Condition category
Nutritional, Metabolic, Endocrine
Date applied
16/12/2019
Date assigned
07/01/2020
Last edited
07/01/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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)13 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: 2100; UK Sample Size: 2100

Participant exclusion criteria

1. Age < 18 or > 43 years at randomisation
2. Body Mass Index > 35
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

http://www.birmingham.ac.uk/index.aspx

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

Publication citations

Additional files

Editorial Notes

16/12/2019: Trial's existence confirmed by the NIHR.