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| Name | Class |
|---|---|
| Lady Hardinge Medical College | OTHER_GOV |
| King George's Medical University | OTHER |
| Indira Gandhi Institute of Child Health | UNKNOWN |
| Institute of Obstetrics and Gynecology |
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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:
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Selective antibiotic group | Experimental | Antibiotics will be administered selectively to a subset of at-risk neonates who develop clinical signs of sepsis. |
|
| Comparison group | Active Comparator | Antibiotics will be pre-emptively administered to all neonates at risk of sepsis. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| All-cause Mortality within 1st 7 days after randomization | Mortality due to any cause | During 1st 7 days after randomization |
| Blood culture-positive sepsis of any severity within 1st 7 days after randomization |
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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:
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
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
Exclusion Criteria:
Subjects will be excluded if they have any 1 of the following:
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.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Sourabh Dutta, MD, Ph.D | Contact | +91-1722755313 | sourabhdutta1@gmail.com | |
| Sajan Saini, MD, DM | Contact | +91-1722756264 | sajansaini1@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Sourabh Dutta, MD, Ph.D | Post Graduate Institute of Medical Education and Research, Chandigarh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Post Graduate Institute of Medical Education and Research (PGIMER) | Chandigarh | 160012 | India |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27924104 | Result | 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. | |
| 24853593 | 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. |
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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
Data will be made available one year after the publication from the study for a period of 3 years
To be decided
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 2, 2024 |
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| UNKNOWN |
| Government Medical College, Chandigarh | OTHER |
| Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak | OTHER |
| Government Medical College, Aurangabad | OTHER_GOV |
| King Edward Memorial Hospital, Mumbai | OTHER_GOV |
Neonates will be randomized to 1 of the following groups:
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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.
|
|
Blood culture proven septicemia
| 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)] | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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. | 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. | 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. | 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 | 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 | 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 | 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 | 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 | 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] | 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] | 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] | 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 | 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 | 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 | 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 | 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. | 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 | 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 | During hospital stay upto 100 days after randomization |
| Duration of hospitalization | Full length of hospital stay, with the period capped at 100 days | 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 | 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. | 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. | During 30 days after randomization |
| 30670451 | 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. |
| 23976885 | 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. |
| 30455342 | 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. |
| 772827 | Result | Wolf RL, Olinsky A. Prolonged rupture of fetal membranes and neonatal infections. S Afr Med J. 1976 Apr 3;50(15):574-6. |
| 25034325 | 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. |
| 27872823 | 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. |
| 30893310 | 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. |
| 23477995 | 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. |
| 29599112 | 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. |
| 32010864 | 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. |
| 27633433 | 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. |
| Apr 2, 2024 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D005322 | Fetal Membranes, Premature Rupture |
| D000071074 | Neonatal Sepsis |
| C563032 | Preterm Premature Rupture of the Membranes |
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D007752 | Obstetric Labor, Premature |
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| ID | Term |
|---|---|
| D000900 | Anti-Bacterial Agents |
| ID | Term |
|---|---|
| D000890 | Anti-Infective Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
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