Plain English Summary
Background and study aims
Polycystic ovary syndrome (PCOS) affects 20% of women. Women with PCOS may not release eggs from their ovaries; this is called anovulation. The first line treatment for anovulation is a medicine called clomifene (formerly known as clomiphene). Current clinical guidelines in the UK recommend the use of clomifene with or without another medicine, metformin, for a maximum of 6 menstrual cycles. Clomifene treatment does not result in pregnancy for approximately 70% of women despite prolonged treatment. Furthermore, clomifene is associated with numerous side effects and a 10-fold increase in the risk of multiple pregnancy.
Recently there has been growing interest in the use of another medicine, letrozole, to treat infertility in women with PCOS. Letrozole works differently to clomifene and has fewer side effects, including a lower risk of multiple pregnancy. A recent review of studies involving all available medicines for women with PCOS and infertility has indicated that letrozole may be more effective than clomifene when used alone, and there may be additional value when it is combined with metformin.
This trial has been developed in consultation with two patient representation groups, Fertility Network UK and the Women’s Network of the RCOG.
Who can participate?
Adult women diagnosed with PCOS seeking fertility treatment to participate in this study
What does the study involve?
Participants will be allocated to clomifene or letrozole, which they will take for 5 days at the beginning of each menstrual cycle. Participants will also be given metformin or a dummy drug to be used alongside clomifene or letrozole but this use will continue up until the first 14 weeks of pregnancy. Clomifene or letrozole treatment will be offered for up to 6 treatment cycles, to match the current guidelines. The allocation of treatment will be decided at random by a computer, and neither the participants nor the researchers will know what treatment a patient is receiving; this arrangement is necessary to test the treatments fairly. The main outcome evaluated will be whether a participant has a live birth. A number of other key outcomes such as ovulation rate, miscarriage, multiple pregnancy and newborn outcomes will also
What are the possible benefits and risks of participating?
Benefits
At the moment there is not enough evidence to say which treatment is best for ovulation induction and a successful pregnancy outcome.
We do not know whether participants will benefit personally from taking part in this study, but the knowledge gained will inform future treatment and potentially lead to improved treatment for ovulation induction for women in the future.
Risks/side effects
The most common side effect of taking clomifene or letrozole is hot flushes, as well as occasional fatigue and dizziness. Metformin can often cause stomach upset and sickness. Treatment with letrozole is off-license as the drug company has not applied for a specific license to allow treatment for fertility and is therefore not approved for ovulation induction.
Where is the study run from?
Birmingham Clinical Trials Unit, UK
When is the study starting and how long is it expected to run for?
March 2020 to July 2023
Who is funding the study?
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC), UK
Who is the main contact?
Lee Priest
l.priest.1@bham.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Mr Lee Priest
ORCID ID
Contact details
Birmingham Clinical Trials Unit (BCTU)
Institute of Applied Health Research
Public Health Building
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 4146665
l.priest.1@bham.ac.uk
Additional identifiers
EudraCT number
2018-004641-16
ClinicalTrials.gov number
Nil known
Protocol/serial number
CPMS 42795
Study information
Scientific title
Letrozole or Clomifene, with or without metformin, for ovulation induction in women with polycystic ovary syndrome: a 2x2 factorial design randomised trial (the LOCI trial)
Acronym
LOCI
Study hypothesis
In women with PCOS and infertility, letrozole plus metformin versus clomifene plus metformin increases the live birth rate (≥34 weeks of gestation) by at least 10%
Ethics approval
Approved 18/12/2019, West Midlands - Edgbaston Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT; +44 (0)2071048089; NRESCommittee.WestMidlands-Edgbaston@nhs.net), ref: 19/WM/0364
Study design
Interventional randomized 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 to request a patient information sheet
Condition
Polycystic ovarian syndrome
Intervention
Participants will be randomised on-line via a secure internet facility at the level of the individual in a 1:1 ratio to either letrozole or clomifene and at the same time randomised to metformin or placebo.
Planned IMP interventions: Letrozole oral tablet 2.5-7.5mg daily or clomifene 50-150mg daily for 5 days of each menstrual cycle for up to 6 treatment cycles, with concomitant randomisation to an escalating dose of metformin to 1500mg or placebo daily. Letrozole, clomifene, metformin and placebo will be provided as over-encapsulated tablets in numbered treatment packages. The Metformin/placebo will be provided at the same time as letrozole/clomifene.
Dose: The ideal dose of letrozole and clomifene for ovulation induction is not known. The choice of 2.5mg for letrozole and allowing for 2 dose escalations up to 7.5mg was made after a) careful review of the existing literature, b) a survey of UK health professionals who use letrozole for this indication, and c) reviewing the safety profile of the drug in a previous large randomised trial involving letrozole.14 Summary of Product Characteristics and the British National Formulary15 suggest a starting dose of 2.5mg. The choice of clomifene 50mg with 2 dose escalations up to 150mg was based on NICE recommendations.3 Our systematic review of literature and UK-wide survey of health professionals supported these regimens. The choice of metformin dose was based on our systematic review of literature and the UK-wide survey of health professionals. However, when clinicians feel the participant should be started on a higher dose because of previous cycle experience or preference, this will be allowed for a maximum of 3 tablets daily.
Route: All drugs are recommended for oral use.
Regimen: Letrozole and clomifene will be given for 5 days starting on day 2 or 3 of the menstrual cycle or following the start of withdrawal bleeding for up to 6 treatment cycles (Table 1). This regimen was the most commonly used in our survey of UK health professionals. The dose of metformin will be increased gradually from 500mg daily for the 1st week, 500mg twice daily for the 2nd week, and 500mg thrice daily from the 3rd week, and continued until the end of treatment or up to 14 weeks of pregnancy (Table 2). The gradual increase of metformin was suggested by our national investigator group to minimise the side-effects of metformin. Metformin will be continued up to 14 weeks of pregnancy as this was the most commonly used regimen in our national survey of UK health professionals. However, when clinicians feel the participant should be started on a higher dose because of previous experience or preference, this will be allowed for a maximum of 3 tablets daily.
Intervention type
Drug
Phase
Phase III
Drug names
Clomifene, letrozole
Primary outcome measure
Live births at and beyond 34 completed weeks of gestation measured using patient records
Secondary outcome measures
Measured using patient records:
1. Miscarriage rate (defined as delivery before 24 weeks of gestation).
2. Ongoing pregnancy at 12 weeks (range 11 to 14 weeks) of gestation.
3. Multiple pregnancies.
4. Ovulation rate
5. Time to pregnancy
Overall trial start date
01/04/2019
Overall trial end date
31/07/2023
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Women diagnosed with PCOS (according to Rotterdam criteria) and evidence of anovulation (anovulation is defined as irregular cycles lasting <21 or more than 35 days or less than 8 periods per year OR absence of raised serum progesterone greater than 20nmol/l 7 days prior to a period)
2. Presentation with infertility or wishing to conceive
3. Male partner with normal sperm count (>=15 million) and progressive motility (>= 32%) in the last 3 years
4. Willing and able to give informed consent
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
Planned Sample Size: 2,100; UK Sample Size: 2,100
Participant exclusion criteria
1. Age <18 or >43 years at randomisation
2. Body Mass Index ≥35 kg/m²
3. Three or more previous ovulation induction treatments with either letrozole or clomifene
4. Currently on metformin treatment or inositol supplements for ovulation induction or for other indications
5. Women opting for alternative methods of ovulation induction or treatment (GnRH agonists and antagonists, gonadotropins), triggering ovulation with hCG, or performing intrauterine or intracervical insemination
6. Contraindications to letrozole, clomifene, metformin use and/or pregnancy (see section 7.2 for full details on contraindications)
7. Woman has previously participated in the LOCI trial
Recruitment start date
01/03/2020
Recruitment end date
31/08/2021
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Ashford and St Peter's Hospitals NHS Foundation Trust
Chertsey
KT16 0PZ
United Kingdom
Trial participating centre
Barts Health NHS Trust
The Royal London Hospital
Whitechapel Road
London
E1 1FR
United Kingdom
Trial participating centre
Barking, Havering and Redbridge University Hospitals NHS Trust
Romford
RM7 0AG
United Kingdom
Trial participating centre
Birmingham Women's and Children's NHS Foundation Trust
Steelhouse Lane
Birmingham
B4 6NH
United Kingdom
Trial participating centre
Bolton NHS Foundation Trust
Bolton
BL4 0JR
United Kingdom
Trial participating centre
Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Trial participating centre
Manchester University NHS Foundation Trust
Cobbett House
Oxford Road
Manchester
M13 9WL
United Kingdom
Trial participating centre
Countess of Chester Hospital
Chester
Cheshire
CH2 1UL
United Kingdom
Trial participating centre
County Durham and Darlington NHS Foundation Trust
Durham
DL3 6HX
United Kingdom
Trial participating centre
Dartford and Gravesham Nhs Trust
Dartford
DA2 8DA
United Kingdom
Trial participating centre
Royal Derby Hospital
Uttoxeter Road
Derby
DE22 3NE
United Kingdom
Trial participating centre
East Lancashire Hospitals Nhs Trust
Blackburn
BB2 3HH
United Kingdom
Trial participating centre
East Suffolk and North Essex Nhs Foundation Trust
Colchester
CO4 5JL
United Kingdom
Trial participating centre
Guy's and St Thomas' NHS Foundation Trust
Great Maze Pond
London
SE1 9RT
United Kingdom
Trial participating centre
Hometon University Hospital NHS Foundation Trust
Homerton Row
London
E9 6SR
United Kingdom
Trial participating centre
Imperial College Healthcare Nhs Trust
London
W2 1NY
United Kingdom
Trial participating centre
King's College Hospital Nhs Foundation Trust
London
SE5 9RS
United Kingdom
Trial participating centre
Leeds Teaching Hospitals NHS Trust
Leeds
LS9 7TF
United Kingdom
Trial participating centre
Liverpool Women's NHS Foundation Trust
Liverpool
L8 7SS
United Kingdom
Trial participating centre
London North West University Healthcare NHS Trust
Harrow
HA1 3UJ
United Kingdom
Trial participating centre
The Newcastle Upon Tyne Hospitals Nhs Foundation Trust
Newcastle-upon-Tyne
NE7 7DN
United Kingdom
Trial participating centre
Frimley Health NHS Foundation Trust
Camberley
GU16 7UJ
United Kingdom
Trial participating centre
NHS Grampian
Aberdeen
AB15 6RE
United Kingdom
Trial participating centre
NHS Greater Glasgow and Clyde
Glasgow
G12 0XH
United Kingdom
Trial participating centre
NHS Lothian
Edinburgh
EH1 3EG
United Kingdom
Trial participating centre
Nottingham University Hospitals Nhs Trust
Nottingham
NG7 2UH
United Kingdom
Trial participating centre
Oxford University Hospitals Nhs Foundation Trust
Oxford
OX3 9DU
United Kingdom
Trial participating centre
Royal Berkshire Nhs Foundation Trust
Reading
RG1 5AN
United Kingdom
Trial participating centre
Salisbury Nhs Foundation Trust
Salisbury
SP2 8BJ
United Kingdom
Trial participating centre
South Tees Hospitals Nhs Foundation Trust
Middlesbrough
TS4 3BW
United Kingdom
Trial participating centre
Southend University Hospital Nhs Foundation Trust
Southend-on-Sea
SS0 0RY
United Kingdom
Trial participating centre
St Helens And Knowsley Hospital Services Nhs Trust
Prescot
L35 5DR
United Kingdom
Trial participating centre
The Hillingdon Hospitals Nhs Foundation Trust
Uxbridge
UB8 3NN
United Kingdom
Trial participating centre
The Rotherham Nhs Foundation Trust
Rotherham
S60 2UD
United Kingdom
Trial participating centre
Whittington Health Nhs Trust
London
N19 5NF
United Kingdom
Trial participating centre
University College London Hospitals Nhs Foundation Trust
London
NW1 2PG
United Kingdom
Trial participating centre
University Hospitals Birmingham Nhs Foundation Trust
Birmingham
B15 2TH
United Kingdom
Trial participating centre
University Hospital Southampton Nhs Foundation Trust
Southampton
SO16 6YD
United Kingdom
Trial participating centre
University Hospitals Coventry And Warwickshire Nhs Trust
Coventry
CV2 2DX
United Kingdom
Trial participating centre
University Hospitals Of Leicester Nhs Trust
Leicester
LE1 5WW
United Kingdom
Trial participating centre
University Hospitals Of North Midlands Nhs Trust
Stoke-on-Trent
ST4 6QG
United Kingdom
Trial participating centre
West Hertfordshire Hospitals Nhs Trust
Watford
WD18 0HB
United Kingdom
Trial participating centre
Wirral University Teaching Hospital Nhs Foundation Trust
Wirral
CH49 5PE
United Kingdom
Trial participating centre
Worcestershire Acute Hospitals Nhs Trust
Worcester
WR5 1DD
United Kingdom
Trial participating centre
Wrightington, Wigan And Leigh Nhs Foundation Trust
Wigan
WN1 2NN
United Kingdom
Trial participating centre
Buckinghamshire Healthcare Nhs Trust
Amersham
HP7 0JD
United Kingdom
Trial participating centre
South Tyneside Nhs Foundation Trust
South Shields
NE34 0PL
United Kingdom
Sponsor information
Organisation
University of Birmingham
Sponsor details
Room 119
Aston Webb Building
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)1214158011
researchgovernance@contacts.bham.ac.uk
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Government
Funder name
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 17/116/01
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
National Institute for Health Research (NIHR) (UK)
Alternative name(s)
NIHR
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal.
IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date
Intention to publish date
14/03/2024
Participant level data
To be made available at a later date
Basic results (scientific)
Publication list