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

Pentaerithrityltetranitrat (PETN) Zur Sekundärprophylaxe Der Intrauterinen Wachstumsretardierung

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Pregnancy Related; Fetal Growth Retardation; Intrauterine Growth Restriction
• Intervention / Treatment: Drug: Placebos; Drug: Pentalong

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 Type: Interventional
• Enrollment (Anticipated): 324
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Berlin Charité Campus Mitte
  • Berlin, Germany, 12351
    • Berlin Vivantes Klinikum Neukölln
  • Baden-Württemberg
    • Tübingen, Baden-Württemberg, Germany, 72076
      • Universitats-Frauenklinik Tubingen
    • Ulm, Baden-Württemberg, Germany, 89075
      • Universitatsklinikum Ulm
  • Bayern
    • München, Bayern, Germany, 81377
      • Klinikum der Universität München
    • München, Bayern, Germany, 81545
      • Städtisches Klinikum München
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany, 53127
      • Universitatsklinikum Bonn
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Universitätsklinikum Dresden
    • Leipzig, Sachsen, Germany, 04103
      • Uniklinikum Leipzig
  • Sachsen-Anhalt
    • Halle, Sachsen-Anhalt, Germany, 06110
      • Krankenhaus St. Elisabeth und St. Barbara
    • Halle, Sachsen-Anhalt, Germany, 06120
      • Universitätsklinik Halle
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Universitatsklinikum Schleswig Holstein
  • Thüringen
    • Jena, Thüringen, Germany, 07747
      • Universitätsklinikum Jena

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebos; Placebos, 2 times daily 1 tablet, intake max. 133 days	Drug: Placebos; Placebos, 2 x daily 1 tablet, intake max. 133 days
Active Comparator: Pentalong; Pentalong, 2 times daily 1 tablet, intake max. 133 days	Drug: Pentalong; Pentalong, 2 x daily 1 tablet, intake max. 133 days; Other Names: Pentaeritrithyl tetranitrate; Pentalong® 50 mg

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Jena University Hospital
• Investigators: Principal Investigator: Tanja Groten, PD Dr., Universital Hospital Jena

Publications and helpful links

General Publications

• Groten T, Lehmann T, Schleussner E; PETN Study Group. Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial. BMC Pregnancy Childbirth. 2019 Sep 14;19(1):336. doi: 10.1186/s12884-019-2456-7.

Helpful Links

• PETN Website
• Publication Study Protocol

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2017
• Primary Completion (Actual): July 31, 2020
• Study Completion (Anticipated): October 31, 2021

Study Registration Dates

• First Submitted: August 28, 2018
• First Submitted That Met QC Criteria: September 12, 2018
• First Posted (Actual): September 13, 2018

Study Record Updates

• Last Update Posted (Actual): February 25, 2021
• Last Update Submitted That Met QC Criteria: February 23, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: PETN
• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Growth Disorders; Fetal Growth Retardation
• Other Study ID Numbers: ZKS_0021PETN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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