Title: Chronic Endometritis and Recurrent Miscarriage - The CERM trial
Chief Investigator: Professor Siobhan Quenby
Sponsor: University Hospitals Coventry and Warwickshire NHS Trust
Funder: NIHR - Efficacy and Mechanism Evaluation (EME) Programme - 17/60/22
Registration Number: EudraCT number 2019-000585-38
Summary (in plain English)
Recurrent miscarriage (two or more miscarriages in a row) is very distressing for women and their partners. Most couples will only receive supportive care because there are not many treatments that can prevent miscarriage. In some women the lining of the womb (the endometrium) is inflamed (endometritis) and researchers have found a link between this and miscarriage. Researchers suspect that endometritis may be caused by an imbalance of the microbiome that live in the reproductive tract (the vagina, cervix, womb, fallopian tubes and ovaries). The microbiome is the name given to all the microbes that live in and on our bodies and is mostly made up of bacteria; everyone’s microbiome is unique. A healthy endometrium is important for the embryo to be able to attach to the womb and it is thought that endometritis disrupts this process, and can lead to a miscarriage. Treating endometritis with antibiotics may have reduced endometritis. An antibiotic called doxycycline is commonly used to treat endometritis. This treatment is available at private clinics and in some European countries but this has not been thoroughly tested.
To find out if doxycycline can reduce miscarriage and increase the number births in women who have experienced two or more early miscarriages, we will carry out a double blind randomised controlled trial, by comparing a 14-day course of doxycycline against a placebo. The trial will take place in NHS hospitals in the United Kingdom and will involve over 3,000 women who have recurrent miscarriage. Not everyone who has recurrent miscarriage has endometritis, so before a participant can take part in the trial an endometrial biopsy will be taken and examined to detect endometritis. We estimate half the women tested will have endometritis and so be able to take part in the trial. Our primary outcomes will be on-going pregnancy at 12 weeks and total live births. In this trial we will analyse the data at regular intervals to see if the trial can stop early if we find better than expected efficacy or futility. Another part of the trial is to look at the microbiome to see how antibiotics affect these. We will take swabs of the vagina, cervix and endometrium to explore whether doxycycline treatment improves CE, conception, early miscarriage, and late miscarriage.
Sample size for endometrial biopsy N=3,062.
Sample size for women who screen positive for CE and wish to enter the randomised controlled trial n=1,500, n=750 in the intervention arm (doxycycline) and n=750 in the control arm (placebo).This trial will use adaptive design methodology so the trial can stop early, with fewer than 1500 patients randomised, in the case of better than expected efficacy or in the case of futility.
Primary Outcome 1
- On-going pregnancy at 12 weeks
Primary Outcome 2
- Total live births
Duration: 48 months
Recurrent miscarriage (RM) causes considerable distress and psychological morbidity for women and their partners. The vast-majority of couples only receive supportive care, as few treatments have been shown to prevent miscarriage. There is evidence to suggest chronic endometritis (CE) is a cause of recurrent miscarriage. CE is a chronic inflammation of the endometrium, diagnosed using CD138 immunohistochemistry. The pathophysiology of CE is poorly understood but may be due to chronic infection, secondary to dysbiosis of the endometrial microbiome. Dysbiosis is caused by the presence of an array of microorganisms and a lack of lactobacilli in the endometrium. The endometrial microbiome has been proposed to be distinct from the vaginal microbiome. A comparison of the microbial profile in recurrent implantation failure patients has shown that those with CE have specific species indicative of dysbiosis and poor pregnancy outcomes. Studies have shown that antibiotics can improve CE. The most frequently used antibiotic regime in published studies is doxycycline, in addition, to its antibacterial properties, doxycycline has a well-documented anti-inflammatory effect, raising the possibility that it is useful for the treatment of CE not associated with endometrial dysbiosis. Although antibiotic treatment is available at private clinics and in some European countries, there is no robust evidence to support this approach and the effect of antibiotics on the microbiome is unclear.
To find out if doxycycline given prior to conception improves the number of on-going pregnancies and total live births in women who have experienced two or more consecutive first trimester miscarriages, we are undertaking a prospective, multi-centre, randomised, double blind adaptive designed trial. We will compare a pre-conception course of doxycycline (100mg twice daily for 14 days) to placebo in up to 1500 women with recurrent miscarriage associated with CE. Participants will be screened for CE using an endometrial biopsy. Screen positive patients will be eligible for randomisation. The use of adaptive design will allow early stoppage in the case of better than expected efficacy or in the case of futility. Primary outcomes will be on-going pregnancy at 12 weeks and total live births. A sub-group will additionally have endometrial and biopsies swabs taken both before and after intervention to assess the effect of doxycycline on, endometritis, decidualisation and the endometrial microbiome.
Email: cerm at warwick dot ac dot uk
Warwick Clinical Trials Unit
Warwick Medical School
University of Warwick
Gibbet Hill Road