Cervical Pessary Treatment for Prevention of s PTB in Twin Pregnancies on Children's Long-Term Outcome

NCT ID: NCT03418311

Last Updated: 2020-05-05

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 672 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-30
• Study Completion Date: 2024-12-31

Brief Summary

Preterm birth (PTB) complicates 13% of all pregnancies worldwide and is the most important cause of neonatal morbidity and mortality. Women with a twin pregnancy are at increased risk of preterm delivery. In the Netherlands, approximately 50% of women with a multiple pregnancy deliver before 37 weeks of gestation (WoG), of whom 9% deliver before 32 weeks. Evidence based treatment guidelines concerning prevention of PTB are not available in Europe. Expectant management is usual care 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. The studies done on this topic included women at different stages of the second trimester so the question of the onset of cervix shortening and its impact on PTB is not answered yet. The critical period for a maximum impact of the pessary treatment on PTB is still to be verified. Up to now only the ProTwinTrial addressed the long-term outcome of the newborns, so here data and evidence is clearly missing. The investigators want to assess the impact of a cervical pessary treatment in twin pregnancies with cervical shortening on children's survival without neurodevelopmental disability at the age of 3 years at 3 different stages of the second trimester (16-20 (early) vs. 20-24 (middle) vs. 24-28 (late) weeks of gestation).

Detailed Description

Impetus is a prospective, multicentre, multinational, open-label, randomised, controlled clinical trail in parallel groups.

For sample size calculation, a the stratified design is accounted for and three equally large gestation groups assumed. For the pessary group a combined event rate of at least 8% for the primary outcome is assumed and for the comparison of the pessary group with the control group an odds ratio of 2.29 is assumed. This odds ratio correspond to the lower bound of a one-sided confidence interval for the event rate given in van´t Hooft (ProTwin Trial). To reach a power of at least 80%, at least 500 patients will be evaluated, 250 in the pessary group and 250 in the control group. To account for a drop out rate of 25%, overall n=672 pregnant women will be recruited.

The primary statistical aim is to compare the primary combined outcome "long-term survival without neuro-developmental disability at 3 years follow up" with a two-sided Cochran-Mantel-Haenszel-Test and a significance level of alpha=0.05. The primary outcome refers to a combined event in any of the twin and will be analysed for all pregnancies with available primary endpoint. The stratified study design is accounted by this stratified test according to the gestation groups.

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 twins, 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 twins. 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. In general, statistical comparisons with the pessary arm and the control arms or other group comparisons for primary and secondary outcomes will be performed with stratified tests as well as comparisons in the gestation subgroups. Events will be analysed for each twin and for single children assuming appropriate random effect regression models. Further subgroup analyses regarding the cervical length will be performed (e.g. Cervical Length (CL) 15 to 25mm and below 15mm). All tests, see also examples in the synopsis, will be two-sided using a significance level of alpha=0.05.

For the primary endpoint a drop out rate of up to 25% is expected due to the long follow-up time (3 years) of the study; but no lost data for the secondary endpoints are expected 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 300 twins: 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 premature rupture of membranes (PRoM) <32 weeks, rate of infection / inflammation, rate of physical or psychological intolerance to pessary, rate of SAR/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 randomisation sequence is computer generated with variable block sizes using a web-based e-CRF (Online-Software Castor is a fully GCP compliant system) stratified for gestation groups and 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. 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 in 2016.

Conditions

Preterm Birth; Premature Birth

Study Design

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

Study Groups

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: NO_INTERVENTION

No interventions assigned to this group

Cervical Pessary-Group

placement of the cervical pessary (non-invasive) at enrollment; removal of the cervical pessary (non-invasive) in a regular preventive examination at WoG 37.

Group Type: EXPERIMENTAL

Cervical Pessary-Group

Intervention Type: DEVICE

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 week of gestation 37+0. Except for placement/removal of cervical pessary the pregnant women will receive the usual care.

Interventions

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 week of gestation 37+0. Except for placement/removal of cervical pessary the pregnant women will receive the usual care.

Intervention Type: DEVICE

Other Intervention Names

Arabin Cervical Pessary

Eligibility Criteria

Inclusion Criteria

• women with a diamniote twin pregnancy at 16-28 weeks of gestation with a shortened cervix ≤ 25 percentile
• women ≥ 18 years and capable of giving consent

Exclusion Criteria

• monoamniote pregnancy
• major fetal abnormalities
• suspected twin-to-twin transfusion syndrome
• intrauterine death of one twin
• uterine malformation
• placenta previa totalis
• Cerclage prior to randomization
• active vaginal bleeding and/or spontaneous rupture of membranes and/or painful regular uterine contractions
• silicone allergy
• current participation in other RCT to avoid treatment conflicts

• 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

Buergerhospital Frankfurt

Locations

University of Adelaide

Adelaide, , Australia

Charite-Universitätsmedizin Berlin

Berlin, , Germany

Vivantes Klinikum im Friedrichshain

Berlin, , Germany

Bürgerhospital Frankfurt/M.

Frankfurt, , 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 49 1768248 ext. 7002

Marita Wasenitz, MA Biology

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

Ioannis Kyvernitakis, MD, PhD

Role: primary

i.kyvernitakis@buergerhospital-ffm.de

+49 69 1500 ext. 5807

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 28 ext. 000

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

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

BHFKIK2018I

Identifier Type: -

Identifier Source: org_study_id