Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
OG08/8802
Study information
Scientific title
The use of metformin and gonadotrophin-releasing hormone antagonist for the treatment of women with polycystic ovary syndrome undergoing in-vitro fertilisation embryo transfer: a single centre prospective double-blind randomised placebo-controlled trial
Acronym
Study hypothesis
To determine whether the use of metformin in conjunction with the short gonadotrophin-releasing hormone (GnRH) antagonist protocol for in-vitro fertilisation (IVF) treatment reduces the incidence of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome (PCOS).
Ethics approval
Pending approval from the Leeds West Research Ethics Committee; date for review is the 8th May 2009
Study design
Single centre prospective double-blind randomised placebo-controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Polycystic ovary syndrome
Intervention
Participants in the trial will be randomised to receive either metformin or placebo in addition to routine medication for the short GnRH antagonist IVF treatment protocol.
Treatment arm: metformin -
Following a spontaneous or induced withdrawal bleed subjects will be seen on day 21 of their menstrual cycle prior to starting IVF treatment. Patients will be randomised to either metformin or placebo. One tablet (metformin 850 mg) would be taken 12-hourly from the day 21 appointment until the day of oocyte retrieval, approximately 21 days. Both patients and investigators will be blinded to whether they are taking placebo or metformin. The metformin will be packaged and labelled as such so that the patient is blinded to whether it is metformin or placebo but with sufficient information to inform how to take the medication. All medications for the treatment cycle, including metformin/placebo, will be dispensed following the day 21 appointment.
Stimulation with 100 IU recombinant follicle stimulating hormone (rFSH) (Puregon) would commence on the evening of day 2 of the cycle following confirmation by transvaginal ultrasound scanning (TVUSS) the endometrial thickness was less than 4 mm and that the ovaries were quiescent (no follicle greater than 10 mm). Women will be asked to return on day 6 of the cycle following 5 days of stimulation, orgalutran 0.25 milligrams will be started. Participants will then be reviewed on alternate days until the lead follicle is greater than 15 mm and daily thereafter. 5,000 units human chorionic gonadotrophin (hCG) will be administered 36 hours prior to oocyte retrieval when there were three or more follicles over 17 mm in diameter.
Oocyte retrieval would be performed under conscious sedation (midazolam and fentanyl) using the standard ultrasound guided transvaginal approach. Oocytes would be inseminated (IVF) or injected (intra-cytoplasmic sperm injection [ICSI]) within 4 hours of oocyte retrieval. Embryo replacement would be carried out 2 days following oocyte retrieval. Embryo transfer would be ultrasound guided using a Wallace embryo replacement catheter. The two best quality embryos would be selected for transfer. Luteal phase progestogen support with per vaginal cyclogest (400 mg) would be commenced and continue until the day of the pregnancy test.
A pregnancy test (serum hCG) would be carried out 14 days following oocyte retrieval. A positive pregnancy test would be recorded if serum hCG was found to be greater than 2 IU/l. A TVUSS would be arranged for all women with a positive pregnancy test at 4 weeks after the embryo transfer.
Treatment arm: placebo -
Following a spontaneous or induced withdrawal bleed subjects will be seen on day 21 of their menstrual cycle prior to starting IVF treatment. Patients will be randomised to either metformin or placebo. One tablet (placebo) would be taken 12-hourly from the day 21 appointment until the day of oocyte retrieval, approximately 21 days. Both patients and investigators will be blinded to whether they are taking placebo or metformin. The placebo will be packaged and labelled as such so that the patient is blinded to whether it is metformin or placebo but with sufficient information to inform how to take the medication. All medications for the treatment cycle, including metformin/placebo, will be dispensed following the day 21 appointment.
Stimulation with 100 IU rFSH (Puregon) would commence on the evening of day 2 of the cycle following confirmation by TVUSS the endometrial thickness was less than 4 mm and that the ovaries were quiescent (no follicle greater than 10 mm). Women will be asked to return on day 6 of the cycle following 5 days of stimulation, orgalutran 0.25 mg will be started. Participants will then be reviewed on alternate days until the lead follicle is greater than 15 mm and daily thereafter. 5,000 units human chorionic gonadotrophin (hCG) will be administered 36 hours prior to oocyte retrieval when there were three or more follicles over 17 mm in diameter.
Oocyte retrieval would be performed under conscious sedation (midazolam and fentanyl) using the standard ultrasound guided transvaginal approach. Oocytes would be inseminated (IVF) or injected (ICSI) within 4 hours of oocyte retrieval. Embryo replacement would be carried out 2 days following oocyte retrieval. Embryo transfer would be ultrasound guided using a Wallace embryo replacement catheter. The two best quality embryos would be selected for transfer. Luteal phase progestogen support with per vaginal cyclogest (400 mg) would be commenced and continue until the day of the pregnancy test.
A pregnancy test (serum hCG) would be carried out 14 days following oocyte retrieval. A positive pregnancy test would be recorded if serum hCG was found to be greater than 2 IU/l. A TVUSS would be arranged for all women with a positive pregnancy test at 4 weeks after the embryo transfer.
Intervention type
Drug
Phase
Phase IV
Drug names
Metformin, gonadotrophin-releasing hormone (GnRH) antagonist
Primary outcome measure
Incidence of confirmed moderate and severe ovarian hyperstimulation syndrome (OHSS) requiring hospitalisation within 6 weeks of IVF treatment cycle. Aim to determine if metformin reduces incidence.
Secondary outcome measures
1. Stimulation based measures:
1.1. Incidence of mild OHSS
1.2. Duration of stimulation (days)
1.3. Total dose of FSH used (units)
1.4. Number of follicles greater than 10 mm
1.5. Number of cycles cancelled
2. Biochemistry based measures:
2.1. Oestradiol concentration on day of oocyte retrieval
2.2. Anti-Mullerian Hormone (AMH) on day of oocyte retrieval
2.3. Testosterone concentration on day of oocyte retrieval
2.4. Fasting insulin concentration on day of oocyte retrieval
2.5. Fasting glucose on day on oocyte retrieval
2.6. Serum VEGF concentration on day of oocyte retrieval
2.7. Full blood count (FBC) on day of oocyte retrieval, embryo transfer and day 3 post transfer
2.8. Urea, creatinine and electrolytes (U&E) on day of oocyte retrieval, embryo transfer and day 3 post transfer
2.9. Liver function tests (LFT) on day of oocyte retrieval, embryo transfer and day 3 post transfer
3. Embryology based measures:
3.1. Number of oocytes collected
3.2. Number of metaphase II oocytes for fertilisation
3.3. Number of embryos
3.4. Number of embryos available for freezing
3.5. Quality of embryos
4. Pregnancy outcomes:
4.1. Biochemical pregnancy rate (positive serum hCG)
4.2. Clinical pregnancy rate (pregnancy demonstrable on USS)
4.3. Live birth rate
Overall trial start date
01/06/2009
Overall trial end date
01/09/2010
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Women with a known diagnosis of PCOS (as defined by the Rotterdam European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine [ESHRE/ASRM] sponsored PCOS consensus workshop group, 2004)
2. Women must have a normal serum follicular stimulating hormone (FSH) concentration (reference range 1 - 8.0 iU/L)
3. Women must be 20 - 39 years of age
4. Women must have a body mass index (BMI) less than or equal to 35 kg/m^2
5. Pre-treatment inclusion criteria to include:
5.1. Serum testosterone level less than 5.0 nmol/l
5.2. Normal prolactin level (reference range less than 600 mU/L)
5.3. Normal thyroid function test level (thyroid stimulating hormone [TSH] reference range 0.2 - 6.0 mIU/L)
5.4. Normal renal, liver and haematological indices
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
200
Participant exclusion criteria
1. Women on other oral-antidiabetic agents or blood-glucose lowering preparations
2. Women taking phenprocoumon
3. Women taking antivirals such as didanosine, stavudine, tenofovir
4. Women taking cimetidine
5. Women taking ketofen
6. Women who have radiological examinations using contrast media within the preceding 48 hours
7. Women with renal or hepatic impairment
8. Women who have had a recent myocardial infarct
9. Women with known vitamin B12 deficiency
Recruitment start date
01/06/2009
Recruitment end date
01/09/2010
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Reproductive Medicine Unit
Leeds
LS2 9NS
United Kingdom
Sponsor information
Organisation
Leeds Teaching Hospitals NHS Trust (UK)
Sponsor details
Research and Development Directorate
The General Infirmary at Leeds
34 Hyde Terrace
Leeds
LS9 6LN
United Kingdom
Sponsor type
Government
Website
Funders
Funder type
Hospital/treatment centre
Funder name
Leeds General Infirmary (UK) - Reproductive Medicine Unit
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list