Condition category
Nutritional, Metabolic, Endocrine
Date applied
07/04/2009
Date assigned
25/06/2009
Last edited
12/07/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Prof Adam Balen

ORCID ID

Contact details

Reproductive Medicine Unit
Clarendon Wing
Leeds General Infirmary
Belmont Grove
Leeds
LS2 9NS
United Kingdom

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 measures

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

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

http://www.leedsteachinghospitals.com/

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

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

12/07/2016: No publications found, verifying study status with principal investigator.