Clinical trial NCT03280147: 7 Days Versus 14 Days of Antibiotics for Neonatal Sepsis
Official 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 Non-inferiority Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infant, Newborn
Neonatal SEPSIS
Anti-bacterial Agents
Recurrence
Keywords: Neonate
Sepsis
Antibiotics
Duration
Lead sponsor: Indian Council of Medical Research
Sponsor class: OTHER_GOV
Collaborators: name: Post Graduate Institute of Medical Education and Research, Chandigarh
name: Chacha Nehru Bal Chikitsalaya, New Delhi
name: Lady Hardinge Medical College
name: Indira Gandhi Institute of Child Health, Bangalore
name: Institute of Obstetrics and Gynecology, Chennai
name: King George's Medical University
name: Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak
name: St Johns Medical College Hospital, Bangalore, India
First posted: 2017-09-12
Enrollment: 261
Sex: ALL
Minimum age (years): 1
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, outcome-assessor blinded, active-controlled, multi-centric, non-inferiority trial
Primary purpose: TREATMENT

Brief summary: The optimum duration of intravenous antibiotic therapy for culture-proven neonatal bacterial sepsis is not known. Current practices, ranging from 7 days to 14 days of antibiotics, are not evidence-based. This is a randomized, active -controlled, multi-centric, non-inferiority trial to compare the efficacy of a 7-day course of intravenous antibiotics versus a 14-day course among neonates weighing \> 1000 g at birth with culture-proven bacterial sepsis that is uncomplicated by meningitis, bone or joint infections deep-seated abscesses. The primary outcome measure is a definite or probable relapse within 21 days after stoppage of antibiotics.

Detailed description: The optimum duration of intravenous antibiotic therapy for uncomplicated neonatal bacterial septicemia is not known. Pediatricians administer anywhere between 7 to 14 days of antibiotics, but these practices are not evidence based. C reactive protein (CRP) guided antibiotic duration is based on limited data and serial quantitative CRP is both cumbersome and not universally available. If it could be demonstrated that a 7-day course of antibiotics is not inferior to a 14-day course of antibiotics in terms of relapse rates of infection, then a 7 day course of antibiotics could be uniformly adopted, resulting in economic savings, shorter duration of hospitalization, less chances of hospital acquired infections, less chances of antibiotic induced adverse events and less antibiotic resistance. To test this hypothesis, a randomized, active-controlled, multi-centric, non-inferiority trial to compare the efficacy of a 7-day course of intravenous antibiotics with a 14-day course has been planned. Subjects weighing more than 1000 g at birth with suspected sepsis will be enrolled and observed for a 7-day period to see if they meet eligibility criteria for randomization. Subjects will be randomized on the 7th day of antibiotics, if the initial blood culture grows a non-Staphylococcus aureus bacterial organism, if they have no meningitis, osteomyelitis, septic arthritis or deep seated abscess and if the sepsis goes into clinical remission by the 5th day and remains in remission up to the 7th day of sensitive antibiotics. Subjects in the 14-day group will receive 7 more days of antibiotics after randomization, whereas those in the 7-day group will receive no further antibiotics after randomization. Subjects will be followed up for a 35-day period after randomization. The key outcome will be treatment failure as measured by "definite or probable relapse" within a 21-day period after completion of antibiotic therapy. Secondary outcomes will include definite relapse within 21 and 28 days after antibiotic completion and within 28 and 35 days after randomization; and probable relapse at similar time points. Other secondary outcomes will include secondary infections and adverse events. A total sample size of 700 (350 in each arm) will be required to detect a non-inferiority margin of 7%, assumed event rate of 10%, with 90% power, one-sided alpha error of 5% and loss to follow-up of approximately 10%. Data safety monitoring board will monitor serious adverse events in the trial and will perform at 1/3rd and 2/3rd of expected recruitment. At the time of interim analysis, the DSMB will revisit the sample size of the study. O'Brien Fleming's stopping criteria will be used for the primary outcome while Pocock's stopping rule will be used for the serious adverse events.

Eligibility criteria: Inclusion Criteria:

Inclusion criteria for the initial observation part of study preceding randomization

1. Neonates aged 0-28 days, either inborn or outborn, who are currently admitted in the Neonatal Unit of the centre.
2. Whose birth weight is greater than or equal to1000 grams (it should be reliably ascertained from records of a hospital)
3. Whose residence is within approximately 15 kms from the center, so that the infant can be brought back to the center for follow-up
4. 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

Inclusion criteria for Randomization applicable after 7 days of therapy of above patients with sensitive antibiotics:

1. Positive blood culture other than Staphylococcus aureus
2. No signs and symptoms of sepsis from end of day 5 through end of day 7 of starting sensitive antibiotics

Exclusion Criteria:

Exclusion criteria for the initial observation part of study preceding randomization:

1. Central Nervous System infection (Central Nervous System infection (meningitis will be defined as CSF Cells \>25 per uL with polys \>60% OR \[(CSF glucose \<20 mg/dL OR CSF:blood\* glu ratio \<0.6) AND (CSF protein \>150 mg/dL in term OR \>180 mg/dL in preterm)\]
2. Septic arthritis, osteomyelitis or deep-seated abscess as clinically judged by the treating team
3. Life threatening congenital malformations as judged by the principal investigator of the centre

Exclusion criteria for randomization applicable after 7 days of therapy of above patients with sensitive antibiotics:

1. Sterile blood culture
2. Suspected contaminants in blood culture.
3. Growth of Staphylococcus aureus in blood culture
4. Growth of fungal organism in blood culture
5. Diagnosis of meningitis, septic arthritis, osteomyelitis, abscess
6. Has not gone into remission on day 5 or have recurrence of symptoms from day 5 through day 7
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

Primary outcomes:
measure: Definite or probable relapse within 21 days post-antibiotic completion as per protocol
timeFrame: From 0-21 days after the end of the planned antibiotic therapy
measure: Definite or probable relapse within 21 days post-antibiotic completion as per intention to treat
timeFrame: From 0-21 days after the end of the planned antibiotic therapy
Secondary outcomes:
measure: Definite relapse within 21 days post-antibiotic completion, as per protocol
timeFrame: From 0-21 days after the end of the planned antibiotic therapy
measure: Definite relapse within 21 days post-antibiotic completion, as per intention-to-treat
timeFrame: From 0-21 days after the end of the planned antibiotic therapy
measure: Definite relapse within 28 days post-antibiotic completion, as per protocol
timeFrame: From 0-28 days after the end of the planned antibiotic therapy
measure: Definite relapse within 28 days post-antibiotic completion, as per intention-to-treat
timeFrame: From 0-28 days after the end of the planned antibiotic therapy
measure: Definite relapse within 28 days post-randomization, as per protocol
timeFrame: From 0-28 days after randomization
measure: Definite relapse within 28 days post-randomization, as per Intention-to-treat
timeFrame: From 0-28 days after randomization
measure: Definite relapse within 35 days post-randomization, as per protocol
timeFrame: From 0-35 days after randomization
measure: Definite relapse within 35 days post-randomization, as per intention to treat
timeFrame: From 0-35 days after randomization
measure: Probable relapse within 21 days post-antibiotic completion, as per protocol
timeFrame: From 0-21 days after the end of the planned antibiotic therapy
measure: Probable relapse within 21 days post-antibiotic completion, as per intention-to-treat
timeFrame: From 0-21 days after the end of the planned antibiotic therapy
measure: Probable relapse within 28 days post-antibiotic completion, as per protocol
timeFrame: From 0-28 days after the end of the planned antibiotic therapy
measure: Probable relapse within 28 days post-antibiotic completion, as per intention-to-treat
timeFrame: From 0-28 days after the end of the planned antibiotic therapy
measure: Probable relapse within 28 days post-randomization, as per protocol
timeFrame: From 0-28 days after randomization
measure: Probable relapse within 28 days post-randomization, as per intention-to-treat
timeFrame: From 0-28 days after randomization
measure: Probable relapse within 35 days post-randomization, as per protocol
timeFrame: From 0-35 days after randomization
measure: Probable relapse within 35 days post-randomization, as per intention-to-treat
timeFrame: From 0-35 days after randomization
measure: Definite relapse or probable relapse within 28 days post-randomization, as per protocol
timeFrame: From 0-28 days after randomization
measure: Definite relapse or probable relapse within 28 days post-randomization, as per Intention-to-treat
timeFrame: From 0-28 days after randomization
measure: Definite relapse or probable relapse within 35 days post-randomization, as per protocol
timeFrame: From 0-35 days after randomization
measure: Definite relapse or probable relapse within 35 days post-randomization, as per intention-to-treat
timeFrame: From 0-35 days after randomization
measure: Secondary sepsis
timeFrame: From 0-35 days after randomization
measure: Adverse events
timeFrame: From 0-35 days after randomization
Other outcomes:
Locations:
city: Rohtak
country: India
facility: Pandit BD Sharma Postgraduate Institute of Medical Sciences
state: Haryana
city: Bangalore
country: India
facility: Indira Gandhi Institute of Child Health
state: Karnataka
city: Chennai
country: India
facility: Madras Medical College (for Institute of Obstetrics and Gynaecology)
state: Tamil NADU
city: Lucknow
country: India
facility: King Georges Medical University
state: Uttar Pradesh
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research
city: New Delhi
country: India
facility: Kalawati Saran Childrens Hospital and Lady Hardinge Medical College
city: New Delhi
country: India
facility: Chacha Nehru Bal Chikitsalaya
Study officials:
affiliation: Post Graduate Institute of Medical Education and Research, Chandigarh
name: Sourabh Dutta
role: PRINCIPAL_INVESTIGATOR
References: