Recruitment
The Reproductive Medicine Unit at the Liverpool Women’s NHS Foundation Trust holds a patient information evening once a month for couples about to undergo assisted conception treatment. It is during this visit that the trial will be fully explained to the women (and their partners) so they have a preliminary idea of the study.
They then return to the clinic to commence treatment approximately 5 to 6 weeks later. They are given a further opportunity to ask any questions regarding the trial and a patient information leaflet is given to them to keep for reference. The patient information leaflet gives the contact details of the Chief Investigator should the couple wish to ask any questions.
Actual treatment is initiated 2 to 3 weeks after the initial clinic appointment. After this they are given an appointment to collect their treatment drugs (note: baseline hormone levels are measured after the patient information evening). It is at this point that their IVF drugs are dispensed. This is the standard procedure.
The treatment begins with downregulation on day 23 of their menstrual cycle when they use Buserelin acetate injection/nasal spray for 3 weeks. At the end of this treatment they have a scan. Ovarian stimulation is then commenced and a scan is performed on day 10 of ovarian stimulation to assess the response. If the response is appropriate, their eggs are collected on days 12 or 13 depending on the response of the ovaries. Two days after the eggs are collected the embryos are transferred. The women are instructed to start taking the progesterone pessaries the night before the embryo transfer (400 mg pessary once). After the embryo transfer they continue with the pessaries 400 mg twice a day until the day of the pregnancy test. At this stage they will have a further opportunity to ask questions regarding the study should they wish to. Patients will be handed a Duration Of Luteal Support (DOLS) trial patient information leaflet and consent form that has been completed by the researcher. They will be asked to retain this with them and complete the relevant sections once agreement has been made to join the trial following a positive pregnancy test (see notes below). A urinary pregnancy test is arranged for 14 days after the embryo transfer. This is standard practice for women undergoing assisted conception on the Reproductive Medicine Unit.
Currently at the Hewitt Centre, approximately 32.5% of women have a positive biochemical pregnancy test 2 weeks after embryo transfer. It is this population that is eligible for trial entry and randomization. Once the patient has confirmed a positive urinary pregnancy test they will be invited to join the trial. Eligibility will be confirmed verbally over the telephone according to the trial entry protocol. The patient will then be asked to sign the consent form that they have with them at home and return it to the Hewitt Centre within 24 h. Once the consent form has been completed by the patient, a trial prescription sheet will be sent to the pharmacy with a stated collection time. The patient can then be randomized and the drugs dispensed according to pharmacy protocol. A blood sample will then be drawn for measurement of baseline hormone levels (progesterone, estradiol, free beta-hCG, pregnancy-associated plasma protein-A (PAPP-A), Activin A, Inhibin A and Inhibin B).
The patient will then be given the drug pack that has been prepared by the pharmacy. This drug pack will contain either the placebo pessaries or the progesterone pessaries. They will continue to take these for a further 8 weeks (in other words, up to 10 weeks post-embryo transfer, which is up to the 12 weeks gestation calculated by the last menstrual period).
Inclusion criteria:
1.
Biochemical pregnancy confirmed by urinary pregnancy test. If positive then they will be eligible to enter the trial.
2.
Progesterone treatment (2 weeks) completed up to the day of the pregnancy test.
3.
Patients treated at Hewitt centre only.
4.
Only those patients who have been treated with the long-stimulation protocol.
Exclusion criteria
1.
All women who are undergoing frozen embryo transfer.
2.
Any women not willing to take part will be excluded.
3.
All diabetic, epileptic and hypertensive patients on treatment.
4.
Poorly controlled asthmatics having had more than one hospital admission in the last year.
5.
Patients with renal and cardiac dysfunction (under the care of nephrologist and cardiologist, respectively).
7.
Severe liver impairment/jaundice.
8.
Previous history of thromboembolism.
9.
Transport centre patients (that is, egg collection outside the main hospital).
Five weeks after the embryo transfer (that is, 7 weeks gestation by last menstrual period) the women will have a first pregnancy scan (this is a standard protocol for all our unit patients). This scan will check for the viability of pregnancy in the form of positive heart beat pulsations. At this point a pelvic Doppler will also be performed to determine the blood velocity in the uterine arteries (the main vessels which supply blood to the womb). This will enable us to compare the blood flow between the two treatment groups.
At this appointment, a further 15 ml venous blood sample will be taken to check for progesterone, estradiol, free beta-hCG, Inhibin A, Inhibin B, PAPP-A, and Activin A. Patients with a viable pregnancy as confirmed by an ultrasound will continue with the pessaries for up to 10 weeks post-embryo transfer (that is, 12 weeks gestation).as explained below:
Patients with a viable pregnancy at this point will be informed of the various antenatal screening methods available to them (that is, triple test, quadruple test, nuchal translucency, etc.) as per unit standard practice.
At the end of the week 10 post-embryo transfer (that is, 12 weeks gestation) the women will be asked to attend the unit for a further pregnancy scan to determine the viability of the pregnancy and record the fetal heart rate (FHR). At this appointment the second uterine artery Doppler is performed to compare the blood velocity between the two groups. A further 15ml venous blood will be taken to check for progesterone, PAPP-A, estradiol, free B-hCG, Inhibin A, Inhibin B and Activin A.
At approximately 34 weeks gestation a courtesy phone call will be made to the patient to enquire how the pregnancy is proceeding. This will be undertaken by the medical/research team heading the trial.
Following delivery, birth details and neonatal outcome will be observed.
Treatment allocation
1.
Following a positive biochemical urinary pregnancy test, the patient will be asked to attend the reproductive unit if not present already. After eligibility has been confirmed the patient will be asked to sign the trial consent form. This will be done by a member of the Hewitt Centre Staff who is trial trained and GCP compliant.
2.
Pharmacy will be alerted that a treatment pack (either active ingredient or placebo) will need to be made available for collection. The pharmacy will be given the patients’ age (less than 37 years old/greater than 37 years old) so that the appropriate randomization sequence is accessed and drug pack dispensed.
3.
The treatment pack will be collected by a member of staff from the reproductive medicine unit along with a treatment pack number. The treatment pack number will be entered with the patients’ details in the trial pharmacy log book. These details will be completed, signed and dated by the Pharmacist for verification purposes.
4.
The treatment pack will be given directly to the patient by a member of the reproductive unit, along with confirming instructions for use. Patient details and treatment pack number will also be entered in to the trial register held on the reproductive medicine unit.
Each study participant will be given a blister pack which contains either 400 mg progesterone pessaries or identical appearing pessaries of placebo. The drug and placebo are provided by Actavis, which had no involvement in study design, data collection, data handling, data analysis, study interpretation, drafting of manuscripts or decisions to publish. Each patient pack will contain 140 pessaries. This supply will enable enough pessaries to last for 8 weeks (that is, until 10 weeks post-embryo transfer/12 weeks gestation by last menstrual period), and also enough additional pessaries to account for natural wastage as often occurs during treatment. Natural wastage refers to the process whereby the treatment pessary is lost due to premature expulsion from either the vagina or rectum prior to the optimum application procedure time.
Excess pessaries that are not used by the patient during the trial period will be collected from the patient at their 12-week follow-up scan. These drugs will be reconciled with pharmacy and disposed of according to hospital policy.
There is a separate randomization sequence for patients stratified less than 37 years of age and patients older than 37 years of age. The randomization sequences were prepared for the trial by Anna Hart (trial statistician) using random sized blocks (2, 4 and 6) using the statistical package available at
http://www.randomization.com . Two randomization lists have been prepared. The first list for enrolled women greater than 37 years of age where all ID prefixes begin with a “1” (total 180, 90 per group) and the second list for patients younger than 37 years old where all the ID numbers begin with a “2” (total 360, 180 per group). Trial investigators are to be kept blind to all randomization sequences.
Patients hospital notes are marked with a sticker labeled “This patient is participating in the DOLS study”.
Patients are informed of the date and time of their subsequent second scan which is to be performed 3 weeks following positive urinary pregnancy test (that is, 5 weeks post-embryo transfer/7 weeks gestation).
The investigators, participants and clinicians are unaware of the treatment assignments. Although treatments are blinded, the head pharmacist and the on-call pharmacist will have access to the randomization codes should the need to break the code arise.
Information on patient characteristics, demographics and treatment are transcribed from the hospital case notes to the case report form.