IgM-Enriched Immunoglobulin for Neonatal Sepsis

Efficacy of Prophylactic IgM-Enriched Immunoglobulin for the Management of Early-Onset Neonatal Sepsis in Very Low Birth Weight Preterm Neonates; A Randomized Controlled Trial

This study compares giving prophylactic IgM enriched Intravenous Immunoglobulin (IVIG) with placebo in 1 hour after birth, in neonates with risk factors of Early-Onset Neonatal Sepsis (EONS). In addition to the intervention, standard regimen antibiotics are also given within 1 hour. The IVIG is given for 3 days and primary and secondary outcomes will be collected. Risk factors are both from maternal and neonate origin.

Study Overview

• Status: Unknown
• Conditions: Inflammation; Infant, Newborn, Disease; Very Low Birth Weight Infant; Neonatal Sepsis, Early-Onset
• Intervention / Treatment: Drug: IgM-enriched IVIG

Detailed Description

This randomized-controlled trial conducted in Cipto Mangunkusumo Hospital, Jakarta, Indonesia aims to determine the efficacy of prophylactic IgM-Enriched IVIG in preventing EONS. A total of 70 very low birth weight (VLBW) neonates with risk factors for EONS including maternal factors of premature rupture of membrane (PROM), fever, urinary tract infection (UTI), chorioamnionitis, and neonatal factor of prematurity and resuscitation history will be collected. These neonates within 1 hour of life will then be administered either placebo or IgM-enriched IVIG 0.25g/kg/day for 3 days, in addition to first-line empiric antibiotic. Randomization is done using simple randomization. Triple masking (Participant, Investigator, Outcomes Assessor) is conducted.

These neonates will then be clinically observed and evaluated for early mortality (mortality below 7 days), hemodynamics, length of stay, blood culture results, C-Reactive Protein (CRP), IT ratio, routine hematological examination, and IgGAME as parameters of improvement and prevention of EONS.

STATA version 12 (Macintosh version) will be used for data management and statistical analyses. The variables will first be presented descriptively, continued with bivariate and multivariate analysis. Bivariate analysis will be conducted between independent and dependent variables using chi-square/Fisher's exact test, Student's t-test, and Kruskal-Wallis. Variables with p-values <0.25 will be included in the multivariate analysis using logistic regression. The investigators will use two-sided p-values in our analysis with a p < 0.05 level of significance.

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 3

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 minute to 1 hour (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Very low birth weight infants (< 1500 g)
• Gestational age below 32 weeks
• Risk of Early-Onset sepsis from maternal and neonate factors
• Inborn neonates

Exclusion Criteria:

• Birth weight < 600 g
• Gestational age < 26 weeks
• Multiple Congenital Anomaly
• Neonates with suspected congenital syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment Group; IgM-enriched IVIG given with dose of 0.25g/kg over 3 hours for 3 days in addition to Antibiotics	Drug: IgM-enriched IVIG; Contains human plasma protein 50mg/ml. With composition of Immunoglobulin M (IgM) 6mg, Immunoglobulin A (IgA) 6mg, Immunoglobulin G (IgG) 38mg (IgG subcl. approx. 63 % IgG1, 26 % IgG2, 4 % IgG3 and 7 % IgG4), Glucose monohydrate, sodium chloride, water for injections; Other Names: Pentaglobin®
PLACEBO_COMPARATOR: Placebo Group; Antibiotics only	Drug: IgM-enriched IVIG; Contains human plasma protein 50mg/ml. With composition of Immunoglobulin M (IgM) 6mg, Immunoglobulin A (IgA) 6mg, Immunoglobulin G (IgG) 38mg (IgG subcl. approx. 63 % IgG1, 26 % IgG2, 4 % IgG3 and 7 % IgG4), Glucose monohydrate, sodium chloride, water for injections; Other Names: Pentaglobin®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early Mortality Rate	Neonates in the treatment group should have lower mortality rate in the first week of life	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive blood culture	Neonates in the treatment group should have less number of positive blood culture than those in the place group	1 week
Duration of NICU stay	Neonates in the treatment group should be discharged earlier than those in the placebo group	Through study completion, an average of 3 months
Quantitative CRP Levels	Neonates in the treatment group should have lower CRP levels than those in the placebo group	1 week
IT Ratio value	Neonates in the treatment group should have lower IT Ratio value than those in the placebo group	1 week
Leukocyte count	Neonates in the treatment group should have lower Leukocyte count than those in the placebo group	1 week
IgGAME (IgG, IgM, IgA, IgE) Levels	Neonates in the treatment group should have higher IgGAME levels than those in the placebo group	1 week

Collaborators and Investigators

• Sponsor: Fakultas Kedokteran Universitas Indonesia
• Investigators: Study Chair: Rinawati Rohsiswatmo, MD, PhD, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo Hospital; Principal Investigator: Nina D Putri, MD, PhD, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo Hospital

Publications and helpful links

General Publications

• Capasso L, Borrelli AC, Parrella C, Lama S, Ferrara T, Coppola C, Catania MR, Iula VD, Raimondi F. Are IgM-enriched immunoglobulins an effective adjuvant in septic VLBW infants? Ital J Pediatr. 2013 Oct 7;39:63. doi: 10.1186/1824-7288-39-63.
• Haque KN, Zaidi MH, Bahakim H. IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Am J Dis Child. 1988 Dec;142(12):1293-6. doi: 10.1001/archpedi.1988.02150120047038.
• Reith HB, Rauchschwalbe SK, Mittelkotter U, Engemann R, Thiede A, Arnold A, Lissner R. IgM-enriched immunoglobulin (pentaglobin) positively influences the course of post-surgical intra-abdominal infections. Eur J Med Res. 2004 Oct 29;9(10):479-84.
• Capasso L, Borrelli AC, Pirozzi MR, Bucci L, Albachiara R, Ferrara T, Raimondi F. IgM and IgA enriched polyclonal immunoglobulins reduce short term mortality in extremely low birth weight infants with sepsis: a retrospective cohort study. Minerva Pediatr (Torino). 2021 Feb;73(1):3-7. doi: 10.23736/S2724-5276.18.04850-8. Epub 2018 Feb 19.
• Capasso L, Borrelli AC, Ferrara T, Coppola C, Cerullo J, Izzo F, Caiazza R, Lama S, Raimondi F. Immunoglobulins in neonatal sepsis: has the final word been said? Early Hum Dev. 2014 Sep;90 Suppl 2:S47-9. doi: 10.1016/S0378-3782(14)50013-8.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 1, 2019
• Primary Completion (ANTICIPATED): June 1, 2020
• Study Completion (ANTICIPATED): August 1, 2020

Study Registration Dates

• First Submitted: July 27, 2019
• First Submitted That Met QC Criteria: July 31, 2019
• First Posted (ACTUAL): August 1, 2019

Study Record Updates

• Last Update Posted (ACTUAL): August 1, 2019
• Last Update Submitted That Met QC Criteria: July 31, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: IgM-enriched Intravenous Immunoglobulin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Body Weight; Sepsis; Toxemia; Inflammation; Birth Weight; Infant, Newborn, Diseases; Neonatal Sepsis
• Other Study ID Numbers: 19-11-432

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No