Published ahead of print on September 28, 2005, doi:10.1164/rccm.200504-656OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200504-656OC
A Randomized Double-Blind Trial of Iseganan in Prevention of Ventilator-associated PneumoniaWashington University School of Medicine, St. Louis, Missouri; University of Geneva Hospitals, Geneva, Switzerland; Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain; Hôpital Pitié-Salpêtrière, Paris, France; Hôpital Européen Georges Pompidou, Paris, France; University Medical Center, Utrecht, The Netherlands; University of Michigan Medical Center, Ann Arbor, Michigan; University of Washington, Seattle, Washington; IntraBiotics Pharmaceuticals, Inc., Mountain View, California; CHU Angers, Angers, France; Ciutat Sanitaria i Universitaria de Bellvitge, Barcelona; and Hospital Universitario Virgen de Arrixaca, Murcia, Spain Correspondence and requests for reprints should be addressed to Marin Kollef, M.D., Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8052, St. Louis, MO 63110. E-mail: mkollef{at}im.wustl.edu
Rationale: Iseganan, an antimicrobial peptide, is active against aerobic and anaerobic gram-positive and gram-negative bacteria as well as fungi and yeasts. The drug has shown little resistance in vitro and to be safe and well tolerated in 800 patients with cancer treated for up to 6 wk. Objectives: To determine the efficacy of iseganan for the prevention of ventilator-associated pneumonia (VAP). Methods: Mechanically ventilated patients in the United States and Europe were randomized to oral topical iseganan or placebo (1:1) and treated six times per day while intubated for up to 14 d. Patients were eligible if randomized within 24 h of intubation and estimated to survive and remain mechanically ventilated for 48 h or more. The primary efficacy endpoint of the study was VAP measured among survivors at Day 14. Measurements and Main Results: A total of 709 patients were randomized and received at least one dose of study drug. The two groups were comparable at baseline except iseganan-treated patients were, on average, 3 yr older. The rate of VAP among survivors at Day 14 was 16% (45/282) in patients treated with iseganan and 20% (57/284) in those treated with placebo (p = 0.145). Mortality at Day 14 was 22.1% (80/362) in the iseganan group compared with 18.2% (63/347) in the placebo group (p = 0.206). No pattern of excess adverse events in the iseganan group compared with placebo was observed. Conclusions: Iseganan is not effective in improving outcome in patients on prolonged mechanical ventilation.
Key Words: pneumonia • mechanical ventilation • prevention Ventilator-associated pneumonia (VAP) is the leading nosocomial infection in the intensive care unit (ICU) (1), ranging from 1 to more than 20 cases per 1,000 ventilator days (2). Well-controlled studies have shown that VAP is associated with increased morbidity, health care utilization, and costs (3–6). Both duration of mechanical ventilation and ICU stay are prolonged in patients who develop VAP (6). All-cause mortality of 20% has been reported in mechanically ventilated patients after approximately 2 wk in the ICU (7). In patients who develop VAP, all-cause mortality rates of 30% have been reported after 14 d in the ICU (6, 8). VAP is estimated to increase the risk of death by 20 to 30% compared with the underlying disease alone (6, 9). The pathophysiology of VAP involves aspiration of bacteria from the aerodigestive tract (10). Consequently, several randomized clinical trials have been performed to evaluate the prophylactic use of topically applied conventional antimicrobials, alone or in combination with short courses of systemic antibiotics, in prevention of VAP. The evidence from individual trials as well as meta-analyses suggests that topical antibiotic prophylaxis reduces VAP by approximately 50% without changing overall mortality (11). Concerns regarding selection and overgrowth of resistant microorganisms to the conventional antibiotics studied, the potential loss of therapeutic options if pneumonia with a resistant pathogen occurs, and the lack of a commercial formulation with a sufficient spectrum of action have limited widespread use of this approach. Protegrins are naturally occurring antimicrobial peptides that are ubiquitous in nature and an important part of host defense. Iseganan HCl is a synthetic protegrin analog that possesses a broad spectrum of activity in vitro against aerobic and anaerobic gram-positive and gram-negative bacteria and yeasts, is rapidly microbicidal in saliva, and has a low propensity for inducing resistance (12–14). The product has been evaluated in more than 800 patients with cancer for up to 6 wk and has been shown to be well tolerated and safe (15–17). In a phase IIa study involving mechanically ventilated patients, iseganan was shown to be safe and to reduce total aerobic oral flora by more than 2 logs, with cumulative decreases seen over 5 d of dosing (18). We undertook a multinational clinical trial to determine if decreases in oral flora by iseganan would translate to a reduction in pneumonia among mechanically ventilated patients who survived for up to 14 d. Some of the results of these studies have been previously reported in the form of an abstract (19).
Study Design We conducted a multinational, double-blind, randomized, placebo-controlled trial of iseganan versus placebo in intubated patients receiving mechanical ventilation for up to 14 d. The primary endpoint was the occurrence of microbiologically confirmed VAP measured among survivors up through Day 14. Secondary endpoints were VAP-free survival (VAP or death) through Day 14 and duration of parenteral antibiotic use and mechanical ventilation measured among survivors through Day 21. Two trials were expected to be conducted in support of product registration, which was agreed on through a special protocol assessment with the Food and Drug Administration; the primary efficacy analysis for registration would have been based on a pooled analysis of VAP-free survival from the two trials.
Study Organization
Patients Patients were excluded from the study for any of the following reasons: current diagnosis of pneumonia; an absolute neutrophil count less than 1,000/mm3; human immunodeficiency virus infection with a last known CD4 count of less than 500/mm3; a recipient of organ transplantation and receiving immunosuppressive therapy; current hematologic malignancy, previously documented cystic fibrosis, severe craniofacial trauma or other medical condition expected to require imminent tracheostomy, patient or patient's family or physician not in favor of aggressive medical management, presence of an advanced directive to withhold life-sustaining treatment, morbid state or expected to survive less than 21 d because of an advanced comorbid medical condition, participation in a clinical trial of any unlicensed drug or device within 30 d before the first dose of study drug, or concurrent participation in a clinical trial of any unlicensed drug or device.
Randomization and Treatment Regimens Eligible patients were consecutively randomized (1:1) to receive 3 ml iseganan oral solution (9 mg) or placebo six times per day for up to 14 d. Study drug administration was discontinued before Day 14 if the patient developed microbiologically confirmed VAP or was extubated. Before each dose of study medication, patients' mouths were rinsed with water or saline and suctioned to remove any debris. Study medication was intended to coat as much of the oropharynx and oral portions of the endotracheal tube as possible and was expected to be retained in the mouth for at least 2 min. Oral care after study drug administration was instructed to not occur within 15 min of dosing. Oral topical medications and oral rinsing were not allowed within 30 and 15 min before study drug administration, respectively. Compliance with study drug was assessed through review of documented doses administered per the patient's medical record.
Definitions and Data Collection Microbiologic specimens were obtained via bronchoalveolar lavage (BAL) (20) and sent to a central laboratory (ICON Laboratories, Dublin, Ireland) on suspicion of clinical pneumonia by the investigator and before antibiotic administration. BAL was also to be performed before the initiation of new antibiotics or the change of existing antibiotics. Clinical pneumonia was defined as new, persistent, or progressive infiltrate(s) on chest radiograph(s) consistent with pneumonia along with at least two of the three following signs: (1) temperature higher than 38.0°C (100.4°F) or lower than 35.0°C (95.2°F), (2) leukocyte count of 10,000/mm3 or greater or 4,500/mm3 or less, or (3) macroscopic appearance of purulent sputum or tracheal secretions. BAL results demonstrating 104 cfu/ml or greater confirmed pneumonia. A mini-BAL could be substituted for BAL if the patient was hemodynamically unstable or presented another contraindication for fiberoptic bronchoscopy. To characterize and quantify oral microflora, oral secretion specimens were obtained with a swab before the first dose of study drug, the last day of study drug administration, at the end of the study (Day 21), and when the patient met the criteria for clinically defined pneumonia. Oral specimens were also sent to the central laboratory for processing. All BAL and mini-BAL specimens sent to the central laboratory were to be sent within 24 h of collection and processed within 48 h of collection.
Statistical Analysis
Recruitment Between September 9, 2003, and June 22, 2004, a total of 725 patients were enrolled, of whom 371 received iseganan and 354 received placebo. Sixteen patients (nine iseganan arm, seven placebo arm) were randomized, but did not receive any study drug. Therefore, 709 patients (362 iseganan arm, 347 placebo arm) are included in the intent-to-treat analysis (Figure 1). Enrollment was stopped on June 22, 2004, before the planned goal of 900 patients was reached, after a recommendation by the DMC. The DMC based its recommendation on the interim analysis of 300 patients that showed a higher rate of VAP and mortality in the iseganan arm.
Patient Characteristics The demographic and baseline characteristics of the 709 patients are shown in Table 1. The two groups were comparable except that patients in the iseganan group were on average 3 yr older than those in the placebo group (60.5 vs. 57.7 yr). More than 80% of patients in both groups had an admitting diagnosis of nontrauma. Study drug compliance was high (91%) and did not differ between the groups.
VAP among Survivors and VAP-free Survival Data for the primary efficacy analysis of VAP among survivors and the secondary endpoint of VAP-free survival (VAP or death) are shown in Table 2 and depicted in Figure 2. There were no significant differences in the rate of VAP among survivors between patients treated with iseganan (45/282, 16%) and those treated with placebo (57/284, 20%; p = 0.145). The 95% confidence interval (CI) of the difference (iseganan–placebo) was –10.4%, 2.2%.
Mortality at Day 14 was 22.1% (80/362) in the iseganan group compared with 18.2% (63/347) in the placebo group (p = 0.206). There were 4% fewer VAP cases (14 vs. 18%) and 4% more deaths (22 vs. 18%) in the iseganan group as compared with placebo. Neither of these differences was statistically significant. VAP-free survival also did not significantly differ between the two groups. The proportion of patients who survived and developed VAP or died within the 14-d treatment period was 34.5% (125/362) and 34.6% (120/347) for iseganan-treated and placebo-treated patients, respectively (p = 0.863). Analyses adjusting for age, admission diagnosis, reason for intubation, type of intubation, and treatment did not meaningfully alter the estimates for the effect of treatment on the rate of VAP among survivors and VAP-free survival. In analyses by strata, there was a difference in the VAP among survivors rate in favor of iseganan in patients with an admitting diagnosis of trauma (iseganan: 21.4%; 12/56 vs. placebo: 34.6%; 18/52; p = 0.038), although the sample size for the trauma strata is small. In the nontrauma stratum, the rate for VAP among survivors was 14.6% (33/226) on iseganan and 16.8% (39/232) on placebo (p = 0.531). Mortality tended to be higher on iseganan in both strata (trauma relative risk, 1.49; 95% CI, 0.46–4.83; p = 0.586; nontrauma relative risk, 1.27; 95% CI, 0.86–1.88; p = 0.224).
Microbiology
Oral specimen results (end of treatment vs. baseline) were available for 281 iseganan patients and 282 placebo patients. A greater reduction in total aerobes was seen for iseganan patients compared with placebo patients (difference, –0.32 log10 cfu/ml; p = 0.04). There were no differences in reductions in total gram-negative organisms and Staphylococcus aureus between the groups.
Safety After the recommendation of the DMC to terminate the trial, data on secondary endpoints, such as days of parenteral antibiotic use and mechanical ventilation, were not collected and thus are not reported here.
Our study is the largest randomized controlled trial of VAP prevention and the first to evaluate an antimicrobial peptide as an oral decontaminant. The DMC recommended stopping the trial early because of a higher, although not statistically significant, rate of VAP and death in the iseganan arm. The DMC determined that the higher rate of VAP in the iseganan arm would be unlikely to significantly reverse with study continuation and that harm, although unlikely, could not be conclusively ruled out. This outcome was unexpected in view of the abundant prior literature on oral decontamination and given the activity of iseganan against relevant pathogens. Patients enrolled in the trial were those prospectively envisioned to benefit from oral decontamination. In designing the iseganan trial, we performed a systematic review of the literature that included both observational studies and intervention trials with similar entry criteria to the iseganan study. Based on the review, the expected rate of VAP among survivors, the study's primary endpoint, was 18.75%. The observed rate among all patients included in the trial was almost exactly as predicted, at 18%. In estimating the appropriate sample size for the study, the predicted mortality rate was particularly important. If a higher than expected mortality occurred, the power of the study would be adversely affected. The literature suggested that 20% of the patients in the placebo arm would die by Day 14. The overall mortality rate in the trial was also estimated at 20%, because iseganan was not expected to influence survival. In the trial, the 14-d mortality rate for all patients was 19%. Thus, it appears the study closely mirrored the design assumptions for these critical parameters. Reports in the literature strongly suggested that prophylaxis of pneumonia could be sufficiently addressed by oral topical administration of antibiotics. Selective decontamination of the digestive tract frequently involves nasal, gastric, and intravenous administration of antibiotics in addition to oral topical prophylaxis. In trials of oral decontamination alone, significant reductions in VAP have been seen (22–25). A relatively large, recent trial also demonstrated an additional benefit of VAP prevention; namely, reduced intravenous antibiotic use (25). Trials investigating gastric or nasal decontamination have also included an oral component, and the combination of these three topical routes has yielded similar results to trials of oral decontamination alone (26–28). Based on these data, it appears oral decontamination by itself should be adequate in preventing VAP. Numerous in vitro experiments have shown that iseganan potently kills Pseudomonas aeruginosa, methicillin-resistant S. aureus, and other common VAP pathogens (12). In multiple human trials, iseganan has been shown to reduce oral flora by two or more logs. (18, 29) In previous selective decontamination of the digestive tract trials of conventional antibiotics, reduction in colonization of pathogenic bacteria has been seen. The findings of the present study indicate that iseganan did not significantly reduce colonization of the oropharynx by common VAP pathogens. The precise relationship between colonization and the development of VAP and the effect on colonization required to prevent VAP are unknown. Although the intervention, with iseganan, was unsuccessful, the trial represents an advance in the design of studies for critically ill patients. The use of disease-free survival as an endpoint is well recognized in other fields such as cancer and heart disease and has facilitated the development of life-saving therapies for critically ill patients. In this trial, the use of VAP among survivors and VAP-free survival as primary and secondary endpoints assured that any reduction in VAP would be due to drug and not to chance. VAP-free survival also reflects the clinical goal of getting patients out of the ICU alive and free of major morbidities. Given the complexity of ICU patients, removing a single morbidity may not translate to a direct survival benefit; however, as successive morbidities are prevented or reduced, the outcome of critically ill patients may improve significantly. In summary, the topical administration of iseganan to the oropharynx of mechanically ventilated patients did not significantly reduce the incidence of VAP among surviving patients.
The POPS-1 Trial Group included the following members: I. Douglas, M.D.; A. Anzueto, M.D.; P. Dellinger, M.D.; J. Fine, M.D.; N. Namias, M.D.; S. Nelson, M.D.; H. Standiford, M.D.; F. Bosch, M.D.; T. Dormans, M.D., Ph.D.; J. G. van der Hoeven, M.D.; M. Van Iterson, M.D.; R. Wesselink, M.D.; E. Clementi, M.D.; D. Dreyfuss, M.D.; B. Dureuil, M.D.; D. Gruson, M.D.; G. Offenstadt, M.D.; L. Papazian, M.D.; B. Regnier, M.D.; C. Richard, M.D.; R. Robert, M.D.; B. Francois, M.D.; C. Martin, M.D.; R. Chiolero, M.D.; R. Zurcher-Zenklusen, M.D.; B. Quartenoud, M.D.; P. Eckert, M.D.; H. Zender, M.D.; F. Alvarez, M.D., Ph.D.; M. Alvarez, M.D.; E. Corral, M.D.; J. Garnacho, M.D.; J. Montejo, M.D., Ph.D.; M. Palomar, M.D., Ph.D.; A. Torres, M.D., Ph.D.; E. Palencia, M.D.; G. Lavery, M.D.; T. Woodcock, M.D.
Supported by IntraBiotics Pharmaceuticals, Inc., Palo Alto, California. This article has an online supplement, which is accessible from this issue's table of content online at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200504-656OC on September 28, 2005 Conflict of Interest Statement: M.K. received $7,500 from 2002 through 2004 for consultant services from Intrabiotics Pharmaceuticals, Inc. D.P. received $12,000 in 2004 for serving on the advisory board of the Seganan study of Intrabiotics Pharmaceuticals, Inc. M.S.G. received $20,000 for serving on the steering committee for this clinical trial. J.C. received $14,000 in 2003–2004 for serving on an advisory board for Intrabiotics, and has participated as a speaker in scientific meetings or courses organized and financed by various pharmaceutical companies (Astra Zeneca, Wyeth, Brahms). J.-Y.F. received $16,000 for serving on an Intrabiotics advisory board in 2003 and 2004. M.B. received $5,000 between 2002 and 2004 for serving in the steering committee of this study and received $30,000 in 2003 as an unrestricted research grant from Intrabiotics Pharmaceutical, Inc. R.H. received $25,000 from Intrabiotics for carrying out unrelated research activities. T.R.F. served as a consultant to IntraBiotics in 2002–2004 and received $30,000. H.F. for the past 3 yr has been Chief Executive Officer of IntraBiotics, which sponsored the trial that is the subject of this publication; he previously served as the company's Vice President, Clinical Affairs, and owns 2,174 shares and has options to purchase another 414,775 shares. L.B. was a consultant to Intrabiotics in 2003 and 2004. A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.-E.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form April 26, 2005; accepted in final form September 23, 2005
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ABSTRACT
METHODS
2 test. A sample size of 900 was calculated to provide 90% power assuming the following: (1) 20% of patients in the placebo group and 10% of the patients in the iseganan group develop microbiologically confirmed VAP and (2) 20% of all patients and 25% of VAP patients in each group will die by Day 14. Trial assumptions were derived from a systematic review of the literature of similar studies. The overall level of significance in the primary endpoint comparison is 0.025 two-tailed, which acknowledges the comparison of the proportion of patients who die in each group. Although it was assumed that iseganan would not affect overall survival, the 
of the study was adjusted for this additional comparison (
104 cfu/ml or mini-BAL results yielded 
