Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates

Phase 3

Not yet recruiting

• Conditions: Sepsis; PROM, Preterm (Pregnancy); Early-Onset Neonatal Sepsis; Preterm Premature Rupture of Membrane; Preterm Birth
• Interventions: Drug: Antibiotics

• Registration Number: NCT06377397
• Lead Sponsor: Indian Council of Medical Research

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")

Study Timeline

• Study First Submitted: 2024-03-26
• Status Verified: 2024-04
• Study Start: 2024-04-15
• Study First Submitted QC: 2024-04-17
• Last Update Submitted: 2024-04-17
• Study First Posted: 2024-04-22
• Last Update Posted: 2024-04-22
• Primary Completion: 2027-04-15
• Study Completion: 2028-04-14

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1500

Inclusion Criteria

Not provided

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Exclusion Criteria

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Selective antibiotic group	Antibiotics	Antibiotics will be administered selectively to a subset of at-risk neonates who develop clinical signs of sepsis.
Comparison group	Antibiotics	Antibiotics will be pre-emptively administered to all neonates at risk of sepsis.

Primary Outcome Measures

Name	Time	Method
Need for intravenous antibiotics for ≥ 48 hours within the 1st 7 days after randomization	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.
Composite of all-cause mortality and/or any episode of culture-positive sepsis and/or severe sepsis* within the 1st 7 days after randomization	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.

Secondary Outcome Measures

Name	Time	Method
Composite of mortality/blood culture positive sepsis/severe sepsis within 1st 72 hours after randomization	Within first 72 hour after randomization	Either mortality and/or blood culture-positive sepsis and/or severe sepsis
Episode of severe sepsis within 1st 7 days after randomization	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 \[Need for intubation and mechanical ventilation, Need for inotropes \>10 mic/kg/min dopamine or \>10 mic/kg/min dobutamine or adrenaline \> 0.05 mic/kg/min, Need for exchange transfusion, Need for platelet concentrates or FFP, Meningitis (defined as either CSF culture positive or Gram stain positive or Cell count \>25/microlitre or glucose \<25 mg/dl or protein \>180 mg/dl)\]
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during hospital stay	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
Composite of mortality/blood culture positive sepsis/severe sepsis during 1st 30 days after randomization	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
Individual components of composite outcome during 1st 30 days	During 1st 30 days after randomization	Separately, all-cause mortality, blood culture-positive sepsis or severe sepsis during the 1st 30 days after randomization
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria	During 1st 30 days after randomization	Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during the 1st 30 days after randomization
Sepsis-related mortality within 1st 72 hours after randomization	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.
Sepsis-related mortality within 7 day after randomization	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.
Sepsis-related mortality during hospital stay after randomization	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.
All-cause Mortality within 1st 7 days after randomization	During 1st 7 days after randomization	Mortality due to any cause
Blood culture-positive sepsis of any severity within 1st 7 days after randomization	Within 1st 7 days after randomization	Blood culture proven septicemia
Individual components of composite outcome within 1st 72 hours after randomization	Within 1st 72 hours after randomization	Separately mortality, blood culture-positive sepsis or severe sepsis
Composite of mortality/blood culture positive sepsis/severe sepsis during hospital stay	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
Individual components of composite outcome during hospital stay	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
Sepsis-related mortality during 1st 30 days after randomization	During 1st 30 days after randomization	Mortality due to sepsis during 1st 30 days after randomization
Clinical sepsis within 1st 72 hours after randomization	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
Clinical sepsis within 7 days after randomization	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
Clinical sepsis during hospital stay	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
Clinical sepsis within 1st 30 days after randomization	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
Episode of Probable EONS within 72 hours after randomization	Within 72 hours after randomization	Episode of Probable EONS \[as per definition from a repertoire of clinical signs, AND with abnormal age-appropriate values of one or more of TLC, ANC, CRP, PCT, chest x-ray suggestive of pneumonia AND with sterile blood culture\]
Episode of Probable EONS within 7 days after randomization	Within 7 days after randomization	Episode of Probable EONS \[as per definition from a repertoire of clinical signs, AND with abnormal age-appropriate values of one or more of TLC, ANC, CRP, PCT, chest x-ray suggestive of pneumonia AND with sterile blood culture\]
Episode of asymptomatic proven EONS within 72 hours after randomization	Within 72 hours after randomization	Episode of asymptomatic proven EONS \[asymptomatic but baseline blood culture positive with non-contaminant organism\]
Need for sepsis workup during 1st 72 hours after randomization	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
Need for sepsis workup during 1st 7 days after randomization	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
Need for sepsis workup during 1st 30 days after randomization	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
Need for sepsis workup during hospital stay	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
Cumulative duration of antibiotic therapy during 1st 7 days after randomization	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.
Cumulative duration of antibiotic therapy during 1st 72 hrs after randomization	During 1st 72 hours after randomization	Cumulative measure of antibiotics therapy during the 1st 72 hours
Cumulative duration of antibiotic therapy during hospital stay	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
Duration of hospitalization	Upto 100 days	Full length of hospital stay, with the period capped at 100 days
Episodes of healthcare associated infection during hospital stay.	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
Adverse effects until day 30 after randomization	During 30 days after randomization	Adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Serious adverse effects until day 30 after randomization	During 30 days after randomization	Serious adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Trial Locations

Locations (1)

Post Graduate Institute of Medical Education and Research (PGIMER); 🇮🇳 Chandigarh, India