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)
Polycystic ovarian syndrome
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 U
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
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