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Antimicrobial Agents and Chemotherapy, August 2006, p. 2751-2755, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00096-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phase II, Randomized, Double-Blind, Multicenter Study Comparing the Safety and Pharmacokinetics of Tefibazumab to Placebo for Treatment of Staphylococcus aureus Bacteremia

J. John Weems Jr.,¹ James P. Steinberg,^2, Scott Filler,³ John W. Baddley,⁴ G. Ralph Corey,⁵ Priya Sampathkumar,⁶ Lisa Winston,⁷ Joseph F. John,⁸ Christine J. Kubin,⁹ Rohit Talwani,¹⁰ Thomas Moore,^11, Joseph M. Patti,¹² Seth Hetherington,^12* Michele Texter,¹² Eric Wenzel,¹² Violet A. Kelley,¹² and Vance G. Fowler Jr.⁵

Greenville Hospital System University Medical Center, Greenville, South Carolina,¹ Emory University, Atlanta, Georgia,² Harbor-UCLA Medical Center, Torrance, California,³ UAB, Birmingham, Alabama,⁴ DUMC, Durham, North Carolina,⁵ Mayo Clinic, Rochester, Minnesota,⁶ University of California San Francisco, San Francisco, California,⁷ VAMC Charleston, Charleston, South Carolina,⁸ Columbia University, New York, New York,⁹ Palmetto Health, Columbia, South Carolina,¹⁰ Privia, The Research Centers of Via Christi, Wichita, Kansas,¹¹ Inhibitex, Alpharetta, Georgia,¹²

Received 23 January 2006/ Returned for modification 24 February 2006/ Accepted 15 May 2006

	ABSTRACT

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Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 µg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.

	INTRODUCTION

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Staphylococcus aureus is a leading cause of healthcare-associated and community-onset bacteremia in the United States and abroad (15, 23, 24). A recent study showed that S. aureus infection was reported as a discharge diagnosis for 0.8% of all hospital inpatients, or an average of 292,045 inpatients per year (19). Infections caused by methicillin-resistant S. aureus (MRSA) in hospitalized patients as well as in otherwise healthy patients with no obvious risk factors are an emerging problem (3, 8, 18). Current therapy for S. aureus bacteremia (SAB), particularly for MRSA bacteremia, is less than adequate. This fact is supported by the high rates of complications, including mortality, relapsing infection, and metastatic infections (infective endocarditis, bone and joint infections, and suppurative abscesses), associated with SAB (1, 2, 6, 7, 11, 14, 22). Taken together, these observations indicate that novel therapies for SAB are urgently needed.

One potential strategy to improve clinical outcomes of SAB is adjunctive therapy using passive immunization with monoclonal antibodies that target S. aureus. Tefibazumab (Aurexis) is a humanized immunoglobulin G1 monoclonal antibody that specifically recognizes clumping factor A (ClfA) with a high affinity. ClfA, a surface adhesin protein found on virtually all strains of S. aureus, is an MSCRAMM (microbial surface components recognizing adhesive matrix molecules) protein that mediates the adhesion of S. aureus to fibrinogen (10, 16, 17). In preclinical animal studies of MRSA bacteremia, prophylactic administration with the anti-ClfA monoclonal antibody was protective in mice against sepsis-induced mortality (10). Additionally, in a rabbit model of established MRSA infective endocarditis, tefibazumab therapy enhanced the efficacy of vancomycin by reducing the levels of S. aureus in the blood, vegetations, and organs (5). In a phase I study of healthy subjects, a dose of 20 mg/kg of body weight maintained plasma levels of tefibazumab above 100 µg/ml, a concentration associated with maximal efficacy in animal models, for up to 21 days (5, 20). In this study, we report the safety and pharmacokinetics of tefibazumab and present a preliminary evaluation of its biologic activity in patients with documented SAB.

(These data were presented at the 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., 16 to 19 December 2005 [J. Weems, J. Steinberg, S. Filler, J. Baddley, S. Hetherington, and V. Fowler, Abstr. 45th Intersci. Conf. Antimicrob. Agents Chemother., abstr. K-425, 2005].)

	MATERIALS AND METHODS

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Study population. Adult patients of 18 years of age with a positive blood culture for S. aureus obtained 72 h prior to initiation of study drug (tefibazumab or placebo) infusion were eligible to participate in this clinical trial. Written informed consent was obtained from each patient or legal guardian. Patients were excluded if they were pregnant or nursing, had polymicrobial bacteremia, had a diagnosis of septic shock, had neutropenia (absolute neutrophil count of 500/mm³), were undergoing any type of dialysis or expected to start dialysis within 30 days, were in a moribund clinical condition with a high likelihood of death within 72 h of randomization, had received an investigational drug within 30 days of study entry, or were considered unlikely to comply with the study procedures or to return for scheduled posttreatment evaluations.

Study design and assessments. This study was a randomized, double-blind, placebo-controlled, multicenter phase II clinical trial evaluating the safety, pharmacokinetics, and activity of a single 20-mg/kg dose of tefibazumab, in addition to antibiotics, in patients hospitalized with documented SAB. The study was conducted at 11 centers in the United States. Enrollment occurred from February 2004 through February 2005. The protocol, study design, and consent forms were approved by the institutional review board at each participating institution. This study was conducted according to the guidelines of good clinical practice, as established by the International Conference on Harmonization (http://www.fda.gov/cder/guidance/959fnl.pdf). An independent data safety monitoring board reviewed data on adverse events and data pertaining to S. aureus infections at predefined intervals.

Patients were stratified by SAB association (i.e., healthcare-associated SAB or non-healthcare-associated SAB), since it was expected that event rates would differ in each population. Subjects were then randomized to receive either tefibazumab at 20 mg/kg plus antibiotics or placebo (0.9% saline) plus antibiotics (7, 9, 11). Antibiotic selection and duration were left to the discretion of the managing clinicians. At baseline, demographic information was collected, and comorbidities associated with the risk for SAB, including alcohol abuse, chronic renal failure, diabetes, inhaled or injected drug use, health care worker status (yes/no), hematological malignancy, human immunodeficiency virus/AIDS, liver disease, neutropenia, nonhematological malignancy, skin disease (excluding wound infection), steroid use, or valvular heart disease, were noted. On day 1, the study drug was administered intravenously for 30 min. Patients were monitored closely during infusion, with the infusion being discontinued permanently upon any signs of anaphylaxis. Adverse events were graded by the investigator as mild, moderate, or severe. Serious adverse events were defined according to the criteria of the International Conference on Harmonization (www.fda.gov/medwatch/report/iche2a.pdf). Throughout the study, safety was also monitored via clinical laboratory measurements and vital sign assessments. Immunogenicity (anti-tefibazumab antibodies) was monitored by an enzyme-linked immunosorbent assay. Blood cultures were obtained daily until they were negative. Nasal cultures for colonization were obtained at study entry and at study day 57 (end of study).

The primary end point for biologic activity was a composite clinical end point (CCE), defined as the occurrence of at least one of the following: development of an SAB-related complication not present at baseline; a microbiologically documented relapse of SAB, defined as having a positive S. aureus blood culture following both the completion of initial antibiotic therapy and at least one negative blood culture for S. aureus; or death. Endocarditis was defined according to the modified Duke criteria (13). Newly onset complications were defined by prespecified clinical features and microbiologic or radiologic evidence. Secondary end points included the development or worsening of sepsis, categorized as sepsis, severe sepsis, or septic shock; time to achieve a negative blood culture; time to defervescence (defined as the first 24-h period with a temperature no greater than 38°C); number of days in the hospital and the intensive care unit (ICU); and number of days requiring mechanical ventilation (12).

Pharmacokinetic analysis. Pharmacokinetic samples were taken from the first 30 consecutive patients enrolled in the study to ensure analyses for approximately 15 patients. Seventeen of these patients received a complete dose of tefibazumab and had a sufficient number of samples available for analysis. All pharmacokinetic assays were performed at Inhibitex, Inc. (Alpharetta, GA). The samples were collected within 30 min prior to infusion of the study drug and then 1, 6, 12, and 24 h after infusion and on study days 3, 4, 15, 29, and 57. An enzyme-linked immunosorbent assay was used to determine the concentration of tefibazumab in the blood (20). Pharmacokinetic analyses were performed using a noncompartmental model.

Statistical analysis. The sample size of 60 patients was selected to provide sufficient data for pharmacokinetic analyses, give an initial evaluation of the safety of tefibazumab among patients with active infections, and estimate the numbers of events, as defined by the CCE, over the total population. The results would provide guidance in designing future larger trials but would not necessarily define a treatment effect in the current study. A sample size of 30 patients in each group provided 28% power to detect a 50% relative difference in frequencies of the clinical end point between treatments, using a two-sided chi-square test at an alpha level of 0.05. A Mantel-Haenszel ² test stratified by healthcare association compared the proportions of patients reaching the composite clinical end point with a two-sided alpha level of 0.05.

Data were analyzed using a modified intent-to-treat population, defined as all patients receiving any study drug (tefibazumab or placebo). Comparisons between treatment groups of the proportions of patients with worsening of sepsis from baseline, days in the hospital and/or ICU, and days on mechanical ventilation were performed with a Mantel-Haenszel ² test stratified by healthcare association. Differences between treatment groups in the time to a negative blood culture and time to defervescence were evaluated with a log rank test.

Trial registry. This study is registered at www.clinicaltrials.gov under registration number NCT00198302.

	RESULTS

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Study population. A total of 63 patients were randomized. Thirty patients received at least a partial dose of tefibazumab, and 30 patients received placebo. Three patients did not receive any study drug; two withdrew consent, and one no longer met the inclusion criteria. A total of 52 patients (87%) completed the study through 8 weeks. Eight patients did not complete the study; of these, five died prior to study completion, and three did not complete the final study visit but were alive at 8 weeks. All data available prior to early discontinuation were included in the analyses.

Baseline characteristics were similar across the treatment groups (Table 1). The mean time between blood culture and infusion of the study drug was 63 h. Only six (10%) patients continued to have positive blood cultures at randomization. Sixteen (53%) patients in the tefibazumab group and 22 (73%) patients in the placebo group were still febrile at randomization (P = 0.117). A total of 47% of initial blood isolates were MRSA, including 11 (37%) isolates from the tefibazumab group and 17 (57%) isolates from the placebo group (P = 0.12). S. aureus was present in the nares of 10 placebo patients and 14 tefibazumab patients. In each group, seven isolates were MRSA.

Safety. The most frequently reported adverse events were hypokalemia, diarrhea, anemia, and insomnia, with no significant differences across the treatment groups (Table 3). Skin reactions (local or generalized), with no relationship to the study drug and occurring at any time during the study, were more common among patients who received tefibazumab than among those who received placebo. Ten patients (33%) in the tefibazumab group reported 13 local or generalized skin reactions (including dermatitis medicamentosa, pruritis, catheter-site phlebitis, rash, and erythema and excluding hypersensitivity [see below]), compared to three events among three patients (10%) in the placebo group. Four of these events among patients randomized to receive tefibazumab were considered possibly related to study treatment by the investigators, compared to none of the events among patients randomized to receive placebo. The time intervals between administration of the study drug and onset of the reported skin reactions varied considerably. None of these events led to interruption of study drug infusion or discontinuation in the study.

View this table: [in this window] [in a new window]   TABLE 3. Adverse events that occurred in 10% of patients

Pharmacokinetics. Pharmacokinetics were assessed in 17 patients. Tefibazumab exhibited first-order kinetics (Fig. 1). The mean plasma ß-phase half-life (± standard deviation [SD]) of tefibazumab was 18.4 ± 6.9 days. The mean volume (±SD) of distribution was 4,961.1 ± 1,597.9 ml, and the mean clearance (±SD) was 17.6 ± 6.6 ml/hour. By study day 15, the mean (±SD) concentration of tefibazumab was 83.5 ± 34.5 µg/ml, with a range of 37.7 to 161.4 µg/ml, and 12 of 17 patients had levels of <100 µg/ml. Notably, the single patient who developed a documented microbiological relapse (by study day 22) had the lowest measured concentration of tefibazumab at day 15 (37.7 µg/ml).

View larger version (8K): [in this window] [in a new window]   FIG. 1. Mean plasma concentrations over time in 17 patients infused with tefibazumab at a dose of 20 mg/kg. Error bars represent 1 standard deviation.

No patients in the tefibazumab group progressed in the severity of sepsis at any time during the study. In the placebo group, two patients developed sepsis and one patient each developed severe sepsis and septic shock (P = 0.112). There were no differences between treatment groups in numbers of days until negative blood culture, numbers of days to defervescence, or total numbers of hospital days. Among a subset of patients who spent at least 1 day in the ICU, those in the tefibazumab group spent fewer days in the ICU than those in the placebo group (6.9 versus 11.6 days). Among those who were on mechanical ventilation for at least 1 day, patients in the tefibazumab group had a greater number of days on mechanical ventilation than those in the placebo group (10.4 versus 5.3 days, respectively). None of these differences was statistically significant.

A total of 43 patients (24 tefibazumab and 19 placebo patients) had paired nasal culture results from the beginning and end of the study. Of 11 patients in the tefibazumab group with a positive nasal culture for S. aureus at baseline, 8 (73%) had a negative culture at the end of the study, compared to 3 of 6 (50%) in the placebo group. Of 13 patients in the tefibazumab group with a negative nasal culture at baseline, 1 (8%) was positive at the end of the study, compared to 3 of 13 (31%) in the placebo group.

	DISCUSSION

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The goals of this clinical trial were to evaluate the safety and pharmacokinetics of tefibazumab at 20 mg/kg and to provide preliminary evidence of its biologic activity in patients with SAB. Although the trial was not designed to demonstrate statistically significant differences in efficacy between treatment arms, there is sufficient evidence to warrant further study in a larger trial.

The safety data from this clinical trial support continued clinical development. As expected for a group of patients with SAB, nearly all experienced at least one adverse event. The majority were attributed to the patients' underlying health conditions and were not considered related to the study drug. With the exception of mild to moderate cutaneous reactions, the adverse event profiles were similar between the placebo and tefibazumab groups. One patient in the tefibazumab group experienced a classic hypersensitivity reaction. Allergic reactions are known to occur with other monoclonal antibody products (4, 21). One serious adverse event of renal failure was considered possibly related to tefibazumab, but this complication may have been due to other causes. The broader analysis of renal system-related events by treatment group did not reveal a pattern of adverse events within this organ system.

The half-life of tefibazumab in patients with SAB was similar to that reported for healthy subjects and subjects with end-stage renal disease (ESRD) requiring hemodialysis (20). Pharmacokinetic differences between the infected population in this study and noninfected populations include a wider range of plasma levels of the drug, increased clearance rates, and larger volumes of distribution. The failure of the infected population in this study to maintain a plasma level of 100 µg/ml at day 21 (a concentration associated with maximal efficacy in animal models) was likely due to their increased clearance rates and larger volumes of distribution at steady state (5). The increased clearance may have been due to the heavier mean weight of the patients in this study (89.2 ± 21.69 kg) than the approximate mean weight of 75 kg of patients in the previous studies.

In this trial, activity was assessed via a CCE and secondary end points. No significant differences related to activity were noted. More patients in the placebo group reached a CCE than did patients in the tefibazumab group. Specifically, there were more deaths in the placebo group than in the tefibazumab group, but the difference was not statistically significant. Only one death (in the placebo group) was directly attributable to SAB. Although there was a higher rate of MRSA infections noted in the placebo group, this did not account for the larger number of patients reaching a CCE. Of the six patients reaching a CCE, two (both in the placebo group) had MRSA infections. All others had MSSA infections. The secondary measures of biologic activity also favored the tefibazumab group. More patients in the placebo group than in the tefibazumab group progressed in severity of sepsis. Additionally, it was found that of the patients who were nasally colonized with S. aureus at baseline, fewer tefibazumab-treated patients remained colonized at the end of the study than placebo-treated patients, and fewer noncolonized patients in the tefibazumab group became colonized by the end of the study. The clinical significance of this finding is unknown.

Considerations for future trials include optimization of the dosing strategy to maintain plasma levels of 100 µg/ml for 21 days in the majority of subjects, in addition to including a patient population expected to achieve a higher event rate. In the current trial, the lower-than-anticipated number of observed events may be due to differences in our patient population from those previously described. In this study, the average APACHE II score was 8.6, only a single SAB relapse was documented (1.7%), and the overall mortality rate was low, at 8%. In contrast, in a study by Fowler et al., the mean APACHE II score of patients with SAB was 15.4, and the overall mortality rate was 22% (7). Similarly, in a report by Jensen et al., the overall mortality rate for patients with SAB was 34%, with a relapse rate of 12% (11). The differences may be a consequence of excluding patients with ESRD and/or septic shock from this study. Lastly, to ensure that significant end points are accurately determined, future trials should include a blinded end-point adjudication committee.

Several limitations in this study should be noted with respect to outcomes. Differences in baseline characteristics, although not statistically significant, make outcome analysis difficult and are a limitation of the study. Adjunctive treatments, such as surgery and timing of catheter removal, were not captured or analyzed. In addition, antibiotic usage was not standardized in the protocol, but antimicrobial therapy was appropriate for nearly all patients. Because ESRD patients on hemodialysis and patients with septic shock at baseline were not included, the results of this study cannot be generalized to all patients who develop SAB.

In conclusion, the safety profile and preliminary clinical data justify a larger, well-controlled trial to assess the efficacy of this novel approach using passive immunization against specific staphylococcal adhesins for the treatment of SAB.

	ACKNOWLEDGMENTS

 
This research was funded by Inhibitex, Inc., and the manuscript was prepared in conjunction with Inhibitex, Inc. The following authors are employees of the sponsoring company, Inhibitex, Inc.: Joseph M. Patti, Seth Hetherington, Michele Texter, Eric Wenzel, and Violet A. Kelley. The authors received financial support in the context of study recruitment and management.

We specifically acknowledge Barry Kapik for statistical support and Amy Burdan for medical writing assistance in preparing the manuscript.

	FOOTNOTES

 
* Corresponding author. Mailing address: Inhibitex, 9005 Westside Parkway, Alpharetta, GA 30004. Phone: (678) 746-1101. Fax: (678) 746-0615. E-mail: shetherington{at}inhibitex.com.

Present address: Emory Crawford Long Hospital, Atlanta, GA 30308.

Present address: Department of Medicine, University of Kansas School of Medicine—Wichita Campus, Wichita, KS 67214-2878.

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