Comparison of letrozole or clomifene for ovulation induction in women with polycystic ovarian syndrome
| ISRCTN | ISRCTN11828358 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11828358 |
| EudraCT/CTIS number | 2018-004641-16 |
| IRAS number | 257918 |
| Secondary identifying numbers | CPMS 42795, IRAS 257918 |
- Submission date
- 16/12/2019
- Registration date
- 07/01/2020
- Last edited
- 13/06/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
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 August 2025
Who is funding the study?
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC), UK
Who is the main contact?
Georgia Mitchell, g.mitchell.1@bham.ac.uk
Contact information
Scientific
Birmingham Clinical Trials Unit (BCTU)
Institute of Applied Health Research
Public Health Building
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0)121 4146665 |
|---|---|
| g.mitchell.1@bham.ac.uk |
Study information
| Study design | Interventional randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| 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) |
| Study acronym | LOCI |
| Study objectives | Current study hypothesis as of 25/02/2025: In women with PCOS and infertility, letrozole versus clomifene, metformin versus placebo, and letrozole plus metformin versus clomifene plus metformin increases the live birth rate (≥34 weeks of gestation) by at least 10%. Previous 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(s) | Approved 18/12/2019, West Midlands - Edgbaston Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT; +44 (0)2071048089; Edgbaston@nhs.net), ref: 19/WM/0364 |
| Health condition(s) or problem(s) studied | 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Clomifene, letrozole |
| Primary outcome measure | Current primary outcome measure as of 25/02/2025: Live births at and beyond 34 completed weeks of gestation, as a proportion of all women randomised - measured by patient records Previous primary outcome measure: Live births at and beyond 34 completed weeks of gestation measured using patient records |
| Secondary outcome measures | Current secondary outcome measures as of 25/02/2025: Measured using patient records: 1. Treatment outcomes: ovulation rate, pregnancy time, cycles for pregnancy/live birth at end of ovulation induction, 240 days since randomisation, booking scan form (11-14 weeks) or at pregnancy outcome (~9 months) 2. Pregnancy end outcomes: ongoing pregnancy, loss, termination, stillbirth, ectopic, multiple births at booking scan (11-14 weeks) or pregnancy outcome 3. Live birth ≥24 weeks: time to delivery, gestational age, mode of birth, birth weight, APGAR score at pregnancy outcome 4. Antenatal outcomes: antepartum haemorrhage, hypertension, pre-eclampsia, cholestasis, gestational diabetes at 28 days post pregnancy outcome 5. Intrapartum outcomes: chorioamnionitis, fetal growth restriction, macrosomia at pregnancy outcome 6. Postpartum outcomes: haemorrhage at pregnancy outcome 7. Maternal outcomes: HDU/ITU admission at 28 days post live birth 8. Neonatal outcomes: discharge, early infection, retinopathy, NEC, intraventricular haemorrhage, RDS, ventilation at 28 days post birth 9. Neonatal survival: 28-day survival at 28 days post live birth 10. Health economic evaluation: EQ-5D-5L at baseline, booking scan (month 4-9), and end of trial (month 2-18) Previous 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 study start date | 01/04/2019 |
| Completion date | 30/08/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 42 Years |
| Sex | Female |
| Target number of participants | Planned Sample Size: 1,700; UK Sample Size: 1,700 |
| Total final enrolment | 1739 |
| Key inclusion criteria | Current inclusion criteria as of 17/10/2022: 1. Women diagnosed with PCOS (according to Rotterdam criteria) and evidence of anovulation (defined as irregular cycles lasting <21 or >35 days, fewer than 8 periods per year, or absence of raised serum progesterone >20 nmol/l seven days prior to a period) 2. Presentation with infertility or wishing to conceive 3. Male partner with normal sperm count (≥15 million/ml) and progressive motility ≥32% or total motility ≥40% in the last 3 years 4. Willing and able to give informed consent 5. Aged ≥18 to ≤42 years at randomisation 6. Body Mass Index ≤35 kg/m² _____ Previous 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 |
| Key exclusion criteria | Current exclusion criteria as of 17/10/2022: 1. More than six previous ovulation induction treatments (cycles) with either letrozole or clomifene in the previous 12 months 2. Intention to continue current use of metformin treatment for ovulation induction or for other indications 3. Metformin use in the previous 14 days 4. 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 5. Contraindications to letrozole, clomifene, metformin use and/or pregnancy 6. Woman has previously participated in the LOCI trial _____ Previous 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 |
| Date of first enrolment | 01/03/2020 |
| Date of final enrolment | 29/02/2024 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
KT16 0PZ
United Kingdom
Whitechapel Road
London
E1 1FR
United Kingdom
RM7 0AG
United Kingdom
Birmingham
B4 6NH
United Kingdom
BL4 0JR
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Oxford Road
Manchester
M13 9WL
United Kingdom
Cheshire
CH2 1UL
United Kingdom
DL3 6HX
United Kingdom
DA2 8DA
United Kingdom
Derby
DE22 3NE
United Kingdom
BB2 3HH
United Kingdom
CO4 5JL
United Kingdom
London
SE1 9RT
United Kingdom
SE5 9RS
United Kingdom
LS9 7TF
United Kingdom
L8 7SS
United Kingdom
HA1 3UJ
United Kingdom
NE7 7DN
United Kingdom
AB15 6RE
United Kingdom
G12 0XH
United Kingdom
EH1 3EG
United Kingdom
NG7 2UH
United Kingdom
OX3 9DU
United Kingdom
SP2 8BJ
United Kingdom
TS4 3BW
United Kingdom
SS0 0RY
United Kingdom
NW1 2PG
United Kingdom
B15 2TH
United Kingdom
SO16 6YD
United Kingdom
CV2 2DX
United Kingdom
LE1 5WW
United Kingdom
ST4 6QG
United Kingdom
CH49 5PE
United Kingdom
WR5 1DD
United Kingdom
WN1 2NN
United Kingdom
HP7 0JD
United Kingdom
NE34 0PL
United Kingdom
Bridgend
Bridgend County Borough
CF31 1RQ
United Kingdom
Newport
NP20 2UB
United Kingdom
Larbert
FK5 4WR
United Kingdom
Farnworth
Bolton
BL4 0JR
United Kingdom
Carmarthen
SA31 2AF
United Kingdom
Sponsor information
University/education
Room 119, Aston Webb Building
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)1214158011 |
|---|---|
| researchgovernance@contacts.bham.ac.uk | |
| Website | http://www.birmingham.ac.uk/index.aspx |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Government
No information available
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/08/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The current data sharing plans for this study are unknown and will be available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Statistical Analysis Plan | version 1.0 | 12/12/2023 | 16/02/2024 | No | No |
| Protocol file | version 7.0 | 28/11/2023 | 20/02/2024 | No | No |
| Protocol file | version 8.0 | 14/02/2025 | 13/06/2025 | No | No |
Additional files
Editorial Notes
13/06/2025: Protocol uploaded.
25/02/2025: The study hypothesis, ethics approval, primary and secondary outcome measures were updated. Total final enrolment added.
20/02/2024: The following changes were made to the study record:
1. Protocol uploaded.
2. The target number of participants was changed from 'Planned Sample Size: 1,600; UK Sample Size: 1,600' to 'Planned Sample Size: 1,700; UK Sample Size: 1,700'.
3. Frimley Health NHS Foundation Trust, The Rotherham Nhs Foundation Trust, and West Hertfordshire Hospitals Nhs Trust were removed from the study participating centres.
16/02/2024: The statistical analysis plan was uploaded as an additional file.
11/10/2023: The study participating centres were updated to remove Homerton University Hospital NHS Foundation Trust, Imperial College Healthcare Nhs Trust, Royal Berkshire Nhs Foundation Trust, St Helens And Knowsley Hospital Services Nhs Trust, The Hillingdon Hospitals Nhs Foundation Trust, and Whittington Health Nhs Trust.
10/10/2023: The following changes were made to the trial record:
1. The recruitment end date
2. The contact was changed.
10/10/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/10/2023 to 29/02/2024.
2. The IRAS number was added.
3. The study participating centres The Princess of Wales (Cwm Tam), The Royal Gwent, Forth Valley Royal Hospital, The Royal Bolton, West Wales General Hospital were added.
16/12/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/08/2021 to 31/10/2023.
2. The overall end date was changed from 28/02/2023 to 30/08/2025.
3. The plain English summary was updated to reflect these changes.
4. The target number of participants was changed from 2100 to 1600.
5. The intention to publish date was changed from 14/03/2024 to 30/08/2026.
17/10/2022: The following changes have been made:
1. The overall trial end date has been changed from 31/07/2023 to 28/02/2023 and the plain English summary updated accordingly.
2. The trial website has been added.
3. The participant inclusion criteria have been changed.
4. The participant exclusion criteria have been changed.
20/09/2021: Internal review.
13/08/2020: Internal review.
16/12/2019: Trial's existence confirmed by the NIHR.
