Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates

NCT ID: NCT06377397

Last Updated: 2024-04-22

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Clinical Phase

PHASE3

Total Enrollment

1500 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-04-15

Study Completion Date

2028-04-14

Brief Summary

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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

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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")

Conditions

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Sepsis PROM, Preterm (Pregnancy) Early-Onset Neonatal Sepsis Preterm Premature Rupture of Membrane Preterm Birth

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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 Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors
Project staff, nurses and resident doctors looking after the neonate will not be blinded. The assessment of the primary outcome will be performed by a blinded adjudicator, who is not involved in the recruitment and monitoring of subjects. A part of the case report form (CRF) containing relevant details of all episodes of sickness in the 1st week of life will be detached from the main form and will be sent to the blinded adjudicator. This part will be linked to the main form only by a unique identification number. No patient identifiers or allocation group will be mentioned on the part sent to the blinded adjudicator.

Study Groups

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Selective antibiotic group

Antibiotics will be administered selectively to a subset of at-risk neonates who develop clinical signs of sepsis.

Group Type EXPERIMENTAL

Antibiotics

Intervention Type 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

Comparison group

Antibiotics will be pre-emptively administered to all neonates at risk of sepsis.

Group Type ACTIVE_COMPARATOR

Antibiotics

Intervention Type 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

Interventions

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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 sepsis at enrollment

Intervention Type DRUG

Other Intervention Names

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

Eligibility Criteria

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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.

\-
Minimum Eligible Age

0 Hours

Maximum Eligible Age

4 Hours

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Lady Hardinge Medical College

OTHER_GOV

Sponsor Role collaborator

King George's Medical University

OTHER

Sponsor Role collaborator

Indira Gandhi Institute of Child Health

UNKNOWN

Sponsor Role collaborator

Institute of Obstetrics and Gynecology

UNKNOWN

Sponsor Role collaborator

Government Medical College, Chandigarh

OTHER

Sponsor Role collaborator

Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak

OTHER

Sponsor Role collaborator

Government Medical College, Aurangabad

OTHER_GOV

Sponsor Role collaborator

King Edward Memorial Hospital, Mumbai

OTHER_GOV

Sponsor Role collaborator

Indian Council of Medical Research

OTHER_GOV

Sponsor Role lead

Responsible Party

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Sourabh Dutta

Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Sourabh Dutta, MD, Ph.D

Role: PRINCIPAL_INVESTIGATOR

Post Graduate Institute of Medical Education and Research, Chandigarh

Locations

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Post Graduate Institute of Medical Education and Research (PGIMER)

Chandigarh, , India

Site Status

Countries

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India

Central Contacts

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Sourabh Dutta, MD, Ph.D

Role: CONTACT

+91-1722755313

Sajan Saini, MD, DM

Role: CONTACT

+91-1722756264

References

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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.

Reference Type RESULT
PMID: 27924104 (View on PubMed)

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.

Reference Type RESULT
PMID: 24853593 (View on PubMed)

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.

Reference Type RESULT
PMID: 30670451 (View on PubMed)

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.

Reference Type RESULT
PMID: 23976885 (View on PubMed)

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.

Reference Type RESULT
PMID: 30455342 (View on PubMed)

Wolf RL, Olinsky A. Prolonged rupture of fetal membranes and neonatal infections. S Afr Med J. 1976 Apr 3;50(15):574-6.

Reference Type RESULT
PMID: 772827 (View on PubMed)

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.

Reference Type RESULT
PMID: 25034325 (View on PubMed)

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.

Reference Type RESULT
PMID: 27872823 (View on PubMed)

Berardi A, Spada C, Reggiani MLB, Creti R, Baroni L, Capretti MG, Ciccia M, Fiorini V, Gambini L, Gargano G, Papa I, Piccinini G, Rizzo V, Sandri F, Lucaccioni L; GBS Prevention Working Group of Emilia-Romagna. Group B Streptococcus early-onset disease and observation of well-appearing newborns. PLoS One. 2019 Mar 20;14(3):e0212784. doi: 10.1371/journal.pone.0212784. eCollection 2019.

Reference Type RESULT
PMID: 30893310 (View on PubMed)

Cantoni L, Ronfani L, Da Riol R, Demarini S; Perinatal Study Group of the Region Friuli-Venezia Giulia. Physical examination instead of laboratory tests for most infants born to mothers colonized with group B Streptococcus: support for the Centers for Disease Control and Prevention's 2010 recommendations. J Pediatr. 2013 Aug;163(2):568-73. doi: 10.1016/j.jpeds.2013.01.034. Epub 2013 Mar 8.

Reference Type RESULT
PMID: 23477995 (View on PubMed)

Joshi NS, Gupta A, Allan JM, Cohen RS, Aby JL, Weldon B, Kim JL, Benitz WE, Frymoyer A. Clinical Monitoring of Well-Appearing Infants Born to Mothers With Chorioamnionitis. Pediatrics. 2018 Apr;141(4):e20172056. doi: 10.1542/peds.2017-2056.

Reference Type RESULT
PMID: 29599112 (View on PubMed)

Chiruvolu A, Petrey B, Stanzo KC, Daoud Y. An Institutional Approach to the Management of Asymptomatic Chorioamnionitis-Exposed Infants Born >/=35 Weeks Gestation. Pediatr Qual Saf. 2019 Dec 5;4(6):e238. doi: 10.1097/pq9.0000000000000238. eCollection 2019 Nov-Dec.

Reference Type RESULT
PMID: 32010864 (View on PubMed)

Investigators of the Delhi Neonatal Infection Study (DeNIS) collaboration. Characterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study. Lancet Glob Health. 2016 Oct;4(10):e752-60. doi: 10.1016/S2214-109X(16)30148-6.

Reference Type RESULT
PMID: 27633433 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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IIRPIG-2023-0000070

Identifier Type: -

Identifier Source: org_study_id

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