Selective Antibiotics When Symptoms Develop Versus Universal Antibiotics for Preterm Neonates

Sepsis Clinical Trial

— SAUNA  

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)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06377397
• Other study ID #: IIRPIG-2023-0000070
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 15, 2024
• Est. completion date: April 14, 2028

Study information

• Verified date: April 2024
• Source: Indian Council of Medical Research
• Contact: Sourabh Dutta, MD, Ph.D
• Phone: +91-1722755313
• Email: sourabhdutta1[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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").

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")

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1500
• Est. completion date: April 14, 2028
• Est. primary completion date: April 15, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Hours to 4 Hours

Eligibility

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.

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Related Conditions & MeSH terms

• Early-Onset Neonatal Sepsis
• Fetal Membranes, Premature Rupture
• Neonatal Sepsis
• Premature Birth
• Preterm Birth
• Preterm Premature Rupture of Membrane
• Rupture
• Sepsis
• Toxemia

Intervention

Drug:
• 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

Locations

Country	Name	City	State
India	Post Graduate Institute of Medical Education and Research (PGIMER)	Chandigarh

Sponsors (9)

Lead Sponsor	Collaborator
Indian Council of Medical Research	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

Country where clinical trial is conducted

India, 

References & Publications (13)

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):35 — View Citation

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. — View Citation

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 an — View Citation

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 Dis — View Citation

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 2 — View Citation

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. — View Citation

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 — View Citation

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 — View Citation

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. — View Citation

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- — View Citation

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. do — View Citation

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. — View Citation

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

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	All-cause Mortality within 1st 7 days after randomization	Mortality due to any cause	During 1st 7 days after randomization
Secondary	Blood culture-positive sepsis of any severity within 1st 7 days after randomization	Blood culture proven septicemia	Within 1st 7 days after randomization
Secondary	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)]	Within 1st 7 days after randomization
Secondary	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	Within first 72 hour after randomization
Secondary	Individual components of composite outcome within 1st 72 hours after randomization	Separately mortality, blood culture-positive sepsis or severe sepsis	Within 1st 72 hours after randomization
Secondary	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	During hospital stay upto 100 days after randomization
Secondary	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	During hospital stay upto 100 days after randomization
Secondary	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	During hospital stay upto 100 days after randomization
Secondary	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	During 1st 30 days after randomization
Secondary	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	During 1st 30 days after randomization
Secondary	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	During 1st 30 days after randomization
Secondary	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.	Within 1st 72 hours after randomization
Secondary	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.	Within 7 days after randomization
Secondary	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.	During hospital stay upto 100 days after randomization
Secondary	Sepsis-related mortality during 1st 30 days after randomization	Mortality due to sepsis during 1st 30 days after randomization	During 1st 30 days after randomization
Secondary	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	Within 1st 72 hours after randomization
Secondary	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	Within 7 days after randomization
Secondary	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	During hospital stay upto 100 days
Secondary	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	During 1st 30 days after randomization
Secondary	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]	Within 72 hours after randomization
Secondary	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]	Within 7 days after randomization
Secondary	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]	Within 72 hours after randomization
Secondary	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	During 1st 72 hours after randomization
Secondary	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	During 1st 7 days after randomization
Secondary	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	During 1st 30 days after randomization
Secondary	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	During hospital stay upto 100 days
Secondary	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.	During 1st 7 days after randomization
Secondary	Cumulative duration of antibiotic therapy during 1st 72 hrs after randomization	Cumulative measure of antibiotics therapy during the 1st 72 hours	During 1st 72 hours after randomization
Secondary	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	During hospital stay upto 100 days after randomization
Secondary	Duration of hospitalization	Full length of hospital stay, with the period capped at 100 days	Upto 100 days
Secondary	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	From after 72 hours until 100 days during hospital stay
Secondary	Adverse effects until day 30 after randomization	Adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.	During 30 days after randomization
Secondary	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.	During 30 days after randomization