This project aims to develop talactoferrin (TLF, recombinant human lactoferrin) as a therapeutic agent to treat prematurely born neonates. The treatment will be given orally shortly after birth to prevent nosocomial infections (NIs) due to abnormal bacterial invasion of neonatal intestinal epithelia and consequently to limit systemic bacteremia and necrotizing enterocolitis (NEC). The overall incidence of prospectively studied NIs in hospitalized neonates has been reported to be 10.8 NI/100 patients. The incidence increases with decreasing birth weight, being as high as 81.8 NI/100 patients in Very Low Birth Weight group (birth weight <1500 g). Recent data from the National Institute of Child Health and Human Development-sponsored """"""""Neonatal Network"""""""" indicated that 29% of infants born at 25 to 28 weeks'gestation and 46% of infants born at less than 25 weeks'gestation experience a serious NIs during hospitalization in the NICU. The most common NI sites were sepsis and NEC. We therefore focus development of TLF on providing a sustained way to prevent and treat consequences of NIs in infants born prematurely and weighing from 750 to 1500 g at birth. The study shall enroll a total of 396 infants in a double-blind, randomized prospective study where TLF or placebo will be administered, in addition to the standard of care, to preterm infants before 24 hours of age. The study shall consist of four study groups: 1) mother's milk + placebo, 2) mother's milk + TLF, 3) formula feeding + placebo, and 4) formula feeding + TLF. The Phase-I part of the study shall determine the safety of TLF (at a dose of 300 mg/kg) when administered orally for 30 days. Using the total of (4 x 30) = 120 patients, safety of TLF shall be evaluated by determining the incidence and severity of adverse clinical events including laboratory and radiographic abnormalities. It is anticipated that adverse events might not be related to TLF, but rather to preterm birth, and TLF may mitigate those complications of prematurity [e.g., bronchopulmonary dysplasia]. The subsequent, continuous Phase-II part of the study shall ascertain the efficacy of TLF to enhance post-natal growth and to attenuate the incidence of nosocomial infections (including bacteremia, pneumonia, urinary infection, necrotizing enterocolitis [NEC] plus """"""""NEC scares"""""""", and meningitis). All 396 patients recruited into the study (Phase I and Phase II) shall be used to evaluate efficacy of TLF. The Primary Endpoint shall be the time to regain birth weight, daily weight gain, and number of days to hospital discharge, Incidence of nosocomial infections [late-onset bacteremia, pneumonia, necrotizing enterocolitis, urinary tract infection, and meningitis] and incidence of """"""""NEC Scares"""""""", """"""""neonatal sepsis syndrome"""""""" or """"""""systemic inflammatory response syndrome"""""""" without proven evidence of infection. Additionally, Secondary Efficacy Parameters shall evaluate the number of days on mechanical ventilation and/or nasal positive airway pressure, number of days on supplemental oxygen, and overall morbidity and mortality (%). A consortium of clinical centers has been formed to ensure adequate number of patients and the rate of recruitment to complete the project within 2 years from its initiation. The consortium includes the Southern Illinois University School of Medicine (St. John's Children's Hospital), The University of Louisville (Kosair Children's Hospital and the University of Louisville Hospital) and University of Southern California (Children's Hospital of Los Angeles and Hollywood Presbyterian Medical Center). Effectiveness of TLF in controlling NIs in neonates would likely find a logical extension to other populations of patients. More than 2,000,000 NIs occur each year in the USA (in infants and adults). This represents a major unmet medical need as well as a significant market. Marketing approval for TLF to treat NIs would be of great benefit to the patients and the community, and would also be of a substantial commercial value.
This proposed clinical study aims to determine the efficacy of orally administered talactoferrin (TLF, human recombinant lactoferrin) in preventing nosocomial infections (NIs) and their sequelae (such as sepsis, necrotizing enterocolitis [NEC], pneumonia, etc.) in infants born prematurely (and having a body-weight range from 750 to 1500 g). The overall incidence of prospectively studied NIs in hospitalized neonates was reported to be 10.8 NI/100 patients (Hentschel 1999). The incidence increases with decreasing birth weight, being as high as 81.8 NI/100 patients in Very Low Birth Weight group (birth weight <1500 g). Recent data from the National Institute of Child Health and Human Development-sponsored Neonatal Network indicated that 29% of infants born at 25 to 28 weeks'gestation and 46% of infants born at less than 25 weeks'gestation experience a serious NIs during hospitalization in the NICU. The most common NI were sepsis and NEC. We therefore focus development of TLF on providing a sustained way to prevent and treat consequences of NIs in infants born prematurely and weighing from 750 to 1500 g at birth. In general, morbidity and mortality from NIs is enormous. In the US, more than 2,000,000 NIs [in infants and adults] occur each year, and 50% to 60% are caused by resistant organisms (Polin 2003). Once demonstrated to be efficacious, the use of oral TLF would be readily applicable for use across the range of age and indications of hospital patients.
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