SepsisPhase 3SAUNANCT06377397
Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates
A Phase 3 study testing Antibiotics in people with Sepsis and PROM, Preterm (Pregnancy), run by Indian Council of Medical Research at 1 site in India.
Trial 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. Read more about this study
- Who is it for?
- Ages 0 to 4 hours
- Conditions the study is for
- Sepsis, PROM, Preterm (Pregnancy), Early-Onset Neonatal Sepsis
- What is being tested?
- Antibiotics
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,500 participants
- Where
- 1 siteIndia
- Study dates
- 15 Apr 2024to 14 Apr 2028
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 to 4 hours
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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:
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- 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
Who cannot join
- 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
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- 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.
- -
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
India1 site
Post Graduate Institute of Medical Education and Research (PGIMER)
Chandigarh, 160012
About this study
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)
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:
- 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.
- 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.
- 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").
Read the 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:
- 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")
- Conditions
- Sepsis, PROM, Preterm (Pregnancy), Early-Onset Neonatal Sepsis, Preterm Premature Rupture of Membrane, Preterm Birth
- Being tested
- Antibiotics
- Keywords
- Prolonged rupture of membranes, Preterm premature rupture of membranes, Early-onset neonatal sepsis, Selective antibiotics, Non-inferiority trial
- Medical subject headings
- Sepsis, Fetal Membranes, Premature Rupture, Neonatal Sepsis, Preterm Premature Rupture of the Membranes, Premature Birth
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AntibioticsDrug
Also called Intravenous antibiotics as per written down empirical antibiotic policy of the unit
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
| Study group | Role | What they receive |
|---|---|---|
| Selective antibiotic group | Experimental | Antibiotics will be administered selectively to a subset of at-risk neonates who develop clinical signs of sepsis. Receives: Drug: Antibiotics |
| Comparison group | Active comparator | Antibiotics will be pre-emptively administered to all neonates at risk of sepsis. Receives: Drug: Antibiotics |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Within 1st 7 days after randomization
Secondary outcomes (33)
All-cause Mortality within 1st 7 days after randomization
Mortality due to any cause
Measured: During 1st 7 days after randomization
Blood culture-positive sepsis of any severity within 1st 7 days after randomization
Blood culture proven septicemia
Measured: Within 1st 7 days after randomization
Episode of severe sepsis 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)]
Measured: Within 1st 7 days after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis within 1st 72 hours after randomization
Either mortality and/or blood culture-positive sepsis and/or severe sepsis
Measured: Within first 72 hour after randomization
Individual components of composite outcome within 1st 72 hours after randomization
Separately mortality, blood culture-positive sepsis or severe sepsis
Measured: Within 1st 72 hours after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis during hospital stay
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
Measured: During hospital stay upto 100 days after randomization
Individual components of composite outcome during hospital stay
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
Measured: During hospital stay upto 100 days after randomization
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during hospital stay
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
Measured: During hospital stay upto 100 days after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis 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
Measured: During 1st 30 days after randomization
Individual components of composite outcome during 1st 30 days
Separately, all-cause mortality, blood culture-positive sepsis or severe sepsis during the 1st 30 days after randomization
Measured: During 1st 30 days after randomization
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during the 1st 30 days after randomization
Measured: During 1st 30 days after randomization
Sepsis-related mortality 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.
Measured: Within 1st 72 hours after randomization
Sepsis-related mortality within 7 day 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.
Measured: Within 7 days after randomization
Sepsis-related mortality during hospital stay after randomization
Mortality due to sepsis during hospital stay. The decision of the treating team will be recorded for attributing mortality to sepsis.
Measured: During hospital stay upto 100 days after randomization
Sepsis-related mortality during 1st 30 days after randomization
Mortality due to sepsis during 1st 30 days after randomization
Measured: During 1st 30 days after randomization
Clinical sepsis 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
Measured: Within 1st 72 hours after randomization
Clinical sepsis 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
Measured: Within 7 days after randomization
Clinical sepsis during hospital stay
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
Measured: During hospital stay upto 100 days
Clinical sepsis within 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
Measured: During 1st 30 days after randomization
Episode of Probable EONS 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]
Measured: Within 72 hours after randomization
Episode of Probable EONS 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]
Measured: Within 7 days after randomization
Episode of asymptomatic proven EONS within 72 hours after randomization
Episode of asymptomatic proven EONS [asymptomatic but baseline blood culture positive with non-contaminant organism]
Measured: Within 72 hours after randomization
Need for sepsis workup 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
Measured: During 1st 72 hours after randomization
Need for sepsis workup 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
Measured: During 1st 7 days after randomization
Need for sepsis workup 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
Measured: During 1st 30 days after randomization
Need for sepsis workup during hospital stay
"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
Measured: During hospital stay upto 100 days
Cumulative duration of antibiotic therapy 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.
Measured: During 1st 7 days after randomization
Cumulative duration of antibiotic therapy during 1st 72 hrs after randomization
Cumulative measure of antibiotics therapy during the 1st 72 hours
Measured: During 1st 72 hours after randomization
Cumulative duration of antibiotic therapy during hospital stay
Cumulative measure of antibiotics therapy during hospital stay, with the period of observation during hospital stay capped at 100 days
Measured: During hospital stay upto 100 days after randomization
Duration of hospitalization
Full length of hospital stay, with the period capped at 100 days
Measured: Upto 100 days
Episodes of healthcare associated infection 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
Measured: From after 72 hours until 100 days during hospital stay
Adverse effects until day 30 after randomization
Adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Measured: During 30 days after randomization
Serious adverse effects until day 30 after randomization
Serious adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Measured: During 30 days after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Apr 2024
- Study start15 Apr 2024 (estimated)
- Primary completion15 Apr 2027 (estimated)
- Study completion14 Apr 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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)
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 1,500 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Indian Council of Medical Research
- Sponsor type
- Other government
- Collaborators
- Lady Hardinge Medical College, King George's Medical University, Indira Gandhi Institute of Child Health, Institute of Obstetrics and Gynecology, Government Medical College, Chandigarh, Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak, Government Medical College, Aurangabad, King Edward Memorial Hospital, Mumbai
- Responsible party
- Principal investigator, Sourabh Dutta, Post Graduate Institute of Medical Education and Research, Chandigarh
- Investigators
- Sourabh Dutta, MD, Ph.D, Principal investigator, Post Graduate Institute of Medical Education and Research, Chandigarh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06377397
- Sponsor's protocol ID
- IIRPIG-2023-0000070
- Acronym
- SAUNA
- Status last verified
- Apr 2024
- First submitted
- 26 Mar 2024
- Last updated
- 22 Apr 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Anonymized, individual patient data pertaining to publications from the study which are in the public domain will be shared with other researchers planning to conduct a study, upon reasonable written request
Publications
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.
PubMed 27924104Lawn 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.
PubMed 24853593Chaurasia 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.
PubMed 30670451Chan 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.
PubMed 23976885Puopolo 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.
PubMed 30455342Wolf RL, Olinsky A. Prolonged rupture of fetal membranes and neonatal infections. S Afr Med J. 1976 Apr 3;50(15):574-6.
PubMed 772827Berardi 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.
PubMed 25034325Berardi 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.
PubMed 27872823Berardi 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.
PubMed 30893310Cantoni 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.
PubMed 23477995Joshi 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.
PubMed 29599112Chiruvolu 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.
PubMed 32010864Investigators 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.
PubMed 27633433
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT06377397
- Acronym / sponsor ID
- SAUNA / IIRPIG-2023-0000070
- 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
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 1,500 participants (estimated)
- Lead sponsor
- Indian Council of Medical ResearchOther government
- Collaborators
- Lady Hardinge Medical College, King George's Medical University, Indira Gandhi Institute of Child Health, Institute of Obstetrics and Gynecology, Government Medical College, Chandigarh, Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak, Government Medical College, Aurangabad, King Edward Memorial Hospital, Mumbai
- Study start
- 15 Apr 2024 (estimated)
- Primary completion
- 15 Apr 2027 (estimated)
- Study completion
- 14 Apr 2028 (estimated)
- First posted
- 22 Apr 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
- 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.
- 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:
- 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")
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- 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)
| Arm | Type | Receives |
|---|---|---|
| Selective antibiotic group | Experimental | Drug: AntibioticsAntibiotics will be administered selectively to a subset of at-risk neonates who develop clinical signs of sepsis. |
| Comparison group | Active comparator | Drug: AntibioticsAntibiotics will be pre-emptively administered to all neonates at risk of sepsis. |
Who may qualify
- Ages
- 0 to 4 hours
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (18 listed)
- Gestational age of 26 to 34 weeks
- Chronological age 4 hours
- Have any one or both of the following risk factors of EONS:
- 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:
Key exclusion criteria (11 listed)
- <!-- -->
- -
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AntibioticsAlso: Intravenous antibiotics as per written down empirical antibiotic policy of the unitIn 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 | Drug | Comparison group, Selective antibiotic group |
Primary outcome
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.
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.
33 secondary outcomes
All-cause Mortality within 1st 7 days after randomization
Time frame: During 1st 7 days after randomization
Blood culture-positive sepsis of any severity within 1st 7 days after randomization
Time frame: Within 1st 7 days after randomization
Episode of severe sepsis within 1st 7 days after randomization
Time frame: Within 1st 7 days after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis within 1st 72 hours after randomization
Time frame: Within first 72 hour after randomization
Individual components of composite outcome within 1st 72 hours after randomization
Time frame: Within 1st 72 hours after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis during hospital stay
Time frame: During hospital stay upto 100 days after randomization
Individual components of composite outcome 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
Time frame: During hospital stay upto 100 days after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis during 1st 30 days after randomization
Time frame: During 1st 30 days after randomization
Individual components of composite outcome during 1st 30 days
Time frame: During 1st 30 days after randomization
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria
Time frame: During 1st 30 days after randomization
Sepsis-related mortality within 1st 72 hours after randomization
Time frame: Within 1st 72 hours after randomization
Sepsis-related mortality within 7 day after randomization
Time frame: Within 7 days after randomization
Sepsis-related mortality during hospital stay after randomization
Time frame: During hospital stay upto 100 days after randomization
Sepsis-related mortality during 1st 30 days after randomization
Time frame: During 1st 30 days after randomization
Clinical sepsis within 1st 72 hours after randomization
Time frame: Within 1st 72 hours after randomization
Clinical sepsis within 7 days after randomization
Time frame: Within 7 days after randomization
Clinical sepsis during hospital stay
Time frame: During hospital stay upto 100 days
Clinical sepsis within 1st 30 days after randomization
Time frame: During 1st 30 days after randomization
Episode of Probable EONS within 72 hours after randomization
Time frame: Within 72 hours after randomization
Episode of Probable EONS within 7 days after randomization
Time frame: Within 7 days after randomization
Episode of asymptomatic proven EONS within 72 hours after randomization
Time frame: Within 72 hours after randomization
Need for sepsis workup during 1st 72 hours after randomization
Time frame: During 1st 72 hours after randomization
Need for sepsis workup during 1st 7 days after randomization
Time frame: During 1st 7 days after randomization
Need for sepsis workup during 1st 30 days after randomization
Time frame: During 1st 30 days after randomization
Need for sepsis workup during hospital stay
Time frame: During hospital stay upto 100 days
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 1st 72 hrs after randomization
Time frame: During 1st 72 hours after randomization
Cumulative duration of antibiotic therapy during hospital stay
Time frame: During hospital stay upto 100 days after randomization
Duration of hospitalization
Time frame: Upto 100 days
Episodes of healthcare associated infection during hospital stay.
Time frame: From after 72 hours until 100 days during hospital stay
Adverse effects until day 30 after randomization
Time frame: During 30 days after randomization
Serious adverse effects until day 30 after randomization
Time frame: During 30 days after randomization
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2024.
- Results publication: PubMed 27924104Sankar 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.
- Results publication: PubMed 24853593Lawn 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.
- Results publication: PubMed 30670451Chaurasia 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.
- Results publication: PubMed 23976885Chan 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.
- Results publication: PubMed 30455342Puopolo 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.
- Results publication: PubMed 772827Wolf RL, Olinsky A. Prolonged rupture of fetal membranes and neonatal infections. S Afr Med J. 1976 Apr 3;50(15):574-6.
- Results publication: PubMed 25034325Berardi 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.
- Results publication: PubMed 27872823Berardi 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.
- Results publication: PubMed 30893310Berardi 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.
- Results publication: PubMed 23477995Cantoni 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.
- Results publication: PubMed 29599112Joshi 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.
- Results publication: PubMed 32010864Chiruvolu 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.
- Individual participant dataSharing planned: Yes. Anonymized, individual patient data pertaining to publications from the study which are in the public domain will be shared with other researchers planning to conduct a study, upon reasonable written request
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Sourabh Dutta, MD, Ph.D principal investigator
Post Graduate Institute of Medical Education and Research, Chandigarh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Antibiotics in people with Sepsis and PROM, Preterm (Pregnancy), run by Indian Council of Medical Research at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 22 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sourabh Dutta, MD, Ph.D (+91-1722755313, sourabhdutta1@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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 (time frame: Within 1st 7 days after randomization). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06377397, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Apr 2024.