Bovine Lactoferrin and Neonatal Survival in Low Birth Weight Babies.

NCT ID: NCT03431558

Last Updated: 2020-04-09

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-05-01
• Study Completion Date: 2020-05-31

Brief Summary

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.

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.

Conditions

Neonatal Sepsis; Necrotizing Enterocolitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

bLF (Bovine lactoferrin)

Intervention Type: COMBINATION_PRODUCT

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.

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

Group Type: EXPERIMENTAL

bLF (Bovine lactoferrin)

Intervention Type: COMBINATION_PRODUCT

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.

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

Group Type: PLACEBO_COMPARATOR

Glucon-D 99.4% (Placebo)

Intervention Type: DRUG

This group will be given 100mg Glucon-D (99.4% glucose) placebo which will be similar in shape, color to the bLF.

Interventions

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.

Intervention Type: COMBINATION_PRODUCT

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.

Intervention Type: DRUG

Other Intervention Names

bLF; Placebo

Eligibility Criteria

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.

• Minimum Eligible Age: 48 Hours
• Maximum Eligible Age: 72 Hours
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Sydney

OTHER

Sponsor Role: collaborator

United States Agency for International Development (USAID)

FED

Sponsor Role: collaborator

Aga Khan University

OTHER

Sponsor Role: lead

Responsible Party

Dr Shabina Ariff

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Shabina Ariff, MBBS,FCPS

Role: PRINCIPAL_INVESTIGATOR

Aga Khan University

Michael J Dibley, MB BS, MPH

Role: STUDY_CHAIR

University of Sydney

Almas Aamir, MSC

Role: STUDY_DIRECTOR

Aga Khan University

Locations

Aga Khan University Hospital

Karachi, Sindh, Pakistan

Site Status: RECRUITING

Countries

Pakistan

Central Contacts

Sajid B Soofi, MBBS,FCPS,

Role: CONTACT

sajid.soofi@aku.edu

+922134864798 ext. 4798

Asghar Ali, MRA,MBA

Role: CONTACT

asghar.ali@aku.edu

92 213 493 0051 ext. 2279

Facility Contacts

Shabina Associate Professor

Role: primary

Shabina.ariff@aku.edu

+92 21 34864357 ext. 4357

Dr. Saajid B Soofi Soofi, FCPS MBBS

Role: backup

Sajid.soofi@aku.edu

+92 21 99244230 ext. 8186

References

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.

Reference Type: BACKGROUND

PMID: 22692418 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15752534 (View on PubMed)

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

PMID: 14568385 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 3470756 (View on PubMed)

The World Bank. Mortality rate, neonatal (per 1,000 live births) [29/02/2016]. Available from: http://data.worldbank.org/indicator/SH.DYN.NMRT.

Reference Type: BACKGROUND

Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull World Health Organ. 1987;65(5):663-737.

Reference Type: BACKGROUND

PMID: 3322602 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12091293 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15494945 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33704071 (View on PubMed)

Related Links

http://data.worldbank.org/indicator/SH.DYN.NMRT

The World Bank Mortality rate ,Neonatal (per,1000 live births) 29/02/2016

http://www.un.org/sustainabledevelopment/health

United.Nations Sustainable development goals

Other Identifiers

SLAB

Identifier Type: -

Identifier Source: org_study_id