Clinical trial NCT02648698
Conditions: Chronic Endometritis
Keywords: chronic endometritis CD138 antibiotic conversion rate.
Sponsor: Fu Xing Hospital, Capital Medical University
Start date: 2016-01-10; Completion date: 2018-12-15
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
120 cases with a diagnosis of chronic endometritis, confirmed by the presence of plasma cells in endometrial biopsy sample identified by immunohistochemical staining using CD138 antibody, have been recruited. The subjects have been randomly divided into two groups, the experimental group have been given antibiotic (Levofloxacin and Tinidazole for 14 days) treatment, the control group did not receive any antibiotic. Initially it was planned for women in the control group to take placebo,but the organization was difficult, so it was changed prior to the start of the study to an open label study. A repeat endometrial biopsy sample have been obtained 2-4 weeks after completion of the antibiotic therapy to assess the response to treatment. The conversion rate will be compared between the two groups

Detailed description:
This study will be carried out at the Hysteroscopy centre of the Fuxing Hospital, Capital Medical University ,Beijing, China. A total of 120 women with chronic endometritis who fulfilled the following inclusion criteria will be recruited:

1. CD138 immunohistochemical staining of endometrial specimen showed presence of one or more plasma cells per 10HPF which confirmed chronic endometritis, according to published criteria.
2. women who were pre-menopausal.
3. no evidence of endometrial hyperplasia or malignancy or structural uterine pathology.
4. agreement to have a second endometrial biopsy \~4 weeks after the initial endometrial biopsy.
5. written informed consent obtained

Exclusion Criteria:

1. women who received steroid hormone therapy within one month of recruitment.
2. allergy or suspected allergy to the chosen antibiotic therapy.
3. women who developed any concurrent infection and received any antibiotic therapy during the period of study other than the one prescribed according to the study protocol.

Power calculation: Assuming that the spontaneous CD138 conversion (from positive to negative ) rate is 25% and that the antibiotic therapy results in 60% conversion rate, the total number of subjects required in each arm of the RCT will be 37, accepting a Type I error of 0.05 and a Type II error of 0.1, and assuming a drop-out rate of 20%, 45 subjects will need to be recruited into each arm. Hence, a total of 90 subjects who fulfilled the inclusion criteria will be required.

Recruitment: Women have been recruited form the day case hysteroscopy unit of the Hysteroscopy center, Fuxing Hospital, Beijing, China. The Hysteroscopy center currently carries out \~600 day case hysteroscopy per month. In all cases, endometrial biopsy specimen will be obtained at the time of hysteroscopy for histological evaluation. Since 2013, all endometrial specimens have been routinely examined with the used of CD138 antibody to establish if there is evidence of chronic endometritis, in addition to routine histopathological examination. Previous audit showed that \~15% of subjects had positive staining for CD138 cells.We recruited the initial 132 subjects according to the inclusion and exclusion criteria succesfully from July 2016 to December 2018.

Randomization:Women who had histological confirmation of CE in an endometrial biopsy specimen and who fulfilled the inclusion criteria were randomized into the antibiotic group and control group in a 1:1 ratio using a computer-generated randomization list and sealed opaque envelopes prepared by the first author. The patients were not blinded to the antibiotic treatment. The pathologist who performed the histological evaluation was blinded to the treatment.

Antibiotic therapy: Women who were randomized to the treatment group were given oral Levofloxacin and Tinidazole daily for 14 days.

Women who were randomized to the control group did not receive any antibiotic. Staff Pharmacist dispense medication.

Consent: written informed consent will be obtained

Repeat endometrial biopsy \& histological evaluation: The repeat endometrial biopsy will be performed after completion of the the antibiotic therapy. Immunohistochemical study using CD138 antibody will be performed.

Arms: arm 1: This group received antibiotic therapy arm 2: This group did not receive antibiotic therapy
Interventions: intervention 1: Antibiotics
Intervention descriptions: intervention 1: Levofloxacin Tab and Tinidazole Tab are combined in the antibiotic group

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
RCT (Randomized Clinical Trial) of 
Antibiotic Therapy in Chronic Endometritis 
 
 
 
 
 
 
 
NCT 02648698 
 
Date: May 30, 2020 
 
 
 
 


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study protocol 
 
Background 
   Chronic endometritis (CE) is a condition characterized by the presence of plasma 
cell in the endometrial stroma. CE may be associated with abnormal uterine bleeding, 
intrauterine pathology such as polyp or fibroid, as well as a variety of reproductive 
failure including infertility, recurrent implantation failure and recurrent pregnancy 
loss. In women with reproductive failure, the reported prevalence of CE maybe as 
high as 41%.  
CE is often treated with antibiotics on the assumption that it is caused by an  
underlying infection. The response of CE to antibiotic therapy has been examined in a 
number of cohort studies. The cure rate, as determined by reduction of plasma cell 
density in a repeat endometrial biopsy specimen following antibiotic therapy was 
found to be 75.4%, 99% and 100%.  
The impact of antibiotic therapy on clinical outcome among subjects with CE 
had also been examined in several cohort studies. Cicinelli et al conducted a 
retrospective study which showed that after antibiotic therapy, the pregnancy rate 
(PR) and live birth rate (LBR) in women who become CE negative was higher than 
those who remained CE positive after antibiotic treatment (65.2% versus 33.0% ; 
60.8% versus 13.3%, respectively) . In another study involing women with recurrent 
implantation failure (RIF) study, Kitaya et al. reported that the LBR in the first 
embryo transform (ET) cycle and cumulative three ET cycles in the cured CE group 
following antibiotic treatment (32.8% and 38.8%, respectively) was significantly 
higher than those of the non-CE group (22.1% and 27.9%, respectively). McQueen et 
al observed that the cumulative LBR was 88% (21/24) for the treated CE group versus 
74% (180/244) for the group without CE. In the CE group, the LBR for those before 
treatment was 7% (7/98) versus 56% (28/50) after treatment.  
Despite the apparently encouraging clinical data from the above observational, 
cohort studies suggesting that antibiotic treatment was effective in curing CE and 


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improving the reproductive outcome, the impact of antibiotic therapy has not yet been 
formally examined in any randomized control trial.  
 
Objective  
To compare the cure rate of chronic endometritis between subjects who did and 
did not receive antibiotic treatment.  
Design 
 Prospective, Single-blind randomized, controlled trial. 
 This RCT was conducted in the Hysteroscopic Centre, Fuxing Hospital, Capital 
Medical University, a national training centre for hysteroscopy in China between 2016 
and 2018. During the period of study, women who were referred to the center for 
hysteroscopy for investigation of reproductive failure including infertility, recurrent 
miscarriage (RM) or recurrent implantation failure (RIF), as well as abnormal 
menstruation had endometrial biopsy obtained for histological examination including 
CD138 immunohistochemical staining as a routine procedure.  
The inclusion criteria for patient participation in this study included: (1) CD138 
immunohistochemical staining of endometrial specimen showed presence of one or 
more plasma cells per 10HPF which confirmed chronic endometritis, according to 
published criteria; (2) women who were pre-menopausal; (3) no evidence of 
endometrial hyperplasia or malignancy or structural uterine pathology; (4) agreement 
to have a second endometrial biopsy ~4 weeks after the initial endometrial biopsy; 
and (5) written informed consent obtained.  
The exclusion criteria included: (1) women who received steroid hormone 
therapy within one month of recruitment; (2) allergy or suspected allergy to the 
chosen antibiotic therapy; (3) women who developed any concurrent infection and 
received any antibiotic therapy during the period of study other than the one 
prescribed according to the study protocol.  
 
 


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A total of 120 subjects were randomized in antibiotic group and control group in 
a 1:1 ratio using a computer-generated randomization list, 6 subjects did not attend 
for second hysteroscopy and endometrial biopsy. At the end, 59 subjects in the 
antibiotic group and 55 subjects in the control group completed the study according 
to the protocol, these 114 cases were included in the final analysis. 
 
Methods  
Women randomized to antibiotic group received oral Levofloxacin 500 mg and 
Tinidazole 1000 mg daily for 14 days. Women randomized to the control group did 
not receive any treatment. Initially it was planned for women in the control group to 
take placebo, but the organization was difficult, so it was changed prior to the start of 


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the study to an open label study. A repeat endometrial biopsy was performed 4-8 
weeks after the initial biopsy to determine if CE was still present.  
The conversion rate of CE (from positive to negative) in two group were 
compared.  
 
 
statistical analysis plan 
The comparison of results between the two groups was made with the use of an 
independent-sample t-test for continuous variables and contingency table analysis for 
categorical variables. A P value of <.05 was considered to be significant. All statistical 
tests were two sided. Statistical analysis was performed with the use of SPSS for PC 
version 21(2016).