Conditions: Bacterial Infections Acute Bacterial Skin and Skin Structure Infection
Keywords: Critical Pathways Health Facilities Clinical Protocols Patient Satisfaction Absenteeism Anti-Bacterial Agents Quality of Life Economics, Medical Health Resources Health resource utilization Acute bacterial skin and skin structure infection (ABSSSI)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 91
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the effect of a new critical pathway (use of guideline-based patient identification criteria and for those who meet these criteria, use of dalbavancin) compared to usual care for the treatment of ABSSI (Acute Bacterial Skin and Skin Structure Infections)

Detailed description:

Arms:
arm 1: The New Critical Pathway under study is defined as (1) use of guideline-based patient identification criteria, and, for those who meet these criteria, (2) use of dalbavancin, administered as a single intravenous (IV) dose of 1500 mg over 30 minutes for the treatment of ABSSSI. arm 2: Participants who receive Usual Care as prescribed by the physician as standard of care in clinical practice for the treatment of ABSSSI.

Interventions: intervention 1: Dalbavancin intervention 2: Usual Care
Intervention descriptions: intervention 1: Dalbavancin administered as a single IV dose of 1500 mg over 30 minutes. intervention 2: Usual care as prescribed by the physician as standard of care in clinical practice for the treatment of ABSSSI.

Protocol document:
Prot_000.pdf: 
NCT03233438 
 
Study ID: CMO‐US‐ID‐0528 
 
 
 
Title: Development of a New Critical Pathway for Treatment of Acute Bacterial Skin and Skin Structure 
Infections 
 
Protocol Date: 03 March 2017 
 
 
 
 


1 
 
 
Development of a New Critical Pathway for Treatment of Acute Bacterial Skin and 
Skin Structure Infections 
 
Contacts: 
 
 
Study sponsor: 
Allergan 
2525 Dupont Drive 
Irvine, CA 92612-1599 
Document type 
Study Protocol 
Development phase: 
Phase 4 
Protocol Number:  
CMO-US-ID 0528 
Version:  
6.0 
Version date:  
March 3rd, 2017 
 
 
 
 
 


Allergan Signature(s)
Development of a New Critical Pathway for Treatment of Acute Bacterial Skin and Skin
Structure Infections
Version 6.0
This study protocol has been subjected to an internal Allergan review. I agree to the terms of this
study protocol.
This document contains confidential information, which should not be copied, referred to, released
or published without written approval from Allergan. Investigators are cautioned that the release
of the information in this protocol may be subject to change and revision.
2




4 
 
Table of contents 
List of tables and figures ..................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Protocol synopsis ................................................................................................................. 9 
1 
Introduction ....................................................................................................................... 16 
1.1 
Background ............................................................................................................ 16 
1.1.1 
Skin and skin-structure infections ......................................................... 16 
1.1.2 
Acute bacterial skin and skin structure infections ................................. 16 
1.1.3 
Treatment of ABSSSI ........................................................................... 17 
1.1.4 
Dalbavancin........................................................................................... 17 
1.1.5 
New Critical Pathway ........................................................................... 18 
1.2 
Purpose .................................................................................................................. 18 
2 
Study objectives ................................................................................................................. 18 
2.1 
Primary objective ................................................................................................... 18 
2.2 
Secondary objectives ............................................................................................. 19 
3 
Study design ...................................................................................................................... 19 
3.1 
Overview ............................................................................................................... 19 
3.1.1 
Study duration ....................................................................................... 21 
3.1.2 
Rationale of study design ...................................................................... 21 
3.2 
Antibiotic treatment ............................................................................................... 22 
3.2.1 
Pre-period .............................................................................................. 22 
3.2.2 
Post-period ............................................................................................ 23 
3.2.3 
Rationale of dose/regimen of antibiotic treatment ................................ 23 
3.2.4 
Rationale for choice of comparator ....................................................... 23 
3.3 
Subject identification ............................................................................................. 24 
3.3.1 
Pre-period .............................................................................................. 24 
3.3.2 
Post-period ............................................................................................ 24 
3.3.3 
Subject follow-up .................................................................................. 24 
3.3.4 
Rationale for subject follow-up ............................................................. 24 
3.4 
Subject inclusion and exclusion criteria ................................................................ 25 
3.4.1 
Inclusion criteria .................................................................................... 25 
3.4.2 
Exclusion criteria .................................................................................. 25 
3.5 
Early study termination.......................................................................................... 27 
4 
Measures and data collection ............................................................................................. 28 
4.1 
Study outcomes ...................................................................................................... 28 
4.1.1 
Baseline characteristics ......................................................................... 28 
4.1.2 
Primary and secondary outcomes .......................................................... 30 


5 
 
 
 
4.2 
Data collection ....................................................................................................... 34 
4.2.1 
Data collection schedule ....................................................................... 34 
4.2.2 
Patient Diary Aid................................................................................... 36 
5 
Safety assessments ............................................................................................................. 36 
5.1 
Adverse events ....................................................................................................... 36 
5.2 
Causality assessment ............................................................................................. 37 
5.3 
Severity assessment ............................................................................................... 37 
5.4 
Serious adverse events ........................................................................................... 38 
5.5 
Medication error .................................................................................................... 38 
5.6 
Procedure for collection of adverse events and serious adverse events ................ 39 
5.7 
Procedure for serious adverse event reporting ....................................................... 39 
5.8 
Procedure for medication error reporting .............................................................. 39 
5.9 
Procedures for reporting pregnancies/lactation exposure ...................................... 39 
5.10 
Potential Hy’s Law cases ....................................................................................... 40 
6 
Data analysis ...................................................................................................................... 40 
6.1 
Cost ........................................................................................................................ 41 
6.2 
Handling of missing data ....................................................................................... 41 
6.3 
Sample size and sample size considerations .......................................................... 41 
6.4 
Data monitoring and quality control ...................................................................... 41 
7 
Study site and study administrative structure .................................................................... 42 
7.1 
Core study team ..................................................................................................... 42 
7.2 
Site study team ....................................................................................................... 42 
8 
Ethical considerations ........................................................................................................ 43 
8.1 
Regulatory and ethical compliance and protection of human subjects.................. 43 
8.2 
Subject confidentiality ........................................................................................... 43 
8.3 
Informed consent procedures ................................................................................. 43 
8.4 
Responsibilities of the investigator and IRB ......................................................... 43 
8.5 
Publication ............................................................................................................. 44 
9 
Protocol deviations and violations ..................................................................................... 44 
9.1 
Protocol amendments............................................................................................. 44 
10  References ......................................................................................................................... 45 
11  Appendices ........................................................................................................................ 48 
11.1 
Measurement of lesion characteristics ................................................................... 48 
 
 
 
 
 
 


6 
 
 
List of tables and figures 
 
 
Table 2. Baseline characteristics ....................................................................................... 28 
Table 3. Primary and secondary outcomes ........................................................................ 30 
 
 
 


7 
 
List of abbreviations 
µL 
Microliter 
µmol 
Micromole 
ABSSSI 
Acute bacterial skin and skin-structure infection 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome 
ANC 
Absolute neutrophil count 
BPM 
Beats per minute 
cm2 
Square centimeters 
CrCl 
Creatinine clearance 
CRF 
Case report form 
dL 
Deciliter 
ED 
Emergency department 
ESRD 
End-stage renal disease 
FDA 
Food and Drug Administration 
g 
Gram 
GCP 
Good Clinical Practice 
HCUP 
Healthcare Cost and Utilization Project 
HIV 
Human immunodeficiency virus 
hr 
Hour 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
IRB 
Institutional review board 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
MRSA 
Methicillin-resistant Staphylococcus aureus 


8 
 
NIS 
National Inpatient Sample 
OPAT 
Outpatient parenteral antibiotic therapy 
PICC 
Peripherally-inserted central catheter 
q12–24h 
Every 12 to 24 hours 
q12h 
Every 12 hours 
q24h 
Every 24 hours 
q48h 
Every 48 hours 
q6–12h 
Every 6 to 12 hours 
q8–12h 
Every 8 to 12 hours 
q8h 
Every 8 hours 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-12 
Short Form-12 Health Survey 
SIRS 
Systemic inflammatory response syndrome 
SOP 
Standard operating procedure 
SSSI 
Skin and skin-structure infection 
TMP 
Trimethoprim 
ULN 
Upper limit of normal 
US 
United States 
 
 


9 
 
Protocol synopsis 
Title of study 
 
Development of a New Critical Pathway for Treatment of Acute 
Bacterial Skin and Skin Structure Infections 
Rationale 
Treatment of ABSSSI lacks a clear approach to risk stratification of 
patients and management upon patient presentation to the emergency 
department. Lack of a clear approach may cause unnecessary hospital 
admissions and extended length of stay (LOS) of ABSSSI patients, 
who otherwise could be treated in an outpatient setting. A paucity of 
research exists regarding hospital care pathways for treatment of 
ABSSSI patients and the place of long-acting parenteral antibiotics. 
Critical pathways, also known as critical paths, clinical pathways, or 
care paths, are management plans that outline steps, such as the 
sequence and timing of actions, necessary for a complex process. 
Therefore, implementation of a new critical pathway may potentially 
demonstrate benefit compared to usual care for the treatment of 
ABSSSI for patients who could otherwise be treated in an outpatient 
healthcare setting. Long-acting parenteral antibiotics may be an 
important component of the pathway, as a means to increase efficiency 
of ABSSSI treatment. The new critical pathway under study is defined 
as (1) use of guideline-based patient identification criteria, and, for 
those who meet these criteria, (2) use of dalbavancin, a long-acting 
antibiotic with an abbreviated administration schedule. For appropriate 
hospitalized patients with ABSSSI, the new critical pathway may 
demonstrate a potential for decreasing hospital length of stay. 
Objectives 
  
To assess the effect of a new critical pathway compared to usual care 
for the treatment of ABSSSI during initial care (the date of enrollment 
to 10-14 days) and follow-up (30 days after initial care) on the 
following outcomes: 
Primary outcome 
 Infection-related total admitted hospital days during initial care 
and follow-up  
Secondary outcomes   
 Total admitted hospital days during initial care and follow-up  
 Infection-related major surgical interventions that required 
operating room time during initial care and follow-up 
 Infection-related hospitalizations during initial care and 
follow-up  
 Infection-related hospitalizations during initial care and 
follow-up that resulted in admission to Intensive Care Unit 
(ICU) 


10 
 
 All cause hospitalizations in the 30 days post discharge from 
the hospital  
 Infection-related ED visits during initial care and follow-up 
 Infection-related outpatient healthcare visits during initial care 
and follow-up 
 Use of a PICC line or central line to administer antibiotic 
therapy during initial care and follow-up 
 Infection-related healthcare visits due to PICC line or central 
line used to administer antibiotic therapy during initial care and 
follow-up 
 Response to treatment at end of treatment visit 
 Serious adverse events (SAEs) during initial care and follow-
up  
 Patient satisfaction with care 
 Patient work and productivity loss  
 Patient Health-related Quality of Life (HRQoL)  
Population 
Study subjects will be recruited among patients who are admitted to 
the hospital for the treatment of ABSSSI and who require coverage for 
a known or suspected Gram-positive infection. Among all such 
individuals, attention will be focused on those who meet all of the 
inclusion criteria and none of the exclusion criteria.  


11 
 
Inclusion criteria 
 Aged ≥18 years 
 Admitted patients who meet clinical definition for ABSSSI 
o Present 
with 
the 
following 
infection 
types: 
cellulitis/erysipelas, 
wound 
infection, 
or 
major 
cutaneous abscess 
 Known or suspected infection caused by susceptible isolates of 
the following Gram-positive microorganisms: Staphylococcus 
aureus (including methicillin-susceptible and methicillin-
resistant strains), Streptococcus pyogenes, Streptococcus 
agalactiae, 
Streptococcus 
dysgalactiae, 
Streptococcus 
anginosus group (including S. anginosus, S. intermedius, S. 
constellatus) 
and 
Enterococcus 
faecalis 
(vancomycin 
susceptible strains).  
 Willing and able to return to the hospital or a designated clinic 
for scheduled visits, or to be in contact with study coordinators 
through telephone communication as required by the protocol 
and the antibiotic treatment administered 


12 
 
Exclusion criteria 
 
 
 
 
 
 Known 
or 
suspected 
Gram-negative 
infections 
including 
bacteremia, 
anaerobic 
infections, 
or 
fungemia, even in the presence of Gram-positive 
infection 
 Known or suspected infections that are severe, life-
threatening, or are not included in the ABSSSI FDA 
guidance1, including the following examples:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


13 
 
 
 
 
 
  
 
 
  
 Injection drug users presenting with a fever 
 
 
 
 
 
 
 Severe neurological disorder leading to severe 
immobility or confined to wheelchair or bed (e.g. 
paraplegia and hemiplegia) 
 Bilateral lower extremity involvement of the 
suspected infection (to exclude patients with chronic 
venous stasis) 
 Unwilling or unable to follow study procedures 
Intervention 
The new critical pathway under study is defined as (1) use of 
guideline-based patient identification criteria, and, for those who 
meet these criteria, (2) use of dalbavancin, a long-acting antibiotic 
with an abbreviated administration schedule. 
Comparator treatment 
Usual care (i.e. investigator choice antimicrobial therapy for a 
suspected or known Gram-positive infection of susceptible 
organisms)  
Study design 
Pre-period versus post-period trial 
Study duration and 
sample size 
The duration of the study will not be predetermined, but rather will 
depend on the number of included sites and eligible subjects at each 
site. Both the pre- and post-periods will run until approximately 86 
subjects are enrolled, or 43 subjects per period. Section 6.3, Sample 
size, provides information on the minimum number of subjects. 
Site 
NYP/Weill Cornell Medical Center 
Baseline characterization 
 Demographics  
 Comorbidities  
 Charlson Comorbidity Index  
 Infection type  
o Cellulitis/erysipelas,  


14 
 
o Wound infection, or  
o Major cutaneous abscess 
 Infection characteristics  
 Healthcare utilization in prior three months 
Outcomes 
 Total admitted hospital days during initial care and follow-up  
 Infection-related total admitted hospital days during initial 
care and follow-up  
 Infection-related major surgical interventions that required 
operating room time during initial care and follow-up  
 Infection-related hospitalizations during initial care and 
follow-up  
 Infection-related hospitalizations during initial care and 
follow-up that resulted in admission to Intensive Care Unit 
(ICU) 
 All cause hospitalizations in the 30 days post discharge from 
the hospital  
 Infection-related ED visits during initial care and follow-up  
 Infection-related outpatient healthcare visits during initial 
care and follow-up 
 Use of PICC line or central line to administer antibiotic 
therapy during initial care and follow-up 
 Infection-related healthcare visits due to PICC line or central 
line used to administer antibiotic therapy during initial care 
and follow-up 
 Response to treatment at end of treatment visit 
 Serious adverse events (SAEs) during initial care and follow-
up  
 Patient satisfaction with care  
 Patient work and productivity loss  
 Patient Health-Related Quality of Life (HRQoL)  
 
 
 
 
 
 
 
 
 
 
 
 
 


15 
 
 
 
 
Data analysis 
Subject characteristics and outcomes will be summarized and 
described for all subjects and compared between the pre- and post-
periods using appropriate statistical methods with adequate power. 
Site characteristics will also be summarized and described. Study 
analyses will be fully described in a separate SAP. 
Data Source and 
Collection 
Case-report forms (CRF) will be developed and employed by trained 
site investigators to prospectively collect information on baseline 
characteristics and outcomes following subject enrollment in the 
study. 
Safety Reporting 
Adverse events (AEs) and serious adverse events (SAEs) will be 
monitored regularly and all SAEs will be reported by each site to the 
sponsor. 


16 
 
1 
Introduction 
1.1 
Background 
1.1.1 
Skin and skin-structure infections 
Skin and skin-structure infections (SSSI) are among the most commonly encountered 
infections in clinical practice, with an estimated 14.2 million outpatient visits for cellulitis 
and abscess reported in 2005 alone.2 The number of visits to the emergency department (ED) 
for SSSI has nearly tripled between 1996 and 2005.3 In recent years,  while some evidence 
suggests that ED visits for ABSSSI in the United States (US) are stabilizing,4 the overall 
burden of these infections to the US healthcare system remains high—between 2000-2012, 
the incidence of patients with at least 1 SSSI-related hospital, ambulatory care, and ED visit 
increased by 38%, 46%, and 56%, respectively.5   
There is evidence that hospital admissions for these infections have also increased 
substantially in recent years.  Based on examinations of the US National Inpatient Sample 
(NIS), Edelsberg and colleagues reported a 29% increase in admissions to hospitals for SSSI 
between 2000 and 2004; increases were greatest among patients aged <65 years (37% vs. 
14% for those aged ≥65 years), urban hospitals (32% vs. 11% for rural hospitals), and among 
those with “superficial” infections (e.g., cellulitis, abscess) (33% vs. 24% for 
deeper/healthcare-associated infections [e.g., post-operative wound infection, infection due 
to vascular device]).6 The Healthcare Cost and Utilization Project (HCUP) 2013 report stated 
that SSSI infections were responsible for over 600,000 hospitalizations annually and were 
considered the eighth-most rapidly growing cause for hospitalization from 1997- 2011.7 
1.1.2 
Acute bacterial skin and skin structure infections 
In an effort to focus on acute infection and increase homogeneity of what had traditionally 
been a relatively diverse population, in 2013 the US Food and Drug Administration (FDA) 
provided guidance to manufacturers developing antibiotics for a subgroup of SSSI known as 
acute bacterial SSSI (ABSSSI). The FDA defined ABSSSI to consist of cellulitis/erysipelas, 
wound infection, and major cutaneous abscess. To be deemed ABSSSI, the infection should 
have a lesion surface area ≥75 squared centimeters (cm2); additional criteria set forth by the 
FDA1 were infection-specific and included: 
 Spreading areas of redness, edema, and/or induration (cellulitis/erysipelas) 
 Purulent drainage from a wound with surrounding redness, edema, and/or induration 
(wound infection) 
 Pus within the dermis or deeper that is accompanied by redness, edema, and/or 
induration (major cutaneous abscess) 
ABSSSI are often caused by Gram-positive pathogens, including but not limited to 
Staphylococcus aureus (both methicillin-resistant [MRSA] and methicillin-susceptible 
strains [MSSA]) and Streptococcus pyogenes.1 


17 
 
1.1.3 
Treatment of ABSSSI 
As with SSSI in general, initial treatment for ABSSSI is typically empiric and based on 
patient characteristics, clinical presentation, treatment guidelines, knowledge of local 
pathogen and resistance patterns, and the antimicrobials that are most likely to be effective 
against them. Given the role of MRSA in this indication, it is not surprising that empiric use 
of anti-MRSA therapy is fairly common; in one recent evaluation of 13,291 patients 
hospitalized for community-acquired complicated SSSI (including but not limited to 
ABSSSI), empiric use of anti-MRSA therapy increased from 61% during 2007 to 73% in 
20108 (p<0.01); Consistent with other research,9 vancomycin was the most commonly used 
agent. 
Patients requiring parenteral antibiotic treatment for ABSSSI have routinely been admitted 
to the hospital, regardless of the degree to which they may require other hospital services 
such as drainage or debridement.9 In one recent examination of 619 adult patients presenting 
to 12 US EDs with SSSI, Talan et al noted that for 85% of patients admitted to the hospital 
(n=94), their doctors indicated that the reason for admission was the requirement for 
parenteral antibiotic therapy, and for approximately 41% of admitted patients (n=39), this 
was the only reason for admission.10 The advent of outpatient parenteral antibiotic therapy 
(OPAT), which has been shown to be a safe and effective means by which parenteral 
antibiotic treatment can be administered,11 has provided an opportunity to rethink this 
paradigm. Current practice guidelines for the management of ABSSSI in EDs and hospitals 
have suggested that patients without a need for admission—defined as presence of 
hemodynamic instability, necrotizing fasciitis, and/or unstable comorbidities—do not require 
admission and instead could be managed as outpatients. Interestingly, these guidelines note 
that the presence of systemic signs of infection such as fever, in the absence of the 
aforementioned risk factors, are not cause in and of themselves for admission.3 Guidelines 
for the selection and management of patients receiving OPAT outline other relevant criteria, 
including psychosocial factors that may threaten the ability to render care on an outpatient 
basis.11 Yet, even with recommendations for outpatient care in clinical guidelines, a lack of 
clear care pathways for ABSSSI patients in the hospital limits use in practice.  The 
development of new antibiotic therapies provides the opportunity to successfully design and 
implement a new care pathway, due to the accelerated dosing schedules and ease of 
administration provided by long-acting parenteral antibiotics. Long-acting parenteral 
antibiotics may be an important component of a care pathway in the hospital for treatment of 
ABSSSI. Currently, there is a paucity of research that exists regarding a new clinical pathway 
in the hospital for treatment of ABSSSI patients and the place of long-acting parenteral 
antibiotics in therapy.  
1.1.4 
Dalbavancin 
Dalbavancin (Dalvance®) is a novel, long-acting, second-generation lipoglycopeptide that is 
indicated for the treatment of ABSSSI caused by susceptible strains of Gram-positive 
bacteria, including Staphylococcus aureus (both MRSA and MSSA), Streptococcus 
pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus 
group, and Enterococcus faecalis (vancomycin-susceptible strains).12 In two pivotal clinical 
trials, the efficacy and safety of two doses of IV dalbavancin administered one week apart 
(1000 milligrams (mg) for the initial infusion [750 mg for those with renal impairment] 


18 
 
administered over 30 minutes, 500 mg for the second infusion [375 mg] administered over 
30 minutes) were shown to be non-inferior to 10–14 continuous days of therapy with 
vancomycin and linezolid, respectively.12-14 A subsequent clinical trial demonstrated that the 
efficacy and safety of a single dose of dalbavancin administered over a 30 minute infusion 
(1500 mg) was non-inferior to the two-dose regimen.16 Dalbavancin can be provided through 
a peripheral line, and does not necessitate central or PICC placement. 
1.1.5 
New Critical Pathway 
Critical pathways, also known as critical paths, clinical pathways, or care paths, are 
management plans that outline steps, such as the sequence and timing of actions, necessary 
for a complex process. The definition of the new critical pathway for this study was 
developed for the treatment of ABSSSI patients who are admitted to the hospital. The new 
critical pathway is (1) use of guideline-based patient identification criteria, and, for those 
who meet these criteria, (2) use of dalbavancin, a long-acting antibiotic with an abbreviated 
administration schedule. Guideline-based patient identification criteria will be developed and 
applied based on criteria for identification of ABSSSI and existing OPAT guidelines.3,11  
1.2 
Purpose  
In addition to a lack of clinical guidelines or critical pathways to inform treatment of ABSSSI 
patients, many contributing factors are responsible for continuing to admit ABSSSI patients 
to receive IV antibiotic therapy, who could otherwise be treated in an outpatient healthcare 
setting. First, physicians may not have experience with or training for use of newer IV 
antibiotics, including use of long-acting IV antibiotics. Information on use of long-acting IV 
antibiotics may be limited to clinical trials, which test agents in highly selected populations 
under optimized settings with limited “real-world” generalizability. Second, physicians may 
have safety concerns related to adequate patient follow-up with the use of long-acting IV 
antibiotics. Third, there may be barriers to provision of OPAT, including institutional time 
spent coordinating care and insurance-related barriers. 
A new study is therefore required to better understand the “real-world” effectiveness of a 
new critical pathway that includes use of a long-acting antibiotic for the treatment of 
ABSSSI. In addition to tangible economic benefits associated with reducing unnecessary 
admissions, implementation of a new critical pathway may reduce utilization of healthcare 
services in the inpatient and outpatient care setting, increase patient  satisfaction, improve 
patient health-related quality of life (HRQoL), and reduce patient productivity 
loss/absenteeism.  
2 
Study objectives 
2.1 
Primary objective 
Estimate the difference in infection-related total admitted hospital days during initial care 
(the date of enrollment to 10-14 days) and follow-up (30 days after initial care) comparing 
ABSSSI patients receiving care before implementation of the new critical pathway and after 
implementation.  


19 
 
2.2 
Secondary objectives 
Estimate the difference in the following outcomes during initial care (the date of enrollment 
to 10-14 days) and follow-up (30 days after initial care) comparing ABSSSI patients 
receiving care before implementation of the new critical and after implementation:  
 Total admitted hospital days during initial care and follow-up  
 Infection-related major surgical interventions that required operating room time 
during initial care and follow-up (number of expected major surgeries, number of 
unexpected major surgeries, and total number of major surgeries) 
 Infection-related hospitalizations during initial care and follow-up  
 Infection-related hospitalizations during initial care and follow-up that resulted in 
admission to Intensive Care Unit (ICU)  
 All cause hospitalizations in the 30 days post discharge from the hospital 
 Infection-related ED visits during initial care and follow-up (number of expected, 
number of unexpected and number of total ED visits during follow-up) 
 Infection-related outpatient healthcare visits (e.g., physicians’ office visits, ED visits, 
infusion center visits, home health visits) during initial care and follow-up (number 
of expected visits, number of unexpected and total number of visits) 
 Use of a PICC line or central line to administer antibiotic therapy during initial care 
and follow-up (number of patients who have a PICC or central line placed) 
 Infection-related healthcare visits (e.g., hospitalizations, ED visits, other outpatient 
visits) due to PICC line or central line used to administer antibiotic therapy during 
initial care and follow-up (number of expected visits, unexpected visits and number 
of total visits) 
 Response to treatment at end of treatment visit 
 Serious adverse events (SAEs) during initial care and follow-up  
 Patient satisfaction with care (subject reported)  
 Patient work and productivity loss (subject reported) 
 Patient Health-related Quality of Life (HRQoL) (subject reported) 
 
3 
Study design 
3.1 
Overview 
This study will employ a “pre-post” pragmatic design, which will consist of both a pre-
period, or an observational baseline period, and a post-period, or an interventional period 
(Figure 1). During the pre-period, the site will implement the first component of the critical 
pathway through implementation of guideline-based criteria to identify patients admitted to 
the hospital, obtain informed consent, and monitor enrolled subjects. The site will initiate 


20 
 
treatment for ABSSSI with “usual care,” defined as site- or physician-specific antibiotic 
treatment of ABSSSI with coverage for a known or suspected Gram-positive infection (e.g., 
vancomycin, linezolid, and daptomycin) to each study subject who meets all inclusion and 
exclusion criteria. During the “post” period, for all subjects who provide informed consent 
and are subsequently enrolled, each participating site will additionally implement the second 
component of the new critical pathway, use of dalbavancin, at the point of care in the hospital 
or other designated site to each study subject who meets all inclusion and exclusion criteria.  
As the study is pragmatic in design, selection criteria will be minimal and optimized for 
selection of “real-world” patients who are ideal candidates for treatment in the outpatient 
healthcare setting, but who are currently admitted to the hospital to receive treatment for 
ABSSSI. Site training is necessary for both adherence to the protocol and implementation of 
the new critical pathway, described in greater detail in Section 7, Study sites and 
administrative structure. Briefly, the investigators on the core study team will provide 
training to other members of the site study team, including all participating site physicians 
and other  healthcare providers (i.e. nurses, pharmacists, and other staff) on protocol 
adherence and implementation of the new critical pathway. Protocol training will occur 
before enrolling subjects in both the pre- and the post-period. Before enrolling subjects in the 
post-period, training on implementation of the new critical pathway will occur over a two- to 
four-week period after the date of the last enrolled subject in the pre-period. In addition, 
ongoing reminders and orientations will be scheduled by the investigators on the core study 
team as needed during both the pre- and post-period. 
For both periods of interest, subject follow-up will begin on the day of study enrollment and 
end 44 days subsequently. This will reflect the 10 to 14-day period during which antibiotics 
are anticipated to be required for care of ABSSSI plus an additional 30 days to ascertain 
outcomes, such as health resource utilization.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


21 
 
3.1.1 
Study duration 
The duration of the study will not be predetermined, but rather will depend on the number of 
eligible subjects. Both the pre- and post-periods will run until the minimum number of 
subjects are enrolled. Refer to Section 6.3, Sample size, for information on the minimum 
number of subjects. 
3.1.2 
Rationale of study design 
The design of this study allows for the site to understand baseline treatment patterns for 
ABSSSI, then after this period, to implement an institution-level intervention. Use of this 
design removes site-level variables as a source of potential confounding and enables 
comparisons of the new critical pathway to usual care in the same setting(s) and similar 
subject populations.  
The study is designed in a “pragmatic” fashion (i.e., minimal inclusion/exclusion criteria, 
which will enable an examination of the impact of the new critical pathway under “real-
world” conditions, with good generalizability/applicability to clinical practice. 


22 
 
3.2 
Antibiotic treatment  
3.2.1 
Pre-period 
During the pre-period, treatment for ABSSSI is initiated with “usual care,” defined as 
investigator’s choice of antibiotic therapy (e.g., vancomycin, linezolid, and daptomycin), to 
each study subject who meets all study selection criteria. It is expected that choice of usual 
care will be site or physician specific. Dosing of each antibiotic agent should follow 
recommended guidelines, demonstrated for antibiotic agents in, but not limited to, Table 1 
below. All included subjects require Gram-positive antimicrobial coverage for a known or 
suspected infection caused by susceptible isolates of the following microorganisms: 
Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), 
Streptococcus 
pyogenes, 
Streptococcus 
agalactiae, 
Streptococcus 
dysgalactiae, 
Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus) and 
Enterococcus faecalis (vancomycin susceptible strains).   


23 
 
3.2.2 
Post-period 
During the post-period, all enrolled subjects will receive treatment for ABSSSI with 
dalbavancin at each participating site. Dalbavancin will be administered as a single IV dose 
of 1500 mg over 30 minutes (1125 mg over 30 minutes if CrCl <30 mL/min, for those not 
on regularly scheduled dialysis).12 Dalbavancin will be provided to sites by study sponsor.  
3.2.3 
Rationale of dose/regimen of antibiotic treatment  
Usual care antibiotic therapy and dalbavancin will each be administered per relevant 
guidelines/manufacturer instructions (dosing provided in Table 1). Duration of treatment 
with usual care will be left to the physician’s discretion, as recommendations for several 
agents include a range (e.g., 10–14 days for linezolid).24  
3.2.4 
Rationale for choice of comparator 
Usual care will comprise investigator’s choice of care and may therefore vary from subject 
to subject. This was selected to allow for comparisons of the new critical pathway, which 
includes use of dalbavancin, with “real world” treatment. 


24 
 
3.3 
Subject identification 
Patients admitted to the hospital with an ABSSSI infection during both the pre- and post-
periods will be assessed for inclusion and exclusion criteria. These criteria will be prepared 
as an annotated checklist for the study coordinator and/or study nurses to implement and 
document using a CRF. Information obtained through the annotated checklist coupled with 
physician assessment will define guideline-based patient identification criteria. 
3.3.1 
Pre-period 
During the pre-period, the study coordinator and/or other study nurses will identify patients 
who may be eligible for the study. All hospital staff may be reminded (through posters or 
memorandums) to inform the study coordinator and/or other study nurses as soon as an 
ABSSSI patient is admitted. The study coordinator will implement inclusion and exclusion 
criteria for the new critical pathway by patient interview and/or chart review. Inclusion 
criteria includes clinical judgment that patient requires coverage for a known or suspected 
Gram-positive infection. Patients who meet all inclusion criteria and none of the exclusion 
criteria based on study coordinator assessment will be enrolled in the study or flagged for 
further review by core study team physicians, who will make the final enrollment decision. 
The treating physician will be blinded to protocol content and study enrollment decision. 
Study coordinator will then complete all additional elements of enrollment, including 
informed consent, and scheduling of follow-up.  
3.3.2 
Post-period 
During the post-period, the study coordinator and/or other study nurses will identify patients 
who may be eligible for the study. As in the pre-period, physicians or other appropriate 
healthcare providers may also identify subjects who are eligible for the study. All hospital 
staff may be reminded (through posters or memorandums) to inform the study coordinator 
and/or other study nurses as soon as an ABSSSI subject is admitted to the hospital. The study 
coordinator or treating physician will implement the checklist and enroll subjects into the 
study. Study coordinator will then complete enrollment, including informed consent, and 
scheduling of follow-up. 
3.3.3 
Subject follow-up 
Within both the pre- and post-periods, follow-up for each subject will begin on the day of 
enrollment (which is anticipated to be the date of treatment initiation) and conclude 44 days 
thereafter. Follow-up will therefore include the presumed “episode” of antibiotic therapy for 
ABSSSI (up to 10-14 days) and subsequent 30-day period.  
3.3.4 
Rationale for subject follow-up 
Each subject will be followed for a 10-14-day period (i.e. initial care), which is the longest 
supported duration of antibiotic therapy for ABSSSI treatment.15 In order to allow similar 
opportunity for collection of outcomes in the pre- and the post-period, the post-period 
similarly assumes 10-14 days. The addition of 30 days after initial care (i.e. follow-up) was 
thought to comprehensively assess outcomes during a relevant timeframe after the 
completion of antibiotic therapy. Therefore, 44 days (initial care and follow-up) for each 


25 
 
subject encompasses both the maximum treatment duration and assessment of relevant 
outcomes in the 30 days following treatment.  
3.4 
Subject inclusion and exclusion criteria 
Study subjects will be recruited among admitted patients with ABSSSI and who require 
coverage for a known or suspected Gram-positive infection. Among all such individuals, 
attention will be focused on those who meet all of the inclusion criteria and none of the 
exclusion criteria.  
3.4.1 
Inclusion criteria 
Eligible study subjects satisfy all of the following inclusion criteria1,10,24 
 Aged ≥18 years 
 Admitted patients who meet clinical definition for ABSSSI10-11 
o Present with the following infection types: cellulitis/erysipelas, wound infection, 
or major cutaneous abscess 
 Known or suspected infection caused by susceptible isolates of the following Gram-
positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and 
methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, 
Streptococcus dysgalactiae, Streptococcus anginosus group (including S. anginosus, S. 
intermedius, S. constellatus) and Enterococcus faecalis (vancomycin susceptible strains).  
 Willing and able to return to the hospital or a designated clinic for scheduled visits, or be 
in contact with the study coordinator through telephone communication, as required by 
the protocol and the antibiotic treatment administered 
3.4.2 
Exclusion criteria 
Study subjects with any of the following criteria will be excluded1,12-14 
 
 
 
 
 Known or suspected Gram-negative infections including bacteremia, anaerobic infections, or 
fungemia, even in the presence of Gram-positive infection     
 Known or suspected infections that are severe, life-threatening, or are not included in the 
ABSSSI FDA guidance, including the following examples: 
 
 
 
 
 
 
 
 
 
 


26 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Injection drug users presenting with a fever 
 
 
 
 
                                                 
a If the patient is a woman of child-bearing potential, from at least the first dose of study drug until the final visit she 
must confirm strict abstinence from sexual intercourse with any male or must confirm use of an effective contraceptive 
method from the following list: A barrier (condoms, diaphragm or cervical cap) with spermicide; Oral or similar 
contraceptive, which includes, but is not limited to: injectable, implanted, or patch hormone therapy, and intrauterine 
device (IUD); Documented surgical sterilization at least 4 weeks prior to baseline; Partner vasectomy at least 6 months 
prior to baseline. 
 


27 
 
 Severe neurological disorder leading to severe immobility or confined to wheelchair or 
bed (e.g. paraplegia and hemiplegia) 
 Bilateral lower extremity involvement of the suspected infection (to exclude patients 
with chronic venous stasis) 
 Unwilling or unable to follow study procedures 
3.5 
Early study termination 
A premature discontinuation will occur when a subject who signed the informed consent 
form (ICF) ceases participation in the study, regardless of circumstances, before the 
completion of all study assessments (i.e., before completing all protocol-stipulated 
activities). Subjects can be prematurely discontinued from therapy after careful 
consideration for any one of the following reasons: 
 Screen failure 
 Failure to receive complete critical pathway by not receiving dalbavancin in the post-
period 
 Withdrawal of consent (a clear reason will be documented) 
 AE (before or after administration of first dose of antibiotic therapy) 
 Protocol deviation/violation, including lack of protocol compliance 
 Lost to follow-up (every effort will be made to contact the subject) 
 Study or site prematurely terminated by the sponsor for any reason 
 If a Gram-negative infection including bacteremia, an anaerobic infection, or fungemia 
develops during the study, or is subsequently found to have been present at baseline, the 
subject should be removed from study treatment and receive appropriate antibiotic(s) to 
treat the Gram-negative infection, anaerobic infection, or fungemia.  
 Other reasons, such as specified administrative reasons or pregnancy 
All subjects who prematurely discontinue from the study, regardless of cause, 
should have a final assessment at early termination (ET). A final assessment will be 
defined as either a physical visit or a telephone call that completes the evaluations 
scheduled for the Final Visit at the end of study (Day 44 visit; refer to Section 4.2, Data 
collection), or an earlier visit, depending on the visit schedule and when ET occurs. 
Subjects who do not complete all scheduled visits/procedures will be requested to have an 
ET Visit. A clear description will be documented and source documentation will be kept by 
the investigator. The reasons for premature discontinuation from the study will be reflected 
on the Study Termination page of the CRF.  
                                                 
Within these limits, the specific form of contraception employed are left to the discretion of the patient, and/or the 
principal investigator, and/or the patient’s physician. 


28 
 
4 
Measures and data collection 
4.1 
Study outcomes 
4.1.1 
Baseline characteristics 
Baseline characteristics will be collected following subject enrollment into the study, and 
will be based on physical examination and medical history. A complete list of baseline 
characteristics is shown in Table 2. 
Table 2. Baseline characteristics 
Measure Type 
Description 
Demographics 
Age (in years)  
Gender  
Race  
Employment status 
Location subject presents from (e.g. from 
home, LTC, SNF, nursing home) 
Comorbidities 
Myocardial infarction 
Congestive heart failure 
Peripheral vascular disease 
Cerebrovascular disease 
Dementia 
Chronic pulmonary disease 
Rheumatologic disease 
Peptic ulcer disease 
Mild liver disease 
Diabetes without complications 
Diabetes with complications 
Renal disease 
Moderate or severe liver disease (Child- 
Pugh Class B and C) 
Any malignancy, including leukemia and 
lymphoma 
Metastatic solid tumor 
If subject has cancer, whether active vs. 
remitted/cured 
Alcohol/drug abuse/illicit needle use 
Malnutrition  
HIV 


29 
 
Measure Type 
Description 
Immunocompromising conditions other 
than HIV 
Altered mental status 
Charlson Comorbidity Indexb (CCI)  
Derived variable based on recorded 
comorbidities:  Calculation of the CCI for 
each subject at baseline to assess the risk of 
1 year mortality  
Infection type 
Cellulitis/erysipelas, wound infection, or 
major cutaneous abscess 
Infection characteristics 
Lesion size (as described in Appendix A) 
and location  
Thrombocytopenia (<150,000 platelet 
count or site-specific definition) 
Hyperglycemia (>120mg/dL blood glucose 
or site-specific definition) 
Hyponatremia (<135 mEq/L blood sodium 
or site-specific definition) 
Acidosis (<7.35 pH of the blood or site-
specific definition or described in medical 
chart) 
Uremia (as described in medical chart) 
Anemia (14-18 g/dL hemoglobin for men 
or 12-16 g/dL hemoglobin for women or 
site-specific definition) 
Fever (>98.6 degrees Fahrenheit or site-
specific definition) 
SIRS criteriac at enrollment, including 
highest or lowest recorded RR and highest 
or lowest recorded BPM/highest or lowest 
recorded fever/highest or lowest WBC count 
or amount of immature cells 
Highest or lowest recorded BP at enrollment
Laboratory results at baseline and during 
follow-up (e.g. Total white blood cell count, 
hemoglobin, 
sodium, 
glucose, 
serum 
creatinine, and C-reactive protein) 
                                                 
b Deyo et al 1992 
c  SIRS criteria include abnormalities in temperature, heart rate, respiration, and white blood cell count. Specifically, 
fever >38.0°C or hypothermia <36.0°C, tachycardia >90 beats/minute , tachypnea >20 breaths/minute or PaCO2 of 
less than 32mmHg, abnormal white blood cell count leukocytosis >12,000/microliter, leucopoenia <4,000/microliter, 
or >10% immature cells (bands).26,27 


30 
 
Measure Type 
Description 
Rapid microbial assay and microbiological 
culture results and type of culture (i.e. blood, 
wound swab, urine) at baseline and during 
follow-up 
Presence of recurrent infection (evidence 
from chart review, provider assessment and 
subject report of a similar ABSSSI in the 
same location on the body) and any ABSSSI 
infections in the prior 6 months 
Healthcare utilization in prior three months
Hospitalizations and primary reason  
Surgical interventions and primary reason 
Admission to the ICU and primary reason 
ED visits or other outpatient visits (e.g., 
infusion center and physician’s office) and 
primary reason 
Use of dialysis 
Use of any medications for chronic diseases 
and specifically use of an antibiotic 
medication 
Prior antibiotic treatment failure  
Receipt of wound care for the presenting 
infection 
4.1.2 
Primary and secondary outcomes 
Primary and secondary outcomes are presented in in Table 3. Outcomes will be assessed 
during initial care (the date of enrollment to 10-14 days) and follow-up (30 days after initial 
care) unless otherwise specified. 
Table 3. Primary and secondary outcomes 
Measure  
Description 
Infection-related total admitted hospital 
days during initial care and follow up  
 
Includes days during the initial 
hospitalization and all other 
hospitalizations  
Total admitted hospital days during initial 
care and follow up  
Includes days during the initial 
hospitalization and all other infection-
related hospitalizations  
Number of major unexpected surgeries 
Number of major expected surgeries 


31 
 
Measure  
Description 
Infection-related major surgical 
interventions that required operating room 
time during initial care and follow up 
Number of all major surgical interventions 
unexpected or expected 
Infection-related hospitalizations during 
initial care and follow up 
Number of infection-related 
hospitalizations  
Infection-related hospitalizations during 
initial care and follow-up that resulted in 
admission to Intensive Care Unit (ICU) 
 
Number of infection-related 
hospitalizations resulting in admission to 
the ICU. 
All cause hospitalizations in the 30 days 
post discharge from the hospital  
Number of all hospitalizations for subjects 
including re-hospitalizations  
 
Infection-related ED visits during initial 
care and follow up 
Number of unexpected visits to ED  
Number of expected visits to ED  
All visits (unexpected and expected) to ED  
Infection-related outpatient healthcare 
visits (e.g., physicians’ office visits, ED 
visits, infusion center visits, home health 
visits) during initial care and follow up 
Unexpected visits, by site (e.g., physicians’ 
office visits, ED visits, infusion center 
visits, home health visits) 
Expected visits, by site (e.g., physicians’ 
office visits, ED visits, infusion center 
visits, home health visits) 
All visits (unexpected and expected), by 
site (e.g., physicians’ office visits, ED 
visits, infusion center visits, home health 
visits) 
Use of PICC line or central line to 
administer antibiotic therapy during initial 
care and follow up 
PICC line or central line placement for 
antibiotic therapy 
Infection-related healthcare visits (e.g., 
hospitalizations, ED visits, other outpatient 
visits) due to PICC line or central line used 
to administer antibiotic therapy during 
initial care and follow up 
 
Unexpected visits due to PICC line (i.e. 
complications) 
Expected visits due to PICC line (i.e. initial 
placement, monitoring of PICC line) 
All visits due to PICC line (both 
unexpected and expected visits) 
Response to treatment at end of therapy 
visit 
Response to treatment (healthcare provider 
assessment) comparing response at the 10-
14 day visit (end of therapy visit). 
Response to treatment will be defined 


32 
 
Measure  
Description 
through an assessment of erythema 
(erythema to be assessed as defined in 
Appendix 11.1: Measurement of lesion 
characteristics) and the absence of fever at 
10-14 days. Response to treatment will 
specifically be defined as: 
Complete response 
Resolution of all baseline signs and 
symptoms, including fever, erythema, pain, 
and tenderness.  
 
Partial response 
Resolution of fever, pain, and tenderness, 
but with residual erythema 
 
Failure 
Persistence of fever, pain, and/or 
tenderness with or without residual 
erythema 
    
Serious adverse events (SAEs) during 
initial care and follow-up  
All SAEs as defined in Section 5 Safety 
assessments 
Patient satisfaction with care (subject 
reported) 
Patient satisfaction with care (Subject-
reported, Section 11.2- questionnaire 
similar to the final implemented version) 
Patient work and productivity loss (subject 
reported) 
Number of days with lost/reduced 
productivity during follow-up, as measured 
through Work Productivity and Activity 
Impairment Questionnaire (Section 11.4)30 
Patient Health-Related Quality of Life 
(HRQoL) (subject reported) 
Health-related quality of life (subject 
reported), as measured through the Medical 
Outcomes Study Short Form-12 (SF-12), 
with acute recall (1 week recall) (Section 
11.5)31  
 
 
 
 
 
 
 


33 
 


34 
 
4.2 
Data collection 
Information on baseline characteristics, outcomes, and other measures will be collected 
following subject enrollment in the study and will be based on the medical record and CRFs 
that will be developed exclusively for use in this study.  
Data collection will involve the use of the site’s electronic data capture (EDC) system 
through use of CRFs, to which only authorized personnel will have access. Subject’s data are 
to be entered into the EDC system by the investigator or designee using their assigned EDC 
user account. After data entry into the EDC system by the investigator or designee, a 
combination of manual and programmatic edit checks will be used to review the data for 
completeness, logic, and adherence to study protocol. As a result of these edits checks, data 
monitoring, and reviews, queries may be electronically issued to the site and should be 
answered electronically via the EDC system. 
4.2.1 
Data collection schedule 
Table 5 describes expected follow-up. Follow-up visits will be scheduled between 48-72 
hours after hospital discharge, 10-14 days after enrollment (end of treatment visit, both 
periods), and 44 days after enrollment (both periods). 48-72 hours after hospital discharge, 
both pre- and post-period patients will be called via telephone. A limited physical visit will 
be conducted 10-14 days after enrollment. However, for subjects unable to be seen back at 
the site, a telephone interview will suffice. Research data will be collected through follow-
up visits at between days 10-14 through an in-person visit (end of treatment visit; if patient 
cannot be seen back at site, telephone call can occur up to 21 days from enrollment) and at 
44 days (telephone call can occur up to 51 days from enrollment), through a telephone 
interview of the subject in both the pre- and post-periods. Additionally, electronic medical 
chart data will be reviewed at the 10-14 day and 44 day time points from enrollment. Any 
additional visits to the visit schedule below will be at the discretion of the subject and treating 
physician.  
 


35 
 


36 
 
4.2.2 
Patient Diary Aid 
Patients will be provided with a bound, paper diary to record specific information about their 
health status on days in which they have an interaction with a health care provider.  The diary 
is intended only as an aid to help patients remember details about health care appointments, 
medications, and medical tests. The diary will not be collected by or returned to study staff.   
5 
Safety assessments 
At each visit, subjects are to be queried regarding any adverse events (AEs) or serious adverse 
events (SAEs) that have occurred since the previous visit. Subjects will be asked to volunteer 
information with a nonleading question such as, “How do you feel since your last visit?” 
Study site personnel will record all pertinent information in the subject’s CRF. All AEs will 
be recorded on the appropriate AE reporting page of the subject’s CRF whether or not they 
are considered causally related to the study drug (any antibiotic given for ABSSSI from 
enrollment, including the pre-period). 
For every AE, the investigator will: 
 Provide an assessment of the seriousness of the event (i.e., is it an SAE?), as well as 
the severity and causal relationship 
 Document all actions taken with regard to the study drug 
 Detail any other treatment measures taken for the AE 
 Document the outcome of the AE 
In addition, subjects will be reminded, as described in the ICF to notify site personnel of any 
AEs occurring from the time the subject signed the ICF until the final follow-up visit. Any 
AEs that are ongoing at the time of the final protocol-defined study visit will be followed 
until the condition returns to pre-study status, has resolved or stabilized, or can be explained 
as being unrelated to the study drug. If a follow-up visit is deemed necessary for appropriate 
safety surveillance, it will take place within 30 days of the final protocol-defined study visit. 
5.1 
Adverse events 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
a product, whether or not considered related to the product. The definition of an AE includes: 
 Worsening of a pre-existing condition or underlying disease  
 Events associated with the discontinuation of the use of a product(s), (e.g., appearance 
of new symptoms) 


37 
 
Please note hospital admissions and/or medical/surgical procedures scheduled prior to 
consenting, but occurring during the study will not be captured as AEs, but will be listed in 
the medical history if related to a pre-existing condition. AEs or abnormal test findings will 
be followed until the event (or its sequelae) or the abnormal test finding resolves or stabilizes 
at a level acceptable to the sponsor/investigator. 
5.2 
Causality assessment 
For each AE, the investigator will provide an assessment of causal relationship to the study 
drug. The causality assessment will be recorded on the appropriate AE reporting page of 
the subject’s CRF. Causal relationship will be assessed by answering the following 
question: 
Is there a reasonable possibility the study drug caused the event? 
Yes: 
There is evidence to suggest a causal relationship between the study drug and 
adverse event; i.e.:  
 There is a reasonable temporal relationship between the study drug and the event, 
and/or  
 The event is unlikely to be attributed to underlying/concurrent disease, other study 
drugs, or other factors, and/or 
 Positive dechallenge and/or rechallenge exist 
 
No: 
There is no evidence to suggest a causal relationship between the study drug 
and adverse event, i.e.: 
 There is no reasonable temporal relationship between the study drug and the event, 
or 
 The subject did not take the study drug, or 
 The event is likely to be attributed to underlying/concurrent disease, other study 
drugs, or other factors, or 
 The event is commonly occurring in the (study) population independent of study drug 
exposure 
5.3 
Severity assessment 
The investigator will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting page of the subject’s CRF. Severity, which is a 
description of the intensity of manifestation of the AE, is distinct from seriousness, which 
implies a subject outcome or AE-required treatment measure associated with a threat to life or 
functionality. Severity will be assessed according to the following scale: 
Mild: 
Minor awareness of signs or symptoms that are easily tolerated without specific 
medical intervention 
Moderate: Discomfort that interferes with usual activities and may require minimal 
intervention 


38 
 
Severe: 
Significant signs or symptoms that are incapacitating with an inability to work or 
perform routine activities and/or that require medical intervention 
5.4 
Serious adverse events 
An SAE is any untoward medical occurrence that at any dose:  
 Results in death 
 Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death at the time of the event, it does not refer to an event that 
hypothetically might have caused death if more severe)  
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event that might not be immediately life threatening or result 
in death or hospitalization but might jeopardize the subject or might require 
intervention to prevent one of the other outcomes listed above. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization 
or development of dependency or abuse. 
 
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting.  
Emergency room visits that do not result in hospitalization should be evaluated for one of the 
other serious outcomes to determine whether they qualify as SAEs. 
5.5 
Medication error 
Medication error refers to any unintended error in the dosing and/or administration of the 
study drug as per instructions in the prescribing information.  Medication errors generally 
fall into 4 categories as follows: 
 Wrong drug 
 Wrong dose (including dosing regimen, strength, form, concentration, amount); 
 Wrong route of administration; 
 Wrong subject (i.e. not administered to the intended subject). 
Medication Errors include occurrences of overdose and underdose of the study drug. 


39 
 
5.6 
Procedure for collection of adverse events and serious adverse events   
All nonserious AEs and SAEs that occur in a subject from the time he or she signs the ICF 
until the final follow-up visit will be assessed and recorded on the source documents and 
CRF, regardless of causal relationship to the study drug. 
5.7 
Procedure for serious adverse event reporting  
All SAEs that occur in a subject from the time he or she signs the ICF until the final follow-
up visit will be reported to the sponsor within 24 hours of awareness of the event using the 
provided SAE Report Form. The completed SAE Report Form will be sent  directly to the 
sponsor by emailing 
. In addition to completing the SAE 
Report Form, each SAE will be entered on the appropriate page of the CRF. The investigator 
will assess the causality for each SAE. 
When death occurs with an SAE, the cause of death will be reported as an SAE. “Fatal” will 
be reported as the outcome for these events. 
The sponsor will contact the investigator, if necessary, to clarify any of the event information. 
The investigator will provide any follow-up information for the event to the sponsor on an 
updated SAE report form as soon as it becomes available. 
If the investigator is notified of a SAE that occurs post-study period, that he or she wishes to 
report to the sponsor (e.g., an event suspected to be causally related to the study drug), the 
event will be reported through the process described above.  
Where appropriate, if required by local regulations or procedures, the investigator will report 
these events to the Institutional Review Board (IRB)/Ethics Committee (EC) and/or national 
regulatory authority in addition to the sponsor. 
5.8 
Procedure for medication error reporting  
Medication errors with or without an associated AE will be recorded as medication errors in 
the CRF. SAEs associated with medication errors will be reported to the sponsor as 
described in Section 5.7. 
5.9 
Procedures for reporting pregnancies/lactation exposure  
Occurrences of pregnancy/lactation exposure in a subject should be reported within 24 hours. 
In cases where a pregnancy/lactation exposure occurs with a SAE, the SAE report form 
should be used to report the SAE and the Pregnancy Reporting form should be used to report 
the pregnancy.  
When a pregnancy occurs without any concurrent SAE, the Pregnancy Reporting form will 
be submitted alone. The pregnancy will be followed through to outcome of pregnancy, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. Any pregnancy discovered from the time of consent to follow-up will be 
reported.  


40 
 
5.10 
Potential Hy’s Law cases  
Every subject that meets potential Hy’s law criteria,  
• 
ALT or AST >/=3xULN AND  
• 
Total Bilirubin >/=2xULN AND  
• 
Alkaline Phosphatase <2xULN 
occurring anytime from the time he or she signs the ICF for the trial until the final follow 
up visit, investigators will notify the sponsor immediately when all the above criteria have 
been met. A potential Hy’s law case will be sent directly to the sponsor by emailing IR-
clinical-SAE@allergan.com  on an AE of Special Interest Form along with the SAE Report 
Form as soon as possible (within 24 hours of learning of the potential Hy’s law). The CRF 
for potential Hy’s law cases will be completed within seven calendar days. Every effort to 
determine the cause of the liver enzyme abnormalities will be made, and close monitoring 
will be initiated in conjunction with the medical monitor and in accordance with the FDA 
“Guidance for Industry: Drug Induced Liver Injury- Pre-Marketing Clinical Evaluation” 
July 2009. 
6 
Data analysis 
Frequency and proportion of subjects deemed eligible and ineligible for study enrollment 
based on each of the inclusion/exclusion criteria will be summarized. The frequency and 
proportion of subjects who successfully complete the study, withdraw, were lost-to-follow-
up, and who terminated the study early, will also be reported. Subject characteristics at 
baseline will be summarized and described for all enrolled subjects and compared between 
the pre- and post-periods. Site characteristics will also be described. Descriptive statistics 
(count, mean, standard deviation, range for quantitative variables, and counts and percentages 
for categorical variables) will be reported for all outcomes. The difference in study outcomes 
between the pre- and post-period will be assessed using appropriate statistical methods, 
accounting for study site, with adequate power. The primary outcome will be tested for 
simple superiority, and subsequently, tested for non-inferiority with a 10% margin between 
the pre- and post-periods. 
The primary analysis of differences in LOS is performed using a 2-sided hypothesis test of 
the modified intent-to-treat principle such that all evaluable patients are included in the 
analysis.  Patients are evaluable if they received at least one dose of antimicrobial therapy 
for their ABSSSI. Differences in length of stay are measured by Mann-Whitney U test.   
The secondary endpoints in this study are intended for hypothesis testing and are not powered 
for statistical significance. Differences in continuous variables of secondary endpoints will 
be measured by Mann-Whitney U test, while difference in proportions will be analyzed by 
Fisher’s exact test 
All analyses will be specified in a detailed statistical analysis plan (SAP) that will be prepared 
subsequently and before database lock. The SAP will include table and figure shells.  


41 
 
6.1 
Cost 
Cost data will not be collected in the study. As these data often vary by site and insurer, 
representative unit cost estimates for each healthcare service/medication identified during the 
collection of outcome measures will be identified. Total costs of care for each study subject 
will then be estimated by multiplying utilization of healthcare services collected via the CRF 
by the corresponding unit costs; mean/median total costs of care during the pre- and post-
periods will then be estimated and compared. The approach to the pre-post comparison and 
unit costs will be defined in the SAP. 
6.2 
Handling of missing data  
The SAP will define how missing values and information from subjects lost to follow-up will 
be handled. Site procedures will be developed to minimize the amount of missing data 
however, as this is a pragmatic trial, missing data is expected. Certain outcomes are based on 
data availability from sites (e.g. laboratory values will be summarized for subjects who had 
data collected). 
The extent of missing values will be examined to assess completeness of data among the 
study cohort. In addition, the characteristics of participants with and without missing data 
will be examined to assess whether participant characteristics have any relationship to 
incompleteness.  
6.3 
Sample size and sample size considerations 
 
The sample size was estimated for a two-sided hypothesis test (two-sample equal-variance 
T-test) with a significance level of 0.05 comparing total hospital time (number of days) 
between the pre- and post-periods with 80% power. Assuming an average hospital length of 
stay of 4.0 days (inclusive of all enrolled subjects), with a standard deviation of 3.0 days, 
and a 2 day reduction in length of stay between the pre- and post-periods, it was estimated 
that 37 subjects in each arm of the trial (total enrollment of 74) would be required to 
demonstrate a mean reduction in hospital stay of 2 day. The final enrollment, including 
adjustments for attrition came to 86 subjects (43 patients in each period).  
However, average length of stay and variance, which is correlated to the primary outcome 
of total hospital time for the study population, is largely unknown. The estimated sample 
size will be targeted, yet a subsequent sample size calculation will be undertaken through 
an interim analysis. The average length of stay and variance for the site will be determined 
once an estimated 25 subjects have been enrolled in the pre-period. Based on a revised 
sample size calculation at the time of the interim analysis, any adjustments to targeted 
sample size will be finalized. 
6.4 
Data monitoring and quality control 
Before any subject enters the study, a representative of the sponsor will meet with the 
investigator and core study team to review the procedures to be followed during the study. 
Functionality training for electronic data capture (EDC) provided through REDCap or other 
suitable data platform will be provided via in-person training or computer to investigators 
and authorized designees on recording the data in the CRFs using the EDC system. All 


42 
 
subject information and data will be considered private health information and kept 
confidential in compliance with HIPAA (Health Insurance Portability and Accountability 
Act of 1996). After the first subject is enrolled, the sponsor will periodically monitor the 
progress of the study by teleconference and/or conducting on-site visits. The sponsor may 
request and review query statuses, possibly warranting more frequent communication 
and/or site visits with the investigator and the study site staff. The investigator will make 
available to the sponsor source documents (written notes and electronic medical records, if 
used), signed consent forms, and all other study-related documents. The investigator and 
the study site staff will be responsible for data entry of subject data into the CRFs via the 
EDC system, resolving data queries generated via the EDC system and providing missing 
or corrected data. The investigator will be responsible for approving all data entry and all 
changes performed on the data, and endorsing the subject data within the EDC system. 
Quality control will be implemented and maintained throughout the conduct of the study.  
Data collection will involve the use of the EDC system provided by the site, to which only 
authorized personnel will have access. Subject’s data will be entered into the EDC system 
by the investigator or designee using their assigned EDC user account as specified in 
Section 4.2 Data collection.  
7 
Study site and study administrative structure 
7.1 
Core study team 
The core study team will consist of primary investigators and sponsor representatives. The 
primary investigators on the core study team will be responsible for training of the site study 
teams, responsible for adherence to the protocol, monitoring and reporting as consistent with 
regulation and law, and coordinating and participating in training sessions for the site study 
teams. The site investigators on the core study team is responsible for coordinating training 
of the site study teams for both protocol adherence and implementation and 
operationalization of the new critical pathway, including site-specific considerations. 
Training will occur before enrollment in the pre- and post-periods for adherence to the 
protocol. Training will additionally occur for implementation of the new critical pathway 
during the 2-4 weeks after the last subject is enrolled during the pre-period of the study. 
7.2 
Site study team 
The site study team at each site will consist of the primary site investigators and study 
administrators, including hospital staff (including physicians, nurses, and/or pharmacists), 
who will be responsible for adhering to the protocol for both the pre- and post-periods. The 
site study team will be further supported by the core study team. The site study team will be 
responsible for participating in training sessions and/or engagement in communication from 
site investigators on the core study team, in regards to study background/rationale, site 
procedures to identify and enroll subjects who are eligible for the study during the pre- and 
post-periods, data collection, and follow-up of subjects. Specifically, for the post-period, 
training on the implementation of the new critical pathway is vital. Training will include site 
procedures, such as how to obtain study drug during the post-period from the hospital 
pharmacy and the location to administer study drug. This will ensure adherence to the 
protocol and that operationalization of the study is consistent during both study periods. 


43 
 
8 
Ethical considerations  
8.1 
Regulatory and ethical compliance and protection of human subjects 
To ensure safety of participating subjects, this study will be conducted in compliance with 
the protocol, the rules and regulations of each institutional review board (IRB), informed 
consent regulations, and standard operating procedures (SOP) of the sponsor, and the site. 
This study will adhere to all applicable local regulatory requirements and be governed 
according to local laws and regulations. The following rules, regulations, and practices will 
be adhered to: Good Clinical Practice (GCP) guidelines, International Conference on 
Harmonisation (ICH) Guidelines, Declaration of Helsinki, and the Belmont Report. 
8.2 
Subject confidentiality 
All necessary measures will take place to ensure subject confidentiality. Only site study team 
members will know the identity of participating subjects, however no identifying information 
will be collected on any study-related documents. Any data provided to the sponsor will be 
provided by using the unique subject ID. The sponsor will not have access to any subject 
identification log. Any data reported or published will be presented as aggregated data, and 
no individual data will be reported to reduce any risk of subject identification. 
8.3 
Informed consent procedures 
 
Patients, after being given an explanation of the study, will give voluntary and written 
informed consent and HIPAA (Health Insurance Portability and Accountability Act of 
1996) authorization (in compliance with 21 CFR, Parts 50 and 312) or other appropriate 
documentation, according to local regulatory requirements, before participating in any 
study-related procedures. 
Informed consent will be obtained from each subject prior to the beginning of any study-
specific activities, and will include consent to collection of clinical, economic and humanistic 
outcomes. This may involve gathering data through chart review or directly eliciting 
information from subjects. Informed consent during the post-period, or interventional period, 
will involve consent to treatment through a new critical pathway and consent to collection of 
clinical, economic and humanistic outcomes. Each eligible subject will have the opportunity 
to read and review the approved informed consent form (ICF) and have the opportunity to 
ask questions to the participating Study Investigator, Study Coordinator, or other study team 
member. Signed copies of the ICF and the HIPAA or other locally applicable form will be 
given to the subject, and both documents will be placed in the investigator’s study files. 
The participating subject may withdraw participation and/or informed consent at any time 
throughout the conduct of the study. Withdrawing participation will relieve the subject from 
any future data collection time points; withdrawing consent will relieve the subject from any 
future data collection time points and remove any historic study data collection.  
8.4 
Responsibilities of the investigator and IRB 
The responsibilities of investigators include creation of and maintenance of a core study team 
(Please refer to Section 7 for more information), adhering to protocol requirements, including 


44 
 
educational requirements for implementation of the intervention in the post-period, and 
ultimately, are the institutional leads to support protocol implementation. The study team will 
be responsible for timely reporting, where appropriate, to the institutional IRB. The 
investigators must demonstrate reasonable efforts to obtain qualified patients for the study. 
The responsibilities of the IRB include adhering to institutional requirements,  performing an 
objective review of the acceptability of the study protocol and analysis plan (i.e. research) in 
terms of institutional requirements, commitments, regulations, applicable law, and 
professional conduct and practice, provide continued monitoring and review of research, 
review of key events (protocol amendments, protocol deviations, adverse events, or non-
compliance), review of any required progress reports, and to report any required information 
to appropriate authorities and/or organizations.  
8.5 
Publication  
All data generated in this study are the property of the sponsor. An integrated clinical and 
statistical analysis report will be prepared at the completion of the study.  
Publication of the results by the investigator will be subject to mutual agreement between the 
investigator and the sponsor and will follow the sponsor’s SOP on publications. 
9 
Protocol deviations and violations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures that is under the investigator’s responsibility and oversight (as defined by 
regulations) without prior written IRB approval or favorable opinion of an appropriate 
amendment and that does not have a major impact on the subject’s rights, safety, or well- 
being, or on the integrity and authenticity of the study data. Deviations may include, but are 
not limited to, departure from inclusion/exclusion criteria, dosing, duration of treatment, 
failure to perform the required assessments at specified time points, scheduling of visits not 
in accordance with specifications, or subject safety. Deviating from the protocol is permitted 
only if absolutely necessary for the safety or clinical management of the subjects and will 
immediately be reported to the sponsor. Protocol deviations will be reported to the sponsor 
either verbally or electronically within 5 working days from the day of discovery. 
A protocol violation is a form of protocol deviation that has a major impact on the subject’s 
rights, safety, or well-being, or on the integrity and authenticity of the study data. Protocol 
violations will be reported to the sponsor within 24 hours, if possible. The IRB will be 
notified within the time period dictated by the IRB associated with this study. 
9.1 
Protocol amendments 
Any amendment to this protocol will be provided to the investigator in writing by the 
sponsor. No protocol amendment will be implemented (with the exceptions noted below) 
before it has been approved by the IRB and the signature page, signed by the investigator, 
has been received by the sponsor. If the protocol is amended to eliminate or reduce the risk 
to subjects, the amendment will be implemented before IRB review and approval. 
However, the IRB will be informed in writing of such an amendment, and approval will be 
obtained within reasonable time limits. 
 


45 
 
10 
References  
1. 
US Department of Health and Human Services, US Food and Drug Administration, US 
Center for Drug Evaluation and Research. Guidance for Industry - Acute Bacterial Skin and 
Skin Structure Infections: Developing Drugs for Treatment. October 2013; 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071185.pdf. Accessed January 29, 
2016. 
2. 
Amin AN, Cerceo EA, Deitelzweig SB, Pile JC, Rosenberg DJ, Sherman BM. Hospitalist 
perspective on the treatment of skin and soft tissue infections. Mayo Clin. Proc. 
2014;89(10):1436-1451. 
3. 
Pollack CV, Jr., Amin A, Ford WT, Jr., et al. Acute bacterial skin and skin structure 
infections (ABSSSI): practice guidelines for management and care transitions in the 
emergency department and hospital. J. Emerg. Med. 2015;48(4):508-519. 
4. 
Pallin DJ, Camargo CA, Jr., Schuur JD. Skin infections and antibiotic stewardship: analysis 
of emergency department prescribing practices, 2007-2010. West. J. Emerg. Med. 
2014;15(3):282-289. 
5. 
Lee GC, Boyd NK, Lawson KA, Frei CR. Incidence and cost of skin and soft tissue 
infections in the United States. Paper presented at: ISPOR 20th Annual International 
Meeting2015; Philadelphia, PA, USA. 
6. 
Edelsberg J, Taneja C, Zervos M, et al. Trends in US hospital admissions for skin and soft 
tissue infections. Emerg. Infect. Dis. 2009;15(9):1516-1518. 
7. 
Healthcare Cost and Utilization Project (HCUP). Statistical Brief #162. Most Frequent 
Conditions in U.S. Hospitals. 2011; http://www.hcup-
us.ahrq.gov/reports/statbriefs/sb162.pdf. Accessed May 31, 2016. 
8. 
Berger A, Weber DJ, Boening AJ, et al. Poster No. 288: Patterns of initial antibiotic therapy 
in hospitalized patients with complicated skin and skin structure infections (cSSSI) in the 
US: 2007 - 2010. Paper presented at: IDSA 49th Annual Meeting2011; Boston, MA, USA. 
9. 
Berger A, Edelsberg J, Oster G, et al. Patterns of initial antibiotic therapy for complicated 
skin and skin structure infections (cSSSI) in US hospitals, 2000-2009. Infect Dis Clin 
Pract. 2013;21:159-167. 
10. 
Talan DA, Salhi BA, Moran GJ, et al. Factors associated with decision to hospitalize 
emergency department patients with skin and soft tissue infection. West. J. Emerg. Med. 
2015;16(1):89-97. 
11. 
Tice AD, Rehm SJ, Dalovisio JR, et al. Practice guidelines for outpatient parenteral 
antimicrobial therapy. IDSA guidelines. Clin. Infect. Dis. 2004;38(12):1651-1672. 
12. 
Allergan. Prescribing information: Dalvance (dalbavancin). 2014; 
http://www.allergan.com/assets/pdf/dalvance_pi. Accessed January 29, 2016. 


46 
 
13. 
Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly 
dalbavancin versus daily conventional therapy for skin infection. N. Engl. J. Med. 
2014;370(23):2169-2179. 
14. 
Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized, double-blind comparison of once-
weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated 
skin and skin structure infections. Clin. Infect. Dis. 2005;41(10):1407-1415. 
15. 
Seltzer E, Dorr MB, Goldstein BP, et al. Once-weekly dalbavancin versus standard-of-care 
antimicrobial regimens for treatment of skin and soft-tissue infections. Clin. Infect. Dis. 
2003;37(10):1298-1303. 
16. 
Dunne MW, Puttagunta S, Giordano P, Krievins D, Zelasky M, Baldassarre J. A 
Randomized Clinical Trial of Single-Dose Versus Weekly Dalbavancin for Treatment of 
Acute Bacterial Skin and Skin Structure Infection. Clin. Infect. Dis. 2015. 
17. 
Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and 
management of skin and soft tissue infections: 2014 update by the Infectious Diseases 
Society of America. Clin. Infect. Dis. 2014;59(2):e10-52. 
18. 
The Medical Letter. Handbook of Antimicrobial Therapy, 18th edition.  
http://secure.medicalletter.org/handbooks#hat. Accessed January 29, 2016. 
19. 
Forest Laboratories I. Prescribing information: Teflaro (ceftaroline fosamil) injection for 
intravenous (IV) use. 2010; 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/200327s000lbl.pdf. Accessed 
January 29, 2016. 
20. 
Theravance I. Prescribing information: VIBATIV (televancin) for injection, for intravenous 
use. 2009; http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022110s000lbl.pdf. 
Accessed January 29, 2016. 
21. 
Merck. Prescribing information: SIVEXTRO (tedizolid phosphate) for injection, for 
intravenous use; SIVEXTRO (tedizolid phosphate) tablet, for oral use. 2014; 
https://www.merck.com/product/usa/pi_circulars/s/sivextro/sivextro_pi.pdf. Accessed 
January 29, 2016. 
22. 
The Medicines Company. Prescribing information: ORBACTIV (oritavancin) for injection, 
for intravenous use. 2014; 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206334s000lbl.pdf. Accessed 
January 29, 2016. 
23. 
Triax Pharmaceuticals L. Prescribing information: MINOCIN, Minocycline For Injection 
100 Mg/Vial Intravenous 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/050444s047lbl.pdf. Accessed 
January 29, 2016. 


47 
 
24. 
Cubist Pharmaceuticals. Tedizolid phosphate for the treatment of acute bacterial skin and 
skin structure infections. March 31, 2014; 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
Anti-InfectiveDrugsAdvisoryCommittee/UCM390790.pdf. Accessed January 29, 2016. 
25. 
Itani KM, Shorr AF. FDA guidance for ABSSSI trials: implications for conducting and 
interpreting clinical trials. Clin. Infect. Dis. 2014;58 Suppl 1:S4-9. 
26. 
Surviving Sepsis Campaign. International Guidelines for Management of Severe Sepsis and 
Septic Shock. 2012; http://www.sccm.org/Documents/SSC-Guidelines.pdf. Accessed 
January 29, 2016. 
27. 
American College of Chest Physicians/Society of Critical Care Medicine Consensus 
Conference: definitions for sepsis and organ failure and guidelines for the use of innovative 
therapies in sepsis. Crit. Care Med. 1992;20(6):864-874. 
28. 
Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory 
response syndrome criteria in defining severe sepsis. N. Engl. J. Med. 2015;372(17):1629-
1638. 
29. 
Cohen J. Infection in the immunocompromised host In: Warrell DA, Cox TM, Firth JD, 
eds. Oxford Textbook of Medicine, 5th edition. 
30. 
Zhang W, Bansback N, Boonen A, Young A, Singh A, Anis AH. Validity of the work 
productivity and activity impairment questionnaire--general health version in patients with 
rheumatoid arthritis. Arthritis Res. Ther. 2010;12(5):R177. 
31. 
Ware JE, Kosinski M, Turner-Bowker DM, Gandek B. How to Score the Version 2 of the 
SF-12 Health Survey (with a supplement documenting version 1). Lincoln, RI: Quality 
Metric; 2002. 
 
 


48 
 
11 
Appendices 
11.1 
Measurement of lesion characteristics 
 
Measurements are to be taken while the infected area is in a nondependent position, e.g., if infection 
was on the leg, the subject was lying down, not sitting or standing. All types of infections are to be 
measured as measurement of erythema upon enrollment and any subsequent physical follow-up visits. 
Maximal dimensions of erythema, both width and length, are to be recorded in centimeters. 
Investigators should attempt to find the infection edge that best distinguished erythema from non-
erythematous skin. Erythema is to be measured in the dimension of maximal length. The maximal 
width is to be measured perpendicular to the axis of the maximal length. The maximal width 
measurement does not have to be in the center if the area of erythema is irregular. The length of the 
infection is to be multiplied by perpendicular width of wound. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


49 
 


50 
 


51 
 


52 
 


53 
 


54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


55 
 


56 
 
 
 
 
 
 
 
 
 
 
 


57 
 


58 
 


59 
 


60 
 


Allergan 
Confidential 
Page 61 
Protocol 
 
 
 
 
61 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
NCT03233438 
 
Study ID: CMO‐US‐ID‐0528 
 
 
Title: Development of a New Critical Pathway for Treatment of Acute Bacterial Skin and Skin Structure 
Infections 
 
Statistical Analysis Plan: 09 May 2018 
 
 
 




Allergan ENHANCE Registry CMO-US-ID-0528 
 
Version 1.0 Dated: 09MAY2018                          CONFIDENTIAL
Page 1 of 41
 
 
 
 
Statistical Analysis Plan 
 
Version 1.0  
Dated: 09May2018 
 
ENHANCE: Development of a New Critical Pathway 
for Treatment of Acute Bacterial Skin and Skin 
Structure Infections 
 
 
Protocol Number: CMO-US-ID-0528 v 6.0 Dated: 
03MAR2017 
 
 

Prepared for 
Allergan 
2525 Dupont Drive 
Irvine, CA 92612-1599 
 




Allergan ENHANCE Registry CMO-US-ID-0528 
 
Version 1.0 Dated: 09MAY2018                          CONFIDENTIAL
Page 2 of 41
 
 
 
Statistical Analysis Plan - Approval 

ENHANCE: Development of a New Critical Pathway for Treatment of 
Acute Bacterial Skin and Skin Structure Infections 
 
Protocol: 
Number: CMO-US-ID-0528 
Version: 6.0 
Date: 03MAR2017 
 
Statistical Analysis Plan 
Version: 1.0 
Date: 09MAY2018 
 
This Statistical Analysis Plan has been reviewed and approved by the 
individuals listed below. 




Allergan ENHANCE Registry CMO-US-ID-0528 
 
Version 1.0 Dated: 09MAY2018                          CONFIDENTIAL
Page 3 of 41
 
 
 
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Analysis populations 
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Sample size 
6.1.3 
Rounding 
6.1.4 
Handling of outliers 
6.1.5 
Handling of missing and/or incomplete data 
6.1.6 
Interim analysis 
6.1.7 
Subgroup analyses 
6.1.8 
Statistical software 
6.1.9 
Quality Control 
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6.2.1 
Patient Disposition 
6.2.2 
Demographic and Baseline Characteristics 
6.2.3 
Infection Characteristics at Baseline and Follow-up 
6.2.4 
Outcomes 
6.2.5 
Clinical Assessments 
6.2.6 
Antibiotic Treatments and Concomitant Medications 
6.2.7 
Safety Assessments 
6.2.8 
Laboratory and Microbiology 
6.2.9 
Healthcare Costs 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ABSSSI 
 
acute bacterial skin and skin-structure infections 
AE 
 
 
adverse event 
AIDS  
 
acquired immune deficiency syndrome 
BMI 
 
 
body mass index 
BP 
 
 
blood pressure 
CCI 
 
 
Charlson Comorbidity Index 
CCR 
 
 
cost:charge ratio 
CI 
 
 
confidence interval 
CRF 
 
 
case report form 
CSR 
 
 
clinical study report 
ED 
 
 
emergency department 
FAS 
 
 
full analysis set 
GFR 
 
 
Glomerular filtration rate 
g/dL 
 
 
grams per deciliter 
HIV 
 
 
human immunodeficiency virus 
HRQoL  
 
health-related quality of life 
ICU 
 
 
intensive care unit 
LOS 
 
 
length-of-stay 
LTC 
 
 
long-term care 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MIC 
 
 
minimum inhibitory concentration 
MCS 
 
 
mental component score 
MOS 
 
 
medical outcomes study 
mEq/L   
 
milliequivalents per liter 
mmHg  
 
milliliter of mercury 
mmol/L 
 
millimolar 
mg/dL  
 
milligrams per deciliter 
MRSA  
 
Methicillin-resistant Staphylococcus aureus 
OPAT  
 
outpatient parenteral antibiotic therapy 
PICC 
 
 
peripherally inserted central catheter 
PCS 
 
 
physical component score 
PRO 
 
 
patient-reported outcome 
SAE 
 
 
serious adverse event 
SAP 
 
 
statistical analysis plan 
SAS 
 
 
statistical analysis system 
SD 
 
 
standard deviation 
SF 
 
 
short-form 
SIRS  
 
Systemic Inflammatory Response Syndrome 
SNF 
 
 
skilled nursing facility 
US 
 
 
United States  
WHO  
 
World Health Organization 
WPAI  
 
Work Productivity and Activity Impairment Questionnaire  


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1.0 Introduction 
This statistical analysis plan (SAP) outlines the planned analysis for data 
collected within Allergan study CMO-US-ID-0528, entitled “Development of a 
New Critical Pathway for Treatment of Acute Bacterial Skin and Skin Structure 
Infections”. This SAP applies to the protocol, Version 6.0, dated March 03th, 
2017, and provides a description of methods for handling the data.   
 
This pragmatic trial has been developed to assess a new critical pathway for 
the treatment of acute bacterial skin and skin-structure infections (ABSSSI); 
it will include the use of guideline-based criteria to identify patients eligible for 
outpatient parenteral antibiotic therapy (OPAT), and, for those who meet these 
criteria, the use of dalbavancin — a novel, single-dose, long-acting, second 
generation lipoglycopeptide indicated for the treatment of ABSSSI caused by 
susceptible strains of Gram-positive bacteria. 
2.0 Study Objectives 
2.1
Primary Objective 
The primary objective of this study is to estimate the difference in infection-
related total admitted hospital days during initial care (the date of enrollment 
to 10-14 days) and follow-up (30 days after initial care) comparing ABSSSI 
patients receiving care before implementation of the new critical pathway and 
after implementation. 
 
2.2
Secondary Objectives 
The secondary objectives of this study are to estimate the difference in the 
following outcomes during initial care (the date of enrollment to 14 days) and 
follow-up (30 days after initial care) comparing ABSSSI patients receiving care 
before implementation of the new critical pathway and after implementation: 
 
x
Total admitted hospital days during initial care and follow-up 
x
Infection-related major surgical interventions that required operating 
room time during initial care and follow-up  
x
Infection-related hospitalizations during initial care and follow-up 
x
Infection-related hospitalizations during initial care and follow-up that 
resulted in admission to Intensive Care Unit (ICU) 
x
All cause hospitalizations in the 30 days post discharge from the hospital 
x
Infection-related emergency department (ED) visits during initial care 
and follow-up 
x
Infection-related outpatient healthcare visits during initial care and 
follow-up 
x
Use of a peripherally inserted central catheter (PICC) line or central line 
to administer antibiotic therapy during initial care and follow-up 
x
Infection-related healthcare visits due to PICC line or central line used 
to administer antibiotic therapy during initial care and follow-up 


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x
Response to treatment at end of treatment visit 
x
Serious adverse events (SAEs) during initial care and follow-up 
x
Patient satisfaction with care (patient reported or completed by a 
caregiver if the patient cannot complete) 
x
Patient work and productivity loss (patient reported or completed by a 
caregiver if the patient cannot complete) 
x
Patient Health-related Quality of Life (HRQoL) (patient reported or 
completed by a caregiver if the patient cannot complete) 
3.0 Study Design 
This study will employ a “pre-post” pragmatic design, which will consist of both 
a pre-period, or an observational baseline period, and a post-period, or an 
interventional period. The pre-period and post-period will consist of 
independent groups of patients.During the pre-period, the site will implement 
the first component of the critical pathway through implementation of 
guideline-based criteria to identify patients admitted to the hospital, obtain 
informed consent, and monitor enrolled subjects. The site will initiate 
treatment for ABSSSI with “usual care,” defined as site- or physician-specific 
antibiotic treatment of ABSSSI with coverage for a known or suspected Gram-
positive infection (e.g., vancomycin, linezolid, and daptomycin) to each study 
patient who meets all inclusion and exclusion criteria. Blinding of treating 
physician to patient enrollment in the study during the pre-period will ensure 
unbiased provision of usual care. During the post-period, for all patients who 
provide informed consent and are subsequently enrolled, each participating 
site will additionally implement the second component of the new critical 
pathway, use of dalbavancin, at the point of care in the hospital or other 
designated site to each study patient who meets all inclusion and exclusion 
criteria.  
 
For both periods of interest, patient follow-up spans the period beginning on 
the day of study enrollment and ends 44 days thereafter, which incorporates 
an initial care period of 14 days (reflecting the 10–14-day period during which 
most antibiotics are anticipated to be required for care of ABSSSI) and a 
subsequent “follow-up” period of 30 days. Study measures will be collected as 
described in the protocol and will be based on medical records, unless 
otherwise indicated. 
 
A schedule of assessments is provided in Appendix A. Follow-up visits will be 
scheduled for approximately 48-72 hours after enrollment (both periods), 10-
14 days after enrollment (both periods), and 44 days after enrollment (both 
periods). Any additional visits to the visit schedule given in Appendix A will be 
at the discretion of the patient and treating physician. 
 
The duration of the study was not predetermined; it is dependent on the time 
required to enroll the necessary number of eligible patients (43 patients per 
time period; 86 patients enrolled in all). 


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4.0 Study Measures 
4.1 
Baseline Characteristics 
The following baseline characteristics will be collected:  
x
Demographic data: Age (in years, derived and described in Appendix 
B), gender, ethnicity, race, employment status, and location patient 
presents from (e.g. from home, long-term care [LTC], skilled nursing 
facility [SNF], nursing home). 
x
Comorbidities: myocardial infarction, congestive heart failure, 
peripheral vascular disease, cerebrovascular disease, dementia, chronic 
pulmonary disease, rheumatologic disease, peptic ulcer disease, mild 
liver disease, diabetes with/without complications, renal disease, 
moderate or severe liver disease (Child-Pugh Class B and C), any 
malignancy (including leukemia and lymphoma), metastatic solid tumor, 
cancer (active, remitted/cured), alcohol/drug abuse/illicit needle use, 
malnutrition, human immunodeficiency virus (HIV), other immuno-
compromising conditions, altered mental status, lymphedema or chronic 
venous stasis, and peripheral vascular disease. 
x
Charlson Comorbidity Index (CCI): A derived variable based on the 
presence/absence of the comorbidities specified above. The formula by 
which the CCI is calculated is detailed in Appendix C. 
x
Infection type: Cellulitis/erysipelas, wound infection, major cutaneous 
abscess 
x
Infection 
and 
clinical 
characteristics 
during 
the 
initial 
assessment at the hospital and end of treatment visit: 
o Lesion size and location 
o Pain and tenderness associated with the lesion 
o Fever (>100.4°F; >38.0°C; or site-specific definition) 
o Systemic inflammatory response syndrome (SIRS) (see Appendix B) 
o Blood pressure (BP, in mmHg) 
o Total white blood cell count (x109/L) 
o Hemoglobin (g/dL) 
o Sodium (mmol/L) 
o Glucose (mg/dL) 
o Serum creatinine (mg/dL) 
o C-reactive protein (mg/dL) 
o Rapid microbial assay 
o Microbiological culture type (i.e. blood, wound swab, urine) and 
results thereof 
o Presence of recurrent infection and/or any ABSSSI infections in the 
prior 6 months 
x
Utilization 
of 
healthcare 
services 
in 
prior 
3 
months: 
Hospitalizations and primary reason, surgical interventions and primary 


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reason, admission to the ICU and primary reason, ED visits or other 
outpatient visits (e.g., infusion center and physician’s office) and 
primary reason, use of dialysis, use of any medications for chronic 
diseases and specifically use of an antibiotic medication, prior antibiotic 
treatment failure (determined by discontinuation of treatment due to 
worsening or recurrent ABSSSI or the occurrence of an adverse event 
related to the antibiotic), and receipt of wound care for the presenting 
infection.  
4.2 
Primary Outcome 
The primary outcome (i.e., infection-related total number of days spent in 
hospital) will be assessed during the 44-day period of interest, including the 
initial-care period (i.e., beginning on the date of enrollment and ending 14 
days thereafter) and the follow-up period (the 30-day period following initial 
care).  
4.3 
Secondary Outcomes 
Secondary outcomes will be assessed during initial care (the date of enrollment 
to day 14) and/or follow-up (30 days after initial care), and include: 
Measure 
Definition 
Period of 
Assessment 
Total admitted hospital 
days 
Total length of stay (LOS) 
of all hospitalizations 
during the 44 days of the 
study (including initial 
hospitalization) 
Initial care and 
follow-up 
Infection-related major 
surgical interventions 
that required operating 
room time 
Number of all, unexpected 
and expected infection-
related major surgical 
interventions that 
required operating room 
time 
Initial care and 
follow-up 
Infection-related 
hospitalizations 
Number of infection-
related hospitalizations 
Initial care and 
follow-up 
Infection-related 
hospitalizations that 
resulted in admission to 
ICU 
Number of infection-
related hospitalizations 
resulting in admission to 
the ICU. 
Initial care and 
follow-up 
All-cause 
hospitalizations in the 30 
days following discharge 
from the initial 
hospitalization 
Number of all 
hospitalizations for 
patients after initial 
hospitalization discharge 
Overall, including 
Initial care and 
follow-up 
Infection-related ED 
visits 
Number of all, unexpected 
and expected infection-
related ED visits 
Initial care and 
follow-up 


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Measure 
Definition 
Period of 
Assessment 
Infection-related 
outpatient healthcare 
visits (e.g., physicians’ 
office visits, ED 
visits, infusion center 
visits, home health 
visits) 
Number of all, unexpected 
and expected infection-
related outpatient 
healthcare visits, 
generated for all patients 
and repeated by site. 
Initial care and 
follow-up 
Use of PICC line or 
central line to administer 
antibiotic therapy 
Number of PICC line or 
central line placement for 
antibiotic therapy 
Initial care and 
follow-up 
Infection-related 
healthcare visits (e.g., 
hospitalizations, ED 
visits, other outpatient 
visits) due to PICC line 
or central line used 
to administer antibiotic 
therapy 
Number of all, unexpected 
and expected infection-
related healthcare visits 
due to PICC line or central 
line used to administer 
antibiotic therapy 
Initial care and 
follow-up 
Response to treatment 
at end of therapy visit 
Response to treatment 
will be defined through an 
assessment of erythema 
and the absence of fever 
at 10-14 days and will be 
categorized as a complete 
response, partial 
response, or failure. 
Initial care 
Serious adverse events 
(SAEs) 
Number of events, 
number of patients and 
percentage of patients 
experiencing SAEs as 
described in protocol 
Initial care and 
follow-up 
Patient satisfaction with 
care 
Summarize patient 
satisfaction with care 
(reported by patient, 
questionnaire provided in 
protocol).  
This will be completed by 
a caregiver if the patient 
cannot complete. 
Follow-up 
Patient work and 
productivity loss 
Number of days with 
lost/reduced productivity, 
as measured through the 
Work Productivity and 
Activity Impairment 
Follow-up 


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Measure 
Definition 
Period of 
Assessment 
(WPAI) questionnaire. 
This will be completed by 
a caregiver if the patient 
cannot complete. 
Patient HRQoL 
Patient reported, as 
measured through the SF-
121(short-form), with 
acute recall (1-week 
recall).  
This will be completed by 
a caregiver if the patient 
cannot complete. 
Initial care (in 
person) and follow-
up (in person). 
Change scores 
calculated for initial 
care 

Healthcare resource usage during the three months prior to the study will be 
based on examination of the patient’s medical records. 


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4.6 
Safety 
At each visit, patients will be queried regarding adverse events (AEs) and 
SAEs, and medication errors that occurred since the previous visit. Specifically, 
patients will be asked to volunteer information with a non-leading question 
such as, “How do you feel since your last visit?” Study site personnel will record 
all pertinent information in the patient’s case report form (CRF), as described 
in details in the protocol.  
5.0 Changes in the Protocol Specified Analyses 
Infection characteristics described in the protocol including hyperglycemia 
(>120mg/dL blood glucose or site-specific definition), thrombocytopenia


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(<150,000 platelet count or site-specific definition), acidosis (<7.35 pH of the 
blood or site-specific definition or described in medical chart), hyponatremia 
(<135 mEq/L blood sodium or site-specific definition), uremia (as described in 
medical chart), and anemia (14-18 g/dL hemoglobin for men or 12-16 g/dL 
hemoglobin for women or site-specific definition) will not be derived from 
laboratory values or reported in analysis. 
The protocol specifies that the Mann-Whitney U test will be utilized for 
comparison of continuous variables in analyses. However, it was later 
determined that the t-test offers better power and easier inference in most 
moderate to large sample size situations where assumptions of the t-test are 
not grossly violated. Therefore, the t-test where possible and reverting to non-
parametric alternatives only in special circumstances. The rationale for this 
change is as follows: 
x
The sample size estimate in the protocol is based on a t-test. As the 
study is powered for a t-test, it would be most appropriate to use a t-
test if possible. 
x
T-tests are generally equally or more powerful than Mann-Whitney U 
tests if the sample size is moderate or large, even if the normality 
assumption is not met2. Non-parametric tests may not have adequate 
power to detect differences for the sample. 
o Per Lumley et al.2: “In small samples most statistical methods do 
require distributional assumptions, and the case for distribution-
free rank-based tests is relatively strong. However, in the large 
data sets typical in public health research, most statistical 
methods rely on the Central Limit Theorem, which states that the 
average of a large number of independent random variables is 
approximately Normally distributed around the true population 
mean. It is the normal distribution of the average that underlies 
the validity of the t-test…” 
o The sample size is sufficient to meet this criterion even if the data 
are right-skewed. This assumption will be reassessed if the data 
are extremely non-normal. 
x
Results from the Mann-Whitney U test may not be easily described nor 
have valuable clinical meaning. The Mann-Whitney U test is a 
comparison of medians only if the distributions of the two groups are 
shaped identically and heavily skewed. In all other situations, the Mann-
Whitney U test is a comparison of the sum of ranks for the two groups. 
It would not be appropriate to provide mean or median point estimates 
and corresponding CIs in this situation as they are likely to conflict with 
the probability resulting from the Mann-Whitney U test. An example of 
such a situation is provided in Lumley et al.2 
x
All assumptions for the t-test will be carefully checked. If there are 
major violations to the assumptions for the t-test, including a strong 
departure from normality, the Mann-Whitney U test or another 
appropriate non-parametric method will be used as applicable.   
 


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Similarly, the protocol specifies that difference in proportions will be analyzed 
by Fisher’s exact test. However, it was later determined the use of a chi-
square test to compare categorical variables accompanied with asymptotic 
95% CIs on differences in proportions. All assumptions of the chi-square test 
will be carefully checked. If the expected value for any cell reported in 
applicable tables is <5, Fisher’s exact test will be used as appropriate.  
6.0 Statistical Plan and Methods 
As the data are analyzed, some deviations from expectations and/or 
assumptions will become apparent (e.g., missing data, distributional 
assumptions, and small sample sizes in some subgroups of interest). In 
instances where these deviations would make the proposed analyses 
inappropriate/infeasible and/or difficult to interpret, modifications to the 
analysis plan will be made accordingly, and noted in the final report. 
6.1
General Considerations 
6.1.1Analysis populations 
Enrolled Set 
The enrolled set consists of all patients who have signed informed consent and 
met all study eligibility criteria. Data will be summarized on disposition and 
baseline characteristics. Output will be summarized by study period (pre-
period vs. post-period). All data listings will be reported for the enrolled set 
unless specified in Section 5.2. 
 
Full Analysis Set 
The full analysis set (FAS) population consists of all enrolled patients. 
Additionally, patients in the pre-period must receive at least one dose of 
antibiotics and patients in the post-period must receive at least one dose of 
dalbavancin for inclusion. All patients in the pre-period and post-period will be 
analysed. Data will be summarized by study period. 
6.1.2Sample size 
An estimated 86 patients are anticipated to be enrolled at one US site. The 
sample size was initially estimated for a two-sided hypothesis test (two-sample 
equal-variance t-test) with a significance level of 0.05 comparing total hospital 
time (number of days) between the pre- and post-periods with 80% power. 
Assuming an average hospital length of stay of 4.0 days (inclusive of all 
enrolled subjects), with a standard deviation of 3.0 days, and a 2 day reduction 
in length of stay between the pre- and post-periods, it was estimated that 37 
subjects in each arm of the trial (total enrollment of 74) would be required to 
demonstrate a mean reduction in hospital stay of 2 day. The final enrollment, 
including adjustments for attrition came to 86 subjects (43 patients in each 
period). 
 


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The average length of stay and variance for the site was determined after an 
estimated 25 subjects were enrolled in the pre-period. The sample size was 
confirmed with the interim analysis and the enrollment of 86 patients will be 
targeted. 
6.1.3Rounding 
Means and medians will be rounded to one decimal more than that which the 
variable was recorded. Standard deviations will be rounded to two decimals 
more than that which the variable was recorded. 
 
Percentages will be rounded to the nearest integer. Percentages for responses 
to a variable will only include patients with non-missing data, i.e. the 
denominator will be the number of patients with non-missing data.  
 
P-values will be reported to three decimal places. Probabilities that are <0.001 
will be presented as “<0.001.” 
6.1.4Handling of outliers 
Outliers will be examined using descriptive statistics, making sure that the 
minimum and maximum of the variable of interest are not unusually small or 
large and that the standard deviation seems appropriate for the data. If an 
outlier(s) is detected (e.g; more than 3 SD from the mean), the accuracy of 
the entry of the data point(s) will be verified (when possible) and corrected if 
appropriate.  
 
Potential outliers will be identified prior to any statistical analysis. The effect 
of the any outliers on the analysis will determined by the statistician. Outliers 
will be included in or excluded from the statistical analyses as appropriate. 
6.1.5Handling of missing and/or incomplete data 
Patients will be missing specific data points for a variety of reasons. With the 
exception of validated instruments, missing values for a given time point will 
not be imputed and analyses will be conducted using an observed case 
approach. For validated instruments, missing items will be handled according 
to instructions from the relevant scoring manuals. Missing dates will be 
handled with an observed case approach. 
6.1.6Interim analysis 
As documented in the protocol, Version 6.0, there was an interim analysis of 
data to check the sample size assumptions based on approximately 25 enrolled 
pre-period patients. A separate report was completed on the interim analysis. 
No further interim analysis is planned. The output that was produced for the 
interim analysis is denoted in the table shells with a ∫ following the title.  


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6.1.7Subgroup analyses 
Currently no subgroup analyses are planned for this study. If applicable, 
analyses will be repeated for subgroups of interest.  
6.1.8Statistical software 
All analyses will be performed by statisticians/data analysts, in accordance 
with Good Programming Practices guidelines, and will follow the statistical 
analysis plan outlined in this document, including the corresponding table 
shells referenced herein. All analyses will be performed using 
 
 or later to format tables and listings. Table, 
listing and figure output will be generated and delivered as Adobe Acrobat 
(PDF) files.  
6.1.9Quality Control 
All output will be validated and/or QC’d according to Mapi standard operating 
procedures. Output tables and figures will be double programmed and undergo 
statistical review prior to being sent to Allergan. 
6.2
Statistical Methods 
Descriptive analyses will be performed as follows: for continuous variables, 
patient counts, percentages, means, 95% confidence intervals (CI) of the 
means, standard deviations (SD), medians, first (25th percentile) and third 
(75th percentile) quartiles, minima and maxima, and number missing (where 
applicable) will be reported. For categorical variables, patient counts and 
percentages for each category, as well as number missing (where applicable), 
will be reported. Where applicable, summaries for continuous variables will 
include frequencies and percentages for discrete categories (e.g., number of 
ED visits: 0, 1, 2, and so forth).  
 
For applicable categorical variables of baseline characteristics (including 
demographics, infection characteristics at baseline and the day 10-14 follow-
up visit, comorbid conditions reported at baseline, and prior healthcare 
resource utilization within past 3 months), the pre-period will be compared 
with the post-period using chi-square tests or Fisher’s exact tests, as 
appropriate. Differences in proportions of the pre-period and post-period and 
their corresponding asymptotic 95% confidence interval (CI) will be reported, 
where applicable. For applicable continuous variables, two-sided Student’s t-
tests and Mann-Whitney U tests will be used where normality assumptions 
have, and have not, been met, respectively. Where applicable, differences in 
descriptive statistics, proportions, and corresponding 95% CI will also be 
provided between the pre- and post-periods. 
 
Hypothesis testing is specified for outcomes in Section 6.2.4. All statistical 
testing, if done, will be at the significance level of 0.05. Other outcomes will 
be analyzed by descriptive analyses and by number of incidences where 
applicable. Planned analyses are presented in Section 6.2.4.2 for secondary 


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outcomes. All planned hypothesis testing and any unplanned deviation from 
hypothesis testing for secondary outcomes will be purely exploratory, as 
adequate power will not be present to determine statistical significance. There 
will be no adjustments made for multiple comparisons.   
6.2.1Patient Disposition 
The number and percentage of enrolled and FAS patients, number and 
percentage of patients who complete the study, and number and percentage 
of patients who discontinue from the study and reason for withdrawal will be 
summarized in tables for all patients. This information will also be reflected in 
a data listing including the patient’s enrollment date, early discontinuation or 
study completion date, and date of death, if applicable. Patients who are 
excluded from the enrolled set due to not meeting inclusion or exclusion 
eligibility criteria will be summarized in listings. 
 
Although tables and listings will not reflect screen failures captured with 
enrollment logs, the clinical study report (CSR) text will address the 
approximate number of screen failures and the most common reasons for 
screen failure. 
6.2.2Demographic and Baseline Characteristics 
All demographic data will be summarized in tables and listings for the enrolled 
and FAS populations. Descriptive statistics will be summarized for age (in 
years), height at baseline (in cm), weight at baseline (in kg) and body mass 
index (BMI) at baseline (inkg/m2). Patient counts and percentages will be 
summarized for age (e.g., <20 years, 20-29 years, 30-39 years, etc.), 
race/ethnicity, gender, employment status (e.g., employed, full time, part 
time, unemployed), admission source (e.g., from home, LTC, SNF, nursing 
home), and insurance information. This information will be captured in listings 
with date of birth. 
 
All baseline characteristics for comorbid conditions will be summarized for the 
FAS population by patient counts and percentages in tables and include the 
following measures: myocardial infarction, congestive heart failure, peripheral 
vascular disease, cerebrovascular disease, dementia, chronic obstructive 
pulmonary disease, connective tissue disease, peptic ulcer disease, mild liver 
disease, moderate or severe liver disease (Child- Pugh Class B and C), 
hemiplegia, lymphedema / chronic venous stasis, diabetes mellitus (with and 
without end-organ damage), moderate to severe chronic kidney disease (e.g., 
actual measurement and GFR, estimated measurement and GFR, unknown 
measurement), leukemia and remission status, lymphoma and remission 
status, metastatic solid tumor and remission status, alcohol abuse, drug abuse 
including illicit needle use, protein calorie malnutrition, immuno-compromising 
conditions such as HIV, acquired immune deficiency syndrome (AIDS), 
receiving ≥20 mg Prednisone daily (or therapeutically equivalent steroid), 
receiving TNF inhibitors, receiving any other immune modulating medication 
including biologics, and receiving chemotherapy. The Charlson Comorbidity 


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Index will be derived and described by descriptive statistics. All data will be 
reflected in listings. 
 
Healthcare resource utilization within the 3 months prior to study enrollment 
will be reported in tables for the FAS population. Number of patients and 
percentages of occurrences (e.g., none, any, 1, 2, ≥3) and primary reasons 
for the following will be reported for hospitalizations, admissions to the ICU, 
surgical interventions, and ED or outpatient visits. Descriptive statistics will 
also be presented for these variables. Additionally, number of patients and 
percentages of coded diagnoses terms will be reported for hospitalizations and 
admissions to the ICU and number of patients and percentages for specified 
surgical procedures. The number and percentages of patients with minor and 
major surgical procedures will be displayed. The table will also reflect the 
number and percentages of patients with dialysis use, prior medications used 
for chronic diseases, antibiotics taken within 3 months of study enrollment 
(any and described by prescription reason and treatment failure and described 
by prescription reason), and wound care for the presenting infection. Listings 
for hospitalizations will capture the type of visit, primary reason for visit, 
primary diagnosis (coded and verbatim), admission date and time, discharge 
date and time, ICU admissions for hospitalizations, and discharge disposition. 
Prior antibiotic medications will be reported in a listing and will include start 
date and end date, medication named (coded and verbatim), reasons for 
prescription, dose with units and frequencies, route, and reason for 
discontinuation.  
6.2.3Infection Characteristics at Baseline and Follow-up 
Infection characteristics at baseline and the day 10-14 follow-up visit will be 
reported in tables for the FAS population. As applicable, patient counts and 
percentages will be summarized for primary infection type, purulent drainage 
from primary lesion, any pain with primary lesion, tenderness of primary 
lesion, primary lesion location, primary lesion size (75cm2 – 150 cm2, ≥150 
cm2) number of additional lesions (e.g., 0, 1, 2, ≥3), fever, SIRS (met i.e., ≥2 
criteria present, by individual criteria, and by number of criteria met), and 
recurrent/ABSSSI infection in prior 6 months. Descriptive statistics will be 
summarized for primary lesion size and pain on a 10-point scale. Differences 
in infection characteristics between the pre- and post-period will be assessed 
using statistical significance testing. All of the aforementioned variables will be 
reflected in listings. 
6.2.4Outcomes 
 
6.2.4.1 Primary Outcomes 
Primary Outcome: Infection-related Total Admitted Hospital Days 
Infection-related total admitted hospital days will be calculated by two 
methods for the FAS population. First, LOS will be calculated by inpatient only 
stays and second, LOS will be calculated by inpatient stays including time spent 
in prolonged observation status (>1 day). Descriptive statistics for the primary 


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outcome will be shown in a table by initial care, follow-up, and overall for the 
pre-period and post-period, and depicted graphically overall using box plots. 
Patient counts and percentages will be given for the primary outcome (e.g., 0 
day, 1 day … > 5 days). Descriptive statistics in the table will be repeated by 
all patients and patients who complete the study for comparison.  
 
The primary analysis will consist of Hypothesis testing using a two sided (two 
sample equal-variance) t-test, with a significance level of 0.05, comparing the 
difference in total time (in days) spent in hospital between the pre- and post-
periods. Violations of assumptions for the t-test in the data will be checked for. 
An appropriate alternative method will be selected if a major violation to an 
assumption is present, such as the Mann-Whitney U test2.  Overall differences 
in descriptive statistics between the pre- and post-periods for infection-related 
total admitted hospital days will be reported. 
 
Because the baseline characteristics of the pre-period may differ from those of 
the post-period, a secondary analysis using a multivariate regression analyses, 
specifically a generalized linear mixed model (GLMM), 
 
. As the outcome is expected to be heavily 
right skewed, the number of hospital days will be modeled assuming a negative 
binomial distribution with log link.  If the model does not converge or fit, an 
alternate distribution will be selected. This model will assume mutual 
independence between the sites. Similar to above, the multivariate analysis 
will be completed for the primary outcome for inpatient stays only as well as 
including time spent under observation, as well as for all patients and patients 
who complete the study for comparison. 
 
Clinically relevant baseline characteristics of interest for the adjusted analysis 
(as described in Section 4.1) including the following variables: age, gender 
(Male, Female), race (White/Caucasian, Black or African American, Other), 
employment status (Full-Time, Part-Time, None), insurance plan type (Private 
commercial 
plan, 
Government 
funded, 
Uninsured, 
Other), 
Charlson 
Comorbidity Index, lesion surface area (<75cm cm2, =>75 cm2 – 150 cm2, 
>150 cm2), infection type (Wound infection, Cellulitis/erysipelas, Abscess), 
prior health resource use (Yes, No, Unknown), prior antibiotic treatment failure 
(Yes, No, Unknown), presence of SIRS criteria (<2 or >=2), presence of 
recurrent infection in prior 6 months (Yes, No, Unknown), any health resource 
use in prior 3 months (Yes, No, Unknown), as well as is patient was 
immunocompromised (Yes, No, Unknown). Patients will be defined as 
immunocompromised if they have evidence of any of the following at baseline: 
Connective tissue disease, diabetes mellitus, leukemia, or malignant 
lymphoma. These characteristics will be selected for the GLMM model by use 
of stepwise selection with the 
 procedure and a statistical 
significance level of <0.1. Categorical variables will be collapsed where 
possible. The primary predictor variable will be a pre/post-period indicator, and 
potentially other selected characteristics will be forced into the model based 
on clinical rationale and distributions observed in the data (specifically 


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imbalance between the pre- and post-periods); as it is assumed that patients 
enrolled in each site will be correlated, a generalized linear mixed model 
(GLMM) will be generated. The GLMM will adjust for correlated data among 
patients at sites by using a RANDOM statement in analyses.  The Kenward and 
Roger method for approximating degrees of freedom will be taken for inference 
on the fixed effects. The final model results will be presented in a table. 
 
6.2.4.2 Secondary Outcomes 
Secondary Outcomes: Total Admitted Hospital Days 
Total admitted hospital days will be calculated by two methods for the FAS 
population. First, LOS will be calculated by inpatient only stays and second, 
LOS will be calculated by inpatient stays including time spent in prolonged 
observation status (>1 day). The total admitted hospital-days will be assessed 
using a similar approach described for the primary analysis and will include all 
hospital stays. Tables will reflect descriptive statistics for total admitted 
hospital days and depicted graphically overall using box plots. Hypothesis 
testing will be performed by a two sided (two sample equal-variance) t-test, 
with a significance level of 0.05, comparing the difference in total time (in 
days) spent in hospital between the pre- and post-periods. Violations of 
assumptions for the t-test in the data will be checked for. An appropriate 
alternative method, such as the Mann-Whitney U test2, will be selected if a 
major violation to an assumption of the t-test is present. Overall differences in 
descriptive statistics between the pre- and post-periods for total admitted 
hospital days will be reported. 
 
Secondary Outcomes: Infection-Related Major Surgical Interventions that 
Required Operating Room Time 
Infection-related major surgical interventions that required operating time will 
be displayed in tables by initial care, follow-up, and overall for the pre-period 
and post-period for the FAS population. Patient counts and percentages will be 
reported for no, any, expected, and unexpected surgical interventions. 
Differences in proportions between the pre- and post-period will be analyzed 
by a chi-square test or Fisher’s exact test, as appropriate, and given with 
asymptotic 95% CIs. 
 
Secondary Outcomes: Infection-Related Hospitalizations 
Infection-related hospitalizations will be displayed in tables by initial care, 
follow-up, and overall for the pre-period and post-period for the FAS 
population. Patient counts and percentages will be reported for none, any, 1, 
2, and ≥3 infection-related hospitalizations. Differences in proportions 
between the pre- and post-period will be analyzed by a chi-square test or 
Fisher’s exact test, as appropriate, and given with asymptotic 95% CIs. 
 
Secondary Outcomes: Infection-Related Hospitalizations that Resulted in 
Admission to ICU 
Infection-related hospitalizations that resulted in admission to ICU will be 
displayed in tables by initial care, follow-up, and overall for the pre-period and 


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post-period for the FAS population. Patient counts and percentages will be 
reported for none, any, 1, 2, and ≥3 infection-related hospitalizations that 
resulted in admission to ICU. Differences in proportions between the pre- and 
post-period will be analyzed by a chi-square test or Fisher’s exact test, as 
appropriate, and given with asymptotic 95% CIs. 
 
Secondary Outcomes: All-Cause Hospitalizations in the 30 Days Post-
Discharge from the Hospital 
All-cause hospitalizations in the 30 days post-discharge from the hospital will 
be displayed in tables for the pre-period and post-period for the FAS 
population. Patient counts and percentages will be reported for none, any, 1, 
2, and ≥3 all-cause hospitalizations in the 30 days post-discharge from the 
hospital. Differences in proportions between the pre- and post-period will be 
analyzed by a chi-square test or Fisher’s exact test, as appropriate, and given 
with asymptotic 95% CIs. 
 
Secondary Outcomes: Infection-Related ED Visits 
Infection-related ED visits will be displayed in tables by initial care, follow-up, 
and overall for the pre-period and post-period for the FAS population. Patient 
counts and percentages will be reported for none, any, 1, 2, and ≥3 infection-
related ED visits. These categories will be repeated for all, expected, and 
unexpected ED visits. Differences in proportions between the pre- and post-
period will be analyzed by a chi-square test or Fisher’s exact test, as 
appropriate, and given with asymptotic 95% CIs. 
 
Secondary Outcomes: Infection-Related Outpatient Healthcare Visits 
Infection-related outpatient healthcare visits will be displayed in tables by 
initial care, follow-up, and overall for the pre-period and post-period for the 
FAS population. Patient counts and percentages will be reported for none, any, 
1, 2, and ≥3 infection-related outpatient healthcare visits. These categories 
will be repeated for all, expected, and unexpected outpatient healthcare visits. 
Differences in proportions between the pre- and post-period will be analyzed 
by a chi-square test or Fisher’s exact test, as appropriate, and given with 
asymptotic 95% CIs. 
 
Secondary Outcomes: Use of PICC Line or Central Line to Administer Antibiotic 
Therapy 
Use of PICC line, central line or no line to administer antibiotic therapy will be 
displayed in tables by initial care, follow-up, and overall for the pre-period and 
post-period for the FAS population. Patient counts and percentages will be 
presented. Differences in proportions between the pre- and post-period will be 
analyzed by a chi-square test or Fisher’s exact test, as appropriate. 
 
Secondary Outcomes: Infection-related Healthcare Visits Due to PICC Line or 
Central Line Used to Administer Antibiotic Therapy 
Infection-related healthcare visits due to PICC line or central line used to 
administer antibiotic therapy will be displayed in tables by initial care, follow-


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up, and overall by the pre-period and post-period for the FAS population. 
Patient counts and percentages will be reported for none, any, 1, 2, and ≥3 
infection-related outpatient healthcare visits. These categories will be repeated 
for all, expected, and unexpected outpatient healthcare visits. Differences in 
proportions between the pre- and post-period will be analyzed by a chi-square 
test or Fisher’s exact test, as appropriate, and given with asymptotic 95% CIs. 
 
Secondary Outcomes: Response to Treatment at End of Treatment Visit 
Response to treatment at end of treatment visit will be a derived variable and 
further detail for the derivation is given in Appendix B. Response to treatment 
at end of treatment visit (complete, partial, failure) will be displayed in tables 
for the pre-period and post-period for the FAS population. Patient counts and 
percentages will be presented. Differences in proportions between the pre- and 
post-period will be analyzed by a chi-square test or Fisher’s exact test, as 
appropriate. 
 
Secondary Outcomes: Serious Adverse Events 
Serious adverse events will be reported in a table as presented in section 6.2.7. 
No formal hypothesis testing will take place. 
 
Secondary Outcomes: Patient Satisfaction with Care 
Descriptive statistics for the patient satisfaction questionnaire will be reported 
within a table by the pre-period and post-period for the FAS population. No 
scoring or formal hypothesis testing will take place. A listing will display the 
date of visit the assessment occurred, questions answered, and the response 
to each question for each patient. 
 
Secondary Outcomes: Patient Work and Productivity Loss 
Descriptive statistics for the WPAI questionnaire will be reported in a table by 
the pre-period and post-period for the FAS population. Summaries will describe 
the distribution of scores derived at day 14. Scores will be calculated and 
summarized following the WPAI Score Guidelines (see Appendix D). A listing 
will display the date of visit the assessment occurred, component scores 
(absenteeism, impairment while working, overall work impairment, activity 
impairment), questions answered, and the response to each question for each 
patient. 
 
Secondary Outcomes: Patient HRQoL 
Descriptive statistics for the SF-12 will be reported within a table by the pre-
period and post-period for the FAS population. Summaries will describe the 
distribution of scores derived at baseline and day 14, as well as the distribution 
of changes in scores from baseline. Scores will be calculated and summarized 
following the SF-12 scoring manual (see Appendix E). A listing will display the 
date of visit the assessment occurred, component scores (mental health and 
physical), questions answered, and the response to each question for each 
patient. 
 


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6.2.5Clinical Assessments 
Vital signs including temperature (°C), method of collection of temperature, 
heart rate (beats per minute), respiratory rate (breaths per minute), systolic 
BP (mmHg), diastolic BP (mmHg), height (cm), weight (kg) and BMI (kg/m2) 


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will be summarized at baseline and the 48-72 hours after enrollment follow-
up visit (post-period only). 
 
Height is collected in both inches (in) and centimeters (cm) and will be reported 
in centimeters in the analysis. If height is reported in inches then it will be 
converted as follows: 
 
 
Height (cm) = reported value (inches) * 2.54 
 
Weight is collected in both pounds (lbs) and kilograms (kg) and will be reported 
in kilograms in the analysis. If weight is reported in pounds then it will be 
converted as follows: 
 
 
Weight (kg) = reported value (lbs) * 0.4536 
 
Temperature is collected in both degrees Celsius and Fahrenheit and will be 
reported in degrees Celsius in the analysis. If temperature is reported in 
degrees Fahrenheit then it will be converted as follows: 
 
 
Temperature (°C) = (reported value (°F) – 32) / 1.8 
 
Clinical assessments will be summarized with descriptive statistics for baseline 
and the day 10-14 visit by the pre-period and post-period for the FAS 
population. Values will be summarized in tables and listings, and in listings, 
reported with the visit date and change form baseline for follow-up values. 
6.2.6Antibiotic Treatments and Concomitant Medications 
Concomitant medications taken three months prior to study start will be coded 
using the WHODRUG dictionary, Version B2 201609 or later, and the number 
and percentage of patients will be summarized in tables. Antibiotic usage 
during the study will also be coded using the WHODRUG dictionary, Version B2 
201609 or later, and summarized in tables. The most current WHODRUG 
dictionary will be used at the time of analysis. These prior non-antibiotic 
medications used for chronic conditions will be reported in listings, including 
the medication name (coded), reason for prescription, route, and start date 
and end date. All medications will be summarized using descriptive statistics 
by the pre-period and post-period for the FAS population. For post-period 
patients, discharge to complete care in an outpatient setting on the same day 
Dalvance was provided and reasons for not being discharged to an outpatient 
setting will be summarized by patient counts and percentages.  
6.2.7Safety Assessments 
The reporting period for adverse events (AEs) begins from the time of the 
signing of the Patient Authorization throughout the patient’s enrollment in the 
study. AE information will be collected in an ongoing fashion through patient 
reporting AEs to their healthcare provider.   


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All AEs will be coded and summarized by the pre-period and post-period for 
the FAS population by system organ class and preferred term based on the 
MedDRA coding dictionary Version 20.0 or later; the most current MedDRA 
coding dictionary will be used at the time of analysis. AEs will be summarized 
as related to treatment if there is evidence to suggest a causal relationship 
between the study drug (any antibiotic given for ABSSSI from enrollment, 
including the pre-period or post-period) and adverse event, and as not related 
if there is no evidence to suggest a causal relationship between the study drug 
and adverse event. For severity, the most severe case of an AE by a patient 
will be reported, with order of most severity as: Severe>Moderate>Mild. 
 
A listing of adverse events will also be given for each patient and will include 
the reported term, seriousness, severity, relationship to treatment, action 
taken with medication, event outcome, and date for each event reported.   
6.2.8Laboratory and Microbiology 
All laboratory and microbiological assessments will be summarized for baseline 
and follow-up visit in tables with descriptive statistics by the pre-period and 
post-period for the FAS population. Laboratory results will be reported for the 
scheduled baseline and day 10-14 visit. The first microbiology result for each 
patient at baseline and follow-up, respectively, will be summarized for each 
time period. Where more than one unit is collected within analysis, values will 
be converted to a common unit and displayed for analysis. Laboratory 
conversions to standard international units are reported in the table below: 
 
Laboratory Unit 
Standard 
International Unit 
Factor 
Sodium mEq/L 
Sodium mmol/L 
x1 
Potassium mEq/L 
Potassium mmol/L 
x1 
Bicarbonate mEq/L 
Bicarbonate mmol/L 
X1 
 
A listing of laboratory and microbiological assessments will also be given for 
each patient and will include the time period the assessment was taken (e.g., 
initial care, follow-up), date of assessment, laboratory test, reported 
laboratory value, reported laboratory unit, specimen type, method of 
collection, if any isolated were grown from the specimen, the organism grown, 
if this organism was tested for susceptibility, what antibiotics were used for 
susceptibility, the level of susceptibility (sensitive, resistant, intermediate, 
indeterminate) and the minimum inhibitory concentration (MIC) with 
corresponding unit. 
6.2.9Healthcare Costs 
Total costs of care for each study patient over the 44-day period of interest 
will be estimated by multiplying estimates of utilization of healthcare services 
collected during the conduct of this study by corresponding unit costs. Unit 


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costs will include: cost of day in hospital, cost of day in ICU, ED visit, healthcare 
visits, surgical procedures, imaging tests, catheter placement (PICC 
line/central line) and microbial culture. Further detail is given in Section 4.5 of 
this document. 
 
Summary statistics for total costs of care will be estimated for the pre- and 
post-periods for the FAS population.
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7.0 List of Potential Tables/Listings/Figures 
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8.0 References 
1. 
Ware J, Kosinski M, Keller S. A 12-Item Short-Form Health Survey: 
Construction of scales and preliminary tests of reliability and validity. 
Medical Care. 1996;34(3):220-233. 
2. 
Lumley T, Diehr P, Emerson S, Chen L. The importance of the 
normality assumption in large public health data sets. Annual Review 
of Public Health. 2002;23:151–169. 
3. 
Surviving Sepsis Campaign. International Guidelines for Management 
of Severe Sepsis and Septic Shock. 2012; 
http://www.sccm.org/Documents/SSC-Guidelines.pdf. Accessed 
January 29, 2016. 
4. 
American College of Chest Physicians/Society of Critical Care Medicine 
Consensus Conference: definitions for sepsis and organ failure and 
guidelines for the use of innovative therapies in sepsis. Critical Care 
Medicine. Jun 1992;20(6):864-874. 
5. 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of 
classifying prognostic comorbidity in longitudinal studies: development 
and validation. Journal of chronic diseases. 1987;40(5):373-383. 
6. 
Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index 
for use with ICD-9-CM administrative databases. Journal of Clinical 
Epidemiology. 1992;45(6):613-619. 
7. 
Reilly Associates. Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem V2.0. 2010; 
http://www.reillyassociates.net/WPAI_SHP.html. 
8. 
Reilly Associates. WPAI Scoring.  
http://www.reillyassociates.net/WPAI_Scoring.html. 
9. 
Ware JE, Sherbourne CD. The MOS 36-item short-form health survey 
(SF-36): I. Conceptual framework and item selection. Med Care. 
1992;30(6):473-483. 
 
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9.0 Appendices 


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Appendix B: Derived Variables 
 
Analysis 
Section (Visit) 
Variable (Units) 
Definition 
General 
(Baseline) 
Enrollment date 
Informed consent date 
General 
(Baseline) 
Baseline date 
Hospital admission date at initial 
episode of care 
General 
(Initial Care) 
Initial care indicator 
If enrollment date ≤ date ≤ 
enrollment date + 13 days then 
= Yes 
Else = No 
General 
(Follow-up) 
Follow-up indicator 
If enrollment date + 14 ≤ date ≤ 
enrollment date + 43 days then 
= Yes 
Else = No 
Demographics 
(Baseline) 
Age (years) 
Round down to nearest 
integer((Initial hospital admission 
date – date of birth + 
1)/365.25), when both dates are 
available. 
 
Demographics 
(Baseline) 
BMI 
weight (kg)/ [height(m)]2 
Where necessary, height and 
weight will be converted to 
proper units. 
Infection 
Characteristics 
(Baseline) 
CCI 
Will be scored as described in 
Appendix C. 
Includes variables for raw score 
and 10 year survival probability. 
Infection 
Characteristics 
(Baseline) 
Immunocompromised =YES if any of the following at 
baseline: 
-
Diabetes mellitus 
-
Leukemia 
-
Malignant lymphoma 
Infection 
Characteristics 
(Baseline) 
Fever 
If temperature>38 ° C then =Yes 
Else =No  
Infection 
Characteristics 
(Baseline) 
SIRS Criteria Met 
SIRS criteria include 
abnormalities in temperature, 
heart rate, respiration, and white 
blood cell count.  
 
Specifically included are:  


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Analysis 
Section (Visit) 
Variable (Units) 
Definition 
x
Fever of more than> 
38.0°C or hypothermia 
with temperature< 36.0°C 
x
Tachycardia with heart 
rate > 90 beats/minute or  
x
Tachypnea with respiratory 
rate of > 20 
breaths/minute or PaCO2 
of less than 32mmHg 
x
Abnormal white blood cell 
count: leukocytosis 
>12,000/microliter, 
leucopoenia 
<4,000/microliter, or 
>10% immature cells 
(bands).3,4 
If 2 or more criteria present = 
Yes 
Else = No  
 
Antibiotic 
Medications 
(Initial Care and 
Follow-up) 
Days Received 
Antibiotic Medication 
∑ (Medication end date – 
Medication start date +1), when 
both dates are available. 
If dates overlap (e.g., end date 
and next start date are identical) 
then subtract 1 from summation 
for each occurrence.  
 
Primary and 
Secondary 
Outcomes 
(All visits) 
Hospitalization LOS 
(days) 
For all-cause: 
∑ (Hospitalization end date – 
Hospitalization start date +1), 
when both dates are available. 
If ongoing at end of study or 
discontinuation date, use study 
completion date or 
discontinuation date as end date. 
For outcomes, LOS will be 
computed two ways: only 
inpatient hospitalizations visits 
and inpatient hospitalizations 
visits with prolonged observation 
status (e.g., time in observation 
status exceeds 1 day).  
For infection-related: 


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Analysis 
Section (Visit) 
Variable (Units) 
Definition 
Subset all-cause hospitalization 
time for patients with infection-
related hospitalization stays 
Primary and 
Secondary 
Outcomes (End 
of Study Visit) 
Completers Flag 
If “Did the patient complete the 
study?” = 1 on the end of study 
visit CRF page and date of study 
completion does not equal 
missing, then =Yes, 
Else = No 
 
This flag will be used to repeat 
certain primary and secondary 
outcomes that could be 
influenced by early 
discontinuation (e.g., LOS) 
Secondary 
Outcomes 
(Follow-up) 
Response to Therapy 
at End of Therapy 
Visit 
The response will be categorized 
as a “Complete Response” if at 
the day 10-14 visit there is a 
reduction in pain or no pain, 
tenderness, nor fever and the 
primary lesion area has reduced 
in size. 
Else, the response will be 
categorized as a “Partial 
Response” if at the day 10-14 
visit there is a reduction in pain 
score orno pain, tenderness, nor 
fever and the primary lesion area 
remained the same size. 
Else, the response will be 
categorized as a “Failure.” 
Secondary 
Outcomes 
(Follow-up) 
WPAI 
Scores and coded variables will 
be derived as described in 
Appendix D. 
Secondary 
Outcomes  
(Initial Care and 
Follow-up) 
SF-12 
SF-12 sub-scores and total 
scores will be compiled using the 
Health Outcomes Scoring 
Software 5.0 by QualityMetric 
Inc. Further detail is given in 
Appendix E. 
Adverse Events 
(Baseline, Initial 
Care and 
Follow-up) 
Highest severity AE 
Severity of most severe AE for 
the patient with order of 
severity: Severe>Moderate>Mild 
Patients who only have AEs 
reported with missing severity, 


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Analysis 
Section (Visit) 
Variable (Units) 
Definition 
highest severity AE will be 
reported as missing 
 
 


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Appendix F: Revision History 

Version  
Issue Date 
Summary of Changes 
1.0 
09MAY2018 
N/A (first version) 
 
 
 
 
 
 
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