Conditions: Surgical Site Infection
Keywords: Infection, Surgical Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 268
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy and safety of delafloxacin administered as IV and oral formulation in comparison with Best Available Therapy (BAT) in patients with superficial or deep incisional surgical site infection following a cardiothoracic/related leg or abdominal surgery.

Detailed description:
This is a randomized, observer-blinded, active-controlled, parallel-group, multicenter, phase IIIb study for the treatment of incisional, superficial or deep, surgical site infection after cardiothoracic /related leg or abdominal surgery (i.e patients who are at risk of microbiologically resistant infections). IV to be switched to oral delafloxacin will be compared to treatments that represent the best available therapy (BAT) for either cardiothoracic/related leg or abdominal surgical site infection (SSI).

Approximately 600 male and female eligible patients will be randomly assigned in a 1:1 ratio to receive delafloxacin or BAT. For patients who are randomised to BAT, the investigator will choose one out of two treatments available (two available for the cardiothoracic/related leg and two available for abdominal SSI) as most appropriate for patient characteristics and local epidemiological pattern.

Duration of study depends on treatment duration (range: minimum 5 to maximum 14 days, as per Investigator's judgment) followed by visits up to 30 days after end of treatment.

Patients will be hospitalized from Screening (within 30 days from surgery) and will remain hospitalized until considered improved or cure as per Investigator's judgment.

Arms:
arm 1: Delafloxacin IV, with the option to switch to delafloxacin oral arm 2: Cardiothoracic / related leg SSI

* Vancomycin IV
* Linezolid IV, with the option to switch to linezolid oral.

In case of suspicion of Gram-negative, additional therapy shall be added as per investigator's choice

Abdominal SSI

* Piperacillin/Tazobactam IV, OR
* Tigecycline IV

In case of suspicion of MRSA, if the pre-selected treatment is Piperacillin/Tazobactam, additional therapy shall be added as per investigator's choice.

Interventions: intervention 1: Delafloxacin intervention 2: Vancomycin intervention 3: Linezolid intervention 4: Piperacillin/Tazobactam intervention 5: Tigecycline
Intervention descriptions: intervention 1: Powder for solution for infusion 300 mg or tablet 450 mg, BID, for 5 to 14 days intervention 2: Powder for solution for infusion 15mg/kg, BID, for 5 to 14 days intervention 3: Solution for infusion or tablet, 600 mg BID, for 5 to 14 days intervention 4: Powder for solution for infusion 4/0.5 g, TID, for 5 to 14 days intervention 5: Powder for solution for infusion 50 mg, TID, for 5 to 14 days

Protocol document:
Prot_000.pdf: 
Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
CLINICAL TRIAL PROTOCOL
VERSION 1.0, 5 APRIL 2019
A randomized,  observer-blinded,  active-controlled, Phase IIIb study to compare
IV / Oral delafloxacin fixed-dose monotherapy with best available treatments in a
microbiologically enriched population with surgical site infections
Study Code
Study Nick Name/Acronym
EudraCT-Number
Investigational 
Medicinal 
Product
Development Phase of Study 
Sponsor
Co-ordinating Investigator
DELA-01
DRESS- DELAFLOXACIN INTRAVENOUS AND ORAL 
MONOTHERAPY IN SURGICAL SITE INFECTIONS
2018-001082-17
Delafloxacin 300 mg powder for solution for IV 
infusion and 450 mg Oral Tablet
IIIb
MENARINI RICERCHE S.p.A.
Via Sette Santi, 1
50131 Florence, Italy
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
CRO  
 
 
 
CONFIDENTIAL 
Page 1 of 99


Study Code: DELA-01 
EudraCT No.: 2018-001082-17
1 SIGNATURES
Clinical Trial Protocol 
Version 1.0,05 Aprii 2019
The signatories bave read thè clinical trial protocol titled  A randomized, observer-bUndedf 
active-conirolledf Phase Illb study to compare IV / Orai delafloxacin ffxed dose 
monotherapy with best available treatments in a mic obiologically enrichedpopulation witli
surgical site infections** - Version 1,0, OS Aprii 2019 - carefiiliy and agree to adhere to its
provisions. Changes to thè protocol bave to he stateri by thè Sponsor in amendments to thè 
clinical trial protocol, which, if they are substantial, bave to be authorized by thè Competent 
Authorities and Ethics Committees before translating them into action.
Sponsor s Re resen  tive Si n ture D  e
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
CONFIDENTIAL
O
D te
(
Page 2 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
PRINCIPAL INVESTIGATOR’S STATEMENT
a) 
Clinical Statement
My signature below documents my agreement with the contents of this clinical trial protocol 
titled “A randomized, observer-blinded, active-controlled, Phase IIIb study to compare IV /
Oral delafloxacin fixed-dose monotherapy with best available treatments in a
microbiologically enriched population with surgical site infections” – Version 1.0, 05 April 
2019 - with regard to the execution of the study and the required documentation / data 
collection. I agree to comply with this clinical trial protocol in its entirety and with the ICH 
guidelines for Good Clinical Practice (GCP).
b) 
Anti-Corruption Statement
I agree to - I will and I will cause any of my collaborators to - perform any activity in 
accordance with the principles any international anti-corruption legislations, such as OECD 
Convention on Combating Bribery of Foreign Public Officials in International Business 
Transactions, UK Bribery Act and US Foreign Corrupt Practices Act, including Italian 
Legislative Decree 231/2001. In particular, along the performance of the study, I will not - 
and I will cause any of my collaborators not to - directly or indirectly offer, pay, give, or
promise to pay or give or receive any payment or gift of any money or thing of value to or
from any government officer to influence any acts or decisions or to induce such officer to use 
its influence to effect or influence the decision of the relevant government body or any other 
decision maker. I accept to promptly inform the Sponsor in writing in case of violations of or 
deviations from any of the above prescriptions in the conduct of the study and I acknowledge
and accept Sponsor’s rights to conduct audits in order to verify compliance with the above
during or in connection with the performance of the study. I agree and accept that a violation 
of any of the above prescriptions may result in the termination of the research activities of the 
site I work in and / or the entire study.
Principal Investigator  
Signature 
Date
...................................................... ........................................................... 
............................
(printed name)
CONFIDENTIAL 
Page 3 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
2 
PROTOCOL SYNOPSIS
A randomized, observer-blinded, active-controlled, Phase IIIb study to compare  IV / Oral
delafloxacin fixed-dose monotherapy with best available treatments in a microbiologically enriched 
population with surgical site infections
Sponsor Code: 
DELA-01
Nick Name/Acronym:  DRESS- DELAFLOXACIN INTRAVENOUS AND ORAL MONOTHERAPY
IN SURGICAL SITE INFECTIONS
Phase
IIIb
Indication
Acute Bacterial Skin and Skin Structure Infection (ABSSSI)
The study target population includes patients with superficial or deep 
incisional Surgical Site Infections (SSI) following cardiothoracic / related 
leg or abdominal surgical interventions.
No. of sites & countries Approx. 70 sites in Europe.
Investigational Medicinal Product/Treatment Regimen and Duration
Test treatment: IV / Oral Delafloxacin

Freeze-dried powder for solution for IV infusion; one vial contains 433 mg delafloxacin
meglumine which corresponds to 300 mg delafloxacin free acid.

Tablet; one tablet contains 649 mg of delafloxacin meglumine which corresponds to 450
mg delafloxacin free-acid
Test treatment will be administered every twelve hours, with the IV infusion lasting 60 minutes.
Reference treatment(s): Pre-selected Best Available Therapy (BAT) for cardiothoracic / related leg 
or abdominal SSI and described in §2.1. Additional therapy to BAT might be added to optimize the 
antimicrobial coverage as per Investigator’s judgment.
For the Reference treatment(s)/additional therapy, the posology scheme should reflect the 
instructions reported in the relevant SmPC.
Duration of Test or Reference treatment(s) is minimum 5 days up to 14 days based on 
Investigator's judgment.
Please refer to §8.5 and §8.6 for further details on Test and Reference treatment(s) and to §8.4.3 
for study treatment restrictions.
Study Design
Randomized, observer-blinded, active-controlled, parallel-group, multicenter, phase IIIb study in 
600 patients with superficial or deep incisional SSI following a cardiothoracic / related leg or 
abdominal surgical procedure, i.e. an expected microbiologically enriched population with SSI. 
Observer blinded design means that the Principal Investigator (PI) or his/her delegates are 
unblinded whereas a blinded observer is designated to conduct pre-specified assessments without 
access to the assigned treatment to patients. Details on their respective responsibilities are reported 
in §8.2.
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Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
Eligible patients will be randomly assigned in a 1 : 1 ratio to receive Test or Reference treatment,
and stratified by site of infection (at least approximately 180 patients either for the cardiothoracic / 
related leg or abdominal SSI) and superficial or deep infections.
The Reference treatment arm includes two options for each SSI. The selection of one of the two 
allowed options for each SSI is upon Investigator’s judgment based on the patient characteristics 
and local epidemiological pattern and will be recorded prior to the Interactive Web Response 
System (IWRS) assignment of Test or Reference treatment. In addition, in case Gram-negatives or 
MRSA bacteria are suspected in the cardiothoracic or abdominal SSI, respectively, additional 
therapy according to the site Standard of Care (SoC) -with the only exclusion of quinolones- can 
be assigned prior to Randomization by the Investigator (see Schematic study design §2.1). The 
additional therapy will be discontinued as soon as possible if those organisms will be not identified 
in baseline cultures as per Local/Regional microbiological results.
Primary Objective
To assess the comparability of delafloxacin and BAT in terms of Clinical Success in patients with 
superficial or deep incisional SSI following a cardiothoracic / related leg or abdominal surgical 
procedure.
Secondary Objectives
To assess the comparability of delafloxacin and BAT in patients with cardiothoracic / related leg or 
abdominal SSI, in terms of:
- 
Effectiveness, microbiological response and sustained efficacy
- 
safety and tolerability
- 
healthcare resources consumption.
Exploratory Objective
To evaluate the time course of infection biomarkers (Procalcitonin-ProCT and C-Reactive Protein- 
CRP serum values) and their correlation with SSI clinical improvement.
Study duration
Study participation of individual patients is based on the treatment duration (range: minimum 5 to 
maximum 14 days, as per Investigator's judgment) and will last at most 45 days as follows:
➢ 
Screening Visit, for study eligibility assessment (within 30 days from surgery)
➢ 
Randomization and treatment administration (Visit 1; Day 1, within 1 day from Screening)
➢ 
Assessment period that includes:
 Visit 2 (Day 3 – 4, between 48 to 72h after first dose)
 Visit 3 (Day 7) (if applicable)
 End of Treatment (EOT) Visit (within 1 day after last dose)
 Test of Cure (TOC) Visit (7 - 14 days after last dose)
 Follow-up (FU) Visit (or phone call) (21 ± 2 days after last dose)
 Late Follow-up (LFU) / End of Study Visit (28 - 30 days after last dose)
The overall clinical phase is expected to start in Q3 2019.
The enrolment of patients will be competitive; however, eligibility of patients with one out of the
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Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
two types of SSI (cardiothoracic / related leg or abdominal surgical procedure) will end when
overcoming the 70% of the overall study population. Additionally, approximately 20% - 30% of 
total sample size of patients is expected to be recruited altogether in Italy, Spain and/or UK.
Inclusion Criteria
Eligible patients shall meet all the following criteria at Screening:
1. Male or female patients aged more than 18 years.
2.
Patients with a history of cardiothoracic / related leg or abdominal surgery, occurred within
30 days and no implant is left in place, and a diagnosis of SSI according to the CDC 
definition1, namely:
Superficial Incisional Surgical Site Infection, involving only skin and subcutaneous tissue of 
the incision, and at least one of the following local findings:
 purulent drainage from the superficial incision;
 organisms isolated from an aseptically obtained culture of fluid or tissue from the
superficial incision;
 superficial incision is deliberately explored by surgeon AND the patient has at
least one of the following signs or symptoms of infection:
o pain or tenderness,
o localized swelling,
o redness or heat;
 diagnosis of superficial incisional SSI made by the Investigator.
Or
Deep Incisional Surgical Site Infection, involving deep soft tissues (e.g. fascia and muscle 
layers) at the incision site and at least one of the following findings:
 purulent drainage from the deep incision but not from the organ / space component
of the surgical site;
 a deep incision spontaneously dehisces or is deliberately opened by a surgeon
when the patient has at least one of the following signs or symptoms of infection:
o fever (> 38 °C),
o localized pain or tenderness;
 an abscess or other evidence of infection involving the deep incision is found on
direct examination, during reoperation, or by histopathologic or radiologic 
examination;
 diagnosis of deep incisional SSI made by the Investigator.
3.
The severity of infection requires an IV treatment and patient hospitalization according to
the Investigator’s judgment.
4.
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
6.
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
7.
 
 
 
 
Exclusion Criteria
Patients who meet any of the following criteria at Screening are not eligible to the study:
1.
Previous IV antimicrobial therapy exceeding 24 hour duration administered during 72 hours
prior to the first dose of study treatment.
2.
Any infection expected to require systemic antimicrobial agents other than study treatment(s)
(§ 2.1).
3.
Medical history of significant hypersensitivity or allergic reaction or contraindication to the
pharmacological classes of study treatment(s) or excipients of their formulation according to 
the Investigator’s judgment.
4.
Medical history of known or suspected central nervous system (CNS) disorders (e.g., severe
cerebral arteriosclerosis, epilepsy).
5.
Medical history of myasthenia gravis.
6.
Medical history of C. difficile diarrhea.
7.
 
 
 
 
 
 
 
 
 
 
 
8.
Organ-space infection.
9.
Complicated Intra-Abdominal Infection (cIAI).
10.
Any chronic or underlying skin condition at the site of infection that may complicate the
assessment of clinical response (e.g., atopic dermatitis or eczema) or any skin condition that, 
in the opinion of the Investigator, would interfere with the SSI healing.
11.
 
 
 
 
 
 
 
 
 
12.
Patients with known underlying diseases leading to deep immunosuppressive status (e.g.,
HIV/Acquired Immune Deficiency Syndrome-AIDS, malignancies and recent chemotherapy) 
that, in the opinion of the Investigator, would compromise the clinical response.
13.
 
 
 
 
 
 
 
 
   
 
  
 
 
 
  
 
   
14.
Patients with end-stage renal disease on hemodialysis or peritoneal dialysis or creatinine
clearance (CrCl) < 15 mL/min using the Cockcroft-Gault formula.
15.
 
   
 
 
 
 
 
.
16.
 
 
 
 
 
 
 
 
  
  
 
  
 
  
.
17.
  
 
 
  
 
  
.
18.
 
 
 
 
 
.
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Study Code: DELA-01 
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EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
19.
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
.
20.
 
.
Study Visits, and Efficacy and Safety assessments
The study encompasses up to 8 site visits (depending upon the individual duration of study
treatment) and ending with the Late Follow Up Visit that represents the End of Study Visit.
Each patient will undergo the study procedures described below and summarized in the study 
flowchart (§2.2). Along the study period, any planned and unplanned procedure (e.g. specialist 
visit, laboratory or radiologic examinations) will be documented and recorded in eCRF.
Pre-screening
Pre-screening of potential patients in person or by reviewing medical history / medication to 
determine their initial eligibility for a study is a common strategy in the recruitment process and 
can be done before informed consent is obtained.
The Investigator will be trained to encourage patients, at time of hospital discharge after surgical
intervention, in coming back to the site in case they should experience any signs or symptoms of 
SSI.
Before performing any study procedures, all potential eligible patients will sign an Informed
Consent Form (ICF) after receiving any clarification by the Investigator. The Investigator will sign 
the ICF as well.
Screening Visit
The Screening Visit will be performed within 30 days after the surgical intervention. Patients may 
be inpatients or outpatients at the time of Screening. Outpatients successfully completing the 
Screening will be hospitalized.
The following procedures shall be performed after the patient provides informed consent:

Check of Inclusion / Exclusion Criteria (§8.4.1 and §8.4.2)

Collection of demographic data and medical history (§8.7.12.1)

Physical examination (§8.7.12.2)

Recording of prior medications (§8.6.5.1)

Infection site assessment (§8.7.11.1)

Documentation of SSI wound care management, if any (§8.6.5.3)

Gram stain and microbiological culture of infection site specimen (§8.7.11.3)

Blood culture (§8.7.11.3)

Vital signs (§8.7.12.2)

12-lead electrocardiogram (ECG) (§8.7.12.5)

Blood sampling for safety laboratory tests (haematology, biochemistry, coagulation,
virology) (§8.7.12.3)

 
 
 
 
 
 
 (§8.7.11.7)

Urinalysis (§8.7.12.3)

Serum (or plasma) and urine pregnancy test, if applicable (§8.7.12.3)
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Study Code: DELA-01 
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EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
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Page 9 of 99
 Recording of any Clinical Event, not associated to any drug intake (§8.8.1.2) and/or any
Adverse Event associated to any drug intake (§8.8.1.1) that occurs for the first time or 
worsens after the signature of the ICF and prior to Investigational Medicinal Product (IMP) 
administration, if any.
Randomization and Treatment Administration - Visit 1 (Day 1)
Visit 1 has to be scheduled within 1 day from Screening, with the following procedures to be 
performed prior to first administration of study treatment:
 Instructions and completion of the Short Form-36 (SF-36v2) Health Survey questionnaire
(§8.7.11.6), to be performed as first procedure
 Re-check of Inclusion and Exclusion criteria (§8.4.1 and §8.4.2)
 Recording of prior and concomitant medications (§8.6.5.1)
 Infection site assessment (§8.7.11.1)
 Documentation of SSI wound care management, since the previous visit, if any (§8.6.5.3)
 Gram stain and microbiological culture of infection site specimen (§8.7.11.3), if clinically
indicated
 
Blood culture, if the previous culture was positive or if clinically indicated (§8.7.11.3) 
 Vital signs (§8.7.12.2)
 Recording of any Clinical Event, not associated to any drug intake (§8.8.1.2) and/or
recording of any Adverse Event associated to any drug intake (§8.8.1.1) that occurs for the 
first time or worsens after the signature of the ICF and prior to IMP administration, if any
 Investigator’s choice of Reference treatment plus any additional therapy, if needed (§2.1)
 Assignment of the randomized treatment as per IWRS (§8.6.2)
 Administration of study medication.
NOTE-1: If Visit 1 falls on the same day of Screening, all the procedures done at Screening should 
not be repeated.
NOTE-2: In case of vancomycin assignment, vancomycin trough levels shall be monitored after 3 
doses (steady state), at Visit 3 and whenever clinically indicated, for dose or duration of infusion
adjustment2. See §8.6.4 for further details.
Day 2 Onwards Daily Assessments
Starting from Day 2 up to maximum the End Of Treatment, laboratory and clinical 
parameters/assessment reported below will be evaluated DAILY by the blinded observer who will 
be responsible to define:
 Eligibility of the patient to switch from IV to the oral formulation (§0).
 Eligibility of the patient to be discharge relevant for assessment of the Hospital Infection-
Related Length of Stay-IRLOS 0).


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
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Page 10 of 99
Whenever possible, the same blinded observer should complete all the assessments for the patient,
every day approximately at the same time, and within 12:00.
The following procedures shall be daily performed until the eligibility criteria are considered as 
met (§0) by the blinded observer:
 Vital signs: BP, HR and Body Temperature (maximum T° recorded from the last 24h)
 Blood sampling for haematology (WBC count only)
 
Assessment of patient ability to tolerate PO diet and no gastrointestinal absorption problem 
 Wound status idoneous for home care management
NOTE-1: At Visit 2 and Visit 3, vital signs and WBC count are also contemplated and shall be 
performed only once.
NOTE-2: date and time of the actual switch to oral formulation (i.e. first intake of the oral
formulation), will be recorded by the Investigator. Assignment of delafloxacin or linezolid oral kit 
will be performed through IWRS by unblinded site staff.
NOTE-3: date and time of the actual hospital discharge (i.e. the time when the letter of discharge is 
issued) will be recorded by the Investigator upon occurrence along the study up to End of Study 
Visit.
NOTE-4: at the time of actual discharge, if the patient is on treatment with
a) IV formulation and outpatient parenteral antimicrobial therapy at site could be implemented as 
allowed by local standard practice, he/she will travel to site to receive drug administration as per 
treatment schedule;
b) oral formulation (i.e. delafloxacin or linezolid), he/she will be provided with the IMP box
(covering maximum 5 days of treatment) and a paper diary to record daily the tablets intake.
Visit 2 (Day 3-4)
The following procedures shall be performed between 48h and 72 h after first dose administration. 
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the study 
visit.
 Recording of AEs occurred since previous visit, if any (§8.8.2)
 Recording of concomitant medications (§8.6.5.1)
 Infection site assessment (§8.7.11.1)
 Documentation of SSI wound care management, since the previous visit, if any (§8.6.5.3)
 Gram stain and microbiological culture of infection site specimen, if clinically indicated
(§8.7.11.3)
 
Blood culture if the previous culture was positive or if clinically indicated (§8.7.11.3) 
 Vital signs (§8.7.12.2)
 Blood sampling for safety laboratory test (haematology, biochemistry, coagulation,
(§8.7.12.3)
 
 
 
 
 
 
 
 (§8.7.11.7)


Study Code: DELA-01 
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EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
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Page 11 of 99
 Urinalysis (§8.7.12.3).
In case of early treatment withdrawal, patients should undergo the EOT Visit, and should be 
followed as described in §8.4.4.
NOTE: The infection site specimen for microbiological culture should be collected before 
initiation of any alternative antibacterial therapy.
Visit 3 (Day 7)
The following procedures shall be performed at Day 7 if the patient is still on treatment. 
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the study 
visit.
 Patient’s completion of the SF-36v2 Health Survey (§8.7.11.6) to be performed as first
procedure
 Recording of AEs occurred, since previous visit, if any (§8.8.2)
 Recording of concomitant medications (§8.6.5.1)
 Infection site assessment (§8.7.11.1)
 Documentation of SSI wound care management, since the previous visit, if any (§8.6.5.3)
 Gram stain and microbiological culture of infection site specimen, if clinically indicated
(§8.7.11.3)
 
Blood culture if the previous culture was positive or if clinically indicated (§8.7.11.3) 
 Vital signs (§8.7.12.2)
 Blood sampling for safety laboratory test (haematology, biochemistry, coagulation)
(§8.7.12.3)
 
 
 
 
 
 
 
 
 Urinalysis (§8.7.12.3)
 Therapeutic Drug Monitoring for vancomycin (§8.6.4)
In case of early treatment withdrawal, patients should undergo the EOT Visit, and should be 
followed as described in §8.4.4.
NOTE: The infection site specimen for microbiological culture should be collected before
initiation of any alternative antibacterial therapy.
End Of Treatment - EOT Visit
The following procedures shall be performed at EOT Visit (within 1 day after last dose 
administration).
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the study
visit as per Investigator’s prescription.
 Patient’s completion of the SF-36v2 Health Survey (§8.7.11.6) to be performed as first
procedure
 Contact IWRS to report treatment completion status (§8.6.2)
 Recording of AEs occurred, since previous visit, if any (§8.8.2)


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
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Page 12 of 99
 Recording of concomitant medications (§8.6.5.1)
 Infection site assessment (§8.7.11.1)
 
Documentation of SSI wound care management, since the previous visit, if any (§8.6.5.3) 
 Gram stain and microbiological culture of infection site specimen (§8.7.11.3)
 Blood culture if the previous culture was positive or if clinically indicated (§8.7.11.3)
 Physical examination (§8.7.12.2)
 Vital signs (§8.7.12.2)
 12-lead ECG (§8.7.12.5)
 Blood sampling for safety laboratory test (haematology, biochemistry, coagulation,
(§8.7.12.3)
 Blood sampling for infection biomarkers (CRP, ProCT) (§8.7.11.7)
 Urinalysis (§8.7.12.3)
 Serum (or plasma) pregnancy test, if applicable (§8.7.12.3)
 Assessment of clinical response (§8.7.11.2).
In case the EOT Visit is performed for early treatment withdrawal, patients should be followed as 
described in §8.4.4.
Test Of Cure - TOC Visit
The following procedures shall be performed at TOC Visit (7 - 14 days after last dose).
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the study 
visit.
 Patient’s completion of the SF-36v2 Health Survey (§8.7.11.6) to be performed as first
procedure
 Recording of AEs occurred, since previous visit, if any (§8.8.2)
 Recording of concomitant medications (§8.6.5.1)
 Infection site assessment (§8.7.11.1)
 
Documentation of SSI wound care management, since the previous visit, if any (§8.6.5.3) 
 Gram stain and microbiological culture of infection site specimen (§8.7.11.3)
 Blood culture if the previous culture was positive or if clinically indicated (§8.7.11.3)
 Vital signs (§8.7.12.2)
 12-lead ECG (§8.7.12.5)
 
Blood sampling for safety laboratory tests (haematology and biochemistry) (§8.7.12.3) 
 Urinalysis (§8.7.12.3)
 Assessment of clinical response (§8.7.11.2).
Follow Up -FU Visit (or phone call)
Recording of AEs and concomitant medications will be performed 21 days (± 2 days) after the last 
dose. Outpatients (i.e. patients already discharged from the hospital) will receive a follow-up 
telephone call to collect this information or will be invited to the site.
Late Follow Up -LFU / End of Study Visit
The following procedures shall be performed at LFU Visit (28 - 30 days after last dose).


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the study
visit. LFU Visit represents the End of Study Visit.
 Patient’s completion of the SF-36v2 Health Survey (§8.7.11.6) to be performed as first
procedure
 Recording of AEs occurred, since previous visit, if any (§8.8.2)
 Recording of concomitant medications (§8.6.5.1)
 Infection site assessment (§8.7.11.1)
 Documentation of SSI wound care management, since the previous visit, if any (§8.6.5.3)
 Assessment of clinical response (§8.7.11.2).
Efficacy Study Endpoints
Primary Endpoint:
Clinical Success defined as the clinical response of “Cure” or “Improved” at TOC (7 - 14 days 
after last dose) in the Intent-to-Treat (ITT) and the Clinical Evaluable (CE) populations.
Secondary Endpoints:
 Clinical Success at EOT and LFU Visits in the ITT and CE populations
 Clinical Success in pre-specified subgroups of patients (§9.3.5) at TOC Visit in the ITT and
CE populations
 Sustained Clinical Success defined as confirmation at LFU Visit of the clinical Success
outcome assessed at TOC Visit in the ITT and CE populations
 Eligibility to switch to oral formulation in the ITT and CE populations according to the
blinded observer’s assessment as per criteria in §0
 Hospital IRLOS (Infection Related Length of Stay) in the ITT and CE populations,
beginning with first dose of study treatment and ending when the patient is considered 
eligible to discharge up to maximum end of treatment according to the blinded observer’s 
assessment as per criteria in §0
 Hospital LOS (Length of Stay) in the ITT and CE populations, beginning with the
diagnosis of the SSI (Screening) and ending with actual discharge
 Microbiological response at EOT and at TOC Visits in the Microbiologically Intent-to-
Treat (MITT) and in the Microbiologically Evaluable (ME) populations
 Clinical response of “cure” at EOT, TOC, LFU Visits in the ITT and CE populations
 Duration of treatment / IV treatment in the ITT and CE populations
 SF-36v2 Quality of Life (QoL) score at EOT, TOC and LFU Visits in the ITT and CE
populations.
Exploratory Endpoint:
ProCT and CRP serum values and correlation with overall IRLOS assessment and each of the 
IRLOS parameters at different timepoints in the ITT population.
Safety Endpoints
 Incidence, intensity (severity), seriousness and treatment-causality of Treatment-Emergent
CONFIDENTIAL 
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Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
AEs (TEAEs, i.e. AEs that occurred after the first study drug intake).
 Frequency of clinically significant changes in vital signs, 12-lead ECG and laboratory
parameters (haematology, biochemistry, coagulation and urinalysis), post-dose versus 
baseline.
NOTE: The latest assessments performed before first study treatment administration will represent
the baseline.
Health Economics Endpoint
Healthcare resources consumption.
Criteria for Evaluation:
Clinical response
Clinical response will be based on the Investigator’s assessment of the patient’s signs and 
symptoms of infection at the EOT, TOC and LFU Visits and classified as Cure, Improved, Failure 
or Indeterminate defined as follows:
 Cure: The complete resolution of all baseline signs and symptoms of SSI.
 Improved: two or more signs and/or symptoms (but not all) were considered resolved
thus the patient has improved to an extent that no additional antibiotic treatment is 
necessary.
NOTE: Clinical Success is defined as Cure or Improved.
 Failure: Response will be classified as failure if
o any administration of antibacterial therapy for SSI is required because of lack of 
efficacy after at least 2 days (i.e. 4 or 6 doses, based on daily posology scheme) of 
study treatment (delafloxacin or Reference treatment with or without additional 
therapy) as defined prior to and confirmed at Randomization by the Investigator,
OR
o the patient would have been in need to continue study treatment for more than 14
days, OR
o the need for unplanned major surgical intervention on SSI after Randomization OR 
o antibiotic therapy is required to treat P. aeruginosa (ONLY for tigecycline treated
patients)
NOTE: If clinical response is considered as Failure at a visit, then it will be considered 
Failure at any subsequent visit.
 Missing: A missing response will be considered a Failure for the analyses on the ITT
population and the patient will be excluded from the CE population.
 Indeterminate: A response cannot be assigned because an assessment was not
completed at the respective visits or because the patient received potentially effective
non-study antibacterial drug therapy for a condition other than SSI. An indeterminate 
response will be considered a Failure for the analyses on the ITT population and the 
patient will be excluded from the CE population.
Microbiological response
Microbiological response will be generated at EOT and TOC assessments at both pathogen and 
patient levels on the basis of the results of the infection site specimen(s) and blood cultures at 
baseline and follow-up and susceptibility testing, performed at the microbiological Centralized
CONFIDENTIAL 
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Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
laboratory.
Data relative to baseline and post baseline organisms isolated at the Centralized laboratory from 
the infection site and blood will be evaluated by a blinded external expert, who will review and 
identify which organisms are causative pathogens of SSI, and will assign the correspondent 
Microbiological response for each causative pathogen among the definitions listed below:

Documented eradicated: The baseline pathogen is absent in the specimen collected at
the relevant timepoint.

Documented persisted: The baseline pathogen is present in the specimen collected at
the relevant timepoint.

Not evaluable: it is not feasible to assess the microbiological response (e.g. there is no
material available for specimen)

New pathogen: a pathogen known to cause SSI different from the baseline causative
pathogen is detected in the specimen.
When it is not feasible to assess the microbiological response, Sponsor will assign one of the 
following options based on the Investigator’s assessment of clinical response:

Presumed eradicated: The patient has a “not evaluable” microbiological response and
a clinical response of “success” at the relevant timepoint.

Presumed persisted: The patient has a “not evaluable” microbiological response and a
clinical response of “failure” at the relevant timepoint.

Indeterminate: The patient has a “not evaluable” microbiological response and a
clinical response of “indeterminate” at the relevant timepoint.
In addition, emergent infections will be separately classified as per the definitions below when a 
microbiological sample taken post-baseline through the TOC is positive for “new” pathogen(s):
Emergent Infections:
Superinfection: A new pathogen known to cause SSI is cultured from the original site of 
infection during treatment with a clinical response of “failure”.
New infection: A new pathogen known to cause SSI is cultured from the original site of
infection after end of treatment with a clinical response of “failure”.
Sample size
A sample size of 600 randomized patients (300 per treatment arm: delafloxacin or Reference 
treatment) will provide about 80% power in the ITT population and higher than 95% in the CE 
population to demonstrate the non-inferiority of delafloxacin versus the Reference treatment arm in 
terms of clinical response (Clinical Success) rate with a non-inferiority margin of 10%, an alpha 
equal to 0.025 (1-side test). Clinical Success rate at TOC of 78.0% and 78.1% in the ITT and of
98.3% and 99.4% in the CE population are assumed respectively for delafloxacin and the
Reference treatment arm.
Assuming about 20% of Screening failures, approximately 750 patients are anticipated to be 
screened to reach a total of 600 randomized patients.
Analysis populations
CONFIDENTIAL 
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Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
Intention-to-treat (ITT): All randomized and treated subjects analyzed according to the
randomized treatment arm (Test or Reference).
Microbiological ITT (MITT): All subjects in the ITT population who have at baseline bacterial 
pathogen(s) identified that is known to cause cardiothoracic/related leg or abdominal SSI.
Clinically Evaluable (CE): All subjects in the ITT population who meet the following criteria:

Diagnosis of cardiothoracic/related leg or abdominal SSI

Received the correct treatment based on the Randomization assignment

Received 80% of the expected doses of study drug in the treatment period

Did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy

Had no protocol deviations that would affect assessment of efficacy at the reference visit.
CE populations will be defined at EOT, TOC and LFU timepoints and for eligibility to switch to 
oral formulation, IRLOS, and LOS.
Microbiologically Evaluable (ME): All subjects in the MITT population who also meet the criteria 
for the CE population. ME populations will be defined at EOT and TOC.
Safety: All subjects who have received at least one dose of study medication.
Statistical Analysis
Primary Efficacy Analysis
The primary efficacy variable (Clinical Success defined as cure or improved at TOC in the ITT and 
CE populations) will be used to assess the non-inferiority of delafloxacin versus the Reference 
treatment arm. The treatment difference (delafloxacin minus Reference treatment arm) will be 
presented with the relative 2-sided 95% confidence interval (CI) on the difference in response rate. 
If the lower limit is greater than -0.10, it will be concluded that delafloxacin is non-inferior to the 
Reference treatment arm for treating patients with cardiothoracic / related leg and abdominal SSI. 
In case the non-inferiority will be confirmed, the superiority of delafloxacin versus the Reference 
treatment arm will be tested by using a Chi²-Test test.
Non-inferiority will be tested on the CE and ITT populations, while superiority only on the ITT
population.
Secondary Efficacy Analysis
All the secondary efficacy endpoints will be descriptively analyzed and tested, when applicable, 
for non-inferiority with the possibility to switch for superiority analogously to the primary efficacy 
variable through an ad hoc inferential analysis, as reported below:

Binary outcomes will be analyzed analogously to the primary efficacy variable.

Continuous variables will be tested by using an ANOVA model with treatment arm as main
factor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
.

Time to event variables will be assessed using a Log-rank test.
CONFIDENTIAL 
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Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17                                                                                       Version 1.0, 05 April 2019
CONFIDENTIAL 
Page 17 of 99
Exploratory Efficacy Analysis
Change vs baseline for ProCT and CRP serum values will be descriptively analyzed in the ITT 
population overall and by site of infection and treatment arm at Visit 2, Visit 3 and EOT Visit. 
Additionally, at the same timepoint a Pearson correlation analysis between ProCT and CRP serum 
values versus the overall IRLOS assessment and each of the IRLOS parameters will be performed.
Safety Analysis
AEs will be coded using the MedDRA dictionary and summarized by treatment arm/individual 
treatment. The incidence of each TEAE and the number of patients with at least one TEAE will be 
summarized by System Organ Class (SOC) and Preferred Term (PT). Clinically significant 
abnormal findings in vital signs, 12-lead ECG and laboratory parameters (haematology, 
biochemistry, coagulation and urinalysis) will be summarized by treatment arm/individual 
treatment as per TEAEs. Safety variables will be analyzed only by descriptive statistics and will be 
run on the Safety population.
Health Economics Analysis
Healthcare resources consumption and related variables useful for the healthcare economic 
evaluation will be described by treatment, site of infection, investigational site, country and overall 
in the Safety Population.
The descriptive results for each variable will be successively linked with a cost term in order to
implement an appropriate health-economic model that will be accurately described in the Health 
Economics Analysis Plan.


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
2.1 
Schematic Study Treatment(s) and Visit Schedule
Study Treatment(s)
Cardiothoracic/ related leg SSI
Test Treatment
Delafloxacin  300 mg IV every 12h
with the option to receive
Delafloxacin 450 mg  tablets  every 12h
as soon as the patient meets eligibility criteria to
switch to oral formulation
Reference Treatment1
Vancomycin , 15 mg/kg IV every 12h
OR
Linezolid, 600 mg IV every 12h
with the option to receive 
Linezolid 600 mg tablets every 12h
as soon as the patient meets eligibility criteria
to switch to oral formulation
Additional therapy
( except quinolones)
for Gram -negatives coverage
if mixed infection is suspected
Abdominal SSI
Test Treatment
Delafloxacin 300 mg IV every 12 h
with the option to receive
Delafloxacin 450 mg  tablets  every 12 h
as soon as the patient meets eligibility criteria to
switch to oral formulation
Reference Treatment1
Piperacillin/ tazobactam
4/0.5  g IV every  8 h
OR
Tigecycline , 100 mg IV loading dose,
followed by 50 mg every 12 h
2
Additional therapy
( except quinolones)
for MRSA coverage if MRSA
infection is suspected
1As per Investigator’s choice, to be documented prior to Randomization.
2 As per Investigator’s choice, prior to Randomization,  additional therapy (selected by the Investigator as per local SoC) might be added to the Reference
treatment in order to expand the coverage. Additional therapy has to be prolonged/discontinued based on microbiological results.
CONFIDENTIAL 
Page 18 of 99
2


 
  
 
 
 
 
 
 
 
 
 
 
Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
Visit Schedule
Screening
visit
Within 30
days from
surgery
Visit 1
Within 1 day
from
Screening
Visit 2
48 to 72 h
after first
dose
Visit 3
Day 7
(if patient is 
on treatment)
End of
Treatment
(EOT) visit 
Within 1 day
after last dose
Test Of Cure
(TOC) visit
7-14 days
after last dose
Follow up
visit/
Phone call
21±2 days
after last dose
Late Follow
up/ End of
study visit
28-30 days
after last dose
Treatment period
(Day 1 to maximum Day 14)
=
Potential timeframe for IRLOS assessment
CONFIDENTIAL 
Page 19 of 99


 
 
 
Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
2.2 
Study flow-chart
Screening 
(within 30 
days from 
surgery)
Visit 1
(Day 1;
within 1 day 
from Screening)
Treatment 
perioda 
Visit 2
(Day 3 - 4;
48 to 72h after
first dose)
Visit 3
(Day 7, if patient 
is on treatment)
EOT Visit 
(within 1 day 
after last dose)
TOC Visit 
(7-14 days after 
last dose)
FU Visit or 
 
(21 ± 2 days 
after last dose)
LFU/End of 
Study Visit 
(28-30 days after 
last dose)
Informed consent 
Xb
Incl / Excl criteria  
X 
Xc
Hospitalizationd 
X
Demographic data / Medical history 
X
Randomization 
 
X
IMP dispensinge 
 
X
Prior and/or Concomitant medications 
X
Physical examinationf 
X 
 
 
 
X
Pregnancy testg 
X 
 
 
 
X
Vital signsh 
X 
Xc 
X 
X 
X 
X
12-lead ECG 
X 
 
 
 
X 
X
TDM for Vancomycini, if appropriate 
 
 
 
X
Haematologyj 
X 
 
X 
X 
X 
X
Biochemistryk 
X 
 
X 
X 
X 
X
Coagulation test 
X 
 
X 
X 
X
Virology (and HbA1c for diabetics only) 
X
 
 
 
 
X 
 
X 
X 
X
Urinalysis 
X 
 
X 
X 
X 
X
Infection site assessment 
X 
Xc 
X 
X 
X 
X 
 
X
Eligibility to discharge assessment (IRLOS)l 
Eligibility to switch to oral formulation
assessmentm
Day 2
Recording of SSI wound care managementn 
X 
Xc 
X 
X 
X 
X 
 
X
Microbiological culture of infection site  
X 
Xc,o 
Xo 
Xo 
X 
X
Blood culture 
X 
Xc,p 
Xp 
Xp 
Xp 
Xp
Study drug administrationq 
 
X
Clinical Events/AE recordingr 
X 
X
AEs recordings 
X
CONFIDENTIAL 
Page 20 of 99
Day 2 


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
SF-36v2 Health Survey QoLt 
Clinical Response
End of Treatment Notification in IWRS
a. Treatment period includes both IV and OS (if applicable) treatment duration.
b. Informed Consent can be administered prior to Screening.
c. If Visit 1 falls on the same day of Screening, this procedure has not to be repeated.
d. If not yet hospitalized, patients will be hospitalized upon successful completion of the Screening; duration of hospitalization (LOS) is per Investigator’s judgment.
e. IMP is dispensed by unblinded staff, as per IWRS, at randomization, for kit re-supply (note: each kit covers 5 treatment days) and for switch to oral formulation. Upon hospital discharge, patients with
oral delafloxacin or linezolid shall receive IMP together with a paper diary for daily recording of tablet intake.
f. Height and weight will be collected only at Screening Visit.
g. At Screening both urine dipstick and serum (or plasma) pregnancy test. At EOT Visit only serum (or plasma) pregnancy test.
h. Starting from Day 2 up to EOT, Systolic BP, HR, and Body Temperature to be performed daily until patient is considered eligible to switch to oral formulation / to be discharged by the blinded observer.
i. Therapeutic drug monitoring for vancomycin to be performed after 3 doses of vancomycin (steady state), at Visit 3, and when clinically indicated.
j. Starting from Day 2 up to EOT, WBC count to be performed daily until blinded observer considered the patient eligible for IV to PO switch and eligible for hospital discharge.
k.  CrCl will be calculated at Screening and when needed for dose adjustment. After EOT Visit, chloride, bicarbonate, magnesium, blood urea nitrogen or urea, creatine phosphokinase, total protein,
alkaline phosphatase, and uric acid will be no longer assessed, unless previous significant results to be monitored.
l. Eligibility assessed by the blinded observer (in the morning, within 12:00), based on Systolic BP, HR, T, WBC count and wound status.
m. Eligibility assessed by the blinded observer (in the morning, within 12:00), based on Systolic BP, HR, T, WBC count and ability to tolerate PO diet/no GI absorption problems.
n. Including wound dressing changes, at the visit or whenever occurred since the previous study visit.
o. If clinically indicated. In case of treatment withdrawal for any reason, the infection site specimen for microbiological culture should be collected before initiation of any alternative antibacterial therapy.
p. Blood culture to be repeated if the previous culture is positive and when clinically indicated.
q. Drug administration is under unblinded site staff responsibilities, and never disclosed to the blinded observer.
r. Clinical events (not associated with drug intake) /AE associated with any drug taken prior to IMP administration since the ICF signature.
s. Recording and follow-up of AEs after first IMP administration to the LFU /End of Study Visit.
t. Questionnaire should be completed prior to any other study visit procedure.
CONFIDENTIAL 
Page 21 of 99
Treatment perioda
Screening
(within 30 
days from 
surgery)
Visit 1
(Day 1;
within 1 day 
from Screening)
Visit 2
(Day 3 - 4;
48 to 72h after 
first dose)
Visit 3
(Day 7, if patient 
is on treatment)
EOT Visit
(within 1 day 
after last dose)
TOC Visit
(7-14 days after 
last dose)
FU Visit or 
(21 ± 2 days 
after last dose)
LFU/End of
Study Visit (28-30 
days after last 
dose)
X
X
X
X
X
X
X
X
X


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
3 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE
Co-ordinating Investigator
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
  
 
 
Sponsor
Menarini Ricerche S.p.A.
Clinical Sciences Department
Via Sette Santi, 1
50131 Florence, Italy
Corporate Director of Clinical
Sciences /
Sponsor’s Representative
 
 
 
 
 
 
 
 
 
 
 
 
Expert Head of Anti-infectives
 
 
 
 
 
 
 
 
 
 
Study Physician / Study Medical
Expert
 
 
 
 
 
 
 
 
 
 
Study Manager
 
 
 
 
 
 
 
 
 
 
Clinical Research Associate
 
 
 
 
 
 
 
 
 
 
Biostatistician
 
 
 
 
 
 
 
 
 
 
Data Manager
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 22 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
Sponsor’s Pharmaceutical
Manufacturer of the IMP
A. Menarini Research & Business Service GmbH
Department of Pharmaceutical Development 
Glienicker Weg 125 D-12489 Berlin, Germany
Head of the Department of
Pharmaceutical Development
Chrysantha Freitas, PhD
E-mail: cfreitas@menarini-berlin.de
Phone: +49 30 6707 3510
Fax: +49 30 6707 3500
Packaging, Labelling, and
Distribution of the IMP
Asgar Ergin, PhD
E-mail: aergin@menarini-berlin.de
Phone: +49 30 6707 2818
Fax: +49 30 6707 2400
Sponsor’s Pharmacovigilance Unit
Laboratorios Menarini S.A. -Menarini Group
Clinical Research
C/ Alfons XII, 587
08918, Badalona, Spain
Study Drug Safety Manager
Isabel Paredes Lario, MD
E-mail: iparedes@menarini.es
Phone: +34 93 462 88 00 ext. 8266 (working hours) 
Mobile: +34 60 678 61 40
Fax: +34 93 462 88 24
CRO
PSI CRO AG
Baarerstrasse 113A
6300 Zug, Switzerland
More information are provided in the separate 
Operational Contact List
Centralized Laboratory
Eurofins  Scientific
Berqschot 71
4817 PA Breda
The Netherlands
2430 New Holland Pike,
D100, Lancaster, PA 17601,
US
More information are provided in the separate 
Operational Contact List
IWRS
Parexel Informatics
PAREXEL International
GmbH, Am Bahnhof Westend 15, 14050 Berlin, 
Germany
More information are provided in the separate
Operational Contact List
CONFIDENTIAL 
Page 23 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
4 
TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL 
1
1. 
SIGNATURES 
2
2. 
PROTOCOL SYNOPSIS 
4
2.1. 
Schematic Study Treatment(s) and Visit schedule 
18
2.2. 
Study flow-chart 
20
3. 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE 
22
4. 
TABLE OF CONTENTS 
24
4.1. 
Glossary 
29
5. 
ETHICAL AND LEGAL ASPECTS 
32
5.1. 
General aspects 
32
5.2. 
Independent ethics committee and legal requirements 
32
5.3. 
Subject information and declaration of consent 
32
5.4. 
Subject insurance 
33
5.5. 
Documentation of study-related data and record retention 
33
5.6. 
Confidentiality 
34
5.7. 
Protocol / protocol modifications 
34
5.8. 
Study commencement 
34
5.9. 
Patient’s safety 
34
5.10. 
Data property / publication policy 
35
5.11. 
Data Protection 
35
5.11.1. 
General Principles on Personal Data Compliance 
35
5.11.2. 
Acknowledgment 
36
5.11.3. 
Data Controllers and Data Processors 
36
5.11.4. 
Duties of the Parties involved in the performance of the study 
37
5.11.5. 
Archiving of the clinical trial master file and patients’ personal data 
39
5.11.6. 
Data Breach 
39
5.11.7. 
Information notice on personal data protection and pseudo-anonymisation 41
5.11.8. 
Genetic Data 
41
5.11.9. 
Transfer of patients’ data outside the European Union 
43
5.11.10. 
Exercise of patients’ data privacy rights 
43
5.11.11. 
Future research 
44
6. 
BACKGROUND INFORMATION 
45
6.1. 
The Disease and Study Rationale 
45
6.2. 
Investigational medicinal product: Delafloxacin N-methylglucamine salt 
46
6.2.1. 
Nonclinical data 
46
CONFIDENTIAL 
Page 24 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
6.2.2. 
Clinical experience 
47
6.3. 
Risk benefit assessment 
50
7. 
STUDY OBJECTIVES 
51
7.1. 
Primary objective 
51
7.2. 
Secondary objectives 
51
7.3. 
Exploratory objective 
51
8. 
INVESTIGATIONAL PLAN 
52
8.1. 
Overall study design and plan description 
52
8.2. 
Observer blinded Design 
53
8.3. 
Discussion of study design, including the choice of doses and timing of
administration 
53
8.4. 
Selection of Study Population 
54
8.4.1. 
Inclusion criteria 
54
8.4.2. 
Exclusion criteria 
55
8.4.3. 
Study treatment restrictions 
56
8.4.4. 
Withdrawal of patients from therapy or from study 
57
8.5. 
Identity of the investigational product(s) 
58
8.5.1. 
Description of investigational medicinal product(s) 
58
8.5.2. 
Packaging, labelling, and storage 
59
8.5.3. 
Drug accountability 
60
8.5.4. 
Destruction of surplus medication 
60
8.6. 
Treatments 
61
8.6.1. 
Treatment administration - frequency and duration of application 
61
8.6.2. 
Randomization and IMP dispensing 
62
8.6.3. 
Treatment compliance 
62
8.6.4. 
Dosage Adjustment / Modification 
63
8.6.5. 
Prior and Concomitant medications and Wound Dressing 
64
8.6.5.1. 
Prior and Concomitant Medications 
64
8.6.5.2. 
Prohibited Medications 
64
8.6.5.3. 
Wound Care Management 
64
8.7. 
Study visits, procedures and assessments 
65
8.7.1. 
Pre-screening and Informed Consent process 
65
8.7.2. 
Screening Visit 
65
8.7.3. 
Randomization and Treatment Administration - Visit 1 (Day 1) 
66
8.7.4. 
Day 2 Onwards Daily Assessments 
67
8.7.5. 
Visit 2 (Day 3 – 4) 
68
8.7.6. 
Visit 3 (Day 7) 
68
CONFIDENTIAL 
Page 25 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
8.7.7. 
End of Treatment - EOT Visit 
69
8.7.8. 
Test of Cure -TOC Visit 
70
8.7.9. 
Follow-up Visit or Phone Call 
70
8.7.10. 
Late Follow-up /End of Study Visit 
70
8.7.11. 
Assessment of Efficacy 
71
8.7.11.1. Infection Site Assessment 
71
8.7.11.2. Clinical response 
71
8.7.11.3. Microbiological Assessment 
72
SSI specimen 
72
Blood Culture 
73
8.7.11.4. Microbiological Response 
73
8.7.11.5. Switch from IV to PO treatment and Hospital discharge 
75
8.7.11.6. Patient reported outcome questionnaire 
76
8.7.11.7. Infection Biomarkers 
76
8.7.12. 
Assessment of Safety 
76
8.7.12.1. Demographic data and Medical History 
76
8.7.12.2. Physical Examinations and Vital signs 
76
8.7.12.3. Clinical Laboratory Evaluation 
77
8.7.12.4. Pregnancy test 
78
8.7.12.5. 12-Lead ECG 
78
8.7.13. 
Study endpoints 
78
8.7.13.1. Primary efficacy endpoint 
78
8.7.13.2. Secondary efficacy endpoints 
78
8.7.13.3. Exploratory efficacy endpoints 
79
8.7.13.4. Safety endpoints 
79
8.7.13.5. Health economics endpoints 
79
8.8. 
Adverse events definitions, monitoring / recording and management 
79
8.8.1. 
Definition 
79
8.8.1.1. 
Adverse Event 
79
8.8.1.2. 
Clinical Event 
79
8.8.1.3. 
Treatment -Emergent Adverse Event 
79
8.8.1.4. 
Drug relationship 
79
8.8.1.5. 
Adverse Drug Reactions 
80
8.8.1.6. 
Seriousness 
81


8.8.1.7. 
Adverse Event / Adverse Drug Reaction intensity (severity) 
81
8.8.1.8. 
Adverse Event / Adverse Drug Reaction expectedness 
81
8.8.1.9. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
81
CONFIDENTIAL 
Page 26 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
8.8.1.10. Individual Case Safety Report 
82
8.8.2. 
Collection, recording and reporting of adverse events 
82
8.8.2.1. 
Management of Serious Adverse Events (SAEs) 
82
8.8.2.2. 
Management of Non-Serious Adverse Events 
84
8.8.3. 
Management of any laboratory abnormalities 
84
8.8.4. 
Management of pregnancy exposure cases 
84
8.8.5. 
Annual Safety Reporting 
85
8.8.6. 
Breaking of the Randomization Code 
85
8.8.7. 
Serious and Non-serious Adverse Events Follow-up 
85
9. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
86
9.1. 
Determination of sample size 
86
9.2. 
Analysis populations 
86
9.3. 
Statistical analysis 
87
9.3.1. 
Descriptive statistics 
87
9.3.2. 
Primary efficacy analysis 
87
9.3.3. 
Secondary efficacy analysis 
88
9.3.4. 
Exploratory efficacy analysis 
89
9.3.5. 
Subgroup analysis 
89
9.3.6. 
Safety analysis 
90
9.3.7. 
Health economics analysis 
90
9.3.8. 
Interim analysis and stopping rules 
91
9.3.9. 
Data imputations 
91
9.4. 
Protocol violations and Data Review 
91
9.5. 
Statistical analysis plan 
91
10. 
DATA QUALITY MANAGEMENT 
92
10.1. 
Data collection 
92
10.1.1. 
Electronic case report forms 
92
10.1.2. 
IWRS 
92
10.1.3. 
Patient reported outcome questionnaire 
93
10.1.4. 
Patient Diary 
93
10.1.5. 
Centralized Laboratory / Examination data 
93
10.1.6. 
Data capture systems versions and validation documentation 
93
10.2. 
Clinical data management 
93
10.3. 
Source data 
94
10.4. 
Quality control / quality assurance 
94
10.4.1. 
Study Monitoring 
94
10.4.2. 
Quality Assurance 
95


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11. 
PREMATURE TERMINATION OF THE WHOLE STUDY 
96
12. 
END OF CLINICAL TRIAL AND ARCHIVING 
96
12.1. 
Archiving of electronic documentation / data 
96
13. 
REFERENCES 
98
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4.1 
Glossary
ABSSSI
Acute Bacterial Skin And Skin Structure Infection/s
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
AUC
Area Under the plasma concentration time Curve
BMI
Body Mass Index
CA
Competent Authority
CDC
Centers for Disease Control and Prevention
CE
Clinically Evaluable
CI
Confidence Interval
cIAI
Complicated Intra-Abdominal Infection
CrCl
Creatinine Clearance
CLSI
Clinical and Laboratory Standards Institute
CNS
Central Nervous System
CRF
Case Report Form
CRO
Clinical Research Organization
CRP
C-reactive Protein
CS
Clinically Significant
CTM
Clinical Trial Medication
DNA
Deoxyribonucleic Acid
DRM
Data Review Meeting
DSUR
Drug Safety Update Report
EC
Ethics Committee
ECDC
European Centre for Disease Prevention and Control
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic Acid
EEA
European Economic Area
eGFR
Estimated Glomerular Filtration Rate
EEA
European Economic Area
EMA
European Medicines Agency
EOT
End Of Treatment
eTMF
Electronic Trial Master File
EU
European Union
FDA
Food and Drug Administration
FQ-NS
Fluoroquinolone Non Susceptible
FU
Follow Up
GCP
Good Clinical Practice
HR
Heart Rate
ICF
Informed Consent Form
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ICSR
Individual Case Safety Report
ICH
International Conference of Harmonization
ID
Identification
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRLOS
(Hospital) Infection-Related Length of Stay
ITT
Intent-to-Treat
IV
Intravenous(ly)
IWRS
Interactive Web Response System
LFU
Late Follow Up
LL
Lower Limit
LOS
(Hospital) Length of Stay
ME
Microbiologically Evaluable
MedDRA
Medical Dictionary for Regulatory Activities
MIC
Minimum Inhibitory Concentration
MIC90
The lowest MIC that inhibits 90% of the strains within a single species
MITT
Microbiologically Intent-to Treat
MRSA
Methicillin-resistant Staphylococcus aureus
MSSA
Methicillin-susceptible Staphylococcus aureus
NSAE
Non-Serious Adverse Event
OS
Oral(ly)
PMNs
Polymorphonuclear leukocytes
Pro-CT
Procalcitonin
PT
Preferred Term
PTE
Post-treatment Evaluation
QA
Quality Assurance
QoL
Quality of Life
QRDR
Quinolone Resistance Determining Region
RR
Respiratory Rate
RTC
Research Toxicology Centre
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SDSM
Study Drug Safety Manager
SF-36v2
Short Form-36 version 2
SIRS
Systemic Inflammatory Response Syndrome
SIV
Site Initiation Visit
SmPC
Summary of Product Characteristics
SoC
Standard of Care
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
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SSI
Surgical Site Infection/s
TEAE
Treatment-Emergent Adverse Event
TDM
Therapeutic Drug Monitoring
TOC
Test Of Cure
UK
United Kingdom
US
United States of America
WBC
White Blood Cell
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5 
ETHICAL AND LEGAL ASPECTS
5.1 
General aspects
This study will be carried out in compliance with the study protocol, the recommendations on 
biomedical research on human subjects of the Declaration of Helsinki3, International 
Conference of Harmonization – Good Clinical Practice (ICH - GCP) Guidelines, EU
regulations in force (EU Regulation No 536/2014 of 16 April 2014), and national
requirements of the participating Country(ies).
The Sponsor has contracted the Contract Research Organization (CRO, for details refer to the 
Study Operational Contact List) to perform some of the Sponsor’s trial related duties and 
functions like site selection and monitoring. The Sponsor will perform medical monitoring,
safety management, data management, statistical analysis and medical writing. The ultimate
responsibility for the quality and the integrity of the study resides with the Sponsor. The study 
will be conducted in agreement with Sponsor’s or CRO’s Standard Operating Procedures’
(SOP) requirements as agreed.
All clinical work conducted under this protocol is subject to GCP rules. This includes
audits / inspections by the Sponsor and / or its delegate (e.g., CRO), and / or by 
national / international Health Authority representatives at any time. All Investigators must 
agree to the audits / inspection of the study site, facilities, and of study-related records by the
Health Authority representatives and / or by the Sponsor, and / or its delegates, which must be
performed in accordance with national laws concerning personal data protection.
5.2 
Independent ethics committee and legal requirements
Before starting the study in a study site, study protocol and relevant documentation must be 
submitted to and approved by the Independent Ethics Committee(s) (IEC) and the Competent 
Authority(ies) (CAs) of the participating country(ies).
In addition, all local national legal requirements for the conduct of a clinical study have to be
followed prior to the start of the study. The CA(s) and IEC(s) of the participating country(ies) 
will be informed about any changes in the study protocol, the end of the study, or the 
premature study termination as appropriate and within the requested time period.
5.3 
Patient information and declaration of consent
Before any study-related procedures may be performed, informed consent must be obtained 
from the patient by means of a signed declaration.
The Informed Consent Form (ICF) must be approved in the corresponding local language and
in accordance with local laws and regulations by the IEC prior to being submitted to the 
patient.
In the patient information leaflet, patients will be given information and fully comprehensive
explanation in easily understandable terms of the study procedures, regarding the benefits,
restrictions, discomforts, and risks in taking part in the study, the properties of the 
Investigational Medicinal Product (IMP), the method of assignment to treatments, and any 
medically accepted and readily available treatment other than the IMP.
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Patients will also be informed about the measures taken to ensure their confidentiality 
according to the pertinent legislation.
After being duly informed and interviewed by the Investigator, the patient freely has to date
(including time) and sign in duplicate the ICF before being enrolled into the study and before 
undergoing any study procedure. The Investigator must store one original of the signed ICF in 
the Investigator’s File, and the patient will be provided with the other one. The process of 
obtaining the ICF has to be documented in the source documents.
If a protocol amendment would affect the terms of the ICF, it will be revised to reflect the
protocol change and submitted to IEC for approval. The Investigator will ensure that this new 
consent form is signed by all patients subsequently entered in the study and those currently in 
the study, before the changes take effect on their participation in the trial. Patients who will 
not sign the new consent form needs to be terminated from the study participation.
5.4 
Patient insurance
The Sponsor Menarini Ricerche S.p.A. has stipulated an insurance policy for patients 
participating in the study, in accordance with local regulatory requirements.
Details on the insurance company, the insurance number and conditions will be made
available to patients in the ICF and / or provided as a separate document, in accordance with 
national requirements.
A copy of the insurance certificate will be provided to each Investigator and will be filed in
the Investigator’s File at the sites and in the electronic Trial Master File (eTMF) of the study.
5.5 
Documentation of study-related data and record retention
It is the responsibility of the Investigator to document all study-related data for each patient in
a case report form (CRF). For this study, an electronic CRF (eCRF) will be used. The 
Investigator has to guarantee the accuracy of the documented data and has to comment any 
missing or spurious data.
In addition to the eCRF the Investigator will maintain adequate records that fully document
the participation of the patient in the clinical study including the study assessments (patient 
source data documentation). Details on the source data documentation are provided in §10.3. 
As required by ICH - GCP guidelines, the Investigator will keep essential documents until at 
least two years after the last approval of a marketing application in an ICH region; until there 
are no pending or contemplated marketing applications in an ICH region, or at least two years 
have elapsed since the formal discontinuation of clinical development of the IMP or 25 years 
from the end of the clinical trial, whichever occurs last (EU-Directive 2001/20 of April 4,
2001, as amended). These documents should be retained for a longer period however, if
required by the applicable regulatory requirements or by an agreement with the Sponsor. 
Subjects’ records have to be archived according to national law requirements.
No study documents should be destroyed without prior written agreement between Sponsor
and Investigator. Should the Investigator wish moving the study record to another location, he
/ she must notify the Sponsor in writing.
Details on the archiving of electronic documents / data are provided in §12.1.
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5.6 
Confidentiality
By signing the study protocol, the Principal Investigator affirms that any information 
provided by the Sponsor will be maintained in confidence, and that such information will be 
divulged to IECs or CAs only under an appropriate understanding of confidentiality with such 
a committee or institution.
In order to maintain the patient’s confidentiality, all data collected by the Investigator will be
recorded pseudonymously in the eCRF. Patient’s data will be identified by a unique patient 
number. The Investigator agrees that within national regulatory restrictions and ethical 
considerations, representatives of the Sponsor, any regulatory agency, and IEC may consult
study source documents in order to verify data in the eCRF. Patient medical records pertinent
to the study will be reviewed by the study monitor to assure adequate source documentation, 
accuracy, and completeness of eCRFs. The review will be conducted in accordance with
relevant SOPs and with strict adherence to professional standards of confidentiality, GCP, and
the relevant data protection legislation.
5.7 
Protocol / protocol modifications
The protocol must be read thoroughly by everybody whom the information therein concerns 
and the instructions must be exactly followed.
Changes in the study protocol will require a protocol amendment. Such amendments will be 
agreed upon and approved in writing by all signatories of the protocol. If amendments are 
substantial, i.e. they are likely to have an impact on the safety of the patients or to change the 
interpretation of the scientific documents in support of the conduct of the study, or if they are 
otherwise significant, the IECs and the CAs in the participating countries have to approve 
these amendments before implementation.
Changes which have no significant impact on medical or scientific validity of the study will 
be agreed upon and approved in writing by all signatories of the protocol and the IECs and the 
CAs will be notified of this protocol amendment.
Any substantial amendments of the protocol will be integrated in an updated study protocol. 
The Principal Investigator must ensure full compliance with the updated study protocol.
5.8 
Study commencement
The study can commence in an individual study site only after all prerequisites are fulfilled 
according to ICH / GCP guidelines, any local regulatory requirements, and the 
Sponsor / CRO’s SOPs.
5.9 
Patient’s safety
If any event(s) related to the conduct of the study or the development of the IMP affects the
safety of the study participants, the Sponsor and the Investigator will take appropriate urgent
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safety measures to protect the patients against any immediate hazard. The CAs and IECs will 
be informed forthwith about these new events and the measures taken.
5.10 Data property / publication policy
All data generated in the study (e.g. eCRFs, patient questionnaires, the structured data files in 
the clinical database system, the results of the statistical evaluation, microbiological data and 
evaluation, and medical interpretation as well as the final clinical study report) are the 
property of Menarini Ricerche S.p.A.
It is intended that study design and main results will be published on www.clinicaltrials.gov
and on other applicable websites (e.g., https://eudract.ema.europa.eu/results-web). In addition,
the results of the study may be published as scientific literature. Results may also be used in 
submissions to CAs. The conditions mentioned below are intended only to protect 
confidential commercial information (patents, etc.), and not to restrict publication.
All information concerning delafloxacin (such as patent applications, formulae, 
manufacturing processes, basic scientific data, or formulation information) supplied to the 
Investigator by Menarini Ricerche S.p.A. and not previously published is considered 
confidential by Menarini Ricerche S.p.A. and will remain the sole property of Menarini
Ricerche S.p.A. The Investigator agrees not to use it for other purposes without written
consent from Menarini Ricerche S.p.A.
Menarini Ricerche S.p.A. will use the information obtained in this clinical study in connection 
with the development of delafloxacin and therefore may be disclose it to other Investigators or 
concerned CAs in the European Union (EU) or abroad. In order to allow for the use of 
information derived from this clinical study, the Investigator and laboratories involved in the 
study have an obligation to provide Menarini Ricerche S.p.A. with complete test results and 
all data recorded during this study.
Prior to submitting the results of this study for publication or presentation, the Investigator 
will allow Menarini Ricerche S.p.A. at least 60 days to review and comment upon the 
publication manuscript. Menarini Ricerche S.p.A. will provide any manuscript of the results 
of this study to the authors at least 30 days before submission for a complete review. In
accordance with generally recognised principles of scientific collaboration, co-authorship
with any Menarini Ricerche S.p.A. personnel will be discussed and mutually agreed upon 
before submission of a manuscript to a publisher.
It is agreed, that the results of the study will not be submitted for presentation, abstract, poster
exhibition, or publication by the Investigator until Menarini Ricerche S.p.A. has 
reviewed / commented and agreed to any publication.
5.11 Data Protection
5.11.1 General Principles on Personal Data Compliance
All clinical trial information shall be recorded, processed, handled, and stored in such a way 
that it can be accurately reported, interpreted and verified; at the same time, the
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confidentiality of records and of the personal data of the patients shall remain protected in 
accordance with the applicable law on personal data protection such as the EU General Data
Protection Regulation 679/2016 and the EU Regulation on clinical trials on medicinal
products for human use 536/2014.
This section defines the appropriate technical and organizational measures that shall be 
implemented to protect information and personal data processed against unauthorized or 
unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss as well 
as to assure the fulfillment of patients’ privacy rights.
5.11.2 Acknowledgment
Sites, the Principal Investigator, the Centralized Laboratory, the Regional laboratory, the 
CRO, the IWRS provider as well as their appointed staff and service providers acknowledge 
that:
(a) 
the performance of the study will imply processing of sensitive personal data;
(b) 
personal data processing is regulated by the applicable European (i.e. the EU General 
Data Protection Regulation 679/2016 and the EU Regulation on clinical trials on 
medicinal products for human use 536/2014) and local laws (i.e. the laws of the country 
where the study is conducted) as well as by the Sponsor’s national legislation. In
particular, it is hereby acknowledged that being the Sponsor a company incorporated
under Italian law, it has to mandatorily comply with Italian legal provisions on data
protection: therefore the Site, the Principal Investigator, the Centralized Laboratory, the 
Regional laboratory, the CRO shall cooperate with the Sponsor to allow the fulfillment 
of such obligations;
(c) 
strict compliance with the applicable data protection laws and this section of the
protocol is deemed by the Sponsor as an essential condition of collaboration with the 
Sites, the Principal Investigator, the Centralized Laboratory, the Regional laboratory, 
the CRO.
5.11.3  
Data Controllers and Data Processors
The Sponsor, the Site, the Principal Investigator and the CRO acknowledge that according to 
the applicable privacy laws, Sponsor and Sites will act as independent data controllers while 
CRO and the Principal Investigator will act as data processors respectively of the Sponsor and 
of Site. Before the beginning of the study, the Site will instruct in writing Principal 
Investigator as its data processor. However, if specific local laws or regulations mandate a 
different definition of the privacy roles, the Sponsor, the Sites, the Principal Investigator and 
the CRO will implement the relevant legal instruments (e.g. if pursuant to the local laws the 
Site is a data processor of the Sponsor, a Data Processing Agreement will be finalized; if 
pursuant to the local laws Sponsor and Site are join controllers, a Joint Controllership 
Agreement will be finalized).
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5.11.4 Duties of the Parties involved in the performance of the study
Collection and use of patients’ personal data (i.e. subjects' data), including their biological 
samples, will be carried out in full respect of the provisions of the information notices 
submitted to patients, as well as the privacy rights, the fundamental freedoms and the dignity 
of data subjects. All the parties involved in this study undertake to adopt adequate measures to 
warrant that data will always be processed securely and in compliance with privacy laws. 
Sites, the Principal Investigator, the Sponsor, the CRO, the IWRS provider, Regional 
laboratory and the Centralized Laboratory - as well as their appointed staff and service 
providers, each in its respective remit and within the limits of their specific role in the study,
shall implement the following safety measures (physical, logical, organizational, technical,
electronic, I.T. etc) to ensure adequate protection of the personal data of the patients involved 
in the study. In particular:
(i) 
DATA SAFETY. Sites and/or the Principal Investigator shall adopt all the necessary
measures to prevent or minimize the risks of theft, fire, flooding, partial or total loss, 
accidental disclosure or illegal/unauthorized access to patient’s data or Sponsor’s proprietary 
confidential information; to this extent, before the beginning of the study, Sites and/or the 
Principal Investigator shall ensure that the actual measures they have implemented are fit-for- 
purpose and law-compliant, and in particular:
- in order to minimise the risk of unauthorized access and theft, the hardware on which
patients’ personal data are stored shall be placed in a restricted-access area, accessible only 
to those individuals who need to retrieve the patients’ personal data included in the 
database for professional purposes; the same safeguards shall be put in place for non- 
electronic databases;
- any electronic database containing the patients’ personal data shall be password-protected
by means of a strong password. Systems shall be set so that passwords must be updated at 
least every three months and feature at least 8 characters, with upper-case and lower-case 
recognition, containing at least three "special" characters, such as upper case letters [A-Z], 
lower case letters [a-z], numbers [0-9], symbols [!, #, $, etc.] or other special characters [Á, 
ë, ö etc.]. Passwords shall not include elements which may easily be associated with the 
assignee or information regarding him/her, such as name and year of birth (e.g.
“johnbrown80”) or easily predictable strings of characters (e.g. “qwerty”, “12345”,
“admin”, “user”, etc.);
- adequate cryptographic protection measures shall be put in place for data “at rest” and “in 
transit” (these include, for example, file system or database cryptography, or any other 
equivalent IT measure which renders data unintelligible to those who are not authorised to
access them);
- high level security measures shall be implemented also on the files or databases which 
contain the “key” to match the patients’ personal data (i.e. name, surname, etc.) with their
respective “Patient IDs” (as defined at point (iv) below);
- Backup processes and other measures that ensure rapid restoration of business critical
systems shall be implemented;
- Updated Antivirus and firewall programs shall be installed on the IT devices.
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Sites shall, regularly test and update the measures listed above.
Sites shall, upon request from the Sponsor and/or the CRO, provide detailed written 
information about the measures listed above.
The CRO shall ensure that the selected sites for the study have implemented the above listed
measures.
(ii) TRANSMISSION OF DATA. All the parties that transfer data through internet and/or to 
the centralized database(s) used to process study’s data or to generate statistical analyses shall 
implement secure protocols based on cryptographic standards which make data unintelligible 
to unauthorized individuals.
(iii) 
SECURITY OF THE CENTRALIZED DATA BASE. The centralized database held
by the Sponsor shall have the following safeguards in place:
- appropriate authentication methods, which differentiate between different users according 
to their respective roles so as to ensure that access to a specific set of subjects' data is 
permitted exclusively to those for whom access to such data is essential in the context of
their work for the study;
- appropriate measures to ensure that the authentication credentials are periodically
updated (i.e.  password change);
(iv) 
PSEUDONYMIZATION. All personal data that may allow identification of the
patients involved in the study shall be adequately dissociated from the other data pertaining to 
the study (“pseudo-anonymisation” process). The Principal Investigator shall adequately 
dissociate the identification data of patients from the data pertaining to the study by linking 
results to an alphanumerical code [“Patient ID”], whose format shall not make it possible to 
identify the patient directly or indirectly, so as to ensure that only anonymous data are 
transmitted to the Sponsor, the Regional laboratory, the Centralized Laboratory, the IWRS 
provider and / or the CRO. Site/Principal Investigator shall securely store a separate list (e.g: 
identification log) with the identification code, together with all signed informed consents, in 
accordance with the security measures as defined above.
As outlined below, samples shall only be stored for as long as strictly necessary for the
study’s performance: in particular, at Centralized laboratory blood samples for laboratory 
tests will be stored no longer than 12 months from sampling while both blood and SSI 
samples for microbiological analysis will be stored until one year after the end of the clinical 
trial. Blood and SSI samples analyzed at Local/Regional laboratory for safety and 
microbiological analyses respectively will be destroyed in accordance with the
Local/Regional laboratory procedures after analyses are completed. Biological samples and
any other examination (e.g. X-ray, ECG) shall bear Patient ID, and in no case will they bear 
other information that may lead to the direct or indirect identification of the patient, especially 
when, in accordance with this protocol, samples shall be forwarded and shared outside the 
clinical Site (e.g. in case of centralized reading or local laboratory analysis).
(v) 
TRAINING. The parties shall ensure that any personnel involved in the study have
received proper training on data protection issues.
All actions related to the implementation of the aforementioned measures shall be provided 
by the Sponsor, the Site and/or the CRO to the competent authorities (including data 
protection authorities) and Ethics Committees if and when requested. If such authorities or the
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Sponsor consider the implementation of the afore mentioned measures insufficient to 
guarantee an adequate level of protection of the patients’ personal data, Site, the Principal
Investigator, the CRO, the IWRS provider, Regional laboratory and the Centralized laboratory
undertake to adopt all the necessary activities to overcome such remarks to assure the full 
compliance with the data protection laws.
5.11.5 Archiving of the clinical trial master file and patients’ personal data
Unless other EU laws require archiving for a longer period, the Sponsor, Site and the 
Principal Investigator shall archive the content of the clinical trial master file, including the 
relevant patients’ personal data, for at least 25 years after the end of the clinical trial. 
However, medical records shall be archived in accordance with the national laws of the 
country where the study is performed. The patient code pairing list (i.e. the list that where the 
Patient ID is linked to the patients’ identification data such as name and surname), shall be 
archived care of the Principal Investigator.
The content of the clinical trial master file shall be archived in a way that ensures that it is 
readily available and accessible, upon request, to the competent authorities.
Any transfer of ownership of the content of the clinical trial master file shall be documented.
The new owner shall undertake the responsibilities set out in this protocol.
The Sponsor appoints the Study Manager (SM) or delegates as responsible person/s for 
archives. Access to archives shall be restricted to those individuals.
The media used to archive the content of the clinical trial master file shall be such that the
content remains complete and legible throughout the period referred to in the first paragraph. 
Any modification to the content of the clinical trial master file shall be traceable.
5.11.6 Data Breach
Data Breach is an incident regarding personal data security and leading to the accidental or
unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, personal data 
transmitted, stored or otherwise processed. In particular: destruction of personal data is where 
the data no longer exists, or no longer exists in a form that is of any use to the Site, Sponsor, 
CRO, Principal Investigator; Centralized Laboratory, Regional laboratory and the IWRS 
provider data loss is when the data may still exist, but the Site, Sponsor, CRO, Principal 
Investigator, Regional laboratory, Centralized Laboratory and the IWRS provider has lost
control or access to it, or no longer has it in its possession; damage is where personal data has
been altered, corrupted, or is no longer complete; data unavailability is where, following a 
data incident  (such as a network outage, a natural or man-made disaster, etc.), personal data 
become temporarily inaccessible to the Site, Sponsor, CRO, Principal Investigator, Regional 
laboratory Centralized laboratory and the IWRS provider.
Anomalous Event is an event that is not part of the standard operational scope of an
infrastructure, network or service and which affects, or is likely to affect, personal data; this 
may include theft or loss of IT devices and other physical events (e.g. an unauthorized access
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to a locked storage room containing paper files with personal data), and/or electronic/IT 
anomalies (e.g. cyber-attacks, default or hacking of cloud services), which may in any way 
entail loss, unavailability, alteration, theft, copy or dissemination of personal data.
Whoever becomes aware in any way of an Anomalous Event and/or of a Data Breach (see
definitions above) affecting the patients’ personal data and/or personal data collected in the 
context of the study, shall, as appropriate, immediately (and in any case no later than 24 hours 
from the knowledge of an Anomalous Event and/or of a Data Breach) inform the SM, the 
sponsor’s Data Protection Officer, who may be contacted at dpo@menarini.com, the Site and 
the PSI Data Protection Officer, who may be contacted at privacy@psi-cro.com and shall 
provide the following information:
(i) 
Anomalous  Event  / Data Breach  Type  (e.g. data loss, unauthorized access, loss of
company device, etc.);
(ii)  Person or source that first reported the Anomalous Event/ Data Breach;
(iii) Date and Time when the person who first reported the Anomalous Event / Data Breach
became aware of it;
(iv)  Anomalous Event / Data Breach Date and Time (actual or presumed);
(v)  
Place (specify if actual or alleged) where the Anomalous Event / Data Breach occurred; 
(vi)  Anomalous Event / Data Breach Description;
(vii)  Indicate the source of the Anomalous Event / Data Breach (e.g. I.P. source) - (if
relevant);
(viii)  Indicate the affected infrastructure / system / application / cloud/ software / hardware /
database and their location;
(ix)  List or describe the processing/storage systems affected by the Anomalous Event/
Data
Breach (if relevant);
(x)  Number of data subjects involved (if known);
(xi)  Amount of allegedly breached data
(xii)  Other relevant information
Once all the above information have been provided, the Sponsor and/or the Site should have a 
reasonable degree of certainty that a security incident has occurred that has led to personal 
data being compromised.
Then, as appropriate, Sponsor and Site, each one in its respective remit, shall manage the Data
Breach in accordance with the applicable data protection regulations.
For Data Breach affecting personal data of patients enrolled within the European Union, 
Sponsor and Site autonomously or jointly -depending on the circumstances and their privacy 
responsibilities as defined by the Regulation 679/2016- shall:
1. Collect the necessary evidence and information;
2. Categorize the breach;
3. Determine the risk probability and level to the rights and freedom of the concerned
patients;
4. Identify and put in place appropriate remedies to minimize the impact of the Data Breach
5. Determine the notification and communication duties vis à vis the competent supervisory
authority and/or the concerned patients.


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5.11.7 Information notice on personal data protection and pseudo-anonymisation
Prior to patients’ enrolment in the study, the Principal Investigator and/or the Site (including 
their personnel) shall provide each patient with adequate, law-compliant “information notices 
and consent forms to process personal data” as included in the ICF (or, as the case may be, 
through a separate, specific form) provided by the Sponsor or delegated CRO and shall collect 
his/her written consent to the processing of personal data according to the actual performance 
conditions in which the study is carried out. The Principal Investigator is responsible to 
archive the signed ICF in accordance with the security measures described above.
Among other things, the ICF (or the separate form) shall inform patients about:
(i)  
the applicable data protection legislation
(ii)  what kind of data shall be collected during the study listing them in detail or by
category;
(iii) the purpose of data processing (e.g. performance of the study, pharmacovigilance,
registration of new drugs) and the legal basis;
(iv) whether granting the consent(s) to process personal data is a necessary or an optional
condition to take part in the study;
(v)  the use of data for future scientific researches / secondary use of data (if any). In such a 
case the future scientific purposes / secondary use shall include further medical and 
scientific research purposes such as studies for the registration of new medicines;
studies which compare the data of this Study with other sources, etc.;
(iv)  the pseudonymisation procedure and scope;
(v)  who can access patients’ data and under what circumstances  (e.g. Principal Investigator 
and Site for patient management along the study, Sponsor and its vendors for collection
and analysis purposes, regulatory authorities for study and marketing approval. The
complete list will be available upon request);
(vi)  the period of data retention/storage as defined in, including the storage of the biological
sample [§ 5.11.4 and 5.11.5 above) ];
(vii)  to which entities/countries outside the EU patients’ data will be transmitted (the
complete list will be available upon request – see §5.11.9)
(viii)  patients’ data protection rights as defined by the EU General Data Protection Regulation
679/2016.
(ix)  Data Controllers / Data Processors and the relevant contact details
(x)  Sponsor’s Data Protection Officer contacts (dpo@menarini.com)
(xi)  in case of genetic data processing the possible findings, also with regard to unexpected
findings that might be disclosed on account of the processing of the genetic data;
5.11.8 Genetic Data
No genetic data will be processed for the study purposes, except for the genetic data needed 
for the pregnancy follow-up.
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- The collection of genetic data for performing genetic tests and screening shall be limited to 
the personal and family information that is absolutely indispensable for pregnancy follow-
up.
- If genetic data are processed in the context of the study for pregnancy follow-up purposes 
(pharmacovigilance) only (i) the collection of genetic data for performing genetic tests and 
screening shall be limited to the personal and family information that is absolutely 
indispensable for pregnancy follow-up; (ii) the source, nature and mechanism for samples 
taking and storage will be under the pregnant health care provider and its local procedures; 
genetic data shall be processed pursuant to the applicable pharmacovigilance laws and
regulations; genetic data shall be communicated/transmitted using high security standard.
The provisions below shall be implemented as applicable from time to time.
- Without prejudice to applicable laws and regulations, except for data and results as per 
Section 5.10, the protocol shall be subject to confidentiality obligations that will assure the
secrecy of the data for at least one year after the conclusion of the study.
- The measures to keep patients’ identification data separated from biological materials and
genetic information are described in Sections 5.11.4 and 5.11.5.
- Access to the premises where genetic data are stored shall be controlled by security staff 
and/or electronic devices also based on biometrics. Any person admitted after closing time,
on whatever grounds, shall have to be identified and their data recorded.
- Preservation, use, and transportation of biological samples shall be carried out in such a
manner as to also ensure their quality, integrity, availability and traceability.
- Genetic data shall be transmitted electronically by certified electronic mail after encrypting 
and digitally signing the information to be transmitted. Web application-based 
communication channels may be used if they rely on secure communication protocols and 
they can guarantee the digital identity of the server providing the service as well as of the 
client station from which the data are accessed by means of digital certificates issued by a
certification authority in pursuance of the law.
- Electronically processed genetic data may be accessed provided that authentication
systems are based on tokens/devices.
- Genetic data and biological samples contained in lists, registers and/or databases shall be 
processed with encryption techniques and/or by means of identification codes and/or any 
other techniques that can make them temporarily unintelligible also to the persons
authorised to access them.
- In order to minimise the risks of accidental disclosure and/or unlawful/unauthorised access, 
patients’ identities will be disclosed only when strictly necessary (e.g. to prevent a physical
prejudice).
- Genetic and medical data will be processed separately from any other personal data that
can identify the patients directly.
- The ICF will detail the possible findings regarding genetic data, also with regard to 
unexpected findings that might be disclosed as result of the test / elaboration of genetic
data;
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- The ICF will detail whether the data subject is allowed to limit the scope of 
communication of his/her genetic data and the transfer of biological samples, including
their possible use for additional purposes;
- The ICF will detail the retention period of genetic data and biological samples (if different
from the general retention period of other data processed in the context of the study).
5.11.9 Transfer of patients’ data outside the European Union
The study performance entails transferring patients’ personal data (coded data) outside the 
EU. To this extent, the Sponsor, the Centralized laboratory, Regional laboratory, the CRO and 
the IWRS provider undertake to export such data in compliance with adequate safeguards/
legal basis as required by the Regulation 679/2016 including the Commission Decisions, the 
Standard Contract Clauses, the Privacy Shield, patients’ specific consent.
The complete list of non-EU countries where data can be exported will be available upon
request.
5.11.10Exercise of patients’ data privacy rights
Each study patient has the right to contact the Sponsor, the Site, the Principal Investigator, the
Centralized Laboratory, the Regional laboratory, the IWRS provider and the CRO to exercise 
the rights afforded to the patient by the law, including the afforded ones under articles 15 to 
22 of Regulation (EU) 2016/679, namely: knowing whether or not any data referring to his/
her is being processed in the context of the study; access his/her data; verify the data’s content, 
origin, exactness, location (including, where applicable, the non EU countries where the data 
might be); obtain a copy of the data including their transmission to another entity indicated by 
the patient; ask that the data are supplemented, updated, amended; in the circumstances set 
forth by the law, ask that the processing of data is restricted, that data are anonymised or 
frozen; oppose to the processing of his/her data for legitimate reasons. Each
patient has the right to lodge a complaint with his/her local supervisory authority and/or to
notify to the Data Protection Officer any use of his/her personal data the patient regards as 
inappropriate.
Each study patient is free to withdraw at any time from the study. In such case, each study
patient may ask the Sponsor, the Site, the Principal Investigator, the Centralized Laboratory, 
the Regional laboratory, the CRO and the IWRS provider to destroy/delete his/her personal 
data including his/her biological samples, unless they have been permanently anonymized, 
thus preventing any further processing or analysis of his/her data. However, data and results 
of tests that may have been used to determine the results of the study shall not be deleted, to 
avoid altering or impairing altogether the results of the study.
Specific rights in relation to the processing of genetic data apply. PLEASE REFER TO
§5.11.8.
If the Site, the Principal Investigator, the Centralized Laboratory, the Regional laboratory, the 
CRO and the IWRS provider receive a request for data privacy rights exercise, the concerned 
recipient shall immediately inform the Sponsor DPO by email at dpo@menarini.com
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Version 1.0, 05 April 2019
The request shall be fulfilled within the term set forth by the applicable privacy laws 
(normally 30 days). The Sponsor, the Site, the Principal Investigator, Regional laboratory, the
Centralized Laboratory, the CRO and the IWRS provider shall implement adequate
organizational measures to reply to patients within the above mentioned deadline.
5.11.11 Future research
With patients’ optional and additional consent, the Sponsor and/or the Site may use the data 
collected during the course of the study for further medical and scientific research purposes.
These may include, for example: retrospective clinical studies; clinical studies pertaining to the
patients’ pathology/medical condition(s) or similar conditions; studies which compare the data of 
this Study with those from other sources to identify the factors involved in a disease; registration 
of new drugs.
In the context of these additional research activities, patients’ data will be processed, anonymized
and transferred abroad, and may be shared with future research partners –in most cases this will 
prevent patients identification; however, in the unlikely event patients full identity really needs to 
be disclosed, the same precautions and safeguards as those described in this protocol will be 
implemented.
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6 
BACKGROUND INFORMATION
6.1 
The Disease and Study Rationale
Acute Bacterial Skin and Skin Structure Infections (ABSSSI) encompass a variety of disease 
presentations and severities, involving the skin and underlying subcutaneous tissue, fascia, or 
muscle and ranging from simple superficial infections to severe necrotizing infections 
(Sartelli et al. 20144). ABSSSI typically require intravenous antibiotic therapy, surgical 
intervention or both, and are increasingly a reason for hospitalization.
Surgical Site Infections (SSI) represent a specific chapter among the soft tissue infections.
They are post-operative infections and because of their multifaceted aspects they are framed
into a separate group. The Centers for Disease Control and Prevention and the European 
Centre for Disease Prevention and Control (CDC and ECDC, respectively) defines SSI as 
postoperative infection occurring within 30 days of a surgical procedure (or within one year 
for permanent implants).
SSI is classified as by the CDC in superficial incisional infection, deep incisional infection,
and organ space infection. Superficial incisional infections are the most common type of SSI. 
The development of a SSI depends on contamination of the wound site at the end of a surgical
procedure and specifically relates to the pathogenicity and inoculum of microorganisms
present, balanced against the host’s immune response.
From 2013 to 2014, in Europe, the percentage of SSI per 100 surgical procedures varied from 
0.6% to 9.5% depending on the type of procedure and on the different population groups that 
undergo these operations and because of the different proportions of clean and contaminated 
operations for each operation type. Among the isolated pathogens, Staphylococcus aureus 
(17.0%) and Escherichia coli (16.9%) were the most commonly reported microorganisms with 
an expected inter-country variation. For cholecystectomy and colon surgery operations, the 
majority of the reported microorganisms were Enterobacteriaceae.
The ECDC released the latest annual data on antimicrobial resistance trends in 30 EU and
European Economic Area (EEA) countries on 20th November 2017, confirming that 
methicillin-resistant Staphylococcus aureus (MRSA) remains a public health priority in 
Europe as 10 out of 30 countries reported MRSA percentages above 25% in 2016.
The presence of MRSA in SSI is independently associated with mortality compared with
patients with methicillin-susceptible Staphylococcus aureus (MSSA). The importance of early 
treatment for MRSA was underscored by a retrospective study showing that patients who 
received therapy within two days after the date of diagnosis had a significantly shorter
duration of intravenous (IV) therapy and hospital Length of Stay (LOS) than patients whose
treatment was initiated later (Nathwani D. et al, 20145). Gram-negative aetiology is also 
common in SSI setting as reported in the SENTRY programme (1998 – 2004), with P. 
aeruginosa being the second most important pathogen after MRSA, followed by E. coli 
(Bassetti M et al, 20146).
It should be noted that the epidemiology of ABSSSI and SSI changes over time, with the
profiles of community- and healthcare-associated causative agents constantly shifting; this is 
further complicated by similar shifts in the prevalence of strains showing resistance to 
antimicrobial agents over time.
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Inappropriate antibiotic treatment is given to approximately 25% of patients, potentially 
prolonging hospital stay and increasing the risk of morbidity and mortality; this may occur 
particularly in patients with diabetes, surgical site infections, anal and perianal region 
infections, and compromised vascular perfusion (e.g. obese patients) where Gram-negative 
pathogens must also be considered when selecting initial empiric therapy (Garau et al, 20157).
Critical medical issues are still in place in the management of patients with ABSSSI and SSI
in particular, addressing empirical antimicrobial coverage, drug-drug interactions, and 
potential toxicities. Considerations related to drug administration include availability of IV 
and oral (OS) formulations for not easier IV access (e.g., in obese patients), or IV / OS 
switching to facilitate hospital discharge, food interaction, therapeutic drug monitoring, and 
fixed dose versus weight-based dosing.
The main goal of this study is to assess the efficacy and safety of delafloxacin (a
fluoroquinolone with a broad spectrum in vitro activity, including Gram-positive, Gram- 
negative, atypical and anaerobes organisms available as IV and OS formulations), in
comparison with best available therapy, selected among the current standard of care. Due to
the multiplicity of the pathogens causative of SSI and the possibility of mixed infections, the 
study design also allows the possibility to add further antimicrobials to the best available 
therapy, among those used at each specific site, when in need of a broader coverage and upon 
Investigator’s judgment. To strength the reliability of the study results, this clinical trial has 
an observer blinded design.
The financial burden of surgery is increased due to the direct costs incurred by prolonged
hospitalization of the patient, diagnostic tests, and treatment. Indeed, Broex et al., 20098
demonstrated that, in European hospitals, patients who develop a SSI constitute a financial 
burden approximately double that of patients who do not develop a SSI. Improving the 
management of SSI may therefore represent an opportunity cost to hospitals by saving 
resources that could be spent elsewhere.
An additional objective of this study is also to collect healthcare resources consumption for
the treatment of SSI in order to quantify, also from an economic point of view, the burden and 
highlighting potential differences in the management of these patients by introducing 
delafloxacin in the current armamentarium.
6.2 
Investigational medicinal product: Delafloxacin N-methylglucamine salt
6.2.1 Nonclinical data
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 Clinical experience
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Version 1.0, 05 April 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Objective response at 
48-72 hours
  
 
  
  
 
  
81.3, 80.7
0.8 ( 3.2, 4.7)
86.5, 85.4
1.2 ( 2.6, 4.9)
  
 
  
  
 
  
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 f
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Risk benefit assessment
In this study, patients will receive delafloxacin 300 mg IV or 450 mg OS Q12h or the selected
Reference treatment that represents the best available therapy (BAT) for either cardiothoracic
/ related leg or abdominal SSI.
The Reference treatments are already on the market for the treatment of ABSSSI since many 
years and their benefits are documented in published literature. In this study, they will be 
administered according to the relative Summary of Product Characteristics (SmPC).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Taking into consideration the wide antimicrobial spectrum and comparable clinical efficacy
shown by delafloxacin in the Phase II and Phase III trials versus different treatments, at least a 
comparable therapeutic benefit is expected for subjects who will be randomized to the 
delafloxacin arm versus the Reference treatment arm.
In particular, because of its spectrum of activity, pharmacokinetic and safety profile, the risk
to benefit ratio of delafloxacin is anticipated to be favorable considering that this study aims 
to enroll a representative rate of difficult-to-treat population affected by a mixed bacterial 
flora and multiple comorbidities, posing them at an increased risk of adverse events and drug- 
drug interactions. To note that the Investigator can choose the most adequate treatment 
between two pre-selected BAT for each type of infection; in addition the antimicrobial cover
of the Reference treatment can be also optimized by the addition of another antibiotic in case
of suspected MRSA or Gram negative bacteria for abdominal or cardiothoracic SSI, 
respectively (the only exclusion is any quinolone). No additional therapy is requested for 
delafloxacin because of its wide antimicrobial cover.
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Version 1.0, 05 April 2019
7 
STUDY OBJECTIVES
7.1 
Primary objective
To assess the comparability of delafloxacin and BAT in terms of Clinical Success in patients 
with superficial or deep incisional SSI, following a cardiothoracic / related leg or abdominal 
surgical procedure.
7.2 
Secondary objectives
To assess the comparability of delafloxacin and BAT in patients with cardiothoracic / related 
leg or abdominal SSI, in terms of:
● effectiveness, microbiological response and sustained efficacy
● safety and tolerability
●  healthcare resources consumption
7.3 
Exploratory objective
To evaluate the time course of infection biomarkers (Procalcitonin-ProCT and C-Reactive 
Protein-CRP serum values) and their correlation with SSI clinical improvement.
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Version 1.0, 05 April 2019
8 
INVESTIGATIONAL PLAN
8.1 
Overall study design and plan description
This is a randomized, observer-blinded, active-controlled, parallel-group, multicenter, phase 
IIIb study for the treatment of incisional, superficial or deep, cardiothoracic / related leg or 
abdominal SSI (i.e. an expected microbiologically enriched population with SSI), comparing 
IV / oral monotherapy delafloxacin with selected Reference treatments which represent the
BAT for either cardiothoracic/related leg or abdominal SSI. The study is intended to be
conducted in approximately 70 sites in Europe.
Eligible patients will be randomly assigned in a 1:1 ratio to receive Test or Reference
treatment and stratified by site of infection (at least approximately 180 patients either for the 
cardiothoracic / related leg or abdominal SSI) and superficial / deep infections.
The Reference treatment arm includes two options for each SSI. The selection of one of the 
two allowed options for each SSI is upon Investigator’s judgment based on the patient 
characteristics and the local epidemiological pattern and will be done prior to the Interactive 
Web Response System (IWRS) assignment of Test or Reference treatment.
A schematic design of study treatments and visits is provided in §2.1.
Approximately 750 male and female patients aged > 18 years with diagnosis of SSI will be 
enrolled. Assuming that approximately 20% of screened patients will not fulfill the eligibility 
criteria, it is anticipated that about 750 patients will be screened to obtain 600 randomized 
patients. The overall clinical phase is expected to start in Q3 2019.
The enrolment of patients will be competitive; however, eligibility of patients with one out of
the two types of SSI (cardiothoracic / related leg or abdominal surgical procedure) will end 
when overcoming the 70% of the overall study population. Additionally, approximately 20% - 
30% of total sample size of patients is expected to be recruited altogether in Italy, Spain and/
or UK.
Study participation of individual patients is based on the treatment duration (range: minimum 
5 to maximum 14 days, as per Investigator's judgment) and will last at most 45 days.
The study will encompass up to 8 site visits (depending upon the individual duration of study
treatment) and ends with the Late Follow Up (LFU) Visit which represents the End of Study 
Visit.
Patients will be hospitalized from Screening and will remain hospitalized as per Investigator’s
judgment. Patients can be discharged while are on treatment: a) if the patient is still on 
treatment with IV formulation, outpatient parenteral antimicrobial therapy at site could be 
implemented wherever allowed by local standard practice (patients will travel to site to 
receive drug administration as per treatment schedule); b) if the patient is switched to oral 
treatment, outpatients will return to the site for the study visits (see §8.6.2).
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Version 1.0, 05 April 2019
Clinical and microbiological standard parameters will be assessed to test comparability of 
delafloxacin versus Reference treatment(s) in terms of efficacy and safety. Additional 
assessments will include: 
 
 
 
 
 
 
 
 
 
,
eligibility of patients to switch to oral formulation and/or to hospital discharge (IRLOS), and
actual hospital discharge (LOS).
No interim analysis is planned.
8.2 
Observer blinded Design
At each study site an unblinded Principal Investigator (referred to as “Investigator”) and a 
blinded observer will be designated. The responsibilities of each role are described below:
Investigator– The Principal Investigator or his/her delegates and site staff are unblinded and
manage all study procedures except the assessment of patient’s eligibility to switch from IV to 
oral formulation and eligibility to hospital discharge relevant to IRLOS. The Investigator and 
designee are responsible for ensuring that patient will receive study treatment as per IWRS 
assignment (i.e. Test or Reference). Prior to Randomization, based on the patient
characteristics and the local epidemiological pattern, the Investigator records which treatment
(among the allowed pre-selected BAT as reported in §2.1) he/she would select in case the 
IWRS actually allocates the patient to the Reference treatment.
Study staff will provide the blinded observer with data relevant to define the eligibility of the
patients to IV/PO switch and hospital discharge for IRLOS assessment.
Blinded observer– This role will be assigned by PI to a physician who will be responsible for 
the assessment of parameters relevant for defining the patient as eligible to IV/PO switch of 
therapy and dischargeable from the hospital (IRLOS assessment).
In his role, the blinded observer will never have to be informed about the actual patient
allocation to Test or Reference treatment arm and about the additional therapy, if any.
To ensure the blinding, the observer will not be permitted to see in any way the study
medications being dispensed to the patient, as well as actual prescription logs and study 
medications will never have to be discussed in presence of the blinded observer. Whenever 
possible, the same blinded observer should complete all the assessments for the patient, every 
day approximately at the same time, and within 12:00.
8.3 
Discussion of study design, including the choice of doses and timing of
administration
DELA-01 has been designed to assess the efficacy and the effectiveness of delafloxacin
compared to well-known best available treatments, that have been selected to address the 
microbiological flora causative of post cardiothoracic and abdominal SSI, on the basis of the
current international guidances (Sartelli et al4, IDSA18). Additional therapy can also be
prescribed by the Investigator to optimize the microbiological activity of Reference 
treatments in case of suspicion of Gram-negatives or MRSA, as described in §8.6.
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The treatment duration, lasting from 5 to 14 days, and dosages have been selected based on 
the results of delafloxacin pivotal trials and according to the SmPCs of the Reference 
treatments.
Delafloxacin has been already studied and compared to the current SoC over the clinical 
development in double blind or double dummy designed pivotal trials.
An observer-blinded, randomized design was selected in order to increase the objectivity in
the clinical assessments and to minimize the intentional or unintentional Investigator’s bias 
with respect to the assigned treatment. The clinical benefit of treatment is intended to be 
evaluated in terms of “Success” (cure or improved) according to the standard medical practice 
when making the decision of antibiotic termination and hospital discharge. The clinical 
response of “Success” (Cure or Improved) is therefore the primary efficacy endpoint to be
assessed at TOC Visit in accordance with the EU specific requirements15 for ABSSSI.
Testing of non-inferiority of delafloxacin vs BAT is also in compliance with current 
international guidelines19 for the development of antibiotics. In particular, non-inferiority is 
considered appropriate for ABSSSI in light of the high medical need of new antibiotics
addressing Multi Drug Resistance pathogens.
8.4 
Selection of Study Population
At least 600 male and female subjects, 18 years of age or older, with clinical evidence of 
superficial or deep incisional cardiothoracic / related leg or abdominal SSI, will be 
randomized in the study. After providing informed consent, the eligibility of the patients to 
enter the study will be assessed according to inclusion and exclusion criteria to be evaluated 
at Screening and confirmed at Visit 1.
8.4.1 Inclusion criteria
Eligible patients shall meet all the following criteria at Screening:
1. Male or female patients aged more than 18 years.
2. Patients with a history of cardiothoracic / related leg or abdominal surgery, occurred 
within 30 days and no implant is left in place, and a diagnosis of SSI according to the
CDC definition1, namely:
Superficial Incisional Surgical Site Infection, involving only skin and subcutaneous 
tissue of the incision, and at least one of the following local findings:
● 
purulent drainage from the superficial incision;
● 
organisms isolated from an aseptically obtained culture of fluid or tissue
from the superficial incision;
● 
superficial incision is deliberately explored by surgeon AND the patient has
at least one of the following signs or symptoms of infection:
o 
pain or tenderness,
o 
localized swelling,
o 
redness or heat;
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● 
diagnosis of superficial incisional SSI made by the Investigator.
Or
Deep Incisional Surgical Site Infection, involving deep soft tissues (e.g. fascia and 
muscle layers) at the incision site and at least one of the following findings:
● 
purulent drainage from the deep incision but not from the organ / space
component of the surgical site;
● 
a deep incision spontaneously dehisces or is deliberately opened by a
surgeon when the patient has at least one of the following signs or 
symptoms of infection:
o 
fever (> 38 °C),
o 
localized pain or tenderness;
● 
an abscess or other evidence of infection involving the deep incision is
found on direct examination, during reoperation, or by histopathologic or 
radiologic examination;
● 
diagnosis of deep incisional SSI made by the Investigator.
3. The severity of infection requires an IV treatment and patient hospitalization according to
the Investigator’s judgment.
4. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.2 Exclusion criteria
Patients who meet any of the following criteria at Screening are not eligible to the study:
1. Previous IV antimicrobial therapy exceeding 24 hour duration administered during 72
hours prior to the first dose of study treatment.
2. Any infection expected to require systemic antimicrobial agents other than study
treatment(s) (§ 2.1).
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3. Medical history of significant hypersensitivity or allergic reaction or contraindication to 
the pharmacological classes of study treatment(s) or excipients of their formulation
according to the Investigator’s judgment.
4. Medical history of known or suspected central nervous system (CNS) disorders (e.g.,
severe cerebral arteriosclerosis, epilepsy).
5. Medical history of myasthenia gravis.
6. Medical history of C. difficile diarrhea.
7. 
 
 
 
 
 
 
 
 
 
 
 
8. Organ-space infection.
9. Complicated Intra-Abdominal Infection (cIAI).
10. Any chronic or underlying skin condition at the site of infection that may complicate the 
assessment of clinical response (e.g., atopic dermatitis or eczema) or any skin condition
that, in the opinion of the Investigator, would interfere with the SSI healing.
11. 
 
 
 
 
 
 
 
 
 
.
12. Patients with known underlying diseases leading to deep immunosuppressive status (e.g.,
HIV/Acquired 
Immune 
Deficiency 
Syndrome-AIDS, 
malignancies 
and 
recent 
chemotherapy) that, in the opinion of the Investigator, would compromise the clinical 
response.
13. 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
14. Patients with end-stage renal disease on hemodialysis or peritoneal dialysis or creatinine
clearance (CrCl) < 15 mL/min using the Cockcroft-Gault formula.
15. 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.3 Study treatment restrictions
As with other quinolones, concurrent administration of oral delafloxacin with magnesium, 
aluminum, or calcium antacids, as well as metal cations such as iron, and multivitamins 
preparations with zinc or didanosine chewable / buffered tablets should be avoided. Oral 
delafloxacin should be taken 2 hours before or 6 hours after taking these products. For the 
intravenous formulation, it is not allowed to administer delafloxacin along with any solution 
containing multivalent cations, e.g., calcium and magnesium, through the same intravenous 
line.
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Study restrictions for the Reference treatments (and additional therapies, if any) must strictly 
follow the instructions reported on the relative SmPC.
8.4.4 Withdrawal of patients from therapy or from study
Participation in the study is strictly voluntary and patients have the right to withdraw from the 
study at any time without explanation. This will not affect their rights for future medical care. 
Patients may also be withdrawn at the Investigator's discretion or at specific Sponsor’s request 
at any time.
Treatment or Study Withdrawal: In the event that the patient withdraws from the treatment or 
from the study for whatever reason, the Investigator must be informed immediately and the
date, reasons, and circumstances for premature discontinuation will be recorded in the
corresponding section of the eCRF. Patients have to prematurely discontinue the treatment/
study if:
● in the opinion of the Investigator, it is not in the best interest of the patient to continue
treatment or study;
● there is a change in compliance with an inclusion or exclusion criterion that is
clinically relevant or affects patient safety;
● protocol violation (e.g. prohibited medication, poor compliance with study
procedures / treatment, need for a major surgical procedure);
● patient’s request.
Any patient, who prematurely terminates the treatment/study after having received the study 
treatment will be encouraged to complete the assessments scheduled at the EOT Visit at the 
time of withdrawal and a final LFU Visit, if applicable (§8.7.7 and §8.7.10).
Consent Withdrawal: Patients who withdraw consent will always be asked about the reason(s) 
and the presence of any AEs: no additional data should be collected since the time of 
withdrawal.  Data already collected will be used and analyzed for the purpose of the study. In 
regard to biological samples already collected, the patient will be asked if samples already 
obtained but not yet analyzed shall be destroyed or analyzed.
Lack of Efficacy / Treatment Related AE: In the event patient interrupts prematurely the study 
treatment for lack of efficacy (including the need for non-study antimicrobial agents such as 
antifungals) or due to a treatment related AE which request treatment discontinuation, the 
patient will undergo EOT Visit at the time of withdrawal and, then, any other study visit as 
per protocol till LFU Visit.
At the time of and after treatment discontinuation the following shall be collected, whenever
applicable (maximum up to LFU Visit):
● Reason for discontinuation
● Description of AE
● Second line antibiotic therapy
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NOTE: the specimens for microbiological cultures should be collected before 
initiation of any alternative antibacterial therapy.
● Hospital ward unit(s) where patient will be moved after treatment discontinuation and
duration of stay in the ward unit.
● Concomitant medications including those relative to AE treatment
● Any specialist visit, laboratory or radiologic examination performed on top of
procedures schedule
● Date of discharge
8.5 
Identity of the investigational product(s)
8.5.1 Description of investigational medicinal product(s)
Delafloxacin IV drug product
The delafloxacin drug product for IV infusion is provided in vials as freeze-dried powder for 
solution for IV infusion. One vial contains 433 mg delafloxacin meglumine which 
corresponds to 300 mg delafloxacin free acid and the following ingredients: sulfobutyl ether 
sodium beta-cyclodextrin, and ethylene-diamine-tetra-acetate disodium (EDTA, amount as 
acid). After reconstitution with 10.5 mL of 0.9% saline solution in the vial, the drug 
concentration is 25 mg/mL in an aqueous solution of 12.0 mL. All inactive excipients used in 
the formulation are of compendial grade. The reconstituted powder must not be frozen and 
may be stored for up to 24 hours under refrigerated (2-8oC) or controlled room temperature 
(20-25 °C) and then further diluted for IV infusion. The reconstituted powder will be further
diluted in a total volume of 250 mL with 0.9% saline solution into IV bag before
administration according to the dose scheme. Preparation must be done under controlled and 
appropriate aseptic conditions.
Delafloxacin oral drug product
The delafloxacin drug product for OS administration is provided as tablets. One tablet 
contains 649 mg of delafloxacin meglumine which corresponds to 450 mg delafloxacin free- 
acid and the following inactive ingredients: microcrystalline cellulose, povidone, 
crospovidone, sodium bicarbonate, sodium phosphate monobasic, citric acid and magnesium 
stearate. All inactive excipients used in the formulation are of compendial grade.
Reference drug products
Authorized market preparations will be used for Reference treatments.
Reconstitution should follow the instructions reported in the respective SmPC.
- Vancomycin
Strength: After reconstitution each vial contains 1 g vancomycin (as hydrochloride salt)
Formulation: 
Powder for solution for infusion
Route: IV infusion
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- Linezolid
Strength: 1 mL contains 2 mg linezolid
Formulation: 
Solution for infusion
Route: 
IV infusion
- Linezolid
Strength: 1 tablet contains 600 mg linezolid
Formulation: 
tablets
Route: 
OS administration
- Piperacillin-Tazobactam
Strength: After reconstitution each vial contains 4 g piperacillin (as sodium salt) and 0.5 
g tazobactam (as sodium salt)
Formulation: 
Powder for solution for infusion
Route: 
IV infusion
- Tigecycline
Strength: After reconstitution each vial contains 50 mg tigecycline
Formulation: 
Powder for solution for infusion
Route: 
IV infusion
Additional therapies to add on to the Reference treatment arm as per Investigator’s choice are 
to be selected among the SoC at the site and as locally available.
8.5.2 Packaging, labelling, and storage
The packaging and labelling of study medication will be under Sponsor’s responsibility. Each 
study treatment will be provided in treatment boxes (kit) covering 5 treatment days to be 
dispensed at Randomization and later on for treatments longer than 5 days.
Delafloxacin IV drug product
The delafloxacin drug product for IV infusion will be provided in single-use glass vials with a 
stopper and an aluminium crimp seal with a flip-off top (primary packaging). Each vial will 
be labelled individually. As secondary packaging the vials will be provided in labelled boxes. 
All labels will be in compliance with the valid international and corresponding national 
requirements. The labels will report instructions on how to administer and store the IMP in 
local language of all countries involved in the study. The storage recommendation for the 
IMP is “Store at 20 to 25°C; excursions permitted to 15°C to 30°C”.
Delafloxacin oral drug product
The delafloxacin oral drug product will be packaged in blisters (primary packaging) which are 
permanently fixed in blister cards (secondary packaging). The IMP will be labelled in 
compliance with the valid international and corresponding national requirements. The label
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Version 1.0, 05 April 2019
will report instructions on how to administer and store the IMP in local language of all 
countries involved in the study. The storage recommendation for the delafloxacin tablets is 
“Store at 20 to 25°C; excursions permitted to 15°C to 30°C”.
Reference Treatments
Reference treatments will be provided using authorized market preparations. The market 
product will not be modified except for re-packaging (secondary packaging and labelling). No 
additional substances or materials apart from secondary packaging materials will be added to 
the product. All labels will be in compliance with the valid international and corresponding 
national requirements.
Storage conditions
At the study site, all the IMP must be kept in a secure area inaccessible to unauthorised 
individuals. In case the medication will be handed over to the patient the Investigator will 
instruct the patient to keep the IMP according to the storage conditions given on the label. 
Additional information is provided in the clinical trial medication (CTM) manual which is 
filed in the Investigator’s site file.
8.5.3 Drug accountability
Upon receipt of IMP, study site personnel or designed pharmacist will open the shipment
package, verify the contents as stated on the enclosed shipping form, and confirm the receipt 
through the IWRS.
The IWRS will be used to record the IMP delivery to the study site and the inventory at the
site, including dates, quantities, batch / serial numbers and expiry dates. Each IMP kit will 
have a unique code number (treatment box number). The assignment of the IMP kit to a 
patient (patient number) will be also done through IWRS.
The Investigator will be responsible for entering in the source documents and in the eCRF the
treatment box number relative to the first IMP box (Randomization, Day 1) and any 
subsequent kit boxes delivered (one kit box covers 5 treatment days) or in case of switching 
from IV to oral formulation.
Study sites will maintain drug accountability forms to document the dispensed and returned 
IMP. In case IMP is given to outpatients, they will be instructed to return to the site used or 
unused oral IMP box at each Visit.
The peel-off labels of IMP will be stuck on the drug accountability paper forms.
8.5.4 Destruction of surplus medication
Throughout the study and at the end of the study, all remaining study treatments will be 
reconciled at the clinical site under the responsibility of the Investigator.
No later than at the Site Close-out Visit, the used and unused delafloxacin kits and Reference
treatments kits shall be returned to the Sponsor for destruction, provided this is not in conflict
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with any national export legislation. Any local destruction of the study treatment requires a 
certificate of destruction, indicating the batch number and the box number.
8.6 
Treatments
8.6.1 Treatment administration - frequency and duration of application
After confirmation of eligibility, patients will be randomly allocated to one of the following 
treatment (please refer to §2.1):
Test Treatment
Delafloxacin 300 mg IV given every 12 hours, with the option to switch to delafloxacin 450 
mg OS every 12 hours as soon as patient meets the eligibility criteria to switch to oral 
formulation as defined in §0, at per blinded observer’s assessment.
Reference Treatments for cardiothoracic / related leg SSI (and additional therapy)
● Vancomycin, 15 mg/kg given IV every 12 hours  OR
● Linezolid, 600 mg IV given every 12 hours, with the option to switch to linezolid 600 
mg OS every 12 hours as soon as patient meets the eligibility criteria to switch to oral
formulation as defined in 0, at per blinded observer’s assessment.
In case of suspicion of Gram-negative in the cardiothoracic SSI, the Investigator shall indicate 
an additional therapy as per local SoC (with the only exclusion of quinolones) to be assigned 
together with the Reference treatment (see Schematic study design 2.1).
Reference Treatments for abdominal SSI and (additional therapy)
● Piperacillin / tazobactam, 4 g / 0.5 g IV given every 8 hours OR
● Tigecycline, 100 mg IV loading dose, followed by 50 mg IV given every 12 hours.
In case of suspicion of MRSA in the abdominal SSI, if the pre-selected treatment is 
piperacillin/tazobactam, the Investigator shall indicate an additional therapy as per local SoC 
(with the only exclusion of quinolones) to be assigned together with the Reference treatment 
(see Schematic study design 2.1).
Delafloxacin infusion will last 60 minutes. For Reference treatments (and additional therapy, 
if any), the infusion duration should reflect the instructions reported in the relevant SmPC.
All treatments will be given for 5 to 14 days, based on the Investigator’s judgment.
Results of microbiological culture will drive the decision to discontinue or not the additional 
therapy; however, study treatment should not be discontinued based solely upon 
microbiological results, being driven by the Investigator clinical judgment.
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Please refer to §8.6.4 for any dosage modifications and to §8.4.3 for study treatment 
restrictions.
8.6.2 Randomization and IMP dispensing
Eligible patients will be randomly assigned in a 1:1 ratio to receive Test or Reference 
treatments and stratified by site of infection (at least approximately 180 patients either for the 
cardiothoracic / related leg or abdominal SSI) and superficial or deep infections.
Eligible patients will be randomized at Visit 1 (Day 1) to Test or Reference arm through the
IWRS system according to the Randomization list generated by Sponsor or delegate. If the 
patient is randomized to the Reference arm, the Investigator shall confirm in the IWRS the 
treatment he/she has preselected out of the two possible Reference treatments for each type of 
SSI before Randomization.
Re-supply of IMP kits, either for prolonging the IV therapy after 5 days or in case of switch to 
the oral one (only for delafloxacin and linezolid), will be managed through IWRS by 
unblinded site staff personnel who will record in IWRS also the end of treatment.
At the time of discharge, patients who are treated with the oral formulation of delafloxacin or 
linezolid (and are in need to continue the treatment) will receive one kit of oral formulation 
(covering maximum 5 treatment days) to continue at home –as per Investigator’s prescription. 
They will return to the site as per Investigator’s prescription (and in any case within the 5 
days of oral treatment covered by the dispensed box). If treatment is in need to be prolonged 
further (up to an overall maximum duration of 14 days), a new kit covering a maximum of 5 
treatment days will be supplied if needed.
8.6.3 Treatment compliance
Study drugs will be dispensed at the study site under the conditions defined in the present 
protocol and will be administered by the unblinded site staff. The date and time of each study 
drug administration will be recorded in the source documents and eCRF.
At time of discharge, if patient is still on treatment with oral formulation, he/she will be
provided with a paper diary to record daily the tablets intake as per Investigator’s 
prescription.
The site staff should recommend the patient to be strictly adherent with the treatment
prescription and verify patient treatment compliance during the following visits by 
performing drug accountability. Outpatients will be required to bring study drug boxes (used 
and unused) and completed paper diary at each site visit.
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8.6.4 Dosage Adjustment / Modification
Dosing adjustment/modification have to be performed respectively at Randomization and 
along the study treatment, whenever clinically indicated as per Investigator’s judgment, based 
on creatinine clearance levels calculated according to the Cockcroft-Gault formula.
Men: [(140 - age (years)) x Weight (kg)]/[72 x serum creatinine (mg/dL)]
Women: 0.85 x value calculated by the above formula.
Please refer to the table below for the dosage adjustment/modification.
Treatment
eGFR (mL/min)
15 ≤ClCr<20 
20 ≤ClCr<30 
30 ≤ClCr≤40 
40 <ClCr<49
Delafloxacin
200 mg IV every
12h
No dosage 
adjustment 
required for oral 
formulation
200 mg IV every
12h
No dosage 
adjustment 
required for oral 
formulation
No dosage
adjustment
No dosage
adjustment
Vancomycin
Dose and dose-
interval based on 
serum vancomycin 
trough levels and 
residual renal 
function as per 
SmPC*.
15 mg/kg every
24h
15 mg/kg every
24h
15 mg/kg every
24h
Linezolid
No dosage
adjustment
No dosage
adjustment
No dosage
adjustment
No dosage
adjustment
Piperacillin/
Tazobactam
Maximum dose
suggested:
4 g / 0.5 g every 
12h
Maximum dose
suggested:
4 g / 0.5 g every 
8h
Maximum dose
suggested:
4 g / 0.5 g every 
8h
No dosage
adjustment
Tigecycline
No dosage
adjustment
No dosage
adjustment
No dosage
adjustment
No dosage
adjustment
*Individual adjustments of the vancomycin dose or infusion duration should be guided by the results of 
serum trough levels, with the intent to maintain a minimum trough concentration of  > 15 µg/mL up to a 
maximum trough concentration of 20 µg/mL.
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8.6.5 Prior and Concomitant medications and Wound Dressing
8.6.5.1 Prior and Concomitant Medications
All medications, including dietary supplements and nonprescription medications, taken since
30 days before the Screening Visit and until first treatment intake, will be recorded in the 
eCRF as prior medications.
NOTE: Patients treated with previous IV antimicrobial therapy exceeding 24 hour duration 
administered during 72 hours prior to start study treatment are not eligible to the study.
All medications, including dietary supplements and nonprescription medications -except 
topical medications with nonspecific antimicrobial activity- taken since the first treatment 
intake will be recorded in the eCRF as concomitant medications at each study visit.
Short-acting antipyretic treatment for fever (> 38°C) and/or relief of symptoms associated
with fever is allowed. Short-acting antipyretics include acetaminophen / paracetamol and 
nonsteroidal anti-inflammatory drugs.
NOTE: Additional antibiotic therapies given in case of suspicion of Gram-negative or MRSA 
involvement (see §8.6.1), will be recorded in a dedicated form of the e-CRF.
8.6.5.2 Prohibited Medications
Antimicrobial treatments other than randomized study treatments and additional therapies, as
reported in §8.6.1, are prohibited.
Starting from 2 weeks before Screening and up to the LFU Visit, the use of systemic 
corticosteroids for more than 10 days at a dose equivalent to > 15 mg prednisone per day is 
prohibited.
ONLY in case of linezolid administration the use of medicinal product which inhibits
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) in the 2 weeks prior to 
Screening till the LFU Visit is prohibited.
Topical use of antibacterial agents (eg, mupirocin, retapamulin, fusidic acid) are not allowed
for the local infection site care.
8.6.5.3 Wound Care Management
Wound care management of the SSI, including any surgical procedures, will be performed as
per local standard practice with the following restriction:
- No topical solution or dressing containing specific antibacterial agents (eg, 
mupirocin, retapamulin, fusidic acid) shall be used; only topical solution with
nonspecific activity (e.g povidone - iodine) may be used.
- No major debridement procedures, or other major surgical procedures to treat the
infection on the SSI area are allowed after Randomization.
- Hyperbaric oxygen therapy is not allowed.
The following procedures are allowed:
- Daily dressing changes to the SSI.
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- Use of routine packing with local anesthetic, as per SoC, will be allowed if deemed 
necessary by the Investigator, so long as the packing does not contain an
antimicrobial compound.
- Minor bedside procedures, such as debridement and / or vacuum-assisted wound
closure, that are part of routine care.
At each visit, and until the patient remains hospitalized, the Investigator will record in eCRF 
the wound care measures adopted since the previous visit and if any of the prohibited 
procedures have been performed.
NOTE: If a major surgical procedure is deemed necessary to treat/eliminate the infection, then 
the patient will be withdrawn from the study and will be considered as clinical failure.
8.7 
Study visits, procedures and assessments
The study encompasses up to 8 site visits (depending upon the individual duration of study 
treatment) and ending with the Late Follow Up Visit that represents the End of Study Visit.
Each patient will undergo the study procedures described below and summarized in the study 
flowchart (§2.2). Along the study period, any planned and unplanned procedure (e.g. 
specialist visit, laboratory or radiologic examinations) will be documented and recorded in 
eCRF.
8.7.1 Pre-screening and Informed Consent process
Pre-screening of potential patients in person or by reviewing medical history / medication to 
determine their initial eligibility for a study is a common strategy in the recruitment process 
and can be done before informed consent is obtained.
The Investigator will be trained to encourage patients, at time of hospital discharge after
surgical intervention, in coming back to the site in case they should experience any signs or 
symptoms of SSI.
Before performing any study procedures, all potential eligible patients will sign an Informed
Consent Form (ICF) after receiving any clarification by the Investigator. The Investigator will 
sign the ICF as well.
8.7.2 Screening Visit
The Screening Visit will be performed within 30 days after the surgical intervention. Patients
may be inpatients or outpatients at the time of Screening. Outpatients successfully completing 
the Screening will be hospitalized.
The following procedures shall be performed after the patient provides informed consent:
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● Check of Inclusion / Exclusion Criteria (§8.4.1 and §8.4.2)
● Collection of demographic data and medical history (§8.7.12.1)
● Physical examination (§8.7.12.2)
● Recording of prior medications (§8.6.5.1)
● Infection site assessment (§8.7.11.1)
● Documentation of SSI wound care management, if any (§8.6.5.3)
● Gram stain and microbiological culture of infection site specimen (§8.7.11.3)
● Blood culture (§8.7.11.3)
● Vital signs (§8.7.12.2)
● 12-lead electrocardiogram (ECG) (§8.7.12.5)
● Blood sampling for safety laboratory tests (haematology, biochemistry, coagulation,
virology) (§8.7.12.3)
● 
 
 
 
 
 
 
 
● Urinalysis (§8.7.12.3)
● Serum (or plasma) and urine pregnancy test, if applicable (§8.7.12.3)
● Recording of any Clinical Event, not associated to any drug intake (§8.8.1.2) and/or 
any Adverse Event associated to any drug intake (§8.8.1.1) that occurs for the first
time or worsens after the signature of the ICF and prior to Investigational Medicinal
Product (IMP) administration, if any.
8.7.3 Randomization and Treatment Administration - Visit 1 (Day 1)
Visit 1 has to be scheduled within 1 day from Screening, with the following procedures to be 
performed prior to first administration of study treatment:
● Instructions and completion of the Short Form-36 (SF-36v2) Health Survey
questionnaire (§8.7.11.6), to be performed as first procedure
● Re-check of Inclusion and Exclusion criteria (§8.4.1 and §8.4.2)
● Recording of prior and concomitant medications (§8.6.5.1)
● Infection site assessment (§8.7.11.1)
● Documentation of SSI wound care management, since the previous visit, if any
(§8.6.5.3)
● Gram stain and microbiological culture of infection site specimen (§8.7.11.3), if
clinically indicated
● Blood culture, if the previous culture was positive or if clinically indicated (§8.7.11.3) 
● Vital signs (§8.7.12.2)
● Recording of any Clinical Event, not associated to any drug intake (§8.8.1.2) and/or
recording of any Adverse Event associated to any drug intake (§8.8.1.1) that occurs 
for the first time or worsens after the signature of the ICF and prior to IMP 
administration, if any
● Investigator’s choice of Reference treatment plus any additional therapy, if needed
(§2.1)
● Assignment of the randomized treatment as per IWRS (§8.6.2)
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● Administration of study medication.
NOTE-1: If Visit 1 falls on the same day of Screening, all the procedures done at Screening 
should not be repeated.
NOTE-2: In case of vancomycin assignment, vancomycin trough levels shall be monitored 
after 3 doses (steady state), at Visit 3 and whenever clinically indicated, for dose or duration
of infusion adjustment2. See §8.6.4 for further details.
8.7.4 Day 2 Onwards Daily Assessments
Starting from Day 2 up to maximum the End Of Treatment, laboratory and clinical 
parameters/assessment reported below will be evaluated DAILY by the blinded observer who 
will be responsible to define:
● Eligibility of the patient to switch from IV to the oral formulation (§0).
● Eligibility of the patient to be discharge relevant for assessment of the Hospital
Infection-Related Length of Stay-IRLOS (§0).
For the eligibility to IV/OS switch and/or IRLOS (to be assessed as much as possible 
approximately at the same time and within 12:00), the following procedures shall be daily 
performed:
 Vital signs: BP, HR and Body Temperature (maximum T° recorded from the last 24h)
 Blood sampling for haematology (WBC count only)
 Assessment of patient ability to tolerate PO diet and no gastrointestinal absorption
problem
 Wound status idoneous for home care management
NOTE 1- At Visit 2 and Visit 3, vital signs and WBC count are also contemplated and shall 
be performed only once.
NOTE-2: date and time of the actual switch to oral formulation (i.e. first intake of the oral
formulation), will be recorded by the Investigator. Assignment of delafloxacin or linezolid 
oral kit will be performed through IWRS by unblinded site staff.
NOTE-3: date and time of the actual hospital discharge (i.e. the time when the letter of 
discharge is issued) will be recorded by the Investigator upon occurrence along the study up 
to End of Study Visit.
NOTE-4: at the time of actual discharge, if the patient is on treatment with
a) IV formulation and outpatient parenteral antimicrobial therapy at site could be 
implemented as allowed by local standard practice, he/she will travel to site to receive drug 
administration as per treatment schedule;
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b) oral formulation (i.e. delafloxacin or linezolid), he/she will be provided with the IMP box 
(covering maximum 5 days of treatment) and a paper diary to record daily the tablets intake.
8.7.5 Visit 2 (Day 3 – 4)
The following procedures shall be performed between 48h and 72 h after first dose 
administration.
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the 
study visit.
● Recording of AEs occurred since previous visit, if any (§8.8.2)
● Recording of concomitant medications (§8.6.5.1)
● Infection site assessment (§8.7.11.1)
● Documentation of SSI wound care management, since the previous visit, if any
(§8.6.5.3)
● Gram stain and microbiological culture of infection site specimen, if clinically
indicated (§8.7.11.3)
● Blood culture if the previous culture was positive or if clinically indicated (§8.7.11.3) 
● Vital signs (§8.7.12.2)
● Blood sampling for safety laboratory test (haematology, biochemistry, coagulation,
(§8.7.12.3)
● 
 
 
 
 
 
 
 
● Urinalysis (§8.7.12.3).
In case of early treatment withdrawal, patients should undergo the EOT Visit, and should be 
followed as described in §8.4.4.
NOTE: The infection site specimen for microbiological culture should be collected before 
initiation of any alternative antibacterial therapy.
8.7.6 Visit 3 (Day 7)
The following procedures shall be performed at Day 7 if the patient is still on treatment. 
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the 
study visit.
● Patient’s completion of the SF-36v2 Health Survey (§8.7.11.6), to be performed as
first procedure
● Recording of AEs occurred, since previous visit, if any (§8.8.2)
● Recording of concomitant medications (§8.6.5.1)
● Infection site assessment (§8.7.11.1)
● Documentation of SSI wound care management, since the previous visit, if any
(§8.6.5.3)
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● Gram stain and microbiological culture of infection site specimen, if clinically
indicated (§8.7.11.3)
● Blood culture if the previous culture was positive or if clinically indicated (§0)
● Vital signs (§8.7.12.2)
● Blood sampling for safety laboratory test (haematology, biochemistry, coagulation)
(§8.7.12.3)
● 
 
 
 
 
 
 
 
● Urinalysis (§8.7.12.3)
● Therapeutic Drug Monitoring for vancomycin, if appropriate (§8.6.4)
In case of early treatment withdrawal, patients should undergo the EOT Visit, and should be 
followed as described in §8.4.4.
NOTE: The infection site specimen for microbiological culture should be collected before 
initiation of any alternative antibacterial therapy.
8.7.7 End of Treatment - EOT Visit
The following procedures shall be performed at EOT Visit (within 1 day after last dose 
administration).
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the
study visit as per Investigator’s prescription.
● Patient’s completion of the SF-36v2 Health Survey (§8.7.11.6), to be performed as
first procedure
● Contact IWRS to report treatment completion status (§8.6.2)
● Recording of AEs occurred, since previous visit, if any (§8.8.2)
● Recording of concomitant medications (§8.6.5.1)
● Infection site assessment (§8.7.11.1)
● Documentation of SSI wound care management, since the previous visit, if any
(§8.6.5.3)
● Gram stain and microbiological culture of infection site specimen (§8.7.11.3)
● Blood culture if the previous culture was positive or if clinically indicated (§8.7.11.3) 
● Physical examination (§8.7.12.2)
● Vital signs (§8.7.12.2)
● 12-lead ECG (§8.7.12.5)
● Blood sampling for safety laboratory test (haematology, biochemistry, coagulation,
(§8.7.12.3)
● 
 
 
 
 
 
 
 
● Urinalysis (§8.7.12.3)
● Serum (or plasma) pregnancy test, if applicable (§8.7.12.3)
● Assessment of clinical response (§8.7.11.2).
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In case of the EOT Visit is performed for early treatment withdrawal, patients should be 
followed as described in §8.4.4.
8.7.8 Test of Cure -TOC Visit
The following procedures shall be performed at TOC Visit (7 - 14 days after last dose). 
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the 
study visit.
● Patient’s completion of the SF-36v2 Health Survey (§8.7.11.6), to be performed as
first procedure
● Recording of AEs occurred, since previous visit, if any (§8.8.2)
● Recording of concomitant medications (§8.6.5.1)
● Infection site assessment (§8.7.11.1)
● Documentation of SSI wound care management, since the previous visit, if any
(§8.6.5.3)
● Gram stain and microbiological culture of infection site specimen (§8.7.11.3)
● Blood culture if the previous culture was positive or if clinically indicated (§8.7.11.3) 
● Vital signs (§8.7.12.2)
● 12-lead ECG (§8.7.12.5)
● Blood sampling for safety laboratory tests (haematology and biochemistry) (§8.7.12.3) 
● Urinalysis (§8.7.12.3)
● Assessment of clinical response (§8.7.11.2).
8.7.9 Follow-up Visit or Phone Call
Recording of AEs and concomitant medications will be performed 21 days (± 2 days) after the 
last dose. Outpatients (i.e. patients already discharged from the hospital) will receive a follow- 
up telephone call to collect this information or will be invited to the site.
8.7.10 Late Follow-up /End of Study Visit
The following procedures shall be performed at LFU Visit (28 - 30 days after last dose). 
Outpatients (i.e. patients already discharged from the hospital) shall return to the site for the 
study visit. LFU Visit represents the End of Study Visit.
● Patient’s completion of the SF-36v2 Health Survey (§8.7.11.6), to be performed as
first procedure
● Recording of AEs occurred, since previous visit, if any (§8.8.2)
● Recording of concomitant medications (§8.6.5.1)
● Infection site assessment (§8.7.11.1)
● Documentation of SSI wound care management, since the previous visit, if any
(§8.6.5.3)
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● Assessment of clinical response (§8.7.11.2).
8.7.11 Assessment of Efficacy
8.7.11.1 
Infection Site Assessment
Signs and symptoms of SSI will be assessed at each visit by the Investigator who will record
the following:
● Anatomical site of infection and classification of superficial or deep SSI (at Screening
only)
● Presence/absence of:
 drainage / discharge
 fluctuance
 heat / localized warmth;
 swelling / induration;
 pain / tenderness;
 erythema/extension of redness (and maximum extension from the wound edge;
mm)
 lymphangitis
 lymphadenopathy (with number and anatomical site of lymph nodes)
8.7.11.2 
Clinical response
Clinical response will be based on the Investigator’s assessment of the patient’s signs and
symptoms of infection at the EOT, TOC, and Late Follow-up Visits and classified as Cure, 
Improved, Failure or Indeterminate defined as follows:
● Cure: The complete resolution of all baseline signs and symptoms of SSI
● Improved: two or more signs and/or symptoms (but not all) were considered resolved thus 
the patient has improved to an extent that no additional antibiotic treatment is
necessary.
NOTE: Clinical Success is defined as Cure or Improved.
● Failure: Response will be classified as failure if
 any administration of antibacterial therapy for SSI is required because of lack of 
efficacy after at least 2 days (i.e. 4 or 6 doses, based on daily posology scheme)
of study treatment (delafloxacin or Reference treatment with or without
additional therapy) as defined prior to and confirmed at Randomization by the 
Investigator, OR
 the patient would have been in need to continue study treatment for more than
14 days OR
 the need for unplanned major surgical intervention on SSI after Randomization
OR
 antibiotic therapy is required to treat P. aeruginosa (ONLY for tigecycline
treated patients)
NOTE: If clinical response is considered as Failure at a visit, then it will be considered 
Failure at any subsequent visit.
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● Missing: A missing response will be considered a Failure for the analyses on the ITT
population and the patient will be excluded from the CE population.
● Indeterminate: A response cannot be assigned because an assessment was not 
completed at the respective visits or because the patient received potentially effective
non-study antibacterial drug therapy for treatment of a condition other than SSI. An
indeterminate response will be considered a Failure for the analyses on the ITT 
population and the patient will be excluded from the CE population.
8.7.11.3 
Microbiological Assessment
SSI specimen
SSI specimen must be obtained from all patients at Screening to identify the causative
pathogen, and repeated at EOT and TOC Visits and whenever it is clinically indicated. In 
addition, SSI specimen should be obtained before initiation of any alternative antibacterial 
therapy.
The specimen may be obtained by biopsy, needle aspiration, surgical sterile techniques
including aspiration of purulent material from an abscess.  Swabs will not be accepted as a 
mean for specimen collection; however, the use of a sterile swab deep inside the cavity of a
post-incision and drainage wound to absorb drainage is allowed.
The method used to obtain the specimen and the specific anatomical site (e.g. chest, abdomen, 
leg) will be documented in the patient's source records and in the eCRF.
SSI specimen(s) (up to 3 specimens/visit) shall provide adequate aliquots for all 
microbiological analyses, i.e. bacterial culture, bacterial morphology and polymorphonuclear 
leucocytes (PMNs) assessment.
Specimen(s) will be collected and shipped from the study site to the Local/Regional
laboratory for Gram stain and culture using adequate materials, timing, and shipping 
conditions which ensure specimen integrity and viability.
Specific instructions for collection, handling and shipping of specimens will be provided in
the Laboratory manual.
Gram stain: Four Gram stain slides of the specimen will be prepared by the Local/Regional 
laboratories for PMNs (n= 2 slides) and bacterial morphology assessments (n=2). One
slide/each assessment will be stained and read at Local/Regional laboratory; the
Local/Regional laboratory will then send all 4 slides (stained and unstained) to Central 
laboratory to confirm results.
An additional Gram stain slide may be retained by the Local/Regional microbiology
laboratory until the conclusion of the study, if required by local regulations.
Culture: Bacterial culture and antimicrobial susceptibility testing will be performed at
Local/Regional laboratory, as applicable, following local practice.
All isolates, including the ones considered contaminants, will be forwarded to the Centralized 
laboratory for confirmation of identity and antimicrobial susceptibility testing and any further 
phenotypic or molecular characterization (please refer to laboratory manual for details).
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Local/Regional laboratory will send the primary bacterial isolates (under ambient condition
on transport medium) and two back-up bacterial isolates (frozen) to the Centralized 
laboratory. Samples will be stored until one year after the end of the clinical trial.
In vitro susceptibility: Susceptibility of target pathogens to delafloxacin and Reference 
Treatments will be determined at the Central laboratory according to CLSI and EUCAST 
guidelines with broth microdilution. Susceptibility to additional antibiotics may also be
evaluated. The results will be also released according to the EUCAST official clinical
breakpoints for delafloxacin, when available.
Blood Culture
A minimum of two sets of blood cultures will be collected from different anatomical sites
from all patients at Screening, with each set including both an aerobic and an anaerobic bottle.
In case of positive results in at least one bottle, an alert will be sent to the Investigator and
other two sets of bottle will be collected immediately following the same procedure defined 
for Screening.
Gram stain: two Gram stain slides will be prepared from every positive blood culture bottle.
One slide should be stained and evaluated at the Local/Regional microbiology laboratory and 
both slides read and unread will be sent to Central laboratory.
Isolates will be forwarded to the Centralized microbiology laboratory for confirmation of
identity, antimicrobial susceptibility testing, and any further molecular or phenotypic 
characterization. For each organism isolated and identified at Local/Regional laboratory, the 
primary isolates (under ambient condition on transport medium) and two back-up isolates 
(frozen, on dry ice) will be sent to the Centralized laboratory.
Additional blood samples will be collected for culture at subsequent visits if the previous
culture is positive and whenever it is clinically indicated following the same procedure 
defined for Screening.
Samples will be stored until one year after the end of the clinical trial. Specific handling and
shipping instructions that will maintain viability of all organisms will be provided in the 
laboratory manual.
8.7.11.4 
Microbiological Response
Microbiological response will be generated at the EOT and TOC assessments at both
pathogen and patient levels on the basis of the results of the infection site specimen(s) and 
blood culture at baseline and follow-up and susceptibility testing performed at the 
microbiological Centralized laboratory.
Data regarding all baseline and post baseline organisms isolated at the Centralized laboratory
from the infection site and blood will be evaluated by blinded external expert, who will 
review and identify which organisms are causative pathogens of SSI, and will assign the 
correspondent microbiological response for each causative pathogen among the definitions 
listed below:
● 
Documented eradicated: The baseline pathogen is absent in the specimen collected
at the relevant timepoint.
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● 
Documented persisted: The baseline pathogen is present in the specimen collected
at the relevant timepoint.
● 
Not evaluable: it is not feasible to assess the microbiological response (e.g. there is
no material available for specimen)
● New pathogen: a pathogen known to cause SSI different from the baseline causative
pathogen is detected in the specimen.
When it is not feasible to assess the microbiological response, Sponsor will assign one of the 
following options based on the Investigator’s assessment of clinical response:
● 
Presumed eradicated: The patient has a “not evaluable” microbiological response
and a clinical response of “success” at the relevant timepoint.
● 
Presumed persisted: The patient has a “not evaluable” microbiological response and
a clinical response of “failure” at the relevant timepoint.
Indeterminate: The patient has a “not evaluable” microbiological response and a 
clinical response of “indeterminate” at the relevant timepoint.
In addition, emergent infections will be separately classified as per the definitions below 
when a microbiological sample taken post-baseline through the TOC is positive for “new” 
pathogen(s):
Emergent Infections:
● 
Superinfection: A new pathogen known to cause SSI is cultured from the original
site of infection during treatment with a clinical response of “failure”.
● 
New infection: A new pathogen known to cause SSI is cultured from the original
site of infection after end of treatment with a clinical response of “failure”.
The following pathogens are examples of primary pathogens that will be used to determine
the microbiological responses in the study. The typical bacterial pathogens include but may 
not be limited to:
Gram-positive organisms
Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible
[MSSA] isolates)
Staphylococcus haemolyticus
Staphylococcus hominis
Staphylococcus lugdunensis
Streptococcus agalactiae
Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus
intermedius, and Streptococcus constellatus)
Streptococcus dysagalactiae
Streptococcus mitis Group (including Streptococcus cristatus, Streptococcus gordonii,
Streptococcus oralis, Streptococcus mitis, and Streptococcus sanguinis)
Streptococcus pyogenes
Enterococci, incl. vancomycin-resistant strains
Gram-negative organisms
Enterobacteriaceae, including multidrug-resistant strains
Pseudomonas aeruginosa, Pseudomonas spp.
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Acinetobacter baumannii, Acinetobacter spp.
Anaerobes
8.7.11.5 
Switch from IV to PO treatment and Hospital discharge
Starting from Day 2 up to maximum the End Of Treatment, the blinded observer will review
DAILY if laboratory and clinical parameters meet all the criteria listed below for considering 
the patient:
● eligible to switch from IV to the oral formulation (relevant for the assessment of
theoretical vs actual duration of IV treatment): all criteria 1 to 5 must be satisfied
● eligible to be discharged (relevant for the assessment of the hospital Infection-Related 
Length Of Stay-IRLOS vs actual hospital Length Of Stay-LOS): all criteria 1 to 4 and
criterion 6 must be satisfied
*maximum T° recorded from the last 24h
Whenever possible, the same blinded observer should review the lab/clinical parameters and 
complete the assessments for the patient, every day approximately at the same time, and 
within 12:00, with WBC results made available on time for the assessment.
Upon the observed blinded assessment is completed, the Investigator has the duty to record:
 date and time of the actual switch to oral formulation (i.e. first intake of the oral
formulation)
 date and time of the actual discharge (i.e. when the letter of hospital discharge is
issued)
NOTE: at the time of actual discharge, if the patient is on treatment with
a) IV formulation and outpatient parenteral antimicrobial therapy at site could be
implemented as allowed by local standard practice, he/she will travel to site to receive 
drug administration as per treatment schedule;
b) oral formulation (i.e. delafloxacin or linezolid), he/she will be provided with the
IMP box (covering maximum 5 days of treatment) and a paper diary to record daily 
the tablets intake.
In case eligibility will not translate into actual IV to PO switch and/or actual hospital 
discharge, the Investigator has the duty to record:
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1)
Systolic blood pressure normal/not clinically significant abnormal
2)
No infection related tachycardia
3)
Afebrile status;  body temperature <38°C for at least 24 hours*
4)
WBC count normalized/not clinically significant abnormal
5)
Patient able to tolerate PO diet/to take PO treatment and no GI absorption problem
6)
Wound status idoneous for home care management


Study Code: DELA-01 
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Version 1.0, 05 April 2019
 reasons which don’t allow the actual switch to oral formulation
 reasons which don’t allow the actual hospital discharge of the patient (e.g., need for
IV treatment, comorbidities, social issue).
NOTE: reason shall not be recorded if the actual hospital discharge occurs within 12 
hours from eligibility to be discharged.
In the event that Investigator discharges the patient prior he /she met the IRLOS criteria, the 
Investigator has the duty to fully justify the reason.
8.7.11.6 
Patient reported outcome questionnaire
The SF-36v2® Health Survey is a short-form health survey with 36 questions, with one-week 
recall period, that yields scores for psychometrically-based physical component summary and
mental component summary and for eight health domains (i.e. physical functioning, role-
physical, bodily pain, general health, vitality, social functioning, role-emotional, mental 
health). Patients will complete the questionnaire by indicating his/her health state by ticking 
(or placing a cross) in the box against the most appropriate statement at each question on 
paper format. The Investigator or delegate will report the collected answers in the eCRF. 
Questionnaire has to be administered at the study site at Visit 1, Visit 3 (if performed), EOT, 
TOC and LFU Visits prior to any other study visit procedure.
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
8.7.12 Assessment of Safety
8.7.12.1 
Demographic data and Medical History
Demographic data and medical history are recorded at Screening. Demographic data include 
age, sex, race and ethnicity. Medical history includes clinically significant medical illnesses 
or underlying / accompanying diseases existing 2 years prior to or on entry to the trial as well 
as the type of surgical intervention the patient underwent and as a result of which the infection 
has been diagnosed. Data related to the SSI (see §8.7.11.1) should be recorded on the 
Infection Site Assessment pages of the eCRF.
8.7.12.2 
Physical Examinations and Vital signs
A complete physical examination will be performed at Screening and at the EOT Visit.
Measurement of height (in whole centimeters) and weight (in kilograms to one decimal place) 
will be performed at Screening only.
Vital signs, i.e. systolic and diastolic-BP (mmHg), HR (beats / minute, assessed by ECG if
needed), RR (breaths / minute), and body T by tympanic digital thermometer (°C ) will be 
measured at Screening, at Visit 1 (prior to any study treatment intake), and at each following 
visit till TOC. Vital signs (except RR) will be also recorded daily for blinded observer review
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until patient is considered eligible to switch to oral formulation and to hospital discharge, and 
up to maximum End Of Treatment. The highest body temperature recorded for the specific 
visit or on 24-hour basis will be reported in the eCRF. Any use of antipyretic or analgesic 
should be recorded.
8.7.12.3 
Clinical Laboratory Evaluation
Safety laboratory testing will be performed by a local laboratory at the timepoints specified in
the Study Flow Chart (§2.2).  Tests to be performed are as follows:
Haematology: A haematology panel test will be taken at Screening, Visit 2, Visit 3 (if 
performed), EOT and TOC Visits to include complete blood count with haematocrit, 
haemoglobin, platelet count, red blood cell count, mean corpuscular volume, and WBC count 
with differential (neutrophil, bands, lymphocyte, monocyte, eosinophil and basophil counts,
absolute and %). At Screening glycated haemoglobin (HbA1c) will be measured only in
patients with medical history of diabetes. WBC count will be repeated daily until in the 
normal range or abnormal but not clinically significant for blinded observer review until 
patient is considered eligible to switch to oral formulation and to hospital discharge, and up to 
maximum EOT.
Biochemistry: A complete serum chemistry panel will be taken at Screening, Visit 2, Visit 3 
(if performed), EOT and TOC Visits to include sodium, potassium, chloride, bicarbonate (or 
alternatively total CO2 concentration obtained through venous blood gas test), magnesium, 
calcium, phosphorus, blood urea nitrogen or urea, creatinine, creatine phosphokinase, 
albumin, glucose, total protein, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, uric acid and total and direct bilirubin. After EOT Visit, chloride, 
bicarbonate, magnesium, blood urea nitrogen or urea, creatine phosphokinase, total protein, 
alkaline phosphatase, and uric acid will be no longer assessed, unless previous significant 
results to be monitored.
CrCl will be calculated at Screening and at any time is clinically indicated for treatment dose
modification by the Cockcroft-Gault formula.
Virology: Hepatitis B virus surface antigen and Hepatitis C virus antibody will be tested only 
at Screening and will not be exclusionary.
Coagulation tests: Prothrombin time/activity, international normalized ratio (INR) will be 
measured at Screening, Visit 2, Visit 3 (if performed) and EOT Visit.
Urinalysis: Urine analysis, i.e. specific gravity, pH, leucocytes, nitrite, protein, glucose, 
ketones, urobilinogen, bilirubin, blood (erythrocytes / haemoglobin) will be performed at 
Screening, Visit 2, Visit 3 (if performed), EOT and TOC Visits as per standard practice at the 
site.  Alternatively, a Roche-Combur dipstick will be provided to the site and same parameters 
analyzed. An overall clinical judgment will be recorded in eCRF.
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Study Code: DELA-01 
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Version 1.0, 05 April 2019
8.7.12.4 
Pregnancy test
At Screening, the pregnancy test will be performed in women of childbearing potential by
commercial dipstick to obtain result in timely manner. A serum or plasma pregnancy test will 
be performed at Screening (to confirm the dipstick result), and at EOT Visit.
8.7.12.5 
12-Lead ECG
Standard 12-lead ECG will be performed at Screening, at EOT and TOC Visits as
summarized in the study flowchart (§2.2), and whenever clinically indicated.
12-lead ECG will be recorded after the patient has been in a supine position and at rest for at 
least 3 minutes. 12-lead ECGs will be performed, using standard equipment available at the 
study sites.
All ECG print-outs should be identified with patient number, as well as with the date and time
of recording. The ECG tracings should be collected and retained with the source documents 
for study monitoring.
8.7.13 Study endpoints
8.7.13.1 
Primary efficacy endpoint
The primary efficacy end-point is the Clinical Success defined as the clinical response of
“Cure” or “Improved” at TOC (7 - 14 days after last dose) in the ITT Intent-to-Treat (ITT) 
and the Clinical Evaluable (CE) populations.
8.7.13.2 
Secondary efficacy endpoints
The study secondary endpoints are:
a) 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
d) Eligibility to switch to oral formulation according to the blinded observer’s
assessment as per criteria reported in §0;
e) Hospital IRLOS (Infection Related Length of Stay), in the ITT and CE populations, 
beginning with first dose of study treatment and ending when the patient is 
considered eligible to discharge (up to maximum EOT) according to the blinded
observer’s assessment as per criteria reported in §0;
f) 
Hospital LOS (Length of Stay), in the ITT and CE populations, beginning with the
diagnosis of SSI (Screening) and ending with actual hospital discharge;
g) Microbiological response at EOT and TOC Visits in the MITT and the
Microbiologically Evaluable (ME) populations;
h) 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 


Study Code: DELA-01 
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Version 1.0, 05 April 2019
8.7.13.3 
Exploratory efficacy endpoints
Time-course of ProCT and CRP serum values and correlation between ProCT and CRP serum
values versus individual parameters and overall IRLOS assessment at different timepoints in 
the ITT population.
8.7.13.4 
Safety endpoints
The study will assess:
● Incidence, intensity (severity), seriousness and treatment-causality of TEAEs (i.e.
AEs that occurred after the first study drug intake).
● Frequency of clinically significant changes in vital signs, 12-lead ECG and laboratory 
parameters (haematology, biochemistry, coagulation and urinalysis), post-dose versus
baseline.
NOTE: The latest assessments performed before first study treatment administration will 
represent the baseline.
8.7.13.5 
Health economics endpoints
Healthcare resources consumption.
Further details will be reported in the Statistical Analysis Plan and Health Economics 
Analysis Plan.
8.8 
Adverse events definitions, monitoring / recording and management
8.8.1 Definition
8.8.1.1 Adverse Event
Any untoward medical occurrence in a patient or clinical trial subject administered with a
medicinal 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), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
8.8.1.2 Clinical Event
Any adverse clinical condition not associated to a drug intake that occurs for the first time or
worsens after signing the informed consent but prior to IMP administration will be classified 
as “Clinical Event”.
8.8.1.3 Treatment -Emergent Adverse Event
Any AE that occurs for the first time or it worsens in terms of seriousness or severity after the
first study drug intake will be classified as Treatment -Emergent Adverse Event (TEAE).
8.8.1.4 Drug relationship
The relationship between an AE and study drug(s) will be judged according to the following
categories:
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1. 
Certain: The AE occurs in a plausible time relation to the administration of the drug
and cannot be explained by a concurrent disease or other drugs or chemicals. The
response to withdrawal of the drug (dechallenge) should be clinically plausible. The 
event must be definitive pharmacologically or phenomenologically, using a satisfactory 
rechallenge procedure if necessary.
2. 
Probable: The AE occurs in a reasonable time relation to the administration of the
drug, it is unlikely to be attributed to a concurrent disease or other drugs or chemicals
and it follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information (AE reappearance after drug reintroduction) is not required to 
fulfill this definition.
3. 
Possible: The AE occurs with a reasonable time relation to the administration of the
drug, but it could also be explained by a concurrent disease or other drugs or chemicals. 
Information on drug withdrawal (dechallenge) may be lacking or unclear.
4. 
Unassessable: The relationship cannot be judged, because of the information is
insufficient or contradictory and cannot be supplemented or verified.
5. 
Unlikely: A causal relationship cannot be definitively ruled out, but
● other drugs, chemicals, or underlying disease provide plausible explanations
and / or
● the temporal relation to the administration of the drug makes a causal relation
improbable (but not impossible).
6. 
Not Related: Any of the following are present:
● existence of a clear alternative explanation
and / or
● unreasonable temporal relationship between drug and event
and / or
● non-plausibility
8.8.1.5 Adverse Drug Reactions
An adverse drug reaction (ADR) is any untoward and unintended response to an IMP that is
related to any dose administered.
The definition implies a reasonable possibility of a causal relationship between the event and 
the IMP. This means that there are facts (evidence) or arguments to suggest a causal 
relationship.
An ADR is considered any AE for which the relationship is considered as:
● Certain
● Probable
● Possible
● Unassessable
An AE is not considered as ADR when the relationship is judged as:
● Unlikely
● Not related
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8.8.1.6 Seriousness
An AE/ADR is considered as Serious when:
● results in death;
● is life - threatening;
NOTE: Life - threatening is considered any AE in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe.
● requires inpatient hospitalization or prolongation of existing hospitalization;
● results in persistent or significant disability / incapacity;
● is a congenital anomaly / birth defect;
● is another medically important condition that may jeopardize the patient or may 
require intervention to prevent one of the outcomes listed above. Any suspected 
transmission of an infectious agent via a medicinal product is considered serious and 
should be assessed under the category of medically important events in the absence of
other seriousness criteria.
An AE / ADR is considered non-serious when it does not fulfill the conditions for the 
definition of SAE / ADR.
NOTE: neither prolonged hospitalization only due to SSI nor planned surgery should be
regarded as SAE.
8.8.1.7 Adverse Event / Adverse Drug Reaction intensity (severity)
The intensity level of a serious or a non-serious AE or ADR is attributed according to the
following definitions:
● Mild: does not interfere with routine activities; in case of laboratory tests, when there
is a mild abnormality.
● Moderate: interferes with the routine activities; in case of laboratory tests, when
there is a moderate abnormality.
● Severe: makes it impossible to perform routine activities; in case of laboratory tests,
when there is a significant abnormality.
8.8.1.8 Adverse Event / Adverse Drug Reaction expectedness
An AE/ADR is considered unexpected when the nature, severity, or outcome of the AE/ADR
is not consistent with the information provided in the reference safety document.
NOTE: For the test product, the safety reference document for assessment of expectedness 
will be the Investigator’s Brochure for delafloxacin in force at the time of the event. For the 
reference products, the safety reference document will be the Section 4.2 of the respective 
SmPC.
8.8.1.9 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any SAE judged by the Investigator or the Sponsor as drug-related (§8.8.1.5), and considered
as unexpected qualifies as a SUSAR.
SUSARs are subject to expedited reporting, as specified in §8.8.2.1 as having a “Reasonable 
Possibility” of relationship with the IMP.
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8.8.1.10 
Individual Case Safety Report
Format and content provided to describe one or several AEs or a disease experience that
occurs to an individual patient at a particular point of time.
8.8.2 Collection, recording and reporting of adverse events
At each visit the Investigator will collect and assess any occurred subjective or objective AE, 
and clinical event occurred to each patient after his/her signature of the informed consent.
The Investigator should manage as AE any laboratory test abnormality (newly occurring after 
the IMP administration or worsening of previously known abnormalities) considered as 
clinically significant (CS): i.e. values significantly above or under normal range or which 
require an intervention or diagnostic tests, or may result in the IMP discontinuation.
Any AE communicated by the patient or by the patient’s relatives or delegates through phone 
calls, letters or emails will also be recorded and assessed. In these cases the Investigator will 
try to obtain medical confirmation and assessment of the occurred AE.
When an AE has occurred, the Investigator shall record on the respective eCRF - AE
recording page any event, both serious and non-serious, whether or not thought to be drug - 
related, observed in or reported by the patient (or relatives / delegates), specifying the 
judgment on the causal relationship with the study treatment. When the Investigator confirms, 
on the eCRF - Case page, that all the collected information on any Individual Case Safety 
Report (ICSR) (serious or not, related or not) has been entered in the eCRF, an e-mail 
notification will be sent to the Sponsor.
The Investigator is expected to record also any AE occurring during the study follow-up 
period until the LFU Visit (28 - 30 days after last dose).
Any available information and diagnostic measure (laboratory and instrumental tests, 
procedures, etc.) shall be recorded in the eCRF-AE pages.
When relevant, also the eCRF pages concerning medical history, concomitant medication, and 
laboratory test will be retrieved by the Sponsor’s Study Drug Safety Manager (SDSM).
8.8.2.1 Management of Serious Adverse Events (SAEs)
Reporting duties of the Investigator
The Investigator must report all the collected information on any ICSR with SAE (whether or 
not deemed related to the investigational drug) in the eCRF - AE pages, no later than 24
hours after the first knowledge of the occurrence of the event.
Once the information is validated in the eCRF - AE page, a notification e-mail will be 
automatically generated and sent to the Sponsor’s SDSM (Study Drug Safety Manager), so 
that the SAE can be retrieved.
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The Investigator will be provided with the paper CRF - AE pages to be used only in case of 
breakdown of the eCRF System. In such case, the Investigator will be responsible for sending 
the paper CRF-AE pages and inserting the data in eCRF as soon as the system works again. 
Whenever the paper CRF - AE page is used, it must be submitted by e-mail to the Sponsor’s 
SDSM:
For the initial SAE the Investigator should enter in the eCRF or on the paper CRF-AE page 
(only if the eCRF does not work) all the available information.
When the paper CRF AE pages are used, also the following fields should be reported in CRF
AE pages:
● Patient ID (patient number)
● Reporters name and telephone number for clarifications
The Sponsor’s confirmation of reception of the SAE report must be kept in the patient’s 
records.
Any questions which arise during the processing and medical review of the SAE will be
managed by means of electronic queries (i.e. queries in the eCRF). In case of breakdown of 
the eCRF System, queries will be sent by e-mail.
Any information provided by the Investigator as a query reply or as a follow-up SAE report
will be processed in the same way as the initial SAE report within the required timeframe. 
When relevant, also the eCRF pages concerning medical history, concomitant medication, and 
laboratory tests will be retrieved by the Sponsor’s SDSM.
Any further information and supporting documentation that become available (copies of
laboratory reports, tests, procedures, autopsy evidence of the cause of death, etc.) shall be 
provided no later than 24 hours after the knowledge, by the Investigator to the Sponsor’s 
SDSM by email.
The Investigator must also comply with the local applicable obligation(s) on the reporting of 
ADRs to the local concerned RA / EC.
Reporting duties of the Sponsor
The Sponsor shall ensure that all relevant information about any SUSAR will be 
expeditiously reported to the CAs and EC (following general and local rules and procedures),
with these deadlines after the first knowledge, intended as the day when the Sponsor or the
CRO receives the notification of the SUSAR:
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● Fatal and life threatening unexpected cases, no later than 7 days;
● Other unexpected serious cases, no later than 15 days.
The Sponsor shall ensure that all relevant new information and supporting documentation that 
subsequently become available, will be also expeditiously reported as follow-up information 
no later than 15 days.
Furthermore, the following safety issues will be subjected to expedited management for the
identification of possible necessary actions:
● SAEs associated with the trial procedures
● Potential clinically significant findings emerging from non-clinical studies
● An anticipated end or suspension for safety reasons of another trial with the same
study drug
When appropriate and applicable the Sponsor will provide the adequate information also to 
the Investigators.
8.8.2.2 Management of Non-Serious Adverse Events
The Investigator must record all the available information concerning any ICSR with non-
serious adverse events (NSAE) (whether or not deemed related to the investigational drug) in 
the corresponding section of the eCRF, within 5 calendar days after the first knowledge of the 
occurrence of the case.
When a new AE is entered, a notification e-mail will be automatically generated and sent to 
the SDSM, so the NSAE can be retrieved.
When relevant, also the CRF pages concerning medical history, concomitant medication, and
laboratory test will be retrieved by the SDSM.
8.8.3 Management of any laboratory abnormalities
Any laboratory test abnormality which is considered by the Investigator as CS is to be 
recorded and managed as NSAE or SAE if it matches with any seriousness criteria (§8.8.2 for 
AE collection).
8.8.4 Management of pregnancy exposure cases
The Investigator is expected to record in the provided “Pregnancy Exposure Report Form” 
any case of pregnancy exposure occurring in a female patient or in a male patient’s partner,
during the treatment and follow-up period until the LFU Visit (28 - 30 days after last dose)
provided that the female patient or the patient’s partner enrolled in the study has signed the 
related pregnancy ICF.
The initial “Pregnancy Exposure Report Form” will be sent by email to the SDSM within 5
days after being made aware of the pregnancy. The Investigator is requested to follow each 
case of pregnancy exposure until the outcome. The follow-up of the “Pregnancy Exposure 
Report Form” will be completed with data of the outcome and sent to the SDSM within 5 
days after knowledge of the delivery. The mentioned form will be distributed to the sites to be 
used for this purpose.
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Pregnant women are excluded from enrolment onto the study; in case a patient becomes 
pregnant during the study drug administration period, she shall be discontinued from 
treatment.
If the pregnancy results in an abnormal outcome (miscarriage or new-born with congenital
abnormality and/or stillbirth), the follow-up of the “Pregnancy Exposure Report Form” will 
be completed and sent to the Sponsor within 24 hours and the abnormal outcome, will be 
recorded in the eCRF as a SAE and managed as above described (see §8.8.2.1). If the eCRF is 
not available anymore, the paper CRF - AE page (or any other support for reporting if the 
paper form is not available either) will be used as a back-up.
8.8.5 Annual Safety Reporting
Once a year throughout the clinical trial, the Sponsor will assure the submission to the 
concerned national CAs and ECs of a safety report (Development Safety Update Report, 
DSUR), taking into account all new safety information received during the reporting period.
8.8.6 Breaking of the Randomization Code
Not applicable.
8.8.7 Serious and Non-serious Adverse Events Follow-up
After the LFU Visit, the Investigator is not requested to actively follow-up the patient unless 
ongoing SAEs or NSAEs of special interest are present. In these cases, the event will be 
followed until the event disappears or the patient’s conditions stabilize. However, if the 
Investigator becomes aware of a SAE with a suspected causal relationship to the study 
treatment that occurs after the end of the clinical trial in a patient treated by him or her, the 
Investigator shall, without undue delay, report the SAE to the Sponsor. These SAEs occurred 
after LFU Visit should be also recorded in the eCRF until it is available. If the eCRF is not
available, the paper SAE form will be used as a backup (or any other support for reporting if
the paper form is not available either).
Additionally, patients who discontinued the treatment for any safety reason will be also 
followed until the event disappears, the patient’s conditions stabilize, or until recovery from 
all toxic effects and longer in case of expected delayed toxicity.
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9 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
9.1 
Determination of sample size
A sample size of 600 randomized patients (300 per treatment arm: delafloxacin or Reference 
treatment) will provide about 80% power in the ITT population and higher than 95% in the 
CE population to demonstrate the non-inferiority of delafloxacin versus Reference treatment 
arm in terms of clinical response (Clinical Success) rate with a non-inferiority margin of 10% 
and an alpha equal to 0.025 (1-side test). Clinical Success rate at TOC of 78.0% and 78.1% in 
the ITT and of 98.3% and 99.4% in the CE population are assumed respectively for 
delafloxacin and the Reference treatment arm. Assuming about 20% of Screening failures,
approximately 750 patients are anticipated to be screened to reach a total of 600 randomized
patients.
9.2 
Analysis populations
The following analysis population will be considered:
ITT population: all randomized and treated subjects analyzed according to the randomized 
treatment arm (Test or Reference).
MITT population: all subjects in the ITT population who have at baseline bacterial
pathogen(s) identified, that is known to cause cardiothoracic / related leg and/or abdominal 
SSI.
CE population: all subjects in the ITT population who meet the following criteria:
● Diagnosis of cardiothoracic or abdominal SSI
● Received the correct treatment based on the Randomization assignment
● Received 80% of the expected doses of study drug in the treatment period
● Did not receive any concomitant, systemic antibacterial therapy except for lack of
efficacy
● Had no protocol deviations that would affect assessment of efficacy at the reference
visit.
CE populations will be defined at EOT, TOC, LFU timepoints and for eligibility to switch to 
oral formulation, IRLOS and LOS.
ME population: all subjects in the MITT population who also meet the criteria for the CE 
population.  ME populations will be defined at EOT and TOC.
Safety population: all subjects who have received at least one dose of study medication.
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9.3 
Statistical analysis
9.3.1 Descriptive statistics
All study variables will be presented by treatment and overall, by using the appropriate 
descriptive statistics according to the variable nature, unless otherwise specified:
● Continuous variables: number of non-missing observations, arithmetic mean, standard
deviation, minimum, median, maximum.
● Categorical variables: number of non-missing observations and column percentages
(N, %).
All statistical analyses, unless otherwise specified, will be based on 2-sided 95% CIs around 
the difference in treatment outcomes.
9.3.2 Primary efficacy analysis
The clinical success response at TOC is defined as cure or improved response within 7 - 14 
days after last dose.
The rate of the efficacy variable is the sample responder rate defined in the following
equation:
=
+
All the statistical comparisons will be a test for non-inferiority of delafloxacin versus the 
Reference treatment arm at a 10% non-inferiority margin (unless otherwise specified), with 
the possibility of switching to the superiority based upon the primary endpoint. No 
multiplicity adjustment will be used for testing superiority if non-inferiority has been 
demonstrated.
The null (H0) and alternative (Ha) hypotheses to be tested in order to establish the non- 
inferiority of delafloxacin are:
H0: Pd – Pr ≤ -0.10
Ha: Pd – Pr > -0.10
where Pd and Pr are the probabilities of responder for delafloxacin and the Reference 
treatment arm, respectively.
If the lower limit (LL) of the two-sided 95% CI is greater than -0.10, it will be concluded that 
delafloxacin is noninferior to the Reference treatment arm for treating patients with 
cardiothoracic or abdominal SSI.
The null (H0) and alternative (Ha) hypotheses to be tested in order to establish the superiority 
of delafloxacin are:
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Version 1.0, 05 April 2019
H0: Pd – Pr ≤ 0
Ha: Pd – Pr > 0
If the LL of the two-sided 95% CI is greater than 0, then delafloxacin will be declared
superior to the Reference treatment arm for treating patients with cardiothoracic or abdominal 
SSI. The relative p-value will be produced by using a Chi2-Test.
Confidence intervals will be calculated using Miettinen and Nurminen method.
The homogeneity of the treatment effects will be analyzed for non-inferiority in the ITT and 
CE populations, while for superiority only on the ITT population.
9.3.3 Secondary efficacy analysis
All the secondary efficacy endpoints will be descriptively analyzed and tested, when 
applicable, for non-inferiority with the possibility to switch for superiority through an ad hoc 
inferential analysis, as reported below:
● IRLOS is defined as the cumulative percentage of patient eligible to discharge along
the study treatment duration, beginning at study treatment initiation (Day 1) and 
ending when the criteria reported in §0 are met. Percentages are statistically analyzed 
analogously to the primary efficacy variable, in the ITT and CE populations. 
Additionally, time to eligibility to discharge will be visually assessed by Kaplan- 
Meier curves and the relative p-value will be obtained by a Log-rank test, in the ITT 
and CE population.
● LOS is defined as the cumulative percentage of patients who are discharged along the
overall study duration, beginning at the Investigator diagnosis of the infection 
(Screening) and ending on the date of actual hospital discharge. Percentages are 
statistically analyzed analogously to the primary efficacy variable, in the ITT and CE 
populations. Additionally, time to actual discharge will be visually assessed by
Kaplan-Meier curves and the relative p-value will be obtained by a Log-rank test, in
the ITT and CE population.
● Eligibility to switch to oral formulation is defined as the cumulative percentage of 
patient eligible to switch along the study treatment duration, beginning at study 
treatment initiation (Day 1) and ending when the criteria reported §0 are met. 
Percentages are statistically analyzed analogously to the primary efficacy variable, in
the ITT and CE populations. Additionally, time to eligibility to switch will be visually
assessed by Kaplan-Meier curves and the relative p-value will be obtained by a Log- 
rank test, in the ITT and CE populations.
● Microbiological efficacy responses at EOT and TOC, as defined in §0, will be
statistically analyzed for the MITT and ME analysis set by patient and pathogen 
analogously to the primary efficacy variable. Statistical testing will be performed only 
if applicable, otherwise only frequencies and the relative percentages will be reported.
● 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
9.3.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.5 Subgroup analysis
The most relevant subgroups that will be analyzed (if applicable) are:
● elderly patients (≥ 65 years)
● patients with diabetes
● patients with body mass index (BMI) ≥ 30kg/m2
● patients with baseline bacteremia
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● patients with polymicrobial infection
● patients with MRSA
● patients with severe renal impairment (CrCl between 15, inclusive, and <30 mL/min) 
● patients with ≥ 2 signs and symptoms at baseline
● patients with baseline COPD
● patients with baseline SIRS, i.e with at least two of the following:
o fever >38°C or < 36°C
o heart rate >90 beats per minute
o respiratory rate >20 breaths per minute or PaCO2 <32 mm Hg
o abnormal white blood cell count (>12,000/mm3 or <4,000/ mm3 or >10%
bands)
 
 
 
 
 
  
 
 
 
 
 
9.3.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.8 Interim analysis and stopping rules
No interim analysis is planned for this study.
9.3.9 Data imputations
A missing clinical response will be imputed as defined in §8.7.11.2
No missing responses are expected for the microbiological response.
9.4 
Protocol violations and Data Review
Categories of protocol violations will be assigned to each potential protocol violation and will 
be integrated in the SAP.
For the primary efficacy analysis, a Data Review Meeting (DRM) will take place at the end of 
the study in order to evaluate and accept the data management report, discuss remaining 
issues (outstanding queries, unresolved errors), and to confirm and approve relevant protocol 
violations. Patients who experience relevant protocol violations, accordingly to what is 
described in §9.2, will be excluded from the CE population.
After final DRM takes place and the database is considered cleaned, the database will be
locked.
9.5 
Statistical analysis plan
The SAP will be finalized before the study initiation. The SAP will describe in detail study 
endpoints and the statistical analyses to be performed, including, if any, also additional 
endpoints and analyses not planned in the protocol.
In case major changes in the original primary endpoint or in the original primary analyses will
occur during the study, these changes will be the subject of a substantial protocol amendment. 
Minor deviations (e.g. not involving changes in the primary endpoint and analysis) which 
might occur during the study will be detailed only in the SAP.
All statistical analyses not pre-specified and run after data locked will be considered
additional / post-hoc analyses.
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10 DATA QUALITY MANAGEMENT
10.1 Data collection
Data collection activities will be carried out under the responsibility of the Sponsor. Patient 
data will be collected using the data capture systems described below. Patients will be 
identified by the patient study identification number (patient ID), assigned at the Screening 
Visit.
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
The data will then be processed, evaluated, and stored in pseudonymised form in accordance 
with applicable data protection regulations.
10.1.1 Electronic case report forms
Clinical data collected during the study at sites will be recorded in an eCRF using Medidata 
RAVE which is a validated system. The eCRF will be developed based on this study protocol 
under the responsibility of the Sponsor that will also perform user acceptance test of the eCRF 
in order to ensure the protocol adherence.
The eCRF will be made available to the study personnel by means of the iMedidata interface
which is a validated system. The accounts will be individual and password-protected. The 
blinded observer will have a restricted access to eCRF in order to preserve the blind 
condition.
The Investigator or designee will be responsible for entering study data into the eCRF in
accordance to the eCRF Completion Guidelines provided by the Sponsor. In order to improve 
the quality of data collection and cleaning, data shall be entered into the eCRF as closely as 
possible to the time when they become available and not later than within 5 working days. 
The eCRF data will not be considered as source data (see §10.3).
Investigators will ensure the accuracy, completeness and consistency of data entered signing
electronically the eCRF using the personal password.
An audit trail within the system will track all changes made to the data.
10.1.2 IWRS
IWRS system ClinPhone RTMS, provided by Parexel International, is a validated system used
by the site personnel for the patient screening (including assignment of the patient number), 
Randomization, kit assignment, patient status change.
The implementation of the system for this study will be detailed in the RTMS specification
document. Sponsor will perform the user acceptance test of the implementation.
Site staff, excluding the blinded observer, will be provided with a personal user name and 
password to access to IWRS.
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An IWRS user manual will be provided to site personnel.
Some data such as patient ID and visit dates, collected through IWRS system, could be 
automatically integrated in eCRF. The integration process will be detailed in a specific
integration document. All the above mentioned documents will be provided by Parexel
International.
10.1.3 Patient reported outcome questionnaire
The Optum™ SF-36v2® Health Survey asks 36 questions that yield an eight-scale profile of 
functional health and well-being, as well as two psychometrically based physical and mental 
health summary measures. The questionnaire will be administered to the patients on paper 
format, the Investigator or delegate will report the collected answers in the eCRF.
10.1.4 Patient Diary
At the time of discharge, the patient, if still on treatment with the oral formulation of the 
therapy, will receive a paper diary to record date and time of each tablet intake. The patient 
has to bring the diary to the site at the next study visit and the completed diary pages have to 
be checked and collected by the Investigator. The Investigator or designee is responsible for 
entering data recorded in the diary into the e-CRF.
10.1.5 Centralized Laboratory / Examination data
Local/Regional and Centralized microbiology laboratory data will be managed according to 
laboratory SOPs. Centralized laboratory data and relevant Local/Regional laboratory data will 
be transferred from Centralized laboratory to Menarini Ricerche S.p.A., Clinical Sciences 
Department. The transfer process will be detailed in a specific transfer document, agreed 
between Centralized laboratory and Sponsor. Descriptive statistical analysis will be 
performed on these data. The data will be also made available to the external Expert 
for microbiological response analysis (§8.7.11.4). The results of the analysis will be recorded 
by the Expert in eCRF.
10.1.6 Data capture systems versions and validation documentation
Versions of the data capture systems can change during the study. The Sponsor will maintain 
a list of the data capture system versions used and the validation documentation of each 
version. The list and the validation documentation will be provided to the site at the Site 
Initiation Visit (SIV) and will be updated at any data capture system version change.
10.2 Clinical data management
Data Management will be carried out under the responsibility of Sponsor. eCRF data will be 
electronically verified through the use of on-line and off-line checks. Discrepancies in the 
data will be resolved by means of electronic queries. Data will be locked by the Data Manager
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when all activities for the trial, including medical revision of the data, are complete and no 
more entries are expected.
Data from sources other than eCRF will be provided to the Data Manager on an agreed 
scheduled basis. The Data Manager has the responsibility to reconcile data captured in the 
eCRF, with external data sources. Discrepancies, found in the reconciliation of the data, will 
be addressed by means of queries.
A clear overview of all clinical data management activities will be given in the Data 
Management Plan.
10.3 Source data
Source data are defined as all data in original records and certified copies of original records 
of clinical findings, observations or other activities in a clinical trial that are necessary for the 
reconstruction and evaluation of the trial.
Original documents and data records include, but are not limited to hospital / patients’
medical records, laboratory notes, ECG records, patients’ identification forms, SF-36v2 
questionnaires, patient diary and pharmacy dispensing records.
Study sites will also maintain a paper drug accountability forms for the CTM to document
dispensed and returned CTM per patient.
Moreover, the blinded observer’s judgment about patient eligibility to switch to oral 
formulation and to discharge as well as the related data will be collected through a paper 
worksheet, which will represent the source data of the assessment to be recorded in eCRF. 
Source data should be held available for perusal by the Sponsor representatives for the study 
or to other authorized persons such as auditors and inspectors of Regulatory Authorities. 
Direct access to source data is defined as the permission to examine, analyze, verify and 
reproduce any records and reports that are important for evaluation of a clinical trial. Any 
party allowed to direct access to study source data and documents should take all reasonable 
precautions within the constraints of the applicable regulatory requirements to maintain the 
confidentiality of patient identities and sponsor proprietary information.
Data should be consistent with the source documents and discrepancies, if any, should be
explained in writing by amending the source documents or with additional documentation, if
needed. All the original documentation pertinent to the study procedures must be available for 
review in each patient’s record.
10.4 Quality control / quality assurance
10.4.1  Study Monitoring
This trial will be monitored in accordance with the ICH Note for Guidance on GCP.
Monitoring will be carried out by PSI CRO AG. This study will follow the CRO quality risk
management process, which is made up of systematic implementation of overall risk 
assessment, critical processes and data identification, risk definition, evaluation and response 
planning, risk monitoring and control, and risk communication and reporting. Based on
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Version 1.0, 05 April 2019
overall initial risk assessment for the study, the project Risk Management Plan will be 
developed. The project Risk Management Plan will contain risk based monitoring strategy, 
which will provide guidance on blend of onsite, offsite and central monitoring.  Throughout 
the study, the Central Monitoring Manager will be responsible for Central Monitoring, 
performing periodic review of the risks, follow-up on the identified issues, and ensuring that 
the process of risks monitoring and review is appropriately documented; the detailed 
description of the Central Monitoring Manager activities will be included into the Monitoring 
Plan. Central monitoring will be executed by risk based monitoring tool. The site monitor will 
perform on site and off site visits to the trial sites throughout the study conduct. Facilities, 
study drug, storage area, eCRF, patient’s source data, and all study documentation will be 
inspected/reviewed by the site monitor for adherence to the protocol and GCP. At each on site 
visit, the monitor will review eCRFs for completion and accuracy. Accuracy will be checked 
by performing source data verification that is a direct comparison of the entries made onto the 
eCRFs against the appropriate source documentation. Any revealed discrepancies will be 
reviewed with the Investigator and his/her staff. The Investigator agrees to allow access to all 
study related materials needed for the proper review of study conduct and to assist the 
monitor during monitoring visits and during data cleaning process. Monitoring procedures 
will be based on risk based monitoring, particularly focusing on critical data, critical 
processes and subject safety, for example, informed consents, adherence to inclusion/
exclusion criteria, drug accountability, documentation of SAEs and proper recording of 
efficacy and safety measurements. All monitoring activities including risk based approach will 
be described in detail in the study-specific monitoring plan.
10.4.2  Quality Assurance
Independent study audit(s) and / or inspection(s) may take place at any time during or after
the trial. The audit / inspection can be carried by the Quality Assurance (QA) of the CRO, the 
QA provider independent from the Sponsor or a CA.  At all times, the confidentiality of 
subject related documents will be maintained.
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11 PREMATURE TERMINATION OF THE WHOLE STUDY
The whole trial may be discontinued at the discretion of the Sponsor in the event of any of the 
following:
● New information leading to unfavorable risk-benefit judgment of the investigational
products due to:
- 
Occurrence of significantly previously unknown AEs or unexpectedly high
intensity or incidence of known AEs
- 
New evidence of unfavorable safety or efficacy findings (from clinical or non-
clinical examinations, e.g. toxicology)
● The Sponsor’s decision that continuation of the trial is unjustifiable for medical or 
ethical reasons or based on emerged data which may impact on the rationale to
perform the study
● Discontinuation of development of the IMP
CAs and IECs will be informed about the discontinuation of the trial in accordance with 
applicable regulations.
12 END OF CLINICAL TRIAL AND ARCHIVING
The clinical study will end with the collection and analysis of study data and the issue of the 
Clinical Study Report. All essential documents will be archived by the Sponsor according to 
the relevant SOP.
12.1 Archiving of electronic documentation / data
As described in §5.5, duplicate electronic media such as CDs / DVDs (one for routine access 
and one for back-up) containing the patient data in PDF format (e.g. eCRFs,  questionnaires) 
for each site will be prepared by the Sponsor or a delegate for archiving purposes. The 
electronic media, of a not re-printable type, will be appropriately labelled recording the
files / data included. The files should contain at least the eData copy clearly reporting the
system name, study code and the eCRF used; for eCRF data also the electronic signature and 
the associated audit trails have to be included.
The Investigator should verify whether the provided electronic media represent a complete
copy of eCRFs generated during the study relevant for the site. The Investigator has to 
confirm the receipt and correctness of the material by signing a dedicated form provided by 
the Sponsor, the signed form has to be collected and archived in the eTMF.
Two copies of the same electronic media prepared for the sites or cumulative electronic media
with the same content will be archived by the Sponsor. In addition the Sponsor is responsible 
to create 2 electronic media (one for routine access and one for back-up) containing an 
integrated SAS database with all study data e.g. eCRF, IWRS, centralized laboratory), with 
appropriate refreshment procedures.
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Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
Investigators and Sponsor will be also responsible to refresh their electronic media 
approximately every 7 years to ensure long term archiving of files / data.
CONFIDENTIAL 
Page 97 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
13 REFERENCES
1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 
EMA/645879/2017- EMA recommends changes to prescribing information for
vancomycin antibiotics. 21 September 2017.
3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
  
 
 
 
 
 
 
 
 
 
 f
 
 
 
 
 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 98 of 99


Study Code: DELA-01 
Clinical Trial Protocol
EudraCT No.: 2018-001082-17 
Version 1.0, 05 April 2019
13. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15. 
Addendum to the guideline on the evaluation of medicinal products indicated for
treatment of bacterial infections. EMA/CHMP/351889/2013. October, 2013.
16. 
Guidance for Industry Acute Bacterial Skin and Skin Structure Infections: Developing
Drugs for Treatment. U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research, October 2013.
17. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
18. 
Practice Guidelines for the Diagnosis and Management of Skin and Doft Tissue
Infections: 2014 Update by the Infectious Diseases Society of America
19. 
Guideline on the evaluation of medicinal products indicated for treatment of bacterial
infections. CPMP/EWP/558/95 rev 2. December, 2011.
CONFIDENTIAL 
Page 99 of 99

SAP_001.pdf: 
DELAFLOXACIN INTRAVENOUS AND ORAL MONOTHERAPY IN SURGICAL SITE INFECTIONS - DRESS Study
Statistical Analysis Plan
Version 1.0
Date: 02 SEP 2019
Study code 
DELA-01
EudraCT-Number 
2018-001082-17
Investigational Medicinal Product
Delafloxacin 300 mg powder for solution for IV infusion 
and 450 mg Oral Tablet
Development phase of study 
III b
Sponsor 
MENARINI RICERCHE S.p.A.
Via Sette Santi, 1
50131 Florence, Italy
Co-ordinating Investigator 


Menarini  icerche S. .A. 
Stud  Code: DELA-OI
SIGNATURE PAGE
Prepared by:
Date
Approved by:  UL  Ia 0
,
.
Statistica! Analysis Pian
Ve sion 1.0, 02 SEP 2019
Page 2 of 50


Menarini Ricerche S.p.A. 
Study Code: DELA-01
TABLE OF CONTENTS
1
INTRODUCTION ............................................................................................................................. 7
2
STUDY OBJECTIVES ..................................................................................................................... 8
2.1 
PRIMARY OBJECTIVE ......................................................................................................... 8
2.2 
SECONDARY OBJECTIVE ................................................................................................... 8
3
INVESTIGATIONAL PLAN ...........................................................................................................  8
3.1 
OVERALL STUDY DESIGN AND PLAN ............................................................................ 8
3.2 
EFFICACY AND SAFETY VARIABLES ........................................................................... 15
3.2.1 
Efficacy Variables ............................................................................................................... 15
4
STATISTICAL METHODS ..........................................................................................................  22
4.1 
DATA QUALITY ASSURANCE ......................................................................................... 22
4.2 
GENERAL PRESENTATION CONSIDERATIONS .......................................................... 22
4.3 
ANALYSIS POPULATIONS ............................................................................................... 23
4.4 
STUDY PATIENTS .............................................................................................................. 25
4.4.1 
Disposition of Patients ......................................................................................................... 25
4.4.2 
Protocol Deviations ............................................................................................................. 27
4.5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................ 27
4.6 
EFFICACY EVALUATION ................................................................................................. 31
4.6.1 
Analysis and Data Conventions .........................................................................................  31
4.6.2 
Handling of Dropouts or Missing Data ............................................................................... 33
4.6.3 
Multiplicity .......................................................................................................................... 33
4.6.4 
Examination of Subgroups .................................................................................................. 34
4.6.5 
Primary Efficacy Variable – ................................................................................................ 34
4.6.6 
Secondary Efficacy Variables ............................................................................................. 35
4.7 
SAFETY EVALUATION ..................................................................................................... 41
4.7.1 
Adverse Events .................................................................................................................... 42
4.7.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ........................... 43
4.7.3 
Clinical Laboratory Evaluation ..........................................................................................  44
4.7.4 
Vital Signs, Physical Findings and Other Observations Related to Safety ......................... 44
4.8 
DETERMINATION OF SAMPLE SIZE .............................................................................. 46
4.9 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS .............. 46
5
GENERAL DEFINITIONS ............................................................................................................  46
5.1 
DATA VALIDATION .......................................................................................................... 46
5.2 
COMPUTER SYSTEMS AND SOFTWARE TO BE USED IN THE ANALYSIS ............ 46
5.3 
CODING SYSTEMS USED ................................................................................................. 47
5.3.1 
Clinical Terms ..................................................................................................................... 47
5.3.2 
Drugs ................................................................................................................................... 47
5.4 
REPORT TYPE, LANGUAGE AND FORMAT ................................................................. 47
6
TABLES FIGURES AND LISTINGS ............................................................................................ 48
6.1 
STATISTICAL ANALYSIS REPORT (TFL) ...................................................................... 48
6.2 
TABLES, HEADINGS, AND FOOTNOTES ....................................................................... 48
6.3 
LIST OF TABLES AND FIGURES ..................................................................................... 48
6.4 
PATIENT DATA LISTING .................................................................................................. 49
7
REFERENCES ................................................................................................................................ 50
Statistical Analysis Plan
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Menarini Ricerche S.p.A. 
          Study Code: DELA-01
LIST OF ABBREVIATIONS
ABSSSI
Acute Bacterial Skin And Skin Structure Infection/s
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
AUC
Area Under the plasma concentration time Curve
BMI
Body Mass Index
CA
Competent Authority
CDC
Centers for Disease Control and Prevention
CE
Clinically Evaluable
CI
Confidence Interval
cIAI
Complicated Intra-Abdominal Infection
CrCl
Creatinine Clearance
CLSI
Clinical and Laboratory Standards Institute
CNS
Central Nervous System
CRF
Case Report Form
CRO
Clinical Research Organization
CRP
C-reactive Protein
CS
Clinically Significant
CTM
Clinical Trial Medication
DNA
Deoxyribonucleic Acid
DRM
Data Review Meeting
DSUR
Drug Safety Update Report
EC
Ethics Committee
ECDC
European Centre for Disease Prevention and Control
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic Acid
EEA
European Economic Area
eGFR
Estimated Glomerular Filtration Rate
EEA
European Economic Area
EMA
European Medicines Agency
EOT
End Of Treatment
eTMF
Electronic Trial Master File
EU
European Union
FDA
Food and Drug Administration
FQ-NS
Fluoroquinolone Non Susceptible
FU
Follow Up
Statistical Analysis Plan
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Menarini Ricerche S.p.A. 
          Study Code: DELA-01
GCP
Good Clinical Practice
HR
Heart Rate
ICF
Informed Consent Form
ICSR
Individual Case Safety Report
ICH
International Conference of Harmonization
ID
Identification
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRLOS
(Hospital) Infection-Related Length of Stay
ITT
Intent-to-Treat
IV
Intravenous(ly)
IWRS
Interactive Web Response System
LFU
Late Follow Up
LL
Lower Limit
LOS
(Hospital) Length of Stay
ME
Microbiologically Evaluable
MedDRA
Medical Dictionary for Regulatory Activities
MIC
Minimum Inhibitory Concentration
MIC90
The lowest MIC that inhibits 90% of the strains within a single species
MITT
Microbiologically Intent-to Treat
MRSA
Methicillin-resistant Staphylococcus aureus
MSSA
Methicillin-susceptible Staphylococcus aureus
NSAE
Non-Serious Adverse Event
OS
Oral(ly)
PMNs
Polymorphonuclear leukocytes
Pro-CT
Procalcitonin
PT
Preferred Term
PTE
Post-treatment Evaluation
QA
Quality Assurance
QoL
Quality of Life
QRDR
Quinolone Resistance Determining Region
RR
Respiratory Rate
RTC
Research Toxicology Centre
SAE
Serious Adverse Event
SDSM
Study Drug Safety Manager
SF-36v2
Short Form-36 version 2
SIRS
Systemic Inflammatory Response Syndrome
Statistical Analysis Plan
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Menarini Ricerche S.p.A. 
          Study Code: DELA-01
SIV
Site Initiation Visit
SmPC
Summary of Product Characteristics
SoC
Standard of Care
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SSI
Surgical Site Infection/s
TEAE
Treatment-Emergent Adverse Event
TDM
Therapeutic Drug Monitoring
TOC
Test Of Cure
UK
United Kingdom
US
United States of America
WBC
White Blood Cell
Statistical Analysis Plan
Version 1.0, 02 SEP 2019 
Page 6 of 50


Menarini Ricerche S.p.A. 
          Study Code: DELA-01
1 INTRODUCTION
The purpose of this document is to provide further details about the statistical analysis methods 
specified in study protocol for the Phase III-b study of IV / oral delafloxacin fixed-dose monotherapy in 
a microbiologically enriched population with surgical site infections.
The study is sponsored by Menarini Ricerche S.p.A.  A brief description of the study objectives and
study design are given in sections 2 and 3 respectively.  Subsequent sections include the definition of 
analysis populations, efficacy and safety endpoints including details about statistical methods and 
hypotheses.
Delafloxacin was approved for treatment of adult patients with ABSSSI by the United States (US) Food 
and Drug Administration FDA on June 19, 2017. US Commercial distribution started in early 2018. 
In this study, patients will receive delafloxacin 300 mg IV or 450 mg OS Q12h or the selected 
Reference Treatment which represent the best available therapy (BAT) for either cardiothoracic /related 
leg or abdominal SSI.
The Reference Treatments are already on the market for the treatment of ABSSSI since many years and
their benefits are documented in published literature. In this study, they will be administered according 
to the relative Summary of Product Characteristics (SmPC).
Considering that this study aims to enroll a representative rate of difficult-to-treat population affected by 
a mixed bacterial flora and multiple comorbidities, posing them at an increased risk of adverse events 
and drug-drug interactions when treated with the standard of care, at least a comparable therapeutic 
benefit is expected for subjects who will be randomized to the delafloxacin arm versus the Reference 
Treatment arm. To note that the Investigator can choose the most adequate treatment between two pre- 
selected BAT for each type of infection; in addition the antimicrobial cover of the Reference Treatment 
can be also optimized by the addition of another antibiotic in case of suspected MRSA or Gram negative 
bacteria for abdominal or cardiothoracic SSI, respectively (the only exclusion is any quinolone). No 
additional therapy is requested for delafloxacin because of its wide antimicrobial cover.
Statistical Analysis Plan
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Menarini Ricerche S.p.A. 
 
          Study Code: DELA-01
2 STUDY OBJECTIVES
2.1 
PRIMARY OBJECTIVE
To assess the comparability of delafloxacin and BAT in terms of Clinical Success in patients with 
superficial or deep incisional SSI following a cardiothoracic / related leg or abdominal surgical 
procedure.
2.2 
SECONDARY OBJECTIVE
To assess the comparability of delafloxacin and BAT in patients with cardiothoracic / related leg or 
abdominal SSI, in terms of:
● Effectiveness, microbiological response and sustained efficacy
● safety and tolerability
● healthcare resources consumption.
2.3 
EXPLORATORY OBJECTIVE
To evaluate the time course of infection biomarkers (Procalcitonin-ProCT and C-Reactive Protein-CRP 
serum values) and their correlation with SSI clinical improvement.
3 INVESTIGATIONAL PLAN
3.1 
OVERALL STUDY DESIGN AND PLAN
This is a randomized, observer-blinded, active-controlled, parallel-group, multicenter, phase IIIb study 
for the treatment of incisional, superficial or deep, cardiothoracic / related leg or abdominal SSI (i.e. an 
expected microbiologically enriched population with SSI), comparing IV / oral monotherapy 
delafloxacin with selected Reference treatments which represent the BAT for either cardiothoracic/
related leg or abdominal SSI. The study is intended to be conducted in approximately 70 sites in Europe.
Eligible patients will be randomly assigned in a 1:1 ratio to receive Test or Reference treatment and
stratified by site of infection (at least approximately 180 patients either for the cardiothoracic / related 
leg or abdominal SSI) and superficial / deep infections.
The Reference treatment arm includes two options for each SSI. The selection of one of the two allowed 
options for each SSI is upon Investigator’s judgment based on the patient characteristics and the local 
epidemiological pattern and will be done prior to the Interactive Web Response System (IWRS) 
assignment of Test or Reference treatment.
A schematic design of study treatments and visits is provided in Figure 1 and Figure 2.
Statistical Analysis Plan
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Menarini Ricerche S.p.A. 
          Study Code: DELA-01
Approximately 750 male and female patients aged > 18 years with diagnosis of SSI will be enrolled. 
Assuming that approximately 20% of screened patients will not fulfill the eligibility criteria, it is 
anticipated that about 750 patients will be screened to obtain 600 randomized patients. The overall 
clinical phase is expected to start in Q3 2019.
The enrolment of patients will be competitive; however, eligibility of patients with one out of the two
types of SSI (cardiothoracic / related leg or abdominal surgical procedure) will end when overcoming 
the 70% of the overall study population. Additionally, approximately 20% - 30% of total sample size of 
patients is expected to be recruited altogether in Italy, Spain and/or UK.
Study participation of individual patients is based on the treatment duration (range: minimum 5 to 
maximum 14 days, as per Investigator's judgment) and will last at most 45 days.
The study will encompass up to 8 site visits (depending upon the individual duration of study treatment)
and ends with the Late Follow Up (LFU) Visit which represents the End of Study Visit.
Patients will be hospitalized from Screening and will remain hospitalized as per Investigator’s judgment. 
Patients can be discharged while are on treatment: a) if the patient is still on treatment with IV 
formulation, outpatient parenteral antimicrobial therapy at site could be implemented wherever allowed 
by local standard practice (patients will travel to site to receive drug administration as per treatment 
schedule); b) if the patient is switched to oral treatment, outpatients will return to the site for the study 
visits.
The clinical benefit of treatment is intended to be evaluated in terms of “Success” (cure or improved) 
according to the standard medical practice when making the decision of antibiotic termination and 
hospital discharge. The clinical response of “Success” (cure or improved) is therefore the primary 
efficacy endpoint to be assessed at TOC Visit in accordance with the EU specific requirements1 for 
ABSSSI.
Testing of non-inferiority of delafloxacin vs BAT is also in compliance with current international
guidelines6 for the development of antibiotics. In particular, non-inferiority is considered appropriate for
ABSSSI in light of the high medical need of new antibiotics addressing Multi Drug Resistance 
pathogens.
Clinical and microbiological standard parameters will be assessed to test comparability of delafloxacin 
versus Reference treatment(s) in terms of efficacy and safety. Additional assessments will include: 
Quality of Life (QoL) by Short Form-36 (SF-36v2) Health Survey, eligibility of patients to switch to 
oral formulation and/or to hospital discharge (IRLOS), and actual hospital discharge (LOS).
No interim analysis is planned.
An observer-blinded, randomized design was selected in order to increase the objectivity in the clinical 
assessments and to minimize the intentional or unintentional Investigator’s bias with respect to the 
assigned treatment. For this reason at each study site an unblinded Principal Investigator (referred to as
Statistical Analysis Plan
Version 1.0, 02 SEP 2019 
Page 9 of 50


Menarini Ricerche S.p.A. 
          Study Code: DELA-01
“Investigator”) and a blinded observer will be designated. The responsibilities of each role are described 
below:
Investigator: The Principal Investigator or his/her delegates and site staff are unblinded and manage all 
study procedures except the assessment of patient’s eligibility to switch from IV to oral formulation and 
eligibility to hospital discharge relevant to IRLOS. The Investigator and designee are responsible for 
ensuring that patient will receive study treatment as per IWRS assignment (i.e. Test or Reference). Prior 
to Randomization, based on the patient characteristics and the local epidemiological pattern, the 
Investigator records which treatment (among the allowed pre-selected BAT) he/she would select in case 
the IWRS actually allocates the patient to the Reference treatment.
Study staff will provide the blinded observer with data relevant to define the eligibility of the patients to
IV/PO switch and hospital discharge for IRLOS assessment.
Blinded observer: This role will be assigned by PI to a physician who will be responsible for the 
assessment of parameters relevant for defining the patient as eligible to IV/PO switch of therapy and 
dischargeable from the hospital (IRLOS assessment).
In his role, the blinded observer will never have to be informed about the actual patient allocation to
Test or Reference treatment arm and about the additional therapy, if any.
To ensure the blinding, the observer will not be permitted to see in any way the study medications being 
dispensed to the patient, as well as actual prescription logs and study medications will never have to be 
discussed in presence of the blinded observer. Whenever possible, the same blinded observer should 
complete all the assessments for the patient, every day approximately at the same time, and within 
12:00.
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Page 10 of 50




Menarini Ricerche S.p.A. 
 
          Study Code: DELA-01
Figure 2:  Schematic Study Outline
Statistical Analysis Plan
Version 1.0, 02 SEP 2019 
 
Page 12 of 50
Test Of Cure
(TOC) visit
7‐14 days 
after last dose
Visit 2
48 to 72 h 
after first dose
Visit 3
Day 7
(if patient is on
treatment)
End of
Treatment
(EOT) visit 
Within 1 day
after last dose
Follow up
visit/
Phone call 
21±2 days
after last dose
Late Follow
up/ End of 
study visit
28‐30 days 
after last dose
Screening visit
Within 30 
days from
surgery
Visit 1
Within 1 day 
from Screening
Treatment period
(Day 1 to maximum Day 14)
=
Potential timeframe for IRLOS assessment


Menarini Ricerche S.p.A. 
Table I: Study flow-chart 
Informed consent 
Incl / Excl criteria 
Hospitalizationa 
Demographic data / Medicai histo1y 
Randonùzation 
IMP dispensinge 
Prior and/or Conconùtant medications 
Physical examination' 
Pregnancy tesË 
Vita! signs
n 
12-lead ECG
TDM for Vancomycini, if appropriate 
Haematologyl 
Biochenùstiy 
Coagulation test 
Virology (and HbAlc for diabetics only) 
Urinalysis 
Infection site assessment 
Eligibility to discharge assessment (IRLOS)l 
Eligibility to switch to ora! fo1mulation 
assessmenf' 
Recording ofSSI wound care management" 
Microbiologica! culnu·e of infection site 
Blood culnu·e 
Sn1dy dmg adnùnistrationq 
Clinica! Events/ AE recording' 
AEs recordingS 
SF-36v2 Health Smvey QoL1 
Statistica! Analysis Pian 
Version 1.0, 02 SEP 2019 
Screening 
V1Sit 1 
(within 30 
(Day 1; 
days from 
within 1 day 
SUl'ge1y) 
from 
Screening) 
x• 
X 
X" 
X 
X 
X 
X 
X 
X 
X 
X 
X" 
X 
X 
X 
X 
X 
X 
X 
X 
X" 
X 
X" 
X 
xc·0 
X 
xc·P 
X 
X 
X 
X 
X 
Study Code: DELA-01 
Trcatmcnt perioda 
Visit2 
V1Sit3 
EOTV1Sit 
TOCVisit 
FUVisitor 
LFU/Endof 
(Day 3- 4; 
(Day 
7, 
if (within 1 day 
(7-14 days • 
StudyVisit 
48 to 72h after 
patient 
IS on 
after last dose) 
after last dose) 
(21 ±2 days 
(28-30 days 
first dose) 
treatment) 
after last dose) 
after last dose) 
 
r 
r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
--
 
--
X 
X 
X 
X 
X 
xo 
xo 
X 
X 
Xl' 
XP 
XP 
Xl' 
 
r 
 
r 
X 
X 
X 
X 
Page 13 of50 


Menarini Ricerche S.p.A. 
 
          Study Code: DELA-01
a. Treatment period includes both IV and OS (if applicable) treatment duration. 
b. Informed Consent can be administered prior to Screening.
c. If Visit 1 falls on the same day of Screening, this procedure has not to be repeated.
d. If not yet hospitalized, patients will be hospitalized upon successful completion of the Screening; duration of hospitalization (LOS) is per Investigator’s judgment.
e. IMP is dispensed by unblinded staff, as per IWRS, at randomization, for kit re-supply (note: each kit covers 5 treatment days) and for switch to oral formulation. Upon hospital discharge,
patients with oral delafloxacin or linezolid shall receive IMP together with a paper diary for daily recording of tablet intake.
f. Height and weight will be collected only at Screening Visit.
g. At Screening both urine dipstick and serum (or plasma) pregnancy test. At EOT Visit only serum (or plasma) pregnancy test.
h. Starting from Day 2 up to EOT, Systolic BP, HR, and Body Temperature to be performed daily until patient is considered eligible to switch to oral formulation / to be discharged by the
blinded observer.
i. Therapeutic drug monitoring for vancomycin to be performed after 3 doses of vancomycin (steady state), at Visit 3, and when clinically indicated.
j. Starting from Day 2 up to EOT, WBC count to be performed daily until blinded observer considered the patient eligible for IV to PO switch and eligible for hospital discharge.
k. CrCl will be calculated at Screening and when needed for dose adjustment. After EOT Visit, chloride, bicarbonate, magnesium, blood urea nitrogen or urea, creatine phosphokinase, total
protein, alkaline phosphatase, and uric acid will be no longer assessed, unless previous significant results to be monitored.
l. Eligibility assessed by the blinded observer (in the morning, within 12:00), based on Systolic BP, HR, T, WBC count and wound status.
m. 
Eligibility assessed by the blinded observer (in the morning, within 12:00), based on Systolic BP, HR, T, WBC count and ability to tolerate PO diet/no GI absorption problems.
n. Including wound dressing changes, at the visit or whenever occurred since the previous study visit.
o. If clinically indicated. In case of treatment withdrawal for any reason, the infection site specimen for microbiological culture should be collected before initiation of any alternative
antibacterial therapy.
p. Blood culture to be repeated if the previous culture is positive and when clinically indicated.
q. Drug administration is under unblinded site staff responsibilities, and never disclosed to the blinded observer.
r. Clinical events (not associated with drug intake) /AE associated with any drug taken prior to IMP administration since the ICF signature.
s. Recording and follow-up of AEs after first IMP administration to the LFU /End of Study Visit.
t. Questionnaire should be completed prior to any other study visit procedure.
Statistical Analysis Plan
Version 1.0, 02 SEP 2019 
 
Page 14 of 50
Treatment perioda
Screening
(within 30 
days from 
surgery)
Visit 1
(Day 1;
within 1 day 
from 
Screening)
Visit 2
(Day 3 - 4;
48 to 72h after 
first dose)
Visit 3
(Day 
7, 
if
patient is on 
treatment)
EOT Visit
(within 1 day 
after last dose)
TOC Visit
(7-14 days 
after last dose)
FU Visit or

(21 ± 2 days 
after last dose)
LFU/End of
Study Visit 
(28-30 days 
after last dose)
Clinical Response
X
X
X
End of Treatment Notification in IWRS
X


Menarini Ricerche S.p.A. 
 
          Study Code: DELA-01
3.2 
EFFICACY AND SAFETY ASSESSMENT
3.2.1 Efficacy Assessment
3.2.1.1 Infection Site Assessment
Signs and symptoms of SSI will be assessed at each visit by the Investigator who will record the 
following:
● Anatomical site of infection and classification of superficial or deep SSI (at Screening only)
● Presence/absence of:
 drainage / discharge
 fluctuance
 heat / localized warmth;
 swelling / induration;
 pain / tenderness;
 
erythema/extension of redness (and maximum extension from the wound edge) 
 lymphangitis
 lymphadenopathy (with number and anatomical site of lymph nodes)
Additionally only at screening visit the following information will be also collected:
● Longest head-to-toe length of erythema/redness
● Longest perpendicular width of erythema/redness
● Longest head-to-toe length of the wound
● Longest perpendicular width of the wound
● Area of the erythema/redness (directly derived as the difference between the area of
erythema/redness and the area of wound)
● Presence/absence of abscess
3.2.1.2 Clinical response
Clinical response will be based on the Investigator’s assessment of the patient’s signs and symptoms of 
infection at the EOT, TOC, and Late Follow-up Visits and classified as Cure, Improved, Failure or 
Indeterminate defined as follows:
● Cure: The complete resolution of all baseline signs and symptoms of SSI
● Improved: two or more signs and/or symptoms (but not all) were considered resolved thus the
patient has improved to an extent that no additional antibiotic treatment is necessary. 
NOTE: Clinical Success is defined as Cure or Improved.
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Menarini Ricerche S.p.A. 
 
          Study Code: DELA-01
● Failure: Response will be classified as failure if
 any administration of antibacterial therapy for SSI is required because of lack of efficacy 
after at least 2 days (i.e. 4 or 6 doses, based on daily posology scheme) of study treatment 
(delafloxacin or Reference treatment with or without additional therapy) as defined prior to
and confirmed at Randomization by the Investigator, OR
 the patient would have been in need to continue study treatment for more than 14 days OR 
 the need for unplanned major surgical intervention on SSI after Randomization OR
 antibiotic therapy is required to treat P. aeruginosa (ONLY for tigecycline treated patients)
NOTE: If clinical response is considered as Failure at a visit, then it will be considered Failure at 
any subsequent visit.
● Missing: A missing response will be considered a Failure for the analyses on the ITT population
and the patient will be excluded from the CE population.
● Indeterminate: A response cannot be assigned because an assessment was not completed at the 
respective visits or because the patient received potentially effective non-study antibacterial drug 
therapy for treatment of a condition other than SSI. An indeterminate response will be 
considered a Failure for the analyses on the ITT population and the patient will be excluded from
the CE population.
3.2.1.3 Microbiological Assessment
3.2.1.3.1 SSI specimen
SSI specimen must be obtained from all patients at Screening to identify the causative pathogen, and 
repeated at EOT and TOC Visits and whenever it is clinically indicated. In addition, SSI specimen 
should be obtained before initiation of any alternative antibacterial therapy.
The specimen may be obtained by biopsy, needle aspiration, surgical sterile techniques including
aspiration of purulent material from an abscess.  Swabs will not be accepted as a mean for specimen 
collection; however, the use of a sterile swab deep inside the cavity of a post-incision and drainage 
wound to absorb drainage is allowed.
The method used to obtain the specimen and the specific anatomical site (e.g. chest, abdomen, leg) will
be documented in the patient's source records and in the eCRF.
SSI specimen(s) (up to 3 specimens/visit) shall provide adequate aliquots for all microbiological 
analyses, i.e. bacterial culture, bacterial morphology and polymorphonuclear leucocites (PMNs) 
assessment.
Specimen(s) will be collected and shipped from the study site to the Local/Regional laboratory for Gram
stain and culture using adequate materials, timing, and shipping conditions which ensure specimen 
integrity and viability.
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Specific instructions for collection, handling and shipping of specimens will be provided in the 
Laboratory manual.
Gram stain: Four Gram stain slides of the specimen will be prepared by the Local/Regional laboratories 
for PMNs (n= 2 slides) and bacterial morphology assessments (n=2). One slide/each assessment will be 
stained and read at Local/Regional laboratory; the Local/Regional laboratory will then send all 4 slides 
(stained and unstained) to Central laboratory to confirm results.
An additional Gram stain slide may be retained by the Local/Regional microbiology laboratory until the
conclusion of the study, if required by local regulations.
Culture: Bacterial culture and antimicrobial susceptibility testing will be performed at Local/Regional 
laboratory, as applicable, following local practice.
All isolates, including the ones considered contaminants, will be forwarded to the Centralized laboratory
for confirmation of identity and antimicrobial susceptibility testing and any further phenotypic or 
molecular characterization (please refer to laboratory manual for details).
Local/Regional laboratory will send the primary samples (under ambient condition) and two back-up
samples (frozen) of the isolate(s) to the Centralized laboratory. Samples will be stored until one year 
after the end of the clinical trial.
In vitro susceptibility: Susceptibility of target pathogens to delafloxacin and Reference treatments will 
be determined at the Central laboratory according to CLSI and EUCAST guidelines for broth and agar 
dilution. Susceptibility to additional antibiotics may also be evaluated. The results will be also released 
according to the EUCAST official clinical breakpoints for delafloxacin, when available.
3.2.1.3.2 Blood Culture
A minimum of two sets of blood cultures will be collected from different anatomical sites from all 
patients at Screening, with each set including both an aerobic and an anaerobic bottle. In case of positive 
results in at least one bottle, an alert will be sent to the Investigator and other two sets of bottle will be 
collected immediately following the same procedure defined for Screening.
Isolates will be forwarded to the Centralized microbiology laboratory for confirmation of identity,
antimicrobial susceptibility testing, and any further molecular or phenotypic characterization. For each 
organism isolated and identified at Local/Regional laboratory, the primary samples (under ambient 
condition) and two back-up samples (frozen) will be sent to the Centralized laboratory.
Additional blood samples will be collected for culture at subsequent visits if the previous culture is
positive and whenever it is clinically indicated following the same procedure defined for Screening. 
Samples will be stored until one year after the end of the clinical trial. Specific handling and shipping 
instructions that will maintain viability of all organisms will be provided in the laboratory manual.
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3.2.1.4 Microbiological Response
Microbiological response will be generated at the EOT and TOC assessments at both pathogen and 
patient levels on the basis of the results of the infection site specimen and blood culture at baseline and 
follow-up and susceptibility testing performed at the microbiological Centralized laboratory.
Data regarding all baseline and post baseline organisms isolated at the Centralized laboratory from the
infection site and blood will be evaluated by blinded external expert, who will review and identify 
which organisms are causative pathogens of SSI, and will assign the correspondent microbiological 
response for each causative pathogen among the definitions listed below:
● Documented eradicated: The baseline pathogen is absent in the specimen collected at the
relevant timepoint.
● Documented persisted: The baseline pathogen is present in the specimen collected at the
relevant timepoint.
● Not evaluable: it is not feasible to assess the microbiological response (e.g. there is no material
available for specimen)
● New pathogen: a pathogen known to cause SSI different from the baseline causative pathogen is
detected in the specimen.
When it is not feasible to assess the microbiological response, Sponsor will assign one of the following 
options based on the Investigator’s assessment of clinical response:
● Presumed eradicated: The patient has a “not evaluable” microbiological response and a clinical
response of “success” at the relevant timepoint.
● Presumed persisted: The patient has a “not evaluable” microbiological response and a clinical
response of “failure” at the relevant timepoint.
● Indeterminate: The patient has a “not evaluable” microbiological response and a clinical
response of “indeterminate” at the relevant timepoint.
In addition, emergent infections will be separately classified as per the definitions below when a 
microbiological sample taken post-baseline through the TOC is positive for “new” pathogen(s). 
Emergent Infections:
● Superinfection: A new pathogen known to cause SSI is cultured from the original site of
infection during treatment with a clinical response of “failure”.
● New infection: A new pathogen known to cause SSI is cultured from the original site of
infection after end of treatment with a clinical response of “failure”.
3.2.1.5 Switch from IV to PO treatment and Hospital discharge
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Starting from Day 2 up to maximum the End Of Treatment, the blinded observer will review DAILY if 
laboratory and clinical parameters meet all the criteria listed below for considering the patient:
● eligible to switch from IV to the oral formulation (relevant for the assessment of theoretical vs
actual duration of IV treatment): all criteria 1 to 5 must be satisfied
● eligible to be discharged (relevant for the assessment of the hospital Infection-Related Length Of
Stay-IRLOS vs actual hospital Length Of Stay-LOS): all criteria 1 to 4 and criterion 6 must be 
satisfied
1)
Systolic blood pressure normal/not clinically significant abnormal
2)
No infection related tachycardia
3)
Afebrile status;  body temperature <38°C for at least 24 hours*
4)
WBC count normalized/not clinically significant abnormal
5)
Patient able to tolerate PO diet/to take PO treatment and no GI absorption problem
6)
Wound status idoneous for home care management
*maximum T° recorded from the last 24h
Whenever possible, the same blinded observer should review the lab/clinical parameters and complete 
the assessments for the patient, every day approximately at the same time, and within 12:00, with WBC 
results made available on time for the assessment.
Upon the observed blinded assessment is completed, the Investigator has the duty to record:
● date and time of the actual switch to oral formulation (i.e. first intake of the oral formulation) 
● date and time of the actual discharge (i.e. when the letter of hospital discharge is issued)
NOTE: at the time of actual discharge, if the patient is on treatment with
a) IV formulation and outpatient parenteral antimicrobial therapy at site could be implemented as 
allowed by local standard practice, he/she will travel to site to receive drug administration as per 
treatment schedule;
b) oral formulation (i.e. delafloxacin or linezolid), he/she will be provided with the IMP box
(covering maximum 5 days of treatment) and a paper diary to record daily the tablets intake.
In case eligibility will not translate into actual IV to PO switch and/or actual hospital discharge, the 
Investigator has the duty to record:
● reasons which don’t allow the actual switch to oral formulation
● reasons which don’t allow the actual hospital discharge of the patient (e.g., need for IV
treatment, comorbidities, social issue).
NOTE: reason shall not be recorded if the actual hospital discharge occurs within 12 hours from 
eligibility to be discharged.
In the event that Investigator discharges the patient prior he /she met the IRLOS criteria, the 
Investigator has the duty to fully justify the reason.
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3.2.1.6 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
3.2.1.7 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
3.2.2 Safety Assessments
3.2.2.1 Demographic data and Medical History
Demographic data and medical history are recorded at Screening. Demographic data include age, sex, 
race and 
ethnicity. Medical history includes clinically significant medical illnesses or 
underlying / accompanying diseases existing 2 years prior to or on entry to the trial as well as the type of 
surgical intervention the patient underwent and as a result of which the infection has been diagnosed. 
Data related to the SSI (see §3.2.1.1) should be recorded on the Infection Site Assessment pages of the 
eCRF.
3.2.2.2 Physical Examinations and Vital signs
A complete physical examination will be performed at Screening and at the EOT Visit. Measurement of 
height (in whole centimeters) and weight (in kilograms to one decimal place) will be performed at 
Screening only.
Vital signs, i.e. systolic and diastolic-BP (mmHg), HR (beats / minute, assessed by ECG if needed), RR 
(breaths / minute), and body T by tympanic digital thermometer (°C ) will be measured at Screening, at 
Visit 1 (prior to any study treatment intake), and at each following visit till TOC. Vital signs (except 
RR) will be also recorded daily for blinded observer review until patient is considered eligible to switch 
to oral formulation and to hospital discharge, and up to maximum End Of Treatment. The highest body
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temperature recorded for the specific visit or on 24-hour basis will be reported in the eCRF. Any use of 
antipyretic or analgesic should be recorded.
3.2.2.3 Clinical Laboratory Evaluation
Safety laboratory testing will be performed by a local laboratory at the timepoints specified in the Study 
Flow Chart (§0).  Tests to be performed are as follows:
Haematology: A haematology panel test will be taken at Screening, Visit 2, Visit 3 (if performed), EOT 
and TOC Visits to include complete blood count with haematocrit, haemoglobin, platelet count, red 
blood cell count, mean corpuscular volume, and WBC count with differential (neutrophil, bands, 
lymphocyte, monocyte, eosinophil and basophil counts, absolute and %). At Screening glycated 
haemoglobin will be measured only in patients with medical history of diabetes. WBC count will be 
repeated daily until in the normal range or abnormal but not clinically significant for blinded observer 
review until patient is considered eligible to switch to oral formulation and to hospital discharge, and up 
to maximum EOT.
Biochemistry: A complete serum chemistry panel will be taken at Screening, Visit 2, Visit 3 (if 
performed), EOT and TOC Visits to include sodium, potassium, chloride, bicarbonate (or alternatively 
total CO2 concentration obtained through venous blood gas test), magnesium, calcium, phosphorus, 
blood urea nitrogen or urea, creatinine, creatine phosphokinase, albumin, glucose, total protein, alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, uric acid and total and direct 
bilirubin. After EOT Visit, chloride, bicarbonate, magnesium, blood urea nitrogen or urea, creatine 
phosphokinase, total protein, alkaline phosphatase, and uric acid will be no longer assessed, unless
previous significant results to be monitored.
CrCl will be calculated at Screening and at any time is clinically indicated for treatment dose 
modification by the Cockcroft-Gault formula.
Virology: Hepatitis B virus surface antigen and Hepatitis C virus antibody will be tested only at 
Screening and will not be exclusionary.
Coagulation tests: Prothrombin time/activity, international normalized ratio (INR) will be measured at 
Screening, Visit 2, Visit 3 (if performed) and EOT Visit.
Urinalysis: Urine analysis, i.e. specific gravity, pH, leucocytes, nitrite, protein, glucose, ketones, 
urobilinogen, bilirubin, blood (erythrocytes / haemoglobin) will be performed at Screening, Visit 2, 
Visit 3 (if performed), EOT and TOC Visits as per standard practice at the site.  Alternatively, a Roche- 
Combur dipstick will be provided to the site and same parameters analyzed. An overall clinical 
judgment will be recorded in eCRF.
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3.2.2.4 Pregnancy test
At Screening, the pregnancy test will be performed in women of childbearing potential by commercial 
dipstick to obtain result in timely manner. A serum or plasma pregnancy test will be performed at 
Screening (to confirm the dipstick result), and at EOT Visit.
3.2.2.5 12-Lead ECG
Standard 12-lead ECG will be performed at Screening, at EOT and TOC Visits as summarized in the 
study flowchart (§0), and whenever clinically indicated.
12-lead ECG will be recorded after the patient has been in a supine position and at rest for at least 3
minutes. 12-lead ECGs will be performed, using standard equipment available at the study sites.
All ECG print-outs should be identified with patient number, as well as with the date and time of 
recording. The ECG tracings should be collected and retained with the source documents for study 
monitoring.
4 STATISTICAL METHODS
4.1 
DATA QUALITY ASSURANCE
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Menarini Ricerche procedures.
4.2 
GENERAL PRESENTATION CONSIDERATIONS
‘Baseline’ is defined as the last available non-missing pre-treatment assessment (including unscheduled 
measurements if available and appropriate), unless otherwise specified.
‘End of Study’ is defined as having completed the EOS visit.
‘Duration of Treatment’ will be calculated relative to the date and time of randomization:
Duration of Treatment (h) = Last Treatment Date/Time - Randomization Date/Time.
The same formula is also applied for the calculation of IV and Oral treatment.
The Screening Visit will be performed within 30 days after the surgical intervention. Patients may be 
inpatients or outpatients at the time of Screening. Outpatients successfully completing the Screening will 
be hospitalized.
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, minimum, 
maximum and number of observations, unless otherwise stated.  The minimum and maximum will be 
reported to the same number of decimal places as the raw data recorded in the database.  The mean,
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median, lower quartile and upper quartiles (if required) will be reported to one more decimal place than 
the raw data recorded in the database.  The SD will be reported to two more decimal places than the raw 
data recorded in the database.  In general, the maximum number of decimal places reported shall be four 
for any summary statistic.
Categorical data will be summarized in terms of the number of patients providing data at the relevant 
time point (n), frequency counts and percentages.  Any planned collapsing of categories will be detailed 
in the SAP text and the data displays.
Percentages will be presented to one decimal place and will be calculated using n as the denominator 
unless otherwise specified.
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-values 
less than 0.001 will be presented as “<0.001”.
Confidence intervals will be presented to one more decimal place than the raw data.
All report outputs will be produced using SAS® version 9.3 or a later version in a secure and validated 
environment.
4.3 
ANALYSIS POPULATIONS
The following analysis population will be considered:
ITT population: all randomized and treated subjects analyzed according to the randomized treatment 
arm (Test or Reference).
MITT population: all subjects in the ITT population who have at baseline bacterial pathogen(s) identified, 
that is known to cause cardiothoracic / related leg and/or abdominal SSI.
CE population: Six CE analysis set based on type and/or timing of the assessment are defined. All 
subjects in the ITT population who meet the following criteria will be include in the relative CE:
● All CE population:
 Diagnosis of cardiothoracic or abdominal SSI
 Received the correct treatment based on the Randomization assignment
 Received 80% of the expected doses of study drug in the treatment period
● CE at EOT (CEEOT) for clinical response:
 Did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy
prior to EOT
 Had no protocol deviations prior EOT that would affect clinical response assessment at
EOT
● CE at TOC (CETOC) for clinical response:
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 Did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy
prior to TOC
 Had no protocol deviations prior EOT that would affect clinical response assessment at
TOC
● CE at LFU (CELFU) for clinical response:
 Did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy
prior to LFU
 Had no protocol deviations prior EOT that would affect clinical response assessment at
LFU
● CE for eligibility to switch to oral formulation (CESWITCH):
 Did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy
prior the eligibility assessment
 Had no protocol deviations prior the eligibility assessment or had no missing information
necessary for the evaluation that would affect the eligibility to switch to oral formulation. 
● CE for IRLOS (CEIRLOS):
 Did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy
prior IRLOS assessment
 Had no protocol deviations prior the IRLOS assessment or had no missing information
necessary for the evaluation that would affect the IRLOS assessment.
● CE for LOS (CELOS):
 Did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy
prior LOS assessment
 Had no protocol deviations prior the LOS assessment or had no missing information
necessary for the evaluation that would affect the LOS assessment.
ME population: all subjects in the MITT population who also meet the criteria for the CE population. ME 
populations will be defined at EOT and TOC.
Safety population: all subjects who have received at least one dose of study medication.
A schematic overview of study population is presented in Figure 3 below:
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Figure 3: Population Overview
4.4 
STUDY PATIENTS
4.4.1 Disposition of Patients
A clear accounting of the disposition of all patients who enter the study will be provided, from screening 
to study completion.
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Participation in the study is strictly voluntary and patients have the right to withdraw from the study at 
any time without explanation. This will not affect their rights for future medical care. Patients may also 
be withdrawn at the Investigator's discretion or at specific Sponsor’s request at any time.
Treatment or Study Withdrawal: In the event that the patient withdraws from the treatment or from the 
study for whatever reason, the Investigator must be informed immediately and the date, reasons, and 
circumstances for premature discontinuation will be recorded in the corresponding section of the eCRF. 
Patients have to prematurely discontinue the treatment/study if:
● in the opinion of the Investigator, it is not in the best interest of the patient to continue treatment
or study;
● there is a change in compliance with an inclusion or exclusion criterion that is clinically relevant
or affects patient safety;
● protocol 
violation 
(e.g. 
prohibited 
medication, 
poor 
compliance 
with 
study
procedures / treatment, need for a major surgical procedure);
● patient’s request.
Any patient, who prematurely terminates the treatment/study after having received the study treatment 
will be encouraged to complete the assessments scheduled at the EOT Visit at the time of withdrawal 
and a final LFU Visit, if applicable.
Consent Withdrawal: Patients who withdraw consent will always be asked about the reason(s) and the 
presence of any AEs: no additional data should be collected since the time of withdrawal.  Data already 
collected will be used and analyzed for the purpose of the study. In regard to biological samples already 
collected, the patient will be asked if samples already obtained but not yet analyzed shall be destroyed or 
analyzed.
Lack of Efficacy / Treatment Related AE: In the event patient interrupts prematurely the study treatment 
for lack of efficacy (including the need for non-study antimicrobial agents such as antifungals) or due to a 
treatment related AE which request treatment discontinuation, the patient will undergo EOT Visit at the 
time of withdrawal and, then, any other study visit as per protocol till LFU Visit.
At the time of and after treatment discontinuation the following shall be collected, whenever applicable
(maximum up to LFU Visit):
● Reason for discontinuation
● Description of AE
● Second line antibiotic therapy
NOTE: the specimens for microbiological cultures should be collected before initiation of any 
alternative antibacterial therapy.
● Hospital ward unit(s) where patient will be moved after treatment discontinuation and duration
of stay in the ward unit.
● Concomitant medications including those relative to AE treatment
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● Demographic data (ITT population):
 Age
 Sex
 Race
 Ethnicity
 Country
 Childbearing potential
● Baseline characteristics (Safety population):
 Physical examination
 VS (HR, BP, RR, Temperature, Height, Weight, BMI, )
 Laboratory safety tests (hematology, biochemistry, virology, coagulation test, urinalysis) 
 Pregnancy test
 Area of the erythema/redness
 Presence/absence of abscess
By-patient listings of all demographic data and baseline characteristics as stated above will be provided.
Medical history will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 21.0, summarized by treatment arm and overall  and listed.
Prior and concomitant medications as specified in the eCRF will be tabulated separately by treatment 
arm and overall. The proportion of patients receiving prior medications (medications ended within 4 
weeks of the screening date) will be summarized by preferred medication name.  A patient will be 
counted at most once for each prior preferred medication, even if the patient took the same medication 
on multiple occasions.  Concomitant medications (medications started on/after the screening date) and 
Prior and Concomitant medications (medications started prior to the screening date but ended after this 
date or still ongoing) will be summarized similarly. Prior and concomitant medications will be classified 
according to the World Health Organization (WHO) Drug Dictionary version B3 201809 and presented 
by ATC code level 3.
Medication start and stop dates/times will be compared to the date of screening date to allow 
medications to be classified as either prior only, both prior and concomitant, or concomitant only. Prior 
and concomitant and concomitant only medication will be summarized in the same table.
If medication start and/or stop dates are missing or partial, the dates will be compared as far as possible 
with the date of screening date.  Medications will be assumed to be concomitant only, unless there is 
clear evidence (through comparison of partial dates) to suggest that the medication started within 4 
weeks prior to the screening date. If there is clear evidence of that, the medication will be assumed to be 
both prior and concomitant, unless there is clear evidence to suggest that the medication stopped prior to
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the screening date. If there is clear evidence to suggest that the medication stopped prior to the screening 
date, the medication will be assumed to be prior only.
4.6 
ESTIMANDS
The “ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on 
statistical principles for clinical trials” (ICH E9 Addendum) indicates the need to appropriately defined 
the target of estimation and the scientific question addressed with the trial or, in other words, the 
treatment effect of interest.
For this purpose ad-hoc estimands will be created.
A description of an estimand includes four attributes:
1. The population, that is, the patients targeted by the scientific question.
2. The variable (or endpoint), to be obtained for each patient, that is required to address the
scientific question.
3. The specification of how to account for intercurrent events to reflect the scientific question of
interest.
4. The population-level summary for the variable which provides, as required, a basis for a
comparison between treatment conditions.
4.6.1 Target Population
The population targeted by the scientific question is defined via the inclusion and exclusion criteria and 
it includes patients with superficial or deep incisional SSI following a cardiothoracic / related leg or 
abdominal surgical procedure treated with Delafloxacin or the selected BAT. Since the non-inferiority 
nature of the study two population are evaluated, ITT population and CETOC population. They are 
defined in section §4.3 .
4.6.2 Variable
The primary endpoint to be obtained for each patient to address the scientific question is the clinical 
success response at TOC.
4.6.3 Intercurrent events
Premature interruption of the study treatment is the primary potential intercurrent event that could occur. 
The most common reasons are expected to be lack of efficacy (including the need for non-study 
antimicrobial agents such as antifungals) or treatment related AE which requests treatment 
discontinuation. In this situation patients will be asked to undergo EOT Visit at the time of withdrawal 
and, then, any other study visit as per protocol till LFU Visit.
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4.6.4 Population-level summary
The population-level summary for the primary variables is the proportion of clinical success response at 
TOC. The basis for the comparison will be made using both the CETOC and the ITT populations. The 
clinical success response is defined and analyzed as described in section §4.6.5 .
4.6.5 Estimand definitions
Clinical success response is defined as cure or improve response within 7-14 days. Otherwise a patient 
will be considered as a failure. In the failure definition also missing outcome are included.
As per primary variable definition in case of any administration of antibacterial therapy for SSI is
required because of lack of efficacy the patient will be considered as failure. In case, instead, treatment
is discontinued due to treatment related AE response won’t be imputed as failure by definition.
In this context the following estimands will be considered:
● Composite Estimand
● Hypothetical Estimand
● Treatment Policy Estimand
4.6.5.1 Composite Estimand
● Population: subjects in the CETOC and ITT populations with superficial or deep incisional SSI 
following a cardiothoracic / related leg or abdominal surgical procedure treated with
Delafloxacin or the selected BAT.
● Variable: clinical success response at TOC
● Intercurrent events: the following intercurrent events approach will be used:
 If a subject discontinued the treatment due to lack of efficacy the response outcome will
be imputed as failure as per variable definition.
 If a subject discontinued the treatment due to treatment related AE the response outcome
will be imputed as failure.
● Population-level summary: the proportion of clinical success response at TOC.
4.6.5.2 Hypothetical Estimand
● Population: subjects in the CETOC and ITT populations with superficial or deep incisional SSI 
following a cardiothoracic / related leg or abdominal surgical procedure treated with
Delafloxacin or the selected BAT.
● Variable: clinical success response at TOC
● Intercurrent events: the following intercurrent events approach will be used:
 If a subject discontinued the treatment due to lack of efficacy the response outcome will
be imputed as failure as per variable definition.
 If a subject discontinued the treatment due to treatment related AE the collected response
outcome will be assumed as missing.
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● Population-level summary: the proportion of clinical success response at TOC.
Please note that since the population-level summary is the proportion of clinical success response at 
TOC the Hypothetical Estimand will coincide with the Composite Estimand.
4.6.5.3 Treatment Policy Estimand
● Population: subjects in the CETOC and ITT populations with superficial or deep incisional SSI 
following a cardiothoracic / related leg or abdominal surgical procedure treated with
Delafloxacin or the selected BAT.
● Variable: clinical success response at TOC
● Intercurrent events: the occurrence of an intercurrent event is irrelevant. Clinical response 
collected after the treatment discontinuation due to lack of efficacy and /or treatment related AE 
will be used regardless the occurrence of intercurrent events and without any imputation even if
a 2nd line therapy is taken.
● Population-level summary: the proportion of clinical success response at TOC.
4.7 
EFFICACY EVALUATION
4.7.1 Analysis and Data Conventions
4.7.1.1 Study Hypotheses
All the statistical comparisons will be a test for non-inferiority of delafloxacin versus the Reference 
treatment arm with the possibility of switching to the superiority based upon the primary endpoint. No 
multiplicity adjustment will be used for testing superiority if non-inferiority has been demonstrated 
following the principles reported in the CPMP/EWP/482/99 EMA guideline: “Points to consider on 
switching between superiority and non-inferiority”.
A non-inferiority test aims to demonstrate that results obtained from the test drug are not appreciably 
worse than the ones of standard drug. A non-inferiority margin (
has to be specified in order to 
characterize the largest difference that you consider to be dismissible (Figure 3).
Figure 3:  Hypotheses of Non-inferiority tests.
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The non-inferiority margin is set as 
10% (unless otherwise specified).
The null (H0) and alternative (Ha) hypotheses to be tested in order to establish the non-inferiority of 
delafloxacin are:
H0: Pd – Pr ≤ -0.10
Ha: Pd – Pr > -0.10
where Pd and Pr are the probabilities of responder for delafloxacin and the reference treatment arm, 
respectively.
If the lower limit (LL) of the two-sided 95% CI is greater than -0.10, it will be concluded that 
delafloxacin is non-inferior to the reference treatment arm for treating patients with cardiothoracic or 
abdominal SSI.
The null (H0) and alternative (Ha) hypotheses to be tested in order to establish the superiority of 
delafloxacin are:
H0: Pd – Pr ≤ 0
Ha: Pd – Pr > 0
4.7.1.2 Estimand approach
In general analysis will be based on the Composite Estimand, coincident to the Hypothetical one. For 
the primary endpoint sensitivity analyses will be performed using the Treatment Policy Estimand.
4.7.1.3 Multi-center Studies
The term ‘Center’ will be used to define each investigator site. As center is not a stratification variable 
for the randomization, it is not included in the main model for the primary analysis. The center effect, as 
random, will be investigated and reported, if significant, in the final report as sensitivity and exploratory 
analysis.
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Additionally within each center more than one Blinded Observer will be involved for the assessment of 
parameters relevant for defining the patient as eligible to IV/PO switch of therapy and dischargeable 
from the hospital (IRLOS assessment). For these endpoints also the Blinded Observer effect will be 
investigated as random effect.
4.7.1.4 Adjustments for Covariates
For the primary efficacy analysis and for the secondary efficacy analyses when specified, site and depth 
of infection will be used as covariate additionally to the treatment arm (Test or Reference) since they 
will be used as stratification factors during the IWRS procedure and the analysis should reflect the 
restriction on the randomisation implied by the stratification as stated in the European guideline EMA/
CHMP/295050/2013: “Guideline on adjustment for baseline covariates in clinical trials”.  The interaction 
between the additional covariates and the treatment will be also examined and kept in the model in case of 
significant effect.
Site of infection will be classed as being one of the following:
 
Cardiothoracic / related leg SSI.
 
Abdominal SSI.
depth of infection will be classed as being one of the following:
 
Superficial infection.
 
Deep infection.
Since site of infection and depth of infection could be potentially highly associate, a Chi-Square 
correlation test between the two variables will be performed.
In case an high correlation is detected (i.e. greater/lower than ±0.8) only the most significant variable
between the two will be included in the model.
Additionally as sensitivity analysis a model without additional covariates will be implemented in order 
to compare the adjusted and the unadjusted estimates.
4.7.2 Handling of Dropouts or Missing Data
A missing clinical response will be imputed as defined in §3.2.1.2. and following the Estimand 
definition described in §4.6 .
No missing responses are expected for the microbiological response.
4.7.3 Multiplicity
There is one primary endpoint comparison for non-inferiority (as detailed in Section §4.6.1.1) for this 
study.  For the switch from non-inferiority to superiority no multiplicity adjustment is needed, since, as 
stated in CPMP/EWP/482/99, the superiority interpretation of results corresponds to a simple closed test 
procedure.
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4.7.4 Examination of Subgroups
The uniformity of the treatment effects for the primary efficacy variable will be examined (if applicable) 
for the following subgroups:
● elderly patients (≥ 65 years)
● patients with diabetes
● patients with body mass index (BMI) ≥ 30kg/m2
● patients with baseline bacteremia
● patients with polymicrobial infection
● patients with MRSA
● patients with severe renal impairment (CrCl between 15, inclusive, and <30 mL/min)
● patients with ≥ 2 signs and symptoms at baseline
● patients with baseline COPD
● patients with baseline SIRS, i.e with at least two of the following:
 fever >38°C or < 36°C
 heart rate >90 beats per minute
 respiratory rate >20 breaths per minute or PaCO2 <32 mm Hg
 abnormal white blood cell count (>12,000/mm3 or <4,000/ mm3 or >10% bands)
● patients with SSI more difficult to treat (i.e. area of the erythema/redness ≥ 75 cm2 and/or
presence of abscess)
The subgroup analysis on clinical success at TOC has been described under §4.6.6.1.
4.7.5 Primary Efficacy Analysis
The clinical success response at TOC is defined as cure or improved response within 7 - 14 days after 
last dose.
The rate of the efficacy variable is the sample responder rate defined in the following equation:
 
 
 
 
All the statistical comparisons will be a test for non-inferiority of delafloxacin versus the reference 
treatment arm as described in section §4.6.1.1. The relative study hypotheses are described as well under 
§4.6.1.1.
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If the LL of the two-sided 95% CI is greater than -0.10, it will be concluded that delafloxacin is non- 
inferior to the Reference treatment arm for treating patients with cardiothoracic or abdominal SSI.
If the LL of the two-sided 95% CI is greater than 0, then delafloxacin will be declared superior to the
Reference treatment arm for treating patients with cardiothoracic or abdominal SSI.
Confidence intervals will be calculated using Miettinen and Nurminen method.
The homogeneity of the treatment effects will be analyzed for non-inferiority in the ITT and the relative 
CE populations, while for superiority only on the ITT population.
The primary analysis will be adjusted by site and depth of infection additionally to the treatment arm as
stated in section §4.6.1.3.
The following SAS program will be implemented:
proc freq data=dataset;
tables site*depth *trt*var / RISKDIFF(CL=MN COLUMN=2 common);
run;
Where:
var = dependent variable of interest.
trt = randomized treatment.
site = site of infection.
depth= depth of infection
4.7.6 Secondary Efficacy Variables
4.7.6.1 Clinical Success
The clinical success response at EOT and LFU will be analyzed in the ITT and CE populations 
analogously to the primary efficacy variable as described in §4.6.5.
The same SAS program used for the primary endpoint are also applied.
4.7.6.2 
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4.7.6.4 Microbiologica! response 
Microbiological efficacy responses at EOT and TOC, as defined in §3.2.1.4, will be statistically 
analyzed for the MITT and ME analysis set by patient and pathogen analogously to the p1imaiy efficacy 
vadable. 
Statistica! testing will be perfonned only if applicable, othe1wise only frequencies and the relative 
percentages will be rep01ted. 
4.7.6.5 Eligibility to switch to oral formulation 
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Eligibility to switch to oral formulation is defined as the cumulative percentage of patient eligible to 
switch along the study treatment duration, beginning at study treatment initiation (Day 1) and ending 
when the criteria reported §3.2.1.5 are met.
Percentages are statistically analyzed analogously to the primary efficacy variable, in the ITT and CE
populations.
Additionally, time to eligibility to switch will be also analysed.
The time to eligibility to switch is defined as the time elapsed between study treatment initiation (Day 1) 
and the time when the criteria reported §3.2.1.5 are met.
The formula for the calculation is:
Time to eligibility to switch = tCM– tTI
where  t CM is the time (hours and minutes) of when the criteria reported §3.2.1.5 are met,
tTI is the time (hours and minutes) of  the study treatment initiation.
In the case the criteria reported §3.2.1.5 are not met, time to eligibility to switch will be calculated as the 
time that occurred between tTI and the end of treatment and the relative patient will be considered as
censored.
Time to eligibility to switch will be compared using a log-rank test.  The 25th, 50th and 75th percentiles 
of the Kaplan-Meier estimate with associated 95% CI’s will be produced and presented with the log- 
rank p-value.  In addition, a Kaplan-Meier plot of will be presented.
The following SAS code will be applied for this analysis:
proc lifetest data=dataset;
time dur*censor(1);
strata trt;
run;
Where:
trt = randomized treatments
dur = time to variable of interest
censor = censoring variable (assuming a value of 1 indicates a censored observation)
The underlying assumptions for the above analysis will be examined by reviewing the data and checking 
the assumption of proportional hazards by analyzing the interaction term ‘treatment*log(duration)’, 
where the logarithmic transformation is implemented to maintain the linearity. If the interaction term is 
not significant the hazards can be considered as proportional.
In addition the estimated hazard functions plot by using the Epanechnikov kernel-smoothed estimates
will be produced as a graphical check.
Should these examinations indicate that an assumption has been violated then an alternative method of 
analysis (e.g. Wilcoxon Test) may be applied.
The following SAS Syntax will be implemented:
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proc phreg data=dataset;
class trt;
model dur*censor(1)=trt trt_time;
trt_time = trt*log(dur);
run;
ods select HazardPlot;
proc lifetest data=dataset plots=H;
time dur * censor (1);
strata trt;
run;
As explained in §3.1  the responsible for the assessment of parameters relevant for defining the patients 
as eligible to IV/PO switch of therapy are different physicians (blinded observers) assigned by the PI. 
To keep under control the variability due to this random effect a sensitivity analysis by using a frailty 
model is implemented.
The following SAS code will be applied for this analysis:
proc phreg data=dataset;
class trt blider_observer;
model dur*censor(1)=trt;
random blider_observer;
run;
4.7.6.6 Hospital IRLOS (Infection Related Length of Stay)
Hospital IRLOS is defined as the cumulative percentage of patient eligible to discharge along the study 
treatment duration, beginning at study treatment initiation (Day 1) and ending when the criteria reported 
in §3.2.1.5  are met.
Percentages are statistically analyzed analogously to the primary efficacy variable, in the ITT and CE
populations.
Additionally, time to Hospital IRLOS will be also defined and analyzed by using the same approach 
adopted for time to eligibility to switch as described in §4.7.6.5.
4.7.6.7 Hospital LOS (Length of Stay)
LOS is defined as the cumulative percentage of patients who are discharged along the overall study 
duration, beginning at the Investigator diagnosis of the infection (Screening) and ending on the date of 
actual hospital discharge. Percentages are statistically analyzed analogously to the primary efficacy 
variable, in the ITT and CE populations.
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Additionally, time to actual discharge will be also defined and analyzed by using the same approach 
adopted for time to eligibility to switch as described in §4.7.6.5. with the exception of the frailty model 
that is not applicable.
4.7.6.8 
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To check the normal distribution of dependent variables within each treatment arm, QQplots and 
Histograms plots will be done as a graphical test. In addition the Shapiro-Wilk test will be performed. 
The null hypothesis of normal distribution, H0, will be tested by using a significance level of 5%.
The following SAS procedure will be implemented:
proc univariate data=dataset normal ;
class ‘independent variable’;
HISTOGRAM ‘dependent variable’;
qqplot ‘dependent variable’;
var ‘dependent variable’;
run;
quit;
To check the homogeneity of the variance of the dependent variables the Bartlett test will be done. The 
null hypothesis, H0, is that all k population variances are equal. The alternative is that at least two are 
different. The null hypothesis is rejected at a significance level of 5% if the value of the Bartlett test 
statistic is greater than the corresponding critical value.
The following SAS procedure will be used:
proc glm data=dataset;
class ‘independent variable’;
model ‘dependent variable’= ‘independent variable’;
means ‘independent variable’/ hovtest=bartlett;
run;
To check whether the residuals of the model have a multivariate normal distribution and if 
heteroscedasticity is present,  a graphical tests will be implemented by adding option “/ VCIRY” to the 
“MODEL” statement in the proc mixed reported above. For the multivariate normal distribution  graph, 
the standardized residuals versus their ranks should form a straight line on the plot, which is visually 
assessed. For the  heteroscedasticity graph,  instead, if the points are equally distributed around the 
straight line and no trends are showed, the hypothesis of heteroscedasticity is rejected.
As alternative, if the assumption required by the REML method are not fulfilled or if the likelihood 
function cannot be evaluated, the MIVQUE0 (Minimum Variance Quadratic Unbiased Estimation) 
method is used, as this method doesn’t require any particular assumptions.
The results of model assumptions will be also reported.
Sensitivity analyses will be also performed for both the approaches described above including the 
following additional covariates in the model: Age, BMI, diabetes (Y/N), depth of infection and the Area 
of the erythema/redness
The duration of IV treatment will be also analyzed only descriptively and considering the same two 
approaches described above.
4.7.6.9 SF-36v2 QoL score
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SF-36 v2 Quality of Life (QoL)  score will be analysed at EOT, TOC and LFU Visits in the ITT and CE 
populations following the rules described in the Quality Metric Health Outcomes Scoring Software user 
guide v4.5 reported in Appendix 1.
Renee N. Saris‐Baglama, Ph.D.; Christopher J. Dewey, B.A. ; Gordon B. Chisholm; Elise Plumb,
B.S.; Jim King, B.S.; Pat Rasicot, M.S.; Mark Kosinski,
 M.A.; Jakob B. Bjorner, M.D., Ph.D. ;John E.
Ware, Jr., Ph.D. Quality Metric Health Outcomes Scoring Software user guide v4.5. Copyright©
2004, 2007, 2009, 2010, 2011
4.7.7 Exploratory efficacy endpoints
Time-course of ProCT and CRP serum values and correlation between ProCT and CRP serum values 
versus individual parameters and overall IRLOS assessment at different timepoints in the ITT 
population.
4.7.7.1 ProCT
Change vs baseline for ProCT serum values will be descriptively analyzed in the ITT population overall, 
and by site of infection and treatment arm at Visit 2, Visit 3 and EOT Visit.
Additionally, at the same timepoint a Pearson correlation analysis between ProCT versus the overall
IRLOS assessment and each of the IRLOS parameters will be performed.
The following SAS procedure will be used:
proc corr data=dataset ;
var variable(s);
with variable(s);
run;
In case data assumptions behind the Pearson correlation (e.g. normality, homoscedasticity, etc.) are not 
met, different approaches (e.g. log-transformation, Spearman correlation, etc.) will be used.
4.7.7.2 CRP
Change vs baseline for ProCT serum values will be analysed as the ProCT serum values as described in 
§4.6.7.1
4.8 
SAFETY EVALUATION
All safety summaries and analyses will be based upon the safety population as defined in Section 4.3. 
No formal statistical testing will be performed and only descriptive statistics provided unless otherwise 
noted.  The number of non-missing values and the mean with the respective SD (for continuous
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variables) or the percentage (for ordinal/categorical variables) will be reported.  Missing safety data will 
not be imputed.
4.8.1 Adverse Events
AEs will be coded using MedDRA Version 22.0.
AEs will be summarized by primary System Organ Class (SOC), Preferred Term (PT) and treatment. 
An overview of AEs will be provided, with the number and percentage of patients reporting an event, 
presented for the following categories:
 Any AEs
 Any serious AEs
 Any AEs leading to study discontinuation.
 Any AEs leading to death
Additionally, the following summaries of AEs will be presented by SOC and PT:
 The number of AEs and the number and percentage of patients with AEs by treatment and
overall.
TEAE will be defined as those adverse events that occur for the first time or worsen in terms of intensity 
(severity)/ seriousness after the drug intake.
Where dates are missing or partially missing, adverse events will be assumed to be treatment-emergent, 
unless there is clear evidence (through comparison of partial dates) to suggest that the adverse event 
started prior to the study treatment administration.
TEAE will be summarized by primary System Organ Class (SOC), Preferred Term (PT) and treatment. 
An overview of TEAEs will be provided, with the number and percentage of patients reporting an event, 
presented for the following categories:
 Any TEAE
 Any serious TEAE
 Any mild/moderate/severe TEAE
 Any causally related TEAE (Adverse drug reaction [ADR])
 Any TEAE leading to study discontinuation.
 Any TEAE leading to death
Additionally, the following summaries of TEAE will be presented by SOC and PT:
 The number and percentage of patients with TEAE by treatment and overall.
 
The number and percentage of patients with TEAE by intensity (mild, moderate and severe). 
 The number and percentage of patients with TEAE by causality (related/not related).
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Any TEAE is defined as related (ADR) if the causality category falls into one of the following: certainly 
related, probably related, possibly related and unassessable/unclassifiable. Otherwise TEAE will be 
considered as not related.
ADRs will be summarized by primary System Organ Class (SOC), Preferred Term (PT) and treatment. 
An overview of ADRs will be provided, with the number and percentage of patients reporting an event, 
presented for the following categories:
 Any ADR
 Any serious ADR
 Any mild/moderate/severe ADR
 Any ADR leading to study discontinuation.
 Any ADR leading to death
Additionally, the following summaries of ADR will be presented by SOC and PT:
 The number and percentage of patients with ADR by treatment and overall.
 The number and percentage of patients with ADR by intensity (mild, moderate and severe).
For each patient and each event, the worst intensity recorded will be attributed and used in the by- 
intensity summaries.  Similarly, the worst causality (most related to treatment) will be attributed and 
used in the by-causality summaries.  If intensity or causality is missing, the worst case will be assumed.
A by-patient listing of all AEs (including non-TEAE) will be provided together with a listing of TEAE.
The same tables will be provided also for the Adverse Events of Special Interest (AESI).
Any recorded AE  that could potentially be related to class-effect AESIs will be identified by medical 
review and use of Standardized  MedDRA queries (SMQ) where possible.
4.8.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events
The number and percentage of deaths (if any) during the study by treatment arm (if numbers allow) will 
be reported.
Serious AEs (SAEs) will be summarized by primary System Organ Class (SOC), Preferred Term (PT)
and treatment.  An overview of SAEs will be provided, with the number and percentage of patients 
reporting an event, presented for the following categories:
 Any SAE
 Any mild/moderate/severe SAE
 Any SAE leading to study discontinuation.
 Any SAE leading to death
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4.8.3 Clinical Laboratory Evaluation
Safety laboratory testing will be performed by a local laboratory at the timepoints specified in the Study 
Flow Chart (Table 1).
Patient’s continuous haematology, biochemistry and coagulation laboratory values will be compared to 
normal ranges provided by the laboratory and flagged as “Low” or “High” in case they are below or 
above the ranges, respectively. Out-of-range laboratory values will also be flagged for abnormality by 
the Investigator (abnormal-not clinically significant [NCS] or abnormal-clinically significant [CS]).
The observed values of haematology, biochemistry and coagulation test results will be summarized for
each timepoint by treatment arm and overall, using descriptive statistics. Also the investigator judgment 
for each parameter will be summarized for each timepoint by treatment arm and overall based on the 
following categories: Normal, Abnormal NCS and Abnormal CS.
Virology and Pregnancy test results will be reported as categorical values: “Positive”, “Negative” or 
“Not Done”.
Also 12-Lead ECG results will be reported as categorical values: “Normal” or “Abnormal”. Abnormal
results will then be flagged by the Investigator as abnormal-not clinically significant [NCS] or abnormal-
clinically significant [CS]).
Categorical results of Virology, Pregnancy test and 12-Lead ECG will be summarized for each
timepoint by treatment arm and overall.
Urinalysis test could be performed using local laboratory or, alternatively, Roche-Combur dipstick. Due 
to the possibility to use different method no parameter results will be provided in eCRF, the Investigator 
should only confirm whether there are abnormal-clinically significant tests and, if any, record them as 
Adverse Events or Medical History.
For Urinalysis no tables will be prepared, urinalysis abnormal-clinically significant test(s)  will be
visible in by-patient listing of Adverse Events or Medical History.
A by-patient listing of all laboratory data (as expected from Urinalysis) will be also presented.
Unscheduled examinations can be performed for safety reasons according to the Investigator’s 
judgement and will be displayed only in listings.
4.8.4 Vital Signs, Physical Findings and Other Observations Related to Safety
At study visits vital signs will include SBP, DBP, HR, RR and T, while for the daily assessments only 
SBP, HR and T are required.
For each vital sign parameter the result will be compared to normal range provided by the Sponsor and,
if out-of-range, flagged for abnormality by the Investigator (abnormal-not clinically significant [NCS] 
or abnormal-clinically significant [CS]).
Continuous results will be summarized for each timepoint by treatment arm and overall, using
descriptive statistics.
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Also the investigator judgment for each parameter will be summarized for each timepoint by treatment 
arm and overall based on the following categories: Normal, Abnormal NCS and Abnormal CS.
No Physical Examination results will be provided in eCRF, the Investigator should only confirm 
whether there are abnormal-clinically significant tests and, if any, record them as Adverse Events or 
Medical History.
Therefore no table will be prepared for Physical Examination, any abnormal-clinically significant test
will be visible in by-patient listing of Adverse Events or Medical History.
Measurement of height (cm) and weight (kg) will be performed at Screening only. The values will be 
summarized in the table of baseline characteristics by treatment arm and overall, using descriptive 
statistics.
By-patient listings of all vital sign parameters will be presented.
Unscheduled values will only be presented in listings.
4.9 
HEALTH ECONOMICS ANALYSIS
Healthcare resources consumption and related variables useful for the healthcare economic evaluation 
will be described by treatment, by site of infection, investigational site, country and overall in the Safety 
population.
Additionally, analyses will be conducted (if applicable) for the following subgroups:
● elderly patients (≥ 65 years)
● patients with diabetes
● patients with body mass index (BMI) ≥ 30kg/m2
● patients with baseline bacteremia
● patients with polymicrobial infection
● patients with MRSA
● patients with severe renal impairment (CrCl between 15, inclusive, and <30 mL/min)
● patients with ≥ 2 signs and symptoms at baseline
● patients with baseline COPD
● patients with baseline SIRS, i.e. with at least two of the following:
o fever >38°C or < 36°C
o heart rate >90 beats per minute
o respiratory rate >20 breaths per minute or PaCO2 <32 mm Hg
o abnormal white blood cell count (>12,000/mm3 or <4,000/ mm3 or >10% bands)
The following information will be used in the analysis:
● Treatment monitoring tests associated with each treatment option
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4.10 DETERMINATION OF SAMPLE SIZE
A sample size of 600 randomized patients (300 per treatment arm: delafloxacin or Reference treatment) 
will provide about 80% power in the ITT population and higher than 95% in the CE population to 
demonstrate the non-inferiority of delafloxacin versus the reference treatment arm in terms of clinical 
response (Clinical Success) rate with a non-inferiority margin of 10%, an alpha equal to 0.025 (1-side 
test). Clinical Success rate at TOC of 78.0% and 78.1% in the ITT and of 98.3% and 99.4% in the CE 
population are assumed respectively for delafloxacin and the Reference treatment arm.
Assuming about 20% of Screening failures, approximately 750 patients are anticipated to be screened to 
reach a total of 600 randomized patients.
4.11 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS
Not Applicable. SAP finalized prior to the first patient in since the unblinded condition.
5 GENERAL DEFINITIONS
5.1 
DATA VALIDATION
Medidata Classic Rave 2019.1.0 will be used, as Electronic Data Capture system for data entry, by site 
personnel and for data cleaning and data locking by the Menarini Data Management team.
5.2 
COMPUTER SYSTEMS AND SOFTWARE TO BE USED IN THE ANALYSIS
SAS v.9.3 (or upper) by SAS Institute Inc., Cary, NC, USA.
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Database and SDTM and ADAM datasets will be created by using SAS Clinical Data Integration Studio 
version 4.9.
All tables and listings will be produced using PROC REPORT or procedure specific output displays
using output delivery system (ODS) within SAS version 9.3 (or upper) and using SAS Office analytics.
5.3 
CODING SYSTEMS USED
5.3.1 Clinical Terms
Concomitant diseases, medical procedures, and AEs will be coded with MedDRA 22.0
5.3.2 Drugs
Drugs will be coded with WHODrugGlobalB3 201903
5.4 
REPORT TYPE, LANGUAGE AND FORMAT
The statistical output will be in Microsoft Word 2010 format and in English language.

Dates will be presented as DDMMMYY.

Numeric values will be decimal-point aligned.

Counts and percentages:
<group 1> 
XXX (XX.X%)

Descriptive statistics:
N 
XXX
Mean 
XXX.X
SD 
XXX.XX
Median 
XXX.X
Minimum 
XXX
Maximum 
XXX

Character values will be left aligned.
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6 TABLES FIGURES AND LISTINGS
6.1 
STATISTICAL ANALYSIS REPORT (TFL)
The TFL (Tables, Listings and Figures) will follow the list of tables, plots, and listings of section 6.3 
and 6.4, which are intended to provide the overall idea of the general output and ordering of the TFL 
and will not necessarily be reproduced in the final TFL document.
6.2 
TABLES, HEADINGS, AND FOOTNOTES
All tables stratified by treatment and gender will also contain the treatment overall column. The tables 
repeated for analysis population will be produced only once if the analysis populations are identical. All 
tables are provided for ITT population unless specified otherwise.
Line 1: 
Study code: DELA-01
Line 3: 
Table/Listing/Figure n: Table name (Study population)
Line 4: 
Table/Listing/Figure n.n: Table name
Line 5: 
Table/Listing/Figure n.n.n: Table name [if applicable]
Line 6: 
Table/Listing/Figure n.n.n.n: Table name [if applicable]
Line 7: 
Table/Listing/Figure n.n.n.n.n: Table name [if applicable]
Footnote: 
Relevant notes (if any)
6.3 
LIST OF TABLES AND FIGURES
Tables:
1 
Patient disposition
Note: all tables by treatment/overall for ITT population (where applicable)
1.1 
Overall patient disposition
1.2 
Presence of patients at study visits
1.3 
Protocol violations by category
2 
Baseline and general characteristics
Note: all tables by treatment/overall for ITT population  (otherwise specified)
2.1 
Demographics and pregnancy test
2.2 
Medical history by MedDRA SOC and PT
2.3 
Physical examination
2.4 
Vital Signs
2.5 
Safety Laboratory Test
2.6 
Prior and concomitant medication by ATC-Code
3 
Safety analysis
Note: all analyses will be done on safety population by treatment/overall, unless otherwise stated
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3.1 
AEs
3.2 
TEAEs
3.3 
ADRs
3.4 
Serious
3.5 
Vital signs
3.6 
Safety Laboratory Test
3.7 
Pregnancy test at End of Study
4 
Efficacy analysis
Note: all tables by treatment/overall for ITT and PP population.
4.1 
Primary analysis
4.2 
Secondary analysis
Figures:
Graph 1: Success Responders
Graph 2: Cure Responders
Graph X: Kaplan-Meier for XXX
6.4 
PATIENT DATA LISTING
Key variables (KV) are the variables present in each patient data listing: Subject number, age, gender, 
planned treatment, study population (Yes/No for Safety, ITT and PP).
Screening Failures will be excluded from the listing.
The following list is intended to provide the overall idea of the general output.
L.1
Patient disposition
L.2
Demography
L.3
Baseline characteristics
L.4
Medical History
L.5
Previous and Concomitant Medication
L.6
Drug Exposure
L.7
All Adverse Events
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L.8
Laboratory results
L.9
Pregnancy Test Data
L.10 
Vital Signs Data
L.11 
Physical Examination Data
L.12 
Clinical Response
L.13 
Microbiological Response
L.14 
Time to event Variables
7 REFERENCES
1.
DELA-01 Study protocol, Final Version 1.0, April 05, 2019 , Menarini Ricerche, S.p.A
2.
International Conference on Harmonisation ICH Topic E9: Statistical principles for clinical
trials. 1998.
3.
International Conference on Harmonisation ICH Topic E10: Choice of control group and related
issues in clinical trials. 2001
4.
Points to consider on switching between superiority and non-inferiority. 2000
5.
Addendum to the guideline on the evaluation of medicinal products indicated for treatment of
bacterial infections. EMA/CHMP/351889/2013. October, 2013.
6.
Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections.
CPMP/EWP/558/95 rev 2. December, 2011.
7.
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Statistical Analysis Plan
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