Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates

NCT06377397 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: IIRPIG-2023-0000070
• Study Type: interventional
• Target: 1,500
• Locations: 1 country
• Sites: 1

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. 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. 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. 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").

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

Outcome Measures

Primary Outcomes (2)

• Composite of all-cause mortality and/or any episode of culture-positive sepsis and/or severe sepsis* within the 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.

  Within 1st 7 days after randomization

• Need for intravenous antibiotics for ≥ 48 hours within the 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.

  Within 1st 7 days after randomization

Secondary Outcomes (33)

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

  During 1st 7 days after randomization

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

  Within 1st 7 days after randomization

• Episode of severe sepsis within 1st 7 days after randomization

  Within 1st 7 days after randomization

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

  Within first 72 hour after randomization

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

  Within 1st 72 hours after randomization

Study Arms (2)

Selective antibiotic group

EXPERIMENTAL

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

Drug: Antibiotics

Comparison group

ACTIVE COMPARATOR

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

Drug: Antibiotics

Interventions

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

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

Comparison group; Selective antibiotic group

Eligibility Criteria

• Age: 0 Hours - 4 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (1)

Post Graduate Institute of Medical Education and Research (PGIMER)

Chandigarh, 160012, India

Location

Related Publications (13)

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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.

  PMID: 30893310 RESULT

• 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.

  PMID: 23477995 RESULT

• 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.

  PMID: 29599112 RESULT

• 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.

  PMID: 32010864 RESULT

• 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.

  PMID: 27633433 RESULT

MeSH Terms

Conditions

Sepsis; Fetal Membranes, Premature Rupture; Neonatal Sepsis; Preterm Premature Rupture of the Membranes; Premature Birth

Interventions

Anti-Bacterial Agents

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Obstetric Labor, Premature

Intervention Hierarchy (Ancestors)

Anti-Infective Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Sourabh Dutta, MD, Ph.D

  Post Graduate Institute of Medical Education and Research, Chandigarh

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sourabh Dutta, MD, Ph.D

CONTACT

+91-1722755313; sourabhdutta1@gmail.com

Sajan Saini, MD, DM

CONTACT

+91-1722756264; sajansaini1@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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)

Study Record Dates

• First Submitted: March 26, 2024
• First Posted: April 22, 2024
• Study Start: April 15, 2024
• Primary Completion (Estimated): April 15, 2027
• Study Completion (Estimated): April 14, 2028
• Last Updated: April 22, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available one year after the publication from the study for a period of 3 years
• Access Criteria: To be decided

Locations

IN (1)