objective is to analyse if Ibuprofen inhibits the
detachment of the oocyte from the follicular wall leading to a reduced oocyte yield.
A secondary objective is to analyse the rate of delayed ovulation in the control group, after
induced ovulation by HCG injection.
Methods
As a first study intervention the patient will receive 400mg of Ibuprofen every 8-12 hours
until the morning of the day of the planned follicular extraction. This is the equivalent of
5 tablets beginning at the time of the HCG injection, which induces ovulation. The follicular
extraction will not take place after 36 hours which is usually the case, but after 42 hours
after HCG injection.
In the case of the trial being stopped for futility after the first 8 completed cycles, the
treatment dose of Ibuprofen will be increased to 800mg and the study will recommence.
Should the follicle not already have ovulated then the treatment will continue as a regular
IVF therapy (with the fertilisation of the oocyte and the following embryo transfer).
As a second study intervention, all patients will give a blood sample (5ml) at the time of
follicle extraction in order to determine the serum concentration of Ibuprofen, thus proving
that it was taken.
The control group will undergo an ultrasound examination to determine whether or not an
unruptured follicle is still present in the ovary, 42h post HCG-injection.
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