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Treatment of Classic Mid-trimester PPROM by Means of Continuous Amnioinfusion (AmnionFlush)

Primary Purpose

Bronchopulmonary Dysplasia, Necrotizing Enterocolitis, Intracranial Hemorrhages

Status
Not yet recruiting
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
Continuous amnioinfusion with Amnion Flush Solution through the intraamniotic catheter
Sponsored by
Martin-Luther-Universität Halle-Wittenberg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bronchopulmonary Dysplasia focused on measuring PPROM, Amnion Flush Solution, outcome, amnioinfusion

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Singleton pregnancy (from 22/0 to 26/0 weeks of gestation)
  • Evidence of PPROM from clinical and instrumental investigations
  • Oligo/anhydramnion (< 2 cm deepest amniotic fluid pocket)

Exclusion Criteria:

  • fetal death
  • placental abnormalities
  • labor
  • evidence of major structural or chromosomal abnormalities
  • signs of chorioamnionitis (maternal fever > 38° C and one or more of the following criteria: uterine tenderness, malodorous vag-inal discharge, maternal leukocytosis > 15000 cells/mm3, maternal tachycardia > 100 beats/min, and fetal heart rate > 160 bpm).

Sites / Locations

  • Martin Luther University, Clinic of Obstetrics and Prenatal Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

control

Amnion Flush group (continuous amnioinfusion)

Arm Description

The patients with classic PPROM between 22/0-26/0 weeks' gestation with oligo/anhydramnion with standard conservative treatment (7 days Amoxicillin/Clarithromycin therapy or 7 days Amoxicillin and once Azithromycin 1 g per os, and corticosteroids like Celestan®, Essex Pharma, Munich, Germany) as RDS prophylaxis will represent the control group (DGGG Guideline AWMF 015-025, February 2019, Version 1.0). The diagnosis of the PPROM must be not early than 20/0 weeks' gestation.

In the "Amnion Flush" group additionally to the standard treatment the amniotic cavity will be punctured with a 18 gauge needle under ultrasound control. The intra-amniotic catheter (0.65 mm Diameter, CE 0481, PakuMed GmbH, Essen, Germany) will be placed under local anesthesia with Xylocaine 1% 10 ml. Amnion Flush Solution (CE 0483, Serumwerk AG Bernburg, Germany) will be carried out with an infusion rate of 100 ml/h (2400 ml/d) under periodic ultrasound using the standard i.v. pump. The deepest pool of amniotic fluid should be stabilized by about 4 cm. The ultrasound control will be performed daily. Induction of the labour or c-section at 34/0 week of gestation or earlier if indicated.

Outcomes

Primary Outcome Measures

Number of Participants with bronchopulmonary dysplasia
Number of Participants with severe bronchopulmonary dysplasia (BPD)
Number of Participants with intraventricular hemorrhage
Number of Participants with intraventricular hemorrhage (IVH 3-4)
Number of Participants with necrotizing enterocolitis
Number of Participants with necrotizing enterocolitis (NEC)

Secondary Outcome Measures

Duration of PPROM to delivery interval
Duration of PPROM to delivbery interval (days)
Gesatational age at delivery
gestational age at delivery
Rate of Newborns with FIRS
Rate of Newborns with FIRS (fetal inflammatory response syndrome) (binary)

Full Information

First Posted
December 21, 2020
Last Updated
January 8, 2021
Sponsor
Martin-Luther-Universität Halle-Wittenberg
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1. Study Identification

Unique Protocol Identification Number
NCT04696003
Brief Title
Treatment of Classic Mid-trimester PPROM by Means of Continuous Amnioinfusion
Acronym
AmnionFlush
Official Title
Treatment of Classic Mid-trimester Preterm Premature Rupture of Membranes (PPROM) With Oligo/Anhydramnion Between 22/0-26/0 Week of Gestation by Means of Continuous Amnioinfusion: a Multicenter Prospectiv Randomized Trial
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Not yet recruiting
Study Start Date
January 1, 2021 (Anticipated)
Primary Completion Date
August 31, 2024 (Anticipated)
Study Completion Date
May 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Martin-Luther-Universität Halle-Wittenberg

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Objective: Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal mem-branes prior to 28 weeks' gestation (WG), complicates approximately 0.4-0.7% of all pregnancies and associated with very high neonatal mortality and morbidity. Antibiotics have limited success to prevent bacteremia, chorioamnionitis and fetal inflammation because of reduced placental transport. The repetitive amnioinfusion doesn't work because of immediately fluid lost after the intervention). The continuous amnioinfusion with Amnion Flush Solution through the perinatal port system in patients with classic PPROM prolonged the PPROM-to-delivery interval to 49 days in average by flush out of bacteria and inflammatory components from the amniotic cavity. Aim: This multicenter trial tests the effect of continuous amnioinfusion on the neonatal survival without major morbidities, like severe bronchopulmonary dysplasia, intraventricular hemorrhage, cystic periventricular leukomalacia and necrotizing enterocolitis. Design: randomized multicenter controlled trial; two-arm parallel design. Control group: 34 PPROM patients between 22/0 (20/0) -26/0 WG treating with antibiotics and corticosteroids in according to DGGG guide-lines. In interventional group (n=34) the standard PPROM therapy will be complemented by "Amnion -Flush" method with the amnioinfusion of artificial amniotic fluid (Amnion Flush Solution, Serumwerk AG, Germany, 2400 ml/d). Subjects: Patients with classic PPROM between 22/0-26/0 WG. Expected outcome:The investigators expect significant reduction of neonatal mortality and morbidity in the "Amnion-Flush" group.
Detailed Description
Objective: Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal mem-branes prior to 28 weeks' gestation (WG), complicates approximately 0.4-0.7% of all pregnancies and associated with very high neonatal mortality and morbidity. Antibiotics have limited success to prevent bacteremia, chorioamnionitis and fetal inflammation because of reduced placental transport. The repetitive amnioinfusion doesn't work because of immediately fluid lost after the intervention). The continuous amnioinfusion with Amnion Flush Solution through the perinatal port system in patients with classic PPROM prolonged the PPROM-to-delivery interval to 49 days in average by flush out of bacteria and inflammatory components from the amniotic cavity. Aim: This multicenter trial tests the effect of continuous amnioinfusion on the neonatal survival without major morbidities, like severe bronchopulmonary dysplasia, intraventricular hemorrhage, cystic periventricular leukomalacia and necrotizing enterocolitis. Design: randomized multicenter controlled trial; two-arm parallel design. Control group: 34 PPROM patients between 22/0 (20/0) -26/0 WG treating with antibiotics and corticosteroids in according to DGGG guide-lines (7 days Amoxicillin/Clarithromycin therapy or 7 days Amoxicillin and once Azithromycin 1 g and corticosteroids' RDS prophylaxis). Experimental group: 34 PPROM patients between 22/0 (20/0) -26/0 WG, continuous amnioinfusion (100 ml/h) in pregnant women with classic PPROM with oligo-/anhydramnion between 22/0- 26/0 weeks' gestation and systemic antibiotic therapy (7 days Amoxicil-lin/Clarythromycin or 7 days Amoxicillin and once Azithromycin 1 g) and corticosteroids' RDS prophylaxis. Duration of intervention: Maximum till 34/0 weeks of gestation, or preterm delivery if indicated. Follow-up per patient: 12 months post-partum. Subjects: Patients with classic PPROM between 22/0 (20/0) -26/0 WG. Primary efficacy endpoint: survival without major morbidity (severe bron-chopulmonary dysplasia (BPD), and/or grades 3 and 4 intraventricular hemor-rhage (IVH 3-4), and/or cystic periventricular leukomalacia (cPVL), and/or necrotizing enterocolitis (NEC)) since randomization (event time). Expected outcome: The envestigators expect significant reduction of neonatal mortality and morbidity in the "Amnion-Flush" group.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchopulmonary Dysplasia, Necrotizing Enterocolitis, Intracranial Hemorrhages
Keywords
PPROM, Amnion Flush Solution, outcome, amnioinfusion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
randomized multicenter controlled trial; two-arm parallel design.
Masking
Outcomes Assessor
Masking Description
The neonatal outcome will be evaluated one year after the delivery by the stuff of the University Center of the Clinical Studies.
Allocation
Randomized
Enrollment
68 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
control
Arm Type
No Intervention
Arm Description
The patients with classic PPROM between 22/0-26/0 weeks' gestation with oligo/anhydramnion with standard conservative treatment (7 days Amoxicillin/Clarithromycin therapy or 7 days Amoxicillin and once Azithromycin 1 g per os, and corticosteroids like Celestan®, Essex Pharma, Munich, Germany) as RDS prophylaxis will represent the control group (DGGG Guideline AWMF 015-025, February 2019, Version 1.0). The diagnosis of the PPROM must be not early than 20/0 weeks' gestation.
Arm Title
Amnion Flush group (continuous amnioinfusion)
Arm Type
Active Comparator
Arm Description
In the "Amnion Flush" group additionally to the standard treatment the amniotic cavity will be punctured with a 18 gauge needle under ultrasound control. The intra-amniotic catheter (0.65 mm Diameter, CE 0481, PakuMed GmbH, Essen, Germany) will be placed under local anesthesia with Xylocaine 1% 10 ml. Amnion Flush Solution (CE 0483, Serumwerk AG Bernburg, Germany) will be carried out with an infusion rate of 100 ml/h (2400 ml/d) under periodic ultrasound using the standard i.v. pump. The deepest pool of amniotic fluid should be stabilized by about 4 cm. The ultrasound control will be performed daily. Induction of the labour or c-section at 34/0 week of gestation or earlier if indicated.
Intervention Type
Combination Product
Intervention Name(s)
Continuous amnioinfusion with Amnion Flush Solution through the intraamniotic catheter
Intervention Description
The amniotic cavity will be punctured with a 18 gauge needle under ultrasound control. The intraamniotic catheter (0.65 mm Diameter, CE 0481, PakuMed GmbH, Essen, Germany) will be placed under local anesthesia with Xylocaine 1% 10 ml. and the amnioinfusion (about 100 ml/h, 2400 ml/day) with artificial amniotic fluid (Amnion Flush Solution, CE 0483, Serumwerk AG Bernburg, Germany) will be carried out with an infusion rate of 100 ml/h under periodic ultrasound using the standard i.v. pump.
Primary Outcome Measure Information:
Title
Number of Participants with bronchopulmonary dysplasia
Description
Number of Participants with severe bronchopulmonary dysplasia (BPD)
Time Frame
through study completion, an average of 1 year
Title
Number of Participants with intraventricular hemorrhage
Description
Number of Participants with intraventricular hemorrhage (IVH 3-4)
Time Frame
through study completion, an average of 1 year
Title
Number of Participants with necrotizing enterocolitis
Description
Number of Participants with necrotizing enterocolitis (NEC)
Time Frame
through study completion, an average of 1 year
Secondary Outcome Measure Information:
Title
Duration of PPROM to delivery interval
Description
Duration of PPROM to delivbery interval (days)
Time Frame
up to 15 weeks
Title
Gesatational age at delivery
Description
gestational age at delivery
Time Frame
34 weeks
Title
Rate of Newborns with FIRS
Description
Rate of Newborns with FIRS (fetal inflammatory response syndrome) (binary)
Time Frame
1 week

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Singleton pregnancy (from 22/0 to 26/0 weeks of gestation) Evidence of PPROM from clinical and instrumental investigations Oligo/anhydramnion (< 2 cm deepest amniotic fluid pocket) Exclusion Criteria: fetal death placental abnormalities labor evidence of major structural or chromosomal abnormalities signs of chorioamnionitis (maternal fever > 38° C and one or more of the following criteria: uterine tenderness, malodorous vag-inal discharge, maternal leukocytosis > 15000 cells/mm3, maternal tachycardia > 100 beats/min, and fetal heart rate > 160 bpm).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michael Tchirikov, MD, Ph.D.
Phone
-345-57-3250
Ext
049
Email
michael.tchirikov@uk-halle.de
First Name & Middle Initial & Last Name or Official Title & Degree
Miriam Tchirikov, MD
Phone
-345-57-3250
Ext
049
Email
miriam.tchirikov@uk-halle.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Tchirikov, MD, Ph.D.
Organizational Affiliation
University Clinic of Obstetrics and Prenatal Medicine
Official's Role
Study Director
Facility Information:
Facility Name
Martin Luther University, Clinic of Obstetrics and Prenatal Medicine
City
Halle
State/Province
Sachsen Anhalt
ZIP/Postal Code
06120
Country
Germany
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Tchirikov, MD, Ph.D.
Phone
0345-573250
Ext
049
Email
michael.tchirikov@uk-halle.de
First Name & Middle Initial & Last Name & Degree
Christian Haiduk
Phone
0345 557 4920
Ext
049
Email
Haiduk.Christian@kks-halle.de

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
26447923
Citation
Tchirikov M, Zhumadilov Z, Winarno AS, Haase R, Buchmann J. Treatment of Preterm Premature Rupture of Membranes with Oligo-/Anhydramnion Colonized by Multiresistant Bacteria with Continuous Amnioinfusion and Antibiotic Administrations through a Subcutaneously Implanted Intrauterine Port System: A Case Report. Fetal Diagn Ther. 2017;42(1):71-76. doi: 10.1159/000438483. Epub 2015 Oct 9.
Results Reference
background
PubMed Identifier
23774012
Citation
Tchirikov M, Bapayeva G, Zhumadilov ZSh, Dridi Y, Harnisch R, Herrmann A. Treatment of PPROM with anhydramnion in humans: first experience with different amniotic fluid substitutes for continuous amnioinfusion through a subcutaneously implanted port system. J Perinat Med. 2013 Nov;41(6):657-63. doi: 10.1515/jpm-2012-0296.
Results Reference
background
PubMed Identifier
28710882
Citation
Tchirikov M, Schlabritz-Loutsevitch N, Maher J, Buchmann J, Naberezhnev Y, Winarno AS, Seliger G. Mid-trimester preterm premature rupture of membranes (PPROM): etiology, diagnosis, classification, international recommendations of treatment options and outcome. J Perinat Med. 2018 Jul 26;46(5):465-488. doi: 10.1515/jpm-2017-0027.
Results Reference
result
PubMed Identifier
36143388
Citation
Tchirikov M, Haiduk C, Tchirikov M, Riemer M, Bergner M, Li W, Henschen S, Entezami M, Wienke A, Seliger G. Treatment of Classic Mid-Trimester Preterm Premature Rupture of Membranes (PPROM) with Oligo/Anhydramnion between 22 and 26 Weeks of Gestation by Means of Continuous Amnioinfusion: Protocol of a Randomized Multicentric Prospective Controlled TRIAL and Review of the Literature. Life (Basel). 2022 Aug 30;12(9):1351. doi: 10.3390/life12091351.
Results Reference
derived

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Treatment of Classic Mid-trimester PPROM by Means of Continuous Amnioinfusion

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