Comparison of the Efficacy of a 7-day Versus 14-day Course of Intravenous Antibiotics in the Treatment of Uncomplicated Neonatal Bacterial Sepsis: a Randomized Controlled Non-inferiority Trial
Phase: PHASE3
Conditions: Infant, Newborn, Neonatal SEPSIS, Anti-bacterial Agents, Recurrence
Sponsor: Indian Council of Medical Research

Title:  
Comparison of the Efficacy of a 7-day Versus 14-day Course of 
Intravenous Antibiotics in the Treatment of Uncomplicated Neonatal 
Bacterial Sepsis: a Randomized Controlled Noninferiority Trial 
NCT number: NCT 03280147 
Date of document: 26 September 2019 

1 
Version dated 26 Sep 2019 
 
 
 
METHODS 
 
Study design 
This is a multi-centric, randomized, active-controlled, non-inferiority trial. Stratification of subjects is done 
according to center and birth weight. 
 
 Eligibility 
All neonates whose birth weight is more than 1000 grams with clinically suspected sepsis for which the 
treating physician decides to start antibiotics will be eligible for screening.  
Inclusion Criteria  
Subjects should satisfy all the following criteria: 
 
Neonates aged 0-28 days, either inborn or out born, who are currently admitted in the Neonatal 
unit of the centre, 
 
Whose birth weight is greater than 1000 grams (it should be reliably ascertained from records of a 
hospital. 
 
Whose residence is within approximately 15 kms from the centre, so that the infant can be brought 
back to the centre for follow up. 
 
Who have suspected septicemia for which a conventional or BACTEC/BACTALERT blood culture is 
sent and for which the treating physician decides to start antibiotics. 
Exclusion Criteria 
 
Central Nervous System infection (meningitis will be defined as CSF Cells >25 per uL with polys 
>60%OR [(CSF glucose <20 mg/dL OR CSF:blood* glu ratio <0.6) AND (CSF protein >150 mg/dL in 
term OR >180 mg/dL in preterm)] 
 
 Septic arthritis, osteomyelitis or deep-seated abscess as clinically judged by the treating team 
 
Life threatening congenital malformations as judged by the principal investigator of the centre 
Parents of the subjects who satisfy the eligibility criteria are approached for participation in the study. 
They are provided a Patient Information Sheet for Enrolment (Appendix 1) and the nature and purpose of 
the observational part of the study will be discussed with them and they will be informed that they may 
be approached again for the randomized controlled trial portion of the study after approximately 7 days 
or more, if the infant meets criteria for randomization. The patient information sheet will also be 
discussed with the parents in a non-technical language. Written informed consent (3 copies) for 
enrolment will be taken from a parent in the presence of a witness (Appendix 2). One copy will be handed 
to the parent, one will be kept with the investigator and 1 will be kept in the hospital records. There will 
be no restrictions on the parent’s right to ask questions related to the study. Patient-related data from 
start of screening up to eligibility for enrolment will be recorded in the “Screening sub-form” of Proforma 
A of case report form.  
Data of observational part of the study 
After obtaining consent for enrolment, the following data will be recorded: maternal and neonatal 
demographic data, maternal risk factors of sepsis, clinical and laboratory features of sepsis, culture and 
sepsis screen reports, antibiotics and their doses. The subjects will be followed up on a daily basis for 
remission of clinical signs (using a standard list of objectively defined signs), change of antibiotics (if any, 
with reasons), and co-interventions. Decisions regarding the kind of antibiotics and changes, if any, from 
the point of enrolment to the point of randomization will be left to the judgment of the treating physician. 

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Version dated 26 Sep 2019 
 
 
Each of the participating Centres will decide on the empirical antibiotics based upon their standard 
empirical antibiotic policy. No changes in policy will be made for the sake of the research study. The 
antibiotics shall be stored, prescribed and dispensed as per the recommendations of Neofax essentials, 
2014. All study subjects will receive routine care as per guidelines of the concerned centre. 
Randomization criteria 
Randomization will be done at the end of the 7th day of therapy with sensitive antibiotics. Of the enrolled 
subjects, only those who satisfy the criteria below will be randomized: 
Eligible for randomization 
 
Positive blood culture other than Staphylococcus aureus 
 
No signs and symptoms of sepsis from end of day 5 through end of day 7 of starting sensitive 
antibiotics (This will be on day 5 through 7 for those who have improved and will be day 8 through 
10 for those where in empiric antibiotics have been resistant requiring a change in antibiotic on day 
3 of enrolment) 
Not eligible for randomization 
 
Sterile blood culture 
 
Suspected contaminants in blood culture. 
 
Growth of Staphylococcus aureus in blood culture 
 
Growth of fungal organism in blood culture 
 
Diagnosis of meningitis, septic arthritis, osteomyelitis, abscess 
 
Has not gone into remission on day 5 or have recurrence of symptoms from day 5 through day 7 
 
If the empiric antibiotic is resistant but neonate has shown improvement of signs and symptoms of 
sepsis and there is ambiguity regarding in vivo sensitivity of antibiotic use 
 
These elaborate criteria have been drawn up because this is an equivalence (non-inferiority) trial. In an 
equivalence trial, extra care has to be taken to exclude subjects who are likely to respond irrespective of 
which treatment arm they are in and also subjects who are not likely to respond irrespective of which 
treatment arm they are in. This is because inclusion of such patients would bias the results towards no 
effect (ie equivalence). 
Data from enrolment until the point of determining eligibility for randomization will be recorded in the 
“Enrolment sub-form” of Proforma A of the case report form.  
 
 Randomization 
Those eligible for randomization will be approached for consent for randomization. Parents will be 
provided Parent Information Sheet for Randomization (Appendix 3) and the details of the Randomized 
Controlled Trial will be discussed with them. Written informed consent (3 copies) for randomization will 
be taken from a parent in the presence of a witness (Appendix 4). One copy will be handed to the parent, 
one will be kept with the investigator and 1 will be kept in the hospital records. Subjects whose parents 
give consent for randomization will be randomly allocated to one of 2 groups:  
Group A: Antibiotics will be stopped at the end of day 7. 
Group B: The same antibiotics will be continued for a total of 14 days.  
Those who do not satisfy the criteria for randomization and those whose parents do not give consent, will 
not be randomized and they will be followed up daily until clinical signs remit and will be administered the 
standard 14 days course of antibiotics.  

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Version dated 26 Sep 2019 
 
 
 
Randomization procedure 
Stratified, block randomization will be employed as described above. Randomly varying block sizes will be 
used and size of the blocks will be concealed until the end of the study. Each block will have equal number 
of allocations to Group A and Group B in a random sequence. Stratification will be by birth weight (1000-
1499, 1500-2000g and >2000 g) and by Centre. Random number lists generated from a website 
http://randomizer.org will be converted into the sequence of allocation to the 2 Groups.  
Concealment of allocation 
Slips bearing the allocated Group will be placed in opaque envelopes, which will be sealed and numbered 
serially on the outside. There would be separate sets of such envelopes, one for each stratum (ie Center 
and birth weight group). In each center, envelopes will be opened in serial order, as each subject is 
included in the study. The name and identification details of the subject will be written on the outside of 
each envelope and all envelopes will be returned to the Principal Investigator in the nodal center. 
 
 Intervention 
Among neonates who are allocated to group A, antibiotics will be stopped on day 7 of sensitive antibiotics 
(ie. immediately after randomization). 
Among neonates who are randomized to group B, antibiotics will be continued until day 14 (ie for 7 more 
days after randomization).  
If either of the groups develops signs and symptoms of sepsis, these babies will not be discharged, 
investigations will be done and appropriate antibiotics will be started. Each Centre will administer 
empirical antibiotics based upon their standard empirical antibiotic policy. No changes in policy will be 
made for the RCT. The antibiotics shall be stored, prescribed and dispensed as per the recommendations 
of Neofax essentials, 2014. All study subjects will receive routine care as per guidelines of the concerned 
centre. 
 
 Blinding 
The following research team members will be blinded: the adjudicators of outcome and the laboratory 
personnel. The following will be unblinded: the principal investigator, the research staff, nurses and 
resident doctors involved in the care of the subjects in hospital. Data related to assessment of the 
outcomes will be recorded in a separate detachable part of the proforma (Proforma-part B). The pages of 
the proforma of a patient will have a unique identification number. Part B will be detached from the main 
proforma and handed to the adjudicators.  
 
 Follow-up 
Any further hospitalization after stoppage of the antibiotic course would be at the discretion of the 
treating unit.  
The follow-up period will extend from the point of randomization for 5 weeks (35 days). Details of all 
episodes of illness during this period (whether in hospital or after discharge) will be filled by the research 
staff. At the time of discharge, parents of all the babies will be given cards with the Investigators’ names 
and contact information printed on them. Parents will be asked to report to the Newborn Unit for each 
episode of illness during the follow up period. Pediatric Emergency staff and Outpatient Department staff 
will also be informed about the special cards and asked to inform the Investigator in case such a baby 
reports for any illness.  

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Version dated 26 Sep 2019 
 
 
 
In addition, all the babies will be followed up in the premises of the newborn unit at 48 hours (± 
12 hours) for any signs of a sepsis syndrome. If the parents do not bring the baby for follow-up, the 
research staff will make a home visit. In addition, parents will be asked to bring the baby back to the 
Follow-Up Clinic by appointment on a weekly basis (+ 2 days) for 35 days after randomization with 
particular emphasis on the visit at 28 days and 35 days. At each visit questions will be asked by the 
assessment team to ascertain whether an episode of a sepsis syndrome has occurred in the preceding 
week that required antibiotics. If the parents do not bring the baby back for weekly follow-up, the 
research staff will make a home visit.  
 
Complete addresses & telephone numbers of the patients will be taken before discharge and 
babies who do not report in will be contacted at their homes.  
 
All episodes of illness in a 35-day period after randomization will be evaluated for antibiotic 
treatment failure. A blood culture and sepsis screen (C reactive protein, complete blood counts,), 
procalcitonin, chest X-ray and CSF examination will be done, depending on the discretion of the treating 
physician. All clinical and laboratory details related to the episode of illness will be recorded on Proforma 
part B, detached and handed over to a blinded Neonatologist (adjudicator) to determine whether the 
episode qualifies to be a relapse of sepsis. In case any radiological imaging is performed, either digital 
(preferable) or hard copies of the images will be sent to the blinded Neonatologist at the nodal Centre 
after removing patient identifiers. In the event that the subject could not be brought back to the unit for 
the episode of illness, and treatment was received outside, every effort will be made by the assessment 
team to contact the treating physician and ascertain all details and such details will be entered in pro 
forma part B. Photocopies of lab reports and notes of other physicians will also be sent to the blinded 
neonatologist, after removing patient identifiers. Proforma part B will not contain any information by 
which the group of randomization may be ascertained.  
 
Primary outcome variables 
The primary outcome will be “definite relapse or probable relapse”. Definite relapse will be defined as the 
occurrence of an episode of illness within the 21-day period after antibiotic completion in which the same 
organism with similar antibiogram is grown, as in the original episode. Probable relapse will be defined as 
the occurrence of an episode of illness within 21-day period that is diagnosed to be: Clinical diagnosis of 
bacterial sepsis, in the setting of a sterile blood culture.  Part B of the proforma, along with all 
investigation reports will be mailed to the nodal center, where a Neonatologist who is unconcerned with 
the rest of the study, will be asked to adjudicate whether the concerned episode is a relapse or not. 
Since this is a non-inferiority trial, the analysis will be done both as per protocol and as per intention to 
treat. Both the analyses will be reported, bearing in mind that the per protocol analysis is actually the 
more conservative of the two, with less bias towards “no effect”.    
In the per protocol analysis, the following subjects will be excluded from analysis: 
a) In the 14-day group: patients whose 8th- 14th day of antibiotics could not be completed for any 
reason (including, but not limited to non-availability of cannula, a fresh episode of sepsis requiring 
change of antibiotics, withdrawal of consent or unscheduled discharge),  
b) Subjects in either group whose primary outcome could not be assessed due to loss to follow-up or 
withdrawal of consent.   
In the intention-to-treat analysis, all randomized subjects will be analyzed according to the group to which 
they were randomized, irrespective of compliance or change of antibiotics due to a fresh episode. 
Subjects in the 7-day group whose primary outcome could not be assessed due to loss to follow-up or 

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Version dated 26 Sep 2019 
 
 
withdrawal of consent will be assumed to have definite relapse and those in the 14-day group to not have 
relapse.  
 
 Secondary outcomes 
“Definite relapse” and “probable relapse” will be separate secondary outcomes, each assessed at 21 days 
and 28 days after antibiotic completion. [This was originally “definite or probable relapse”].  
 
Episodes of relapses (# 1-4) will be analyzed both as per protocol and as per intention-to-treat: 
1. “Definite relapse”: by 21 days after antibiotic completion. 
2. “Probable relapse”: by 21 days after antibiotic completion. 
3. “Definite relapse”: by 28 days after antibiotic completion. 
4. “Probable relapse”: by 28 days after antibiotic completion. 
Episodes of relapses (# 5-7) will be analyzed as per intention-to-treat: 
5. “Definite or probable relapse” in the 28-day period after randomization and 35-day period after 
randomization 
6. “Definite” in the 28-day period after randomization and 35-day period after randomization 
7. “Probable” in the 28-day period after randomization and 35-day period after randomization] 
The following will also be analysed in the 35-day period of observation after randomization: 
(A) Episodes of secondary infections during the observation period. These may be bacterial or fungal.  
(B) Adverse events: All fresh adverse events occurring after randomisation would be recorded. Adverse 
events with onset prior to randomisation would be recorded only if there is worsening after 
randomisation. Adverse events are listed and defined as per Appendix 5.  
 
Sample Size Calculation 
The sample size was calculated to be 350 in each arm based on the following assumptions: Event rate for 
the composite primary outcome of “definite or probable relapse” assumed to be 10% (combining both 7- 
and 14-day treatment arms) based on the earlier study (Chaudhary G, Dutta S, Narang A, Journal of 
Tropical Pediatrics 2006), non-inferiority margin of 7%, one sided alpha level as 5% and power of 90% and 
loss to follow- up of approximately 10%. 
 
 Mid-term analysis and stopping rules 
The original was: Mid-term analyses will be performed after a total of one-third and two-third subjects are 
recruited. A separate Data Safety Monitoring Board will monitor serious adverse events in the trial and 
perform mid-term analyses at 1/3rd and 2/3rd recruitment. O’Brien-Fleming stopping rules and p values for 
superiority will be used for the interim analyses.  
Data Safety Monitoring Board revised it to: DSMB will monitor serious adverse events in the trial and 
perform one interim analysis. The timing of this analysis would be based on either of the following: when 
about 50% of the expected primary outcomes have occurred (expected outcome events for the entire trial 
is 100 and therefore first interim analysis will be when approximately 50 events have occurred) or when 
350 subjects have completed their follow-up as per protocol whichever is earlier. At the time of interim 
analysis, the DSMB will revisit the sample size of the study. O’Brien Fleming stopping criteria would be 
used for the primary outcome while Pocock’s stopping rule for the serious adverse events. 
If treatment failure rates are found significantly higher in the 7-day group in mid-term analysis, the trial 
will be stopped. If a death occurs due to bacteriologically confirmed relapse from the same organism 

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during the 28-day follow-up, the allocation group of that subject will be immediately ascertained. If it 
happens to be in the 7-day group, the trial will be stopped. The Data Safety Monitoring Board will also 
decide whether a death or other serious adverse event can be attributed to the intervention in the 
randomized controlled trial, and what compensation, if any, should be awarded.  
 Data analysis 
The baseline variables shall be described using descriptive statistics. As all the outcome variables are 
categorical, x2 test with Yates correction or Fisher’s Exact test as applicable will be used. Sub-group 
analysis has been planned for the following sub-groups: 1000-1500 g, 1501-2000 g, >2000 g, those 
infected with gram positive organisms and those with radiological pneumonia. For the sub-group 
analyses, level of significance will be kept as p< 0.01. Analysis shall be done using the statistical software 
packages SPSS version 10. 
  
Quality control 
Internal: All research officers and Principal investigators have undergone training in all aspects of the 
study 10% of Records are regularly checked by principal investigator or co-investigator in each centre10 % 
of computer data entry will be verified by Principal investigator and co-investigator 
External: A Data safety monitoring board is constituted. Periodic meetings of the DSMB are held regularly. 

7 
 
October 2018 
Eligible for randomization 
Eligibility for RCT part of study 
 Blood culture +ve with non- S aureus 
 No signs of sepsis by end of day 5 of sensitive antibiotics 
 Remains without signs of sepsis until day 7 
Consent for RCT part of study? 
 
TRIAL FLOW 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Consent received. 
 Enrolled in observational part of study 
 Observed daily until day 7 of sensitive antibiotics 
Consent for observational part of study? 
Consent not received 
 Exclusion criteria for observational study 
 Meningitis 
 Osteomyelitis, septic arthritis, deep abscess 
 Life threatening malformation 
Analyze (compare groups A & B) 
“Definite or probable” relapse in 
21-d period after scheduled antibiotic stoppage by PP & ITT 
28-d period after scheduled antibiotic stoppage by PP & ITT 
28-d period after randomization by ITT 
35-d period after randomization by ITT 
Follow-up for 35 days 
after randomization 
Follow-up for 35 days 
after randomization 
 0-28 days old, currently admitted
 >1500 grams birth weight
 Residence within approx. 15 kms
 Suspected sepsis: Blood culture sent, antibiotics started
 Receiving appropriate antibiotics
Group A 
No further antibiotics 
Group B 
7 more days of antibiotics 
 Consent for RCT part received 
 Enrolled in RCT 
 Randomized at end of day 7 of 
sensitive antibiotics 
Consent for RCT 
part of study not 
received 
Excl. criteria for RCT 
 Blood culture sterile 
 Grows S aureus 
 Grows fungus 
 Grows contaminant 
 Develops 
meningitis/osteomyel 
itis/arthritis/abscess 
 No remission by D-5 
 Remission not 
sustained day 5-7 
 Ambiguity about 
sensitivity of 
antibiotics 

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S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
1 
Apnea 
 
Apnea needing methyl 
xanthine therapy or non- 
invasive respirator 
support 
 
Need of invasive 
respiratory support 
 
Death 
Definition: A disorder characterized by cessation of breathing for at least 20 seconds or accompanied by bradycardia 
2 
AKI/ARF 
 
 Serum creatinine 
increase of >=0.3 ma/dl 
within 48h OR 
 
1.5-1.9 times the lowest 
previous value within & 
days OR 
 
Urine 
output(ml/kg/h):<0.5 for 
12h 
 
Serum creatinine: 2-2.9 
times the lowest previous 
value OR 
 
Urine output 
(ml/kg/h):<0.5 for>=12 h 
 
Serum creatinine: >=3 
times the lowest 
previous value OR 
 
>=2.5 absolute value 
 
Urine output (ml/kg/h): 
<0.3 for >=24 h OR 
anuria for >=12h 
 
OR need of dialysis 
 
Death 
Definition: A disorder characterized by – Sudden impairment in kidney function that results in the inability to maintain adequate fluid, electrolyte, and waste 
product homeostasis 
3 
Arrhythmias 
 
Incidental detection, 
transient and NOT 
causing cardiac shock 
and NOT needing any 
therapy 
 
Asymptomatic but need 
of medical therapy 
 
Symptomatic causing 
cardiac failure and need 
of medical therapy 
 
Symptomatic needing 
cardio version or 
surgical therapy 
 
Death 
Definition: A disorder characterized by abnormal heart rhythm diagnosed by ECG 
4 
Anaemia 
 
Asymptomatic 
anaemia NOT needing 
blood transfusion 
 
Anaemia needing blood 
or exchange transfusion 

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S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
Definition: A disorder characterized by abnormal heart rhythm diagnosed by ECG 
5 
Accidental injury 
 
Minor external 
bleeding or injury, 
 
Need of minor surgery 
 
Fracture OR 
 
Need of major surgery 
OR 
 
Major bleeding 
 
Significant intracranial 
bleeding 
 
Accomplished by 
cardiorespiratory 
compromise 
 
Death 
Definition: A disorder Characterized by injury to body due to accident like fall or violent contact with external object, including accidental asphyxia 
6 
BPD 
 
Need of oxygen or 
respiratory support for 
at least 28 days but 
free of oxygen at 56 
days/36 weeks PMA 
(mild BPD) 
 
Need of oxygen or 
respiratory support for at 
least 28 days but need of 
oxygen less than 30% at 
56 days/36 weeks PMA 
(moderate BPD) 
 
Need of oxygen or 
respiratory support for at 
least 28 days but need of 
oxygen more than 30% 
or positive respiratory 
pressure at 56 days/36 
weeks PMA (severe 
BPD) 
 
 Severe BPD with 
frequent BPD spells, 
OR Persistent 
desaturations 
 
Presence of cor 
pulmonale 
 
Death 
Definition: A disorder Characterized by prolonged (>28 days) requirement of oxygen therapy or respiratory support, respiratory distress and X-ray picture showing 
diffuse haziness or areas of hyperinflation and collapse/fibrosis 
7 
Cholestasis/ 
hepatitis 
 
Asymptomatic 
cholestasis 
(TSB<12mg/dl) 
 
Cholestasis associated 
with complications like 
significant bleeding, 
encephalopathy, 
impairing growth OR 
 
TSB 12mg/dL or more 
 
Cholestasis associated 
with hepatic failure 
 
Death 

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Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
Definition: A disorder characterized by inflammation of hepatic parenchyma and/or biliary tract which manifests as raised blood levels of liver enzymes and serum 
bilirubin 
8 
Extravasation injury 
 
Skin erythema and 
small swelling of 
extremity 
 
Large swelling, OR 
 
Superficial skin necrosis 
 
Deep skin necrosis 
Definition: A disorder characterized by injury caused to skin due to extravasation of intravenous fluid 
9 
Encephalopathy 
 
Transient (lasting less 
than 72 h) and mild 
abnormality in gestation 
– appropriate muscle 
tone, consciousness and 
reflexes, OR 
 
HIE stage 1 
 
Prolonged (72h or more) 
OR 
 
Moderate to severe, OR 
 
HIE stage 2 
abnormalities in 
gestation- appropriate 
muscle tone, 
consciousness and 
reflexes OR 
 
Presence of seizures 
 
Encephalopathy 
causing 
cardiorespiratory 
compromise resulting 
in need of incubation or 
inotropic support, OR 
 
HIE stage 3 
 
Death 
Definition: A disorder characterized by abnormality in muscle tone, consciousness and reflexes 
10 
Gastroenteritis 
 
Gastroenteritis without 
dehydration 
 
Gastroenteritis with 
moderate dehydration 
 
Gastroenteritis with 
severe dehydration 
 
Gastroenteritis with 
shock 
 
Death 
Definition: A disorder characterized by inflammation of gastrointestinal tract manifesting as loose motions, vomiting, fever and dehydration. If gastroenteritis is a 
manifestation of sepsis- include it under heading of sepsis not under gastroenteritis heading. 

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Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
11 
Gangrene 
 
Gangrene of distal 
phalanx 
 
Gangrene extending >1 
phalanx of any digit or 
matacarpals/metatarsals 
 
Gangrene including 
long bones of limbs 
Definition: A disorder characterized by gangrene of a part of body 
 
Note: if gangrene is caused due to sepsis, then sepsis may only be reported as SAE. 
However, if gangrene is caused due to sampling, in such cases, gangrene may be reported as SAE. 
12 
Hypoglycemia 
 
Blood glucose 20-40 
single 
episode, 
asymptomatic, treated 
with oral feeds 
 
More than one episode of 
blood 
glucose 
20-40 
mg/dL OR 
 
Blood glucose<20 OR 
 
Symptoms 
other 
than 
seizures OR 
 
Need 
for 
glucose 
infusion  up 
to 
12 
mg/kg/min 
 
Seizures OR 
 
Need 
of 
intravenous 
glucose 
infusion 
@>12mg/kg/min 
or 
persisting for >7 days 
Definition: A disorder characterized by blood glucose concentration less than 40 mg/dL 
13 
Hyperglycemia 
 
NOT needing 
treatment with insulin 
 
Need of treatment with 
insulin 

Definition: A disorder characterized by blood glucose concentration greater than 150mg/dL 
14 
Hypothermia 
 
Axillary temperature 
36.0°C-36.4°C 
 
Axillary temperature 
32.0°C-35.9°C 
 
Axillary temperature 
<32.0°C 

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Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
Definition: A disorder characterized by axillary temperature less than 36.5°C 
15 
Hyperthermia 
 
Axillary temperature 
37.6°C-38.0°C 
 
Axillary temperature 
38.1°C-40.0°C 
 
Axillary 
temperature>40.0°C 
Definition: A disorder characterized by axillary temperature more than 37.5°C 
16 
Hypernatremia 
 
Serum sodium 146- 
150 mEq/L 
 
Serum sodium 151-160 
mEq/L 
 
Serum sodium 161-170 
mEq/L 
 
Serum sodium 
>170mEq/L OR 
 
One accompanied by 
clinical features of 
seizures or altered 
consciousness 
 
Death 
Definition: A disorder characterized by increase in concentration of sodium ion in blood 
17 
Hyperkalemia 
 
Serum potassium 5.5-6.5 
mEq/L 
 
Serum potassium 6.5-8.0 
mEa/L 
 
Serum potassium>8 
mEq/L 
 
Death 
Definition: A disorder characterized by increase in concentration of sodium ion in blood 
18 
Hyponatremia 
 
Serum sodium 130- 
134 mEq/L 
 
Serum sodium 120-129 
mEq/L 
 
Serum sodium 110-119 
mEq/L 
 
Serum sodium <110 
mEq/L OR 
 
One accompanied by 
clinical features of 
seizures or altered 
consciousness 
 
Death 
Definition: A disorder characterized by decrease in concentration of sodium ion in blood 

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Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
19 
Hyperbilirubinemia 
 
Hyperbilirubinemia 
without need of 
therapy 
 
Hyperbilirubinemia 
needing treatment with 
phototherapy 
 
Hyperbilirubinemia 
needing treatment with 
blood exchange 
transfusion 
 
Hyperbilirubinemia 
with acute bilirubin 
encephalopathy 
 
Death 
Definition: A disorder characterized by increase in indirect bilirubin levels in blood 
20 
Neutropenia (as per 
Manroe or 
Mouzihno chart) 
 
Asymptomatic NOT 
associated with 
systemic infection, 
NOT needing any 
therapeutic 
intervention 
 
Asymptomatic and NOT 
associated with systemic 
infection, but needing 
therapeutic intervention 
 
Associated with systemic 
infection 
Definition: A disorder characterized by decrease (below gestation and postnatal age specific threshold) in number of neutrophils in peripheral blood film. 
21 
NEC 
 
NEC stage 1 as per 
Walsh Kleigmann 
modification of Bell’s 
classification 
 
NEC stage 2 per walsh 
Kleigmann modification 
of bell’s classification 
 
NEC stage 3 as per 
Walsh Kleigmann 
modification of Bell’s 
classification 
 
Death 
Definition: A disorder characterized by inflammation of gut which may progress to intestinal necrosis 
22 
Osteopenia 
 
Asymptomatic NOT 
needing treatment 
 
Causing fracture or 
prolongation of 
respiratory support 
Definition: A disorder characterized by formation of ulcers over pressure sites 

14 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
23 
Pressure sore 
 
Small (<2cm)- healing 
happens in <1 week 
 
Major 
pressure 
sore 
(>2cm) 
and 
requiring 
surgical intervention or 
non-healing pressure 
sore 
Definition: A disorder characterized by formation of ulcers over pressure sites 
24 
Polycythemia 
 
Asymptomatic NOT 
needing treatment 
 
Symptomatic needing 
treatment with fluid 
relaxation or partial 
exchange transfusion 
 
Associated with 
complication such as 
NEC, thrombosis 
Definition: A disorder characterized by increased haemoglobin or packed cell volume with haematocrit value 65% or more in blood as per gestation and postnatal 
gestation norms. 
25 
Pleural effusion 
 
Minimal fluid in the 
pleural cavity requiring 
no/minimal change in 
respiratory support 
 
Free fluid in the pleural 
cavity requiring 
significant increase in 
respiratory support or 
requiring ICD drainage 
 
Fluid in pleural cavity 
resulting in circulatory 
collapse 
 
Death 
Definition: A disorder characterized by presence of free fluid in pleural cavity 
26 
Peritonitis 
 
Peritonitis 
unaccompanied by 
perforation of gut 
 
Peritonitis 
accompanied by 
perforation of gut 
 
Death 
Definition: A disorder characterized by inflammation of peritoneal membranes. 

15 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
27 
PDA 
 
Asymptomatic PDA 
 
PDA needing medical 
treatment 
 
PDA needing surgical 
treatment or resulting in 
cardiac failure 
 
PDA causing life 
threatening 
complications such as 
AKI, severe pulmonary 
haemorrhage NEC 
stage 3 
 
Death 
Definition: A disorder characterized by persistent non-closure of ductus arteriosus 
28 
PVL 
 
Periventricular flare 
without cyst formation 
 
Periventricular 
leukomalacia with cysts 
formation in frontal, 
parietal regions 
 
Periventricular 
leucomalacia with cysts 
formation in occipital 
periventricular white 
matter 
Definition: A disorder characterized by hypoxic-ischemic injury to periventricular brain resulting in disability 
29 
Periventricular – 
intraventricular 
haemorrhage 
(P/IVH) 
 
Grade 1 IVH 
 
Grade 2 IVH 
 
Grade 3 IVH, OR 
 
PVHI, OR 
 
Any grade IVH 
manifesting as seizure or 
post haemorrhagic 
hydrocephalus 
 
Post – haemorrhagic 
hydrocephalus needing 
shunt placement, OR 
 
IVH causing significant 
respiratory compromise 
requiring ventilation or 
hemodynamic 
compromise requiring 
vasopressors 
 
Death 
Definition: A disorder characterized by bleeding into periventricular – intraventricular space in brain 

16 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
30 
Pulmonary 
hemorrage 
 
Occasional small bleed 
occurring 
spontaneously or 
during endotracheal 
suction requiring 
no/minimal change in 
respiratory support 
 
Recurrent small bleeds, 
does not require a 
transfusion/significant 
hike in respiratory 
support. 
 
Need for 
blood/component 
transfusion, OR 
 
Need for significant 
augmentation of 
respiratory support, OR 
 
Prolongation of 
ventilation 
 
Shock requiring 
vasopressors 
 
Death 
Definition: A disorder characterized by bleeding from the bronchial wall and / or lung parenchyma manifested as endotracheal bleeding or bleeding from mouth in 
a non- intubated baby. 
31 
ROP 
 
Any ROP which is less 
severe than type ½ 
(this does not refer to 
stage 1 or 2) ROP. 
 
Type 2 ROP as described 
in ETROP study 
 
Type 1 ROP as described 
in ETROP study or ROP 
needing treatment 
Definition: A disorder characterized by abnormal fibro vascular proliferation in retina 
 
Type 1 ROP – any of 3: (1) Zone I, any stage ROP with plus disease, (2) Zone I, stage 3 ROP without plus disease, or (3) Zone II, stage 2 or 3 ROP with plus 
disease 
Type 2 ROP – any of two : (1) Zone I, stage 1 or 2 ROP without plus disease, (2) Zone II, stage 3 ROP without plus disease 

17 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
32 
Seizures 
 
Single episode of 
seizures without 
cardiorespiratory 
compromise due to 
transient metabolic 
abnormalities like 
hypoglycaemia, 
hypocalcaemia 
 
Multiple episodes of 
seizures OR 
 
Seizures needing 
treatment with 
antiepileptic drug 
 
Status epilepticus OR 
 
Seizures causing 
cardiorespiratory 
compromise 
 
Death 
Definition: A disorder characterized by abnormal involuntary movements of muscles 
33 
Spontaneous 
Intestinal 
Perforation (SIP) 
 
SIP NOT needing 
surgical management by 
laparotomy and NOT 
 
causing cardiorespiratory 
compromise 
 
SIP needing surgical 
management by 
laparotomy or leading 
 
to cardiorespiratory 
compromise 
 
Death 
Definition: A disorder characterized by perforation of intestine without any clinical or intraoperative or pathological evidence of NEC 
34 
Shock 
 
Hypotension or 
decreased organ 
perfusion lasting for <6 
hours needing volume 
expander and resolving 
without consequence 
 
Hypotension 
 
or 
decreased 
organ 
perfusion 
needing 
/vasopressor(s)/ 
ionotropes 
 
Catecholamine resistant 
shock 
 
Death 
Definition: A disorder characterized by inability of circulatory system to meet metabolic requirement of tissues 

18 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
35 
Sepsis (irrespective 
of etiology-bacterial, 
viral,fungal,protozoa 
l) includes 
pneumonia, 
meningitis or bone- 
joint infection 
 
Culture negative sepsis, 
OR 
 
Ventilator associated 
pneumonia requiring no/ 
minimal increase in 
respiratory support 
 
Culture positive sepsis 
OR 
 
Meningitis OR 
 
Encephalitis, OR 
 
Presence of sclerema, 
OR 
 
Ventilator associated 
pneumonia requiring 
 
significant increase in 
respiratory support 
 
Septic shock requiring 
vasopressors, OR 
 
Multi – organ 
dysfunction such as 
presence of AKI, DIC- 
bleeding, OR 
 
Ventilator associated 
pneumonia resulting in 
 
persistent desaturations 
despite high level 
ventilator support 
 
Death 
Definition: A disorder characterized by the presence of pathogenic microorganism in the blood stream that cause a rapidly progressing systemic reaction that may 
lead to shock and / or end organ failure 
36 
Thromboembolism 
 
Asymptomatic , NOT 
needing treatment 
 
Causing gangrene of 
distal phalanx 
 
Causing gangrene 
extending > 1 phalanx of 
any digit or 
metacarpals/metatarsals 
 
Causing gangrene 
including long bones of 
limbs or any internal 
organ like  brain, 
kidney or lungs 
Definition: A disorder characterized by thromboembolic phenomenon involving a vascular system 
37 
Thrombocytopenia 
 
NOT associated with 
bleeding and above the 
threshold for platelet 
transfusion 
 
NOT associated with 
active bleeding but 
needing platelet 
tranfusion 
 
Associated with bleeding 
or platelet count less than 
20,000. 
 
Associated with 
intracranial bleeding 
 
Death 

19 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
Definition: A disorder characterized by decrease in number of platelets (less than 150,000/μL in peripheral blood 
38 
Liver dysfunction 
Asymptomatic raised liver 
liver enzymes, treatment 
not indicated 
- 
Symptomatic liver 
dysfunction 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
Definition: A disorder characterized by a pathologic process involving liver parenchyma 
39 
Anaphylaxis 
- 
- 
Symptomatic bronchospasm, 
with or without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, 
causing a hypersensitivity immune response. 

20 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
40 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., direct 
antiglobulin test; DAT; 
Coombs'; schistocytes; 
decreased haptoglobin) 
ized by laboratory test 
results that indicate RBC 
destruction 
Evidence of hemolysis and 
>=2 gm decrease in 
hemoglobin 
Transfusion or medical 
intervention indicated (e.g., 
steroids) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Definition: Disorder characterized by widespread destruction of platelets 
41 
Deranged 
coagulogram 
INR or APTT >1 - 1.5 x 
ULN; 
INR >1 - 1.5 times above 
baseline if on 
anticoagulation 
INR or APTT >1.5 - 2.5 x 
ULN; INR >1.5 - 2.5 times 
above baseline if on 
anticoagulation 
INR or APTT >2.5 x ULN; 
INR >2.5 times above 
baseline if on anticoagulation 
- 
- 
Definition: A finding based on laboratory test results that indicate an increase in the ratio of the patient's prothrombin time to a control sample in the blood 
42 
Disseminated 
intravascular 
coagulation 
- 
Lab findings of DIC with no 
bleeding 
Laboratory findings and 
bleeding 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Definition: a disorder characterised by systemic pathological activation of blood clotting mechanisms which result in clot formation throughout the body. 

21 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
43 
Arthritis 
Mild pain associated with 
erythema, inflammation 
Moderate pain or joint 
swelling, limitation of 
movement 
Severe pain associated with 
signs of inflammation, 
erythema or joint swelling; 
irreversible joint damage; 
disabling 
- 
- 
Definition: a disorder characterised by inflammation involving a joint 
44 
Rash 
Macules/ papules/ pustules 
covering <10% body 
surface area with or 
without symptoms 
Macules/ papules/ pustules 
covering 10% - 30% body 
surface area with or without 
symptoms 
Macules/ papules/ pustules 
covering >30% body surface 
area with or without 
symptoms 
- 
- 
Definition: a skin disorder characterised by the presence of macules or papules are pustules 
45 
Superficial 
thrombophlebitis 
- 
Present 
- 
- 
- 
Definition: a disorder characterised by a blood clot in inflammation involving a superficial vein of the extremities 
46 
Urticaria 
Urticarial lesions covering 
<10% BSA; topical 
intervention indicated 
Urticarial lesions covering 10 
30% BSA; oral intervention 
indicated 
Urticarial lesions covering 
>30% BSA; IV intervention 
indicated 
Definition: A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins 

22 
Version dated 26 Sep 2019 
 
 
 
S. No 
Adverse Event 
Grades 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life Threatening) 
5 (Death) 
(To be reported as SAE) 
47 
Diarrhea 
Increase of <4 stools per 
day over baseline 
Increase of 4 - 6 stools per 
day over baseline 
Increase of >=7 stools per 
day over baseline; 
incontinence; hospitalization 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Definition: a disorder characterized by frequent watery bowel movements 
48 
Vomiting 
1 - 2 episodes (separated 
by 5 minutes) in 24 hrs 
3 - 5 episodes (separated by 5 
minutes) in 24 hrs 
>=6 episodes (separated by 5 
minutes) in 24 hrs; tube 
feeding, TPN or 
hospitalization indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth 

Version dated 15 October 2018