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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pentaerithrityltetranitrat (PETN) Zur Sekundärprophylaxe Der Intrauterinen Wachstumsretardierung

Conditions
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Fetal Growth Retardation, Pregnancy Related, Intrauterine Growth Restriction

Intervention / Treatment
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* Drug: Pentalong
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebos<br>Placebos, 2 times daily 1 tablet, intake max. 133 days | Drug: Placebos<br>* Placebos, 2 x daily 1 tablet, intake max. 133 days<br>|
| Active Comparator: Pentalong<br>Pentalong, 2 times daily 1 tablet, intake max. 133 days | Drug: Pentalong<br>* Pentalong, 2 x daily 1 tablet, intake max. 133 days<br>* Other names: Pentalong® 50 mg;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PETN