Clinical trial NCT06377397: Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates
Official title: 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)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Sepsis
PROM, Preterm (Pregnancy)
Early-Onset Neonatal Sepsis
Preterm Premature Rupture of Membrane
Preterm Birth
Keywords: Prolonged rupture of membranes
Preterm premature rupture of membranes
Early-onset neonatal sepsis
Selective antibiotics
Non-inferiority trial
Lead sponsor: Indian Council of Medical Research
Sponsor class: OTHER_GOV
Collaborators: name: Lady Hardinge Medical College
name: King George's Medical University
name: Indira Gandhi Institute of Child Health
name: Institute of Obstetrics and Gynecology
name: Government Medical College, Chandigarh
name: Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak
name: Government Medical College, Aurangabad
name: King Edward Memorial Hospital, Mumbai
First posted: 2024-04-22
Enrollment: 1500
Sex: ALL
Minimum age (years): 0
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Neonates will be randomized to 1 of the following groups:

1. Group 1: Intervention group (Selective antibiotic group)
2. Group 2: Comparison group (Universal antibiotic group)
Primary purpose: TREATMENT

Brief summary: 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").

Detailed description: 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")

Eligibility criteria: Inclusion criteria:

* 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:

  1. Apnea (Standard definition) requiring intervention at any time until enrolment.
  2. Need for a fluid bolus or inotropic support at any time until enrolment.
  3. Seizures or seizure-like activity at any time until enrolment.
  4. Upper GI bleed in the absence of a history of ante-partum hemorrhage at any time until enrolment.
  5. Pus from any site at any time until enrolment.
  6. 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\*\*
  7. Chest Xray (if performed) with radiological features of pneumonia.
  8. Need for intubation and mechanical ventilation.
  9. Temperature \>37.5°C or \<36°C, unexplained by environmental causes
  10. Feed intolerance \[bilious or bloodstained vomiting (or gastric residuals) or visibly distended abdomen or \>50% of the previous feed volume as gastric residuals\]
  11. Lethargy or unarousability
  12. Sclerema

      Exclusion Criteria:

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

  <!-- -->

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

     -

Primary outcomes:
measure: Composite of all-cause mortality and/or any episode of culture-positive sepsis and/or severe sepsis* within the 1st 7 days after randomization
timeFrame: Within 1st 7 days after randomization
measure: Need for intravenous antibiotics for ≥ 48 hours within the 1st 7 days after randomization
timeFrame: Within 1st 7 days after randomization
Secondary outcomes:
measure: All-cause Mortality within 1st 7 days after randomization
timeFrame: During 1st 7 days after randomization
measure: Blood culture-positive sepsis of any severity within 1st 7 days after randomization
timeFrame: Within 1st 7 days after randomization
measure: Episode of severe sepsis within 1st 7 days after randomization
timeFrame: Within 1st 7 days after randomization
measure: Composite of mortality/blood culture positive sepsis/severe sepsis within 1st 72 hours after randomization
timeFrame: Within first 72 hour after randomization
measure: Individual components of composite outcome within 1st 72 hours after randomization
timeFrame: Within 1st 72 hours after randomization
measure: Composite of mortality/blood culture positive sepsis/severe sepsis during hospital stay
timeFrame: During hospital stay upto 100 days after randomization
measure: Individual components of composite outcome during hospital stay
timeFrame: During hospital stay upto 100 days after randomization
measure: Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during hospital stay
timeFrame: During hospital stay upto 100 days after randomization
measure: Composite of mortality/blood culture positive sepsis/severe sepsis during 1st 30 days after randomization
timeFrame: During 1st 30 days after randomization
measure: Individual components of composite outcome during 1st 30 days
timeFrame: During 1st 30 days after randomization
measure: Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria
timeFrame: During 1st 30 days after randomization
measure: Sepsis-related mortality within 1st 72 hours after randomization
timeFrame: Within 1st 72 hours after randomization
measure: Sepsis-related mortality within 7 day after randomization
timeFrame: Within 7 days after randomization
measure: Sepsis-related mortality during hospital stay after randomization
timeFrame: During hospital stay upto 100 days after randomization
measure: Sepsis-related mortality during 1st 30 days after randomization
timeFrame: During 1st 30 days after randomization
measure: Clinical sepsis within 1st 72 hours after randomization
timeFrame: Within 1st 72 hours after randomization
measure: Clinical sepsis within 7 days after randomization
timeFrame: Within 7 days after randomization
measure: Clinical sepsis during hospital stay
timeFrame: During hospital stay upto 100 days
measure: Clinical sepsis within 1st 30 days after randomization
timeFrame: During 1st 30 days after randomization
measure: Episode of Probable EONS within 72 hours after randomization
timeFrame: Within 72 hours after randomization
measure: Episode of Probable EONS within 7 days after randomization
timeFrame: Within 7 days after randomization
measure: Episode of asymptomatic proven EONS within 72 hours after randomization
timeFrame: Within 72 hours after randomization
measure: Need for sepsis workup during 1st 72 hours after randomization
timeFrame: During 1st 72 hours after randomization
measure: Need for sepsis workup during 1st 7 days after randomization
timeFrame: During 1st 7 days after randomization
measure: Need for sepsis workup during 1st 30 days after randomization
timeFrame: During 1st 30 days after randomization
measure: Need for sepsis workup during hospital stay
timeFrame: During hospital stay upto 100 days
measure: Cumulative duration of antibiotic therapy during 1st 7 days after randomization
timeFrame: During 1st 7 days after randomization
measure: Cumulative duration of antibiotic therapy during 1st 72 hrs after randomization
timeFrame: During 1st 72 hours after randomization
measure: Cumulative duration of antibiotic therapy during hospital stay
timeFrame: During hospital stay upto 100 days after randomization
measure: Duration of hospitalization
timeFrame: Upto 100 days
measure: Episodes of healthcare associated infection during hospital stay.
timeFrame: From after 72 hours until 100 days during hospital stay
measure: Adverse effects until day 30 after randomization
timeFrame: During 30 days after randomization
measure: Serious adverse effects until day 30 after randomization
timeFrame: During 30 days after randomization
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education and Research (PGIMER)
Study officials:
affiliation: Post Graduate Institute of Medical Education and Research, Chandigarh
name: Sourabh Dutta, MD, Ph.D
role: PRINCIPAL_INVESTIGATOR
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