Prevention of sPTB With Early Cervical Pessary Treatment in Women at High Risk for PTB

The "Prometheus Trial" is a prospective, multicentre, multinational, open-label, randomised, controlled clinical trial in parallel groups.

Up to now the risk factor previous PTB has only been investigated in randomised controlled trials (RCTs) for 17-hydroxyprogesterone caproate (17-OHPC) which is not available in most european countries or in RCTs where the risk factor previous PTB was combined with the risk factor cervical shortening.

Looking at the evidence of therapeutic effectiveness of vaginal progesterone these risk factors should be addressed separately. Vaginal progesterone proved to be ineffective in the prevention of recurrent PTB but effectively reduced PTB in women with a short cervix.

For cervical pessary therapy there is up to now only one cohort analysis for the combined risk factors available proving the placement of a cervical pessary to be as effective as cerclage or treatment with 200 mg vaginal progesterone in reducing preterm birth rate.

The risk factor 'history of at least one cold knife conisation' for PTB was up to now only addressed in a pilot study investigating the effect of pessary treatment in asymptomatic women with a singleton pregnancy along with a short sonographic cervix and it suggested a beneficial effect on the prolongation of the pregnancy.

In approximately 1/3 of pregnancies leading to PTB cervical shortening develops. Here the placement of a cervical pessary is a good therapeutic option. For this risk factor good evidence is available for cervical pessary treatment in singleton and twin pregnancies. This is the first RCT aiming to investigate the impact of a preventive cervical pessary therapy for the prevention of recurrent PTB in women with a history of PTB and/or history of at least one conisation.

Furthermore this RCT is a part of the first worldwide prospective metaanalysis in the medicine Global Obstetrics Network "http://www.globalobstetricsnetwork.org/projects/". The primary outcome "Children´s survival without neurodevelopmental disability at the age of 3 years" measures the long-time outcome of the intervention according to the CROWN criteria.

Cervical pessary treatment is a non-invasive, well-tolerated and cost-effective treatment option which could be easily implemented in daily practice if it proves to have a preventive effect of PTB. This especially applies for developing countries, where for example serial cervix length measurements to detect cervical shortening are not feasible.

Statistics:

The primary statistical aim is to compare the primary combined outcome "long-term survival without neuro-developmental disability at 3 years follow up" between the two treatment groups with a two-sided chi-square test. In general, statistical comparisons will be two-sided and use appropriate tests according to the scale of the outcome. A multivariate logistic regression will be fitted to control for possible confounders. Relative risks and 95% confidence interval as well as adjusted odds ratios will be calculated for the binary outcomes. Statistical significance will be accepted in all cases with a p≤0.05.

The main statistical evaluation will be performed at two time points.

1. The complete data set for the secondary endpoints will be available after the last women enrolled in this study has delivered her neonate, so the analysis of these outcome parameter will be done right after this event.
2. The primary outcome will be evaluated 3 years after the last woman enrolled in this study has delivered her neonate.

A descriptive analysis by preterm birth will be carried out calculating means and medians for quantitative variables and proportions with 95% confidence intervals for categorical variables.

Additionally an explorative subgroup analysis of the study collective will be performed comparing the efficacy of the cervical pessary treatment in women with a normal cervical length at 12 -16 weeks of gestation and in women who have developed a cervical shortening (< 25 mm) as an additional risk factor.

A drop out rate of up to 25% for the primary endpoint is expected due to the long follow-up time (3 years) of the study; but it is not expected to have lost data for the secondary endpoints because for these parameters the study has a short follow-up time till time to birth only.

An interim analysis shall be conducted on key safety parameters after birth of 150 neonates: the following safety endpoints will be assessed by a one-sided test with alpha=1%

• on level of the neonates: rate of preterm birth, time to birth, birth weight, death, neonatal morbidity, harm of intervention
• and on the maternal level: rate of hospitalisation for threatened preterm labour < 32 weeks, rate of PRoM <32 weeks, rate of infection / inflammation, rate of physical or psychological intolerance to pessary, rate of severe adverse reaction (SAR) / severe adverse event (SAE), death.

The trial will be terminated as negative if a disadvantage for the pessary-treatment can be found in one of these tests. To guarantee a high safety level the significance level is chosen more conservatively than in a Bonferroni correction. All analysis will be carried out with SPSS® version 19.0 or later ("IBM Company SPSS Inc." Headquarters, Chicago, Illinois. USA) and R version 3.2.3 or later (R Foundation for Statistical Computing, Vienna, Austria).

Methods against bias:

• all women will be randomly allocated to the cervical pessary group or the control-group in a 1:1 ratio. The randomization sequence is computer generated with variable block sizes using a web-based electronic case report form (e-CRF) (Online-Software Castor is a fully Good Clinical Practice compliant system) stratified for centers. The allocation code will be disclosed after the patient´s initials will be confirmed. The investigators or the trial coordinator will not have access to the randomization sequence.
• Exclusion criteria were chosen to ensure an equal risk distribution for pregnancy complications and fetal morbidity / mortality rate for both study groups.
• The study is open label since masking the intervention is not possible. Investigator training: All investigators should be trained in pessary application and cerclage placement. Quality protocols should be submitted according to the "Clara-Angela Foundation" -requirements for pessary placement.

Outcome assessors will be blinded to the interventions. Group allocations will base on an intention to treat basis with a per protocol allocation as sensitivity analysis.

The study will be registered and the study protocol is available. Outcome measures meet the core-outcome set for the evaluation of interventions to prevent PTB published by the CROWN-initiative.