Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates

Официальное название

Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates At-risk of Early-onset Bacterial Sepsis: a Multicentric, Randomized, Controlled, Non-inferiority Trial (the SAUNA Trial)

Обзор

Preterm infants are born at less than 37 weeks of pregnancy. Sometimes a break or tear in the fluid filled bag that surrounds and protects the infant during pregnancy leads to an untimely birth. This state puts the infant at risk of serious condition called sepsis. Sepsis is a condition in which body responds inappropriately to an infection. Sepsis may progress to septic shock which can result in the loss of life. Doctors give antibiotics to treat sepsis. The goal of this research study is to find out: 1. Among neonates at risk of early-onset neonatal sepsis, whether a policy of administering antibiotics selectively to a subset of at-risk infants who later develop signs of sepsis is not inferior to administering antibiotics to all at-risk infants in the 1st week of life. 2. To find out if infants receiving selective antibiotics (as above) compared to those receiving antibiotics from birth (as above) require fewer antibiotic courses of 48 hours duration or more in the 1st week of life. 3. To find out whether infants receiving selective antibiotics (as above) compared to those receiving antibiotics from birth (as above) are significantly different with respect to a wide range of secondary outcomes (listed under "Outcomes").

Подробное описание

Sepsis is the major cause of neonatal mortality and early-onset neonatal sepsis (EONS) accounts for more than two-thirds of all cases of neonatal sepsis. Prolonged rupture of membranes (PROM) and preterm premature rupture of membranes (pPROM) are important risk factors of EONS. There is equipoise in the published literature whether antibiotics must be immediately initiated among all preterm neonates (\<35 weeks gestation) delivered following PROM or pPROM who are asymptomatic at birth or whether antibiotics can be selectively administered if and when the at-risk neonates become symptomatic.

Among neonates \<35 weeks gestation born with PROM \>18 hours or pPROM and who are either asymptomatic or have no symptoms of sepsis at 4 hrs postnatally (P), is selectively administering antibiotics to neonates who later develop clinical sepsis \[I\] compared to administering antibiotics pre-emptively to all at-risk neonates \[C\] non-inferior with respect to the composite outcome of "mortality and/or culture-positive sepsis and/or severe sepsis" \[O\] within 7 days after enrolment \[T\] by an absolute margin of 7% \[E\] in a randomized controlled trial (S)? The trial will also have a superiority outcome: "need for antibiotic treatment lasting greater than 48 hours within 7 days after enrolment". The absolute superiority margin will be 50%.

The main objectives are as follows:

1. To determine whether antibiotics administered selectively to at-risk preterm neonates \[\<35 weeks gestation with prolonged rupture of membranes (PROM) or preterm premature rupture of membranes (pPROM)\] when they develop signs of sepsis compared to administering antibiotics from birth to all at-risk neonates is non-inferior with respect to the primary outcome of "mortality or any episode of culture-positive sepsis or severe sepsis" in the 1st week of life 2. To determine whether neonates receiving selective antibiotics (as above) compared to those receiving antibiotics from birth (as above) are superior with respect to the co-primary outcome of fewer antibiotic courses of 48 hours duration or more in the 1st week of life 3. To determine whether neonates receiving selective antibiotics (as above) compared to those receiving antibiotics from birth (as above) are significantly different with respect to a wide range of secondary outcomes (listed under "Outcomes")

Вмешательства

• Препарат Antibiotics
  In experimental arm, intravenous antibiotics as per the written down empirical antibody policy of the unit will be administered selectively to those newborn infants who later develop clinical signs of sepsis according to a predefined repertory of clinical signs. In active comparator arm, intravenous antibiotics as per the written down empirical antibody policy of the unit will be administered pre-emptively to all newborn infants from enrollment even if they do not have any clinical signs of sep

Первичные конечные точки

• Composite of all-cause mortality and/or any episode of culture-positive sepsis and/or severe sepsis* within the 1st 7 days after randomization [Срок оценки: Within 1st 7 days after randomization]
• Need for intravenous antibiotics for ≥ 48 hours within the 1st 7 days after randomization [Срок оценки: Within 1st 7 days after randomization]

Вторичные конечные точки (12)

• All-cause Mortality within 1st 7 days after randomization [Срок оценки: During 1st 7 days after randomization]
• Blood culture-positive sepsis of any severity within 1st 7 days after randomization [Срок оценки: Within 1st 7 days after randomization]
• Episode of severe sepsis within 1st 7 days after randomization [Срок оценки: Within 1st 7 days after randomization]
• Composite of mortality/blood culture positive sepsis/severe sepsis within 1st 72 hours after randomization [Срок оценки: Within first 72 hour after randomization]
• Individual components of composite outcome within 1st 72 hours after randomization [Срок оценки: Within 1st 72 hours after randomization]
• Composite of mortality/blood culture positive sepsis/severe sepsis during hospital stay [Срок оценки: During hospital stay upto 100 days after randomization]
• Individual components of composite outcome during hospital stay [Срок оценки: During hospital stay upto 100 days after randomization]
• Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during hospital stay [Срок оценки: During hospital stay upto 100 days after randomization]
• Composite of mortality/blood culture positive sepsis/severe sepsis during 1st 30 days after randomization [Срок оценки: During 1st 30 days after randomization]
• Individual components of composite outcome during 1st 30 days [Срок оценки: During 1st 30 days after randomization]
• Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria [Срок оценки: During 1st 30 days after randomization]
• Sepsis-related mortality within 1st 72 hours after randomization [Срок оценки: Within 1st 72 hours after randomization]

Критерии участия

Критерии включения

• Gestational age of 26 to 34 weeks
• Chronological age 4 hours
• Have any one or both of the following risk factors of EONS:

• Prolonged rupture of membranes >18 hours
• Pre-labour rupture of membranes \[as all subjects will be preterm, this is effectively pPROM\]
• Are either asymptomatic or have no signs attributable to sepsis at 4 hours. This will be defined as absence of the following clinical signs or need for interventions mentioned below:

• Apnea (Standard definition) requiring intervention at any time until enrolment.
• Need for a fluid bolus or inotropic support at any time until enrolment.
• Seizures or seizure-like activity at any time until enrolment.
• Upper GI bleed in the absence of a history of ante-partum hemorrhage at any time until enrolment.
• Pus from any site at any time until enrolment.
• Need for CPAP >6 cms of water with FiO2 >35% at 6-8 hours OR need for CPAP £6 cms and FiO2 £35% but with increasing requirement of support\*\*
• Chest Xray (if performed) with radiological features of pneumonia.
• Need for intubation and mechanical ventilation.
• Temperature >37.5°C or <36°C, unexplained by environmental causes
• Feed intolerance \[bilious or bloodstained vomiting (or gastric residuals) or visibly distended abdomen or >50% of the previous feed volume as gastric residuals\]
• Lethargy or unarousability
• Sclerema

Критерии исключения

Subjects will be excluded if they have any 1 of the following:

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• Life-threatening congenital malformation
• Severe perinatal asphyxia (Apgar score <5 at 10 minutes or cord pH <7.0)
• Clinical chorioamnionitis# \[see definition below\]
• Foul-smelling liquor
• Multiple gestation
• Received a dose of antibiotics
• Positive amniotic fluid culture (if performed and available prior to randomization)
• Treating neonatologist unwilling to enroll the patient in the trial on the grounds that the patient needs antibiotics.

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Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Индия · 1 центр

• Post Graduate Institute of Medical Education and Research (PGIMER) — Chandigarh

Публикации

• Sankar MJ, Neogi SB, Sharma J, Chauhan M, Srivastava R, Prabhakar PK, Khera A, Kumar R, Zodpey S, Paul VK. State of newborn health in India. J Perinatol. 2016 Dec;36(s3):S3-S8. doi: 10.1038/jp.2016.183. PMID 27924104
• Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, Lalli M, Bhutta Z, Barros AJ, Christian P, Mathers C, Cousens SN; Lancet Every Newborn Study Group. Every Newborn: progress, priorities, and potential beyond survival. Lancet. 2014 Jul 12;384(9938):189-205. doi: 10.1016/S0140-6736(14)60496-7. Epub 2014 May 19. PMID 24853593
• Chaurasia S, Sivanandan S, Agarwal R, Ellis S, Sharland M, Sankar MJ. Neonatal sepsis in South Asia: huge burden and spiralling antimicrobial resistance. BMJ. 2019 Jan 22;364:k5314. doi: 10.1136/bmj.k5314. PMID 30670451
• Chan GJ, Lee AC, Baqui AH, Tan J, Black RE. Risk of early-onset neonatal infection with maternal infection or colonization: a global systematic review and meta-analysis. PLoS Med. 2013 Aug;10(8):e1001502. doi: 10.1371/journal.pmed.1001502. Epub 2013 Aug 20. PMID 23976885
• Puopolo KM, Benitz WE, Zaoutis TE; COMMITTEE ON FETUS AND NEWBORN; COMMITTEE ON INFECTIOUS DISEASES. Management of Neonates Born at >/=35 0/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics. 2018 Dec;142(6):e20182894. doi: 10.1542/peds.2018-2894. PMID 30455342
• Wolf RL, Olinsky A. Prolonged rupture of fetal membranes and neonatal infections. S Afr Med J. 1976 Apr 3;50(15):574-6. PMID 772827
• Berardi A, Fornaciari S, Rossi C, Patianna V, Bacchi Reggiani ML, Ferrari F, Neri I, Ferrari F. Safety of physical examination alone for managing well-appearing neonates >/= 35 weeks' gestation at risk for early-onset sepsis. J Matern Fetal Neonatal Med. 2015 Jul;28(10):1123-7. doi: 10.3109/14767058.2014.946499. Epub 2014 Sep 10. PMID 25034325
• Berardi A, Buffagni AM, Rossi C, Vaccina E, Cattelani C, Gambini L, Baccilieri F, Varioli F, Ferrari F. Serial physical examinations, a simple and reliable tool for managing neonates at risk for early-onset sepsis. World J Clin Pediatr. 2016 Nov 8;5(4):358-364. doi: 10.5409/wjcp.v5.i4.358. eCollection 2016 Nov 8. PMID 27872823

Идентификаторы

NCT: NCT06377397 · IIRPIG-2023-0000070

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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