Telavancin for Acute Bacterial Skin and Skin Structure Infections, a Post Hoc Analysis of the Phase 3 ATLAS Trials in Light of the 2013 FDA Guidance

Abstract

Two phase 3 ATLAS trials demonstrated noninferiority of telavancin compared with vancomycin for complicated skin and skin structure infections. Data from these trials were retrospectively evaluated according to 2013 U.S. Food and Drug Administration (FDA) guidance on acute bacterial skin and skin structure infections. This post hoc analysis included patients with lesion sizes of ≥75 cm² and excluded patients with ulcers or burns (updated all-treated population; n = 1,127). Updated day 3 (early) clinical response was defined as a ≥20% reduction in lesion size from baseline and no rescue antibiotic. Updated test-of-cure (TOC) clinical response was defined as a ≥90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively (difference, 1.7%, with a 95% confidence interval [CI] of −4.0% to 7.4%). Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, −0.7% to 10.3%). Adopting current FDA guidance, this analysis corroborates previous noninferiority findings of the ATLAS trials of telavancin compared with vancomycin.

INTRODUCTION

Telavancin is an intravenous lipoglycopeptide antibacterial agent exhibiting concentration-dependent bactericidal effects against many Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA), via a dual mechanism of action that combines inhibition of cell wall synthesis and disruption of membrane barrier function (1, 2). Telavancin is active against vancomycin-intermediate strains of S. aureus as well as heteroresistant strains (3, 4). Based on the results of two large, randomized, double-blind phase 3 trials (the Assessment of Telavancin in Complicated Skin and Skin Structure Infections [ATLAS] studies) (5), telavancin is approved in the United States and Canada for the treatment of adult patients with complicated skin and skin structure infections (cSSSI) due to susceptible Gram-positive pathogens (6, 7).

The U.S. Food and Drug Administration (FDA) issues guidance documents for developing drugs for specific indications, which provide recommendations for study design, inclusion and exclusion criteria, clinical endpoints, and statistical considerations. The guidance for evaluating acute bacterial skin and skin structure infections (ABSSSI) at the time of the telavancin phase 3 ABSSSI studies was dated from 1998 (8). The FDA updated and finalized a new guidance in October 2013 that reflects the agency's current thinking regarding the development of antibiotics for the treatment of ABSSSI (9). The most relevant changes in the new guidance include a minimum lesion area of 75 cm², exclusion of ulcers and burns, and use of an earlier primary endpoint (clinical response at 48 to 72 h of therapy) as opposed to cure rates at test-of-cure (TOC) visit, 7 to 14 days after the last dose of study medication in the original ATLAS analysis (9).

The original analysis of the ATLAS studies, according to the previous FDA guidance, demonstrated noninferiority of telavancin (10 mg/kg once daily) compared with vancomycin (1 g every 12 h; dosage adjusted per local site standards) for the treatment of patients with ABSSSI. This reanalysis of the ATLAS studies evaluated whether telavancin is at least as effective as vancomycin for the treatment of patients with ABSSSI according to the revised definition and the new primary endpoint, as outlined in the current (2013) FDA guidance.

MATERIALS AND METHODS

A post hoc analysis of the original data set was performed using the locked database from the ATLAS new drug application (NDA) submission. The selection of patients for inclusion for the purposes of the reanalysis was done programmatically by the Biometrics Department at Theravance Biophama US, Inc., to include patients who had a minimum lesion area of 75 cm² at baseline (except for those with ulcers and burns) and a postbaseline measurement at day 3 or the TOC visit. Analysis of clinical response rate was identical to that performed for the primary efficacy endpoint in the ATLAS NDA submission. Revised data sets and tabular summaries were available to all authors.

The ATLAS program consisted of two identical parallel, randomized, double-blind, active-control, phase 3 ABSSSI studies which were conducted with a prespecified pooled-analysis design. Details regarding the original inclusion and exclusion criteria are described elsewhere (5). Briefly, patients were eligible if they were men or nonpregnant women aged ≥18 years with a diagnosis of ABSSSI (deep extensive cellulitis, major abscess requiring surgical drainage, or infected wound, ulcer, or burn) caused by a suspected or confirmed Gram-positive organism that warranted ≥7 days of parenteral antibacterial therapy. Purulent drainage and/or collection or at least three signs or symptoms of infection also were required. Patients were not enrolled if they had received >24 h of previous antibiotic therapy (unless the pathogen was resistant or the prior therapy had failed) or had osteomyelitis, necrotizing fasciitis, chronic diabetic foot ulcers, gangrene, burns involving >20% of the body surface, mediastinitis, neutropenia (<500 cells/mm³), uncompensated heart failure, or a corrected QT interval of >500 ms. In addition, for this post hoc analysis, all patients with ulcers and burns were excluded, and only patients with a minimum lesion area of 75 cm² were included (calculated by length × width; manually measured using longest length in head-to-toe orientation and widest perpendicular width [90° angle]), leaving an ABSSSI population as defined by the FDA 2013 guidance.

Antimicrobial therapy.

Patients were randomized to receive either intravenous telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) in a 1:1 ratio. Individualized vancomycin dosing was permitted (including adjustment using serum vancomycin level monitoring), as dictated by standard practice at the individual participating sites. Vancomycin dosing could be adjusted for body weight and/or renal function in accordance with local standard practice while keeping the investigators involved in clinical evaluations blinded to the study treatment. In patients with moderate to severe renal impairment, the dose of telavancin was adjusted as previously described (5). Study medications were administered for 7 to 14 days. Switching to oral antimicrobials was not permitted. The addition of aztreonam and/or metronidazole was allowed for patients with proven or suspected polymicrobial infections.

Original clinical and microbiological evaluations.

Clinical assessments were conducted at baseline and daily through the end-of-therapy (EOT) evaluation (performed within 72 h after administration of the last dose of study medication). Test-of-cure (TOC) evaluation was conducted 7 to 14 days after the last dose of study medication. At each evaluation, investigators assessed the signs, symptoms, and extent of the infection; surgical procedures; adverse events (AEs); and concomitant medications. Microbiological specimens for Gram staining and culture were obtained from all patients at baseline. These procedures were repeated at the TOC evaluation only if purulent drainage or other evidence of continuing infection was present. Surface swab cultures were not permitted. Specimens for culture could be obtained via biopsy, needle aspiration, or a similar acceptable method to avoid surface contamination. Confirmatory identification of the pathogens and susceptibility testing were conducted at a central laboratory (Covance Inc., Indianapolis, IN).

Original and updated clinical response.

In the original analysis, clinical response was determined by the study site investigator based on clinical assessments and was classified as cure, failure, or indeterminate. Clinical cure was defined as resolution of clinically significant signs and symptoms associated with ABSSSI or improvement to the extent that the infectious process had been controlled and no further antimicrobial therapy was necessary at the TOC evaluation. Failure was defined as an inadequate response to study therapy, which included patients who underwent more than two surgical procedures that were more significant than routine debridement after the initiation of study medication. An indeterminate response was defined as the inability to determine outcome (e.g., patients receiving a nonprotocol, potentially effective antibiotic or patients who did not have their EOT or TOC visits within the protocol-specified windows).

For the purpose of this post hoc analysis, the updated clinical response (i.e., early clinical response) was adapted in accordance with the current (2013) FDA guidance. Patients were considered a clinical success at day 3 (±1 day) if they had a ≥20% reduction in lesion size from baseline and did not require rescue antimicrobial medication. In agreement with the new guidance, the clinical response at the TOC visit was redefined as a success by a study visit within 6 to 28 days of enrollment with a ≥90% reduction in lesion size from baseline, no increase in lesion size compared with that at day 3, and no requirement for additional antibiotics or significant surgical procedures. This was believed to be a conservative definition for successful treatment and consistent with the FDA guidance-suggested term “resolution” of the infection.

Original and updated analysis populations.

Definitions for the original analysis groups for efficacy include (i) all treated (AT) patients, who had a confirmed ABSSSI diagnosis and received at least one dose of study medication, and (ii) clinically evaluable patients, who were those in the AT group that complied with key exclusion and inclusion criteria and had a clinical response of either cure or failure at the TOC visit (patients were excluded from this subgroup if they had only a Gram-negative pathogen[s] or had a polymicrobial infection with a Gram-negative pathogen resistant to aztreonam isolated at baseline) (5). In this post hoc analysis, the updated AT population was considered the same population as in the original data set but also excluded patients with ulcers, burns, or a baseline lesion either <75 cm² in area or not reported. Safety was evaluated in all updated AT patients (updated safety population), and treatment assignment was made based on actual treatment received.

Statistical analysis.

All analyses were performed on aggregated data from the ATLAS studies because the studies were conducted contemporaneously under identical protocols with the prespecified intent of aggregating study results to draw inferences for patients with MRSA. The confidence intervals (CIs) for the between-treatment differences in clinical response were obtained using asymptotic approximations, stratifying by study. These were calculated using the extended Mantel-Haenszel approach.

RESULTS

A total of 1,867 patients were randomized to receive at least one dose of study medication in the ATLAS 1 and ATLAS 2 trials (AT population) (5). Based on the 2013 FDA guidance for ABSSSI, the updated AT population in this post hoc analysis included 1,127 patients (538 for telavancin and 589 for vancomycin). Reasons for exclusion from the updated AT population are provided in Table 1. Despite having lesion sizes meeting inclusion criteria and being otherwise eligible for inclusion in the reanalysis, 1% (15/1,127) of patients had missing lesion sizes at day 3, 6% (65/1,127) at the TOC visit, and <1% (4/1,127) at both day 3 and the TOC visit.

TABLE 1.

Reasons for exclusion from the updated AT population per 2013 FDA guidance^a

Reason for exclusion	Original AT population excluded from updated AT population per 2013 FDA guidance, no. (%)
	Telavancin (n = 390)	Vancomycin (n = 350)	Total (n = 740)
Missing lesion size at baseline	12 (3)	15 (4)	27 (4)
Baseline lesion of <75 cm2	337 (86)	304 (87)	641 (87)
Presence of ulcer or burns	41 (11)	31 (9)	72 (10)

^aAT, all-treated; FDA, U.S. Food and Drug Administration.

The baseline characteristics of the updated AT population were similar to those of the original population and were well matched between the telavancin and vancomycin groups (Table 2). However, more patients in the updated AT population had deep or extensive cellulitis (49.9%) and larger median lesion sizes (>250 cm²) at baseline (Table 3). The percentage of patients with bacteremia and the distribution of infection site pathogens were similar between the original AT and updated AT populations.

TABLE 2.

Baseline patient characteristics of the original AT population compared with the updated AT population per the 2013 FDA guidance

Characteristic	Value for:
	Original AT population		Updated AT population per 2013 FDA guidance
	Telavancin (n = 928)	Vancomycin (n = 939)	Telavancin (n = 538)	Vancomycin (n = 589)
Age (yr), mean ± SD	49 ± 16.6	49 ± 16.6	49 ± 16.3	49 ± 16.3
Age of ≥65 yr (%)	18.8	19.1	19.1	20.0
Male (%)	55.7	59.5	58.2	58.4
Presence of diabetes (%)	22.8	23.2	21.4	24.4
Any surgical intervention (%)	25.4	26.1	26.0	31.1
Renal status (%)a
Normal	64.7	65.5	67.1	64.5
Mild impairment	22.6	22.5	19.5	23.8
Moderate impairment	8.1	8.8	9.5	8.3
Severe impairment	4.5	3.2	3.7	3.4

^aRenal status determined based on creatinine clearance at baseline: normal, >80 ml/min; mild, >50 to 80 ml/min; moderate, 30 to 50 ml/min; severe, <30 ml/min.

TABLE 3.

Baseline infection characteristics of the original AT population compared with the updated AT population per the 2013 FDA guidance^a

Infection characteristic	Value for:
	Original AT population		Updated AT population per 2013 FDA guidance
	Telavancin (n = 928)	Vancomycin (n = 939)	Telavancin (n = 538)	Vancomycin (n = 589)
Infection type (%)
Major abscess	41.8	42.8	38.7	37.2
Deep/extensive cellulitis	36.1	37.9	48.7	50.9
Primary site of infection (%)
Upper extremities	16.6	18.1	18.0	17.8
Lower extremities	51.1	50.4	58.4	57.0
Median (Q1, Q3) area of lesion (cm2)	140 (48, 409)	132 (48, 369)	309 (150, 702)	256 (132, 675)
Bacteremia (%)	3.9	2.1	4.3	2.7
Primary infection site pathogen (%)
Gram-positive	69.5	71.5	65.4	67.6
S. aureus	60.0	63.0	55.9	59.1
MRSA	37.7	39.3	34.4	36.8
MSSA	22.7	24.1	21.9	22.6

^aMSSA, methicillin-susceptible S. aureus; Q, quartile.

In the updated AT population, early clinical responses were similar between the treatment groups: 62.6% for telavancin and 61.0% for vancomycin (treatment difference, 1.7% [95% CI, −4.0% to 7.4%]) (Table 4).

TABLE 4.

Early clinical response at day 3 and at TOC visit in the updated AT population per the 2013 FDA guidance

Time of evaluation	Response rate, % (na/N)		Treatment difference (%) between telavancin and vancomycin (95% CI)
	Telavancin	Vancomycin
Day 3	62.6 (337/538)	61.0 (359/589)	1.7 (−4.0, 7.4)
TOC visit	68.0 (366/538)	63.3 (373/589)	4.8 (−0.7, 10.3)

^aFor day 3, n shows the number of responders with a ≥20% reduction in lesion from baseline; for the TOC visit, n shows the number of responders with a ≥90% reduction in lesion from baseline; N, number in the updated AT population for each group.

For this reanalysis, reasons for failure in early clinical response were comparable between the two treatment groups. Approximately 36% of patients in both the telavancin and vancomycin groups failed due to a reduction in lesion size of <20% from baseline. Less than 1% of patients required rescue antibiotic therapy between days 1 and 3 for both treatment groups. No deaths were reported among telavancin-treated patients, while 1 patient in the vancomycin group died, on or before day 3.

Updated clinical response rates at TOC were also similar between the treatment groups (telavancin, 68.0%, and vancomycin, 63.3%; treatment difference, 4.8% [95% CI, −0.7% to 10.3%]) (Table 4). Reasons for clinical failure at TOC were similar across treatment groups (Table 5).

TABLE 5.

Reasons for clinical failure with <90% reduction in lesion size at TOC in the updated AT population per the 2013 FDA guidance

Parameter	% in treatment group
	Telavancin (n = 538)	Vancomycin (n = 589)
Total	26.4	28.0
Reduction in lesion size of <90% from baseline	17.3	18.8
Increase in lesion size on day 3	0	0
Requiring rescue antimicrobial medication between day 3 and TOC visit	2.4	1.5
Requiring significant surgical procedure between day 3 and TOC visit	6.7	7.6

Details regarding safety and tolerability in the original ATLAS studies have been thoroughly described elsewhere (5). In the updated safety population, at least one AE was reported for 83% of telavancin-treated patients and 75% of vancomycin-treated patients (Table 6). The percentages of patients with serious AEs were 7% and 5% for telavancin- and vancomycin-treated patients, respectively. AEs resulting in drug discontinuation were reported by 9% of patients receiving telavancin and 7% of patients receiving vancomycin. Deaths were reported for <1% and 1% of patients in the telavancin and vancomycin groups, respectively.

TABLE 6.

Summary of AEs in the updated safety population per the 2013 FDA guidance

Variable	No. (%) of patients
	Telavancin (n = 539)	Vancomycin (n = 588)
Any AE	445 (83)	439 (75)
Any renal AE	17 (3)	7 (1)
Blood creatinine increased	5 (<1)	3 (<1)
Renal failure, acute	4 (<1)	0 (0)
Renal failure, chronic	0 (0)	1 (<1)
Renal impairment	3 (<1)	1 (<1)
Renal insufficiency	6 (1)	2 (<1)
Any serious AE	38 (7)	31 (5)
Any AE resulting in drug discontinuation	48 (9)	39 (7)
Death	4 (<1)	7 (1)

The incidence of nephrotoxicity in the updated safety population is similar to the findings of the original ATLAS analysis (5). In the updated safety population, the incidences of renal events were 3% and 1% in the telavancin and vancomycin groups, respectively. Renal events were rated as severe in 1% of telavancin-treated patients and <1% of vancomycin-treated patients. Serum creatinine concentration was increased to ≥1.5 mg/dl and ≥50% above baseline in 6% and 3% of patients in the telavancin and vancomycin groups, respectively. In all patients, serum creatinine returned to baseline values or was resolving at the TOC evaluation (5).

DISCUSSION

Since the ATLAS phase 3 ABSSSI studies were conducted, the FDA has collaborated with the Biomarkers Consortium for the Foundation for the National Institutes of Health to evaluate past evidence on endpoints and develop updated recommendations for the evaluation of skin and skin structure infections (10). The historical evidence for drug effects was reviewed in detail (i.e., the difference in outcomes between the test drug and control group for antibiotic treatment of skin infections), and the results suggested that the largest treatment effects occurred early in the course of disease (10). Consequently, the current (2013) FDA guidance for evaluating ABSSSI proposes an earlier clinical response, at day 3, and the early endpoint serves as the link to the historical evidence of drug effect in previous studies, as required in the design of noninferiority studies (11). Furthermore, absence of fever was not included in the early endpoint, primarily because it was not considered a causal pathway of the disease, and in part because it may be confounded by antipyretic therapy (10).

We wanted to apply the new FDA guidance to the original telavancin ATLAS studies to corroborate earlier findings that telavancin was noninferior to vancomycin. This reanalysis confirmed that telavancin (10 mg/kg once daily) is at least as effective as vancomycin (twice daily) for the treatment of patients with ABSSSIs, according to the revised definition and the new primary endpoint as outlined in the current guidance. These data are meaningful to clinicians and their patients with skin and skin structure infections because patients enrolled in the ATLAS studies comprise an at-risk population, including a significant proportion of patients with diabetes, abnormal renal function, obesity, and peripheral vascular disease (5). The updated AT population in this reanalysis had larger lesions and more often had deep extensive cellulitis rather than large abscesses, as recommended by the new FDA guidance. In addition, rates of resolution of the lesion by ≥90% of the size at the TOC visit also were comparable between treatment groups. Taken together, these results indicate that telavancin is effective in the treatment of patients with large and complicated ABSSSI using either clinical or size-dependent endpoints.

From the safety and tolerability perspective, the types of renal AEs were consistent with those reported in the original analysis. Although uncommon, the incidence of renal impairment was higher in the telavancin group than in the vancomycin group, which was consistent with the findings demonstrated in the original analysis.

The current analysis has several limitations. First, this was a post hoc and not a prospective analysis incorporating revised inclusion and exclusion criteria and revised endpoints, as outlined by the updated (2013) FDA guidance for ABSSSI. Second, this used a subset of the original population. Applying the revised FDA criteria resulted in the exclusion of ∼40% of the original ATLAS AT population from this analysis. Finally, as described above, lesion size was not consistently collected for a small number of patients. Although we found that in the subpopulation addressed in this analysis, telavancin was shown to be noninferior to vancomycin in treating ABSSSI, this analysis is not a substitute for a prospective trial, and the stated limitations suggest that the population studied in this analysis may not reflect a true sample of patients who would now be enrolled prospectively in a new study.

Despite these limitations, the current analysis reinforces the efficacy results observed with telavancin using either investigator-determined clinical cure as in the original studies (5) or early clinical endpoints as in this post hoc analysis. Of note, this post hoc analysis may be less biased because outcomes are determined programmatically based on decrease in lesion area compared to the investigator-determined response for the primary endpoint.

In conclusion, telavancin was shown to be noninferior to vancomycin for the treatment of ABSSSI using the updated (2013) FDA guidance definitions and outcomes.