NUZYRA (Page 6 of 7)

14.2 Acute Bacterial Skin and Skin Structure Infections

A total of 1390 adults with ABSSSI were randomized in two multicenter, multinational, double-blind, double-dummy trials (Trial 2 NCT #02378480 and Trial 3 NCT #02877927). Both trials compared 7 to 14 days of NUZYRA to linezolid. Patients with cellulitis, major abscess, or wound infection were enrolled in the trials.

In Trial 2, 329 patients were randomized to NUZYRA (100-mg intravenously every 12 hours for 2 doses followed by 100-mg intravenously every 24 hours, with the option to switch to 300-mg orally every 24 hours) and 326 patients were randomized to linezolid (600-mg intravenously every 12 hours, with the option to switch to 600-mg orally every 12 hours). Patients in the trial had the following infections: cellulitis (38%), wound infection (33%) and major abscess (29%). The mean surface area of the infected lesion was 455 cm2 in NUZYRA-treated patients and 498 cm2 in linezolid-treated patients. The mean age of patients was 47 years. Subjects were predominantly male (65%) and white (92%), and mean BMI was 28.1 kg/m2. Among NUZYRA-treated patients, common comorbid conditions included drug abuse (53.9%), hepatitis C (29.1%), hypertension (20.4%), anxiety (19.5%), and depression (15.5%). Trial 2 was conducted globally including approximately 60% of patients enrolled in the United States.

In Trial 3, 368 patients were randomized to NUZYRA (450-mg oral once a day on Days 1 and 2, followed by 300-mg orally once a day) and 367 were randomized to linezolid (600-mg orally every 12 hours). All patients were enrolled in the United States. Patients in the trial had the following infections: wound infections (58%), cellulitis (24%), and major abscess (18%). The mean surface area of the infected lesion was 424 cm2 in NUZYRA-treated patients and 399 cm2 in linezolid-treated patients. The mean age of patients was 44 years. Subjects were predominantly male (63%) and white (91%) and mean BMI was 27.9 kg/m2. The most common comorbid conditions included drug abuse (72.8%), tobacco use (12.0%), and chronic hepatitis C infection (31.5%).

In Trials 2 and 3, approximately 12% of NUZYRA treated patients had CrCl <90 ml/min.

In both trials, efficacy was determined by the successful early clinical response at 48 to 72 hours after the first dose in the mITT population and was defined as a 20% or greater decrease in lesion size. Table 10 summarizes the clinical response rates in the two trials. The mITT population was defined as all randomized subjects without a sole Gram-negative causative pathogen at screening.

Table 10: Clinical Success * at the ECR Timepoint in the mITT Population in Trial 2 and Trial 3
Study NUZYRA (%) Linezolid (%) Treatment Difference (Two-Sided 95% CI)
*
Clinical success at early clinical response (ECR) at 48 to 72 hours after the first dose, was defined as a 20% or greater decrease in lesion size without any reasons for failure (less than 20% reduction in lesion size, administration of rescue antibacterial therapy, use of another antibacterial or surgical procedure to treat for lack of efficacy, or death).
95% confidence interval for the treatment difference.
Trial 2 84.8 85.5 -0.7 (-6.3, 4.9)
Trial 3 87.3 82.2 +5.1 (-0.2, 10.5)

Clinical response at the post therapy evaluation (PTE, 7 to 14 days after last dose) visit in the mITT and clinically evaluable (CE) populations was defined as survival after completion of study treatment without receiving any alternative antibacterial therapy other than NUZYRA, without unplanned major surgical intervention, and sufficient resolution of infection such that further antibacterial therapy is not needed (see Table 11). Clinical response rates at PTE by most common pathogen in the microbiological-mITT population, defined as all patients in the mITT population, who had at least 1 Gram- positive causative pathogen identified at baseline are provided in Table 12. The CE population consisted of all mITT patients who had a diagnosis of ABSSSI, received a minimum number of expected doses of study drug, did not have any protocol deviations that would affect the assessment of efficacy, and had investigator assessment at the PTE Visit.

Table 11: Investigator’s Overall Assessment of Clinical Response at PTE in mITT and CE Population in Trial 2 and Trial 3
Study Population NUZYRA n/N (%) Linezolid n/N (%) Treatment Difference (Two-Sided 95% CI) *
*
95% confidence interval for the treatment difference.
Trial 2 mITT 272/316 (86.1) 260/311 (83.6) +2.5 (-3.2, 8.2)
CE 259/269 (96.3) 243/260 (93.5) +2.8 (-1.0, 6.9)
Trial 3 mITT 296/353 (83.9) 284/353 (80.5) +3.4 (-2.3, 9.1)
CE 272/278 (97.8) 272/285 (95.4) +2.4 (-0.6, 5.8)
Table 12: Investigator’s Overall Assessment of Clinical Response at PTE by Baseline Pathogen in Trials 2 and 3 (micro-mITT population)
Pathogen NUZYRA n/N (%) Linezolidn/N (%)
Staphylococcus aureus 305/369 (82.7) 306/378 (81.0)
Methicillin-susceptible Staphylococcus aureus (MSSA) 164/201 (81.6) 181/226 (80.1)
Methicillin-resistant Staphylococcus aureus (MRSA) 146/173 (84.4) 128/157 (81.5)
Staphylococcus lugdunensis 10/11 (90.9) 2/3 (66.7)
Streptococcus anginosus group 84/104 (80.8) 59/82 (72.0)
Streptococcus pyogenes 28/40 (70.0) 25/34 (73.5)
Enterococcus faecalis 17/18 (94.4) 21/25 (84.0)
Enterobacter cloacae 11/14 (78.6) 9/11 (81.8)
Klebsiella pneumoniae 8/11 (72.7) 6/11 (54.5)

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