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NCT Number: NCT06377397

Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates

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").

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Key information

Conditions

Sepsis Congenital, Hereditary, and Neonatal Diseases and Abnormalities Early-Onset Neonatal Sepsis Female Urogenital Diseases and Pregnancy Complications Fetal Membranes, Premature Rupture Infant, Newborn, Diseases Infections Inflammation Neonatal Sepsis Obstetric Labor Complications Obstetric Labor, Premature PROM, Preterm (Pregnancy) Pathologic Processes Pathological Conditions, Signs and Symptoms Pregnancy Complications Premature Birth Preterm Birth Preterm Premature Rupture of Membrane Preterm Premature Rupture of the Membranes Systemic Inflammatory Response Syndrome Urogenital Diseases

Age range

0 hour–4 hour

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Post Graduate Institute of Medical Education and Research (PGIMER)

Chandigarh, 160012, India

About this study

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:

  • 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
  • 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
  • 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")

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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:
  • 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

Exclusion criteria

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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Treatment and study plan

Antibiotics

Drug

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 sepsis at enrollment

Other names: Intravenous antibiotics as per written down empirical antibiotic policy of the unit

Primary outcomes

  1. Composite of all-cause mortality and/or any episode of culture-positive sepsis and/or severe sepsis* within the 1st 7 days after randomization

    Time frame: Within 1st 7 days after randomization

    Either mortality due to any cause and/or an episode of culture-positive sepsis and/or severe sepsis. These outcomes will be measured within the "1st 7 days after randomization", which for all practical purposes, is equivalent to the "1st 7 days of life" since participants will be randomized at about 4 hours of life. Hence, the duration expressed after randomization and of life will be used interchangeably for this outcome and other outcomes.

  2. Need for intravenous antibiotics for ≥ 48 hours within the 1st 7 days after randomization

    Time frame: Within 1st 7 days after randomization

    Requirement for intravenous antibiotic courses whose duration is ≥ 48 hours with the onset of the course within the first 7 days after randomization. For all practical purposes, this would be equivalent to the 1st 7 days of life since participants will be randomized at about 4 hours of life.

Secondary outcomes

  1. All-cause Mortality within 1st 7 days after randomization

    Time frame: During 1st 7 days after randomization

    Mortality due to any cause

  2. Blood culture-positive sepsis of any severity within 1st 7 days after randomization

    Time frame: Within 1st 7 days after randomization

    Blood culture proven septicemia

  3. Episode of severe sepsis within 1st 7 days after randomization

    Time frame: Within 1st 7 days after randomization

    Any episode of severe sepsis during 1st 7 days after randomization. Severe sepsis be defined as clinical signs of sepsis AND either a positive blood culture or laboratory evidence of sepsis (either CRP OR Procalcitonin above the age-appropriate cut-off value OR any two of the CBC parameters outside the age-appropriate ranges OR chest x-ray suggestive of pneumonia) AND one or more of the following indices of severity [Need for intubation and mechanical ventilation, Need for inotropes >10 mic/kg/min dopamine or >10 mic/kg/min dobutamine or adrenaline > 0.05 mic/kg/min, Need for exchange transfusion, Need for platelet concentrates or FFP, Meningitis (defined as either CSF culture positive or Gram stain positive or Cell count >25/microlitre or glucose <25 mg/dl or protein >180 mg/dl)]

  4. Composite of mortality/blood culture positive sepsis/severe sepsis within 1st 72 hours after randomization

    Time frame: Within first 72 hour after randomization

    Either mortality and/or blood culture-positive sepsis and/or severe sepsis

  5. Individual components of composite outcome within 1st 72 hours after randomization

    Time frame: Within 1st 72 hours after randomization

    Separately mortality, blood culture-positive sepsis or severe sepsis

  6. Composite of mortality/blood culture positive sepsis/severe sepsis during hospital stay

    Time frame: During hospital stay upto 100 days after randomization

    Either mortality due to any cause and/or blood culture-positive sepsis and/or severe sepsis during hospital stay, with maximum duration of observation during hospital stay being capped at 100 days

  7. Individual components of composite outcome during hospital stay

    Time frame: During hospital stay upto 100 days after randomization

    Separately mortality, blood culture-positive sepsis or severe sepsis during hospital stay, with maximum duration of observation during hospital stay being capped at 100 days

  8. Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during hospital stay

    Time frame: During hospital stay upto 100 days after randomization

    Necrotizing enterocolitis stage II-III by modified Bell's staging criteria during hospital stay, with maximum duration of observation during hospital stay being capped at 100 days after randomization

  9. Composite of mortality/blood culture positive sepsis/severe sepsis during 1st 30 days after randomization

    Time frame: During 1st 30 days after randomization

    Either all-cause mortality and/or blood culture-positive sepsis and/or severe sepsis during the 1st 30 days after randomization

  10. Individual components of composite outcome during 1st 30 days

    Time frame: During 1st 30 days after randomization

    Separately, all-cause mortality, blood culture-positive sepsis or severe sepsis during the 1st 30 days after randomization

  11. Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria

    Time frame: During 1st 30 days after randomization

    Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during the 1st 30 days after randomization

  12. Sepsis-related mortality within 1st 72 hours after randomization

    Time frame: Within 1st 72 hours after randomization

    Mortality due to sepsis within 1st 72 hours. The decision of the treating team will be recorded for attributing mortality to sepsis.

  13. Sepsis-related mortality within 7 day after randomization

    Time frame: Within 7 days after randomization

    Mortality due to sepsis within 7 days after randomization. The decision of the treating team will be recorded for attributing mortality to sepsis.

  14. Sepsis-related mortality during hospital stay after randomization

    Time frame: During hospital stay upto 100 days after randomization

    Mortality due to sepsis during hospital stay. The decision of the treating team will be recorded for attributing mortality to sepsis.

  15. Sepsis-related mortality during 1st 30 days after randomization

    Time frame: During 1st 30 days after randomization

    Mortality due to sepsis during 1st 30 days after randomization

  16. Clinical sepsis within 1st 72 hours after randomization

    Time frame: Within 1st 72 hours after randomization

    Episodes of clinical EONS (as per definition from a repertoire of clinical signs with normal lab parameters) within 1st 72 hours

  17. Clinical sepsis within 7 days after randomization

    Time frame: Within 7 days after randomization

    Episodes of clinical EONS (as per definition from a repertoire of clinical signs with normal lab parameters) within 7 days

  18. Clinical sepsis during hospital stay

    Time frame: During hospital stay upto 100 days

    Episodes of clinical EONS (as per definition from a repertoire of clinical signs with normal lab parameters) during hospital stay, with maximum duration of observation during hospital stay being capped at 100 days after randomization

  19. Clinical sepsis within 1st 30 days after randomization

    Time frame: During 1st 30 days after randomization

    Episodes of clinical EONS (as per definition from a repertoire of clinical signs with normal lab parameters) within 1st 30 days of life

  20. Episode of Probable EONS within 72 hours after randomization

    Time frame: Within 72 hours after randomization

    Episode of Probable EONS [as per definition from a repertoire of clinical signs, AND with abnormal age-appropriate values of one or more of TLC, ANC, CRP, PCT, chest x-ray suggestive of pneumonia AND with sterile blood culture]

  21. Episode of Probable EONS within 7 days after randomization

    Time frame: Within 7 days after randomization

    Episode of Probable EONS [as per definition from a repertoire of clinical signs, AND with abnormal age-appropriate values of one or more of TLC, ANC, CRP, PCT, chest x-ray suggestive of pneumonia AND with sterile blood culture]

  22. Episode of asymptomatic proven EONS within 72 hours after randomization

    Time frame: Within 72 hours after randomization

    Episode of asymptomatic proven EONS [asymptomatic but baseline blood culture positive with non-contaminant organism]

  23. Need for sepsis workup during 1st 72 hours after randomization

    Time frame: During 1st 72 hours after randomization

    ["Sepsis workup" defined as one or more of CBC, CRP, Procalcitonin, blood culture] during 1st 72 hours of life

  24. Need for sepsis workup during 1st 7 days after randomization

    Time frame: During 1st 7 days after randomization

    "Sepsis workup" defined as one or more of CBC, CRP, Procalcitonin, blood culture during 1st 7 days of life

  25. Need for sepsis workup during 1st 30 days after randomization

    Time frame: During 1st 30 days after randomization

    "Sepsis workup" defined as one or more of CBC, CRP, Procalcitonin, blood culture during 1st 30 days of life

  26. Need for sepsis workup during hospital stay

    Time frame: During hospital stay upto 100 days

    "Sepsis workup" defined as one or more of CBC, CRP, Procalcitonin, blood culture during hospital stay, with the period of observation during hospital stay being capped at 100 days

  27. Cumulative duration of antibiotic therapy during 1st 7 days after randomization

    Time frame: During 1st 7 days after randomization

    Cumulative duration of antibiotic therapy during the 1st 7 days, which may include the sum of the durations of multiple courses of antibiotics, either in continuation or discontinuous. If any course of antibiotics continues beyond the 1st 7 days after randomization, only that portion of the antibiotic course would be included until the 1st 7 days after randomization.

  28. Cumulative duration of antibiotic therapy during 1st 72 hrs after randomization

    Time frame: During 1st 72 hours after randomization

    Cumulative measure of antibiotics therapy during the 1st 72 hours

  29. Cumulative duration of antibiotic therapy during hospital stay

    Time frame: During hospital stay upto 100 days after randomization

    Cumulative measure of antibiotics therapy during hospital stay, with the period of observation during hospital stay capped at 100 days

  30. Duration of hospitalization

    Time frame: Upto 100 days

    Full length of hospital stay, with the period capped at 100 days

  31. Episodes of healthcare associated infection during hospital stay.

    Time frame: From after 72 hours until 100 days during hospital stay

    Defined as any episode of culture positive sepsis with onset after 72 hours of life or any episode of culture-positive sepsis if baseline blood culture was sterile, with the period of observation during hospital stay capped at 100 days

  32. Adverse effects until day 30 after randomization

    Time frame: During 30 days after randomization

    Adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.

  33. Serious adverse effects until day 30 after randomization

    Time frame: During 30 days after randomization

    Serious adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Study contacts

Contact information is provided by the study sponsor or research team.

Sajan Saini, MD, DM

CONTACT

[email protected]

+91-1722756264

Sourabh Dutta, MD, Ph.D

CONTACT

[email protected]

+91-1722755313

Sponsors and collaborators

Lead sponsor

Indian Council of Medical Research

Other Gov

Collaborators

  • Government Medical College, Aurangabad
  • Government Medical College, Chandigarh
  • Indira Gandhi Institute of Child Health
  • Institute of Obstetrics and Gynecology
  • King Edward Memorial Hospital, Mumbai
  • King George's Medical University
  • Lady Hardinge Medical College
  • Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak

Registry information

Official study 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)

Acronym: SAUNA

Important dates

Study start
2024
Primary completion
2027
Study completion
2028
First posted
Apr 22, 2024
Registry last updated
Apr 22, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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