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)
Funder: Department of Health and Social Care

Abstract: BACKGROUND_x000D_ This proposal responds to a commissioned call by the NIHR HTA Board. Polycystic ovary syndrome (PCOS) affects 20% of women. It is one of the leading causes of infertility in the UK (fertilitynetworkuk.org). 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. _x000D_ _x000D_ 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. Multiple pregnancy is the single greatest risk of fertility treatment as it carries a threat to the health of the mother and unborn children. Therefore, there is an urgent need for more effective and safer treatment options._x000D_ _x000D_ 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. The World Health Organisation supports its use, but the current lack of research evidence prevented UK guideline developers (NICE) from including letrozole in their latest recommendations. 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. However, uncertainties remain due to the poor quality of existing clinical trials. The most effective drug or combination of drugs needs to be determined in a high quality research study to ensure that women are offered the best available care with minimum side effects and spared the need for more invasive and costlier fertility treatments._x000D_ _x000D_ THE RESEARCH TRIAL_x000D_ This trial has been developed in consultation with two patient representation groups, Fertility Network UK and the Women’s Network of the RCOG. We plan to ask women diagnosed with PCOS seeking fertility treatment to participate in this study. 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 be assessed. We will also perform a health economic evaluation to understand the cost implications. Furthermore, we will seek permission from patients for longer term follow up of the children conceived on treatments; this will be undertaken as a future project.

Lay abstract: Design: A 2x2 factorial randomised, double-blind, placebo-controlled multi-centre study, with health economic evaluation and a six month internal pilot to ensure ability to recruit and randomise._x000D_ _x000D_ Setting: Fertility clinics at secondary and tertiary level hospitals across the UK._x000D_ _x000D_ Target population: Women with PCOS and infertility. Exclusion criteria: women who have previously had more than three cycles of ovulation induction with clomifene or letrozole, or have contraindications to any of the trial drugs._x000D_ _x000D_ Health technologies assessed: Letrozole for 5 days starting on day 2 or 3 of the menstrual cycle, plus metformin or placebo daily. Initial letrozole dose will be 2.5mg daily and increased to a maximum dose of 7.5mg daily until ovulation is confirmed for a maximum of 6 treatment cycles. 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 until 14 weeks of pregnancy. The comparison will be clomifene for 5 days starting on day 2 or 3 of the menstrual cycle, plus metformin or placebo daily. Initial clomifene dose will be 50mg daily and increased to a maximum dose of 150mg in a similar way to letrozole for a maximum of 6 treatment cycles. Metformin or placebo regimen will be administered as described in the intervention arm above._x000D_ _x000D_ Treatment allocation: Participants will be allocated to the interventional arms via a third-party minimisation algorithm, ensuring balance for age, BMI, previous pregnancy and cycle regularity._x000D_ _x000D_ Outcomes: Primary – live birth greater than or equal to 34 weeks of gestation. Key secondary – pregnancy loss (defined as pregnancy loss before 24 weeks of gestation), number of ovulation induction cycles to live birth. Other secondary - ovulation rate, multiple pregnancy, neonatal outcome at 28 days after birth and other key outcomes including resource use outcomes to facilitate the health economic evaluation._x000D_ _x000D_ Follow up: A maximum of 6 treatment cycles with follow-up up to 28 days after live birth. _x000D_ _x000D_ Statistical analysis and sample size: The sample size will be at least 1600, allowing >80% power (at p=0.05) to detect a 10% difference in the letrozole vs clomifene comparison and the same power to detect differences in the metformin vs placebo comparison. The 10% absolute increase was identified in our survey as clinically minimally important and is supported by our systematic review. This sample size will ensure that the study will have 1050 participants and 90% power (at p=0.05) to answer the question posed in the commissioning brief (letrozole + metformin vs clomifene + metformin). No interaction of metformin with letrozole or clomifene in terms of outcome is expected as the biological mechanisms are different, but this will be examined in our analysis._x000D_ _x000D_ Health economics: A cost-effectiveness analysis will be undertaken, with cost per additional livebirth = 34 weeks of gestation as the primary health economic outcome. The economic evaluation will explore the cost-effectiveness of letrozole versus clomifene and the value of adding metformin. The analysis will be carried out from an NHS/PSS perspective based on the outcomes of cost per live birth and cost per QALY, estimated through individual responses to the EQ-5D-5L. Resource use associated with ovulation induction for PCOS and complications will be prospectively collected and unit costs will be applied from standard national UK sources. An incremental analysis will be conducted and decision uncertainty will be shown using cost-effectiveness acceptability curves.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH