Prevention of Nosocomial Infections in Critically Ill Patients with Lactoferrin (PREVAIL) Study

Transcription

1 Prevention of Nosocomial Infections in Critically Ill Patients with Lactoferrin (PREVAIL) Study A Randomized Double Blind Phase II Study Dr. John Muscedere, Queen s University, Kingston, Canada Co-Investigators: N. O Callaghan, D. Maslove, J.G. Boyd, X. Jiang, S. Reynolds, M. Albert, R. Hall, A. Day, F. Lamontagne

2 Acknowledgements Study Funding: Lotte & John Hecht Memorial Foundation SEAMO Innovation Fund Lactoferrin provided by Advanced Orthomolecular Research Conflicts of Interest Consultant with Poly-Phor Pharma

3 The Problem: Nosocomial Infections in the ICU Frequency: 15 25% of ICU patients will develop a nosocomial infection (NI) One of most common/serious: Pneumonia, Resp. Tract Infections NIs associated with increased morbidity, mortality and health care costs Most at risk: mechanically ventilated patients Cause: Oropharyngeal-gastric colonization, instrumentation, immunosuppression Need: better preventive strategies, therapies Lactoferrin:?utility for NIs

4 Lactoferrin Iron binding glycoprotein (about 80 kda): transferrin family of proteins Fe depleted and Fe replete forms - depleted form most biologically active Widely conserved among mammalian species Present in most human secretions Breast milk, colostrum (3 7 mg/ml), tears, vaginal, saliva, respiratory Wide range of biological activity Contributes to host defenses both systematically and at mucosal surfaces Antimicrobial activity Immunological activity

5 Lactoferrin - Biological activity Lactoferrin 5

6 Lactoferrin- Antimicrobial activity Antimicrobial activity Lactoferrin is released from neutrophil specific granules at areas of inflammation. Both bactericidal and bacteriostatic properties Mechanism Binds Fe (essential to microbial growth) Destabilizes outer membrane of gram negative bacteria Effect demonstrated against E. coli, S. aureus, P. aeruginosa Can enhance the MIC and MBC of some antibiotics Antifungal activity- activity against Candida 6

7 Lactoferrin- Biological activity The effects of Lactoferrin (LF) on P. aeruginosa biofilm formation Left image: Without LF cells congregate. Right image: With LF cells do not congregate. Reduced biofilm with increasing LF concetrations 7 O May, J Med Micro 2009

8 Lactoferrin- Effect on GI Flora Beneficial Effects on GI flora Lactoferrin promotes growth of bifidobacteria- gram +ve, anaerobic Effect of Lactobacillus (LGG), Lactoferrin (LF) on growth of enteroinvasive E. Coli 8 Kim, Biometals 2004 Sherman, Biometals 2004

9 Human Evidence Helicobacter Pylori eradication: Adjunct to antibiotic therapy 9 RCTs, 1343 pts, OR of eradication: 2.26 Prevention of neonatal sepsis 321 Neonates: blf vs. control blf associated with reduced sepsis, fungal infections and trend towards reduced mortality ELFIN trial: 2203 neonates enrolled- Completed enrollment Zou, Helicobacter 2009 Manzoni, JAMA

10 Human Evidence Two phase 2 studies conducted of human recombinant Lactoferrin for the treatment of severe sepsis Vincent JL, CCM 2015 Guntupalli K, CCM 2013

11 Program of Research RESEARCH QUESTION: Does Lactoferrin decrease the incidence of nosocomially acquired infections and improve clinical outcomes in mechanically ventilated patients? Pre-clinical Proof of Concept Final Scoping review (including preclinical studies) Phase 2 Study Definitive study

12 PREVAIL PHASE 2 STUDY DESIGN Prevention of Nosocomial Infections in critically ill patients with Lactoferrin (PREVAIL Study) Double-blind, placebo-controlled Randomized 1:1 to receive either bovine Lactoferrin (blf) or placebo in addition to standard care blf delivered to oropharynx and nasogastrically Active Treatment Period up to 28 days or ICU discharge Long-Term Follow-up Period 90 days Multi-center- 6 centers Muscedere et al. PREVAIL Protocol, Trials 2017

13 Endpoints For Phase 2 Study Primary Antibiotic Free Days Days alive and antibiotic free in the 28 days post randomization Powered to detect a 25% increase in antibiotic free days with 210 patients Feasibility Metrics Recruitment rate Secondary: Clinical Outcomes Nosocomial infections, LOS, MV duration, morbidity, mortality up to 90 days Study not powered to detect differences in clinical outcomes

14 Endpoints For Phase 2 Study Measures of biological activity. 1. Microbiological Tracheal Colonization serial cultures (Baseline, 3, 7, 14, 21, 28 days) 2. Systemic Inflammation Biomarkers (PCT, IL-6, IL-10, CRP etc.)- Multiplex 17 (Baseline, 3, 7, 14, 21, 28 days) 3. Immune Function Ex-vivo LPS stimulation assay 4. Gene Expression

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

16 Exclusion Criteria 1. Patients not expected to be in ICU 72 hours after randomization. 2. Contra-indication to enteral feeding. 3. Lack of access to the oral cavity. 4. Allergy or sensitivity to Lactoferrin, bovine derived proteins/bovine milk 5. Immunocompromised patients 6. Patients with fulminant liver failure or end stage liver disease (Child s Class C) 7. Life expectancy, due to pre-existing conditions, less than six months. 8. Requirement for chronic antibiotic therapy (endocarditis, osteomyelitis) 9. Women who are pregnant or lactating. 10. Enrolment in industry sponsored interventional trial (co-enrolment in academic studies allowed if there was no potential interaction between the protocols). 11. Prior randomization in this study.

17 Trial Procedures blf dissolved in water given orally as part of an oral care regimen and through a nasogastric tube. Total dose 2 g/day in 200 ml H 2 O given as 50 ml QID 15 cc (150 mg) used for oral care 35 cc (350 mg) given through the nasogastric tube. Blinding procedure- opaque syringes, pharmacist All potential infections underwent blinded review and adjudication

18 Consort Diagram

19 Baseline Characteristics

20 Primary Outcomes 28 day antibiotic free days (alive and off antibiotics in the 28 days after enrollment) Average enrollment (per site) n = 6 sites Placebo (n=105) Lactoferrin (n=107) p value 18.5 ± ± * 0.67 patients per week *Non-parametric test (i.e., Mann Whitney U test) was used for a more conservative estimate of p value.

21 Clinical Outcomes Placebo (n=105) Lactoferrin (n=107) p value Patients with suspicion of nosocomial infection: n (%) 58 (55.2%) 60 (56.1%) 0.90 Nosocomial Infections per patient: n (SD) 0.4± ± Pneumonia: n ICU LOS: days (SD) 15.0 ± ± Hospital LOS: days (SD) 28.1 ± ± Duration of Mechanical 8.1 ± ± Ventilation: days (SD) Duration of Vasopressor Usage: days (SD) 2.7 ± ± ICU Mortality: n (%) 30 (28.6 %) 39 (36.4%) 0.22 Hospital Mortality: n (%) 32 (30.5 %) 44 (41.1%) Day Mortality: n (%) 34 (32.4 %) 48 (44.9%) 0.06

22 Subgroup analysis: 90 day mortality Placebo Lactoferrin

23 Bioplex values Cytokines Comparing 4 groups: p< No significant difference in ex-vivo LPS stimulation TNFa-single plex-arm A TNFa-single plex-arm B TNFa-single plex LPS-Arm A TNFa-single plex LPS-Arm B Base D4 D7 D14 D21 D28

24 Cytokines No significant differences in any measured cytokine

25 Gene Expression

26 Gene Expression

27 Gene Expression: Differentially expressed pathways (early vs. late)

28 Conclusion The utilization of Lactoferrin for the prevention of nosocomial infections did not increase antibiotic free days Enrollment targets met pre-defined thresholds There was no evidence of efficacy based on clinical outcomes, biomarkers or immunological function Gene expression data supports biological activity Our data does not support the conduct of a large scale phase 3 randomized controlled trial powered on clinically important outcomes.

29 Thank You Questions?

30 Mortality