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7 Days Versus 14 Days of Antibiotics for Neonatal Sepsis

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ClinicalTrials.gov Identifier: NCT03280147
Recruitment Status : Not yet recruiting
First Posted : September 12, 2017
Last Update Posted : December 5, 2018
Sponsor:
Collaborators:
Postgraduate Institute of Medical Education and Research, Chandigarh
Chacha Nehru Bal Chikitsalaya, New Delhi
Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak
Institute of Child Health, Chennai
St Johns Medical College Hospital, Bangalore, India
Lady Hardinge Medical College
Information provided by (Responsible Party):
Sourabh Dutta, Postgraduate Institute of Medical Education and Research

Tracking Information
First Submitted Date  ICMJE September 9, 2017
First Posted Date  ICMJE September 12, 2017
Last Update Posted Date December 5, 2018
Estimated Study Start Date  ICMJE January 1, 2019
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 4, 2018)
  • Definite or probable relapse within 21 days post-antibiotic completion as per protocol [ Time Frame: From 0-21 days after the end of the planned antibiotic therapy ]
    Among participants who adhered to study protocol- Definite relapse: Episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode, Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Definite or probable relapse within 21 days post-antibiotic completion as per intention to treat [ Time Frame: From 0-21 days after the end of the planned antibiotic therapy ]
    Among all randomized patients- Definite relapse: Episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode, Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
Original Primary Outcome Measures  ICMJE
 (submitted: September 9, 2017)
Definite relapse within 21 days post-antibiotic completion [ Time Frame: From 0-21 days after the end of the planned antibiotic therapy ]
Episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 4, 2018)
  • Definite relapse within 21 days post-antibiotic completion, as per protocol [ Time Frame: From 0-21 days after the end of the planned antibiotic therapy ]
    Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse within 21 days post-antibiotic completion, as per intention-to-treat [ Time Frame: From 0-21 days after the end of the planned antibiotic therapy ]
    Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse within 28 days post-antibiotic completion, as per protocol [ Time Frame: From 0-28 days after the end of the planned antibiotic therapy ]
    Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse within 28 days post-antibiotic completion, as per intention-to-treat [ Time Frame: From 0-28 days after the end of the planned antibiotic therapy ]
    Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse within 28 days post-randomization, as per protocol [ Time Frame: From 0-28 days after randomization ]
    Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse within 28 days post-randomization, as per Intention-to-treat [ Time Frame: From 0-28 days after randomization ]
    Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse within 35 days post-randomization, as per protocol [ Time Frame: From 0-35 days after randomization ]
    Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse within 35 days post-randomization, as per intention to treat [ Time Frame: From 0-35 days after randomization ]
    Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Probable relapse within 21 days post-antibiotic completion, as per protocol [ Time Frame: From 0-21 days after the end of the planned antibiotic therapy ]
    Among participants who adhered to study protocol Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Probable relapse within 21 days post-antibiotic completion, as per intention-to-treat [ Time Frame: From 0-21 days after the end of the planned antibiotic therapy ]
    Among all randomized patients Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Probable relapse within 28 days post-antibiotic completion, as per protocol [ Time Frame: From 0-28 days after the end of the planned antibiotic therapy ]
    Among participants who adhered to study protocol Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Probable relapse within 28 days post-antibiotic completion, as per intention-to-treat [ Time Frame: From 0-28 days after the end of the planned antibiotic therapy ]
    Among all randomized patients Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Probable relapse within 28 days post-randomization, as per protocol [ Time Frame: From 0-28 days after randomization ]
    Among participants who adhered to study protocol Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Probable relapse within 28 days post-randomization, as per intention-to-treat [ Time Frame: From 0-28 days after randomization ]
    Among all randomized patients Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Probable relapse within 35 days post-randomization, as per protocol [ Time Frame: From 0-35 days after randomization ]
    Among participants who adhered to study protocol Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Probable relapse within 35 days post-randomization, as per intention-to-treat [ Time Frame: From 0-35 days after randomization ]
    Among all randomised patients Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Definite relapse or probable relapse within 28 days post-randomization, as per protocol [ Time Frame: From 0-28 days after randomization ]
    Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Definite relapse or probable relapse within 28 days post-randomization, as per Intention-to-treat [ Time Frame: From 0-28 days after randomization ]
    Among all randomized patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Definite relapse or probable relapse within 35 days post-randomization, as per protocol [ Time Frame: From 0-35 days after randomization ]
    Among participants who adhered to study protocol Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Definite relapse or probable relapse within 35 days post-randomization, as per intention-to-treat [ Time Frame: From 0-35 days after randomization ]
    Among all randomised patients Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Secondary sepsis [ Time Frame: From 0-35 days after randomization ]
    Sepsis due to bacterial organisms other than the original etiologic bacteria or with a different antibiogram or with a fungal organism
  • Adverse events [ Time Frame: From 0-35 days after randomization ]
    Adverse events as per a list of adverse events, graded as per severity, and defined a priori
Original Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2017)
  • Definite or probable relapse within 21 days post-antibiotic completion [ Time Frame: From 0-21 days after the end of the planned antibiotic therapy ]
    Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Definite or probable relapse within 28 days post-antibiotic completion [ Time Frame: From 0-28 days after the end of the planned antibiotic therapy ]
    Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Definite relapse within 28 days post-randomization [ Time Frame: From 0-28 days after randomization ]
    Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse within 35 days post-randomization [ Time Frame: From 0-35 days after randomization ]
    Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode
  • Definite relapse or probable relapse within 28 days post-randomization [ Time Frame: From 0-28 days after randomization ]
    Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Definite relapse or probable relapse within 35 days post-randomization [ Time Frame: From 0-35 days after randomization ]
    Definite relapse defined as: episode of blood-culture-positive relapse of neonatal sepsis caused by the same organism having the same antibiogram as the original episode Probable relapse: episode of illness without positive cultures adjudicated by a blinded adjudicator to be a relapse of the original episode of sepsis.
  • Secondary sepsis [ Time Frame: From 0-35 days after randomization ]
    Sepsis due to bacterial organisms other than the original etiologic bacteria or with a different antibiogram or with a fungal organism
  • Adverse events [ Time Frame: From 0-35 days after randomization ]
    Adverse events as per a list of adverse events, graded as per severity, and defined a priori
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 7 Days Versus 14 Days of Antibiotics for Neonatal Sepsis
Official Title  ICMJE 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
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 > 1500 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 1500 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 1000 (500 in each arm) will be required to detect a non-inferiority margin of 5%, 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 one mid-term analysis when about 50% of the expected primary outcomes have occurred or when 50% of the 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's stopping criteria will be used for the primary outcome while Pocock's stopping rule will be used for the serious adverse events.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized, outcome-assessor blinded, active-controlled, multi-centric, non-inferiority trial
Masking: Single (Outcomes Assessor)
Masking Description:
Outcome assessor will be provided objective clinical information related to episodes of all illnesses during follow-up with all patient identifiers removed and the record identified only by a unique code number. All imaging films and investigation reports provided to the outcome assessor will be similarly bereft of patient identifiers and coded by a unique code number. The outcome assessor will not be involved in the rest of the study. The outcome assessor will adjudicate whether the given episode of illness is a relapse.
Primary Purpose: Treatment
Condition  ICMJE
  • Infant, Newborn
  • Neonatal SEPSIS
  • Anti-bacterial Agents
  • Recurrence
Intervention  ICMJE
  • Drug: 7-day course of antibiotics
    Subjects in the "7-day course of antibiotics" arm of the study will receive no further antibiotics after randomization as they would have already received 7 days of sensitive antibiotics before randomization. The choice of antibiotics would be guided by the blood culture and sensitivity report. Thus, subjects in this arm of the study could get a variety of antibiotics, depending on the sensitivity reports. Hence, names of specific antibiotics and/or their brand names have not been mentioned.
  • Drug: 14-day course of antibiotics
    Subjects in the "14-day course of antibiotics" arm of the study will receive 7 more days of antibiotics after randomization as they would have already received 7 days of sensitive antibiotics before randomization. The choice of antibiotics would be guided by the blood culture and sensitivity report. Thus, subjects in this arm of the study could get a variety of antibiotics, depending on the sensitivity reports. Hence, names of specific antibiotics and/or their brand names have not been mentioned.
Study Arms  ICMJE
  • Experimental: 7-day course of antibiotics
    Randomization of subjects will be performed at the end of 7 days of sensitive intravenous antibiotic administration, provided the subjects meet randomization criteria. Those who are randomized to the 7-day group will not receive any further antibiotics.
    Intervention: Drug: 7-day course of antibiotics
  • Active Comparator: 14-day course of antibiotics
    Randomization of subjects will be performed at the end of 7 days of sensitive intravenous antibiotic administration, provided the subjects meet randomization criteria. Those who are randomized to the 14-day group will receive 7 more days of the same antibiotics, to make it a total of 14 days.
    Intervention: Drug: 14-day course of antibiotics
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: December 4, 2018)
1000
Original Estimated Enrollment  ICMJE
 (submitted: September 9, 2017)
700
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 1500 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. Suspected meniingitis (meningitis will be defined as one or more of CSF cell count more than or equal to 25 per microliter with > 60% neutrophils; glucose 180 mg/dL in preterm or positive gram stain report)
  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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 28 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reeta Rasaily +91-9818635958 reeta.rasaily@gmail.com
Listed Location Countries  ICMJE India
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03280147
Other Study ID Numbers  ICMJE 5/7/329/2009-RHN
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Sourabh Dutta, Postgraduate Institute of Medical Education and Research
Study Sponsor  ICMJE Indian Council of Medical Research
Collaborators  ICMJE
  • Postgraduate Institute of Medical Education and Research, Chandigarh
  • Chacha Nehru Bal Chikitsalaya, New Delhi
  • Pandit Bhagwat Dayal Sharma, PGIMS, Rohtak
  • Institute of Child Health, Chennai
  • St Johns Medical College Hospital, Bangalore, India
  • Lady Hardinge Medical College
Investigators  ICMJE
Principal Investigator: Sourabh Dutta Postgraduate Institute of Medical Education and Research
PRS Account Indian Council of Medical Research
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP