14 CLINICAL STUDIES

Clinical Studies of DALVANCE in Adult Patients with Acute Bacterial Skin and Skin Structure Infections

DALVANCE Two-dose Regimen (1,000 mg Day 1; 500 mg Day 8)

Adult patients with ABSSSI were enrolled in two Phase 3, randomized, double-blind, double-dummy clinical trials of similar design (Trial 1 and Trial 2). The Intent-to-Treat (ITT) population included 1,312 randomized patients. Patients were treated for two weeks with either a two-dose regimen of intravenous DALVANCE (1,000 mg followed one week later by 500 mg) or intravenous vancomycin (1,000 mg or 15 mg/kg every 12 hours, with the option to switch to oral linezolid after 3 days). DALVANCE-treated patients with creatinine clearance of less than 30 mL/min received 750 mg followed one week later by 375 mg. Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens.

The specific infections in these trials included cellulitis (approximately 50% of patients across treatment groups), major abscess (approximately 30%), and wound infection (approximately 20%). The median lesion area at baseline was 341 cm2. In addition to local signs and symptoms of infection, patients were also required to have at least one systemic sign of disease at baseline, defined as temperature 38°C or higher (approximately 85% of patients), white blood cell count greater than 12,000 cells/mm3 (approximately 40%), or 10% or more band forms on white blood cell differential (approximately 23%). Across both trials, 59% of patients were from Eastern Europe and 36% of patients were from North America. Approximately 89% of patients were Caucasian and 58% were males. The mean age was 50 years and the mean body mass index was 29.1 kg/m2.

The primary endpoint of these two ABSSSI trials was the clinical response rate where responders were defined as patients who had no increase from baseline in lesion area 48 to 72 hours after initiation of therapy, and had a temperature consistently at or below 37.6°C upon repeated measurement. Table 5 summarizes overall clinical response rates in these two ABSSSI trials using the pre-specified primary efficacy endpoint in the ITT population.

Table 5. Clinical Response Rates in ABSSSI Trials at 48-72 Hours after Initiation of Therapy1,2
	DALVANCE n/N (%)	Vancomycin/Linezolid n/N (%)	Difference (95% CI)3
Trial 1	240/288 (83.3)	233/285 (81.8)	1.5 (-4.6, 7.9)
Trial 2	285/371 (76.8)	288/368 (78.3)	-1.5 (-7.4, 4.6)

1 There were 7 patients who did not receive treatment and were counted as non-responders: 6 DALVANCE patients (3 in each trial) and one vancomycin/linezolid patient in Trial 2.

2 Patients who died or used non-study antibacterial therapy or had missing measurements were classified as non-responders.

3 The 95% Confidence Interval (CI) is computed using the Miettinen and Nurminen approach, stratified by baseline fever status.

A key secondary endpoint in these two ABSSSI trials evaluated the percentage of ITT patients achieving a 20% or greater reduction in lesion area from baseline at 48-72 hours after initiation of therapy. Table 6 summarizes the findings for this endpoint in these two ABSSSI trials.

Table 6. Patients in ABSSSI Trials with Reduction in Lesion Area of 20% or Greater at 48-72 Hours after Initiation of Therapy1,2
	DALVANCE n/N (%)	Vancomycin/Linezolid n/N (%)	Difference (95% CI)3
Trial 1	259/288 (89.9)	259/285 (90.9)	-1.0 (-5.7, 4.0)
Trial 2	325/371 (87.6)	316/368 (85.9)	1.7 (-3.2, 6.7)

1 There were 7 patients (as described in Table 5) who did not receive treatment and were counted as non-responders.

2 Patients who died or used non-study antibacterial therapy or had missing measurements were classified as non-responders.

3 The 95% CI is computed using the Miettinen and Nurminen approach, stratified by baseline fever status.

Another secondary endpoint in these two ABSSSI trials was the clinical success rate assessed at a follow-up visit occurring between Days 26 to 30. Clinical Success at this visit was defined as having a decrease in lesion size (both length and width measurements), a temperature of 37.6°C or lower, and meeting pre-specified criteria for local signs: purulent discharge and drainage absent or mild and improved from baseline, heat/warmth & fluctuance absent, swelling/induration & tenderness to palpation absent or mild.

Table 7 summarizes clinical success rates at a follow-up visit for the ITT and clinically evaluable population in these two ABSSSI trials. Note that there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at the follow-up visits. Therefore, comparisons of DALVANCE to vancomycin/linezolid based on clinical success rates at these visits cannot be utilized to establish non-inferiority.

Table 7. Clinical Success Rates in ABSSSI Trials at Follow-Up (Day 26 to 30) 1,2
	DALVANCE n/N (%)	Vancomycin/Linezolid n/N (%)	Difference (95% CI)3
Trial 1
ITT	241/288 (83.7%)	251/285 (88.1%)	-4.4% (-10.1, 1.4)
CE	212/226 (93.8%)	220/229 (96.1%)	-2.3% (-6.6, 2.0)
Trial 2
ITT	327/371 (88.1%)	311/368 (84.5%)	3.6% (-1.3, 8.7)
CE	283/294 (96.3%)	257/272 (94.5%)	1.8% (-1.8, 5.6)

1 There were 7 patients (as described in Table 5) who did not receive treatment and were counted as failures in the analysis.

2 Patients who died, used non-study antibacterial therapy, or had an unplanned surgical intervention 72 hours after the start of therapy were classified as Clinical Failures.

3 The 95% CI is computed using the Miettinen and Nurminen approach, stratified by baseline fever status.

Table 8 shows outcomes in patients with an identified baseline pathogen, using pooled data from Trials 1 and 2 in the microbiological ITT (microITT) population. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical success rates at follow-up (Day 26 to 30), as defined above.

Table 8. Outcomes by Baseline Pathogen (Trial 1, 2; MicroITT) 1
Early Clinical Response at 48-72 hours
	Early Responder2		≥ 20% reduction in lesion size		Clinical Success at Day 26 to 30
Pathogen	DALVANCE n/N (%)	Comparator n/N (%)	DALVANCE n/N (%)	Comparator n/N (%)	DALVANCE n/N (%)	Comparator n/N (%)
Staphylococcus aureus Methicillin-susceptible Methicillin-resistant	206/257 (80.2) 134/167 (80.2) 72/90 (80.0)	219/256 (85.5) 163/189 (86.2) 56/67 (83.6)	239/257 (93.0) 156/167 (93.4) 83/90 (92.2)	232/256 (90.6) 173/189 (91.5) 59/67 (88.1)	217/257 (84.4) 142/167 (85.0) 75/90 (83.3)	229/256 (89.5) 171/189 (90.5) 57/67 (85.1)
Streptococcus agalactiae	6/12 (50.0)	11/14 (78.6)	10/12 (83.3)	10/14 (71.4)	10/12 (83.3)	11/14 (78.6)
Streptococcus pyogenes	28/37 (75.7)	24/36 (66.7)	32/37 (86.5)	27/36 (75.0)	33/37 (89.2)	32/36 (88.9)
Streptococcus anginosus group	18/22 (81.8)	23/ 25 (92.0)	21/22 (95.5)	25/25 (100.0)	21/22 (95.5)	23/25 (92.0)
Enterococcus faecalis	8/12 (66.7)	10/13 (76.9)	12/12 (100.0)	12/13 (92.3)	12/12 (100.0)	11/13 (84.6)

All DALVANCE dosing regimens in Trials 1 and 2 consisted of two doses.

1 There were 2 patients in the DALVANCE arm with methicillin-susceptible S. aureus at baseline who did not receive treatment and were counted as non-responders/failures.

2 Early Responders are patients who had no increase from baseline in lesion area 48 to 72 hours after initiation of therapy, and had a temperature consistently at or below 37.6°C upon repeated measurement.

DALVANCE 1,500 mg Single Dose Regimen

Adult patients with ABSSSI were enrolled in a Phase 3, double-blind, clinical trial. The ITT population included 698 patients who were randomized to DALVANCE treatment with either a single 1,500 mg dose or a two-dose regimen of 1,000 mg followed one week later by 500 mg (Trial 3). Patients with creatinine clearance less than 30 mL/min had their dose adjusted (Section 2.2). Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens. The specific infections and other patient characteristics in this trial were similar to those described above for previous ABSSSI trials.

The primary endpoint in this ABSSSI trial was the clinical response rate where responders were defined as patients who had at least a 20% decrease from baseline in lesion area 48 to 72 hours after randomization without receiving any rescue antibacterial therapy. The secondary endpoint was the clinical success rate at a follow-up visit occurring between Days 26 and 30, with clinical success defined as having at least a 90% decrease from baseline in lesion size, a temperature of 37.6°C or lower, and meeting pre-specified criteria for local signs: purulent discharge and drainage absent or mild and improved from baseline (for patients with wound infections), heat/warmth and fluctuance absent, swelling/induration and tenderness to palpation absent or mild. Table 9 summarizes results for these two endpoints in the ITT population. Note that there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at the follow-up visit. Therefore, comparisons between treatment groups based on clinical success rates at this visit cannot be utilized to establish non-inferiority.

Table 9. Primary and Secondary Efficacy Results in ABSSSI Patients (Trial 3) 1,2
	DALVANCE, n/N (%)
	Single Dose (1,500 mg)	Two doses (1,000 mg Day 1/500 mg Day 8)	Difference (95% CI)3
Clinical Responders at 48-72 Hours (ITT)	284/349 (81.4)	294/349 (84.2)	-2.9 (-8.5, 2.8)
Clinical Success at Day 26-30 (ITT)	295/349 (84.5)	297/349 (85.1)	-0.6 (-6.0, 4.8)
Clinical Success at Day 26-30 (CE)	250/271 (92.3)	247/267 (92.5)	-0.3 (-4.9, 4.4)

1 There were 3 patients in the two-dose group who did not receive treatment and were counted as non-responders.

2 Patients who died or used non-study antibacterial therapy or had missing measurements were classified as non-responders.

3 The 95% Confidence Interval (CI) is computed using the Miettinen and Nurminen approach.

Abbreviations: ITT-intent to treat; CE-clinically evaluable

Table 10 shows outcomes in patients with an identified baseline pathogen from Trial 3 in the microbiological ITT (microITT) population. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical success rates at follow-up (Day 26 to 30), as defined above.

Table 10. Outcomes by Baseline Pathogen (Trial 3; MicroITT)
Early Clinical Response at 48-72 hours
	≥ 20% reduction in lesion size		Clinical Success at Day 26 to 30
Pathogen	Single dose (1,500 mg) n/N (%)	Two doses (1,000 mg Day 1/ 500 mg Day 8) n/N (%)	Single dose (1,500 mg) n/N (%)	Two doses (1,000 mg Day 1/ 500 mg Day 8) n/N (%)
Staphylococcus aureus Methicillin-susceptible Methicillin-resistant	123/139 (88.5) 92/103 (89.3) 31/36 (86.1)	133/156 (85.3) 89/96 (89.6) 48/61 (78.7)	124/139 (89.2) 93/103 (90.3) 31/36 (86.1)	140/156 (89.7) 86/96 (89.6) 55/61 (90.2)
Streptococcus agalactiae	6/6(100.0)	4/6 (66.7)	5/6 (83.3)	5/6 (83.3)
Streptococcus anginosus group	31/33 (93.9)	19/19 (100.0)	29/33 (87.9)	17/19 (89.5)
Streptococcus pyogenes	14/14 (100.0)	18/22 (81.8)	13/14 (92.9)	19/22 (86.4)
Enterococcus faecalis	4/4 (100.0)	8/10 (80.0)	4/4 (100.0)	9/10 (90.0)

In Trials 1, 2, and 3, all patients had blood cultures obtained at baseline. A total of 40 ABSSSI patients who received DALVANCE had bacteremia at baseline caused by one or more of the following bacteria: 26 S. aureus (21 MSSA and 5 MRSA), 6 S. agalactiae, 7 S. pyogenes, 2 S. anginosus group, and 1 E. faecalis. In patients who received DALVANCE, a total of 34/40 (85%) were clinical responders at 48-72 hours and 32/40 (80%) were clinical successes at Day 26 to 30.

Clinical Study of DALVANCE in Pediatric Patients with Acute Bacterial Skin and Skin Structure Infections

The pediatric trial was a multicenter, open-label, randomized, actively controlled trial (NCT02814916, Trial 4) conducted in pediatric patients 3 months of age to less than 18 years with ABSSSI, not known or expected to be caused exclusively by Gram-negative organisms. Patients were randomized in a 3:3:1 ratio to receive either DALVANCE single-dose regimen, DALVANCE two-dose regimen, or comparator. The comparator regimens included IV vancomycin for methicillin-resistant Gram-positive infections, or IV oxacillin or flucloxacillin for methicillin-susceptible Gram-positive infections. Patients in the comparator arm received IV treatment for a minimum of 72 hours before an optional switch to oral therapy to complete a total of 10-14 days of antibacterial drug therapy. Additional 5 patients from birth to < 3 months of age were enrolled and assigned to the DALVANCE single-dose regimen.

A study population of 191 pediatric patients received study medication (DALVANCE single dose regimen n=83, DALVANCE two-dose regimen n=78, comparator n=30); 62% of the patients were male and 89% were white, and 83% were from Eastern Europe. The pediatric age groups who received DALVANCE were as follows: 12 to < 18 years (n=58), 6 to < 12 years (n=49), 2 to < 6 years (n=35), 3 months to < 2 years (n=14), and birth < 3 months (n=5). Patients had diagnoses of major cutaneous abscess (53%), cellulitis (29%), or surgical site/traumatic wound infection (18%). The predominant pathogen at baseline was Staphylococcus aureus (84%).

The primary objective was to evaluate the safety and tolerability of DALVANCE. The trial was not powered for a comparative inferential efficacy analysis. Efficacy was assessed in the modified intent-to-treat population (n=183) which included all randomized patients who received any dose of study drug and had a diagnosis of ABSSSI caused by Gram-positive organism(s). Patients with ABSSSI only caused by Gram-negative organisms were excluded. The five patients in the age group birth to < 3 months of age were not included in efficacy analyses since they were enrolled with expanded inclusion criteria and only received the single dose DALVANCE regimen. An early clinical response at 48–72 hours was defined as ≥ 20% reduction in lesion size compared to baseline and no receipt of rescue antibacterial therapy. The proportion of patients with early clinical response, was 97.3% (73/75) in the DALVANCE single-dose arm, 93.6% (73/78) in the DALVANCE two-dose arm, and 86.7% (26/30) in the comparator arm. The difference in responder rates between the dalbavancin single-dose and comparator arms was 10.7%, with an exact 97.5% confidence interval (CI) of (-1.7%, 31.6%). The difference in responder rates between the dalbavancin two-dose and comparator arms was 6.9%, with an exact 97.5% CI of (-6.4%, 27.7%).

Clinical cure was defined as resolution of the clinical signs and symptoms of infection, when compared to baseline, and no additional antibacterial treatment for the disease under study. In patients, 3 months of age or older in the mITT population, the clinical cure rate at the test of cure (TOC) visit (28 ± 2 days) was 94.7% (71/75) in the DALVANCE single-dose arm, 92.3% (72/78) in the DALVANCE two-dose arm and 100% (30/30) in the comparator arm. The difference in cure rates between the dalbavancin single-dose and comparator arms was -5.3%, with an exact 97.5% CI of (-15.1%, 10.5%). The difference in cure rates between the dalbavancin two-dose and comparator arms was -7.7%, with an exact 97.5% CI of (-17.9%, 8.3%).