Bovine Lactoferrin and Neonatal Survival in Low Birth Weight Babies.

Can Bovine Lactoferrin Prevent Neonatal Infections in Low Birth Weight Babies in Karachi, Sindh, Pakistan.

Pakistan has the third highest number of neonatal deaths worldwide. During the last two decades (1990-2013), neonatal mortality rate in the country has declined by only 1.0% per year. Severe infection is the second most leading cause of neonatal mortality, account for 28% of all deaths in Pakistan. Majority of neonatal deaths occur in infants who LBW (birth weight <2500g) and LBW comprises of both preterm / small for gestational age newborns. Breastfeeding helps protect infants from infections by serving as a source of nutrition uncontaminated by environmental pathogens. The protection is due to the multiple anti-infective, anti-inflammatory, and immuno regulatory factors transmitted through milk including secretory antibodies, glycan's, Lactoferrin, leukocytes, cytokines & other components produced by the mother's immune system.

Reduction in neonatal infections and deaths is the aim of this study. The study is being conducted at the Aga Khan University in collaboration with University of Sydney.

Study Overview

• Status: Unknown
• Conditions: Necrotizing Enterocolitis; Neonatal Sepsis
• Intervention / Treatment: Combination product: bLF (Bovine lactoferrin); Drug: Glucon-D 99.4% (Placebo)

Detailed Description

Globally, severe infection is the second leading cause of neonatal mortality. It is one of the indirect leading causes of death in a world. According to Annual report, 28% neonatal deaths were due to preterm baby, 26% due to severe infection , 23% due to asphyxia and 7% neonatal tetanus. Every year, three - fourth deaths occurred in first week and four million babies die each year within first four weeks of birth, whereas, 99% of cases were reported by low and middle income countries.Severe infections are the second major cause of death among neonates in Pakistan. Breastfeeding helps to protect infants from infections due to the multiple anti-infective, anti-inflammatory, and immuno regulatory factors such as secretory antibodies, glycan, Lactoferrin etc. Lactoferrin, the second most abundant protein in human milk has multiple putative functions. A trial in Italy found that the incidence of late-onset sepsis and sepsis related deaths were significantly lower in very LBW infants who were given daily (Bovine Lactoferrin) bLF compared to placebo. One small trial from India, found there was a 79% reduction in neonatal infections in LBW infants who received daily bovine Lactoferrin (bLF) from birth until 28 days. Evidence gaps remain about the appropriate daily prophylactic dose, the optimal method to deliver, and the effectiveness of bLF to prevent neonatal sepsis in LBW infants in low & middle-income countries.The overall goal of the project is to improve newborn survival among low birth weight (LBW) Pakistani infants through provision of a daily prophylactic dose of bLF. The project aim is to prevent neonatal infections, as opposed to the current approach which treats neonatal infections when they occur. The current approach depends on early detection of infections in newborns through post-natal care and treatment with antibiotics, with the potential risk of inappropriate use of antibiotics.A two stage study will be conducted including formative research followed by RCT to evaluate the appropriate daily dose of bLF. At the end of the study the investigators will have developed and tested an appropriate method to deliver bLF to newborns at home & identified the most appropriate dose of bLF to prevent neonatal sepsis in LBW newborns.

This study will be conducted at the Aga Khan University and Hospital, Karachi in two phases. A qualitative study will be conducted followed by a RCT. 300 LBW new born babies will be recruited;all standard operating procedures will be followed for administration of bLF to the neonates. Each arm of the study will be allocated 100 newborns.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Asghar Ali, MRA,MBA; Phone Number: 2279 92 213 493 0051; Email: asghar.ali@aku.edu
• Study Contact Backup: Name: Sajid B Soofi, MBBS,FCPS,; Phone Number: 4798 +922134864798; Email: sajid.soofi@aku.edu

Study Locations

• Pakistan
  • Sindh
    • Karachi, Sindh, Pakistan, 74800
      • Recruiting
      • Aga Khan University Hospital
      • Contact: Shabina Associate Professor; Phone Number: 4357 +92 21 34864357; Email: Shabina.ariff@aku.edu
      • Contact: Dr. Saajid B Soofi Soofi, FCPS MBBS; Phone Number: 8186 +92 21 99244230; Email: Sajid.soofi@aku.edu
      • Sub-Investigator: Neeloy A Alam
      • Sub-Investigator: William T Mordi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 days to 3 days (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Neonates with:

birth weight ≤ 2500 g and ≥ 1000 grams. gestational age ≥ to 28 +0 weeks to 36+6. family planned on staying in the study area for at least 1 month • parents/ caretaker willing to provide consent. newborn initiated enteral feeding via (gavage feeding with expressed breast milk or formula, direct breast feeding or cup and spoon feeding at or within 48 hours of birth.)

Exclusion Criteria:

Neonate with congenital anomalies. early-onset sepsis. birth weight less than 1000 g. gestational age less than or equal to 27weeks+6 days. history of Chorioamnionitis or maternal group B streptococcus colonization. Reversed or absent end-diastolic flow on maternal umbilical artery Doppler where available.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; bLF (Bovine Lactoferrin plus Glucan D 99.4%) Dose: 150 mg Frequency: a single daily dose mixed with milk (preferentially breast milk otherwise formula milk). Duration: 1 month	Combination product: bLF (Bovine lactoferrin); BLF administration in two different strengths (150 & 300mg) will be given on the third day of life with a single daily dose mixed with milk for 1 month.; Other Names: bLF
Experimental: Group 2; bLF (Bovine Lactoferrin plus Glucan D 99.4%) Dose: 300mg Frequency: a single daily dose mixed with milk (preferentially breast milk otherwise formula milk). Duration: 1 month	Combination product: bLF (Bovine lactoferrin); BLF administration in two different strengths (150 & 300mg) will be given on the third day of life with a single daily dose mixed with milk for 1 month.; Other Names: bLF
Placebo Comparator: Group 3; Placebo: Only Glucan-D (99.4% glucoseDose: 150 mg Frequency: a single daily dose mixed with milk (preferentially breast milk otherwise formula milk). Duration: 1 month	Drug: Glucon-D 99.4% (Placebo); This group will be given 100mg Glucon-D (99.4% glucose) placebo which will be similar in shape, color to the bLF.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Late onset sepsis (LOS) in Low Birth Weight.	Reduction in late onset sepsis (LOS) in Low Birth Weight babies.	1 month
Optimal dosage of bLF	Deduce optimal dosage of bLF in LBW babies.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Necrotizing Enterocolitis in LBW babies	Incidence of Necrotizing Enterocolitis in Low Birth Weight babies	1 month
Neonatal Mortality at 1 month of life.	Incidence of Neonatal Mortality at 1 month of life.	1 month

Collaborators and Investigators

• Sponsor: Aga Khan University
• Collaborators: United States Agency for International Development (USAID); University of Sydney
• Investigators: Principal Investigator: Shabina Ariff, MBBS,FCPS, Aga Khan University; Study Chair: Michael J Dibley, MB BS, MPH, University of Sydney; Study Director: Almas Aamir, MSC, Aga Khan University

Publications and helpful links

General Publications

• Lawn JE, Cousens S, Zupan J; Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: when? Where? Why? Lancet. 2005 Mar 5-11;365(9462):891-900. doi: 10.1016/S0140-6736(05)71048-5.
• Khan A, Kinney MV, Hazir T, Hafeez A, Wall SN, Ali N, Lawn JE, Badar A, Khan AA, Uzma Q, Bhutta ZA; Pakistan Newborn Change and Future Analysis Group. Newborn survival in Pakistan: a decade of change and future implications. Health Policy Plan. 2012 Jul;27 Suppl 3:iii72-87. doi: 10.1093/heapol/czs047.
• Hug L, Sharrow D, You D. Levels & trends in child mortality: report 2017. Estimates developed by the UN Inter-agency Group for Child Mortality Estimation. 2017.
• Farnaud S, Evans RW. Lactoferrin--a multifunctional protein with antimicrobial properties. Mol Immunol. 2003 Nov;40(7):395-405. doi: 10.1016/s0161-5890(03)00152-4.
• Anderson BF, Baker HM, Dodson EJ, Norris GE, Rumball SV, Waters JM, Baker EN. Structure of human lactoferrin at 3.2-A resolution. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1769-73. doi: 10.1073/pnas.84.7.1769.
• The World Bank. Mortality rate, neonatal (per 1,000 live births) [29/02/2016]. Available from: http://data.worldbank.org/indicator/SH.DYN.NMRT.
• Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull World Health Organ. 1987;65(5):663-737.
• Rahman S, Hameed A, Roghani MT, Ullah Z. Multidrug resistant neonatal sepsis in Peshawar, Pakistan. Arch Dis Child Fetal Neonatal Ed. 2002 Jul;87(1):F52-4. doi: 10.1136/fn.87.1.f52.
• Morrow AL, Rangel JM. Human milk protection against infectious diarrhea: implications for prevention and clinical care. Semin Pediatr Infect Dis. 2004 Oct;15(4):221-8. doi: 10.1053/j.spid.2004.07.002.
• Ariff S, Soofi S, Aamir A, D'Almeida M, Aziz Ali A, Alam A, Dibley M. Bovine Lactoferrin to Prevent Neonatal Infections in Low-Birth-Weight Newborns in Pakistan: Protocol for a Three-Arm Double-Blind Randomized Controlled Trial. JMIR Res Protoc. 2021 Mar 11;10(3):e23994. doi: 10.2196/23994.

Helpful Links

• The World Bank Mortality rate ,Neonatal (per,1000 live births) 29/02/2016
• United.Nations Sustainable development goals

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2018
• Primary Completion (Anticipated): May 1, 2020
• Study Completion (Anticipated): May 1, 2020

Study Registration Dates

• First Submitted: February 6, 2018
• First Submitted That Met QC Criteria: February 12, 2018
• First Posted (Actual): February 13, 2018

Study Record Updates

• Last Update Posted (Actual): April 9, 2020
• Last Update Submitted That Met QC Criteria: April 8, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Bovine Lactoferrin, Neonatal infection, Low Birth Weight
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Gastrointestinal Diseases; Infant, Newborn, Diseases; Body Weight; Gastroenteritis; Intestinal Diseases; Sepsis; Birth Weight; Enterocolitis; Enterocolitis, Necrotizing; Neonatal Sepsis; Anti-Infective Agents; Lactoferrin
• Other Study ID Numbers: SLAB

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
• product manufactured in and exported from the U.S.: No