Pentaerithrityl Tetranitrate (PETN) for Secondary Prevention of Intrauterine Growth Restriction

Phase 3

• Conditions: Intrauterine Growth Restriction; Pregnancy Related; Fetal Growth Retardation
• Interventions: Drug: Placebos; Drug: Pentalong

• Registration Number: NCT03669185
• Lead Sponsor: Jena University Hospital

Brief Summary

Approximately 10% of all pregnancies experience mal perfusion of the placenta resulting in fetal growth restriction (FGR) of the fetus. FGR is the most important cause of perinatal mortality and morbidity. Impaired placental function determined by insufficient transformation of the uterine arteries and mal-perfusion of the placenta is the leading cause of FGR. So far, there is no treatment option for pregnancies complicated by FGR and the clinical management is restricted to close monitoring, assessing for the optimal time point of delivery of the fetus threatened by intrauterine death. In a pilot study a risk reduction of 38% for the development of severe FGR and FGR or death could be demonstrated by giving the organic nitrate pentaerithrityl-tetranitrate (PETN) to patients recognized at risk for FGR by impaired uterine artery Doppler at mid gestation (Schleussner, 2014). To confirm these results this prospective randomized placebo controlled double-blinded multicentre trial, was initiated.

Detailed Description

Affecting approximately 10% of pregnancies, fetal growth restriction (FGR), is the most important cause of perinatal mortality and morbidity. Impaired placental function determined by insufficient transformation of the uterine arteries and mal-perfusion of the placenta is the leading cause of FGR. So far, there is no treatment option for pregnancy complicated by FGR and the clinical management is restricted to close monitoring, assessing for the optimal time point of delivering the fetus threatened by intrauterine death. In a prospective randomized controlled trial a risk reduction of 38% (relative risk RR=0.609, 95% CI 0.367 to 1.011) for the development of IUGR and IUGR or death (RR=0.615, 95% CI 0.378 to 1.000) could be demonstrated by delivering the organic nitrate pentaerithrityl-tetranitrate (PETN) to patients recognized at risk for FGR by impaired uterine artery Doppler at mid gestation (Schleussner, 2014). To confirm these results a prospective randomized placebo controlled double-blinded multicentre trial was now initiated.

Eligible patients are pregnant women at risk of developing FGR meeting the inclusion criteria: abnormal uterine artery Doppler ultrasound, defined by a mean PI exceeding 1.6, singleton pregnancy, informed consent and 19+0 to 22+6 weeks of gestation. The composite endpoint of severe FGR (\< birth weight below the 3rd centile) and intrauterine or neonatal death was defined as primary efficacy endpoint. and perinatal death. Key secondary endpoints are development of FGR (defined by birth weight \< 10th percentile), severe FGR (\< birth weight below the 3rd centile), intrauterine or neonatal death, placental abruption and preterm birth.

Study Timeline

• Study Start: 2017-07-26
• Study First Submitted: 2018-08-28
• Study First Submitted QC: 2018-09-12
• Study First Posted: 2018-09-13
• Primary Completion: 2020-07-31
• Status Verified: 2021-02
• Last Update Submitted: 2021-02-23
• Last Update Posted: 2021-02-25
• Study Completion: 2021-10-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 324

Inclusion Criteria

• abnormal uterine artery Doppler at 19+0 to 22+6 weeks of gestation, defined by a mean pulsatility index (PI) Exceeding 1.6
• singleton pregnancy
• age>/= 18 years
• informed consent

Exclusion Criteria

• known fetal chromosomal or suspected major structural defects at time of enrollment
• premature rupture of membranes at time of enrolment; maternal disease defined as contraindication for intake of PETN
• anamnestic known insensitivity to Pentalong® or its ingredients or to medications with similar chemical structure
• participation of the patient in another clinical trial (parallel or within the waiting period of a previous clinical trial)
• multiple pregnancy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebos	Placebos	Placebos, 2 times daily 1 tablet, intake max. 133 days
Pentalong	Pentalong	Pentalong, 2 times daily 1 tablet, intake max. 133 days

Primary Outcome Measures

Name	Time	Method
Number of participants who develop intrauterine/fetal growth restriction or perinatal death.	19 weeks of pregnancy - seventh day of life	Efficiency of PETN to prevent the development of intrauterine/fetal growth restriction or perinatal death.

Secondary Outcome Measures

Name	Time	Method
infant outcome	birth to discharge from NICU	rate of newborns with intraventricular cerebral haemorrhage (grade II - IV) or necrotizing enterocolitis, b.o.
mortality	19 weeks of pregnancy - seventh day of life	number of perinatal deaths
birth weight	19-40 weeks of pregnancy	percentage of children with birth weight below the 3rd, 5th or 10th percentile
Number of participants who developed FGR	19-40 weeks of pregnancy	Number of participants who developed FGR, which necessitates delivery before 30 and 34 week of gestation
admission to NICU	Birth to discharge from the hospital	rate of newborns transferred to neonatal intensive care unit
number of premature deliveries	19 to 37 weeks of gestation	number of premature deliveries before completed 34 and 37 weeks of gestation
severe morbidity	19 weeks of pregnancy - seventh day of life	severe morbidity as a combined result of severe FGR (birth weight below the 3rd or 5th percentile) or perinatal death or premature abruption of placenta

Trial Locations

Locations (14)

Universitätsklinikum Ulm; 🇩🇪 Ulm, Baden-Württemberg, Germany

Klinikum der Universität München; 🇩🇪 München, Bayern, Germany

Städtisches Klinikum München; 🇩🇪 München, Bayern, Germany

Universitätsklinik Halle; 🇩🇪 Halle, Sachsen-Anhalt, Germany

Universitätsklinikum Dresden; 🇩🇪 Dresden, Sachsen, Germany

Krankenhaus St. Elisabeth und St. Barbara; 🇩🇪 Halle, Sachsen-Anhalt, Germany

Uniklinikum Leipzig; 🇩🇪 Leipzig, Sachsen, Germany

Universitätsklinikum Schleswig Holstein; 🇩🇪 Kiel, Schleswig-Holstein, Germany

Universitätsklinikum Jena; 🇩🇪 Jena, Thüringen, Germany

Berlin Charité Campus Mitte; 🇩🇪 Berlin, Germany

Berlin Vivantes Klinikum Neukölln; 🇩🇪 Berlin, Germany

Universitäts-Frauenklinik Tübingen; 🇩🇪 Tübingen, Baden-Württemberg, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Niedersachsen, Germany

Universitätsklinikum Bonn; 🇩🇪 Bonn, Nordrhein-Westfalen, Germany