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

Impact of Cervical Pessary Treatment for Prevention of Spontaneous Preterm Birth in Twin Pregnancies With Cervical Shortening on Children's Long-Term Survival Without Neurodevelopmental Disability: THE IMPETUS-TRIAL

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Premature Birth; Preterm Birth
• Intervention / Treatment: Device: Cervical Pessary-Group

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.

• Study Type: Interventional
• Enrollment (Anticipated): 672
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ioannis Kyvernitakis, MD, PhD; Phone Number: 7002 +49 49 1768248; Email: janniskyvernitakis@gmail.com
• Study Contact Backup: Name: Marita Wasenitz, MA Biology; Phone Number: 1514 +49 69 1500; Email: m.wasenitz@buergerhospital-ffm.de

Study Locations

• Australia
  • Adelaide, Australia
    • University of Adelaide
    • Contact: Ben Willem Mol, MD, PhD; Phone Number: 2170 +61 4 3412; Email: ben.mol@adelaide.edu.au
• Germany
  • Berlin, Germany, 10249
    • Vivantes Klinikum im Friedrichshain
    • Contact: Lars Hellmeyer, MD, PhD; Phone Number: 1442 +49 30 130 23; Email: Lars.Hellmeyer@vivantes.de
    • Principal Investigator: Lars Hellmeyer, MD, PhD
  • Berlin, Germany, 10117
    • Charite-Universitatsmedizin Berlin
    • Contact: Jens Stupin, MD, PhD; Phone Number: 50 +49 30 450; Email: jens.stupin@charite.de
  • Frankfurt, Germany, 60590
    • Universitätsklinikum Frankfurt
    • Contact: Frank Louwen, MD, PhD; Phone Number: 7703 +49 69 6301; Email: Louwen@em.uni-frankfurt.de
  • Frankfurt, Germany, 60318
    • Bürgerhospital Frankfurt/M.
    • Contact: Ioannis Kyvernitakis, MD, PhD; Phone Number: 5807 +49 69 1500; Email: i.kyvernitakis@buergerhospital-ffm.de
  • Hamburg, Germany, 22087
    • Asklepios Kliniken Krankenhaus Barmbeck
    • Contact: Holger Maul, MD, PhD; Phone Number: 662 +49 40 2546; Email: h.maul@asklepios.com
  • Homburg, Germany, 66424
    • Universitätsklinikum des Saarlandes
    • Contact: Amr Hamza, MD, PhD; Phone Number: 000 +49 6841 16 28; Email: amr.hamza@uks.eu
• Greece
  • Athen, Greece
    • University Hospital of Athens
    • Contact: George Daskalakis, MD, PhD; Phone Number: +30 694 5235757; Email: gdaskalakis@yahoo.com
  • Thessaloníki, Greece
    • Medical School of Aristotle-University of Thessaloniki
    • Contact: Apostolos Athanasiadis, MD, PhD; Phone Number: +30 6944 315785; Email: apostolos3435@gmail.com
• Spain
  • Barcelona, Spain, 08035
    • Vall d'Hebron University Hospital
    • Contact: Elena Carreras, MD, PhD; Phone Number: 00 +34 934 89 30; Email: ecarreras@vhebron.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: 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.
EXPERIMENTAL: 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.	Device: 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.; Other Names: Arabin Cervical Pessary

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Children's survival without neurodevelopmental disability at the age of 3.	Recording of the mortality rate of the newborns; neurodevelopmental disability will be assessed by the Ages & Stages Questionnaire and by medical examination of the newborn at the age of 3 years	assesment of the newborns at age of 3 years (corrected age for prematurity)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of preterm birth	rate of delivery before weeks of gestation 36+6 / 33+6 / 31+6 / 29+6 / 27+6	randomisation till birh, maximum 21 weeks
time till birth	time span from enrollment to birth	randomisation till birth, maximum 25 weeks
birth weight of neonate	birth weight in gram recorded at the hospital	at birth
Fetal or neonatal death	death of the neonate before birth / within first 24 hrs	at birth, within first 24 hours
Need (days) for neonatal special care unit	Number of days the neonate is transferred to ICU for medical intervention other than supervision	birth till discharge from hospital, recorded for at least first 48 hrs after birth
neonatal morbidity	rate of major adverse neonatal outcomes (Intraventricular Haemorrhage III-IV, Retinopathy of prematurity, Respiratory Distress Syndrome II-IV, Need for ventilation > 72 h, Necrotising enterocolitis, Proven or suspected sepsis (antibiotics >5 days)	birth till discharge from hospital, recorded for at least first 48 hrs after birth
harm from intervention (neonate)	recording any harm of the neonate deriving from the cervical pessary	birth till discharge from hospital, recorded for at least first 48 hrs after birth
maternal death	rate of maternal death due to pregnancy / birth	enrollment till discharge from hospital, recorded for at least first 48 hrs after birth
rate of significant maternal adverse events	rate of heavy bleeding, cervical tear due to pessary placement, uterine rupture	enrollment till discharge from hospital, recorded for at least first 48 hrs after birth
infection / inflammation	rate of maternal infection / inflammation during pregnancy / birth	enrollment till discharge from hospital, recorded for at least first 48 hrs after birth
physical or psychological intolerance to cervical pessary	rate of maternal physical or psychological intolerance to cervical pessary during pregnancy	time from placement of cervical pessary at enrollment till removal of cervical pessary at WoG 37, maximum 21 weeks
hospitalisation for threatened preterm labour before 31 +6 weeks of gestation	recording of days of hospitalisation for threatened preterm labour before 31 +6 weeks of gestation and recording tocolytic treatment (type/ days/dose)	enrollment till birth, maximum 21 weeks
premature rupture of membranes (ProM) before 31 +6 weeks of gestation	rate of women with premature rupture of membranes (ProM) before 31 +6 weeks of gestation	enrollment till birth, maximum 21 weeks

Collaborators and Investigators

• Sponsor: Bürgerhospital Frankfurt
• Investigators: Study Director: Ioannis Kyvernitakis, MD, PhD, Buergerhospital Frankfurt

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 1, 2020
• Primary Completion (ANTICIPATED): December 1, 2024
• Study Completion (ANTICIPATED): December 1, 2024

Study Registration Dates

• First Submitted: January 23, 2018
• First Submitted That Met QC Criteria: January 30, 2018
• First Posted (ACTUAL): February 1, 2018

Study Record Updates

• Last Update Posted (ACTUAL): May 5, 2020
• Last Update Submitted That Met QC Criteria: May 4, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Prevention; short cervix; Cervical Pessary; Twin pregnancy
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth
• Other Study ID Numbers: BHFKIK2018I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No