Randomized Controlled Trial of Talactoferrin Oral Solution

in Preterm Infants
Michael P. Sherman, MD, PhD1, David H. Adamkin, MD2, Victoria Niklas, MD3,*, Paula Radmacher, PhD2, Jan Sherman, PhD1,4,
Fiona Wertheimer, DO3, and Karel Petrak, PhD5,
Objective To evaluate the safety and explore the efficacy of recombinant human lactoferrin (talactoferrin [TLf]) to
reduce infection.

Study design We conducted a randomized, double blind, placebo-controlled trial in infants with birth weight of
750-1500 g. Infants received enteral TLf (n = 60) or placebo (n = 60) on days 1 through 28 of life; the TLf dose was
150 mg/kg every 12 hours. Primary outcomes were bacteremia, pneumonia, urinary tract infection, meningitis, and
necrotizing enterocolitis (NEC). Secondary outcomes were sepsis syndrome and suspected NEC. We recorded clinical,
laboratory, and radiologic findings, along with diseases and adverse events, in a database used for statistical analyses.
Results Demographic data were similar in the 2 groups of infants. We attributed no enteral or organ-specific
adverse events to TLf. There were 2 deaths in the TLf group (1 each due to posterior fossa hemorrhage and postdischarge sudden infant death), and 1 death in the placebo group, due to NEC. The rate of hospital-acquired infections was 50% lower in the TLf group compared with the placebo group (P < .04), including fewer blood or line
infections, urinary tract infections, and pneumonia. Fourteen infants in the TLf group weighing <1 kg at birth had
no gram-negative infections, compared with only 3 of 14 such infants in the placebo group. Noninfectious outcomes
were not statistically significantly different between the 2 groups, and there were no between-group differences in
growth or neurodevelopment over a 1-year posthospitalization period.
Conclusion We found no clinical or laboratory toxicity and a trend toward less infectious morbidity in the infants
treated with TLf. (J Pediatr 2016;-:---).
Trial registration ClinicalTrials.gov: NCT00854633.

ospital-acquired infections represent the majority of diseases affecting preterm infants in neonatal intensive care units
(NICUs).1 Because hospital-acquired infections are associated with increased length of hospital stay and significant increases in the cost of care, the American Academy of Pediatrics has called for strategies to reduce hospital-acquired
infections in NICUs.2,3 Among hospital-acquired infections, bacteria resistant to broad-spectrum antibiotics cause >50% of
patient-associated diseases,4 which has led to an emphasis on antibiotic stewardship.
Modified health care practices have reduced hospital-acquired infections in extremely preterm infants,2,3 but do not address
the underlying immaturity of the mucosal and systemic immune systems.5 Maternal milk is known to reduce the occurrence of
bacteremia and necrotizing enterocolitis (NEC).6,7 Biomolecules in human milk are proposed to synchronously modify the
intestinal microbiome and nascent gut and boost systemic immunity, thereby reducing susceptibility to infection.5,8 Extremely
preterm infants (birth weight <1 kg) are the most vulnerable to infection because maternal colostrum is limited immediately
after birth, or because intestinal dysmotility hinders full enteral feedings for days to weeks.
Human milk proteins enhance the development of intestinal epithelia,
facilitate a healthy intestinal microflora, establish host defenses, and heighten
From the Division of Neonatology, Department of Child
mucosal defenses. We propose that the human milk protein lactoferrin partly
Health, University of Missouri, Columbia, MO; Division
explains these beneficial effects.9,10 Commercial recombinant human lactoferrin
of Neonatal Medicine, Department of Pediatrics,
University of Louisville, Louisville, KY; Division of
(talactoferrin [TLf]) TLf became available 20 years ago.11 We found that feeding
Neonatal Medicine, Childrens Hospital Los Angeles,
1

Keck School of Medicine at the University of Southern

California, Los Angeles, CA; 4Sinclair School of Nursing,
University of Missouri, Columbia, MO; and 5Agennix Inc,
Houston, TX

AE
bLF
CoNS
FDA
IND
NEC
NICU
RCT
SAE
TLf
VLBW

Adverse event
bovine lactoferrin
Coagulase-negative staphylococci
Food and Drug Administration
Investigational New Drug
Necrotizing enterocolitis
Neonatal intensive care unit
Randomized controlled trial
Serious adverse event
Talactoferrin
Very low birth weight

*Current address: Prolacta, City of Industry, CA.

Current address: F.J.S. de Oro, 2835 Piso 5-2, 1425
Capital Federal Buenos Aires, Argentina.
Funded by the National Institutes of Health (HD057744 to
Agennix, Inc [PI: K.P. and M.S.]). K.P. served as project
coordinator and Vice-President for Research at Agennix,
Inc until 2012. The other authors declare no conflicts of
interest.
Portions of the study were presented at a Mead Johnson
Pediatric Nutrition Institute, Boston, MA, April 23-24,
2015.
0022-3476/$ - see front matter. 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jpeds.2016.04.084

THE JOURNAL OF PEDIATRICS

www.jpeds.com

TLf prophylactically to neonatal rats prevented morbidity

and mortality caused by enteroinvasive Escherichia coli.12
Our research then became focused on enteral lactoferrin deficiency that occurs in the early life of immature infants. We
hypothesized that administering TLf would be safe, and conducted a randomized controlled trial (RCT) to assess its
safety and efficacy in very low birth weight (VLBW) infants.

Methods
In this double-blinded RTC, TLf or placebo was administered
to infants with birth weight between 750 and 1500 g starting
within 24 hours of birth and continuing through 28 days of
life (ClinicalTrials.gov: NCT00854633). We excluded infants
who had a major congenital malformation, chromosomal abnormality, documented prenatal or intrapartum neonatal
infection, or absence of parental consent, or were moribund
at birth. We enrolled and randomized subjects between July
1, 2009, to March 17, 2012. Hospital discharge was followed
by a 1-year outpatient follow-up period. Agennix Inc (Houston, Texas), the trial sponsor, ended the final data analyses in
December 2013.
Agennix provided TLf to 3 academic health care systems in
the US. Agennix used good manufacturing practice and suspended TLf in sterile, endotoxin-free, phosphate-buffered saline. The excipient served as the placebo with excellent color
matching. The Institutional Review Board for each site
approved the study. We obtained written consent from the
parents or legal guardians before 24 hours of age. Thereafter,
each institutional pharmacy randomized a subject via a central computer system (inVentiv Clinical Solutions, Houston,
Texas). The inVentiv Web Response system also recorded
data about participants in this RCT. Agennix sponsored the
research under Food and Drug Administration (FDA) Investigational New Drug (IND) policies and procedures. The
study design included a Data Safety Monitoring Board, a
centralized serious adverse event reporting system, and periodic onsite monitoring visits that verified clinical, health
care, laboratory, and radiologic data and pharmacy record
keeping.
We randomized infants to receive either TLf solution
(150 mg/mL) at a dose of 300 mg/kg/day or an identical volume of the excipient. Doses were administered every 12 hours
via nasogastric tube from days of life 1 through 28 or until
discharge, whichever occurred first. We extrapolated the
dose of TLf from lactoferrin consumed during enteral breast
milk feeding (150 mL/kg/day) with the content of lactoferrin
in human milk estimated at 2 mg/mL. In all subjects, we
administered the first dose before 24 hours of age. We
adjusted the dose at weekly intervals if the weight increased
by $10% from a previous weight.
Primary and Secondary Outcomes
The primary outcome was a significant reduction in hospitalacquired infections, including bacteremia, pneumonia, urinary tract infection, meningitis, and NEC. Our criteria
were based on Centers for Disease Control and Prevention
2

Volume definitions for hospital-acquired infections.13 The sponsor

established strict criteria for infection, including bloodstream
infections, pneumonia, urinary tract infections, meningitis
and NEC.14 A diagnosed infection required antibiotics for
$72 hours.
Secondary outcomes were mortality, duration of hospitalization, time to regain birth weight, and the time to reach
full enteral feeds. Disease-related morbidities included
medically or surgically treated patent ductus arteriosus,
intracerebral hemorrhage, periventricular leukomalacia,
retinopathy of prematurity, chronic lung disease (defined
as O2 therapy at 36 weeks postconceptual age), suspected
NEC, clinical sepsis syndrome, and neonatal inflammatory
response syndrome. We defined a clinical sepsis syndrome
as a negative blood culture, but with clinical and laboratory
findings necessitating empiric antibiotic therapy. These
criteria included elevated inflammatory markers, namely
serial C-reactive protein level $1.5 mg/dL, abnormal serial
white blood cell count or an elevated immature/total
neutrophil ratio ($0.3), central thermal instability, apnea
and bradycardia, or respiratory distress. We established suspected NEC as a clinical scenario that involved a cessation
of enteral feedings and initiation of antibiotics based on
gastric residuals, occult or gross blood in the stool, abdominal distention, and radiographs showing dilated bowel
loops and an abnormal bowel gas pattern, but without a
sentinel loop or pneumatosis intestinalis.
Safety Assessment
We used the MedDRA system to report safety outcomes to
the FDA.15 All investigators underwent training in the use
of this grading and severity scoring system. This system reports adverse events (AEs) and severe adverse events
(SAEs) on a daily basis using an FDA-accepted measurement
scale.15 The FDA mandates daily recording of clinical information during the 28-day prophylactic period, with weekly
recording until discharge. At the 6- and 12-month postdischarge visits, we collected growth measurements, including
head circumference, health outcomes, and developmental
progress using the Bayley screener III.16 If the subject did
not return, we contacted the primary care physician or parents by telephone, or parents by US mail, to ascertain the infants clinical status.
Agennix did not require any specific collection of clinical
findings, laboratory tests, or radiologic studies. The FDA
IND program requires information on daily weight and
abdominal circumference, vital signs, physical examination
findings, type and duration of respiratory support, O2 saturation, volume and type of enteral feeding, intravenous fluids
and total parenteral nutrition volume and composition, urinary output, gastric residual volumes, number and description of feces passed, and concomitant medications. The
study protocol collected laboratory and radiographic test
data as ordered by the supervising neonatal attending. Test
data included complete blood count, C-reactive protein,
complete metabolic and electrolyte panels, blood gas analyses, gross or occult blood in feces, and results of all
Sherman et al

- 2016

ORIGINAL ARTICLES

radiographic studies. The cumulative weight gain from birth

and the duration of hospitalization served as biomarkers of
nutritional support.
Sample Size and Statistical Analysis
This RCT focused on safety. We based the original sample
size for the Phase 1 study on the recommendations of Cohen
(similar to G* Power 3.1) for an ANOVA with 4 groups. Using a power of 0.80, an effect size of 0.5, and an a value of
0.05, a minimum of 48 total subjects were needed to complete the safety phase of the study. We based the Phase 2 sample size calculations on the same statistical parameters, but
with a reduction in effect size to 0.175, resulting in a minimum total sample of 360 subjects. Allowing for 10% attrition, we estimated that 396 subjects were necessary.
Because of reduced funding, we decreased our sample size
from 396 to 120 VLBW infants in 2 groups, TLf (n = 60)
and placebo (n = 60). Thus, the investigation was underpowered to identify significant primary or secondary outcomes.
We entered clinical, laboratory, and radiologic findings;
disease states; and AEs into the inVentiv SAS database. We
performed statistical analyses using SAS version 9.3 (SAS
Institute, Cary, North Carolina). Descriptive statistics
included frequencies, percentages, and measures of central
tendency. We analyzed ratio-level data, such as blood count
values, C-reactive protein, and the volume of gastric residuals, using an independent-samples t test. For nonnormally distributed data, we used the Mann-Whitney U
test. Nominal data were analyzed using the c2 test of independence or the Fisher exact test for cells with a value <5.
To calculate cumulative weight gain at discharge, we used a
mixed-effects regression model that accounted for treatment,
feeding strata, birth weight, and days since birth as explanatory variables. Clinical significance was determined using risk
indices, namely relative risk, 95% CI, and number needed to
treat. The safety monitoring board used these measures to
ascertain TLf-related AEs and to determine primary and secondary outcomes.

Results
Table I presents demographic data for the preterm infants and
mothers associated with the clinical trial. Mothers declared
their decision regarding breast milk or formula feeding
during the consent process. The pharmacy considered each
mothers feeding decision during randomization. Thus, the
assignments were equal in the TLf vs placebo and enteral
nutrition with mothers milk and formula. Human donor
milk was not used during the trial.
The Figure (available at www.jpeds.com) presents a
CONSORT diagram of the study. Thirty-seven of 60 infants
(62%) completed the entire 28-day TLf treatment course, and
44 of 60 infants (73%) completed the entire placebo arm.
One infant assigned to the TLf arm died of brain stem
hemorrhage at 30 hours of age and was excluded from the
outcome assessment. One infant in the TLf arm died of
sudden infant death syndrome after discharge, and 1 infant in

Table I. Maternal and infant demographic data

Characteristics

TLf group
(n = 60)

Gestational age, wk, mean  SD*

28  6/7
Birth weight, g, mean  SD*
1152  206

14 (23)
Birth weight 750-1000 g, n (%)
46 (75)
Birth weight 1001-1500 g, n (%)
9 (15)
Small for gestational age status, n (%)
33 (55)
Male sex, n (%)
z
5 and 8
Apgar score, 1 and 5 min, median
18 (30)
Multiple births, n (%)
42 (70)
Preterm labor, n (%)
19 (32)
Premature rupture of membranes, n (%)

8 (13)
>12-hour rupture of membranes, n (%)
32 (53)
Maternal antibiotics, n (%)
48 (80)
One or more doses of betamethasone, n (%)
49/11
Cesarean/vaginal delivery, n

Race/ethnicity, n
White
36
African American
5
Asian
1
Multiracial
5
Hispanic
13

Placebo group
(n = 60)
28  6/7
1143  220
14 (23)
46 (75)
11 (18)
36 (60)
7 and 8
13 (22)
41 (68)
21 (35)
15 (25)
35 (58)
45 (75)
48/12
33
11
0
4
12

All comparisons had P value $.25.

*P values by the independent t test.
P values by the c2 test.
zP values by the Mann-Whitney U test.

the placebo arm died of NEC with sepsis. Among the 23

infants in the TLf arm who did not complete the entire
course of treatment, the reasons for discontinuing therapy
included discharge before the 28th day (n = 4), death (n = 1),
and medical or surgical therapy for a hemodynamically
significant patent ductus arteriosus, suspected NEC, or
enteral feeding problem (n = 18). Among the 13 infants who
did not complete the placebo course, reasons for
incompletion included discharge to home before the 28th day
(n = 13), withdrawal of consent (n = 1), and cessation of
placebo by the attending neonatologist (n = 4).
Table II (available at www.jpeds.com) shows drug
exposure and compliance. The number of doses received,
duration of drug exposure, and total drug intake were not
statistically different between the 2 study groups. Drug
compliance was 94.6% in the TLf group and 96% in the
placebo group.
At the 6-month follow-up visit, we assessed health and
developmental status in 88% of the subjects in the TLf group
and 80% of those in the placebo group. At the 12-month
follow-up visit, these percentages were 55% and 52%. Telephone conversations with parents identified reasons for
missed appointments including the infants good health
and development, parents reluctance to take time off from
work, and excessive distance to travel for visits.
Safety Outcomes
Table III presents data on the incidence and types of AEs
occurring in the study population. The overall rate of at least
one treatment-emergent AE was similar in the 2 study arms.
We identified AEs related most often to preterm birth rather
than to the use of TLf or placebo. Gastrointestinal (76%),
blood and lymphatic (60%), nutritional and metabolic

Randomized Controlled Trial of Talactoferrin Oral Solution in Preterm Infants

THE JOURNAL OF PEDIATRICS

NICU stay (relative risk, 0.52; 95% CI, 0.26-0.99; P < .045).
There were no cases of meningitis in either group. Two
infants in the TLf group developed NEC, both of whom
survived, and 1 formula-fed infant in the placebo group
died from NEC.
Table VI lists the types of bacteria that caused the
infections. In the TLf group, there was a reduction in
gram-positive bacterial isolates, with coagulase-negative
staphylococci (CoNS) accounting for most of these isolates.
In 14 infants with birth weight <1 kg, we identified no
cases of gram-negative bacterial infection and 2 cases of
CoNS-related bacteremia (14%). In the placebo group, 5 of
14 infants (36%) with birth weight <1 kg had bacteremia
caused by CoNS (n = 2) or Klebsiella pneumoniae (n = 1),
or pneumonia caused by Klebsiella oxytoca (n = 2).

Table III. Summary of AEs

Study AEs

Total,
n (%)

At least 1 AE, n (%)

118 (98.3)
At least 1 AE of grade
52 (43)
3/4/5, n (%)
At least 1 SAE, n (%)
15 (13)
At least 1 TLf or placebo
0
AE, n (%)
At least 1 AE causing drug 22 (18)
discontinuation, n (%)
AEs related to study
drug, n (%)
Not related
106 (88)
Possibly related
12 (10)
AEs by degree of
severity, n (%)
Grade 1
29 (24)
Grade 2
37 (31)
Grade 3
46 (38)
Grade 4
4 (3)
Grade 5
2 (2)
Deaths, n
3
Treatment-related
0
deaths, n

Volume -

www.jpeds.com

TLf
Placebo
P
group, n (%) group, n (%) value
58 (97)
27 (45)

60 (100)
25 (42)

.99
.91

7 (12)
0

8 (13)
0

.95
-

14 (23)

8 (13)

.33

53 (88)
5 (8)

53 (88)
7 (12)

.94
.83

14 (23)
17 (28)
25 (42)
1 (2)
1 (2)
2
0

15 (25)
20 (33)
21 (35)
3 (5)
1 (2)
1
0

.94
.84
.83
.65
.48
1.0
-

MedDRA Version 14.1 defined classes, organ systems, and preferred terms. Scoring criteria are
available at http://www.meddra.org/.

(72%), and respiratory disorders (72%) were the most

commonly reported treatment-emergent AEs. These AEs
were often the reason for study drug or placebo
discontinuation. The rate of at least 1 SAE was also similar in
the TLf and placebo arms. All SAEs were associated with
complications of very preterm birth rather than with
administration of TLf or placebo. The Data Safety
Monitoring Board never halted the progression of the RCT.
Primary Outcomes
Table IV summarizes primary outcome data. Table V
(available at www.jpeds.com) shows the demographics of
infant having the first episode of a hospital-acquired
infection. Compared with the placebo group, the TLf group
had a lower risk of hospital-acquired infections during the

Secondary and Other Efficacy Outcomes

Tables VII and VIII (available at www.jpeds.com)
summarize Secondary Outcomes in breast-fed and
formula-fed infants, respectively. Secondary outcomes,
including cumulative weight gain from birth and duration
of hospitalization, did not differ by study arm or feeding
type. Follow-up records in the SAS database after hospital
discharge identified no abnormalities in growth or
development between the TLf and placebo groups. We
proposed that TLf might reduce inflammation in treated
infants9; however, the peak C-reactive protein level was not
significantly different between the TLf group (n = 30) and
the placebo group (n = 38) (1.6  1.6 mg/dL vs
2.8  6.0 mg/dL, respectively).

Discussion
To date, 4 investigative groups have published clinical trial
information using enteral administration of bovine lactoferrin (bLF) to prevent late-onset sepsis and NEC during hospitalization of infants with birth weight #2000 g.17-20 The
current RCT is a Phase 1/2 trial that provides safety and preliminary efficacy data associated with enteral administration

Table IV. First-episode hospital-acquired infections

n (%)*
Treatment types
Hospital-acquired infectionz
Blood/line infection with CoNS; 2 positive cultures required1
Urinary tract infection, aseptic catheter or suprapubic tap; isolated
pathogen >104 CFU/mL in urine
Tracheal aspirate, pathogen-related pneumonia + Centers for Disease
Control and Prevention criteria14
Intestine, NEC Bell stage II or higher15
Infections per NICU stay
Total hospital days
Hospital-acquired infection/1000 hospital days

Statistics: TLf vs placebo group

TLf group
(n = 59)

Placebo group
(n = 60)

RR (% CI)

NNT

P value

10 (17)
6 (10)
0 (0)

20 (33)
10 (17)
5 (8)

0.52 (0.26-0.99)
0.64 (0.3-1.7)
0.10 (0.01-1.8)

6
14
13

<.04
.52
.09

2 (3)

4 (7)

0.52 (0.1-2.8)

25

.72

2 (3)

1 (2)

0.23 (0.1-1.0)

61

3460
2.0

3446
4.4

0.52 (0.1-2.8)

25

1.0
NS
.10

NNT, number needed to treat; NS, not significant; RR, relative risk.
*The number of hospital-acquired infections/total number of infants per group.
P value from c2 test for infectious comparisons; hospital-acquired infection/1000 hospital days from t test; significance P # .05.
zFirst identified episode of hospital-acquired infection in bloodstream, spinal fluid, urine, and lung fluid.

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ORIGINAL ARTICLES

Table VI. Bacteria identified with first hospital-acquired infection

Bacteria/total hospital-acquired infection

TLf vs placebo

Bacterial isolate*

TLf group
(n/N = 8/59; 14%), n/N (%)

Placebo group
(n/N = 20/60; 33%), n/N (%)

RR (95% CI)

NNT

P valuez

Gram-negative bacteria
Gram-positive bacteria
CoNS per gram-positive infectionx

4/8 (50)
4/8 (50)
3/4 (75)

5/20 (25)
15/20 (75)
11/15 (73)

1.6 (0.5-4.8)
0.76 (0.3-1.8)
0.74 (0.3-2.2)

8
3
5

.96
.04
.09

*All n are based on the type of bacteria identified by Gram stain result and culture identification methods for the first episode of hospital-acquired infection.
Number of each type of infection/total number of study subjects by type (%).
zP values from the c2 test; significance P # .05.
xNumber of CoNS infections per total gram-positive bacterial infections.

of TLf. The study used a recombinant human lactoferrin produced under good manufacturing practices and with FDA
approval as an IND. This study also used the MedDRA system to measure safety during and after administration of
TLf, an instrument used by the International Conference
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.12 The results
demonstrate the safety of the TLf molecule and provide an
initial report of efficacy related to reducing hospitalacquired infections and possibly other noninfectiousrelated outcomes.
The 4 previous studies using bLF in preterm infants reported a reduced rate of infection of variable magnitude,
and 1 report using prophylaxis with bLF noted a reduction
in late-onset sepsis among infants with birth weight
<1 kg.17 In the current TLf trial, we found a 14% rate of infection in infants with birth weight <1 kg given enteral TLf vs
36% in babies given placebo. Our results are in agreement
with those reported by Manzoni et al,17 with a comparable
reduction in infection rates in extremely preterm infants.
In all studies using bLF, the biological agent was generally regarded as a safe food supplement. In contrast, the source of
TLf was biotechnology rather than a food supplement isolated from bovine milk. Furthermore, compared with the
aforementioned RCT using bLF,17 TLf showed similar therapeutic efficacy as bLf in reducing gram-positive bacterial infections (Table VI). We propose that this decline caused the
overall reduction in hospital-acquired infections in infants
treated with TLf compared with those treated with placebo
(Table IV).
There were no urinary tract infections in the TLf group
but some in the placebo group; however, the difference was
not statistically significant. An association between urinary
infections and NEC was reported recently.21 Because the
fecal microbiome is a microbial reservoir for urogenital
colonization, we suggest a possible relationship between
enteric prophylaxis with TLf and reduced urinary infections, and would encourage examination of this association
in upcoming clinical trials of bLF. Future studies of lactoferrin prophylaxis should study the fecal microbiome,
because the microbiota present may be transferred to other
body sites. Metagenomic technology can accurately classify
the fecal translocation of pathogenic bacteria originating in
the feces.22

Finally, studies in progress should evaluate the safety of

lactoferrin by using an internationally accepted method like
MedDRA. Based on the suggested mechanisms of action
for lactoferrin,9,19 we suggest that future RCTs should also
report on differences in inflammatory biomarkers between
lactoferrin and placebo control subjects. One attractive strategy may be to examine inflammation in twins who are
randomized to enteral lactoferrin vs placebo. Thoughtful adaptations of the traditional RCT design may provide opportunities to test whether lactoferrin supplementation will
reduce infectious and other morbidities in VLBW infants. n
The authors appreciate the care provided by our fellow neonatologists,
neonatal-perinatal medicine fellows, neonatal intensive care nurses,
respiratory care practitioners, and pharmacists during this RCT.
Submitted for publication Jan 14, 2016; last revision received Mar 22, 2016;
accepted Apr 25, 2016.
Reprint requests: Michael P. Sherman, MD, PhD, Womens & Childrens
Hospital, University of Missouri Healthcare, Suite 206 Neonatology, 404 Keene
St, Columbia, MO 65201. E-mail: shermanmp@missouri.edu

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March_2010/Day_3/Regulatory_Perspective_SBrajovic.pdf. Accessed April
26, 2016.
16. Weiss LG, Oakland T, Aylward GP, Eds. Bayley III. Clinical use and
interpretation. Burlington, MA: Elsevier Inc.; 2010.

Volume 17. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, et al.
Bovine lactoferrin supplementation for prevention of late-onset sepsis in
very low-birth-weight neonates: a randomized trial. JAMA 2009;302:
1421-8.
18. Manzoni P, Meyer M, Stolfi I, Rinaldi M, Cattani S, Pugni L, et al. Bovine
lactoferrin supplementation for prevention of necrotizing enterocolitis
in very-low-birth-weight neonates: a randomized clinical trial. Early
Hum Dev 2014;90(Suppl 1):S60-5.
19. Akin IM, Atasay B, Dogu F, Okulu E, Arsan S, Karatas HD, et al. Oral
lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis
of premature neonates and effect on T-regulatory cells. Am J Perinatol
2014;31:1111-20.
20. Ochoa TJ, Zegarra J, Cam L, Llanos R, Pezo A, Cruz K, et al. Randomized
controlled trial of lactoferrin for prevention of sepsis in Peruvian neonates less than 2500 g. Pediatr Infect Dis J 2015;34:571-6.
21. Pineda LC, Hornik CP, Seed PC, Cotten CM, Laughon MM, Bidegain M,
et al. Association between positive urine cultures and necrotizing enterocolitis in a large cohort of hospitalized infants. Early Hum Dev 2015;91:
583-6.
22. Sherman MP, Minnerly J, Curtiss W, Rangwala S, Kelley ST. Research on
neonatal microbiomes: what neonatologists need to know. Neonatology
2014;105:14-24.

Sherman et al

- 2016

ORIGINAL ARTICLES

Figure. Trial profile.

Table II. Study drug exposure and compliance

Dosing
Number of doses received, mean  SD
Duration of drug exposure, d,
mean  SD*
Total drug intake, mg, mean  SD
Compliance, %z

TLf group
(n = 60)
46  14
25  7
5461  4739
94.9

Placebo group
(n = 60)
49  10
26  5
6221.50  4999
96.0

*Duration of drug exposure = (date of last dose  date of first dose) + 1.

Total drug exposure = sum (dose (mg/kg)  daily weight (kg)).
z% compliance = 100  (no. of complete or partial doses) O (no. of doses taken + no. of
missed doses).

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Table V. Patient demographic data for first episode of

hospital-acquired infection
Characteristics
Time of onset, days of life,
mean  SD*
Gestational age, wk, mean  SD*
Birth weight, g, mean  SD*
Infections <1000 g, n/N (%)
Infections >1001 g, n/N (%)z

TLf group
(n = 59)

Placebo group
(n = 60)

P
value

19  4

16  2

.40

27  1
994  61
2 of 14 (14)
5 of 45 (11)

27  1
1003  58
8 of 14 (57)
6 of 46 (13)

.80
.92
.14
.96

*P values by the t test.

P values by the Fisher exact test.
zP values by the c2 test for independence.

Table VII. Secondary outcomes in breastfed infants

TLf group (n = 45)*

Placebo group (n = 46)*

Secondary efficacy endpoints/outcomes

n (%)

n (%)

P value

Suspected NEC
Neonatal sepsis syndrome or inflammatory response syndrome
Death
Other outcomes

45
45
45
45

6/46 (11)
3/46 (8)
3/60 (3)
11/46 (24)

46
46
46
46

8/46 (15)
1/46 (2)
0/60 (2)
11/46 (22)

.89
.61
.26
.89

Growth and care characteristics

Mean SD

Mean SD

P valuez

44
37
36
37
45
45

44
23  13
10  9
13  14
60  31
1702  20

46
46
30
35
46
46

55
20  15
99
19  19
59  29
1663  20

.26
.24
.76
.32
.83
.15

Days to regain birth weight

Days to full enteral feeds
Days of assisted ventilation therapy
Days of oxygen therapy
Duration of hospital stay, d
Cumulative weight gain at discharge, g
*n denotes the number of events/total number of infants in a feeding group.
P values based on the c2 or Fisher exact test.
zP values based on the Mann-Whitney U test.

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Sherman et al

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ORIGINAL ARTICLES

Table VIII. Secondary outcomes in formula-fed infants

TLf group (n = 15)*

Placebo group (n = 14)*

Secondary efficacy endpoints/outcomes

n (%)

n (%)

P value

NEC scares
Neonatal sepsis syndrome or inflammatory response syndrome
Death
Other endpoints/outcomes

15
15
15
15

1 (8)
0 (0)
0 (0)
1 (8)

14
14
14
14

1 (7)
0 (0)
0 (0)
2 (14)

1.0
1.0

Growth and care characteristics

Mean SD

Mean SD

P valuez

15
13
8
13
15
13

45
16  8
69
16  10
51  22
1713  31

14
10
10
9
14
9

25
22  15
11  11
29  33
58  29
1710  30

.50
.58
.18
.48
.82
.94

Days to regain birth weight

Days to full enteral feeds
Days of assisted ventilation therapy
Days of oxygen therapy
Duration of hospital stay, d
Cumulative weight gain at discharge, g
*n denotes the number of events/total number of infants in a feeding group.
P values based the c2 or Fisher exact test.
zP values based on the Mann-Whitney U test.

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