Prevention of Nosocomial Infections in Critically Ill Patients With Lactoferrin: The PREVAIL Study (PREVAIL)

A Phase 2 Randomized Controlled Trial to Determine the Efficacy of Lactoferrin for the Prevention of Nosocomial Infections.

Lactoferrin is a protein that is a component of the immune system. It has many properties that could make it the ideal agent for the prevention of hospital-acquired infections. Lactoferrin has antibacterial properties (is able to kill or stop the growth of disease causing bacteria and fungal organisms), it improves immune function, and can increase the growth of beneficial bacteria in the bowel. Lactoferrin has been approved by Health Canada as a Natural Health product and is sold in health food stores as a supplement. However, given the potential beneficial effects of Lactoferrin, it requires further study as to its effects in acutely and seriously ill patients. One potential use which has not been studied is for the prevention of infections in critically adult ill patients. The aim of this study is to determine the utility of Lactoferrin in this patient population.

The Lactoferrin that the investigators will be using in this study is extracted from cow's milk, where it naturally occurs. Cow lactoferrin has similar properties as that normally produced in the human body. This study is being conducted to determine how well a solution of Lactoferrin given orally and through a feeding tube helps to prevent infections and inflammation in critically ill patients in addition to usual care and other measures that are known to be partially effective for the prevention of infections.

Study Overview

• Status: Completed
• Conditions: Critically Ill
• Intervention / Treatment: Dietary supplement: Lactoferrin; Other: Placebo

Detailed Description

Hypothesis/Objectives

Nosocomial infections are common in critically ill, mechanically ventilated patients and remain a source of morbidity and mortality in this vulnerable patient population. Multiple potential etiologies for the increased susceptibility to nosocomial infections have been posited including instrumentation for monitoring and treatment, alterations of immunological function, replacement of normal gastro-intestinal (GI) flora with pathogens and increased permeability of bowel mucosa. Current preventive measures are only partially effective but the most studied and most efficacious preventive measure for nosocomial infections is selective decontamination of the digestive tract (SDD) with antimicrobial therapy although it is rarely used secondary to concerns over the development of antimicrobial resistance. There is a need to study and utilize novel measures for SDD which maintain the benefits of SDD but minimize the negative consequences of increased antibiotic use driving antimicrobial resistance. Lactoferrin, a molecule which is part of the innate immune system has many properties that would make it the ideal agent for the prevention of nosocomial infections. It maintains GI integrity, has antibacterial properties, improves immune function, and has beneficial effects on the bacterial flora in the GI tract. As a result, the overall hypotheses and objectives of this research program are as follows:

OVERALL HYPOTHESIS: The administration of oral and nasogastric Lactoferrin to critically ill mechanically ventilated patients will reduce nosocomial infections, reduce antibiotic usage, result in improved outcomes and improve survival.

HYPOTHESIS for PHASE 2 Study: A Phase 2 randomized controlled trial to determine the effectiveness of Lactoferrin for the prevention of nosocomial infections will demonstrate that the utilization of Lactoferrin results in increased antibiotic free days and is supported by the biomarker and mechanistic data obtained.

OBJECTIVES:

1. Objective 1: The primary objective of this Phase 2, multicenter, randomized controlled trial (RCT) is to determine the effect of Lactoferrin on antibiotic free days. These data will inform a future large scale Phase 3 RCT powered on clinically important outcomes such as mortality.
2. Objective 2: The second objective will be to assess the feasibility of conducting a future large scale Phase 3 RCT powered on clinically important outcomes.
3. Objective 3: To obtain information on the effect of Lactoferrin on clinical outcomes including antibiotic utilization, nosocomial infections, length of stay, measures of organ dysfunction and mortality. This study will not be powered for the detection of clinically important differences but will inform power calculations for the definitive Phase 3 trial.
4. Objective 4: To determine the effect of treatment with Lactoferrin on inflammatory biomarkers, immunological function, gastro-intestinal integrity and tracheal colonization.

• Study Type: Interventional
• Enrollment (Actual): 214
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult patients (>18 years old)
2. Duration of mechanical ventilation < 48 hours and
3. Expected duration of mechanically ventilation > 72 hours.

Exclusion Criteria:

1. Patients not expected to be in ICU for more than 72 hours from time of randomization (due to imminent death, withdrawal of aggressive care or discharge).
2. The presence of a contra-indication to enteral feeding.
3. Lack of access to the oral cavity.
4. Allergy or sensitivity to Lactoferrin or bovine derived proteins or bovine milk
5. Immunocompromised patients (post-organ transplantation, Acquired Immunodeficiency Syndrome [AIDS], neutropenia [<1000 absolute neutrophils], corticosteroids [>20 mgs/day of prednisone or equivalent for more than 6 months])
6. Patients with fulminant liver failure or end stage liver disease (Child's Class C)
7. Life expectancy, due to pre-existing conditions such as cancer, is less than six months.
8. Women who are pregnant or lactating.
9. Enrollment in industry sponsored interventional trial (co-enrollment in other academic studies would be allowed with the proviso that there was no potential interaction between the protocols).
10. Prior randomization in this study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lactoferrin; Patients randomized to the Lactoferrin arm will receive Lactoferrin delivered to the oral cavity as a mouth swab and Lactoferrin down a nasogastric tube; a total of 2 grams administered in 4 divided doses per day.	Dietary supplement: Lactoferrin; Lactoferrin is an 80 kilodalton (kD) naturally occurring multifunctional glycoprotein of the transferrin family which is an important component of the human innate immune system. Lactoferrin is distributed widely in humans with the main sources of production being exocrine glands and specific granules of neutrophils. It is present in virtually all human secretions. The highest concentrations are found in milk and colostrum. Lactoferrin has multiple biological functions which make it of interest as a therapeutic agent in the critically ill. These include the ability to bind iron, antimicrobial activity including antibacterial, antifungal, antiviral properties, the ability to bind endotoxin, promotion of beneficial bacteria in the gastro-intestinal tract and immunomodulatory activity.
Placebo Comparator: Placebo (sterile water); Placebo (sterile water) will also be delivered down the nasogastric tube; administered in 4 divided doses per day.	Other: Placebo; Sterile water will be utilized as the placebo control in this double blind randomized-controlled trial.; Other Names: Sterile water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antibiotic free days.	Alive and free of antibiotics in the 28 days after study enrollment. These data will inform a future large scale Phase 3 RCT powered on clinically important outcomes such as mortality.	28 Days after study enrollment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of conducting a Phase 3 study powered on clinically important outcomes such as mortality, length of stay and duration of mechanical ventilation.	Feasibility will be assessed on recruitment rates and acceptability/adherence to the study protocol.	90 days post study enrollment.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurence of nosocomial infections.	All nosocomial infections occuring 72 hours after ICU admission. This study is not powered for this outcome but will inform sample calculations for the definitive Phase 3 trial.	28 days post study enrollment.
Immunological competence.	Immunological function will be assessed with an ex-vivo Lipopolysaccharide stimulation assay.	Baseline, Day 7, 14, 21 or 28 post study enrollment or ICU discharge.

Collaborators and Investigators

• Sponsor: Queen's University
• Investigators: Principal Investigator: John G Muscedere, MD, Queen's University, Kingston General Hosptial

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): September 12, 2016
• Study Completion (Actual): September 12, 2016

Study Registration Dates

• First Submitted: November 18, 2013
• First Submitted That Met QC Criteria: November 21, 2013
• First Posted (Estimate): November 27, 2013

Study Record Updates

• Last Update Posted (Actual): February 20, 2017
• Last Update Submitted That Met QC Criteria: February 17, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: lactoferrin; Critically Ill; Intensive care; Nasogastric tube; Orogastric tube; mechanically ventilated; nosocomially acquired infections; length of stay; placebo controlled; antibiotic free days
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Iatrogenic Disease; Infections; Critical Illness; Cross Infection; Anti-Infective Agents; Lactoferrin
• Other Study ID Numbers: DMED-1569-13

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Upon request only

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