AUTOP 2: Screen-and-treat Strategy for Vaginal Flora Abnormalities by Molecular Biology in Pregnant Women at High Risk of Preterm Birth

Official title

Screen-and-treat Strategy for Vaginal Flora Abnormalities by Molecular Biology in Pregnant Women at High Risk of Preterm Birth: A Multicentre, Randomized Study (AUTOP 2)

Overview

Preterm birth is a major cause of mortality and long-term disability. Bacterial vaginosis (BV) is a frequent form of dysbiosis that is often asymptomatic and increases the risk of preterm birth. BV is usually diagnosed using conventional tools such as the Nugent score. Molecular diagnosis of BV has now been shown to be more reproducible and to provide a more accurate characterization of dysbiosis. The main objective of this study is to evaluate the effectiveness of a self screen and treat strategy for vaginal flora dysbiosis, based on molecular point of care (POC) multiplex technology before 18 weeks' gestation, in reducing the rate of preterm birth among pregnant women at high risk, compared with usual care. The hypothesis is that a Screen-and-Treat strategy using molecular biology among women with previous preterm or/and an history of late abortion could be effective in reducing preterm births by 40%.

Detailed description

Preterm birth is an important cause of death and disabilities. Bacterial vaginosis (BV) is a common vaginal dysbiosis or abnormal microbiota, with a predominance of anaerobic bacteria with a lack of Lactobacillus with various diagnosis methods. Often asymptomatic, BV increases the risk of preterm birth according to the gestational age at diagnosis. BV is usually diagnosed by conventional diagnosis such as Nugent score. Molecular diagnosis of BV has now been demonstrated to be more reproducible, accurate and to better define dysbiosis.

AUTOP was a large randomized multicentre trial to evaluate a "Screen and Treat" strategy for bacterial vaginosis using molecular diagnosis of self-collected vaginal samples in low-risk pregnant women during early pregnancy, with an evaluation of treatment success, and including vaginal swab controls.

Among 6,671 randomized women, the Intent to treat analysis of the primary clinical outcome showed no evidence of a reduction in the rate of preterm birth with the screen and treat strategy compared with usual care. The rate of preterm birth was 3.9% (events=127) among 3,333 women in the screen and treat strategy group and 4.6% (events=153) among 3,338 in the control group (aOR, 0.82 \[95%CI, 0.65 to 1.05\]; P=.12). In the subgroup of nulliparous women (n=3,438), Screening and treating strategy was significantly more effective than usual care (aOR 0.61, 95% CI 0.44 to 0.82; Pinteraction=0.001).

AUTOP I has been submit to JAMA at the beginning of 2023. AUTOP was the first randomized study that evaluates the impact of Screen and Treat strategies using molecular biology during pregnancy, except one ongoing study.

The main objective of AUTOP 2 is to evaluate the effectiveness of a self screen and treat strategy for vaginal flora dysbiosis, based on molecular point of care (POC) multiplex technology before 18 weeks' gestation, in reducing the rate of preterm birth among pregnant women at high risk, compared with usual care.

AUTOP 2 is a multicenter, prospective, randomized and parallel, open-label comparative, phase 3 study comparing 2 groups of pregnancy management in a population of pregnant women at high risk of preterm birth:

* The experimental group (group A) with self vaginal screening with molecular multiplex biology. * The usual care group (group B) with no screening with multiplex molecular biology. Women will be screened for BV with conventional tools (pH, Amsel or Nugent score) as recommended by ANAES. Women under 25 years of age who are sexually active and/or at risk for sexually transmitted infections will be screened for Chlamydia trachomatis, as recommended by HAS.

The recruitment goal is of 1794 women (897 per group).The period of inclusion has been scheduled to be 24 months s. Each woman will be followed until her newborn is discharged from the hospital, for a maximum of 4 months after delivery. Therefore, the maximum participation period is 12 months.

A reduction in prematurity and/or late abortions in the group screening and treatment of vaginal flora abnormalities is expected. This strategy could be implemented routinely if the results were significant.

Interventions

• Diagnostic test Vaginal flora abnormalities screening and quantification using molecular biology technique
  Vaginal self-sampling is a simple and validated method of sampling used for the molecular biology technique and the quantification of microorganisms involved in vaginal flora imbalance bacteriosis.The patient performs a self-sampling with a cotton swab transferred into a transport medium tube. The sample is sent to the laboratory where Multiplex Point of Care polymerase chain reaction (PCR) is performed.
• Drug Azithromycin
  In case of Chlamydia trachomatis infections: Azithromycin 1 g per os during the second and third trimester of pregnancy .
• Drug Ceftriaxone
  In case of Neisseria gonorrhoeae infections: Ceftriaxone 1 g IM as a single dose.
• Drug Metronidazole
  In case of Trichomonas vaginalis infections: Metronidazole 500 mg 2 times/day for 7 days, whatever the trimester of pregnancy is . In case of Gardnerella vaginalis infection: Metronidazole 500 mg orally 2 times/day for 7 days . In case of Atopobium/Fannyhessea vaginae and/or Gardnerella vaginalis positivity: Metronidazole 500 mg orally 2 times/day for 7 days .
• Drug Clotrimazole
  In case of Candida albicans infection: 500 mg in a single dose. If necessary, this treatment could be repeated up to 6 times .
• Drug Doxycyclin
  During first trimester of pregnancy ,in case of Chlamydia trachomatis infections at a dose of 200 mg/day 7 days .

Primary outcome measures

• The rate of preterm birth [Time frame: From the enrollment to the delivery]

Eligibility criteria

• Pregnant woman over 18 years of age;
• Single intra uterine pregnancy after 8 weeks and before 18 weeks of gestation (i.e. ≥ 8 weeks and ≤ 18 weeks). Woman can present symptomatic vaginal discharge, or can be asymptomatic or symptomatic with regard to the diagnosis of bacterial vaginosis (BV) with usual technics;
• With a history of :

• preterm birth before 37 weeks of gestation (even if the preterm birth was following preterm rupture of membranes);
• and / or late miscarriage or fetal loss (i.e. miscarriage or foetal loss between 14 and 22 weeks of gestation), even if one any of her last birth occurred at term.
• Woman having a reliable connexion by phone
• Woman who has understood the study process and objectives and agreed to sign an informed consent form;
• affiliated to a social security regimen or equivalent.

Any eligible woman who will agree to participate in the study after being invited must sign a consent form before being included in the study. Women meeting all of these eligibility criteria will be invited even if they have oral or vaginal progestative treatment, cerclage or pessary, partially septate or arcuate uterus.

Exclusion criteria

• \- Woman of legal age under legal protection;
• Women deprived of their freedom for administrative or legal reasons;
• Woman who has not signed a consent form
• Nulliparous;
• Ectopic pregnancy;
• Non-evolutive pregnancy or IUFD
• Multiple pregnancy
• Serious fetal malformation identified at first trimester screening such as cardiopathy, exencephaly, anasarque, gastroschisis, omphalocele, diaphragmatic hernia, cerebral or spinal major anomaly.
• Woman participating in any clinical trial or intent to participate in another clinical trial, which may have an impact on flora or on prematurity rate, with or without investigational product at any time during the conduct of this study
• Woman presenting contraindications to the study treatments: Hypersensitivity to the active substance or to any of the excipients
• Woman presenting uterine malformation ( unicornuate, bicornuate, full septate)
• Woman with preterm birth history because of twin pregnancy
• Woman having received anti-infective treatment in the week preceding inclusion

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06349122 · 2023-509421-41-03

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗