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

NCT ID: NCT03418012

Last Updated: 2020-05-05

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 310 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-30
• Study Completion Date: 2024-10-31

Brief Summary

Prevention of preterm birth (PTB) is a key factor for a positive short-term and long-term outcome of the newborn children as mortality and morbidity are inversely related to gestational age at delivery. Consequently every week of prolonged pregnancy will have a tremendous effect concerning the outcome of the new-borns, subsequently for their parents and society as well.

The proposed RCT aims to evaluate the impact of a preventive pessary treatment on the prevention of preterm birth in women with a singleton pregnancy who are at high risk of spontaneous preterm birth (sPTB) due to a history of at least one previous preterm delivery and/or a history of previous cervical surgery. In accordance with the results by "van´t Hooft et al. 2016" an approximately 20% higher percentage of children's long-term survival without neurodevelopmental disability is expected for the pessary group in comparison with usual management (=control group) on basis of a reduction of prematurity < 34 week of gestation (WoG).

The primary outcome measure for the effect of the pessary treatment in comparison to expectant management will be the children's long-term survival (3yrs) without neurodevelopmental disability. Secondary endpoints assess the impact of a preventive pessary placement on the prevention of preterm birth and its resulting risk on mortality and morbidity for the neonates.

Detailed Description

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.

Conditions

Preterm Birth; Premature Birth

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Cervical Pessary-Group

Cervical Pessary Group: placement of the cervical pessary (non-invasive) at enrolment including a transvaginal ultrasound to verify its correct fit. Removal of the cervical pessary (non-invasive) in a regular preventive examination at WoG 37

Group Type: EXPERIMENTAL

cervical pessary

Intervention Type: DEVICE

Intervention: Device: Cervical pessary: After Having excluded a vaginal infection insertion of the cervical pessary (silicone ring) directly after enrollment. After insertion verification of correct fit of the cervical pessary by transvaginal ultrasound. Removal of the pessary at 37+0 weeks of gestation, or before if any unexpected event occurs. Except for the insertion of the pessary the obstetrical management during the remainder of the pregnancy will be usual management.

Control-Group

Control-Group women receive management as usual; i.e. expectant management with interventions only in terms of a tertiary prevention of PTB according to guidelines for premature rupture of membranes, premature labour or other pregnancy complications

Group Type: OTHER

Control-Group

Intervention Type: OTHER

Intervention: Other: expectant management: expectant management is usual care; interventions only in terms of a tertiary prevention of PTB according to guidelines for premature rupture of membranes, premature labour or other pregnancy complications

Interventions

cervical pessary

Intervention: Device: Cervical pessary: After Having excluded a vaginal infection insertion of the cervical pessary (silicone ring) directly after enrollment. After insertion verification of correct fit of the cervical pessary by transvaginal ultrasound. Removal of the pessary at 37+0 weeks of gestation, or before if any unexpected event occurs. Except for the insertion of the pessary the obstetrical management during the remainder of the pregnancy will be usual management.

Intervention Type: DEVICE

Control-Group

Intervention: Other: expectant management: expectant management is usual care; interventions only in terms of a tertiary prevention of PTB according to guidelines for premature rupture of membranes, premature labour or other pregnancy complications

Intervention Type: OTHER

Other Intervention Names

Arabin Cervical Pessary

Eligibility Criteria

Inclusion Criteria

• Women with a singleton pregnancy and a history of at least one previous preterm delivery before 34+0 weeks and/or a history of at least one previous cervical surgery
• 12+0 - 16+0 weeks of gestation at time of randomization
• only women with minimum age of 18 and capable of giving consent

Exclusion Criteria

• major fetal abnormalities
• uterine malformation, placenta previa totalis
• Cerclage prior to randomization
• At randomisation: active vaginal bleeding and/or spontaneous rupture of membranes and/or painful regular uterine contractions
• silicone allergy
• current participation in other RCT

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Bürgerhospital Frankfurt

OTHER

Sponsor Role: lead

Responsible Party

Ioannis Kyvernitakis

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ioannis Kyvernitakis, MD, PhD

Role: STUDY_DIRECTOR

Asklepios Clinic Barmbek

Locations

University of Adelaide

Adelaide, , Australia

Charité - Universitätsmedizin

Berlin, , Germany

Vivantes Klinikum im Friedrichshain

Berlin, , Germany

Universitätsklinikum Frankfurt

Frankfurt, , Germany

Asklepios Kliniken Krankenhaus Barmbeck

Hamburg, , Germany

Universitätsklinikum des Saarlandes

Homburg, , Germany

University Hospital of Athens

Athens, , Greece

Medical School of Aristotle-University of Thessaloniki

Thessaloniki, , Greece

Vall d'Hebron University Hospital

Barcelona, , Spain

Countries

Australia; Germany; Greece; Spain

Central Contacts

Ioannis Kyvernitakis, MD, PhD

Role: CONTACT

janniskyvernitakis@gmail.com

+49 1768248 ext. 7002

Marita Wasenitz, MA

Role: CONTACT

m.wasenitz@buergerhospital-ffm.de

+49 69 1500 ext. 1514

Facility Contacts

Ben Willem Mol, MD, PhD

Role: primary

ben.mol@adelaide.edu.au

+61 4 3412 ext. 2170

Jens Stupin, MD, PhD

Role: primary

jens.stupin@charite.de

+49 30 450 ext. 50

Lars Hellmeyer, MD, PhD

Role: primary

Lars.Hellmeyer@vivantes.de

+49 30 130 23 ext. 1442

Frank Louwen, MD, PhD

Role: primary

Louwen@em.uni-frankfurt.de

+49 69 6301 ext. 7703

Holger Maul, MD, PhD

Role: primary

h.maul@asklepios.com

+49 40 2546 ext. 662

Amr Hamza, MD, PhD

Role: primary

amr.hamza@uks.eu

+49 6841 16 ext. 28101

George Daskalakis, MD, PhD

Role: primary

gdaskalakis@yahoo.com

+30 694 5235757

Apostolos Athanasiadis, MD, PhD

Role: primary

apostolos3435@gmail.com

+30 6944 315785

Elena Carreras, MD, PhD

Role: primary

ecarreras@vhebron.net

+34 934 89 30 ext. 00

References

Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA, Aboelfadle Mohamed A. Cervical pessary for preventing preterm birth in singleton pregnancies. Cochrane Database Syst Rev. 2022 Dec 1;12(12):CD014508. doi: 10.1002/14651858.CD014508.

Reference Type: DERIVED

PMID: 36453699 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

BHFKIK2018P

Identifier Type: -

Identifier Source: org_study_id