Clinical trial NCT03915470
Conditions: Staphylococcal Infections Surgical Site Infection
Keywords: Post-operative Post-surgical Infection prevention Staphylococcus aureus MSSA MRSA
Sponsor: Destiny Pharma Plc
Start date: 2019-08-29; Completion date: 2021-03-29
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study looks at the difference between XF-73 and placebo in reducing the carriage of a bacteria S. aureus in the nose before, during and after heart surgery. Only people who normally have S.aureus in their nose will be enrolled onto the study. This will be confirmed by analysis of a nasal swab (a cotton bud placed in the nose) before entering the study. It is expected 125 people will participate in this study. Participation will be confirmed by analysis of a nasal swab (a cotton bud placed in the nose) before entering the study. XF-73 or placebo will be given 5 times, with an equal chance of participants receiving either XF-73 or placebo. During the hospital stay more nasal swabs will be taken to determine the amount of S.aureus present in the participant's nose. Other tests such as blood samples, blood pressure and an examination of the nose and sense of smell will be performed as part of the safety assessment. After the hospital stay participants will be followed up for 30 days or if a device has been inserted into the body as part of the surgery for 90 days to look at the rates of post-operative infection between the placebo and XF-73 groups. The study will run for about 18 months. During this period, an independent data monitoring committee will review the study to make sure that the balance of benefits and risks of participating in the study does not change.

Detailed description:
This is a multi-centre, double blind, randomized, placebo-controlled study of multiple applications of a single concentration of XF-73 nasal gel to assess the microbiological effect of XF-73 on commensal S. aureus nasal carriage in patients scheduled for surgical procedures deemed to be at high risk of post-operative S. aureus infection. The study is divided in 4 periods: screening (days -14 to -1) randomization (days -10 to -1), treatment (days -1 and 0) and follow-up (post-last study dose to day 30 or day 90 if an implant is inserted during surgery). Day 0 is the calendar day in which surgery takes place. Only patients who test positive to S. aureus by a centrally-performed rapid diagnostic test will be enrolled in the study. Approximately 125 patients will be randomly allocated in a 1:1 ratio to 0.2% w/w XF-73 nasal gel treatment OR placebo to match XF-73 nasal gel.

The study drug, 0.2% w/w XF-73, or matched placebo will be administered 4 times into each nostril over 24 hours prior to surgery and then a single application immediately upon closure of surgical wound. Additionally, patients may undergo chlorhexidine skin decolonisation ahead of surgery and receive perioperative prophylactic systemic antibiotics in accordance with local practice.

Efficacy will be assessed by S. aureus colonisation from screening to 7 days after surgery as well as by incidence of post-operative staphylococcal infections and use of anti-staphylococcal antibiotics post-surgery. Safety will be assessed by reported adverse events (AEs) from screening up to Day 7 as well as vital signs, physical examination (ENT), clinical laboratory assessments (haematology, clinical chemistry, and urinalysis) and Smell Identification Tests at different time points throughout the study.

The maximum study duration will be 45 or 105 days for each individual (from screening to post-study follow-up visit) depending on whether a foreign implant was inserted during surgery.

An independent data monitoring committee (IDMC) will be set up which will review the safety information from the study, the incidence of post-operative staphylococcal infections and to ensure that the balance of benefits and risks of participating in the study does not change.

Arms: arm 1: 0.3 mL applications in each naris of 0.2% w/w XF-73 nasal gel for a cumulative dose of 6.0 mg of XF-73. arm 2: 0.3 mL applications in each naris of placebo to match XF-73 nasal gel.
Interventions: intervention 1: XF-73 intervention 2: Placebo
Intervention descriptions: intervention 1: XF-73 is a dicationic porphyrin derivative having potent bactericidal properties with a novel mode of action. intervention 2: Placebo to match XF-73 nasal gel for colour and viscosity.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Phase 2 Study to Assess the Effect of a Repeated Dose of Exeporfinium Chloride (XF-
73) Nasal Gel on the Microbiological Burden of Commensal Staphylococcus aureus
Nasal Carriage in Surgical Patients at Risk of Post-Operative Staphylococcal Infections.
Protocol Number: 
XF-73B07 
Investigational Medicinal Product: 
Exeporfinium chloride (XF-73) 
Indication: 
Prevention of post-operative 
staphylococcal infections 
Phase: 
2 
Sponsor: 
Destiny Pharma plc 
Sussex Innovation Centre 
Science Park Square,  
Falmer 
Brighton, BN1 9SB 
United Kingdom 
Sponsor Chief Medical Officer: 
IND Number: 
109303 
Protocol Version and Date: 
Version 2.1, 04 Jun 2020 
The study will be conducted according to the protocol and in compliance with versions of 
Good Clinical Practice (GCP), the Declaration of Helsinki, and other applicable 
regulatory requirements in effect during the time of the conduct of the study. 
This document contains confidential information of Destiny Pharma plc 
Do not copy or distribute without written permission from the Destiny Pharma plc. 
CONFIDENTIAL 
NCT03915470


Destiny Pharma plc 
Clinical Protocol v2.1 
XF-73B07 
CONFIDENTIAL 
 
2 
SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title:  
A Phase 2 Study to Assess the Effect of a Repeated Dose of Exeporfinium Chloride (XF-73) 
Nasal Gel on the Microbiological Burden of Commensal Staphylococcus aureus Nasal Carriage 
in Surgical Patients at Risk of Post-Operative Staphylococcal Infections. 
 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as with 
the moral, ethical and scientific principles governing clinical research as set out in the current 
version of the Declaration of Helsinki (Brazil 2013), and the guidelines on Good Clinical 
Practice. 
 
 
 
_____________________________________ 
_____________________ 
 
Date 
Chief Medical Officer 
Destiny Pharma plc 
 
 
_____________________________________ 
_____________________ 
 
Date 
Director of Clinical Projects 
Destiny Pharma plc 
 


Destiny Pharma plc 
Clinical Protocol v2.1 
XF-73B07 
CONFIDENTIAL 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Title:  
A Phase 2 Study to Assess the Effect of a Repeated Dose of Exeporfinium Chloride (XF-73) 
Nasal Gel on the Microbiological Burden of Commensal Staphylococcus aureus Nasal Carriage 
in Surgical Patients at Risk of Post-Operative Staphylococcal Infections. 
 
I have read and understood all sections of the protocol. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the final protocol, the International Conference on Harmonisation Tripartite 
Guideline: Good Clinical Practice E6 (R2) and all applicable government regulations. I will not 
make changes to the protocol before consulting with Destiny Pharma plc or implement protocol 
changes without independent ethics committee approval except to eliminate an immediate risk to 
subjects. I agree to administer study treatment only to subjects under my personal supervision or 
the supervision of a sub-Investigator. 
I will not supply the investigational product to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or appear 
in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Destiny Pharma plc. 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
 
_____________________________________ 
Print Name (block capitals) 
 
 
_____________________________________ 
Site Number, Name and Address (block capitals) 
 


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1 
PROTOCOL SYNOPSIS 
Title: 
A Phase 2 Study to Assess the Effect of Repeated Dose of Exeporfinium 
Chloride (XF-73) Nasal Gel on the Microbiological Burden of Commensal 
Staphylococcus aureus Nasal Carriage in Surgical Patients at Risk of Post-
Operative Staphylococcal Infections. 
IND Number: 
109303 
Protocol Number: 
XF-73B07 
Phase: 
2 
Sponsor: 
Destiny Pharma plc 
Chief Medical Officer: 
 
Objectives and Endpoints: 
Primary Objective 
Endpoint 
To demonstrate the efficacy of a 
0.2% XF-73 nasal gel in reducing 
the microbiological burden of nasal 
S. aureus measured as change in 
colony forming units (CFU) per 
millilitre (mL) from baseline to 
immediately prior to surgery in a 
patient population at risk of post-
operative staphylococcal infection 
Change in S. aureus log CFU/mL 
from baseline to pre-surgery 
 
Secondary Objectives will 
include 
Endpoint 
To determine the effect of a 0.2% 
XF-73 nasal gel on S. aureus nasal 
burden from baseline to pre-
surgery and from baseline to 
immediately post-surgery 
measured as area under the curve 
(AUC) of S. aureus log CFUs/mL 
over time. 
• Difference in AUC of S. aureus 
log CFU/mL from baseline to 
pre-surgery. 
• Difference in AUC of S. aureus 
log CFU/mL from baseline to 
immediately post-surgery 
To determine the effect of a 0.2% 
XF-73 nasal gel on S. aureus nasal 
burden measured as CFUs/mL in 
follow-up after last administration. 
• Change in S. aureus log 
CFU/mL from immediately 
after surgery to 48 hours after 
surgery 
• Change in S. aureus log 
CFU/mL from immediately 
after surgery to 7 days after 
surgery 
To explore the efficacy of XF-73 
in reducing the burden of S. aureus 
carriage at the patient level. 
• Percentage of patients reaching 
a specific reduction in S. aureus 
carriage prior to surgery, 
immediately post-surgery and 
on Day 6 ± 24hrs. 
To assess the effect of XF-73 on 
S. aureus nasal carriage in the 
prevention of post-operative 
• Difference in the incidence of 
staphylococcal post-operative 
infections during the 30-day 


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staphylococcal infections (surgical 
site infection, blood stream 
infections, and others) during the 
30 days post-surgery (90 days in 
the case of a foreign implant).  
period after surgery (90 days in 
the case of foreign implant) 
To describe the safety and 
tolerability of multiple 
administrations of a 0.2% XF-73 
nasal gel in a population of 
surgical patients at risk of post-
operative staphylococcal 
infections. 
• Incidence of treatment-
emergent adverse events from 
the first dose of study 
medication to 7 days after last 
dose of study medication.  
• Changes in vital signs, safety 
clinical laboratory assessments, 
nasal examination, and brief 
smell identification test (B-
SIT). 
 
Exploratory Objective 
Endpoint 
To describe the use of post-
operative anti-staphylococcal 
antibiotics, except those provided 
for prophylaxis as local standard of 
care (SOC), during the 30-day 
post-surgery period (90 days in the 
case of an object implant) reported 
separately 
• Reason for post-operative 
prescription of anti-
staphylococcal antibiotics 
during the 30-day post-
operative period (90 days post-
surgery in the case of an object 
implant) 
Design: 
This is a Phase 2, multi-centre, randomized, double-blind, parallel, 
placebo-controlled study conducted in patients undergoing surgical 
procedures at risk of post-operative staphylococcal infections.  
Study Population: 
Patients undergoing surgical procedures at risk of post-operative 
staphylococcal infections. 
Inclusion Criteria: 
Individuals who meet all of the following criteria are eligible to participate 
in the study. 
1. Male or female patients between 18 and 75 years of age. 
2. Patients who are confirmed nasal S. aureus carriers by PCR screen 
assay, and due to undergo a surgical procedure associated with risk of 
post-operative staphylococcal infections. 
3. Patients who are willing to provide written informed consent. 
4. Patients who are willing and able (as per Investigator judgement) to 
complete all protocol specified visits and assessments. 
5. Woman of childbearing potential* with a negative urine pregnancy test 
(sensitive to 25 IU human chorionic gonadotropin [hCG]).  
 
* Women of childbearing potential are defined as those women between 
menarche and menopause who have not undergone permanent sterilisation. 
Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 


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Exclusion Criteria: 
Individuals who meet any of the following criteria are not eligible to 
participate in the study. 
1. Pregnancy (current) currently lactating. 
2. Uncontrolled acute or chronic illness (as determined by the 
Investigator) in addition to those requiring the planned surgical 
intervention. 
3. History of atopy, allergic reaction, or hypersensitivity to the study 
mediation or its components. 
4. Current upper respiratory tract infection, cold or influenza with 
significant nasal symptoms that might impact on the patient’s ability to 
comply with the gel application procedure. 
5. History of photosensitivity. 
6. Family history of porphyria. 
7. Use of intra-nasal, topical or systemic antibiotics or anti-infectives 
within the last 4 weeks before screening. (Patients who screen positive 
for nasal carriage of S. aureus and receive topical or systemic 
antibiotics or anti-infectives which are not part of their prophylactic 
peri-operative SOC between screening and first dose of IMP will be 
excluded from the study.) The use of intra-nasal antibiotics or anti-
infectives other than the study medication prior to surgery is not 
allowed. 
8. Use of other prescribed or over-the-counter nasal medication in the last 
14 days or oral decongestants in the last 7 days before first 
administration of study drug. 
9. Participation in a clinical trial within the last 12 weeks before first 
administration of study drug. 
10. Contemporaneous clinically significant abnormalities in vital signs or 
laboratory analyses reported within 14 days prior to randomization 
which in the opinion of the Investigator would preclude from the safety 
assessment of the medication under study. 
11. Nasal polyps or significant anatomical or other nasal abnormality that 
would prevent from appropriate administration of the study treatment 
or represent an excessive risk for the patient’s participation. 
12. History of nasal surgery including cauterization. 
13. A recent history of frequent epistaxis and/or an episode of epistaxis 
within 3 months of the planned surgery. 
14. Use of in-situ nasal jewellery or existence of open nasal piercings. 
Number of Patients: 
It is planned that approximately 125 patients will need to be recruited in 
order to have around 80 patients with sufficient burden of S. aureus nasal 
carriage which will allow for the detection of an effect of XF-73 nasal gel 
over placebo.  
Countries/Number of 
Sites: 
USA (~ 10 sites), Georgia (~10 sites), Serbia (~5) 


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Investigational Medicinal 
Product: 
Patients will be randomised in a double-blind manner to either the active or 
placebo arm. The active and placebo study drugs used in the study are as 
follows: 
0.2% w/w XF-73 Nasal Gel (0.3 ml nasal gel equating to 0.6 mg XF-73 per 
naris)  
Placebo to Match XF-73 Nasal Gel (0.3 ml nasal gel per naris) 
Duration of Participation: 
The study duration will be either up to 6 or 12 weeks for each individual 
(from screening to last post-study follow-up visit at either 30 or 90 days). 
The overall duration of the study will be approximately 15 months starting 
Q3 2019 to Q4 2020 
Criteria for Evaluation: 
 
Efficacy Assessments: 
• 
Measurement of S. aureus CFU/mL 
• 
Incidence of post-operative staphylococcal infections 
Safety Assessments: 
• 
Incidence of TEAEs  
• 
Clinical laboratory parameters 
• 
Vital signs 
• 
Physical examinations 
• 
Nasal examination 
• 
Brief Smell identification test (B-SIT). 
Concomitant Medication: 
At randomization, patients will be asked what medications they have taken 
during the last 30 days. At each subsequent study visit, patients will be 
asked what concomitant medications they are currently taking. Special 
attention will be placed in recording the concomitant use of anti-infectives 
and antibiotics. 
The use of intra-nasal antibiotics or anti-infectives other than study 
medication prior to surgery is not allowed. 
The use of skin decolonization products (e.g. chlorhexidine) and systemic 
perioperative prophylactic antibiotics (e.g. intravenous vancomycin) as part 
of the SOC will be recorded.  


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Statistical Methods: 
A Statistical Analysis Plan (SAP) describing the planned final analysis in 
detail with tables, figures and listings templates will be developed as a 
separate document 
Primary analysis will be on the endpoint of change in log10 CFU from 
baseline to pre-surgery using an analysis of covariance (ANCOVA) model 
including baseline CFU as a covariate. A similar analysis will also be 
performed for the endpoint of change from baseline to the post-surgery 
measurement. 
Secondary efficacy analyses will include; 
• 
Change in log10 CFU from baseline to post-surgery using an ANCOVA 
model including baseline CFU as a covariate. 
• 
A log10 AUC for CFUs will also be undertaken utilising data for all 
time points up until the pre-surgery assessment. This analysis of log10 
AUC CFUs will also including baseline log10 CFU as a covariate. 
• 
A log10 AUC for CFUs will also be undertaken utilising data for all 
time points up until the post-surgery assessment. This analysis of log10 
AUC CFUs will also including baseline log10 CFU as a covariate. 
• 
Percentage of patients reaching a specific reduction in S. aureus 
carriage prior to surgery, immediately post-surgery and on Day 6 ± 
24hrs. 
• 
Proportion of patients with nasal carriage below a set value (value 
TBD) 
• 
Summary of data for nasal carriage according to SQS along with an 
analysis of proportional odds. 
• 
Summary of the proportion of patients with a 2-log drop (TBD) 
All available data from patients in the Safety Population will be included in 
the assessment of safety and tolerability. All safety and tolerability data will 
be listed and summarised by treatment group using appropriate descriptive 
statistics. Formal statistical comparisons between the different treatment 
groups will not be conducted. 
All AEs will be coded using the MedDRA terminology. 


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Table 1.1: 
Schedule of Assessments 
Assessment 
Screening 
Visit 
Randomisation 
Visit 
Treatment Period 
Follow-up Period 
Study Day 
Day -14 
to  
Day -1* 
Day -10 to 
Day -1* 
Day -1 to Day 0 
48h ± 24h 
post 
wound 
closure 
Day 6± 
24h 
Day 30 
(and 
Day 90) a 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Screening consent 
X 
 
 
 
 
 
 
 
 
 
Nasal Swab for 
S. aureus 
(quantitative and 
rapid screen k)  
X k 
 
Xi 
 
X i 
X i 
X i 
X 
X 
 
Study consent 
 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria  
 
X 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical /Surgical 
History  
 
X 
X m 
 
 
 
 
 
 
 
Prior Medication 
History 
 
X 
X m 
 
 
 
 
 
 
 
Physical 
Examination b 
 
X 
X 
 
 
 
 
X 
X 
 
Examination of 
Nose and Nasal 
Passages by ENT c 
 
X c 
X c 
 
 
 
 
X 
 
 
Vital Signs d 
 
Xn 
 
 
 
 
X 
X 
X 
 
Clinical Chemistry 
and Haematology e 
 
Xn 
 
 
 
 
X (Post 
dose) 
X 
X 
 
Urinalysis f 
 
X 
 
 
 
 
X (Post 
dose) 
X 
 
 


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Table 1.1: 
Schedule of Assessments 
Assessment 
Screening 
Visit 
Randomisation 
Visit 
Treatment Period 
Follow-up Period 
Study Day 
Day -14 
to  
Day -1* 
Day -10 to 
Day -1* 
Day -1 to Day 0 
48h ± 24h 
post 
wound 
closure 
Day 6± 
24h 
Day 30 
(and 
Day 90) a 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Pregnancy Test 
 
X 
 
 
 
 
 
 
X 
 
Record standard of 
care in skin 
decontamination and 
peri-operative 
prophylactic 
regimen 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Record blood 
glucose levels and 
temperature during 
surgery j 
 
 
 
 
 
X 
X 
 
 
 
Brief Smell 
Identification Test 
 
X g 
X g 
 
 
 
 
 
X 
 
Adverse Events  
 
Xl 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomisation  
 
X g 
X g 
 
 
 
 
 
 
 
Study Drug 
Administration h 
 
 
X 
X 
X 
X 
X 
 
 
 
Record 
staphylococcal 
infections and use of 
antibiotics 
 
 
 
 
 
 
 
X 
X 
X 
ENT=Ear, Nose, and Throat specialist 


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*)  All screening and randomisation activity to be completed ahead of Dose 1 
a) The Day 90 Follow-up Visit is for patients who have had a foreign implant during surgery. 
b) A complete physical examination, including height and weight, (skin; head, eyes, ears, nose, and throat; lymph nodes; heart, lungs, and abdomen; extremities 
and joints; and neurological examination, but no breast, genital, or rectal examinations) will be done at the Randomisation Visit OR before nasal swab prior 
to dose 1. Brief symptom-driven physical examinations (including the nose and nasal passages) will be done at other visits.  
c) Nasal examination by ENT specialist at randomisation OR before nasal swab prior to dose 1, and again at 48+/-24h (post wound closure nasal swab). Nasal 
examination by ENT specialist at other timepoints if investigator mandated (i.e. symptoms/signs directed) 
d) Vital signs including blood pressure and heart rate, taken in supine position.  
e) Clinical safety lab tests will consist of the following: Haematology: Complete Blood Count (CBC), including Red blood cell (RBC) count, Haemoglobin, 
Haematocrit, RBC indices and red cell diameter width (RDW), white blood cell (WBC) total and differential count, and Platelet count; Serum Chemistry: 
Serum Sodium, Potassium, Carbon dioxide (CO2) (bicarbonate), Chloride, Blood urea nitrogen (BUN), Creatinine, Glucose (Screening), Glucose 
(Admission, Discharge and Follow up); record the time the patient last ate for all glucose levels, Calcium, Magnesium, Phosphate, Uric acid, Alanine 
aminotransferase (ALT), Aspartate aminotransferase (AST), Total bilirubin, Alkaline phosphatase, Total protein, and Albumin 
f) 
Urinalysis dip-stick for at least test (pH, spec gravity, proteins, glucose, ketones, bilirubin, nitrites, WBC, blood). If there are abnormal findings samples will 
be sent for microscopic examination Microbiological testing to undertaken at the Investigators decision 
g) Baseline Brief Smell Identification Test and Randomization may occur between Day -10 and Day -1 prior to Dose 1. 
h)  XF-73 or placebo will be administered 4 times into each nostril prior to surgery and then a single application immediately after wound closure. 
i) 
Nasal swabs are taken within 1 hour before the corresponding dose. 
j) 
The number of total glucose/core temperature determinations between admission to hospital for surgery and the period 48±24hours after surgery is 
determined by how many are over 200 mg/dL for glucose or below 35.5 °Celsius for temperature. 
k) Only rapid screen nasal swab required at Screening. No quantitative testing will be performed. 
l)     Record AEs that according to investigator’s judgement are related with the screening procedures. 
m)   If changes from randomization visit. 
n)  Standard of care or study mandated vital signs or laboratory analyses reported within 14 days prior to randomization should be used to determine 
inclusion/exclusion criteria. 
 


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2 
TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ...................................................................................... 4 
2 
TABLE OF CONTENTS .................................................................................... 12 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................. 16 
4 
INTRODUCTION................................................................................................ 19 
4.1 
Background ...................................................................................................... 19 
4.2 
Rationale .......................................................................................................... 21 
4.3 
Risk-Benefit Assessment ................................................................................. 21 
5 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 23 
5.1 
Primary Objective and Endpoint .................................................................. 23 
5.2 
Secondary Objectives and Endpoint ............................................................. 23 
5.3 
Exploratory Objective and Endpoint ............................................................ 24 
6 
OVERALL DESIGN AND PLAN OF THE STUDY ....................................... 25 
6.1 
Overview .......................................................................................................... 25 
6.2 
Discussion of Study Design ............................................................................. 27 
6.2.1 
Rationale for the Dosage of XF-73 ...................................................... 27 
6.2.2 
Use of Placebo ..................................................................................... 29 
7 
STUDY POPULATION ...................................................................................... 31 
7.1 
Inclusion Criteria ............................................................................................ 31 
7.2 
Exclusion Criteria ........................................................................................... 31 
7.3 
Patient Withdrawal ......................................................................................... 32 
7.3.1 
Reasons for Withdrawal ....................................................................... 32 
7.3.2 
Replacement of Patients ....................................................................... 32 
7.4 
Patient Identification and Randomization .................................................... 32 
7.5 
Stopping and Discontinuation ........................................................................ 33 
8 
STUDY DRUG ..................................................................................................... 34 
8.1 
Identity of Study Drugs .................................................................................. 34 
8.1.1 
0.2% w/w XF-73 Nasal Gel ................................................................. 34 
8.1.2 
Placebo to Match XF-73 Nasal Gel ..................................................... 34 
8.2 
Maintenance of the Blind ................................................................................ 35 
8.3 
Administration of Study Drug ....................................................................... 35 
8.4 
Packaging, Labelling and Storage ................................................................. 36 
8.5 
Drug Accountability ........................................................................................ 36 
8.6 
Compliance ...................................................................................................... 37 
8.7 
Concomitant Medications ............................................................................... 37 
8.8 
Treatment of Overdose ................................................................................... 37 
9 
PARAMETERS AND METHODS OF ASSESSMENT .................................. 38 
9.1 
Microbiological Assessments .......................................................................... 38 


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9.1.1 
Screening.............................................................................................. 38 
9.1.2 
Treatment and Follow-up Periods ........................................................ 38 
9.1.3 
Microbiological Specimen Collection and Culture for S. aureus ........ 39 
9.2 
Efficacy Parameters ........................................................................................ 39 
9.3 
Safety Parameters ........................................................................................... 39 
9.3.1 
Adverse Events .................................................................................... 39 
9.3.1.1 
Definitions ...................................................................................... 39 
9.3.1.2 
Recording Adverse Events ............................................................. 41 
9.3.1.3 
Responsibilities of the Investigator ................................................ 42 
9.3.1.4 
Responsibilities of the Sponsor ...................................................... 42 
9.3.1.5 
Evaluation of Adverse Events ........................................................ 43 
9.3.1.6 
Notifying of Adverse Events ........................................................... 43 
9.3.2 
Pregnancy ............................................................................................. 44 
9.3.3 
Laboratory Parameters ......................................................................... 44 
9.3.4 
Vital Signs ............................................................................................ 45 
9.3.5 
Physical Examinations ......................................................................... 45 
9.3.6 
Assessment of Nose, Nasal Passages, and Sense of Smell .................. 45 
9.3.6.1 
Nasal Examination by ENT specialist............................................ 45 
9.3.6.2 
Brief Smell Identification Test™ ................................................... 45 
10 
STUDY CONDUCT ............................................................................................. 47 
10.1 
Observations by Visit ...................................................................................... 47 
10.1.1 
Screening Visit (Day -14 to Day -1) .................................................... 47 
10.1.2 
Randomization Visit (Day -10 to Day -1) ............................................ 47 
10.1.3 
Treatment Period (Days -1 to Day 0) ................................................... 48 
10.1.3.1 
First dose visit (Day -1) ................................................................. 48 
10.1.3.2 
Second dose visit (Day -1) ............................................................. 49 
10.1.3.3 
Third dose visit (Day 0) ................................................................. 49 
10.1.3.4 
Fourth dose visit (Day 0) ............................................................... 49 
10.1.3.5 
Fifth dose visit (Day 0) .................................................................. 49 
10.1.4 
Follow-up Period ................................................................................. 50 
10.1.4.1 
Post-surgical visit (48h ± 24h post closure of surgical incisions). 50 
10.1.4.2 
Follow Up (Day 6 (± 24 hours) ..................................................... 50 
10.1.4.3 
Follow-up (Day 30)........................................................................ 51 
10.1.4.4 
Follow-up Day 90 (Only if object implant in surgery) .................. 51 
11 
STATISTICAL METHODS ............................................................................... 52 
11.1 
Disposition of Patients ..................................................................................... 52 
11.2 
Protocol Deviations ......................................................................................... 52 
11.3 
Analysis Populations ....................................................................................... 52 
11.3.1 
All Enrolled Patients ............................................................................ 52 
11.3.2 
Safety Population ................................................................................. 52 
11.3.3 
Intent-To-Treat Population .................................................................. 52 
11.3.4 
Modified Intent-To-Treat Population .................................................. 52 
11.3.5 
Microbiological Intent-To-Treat Population........................................ 52 
11.3.6 
Per-protocol Population ....................................................................... 53 
11.4 
General Considerations .................................................................................. 53 


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11.5 
Demographics, Baseline Characteristics and Concomitant Medications .. 53 
11.6 
Treatment Compliance ................................................................................... 53 
11.7 
Efficacy Analyses ............................................................................................. 53 
11.8 
Safety Analyses ................................................................................................ 54 
11.9 
Interim Analyses .............................................................................................. 54 
11.10 Determination of Sample Size ........................................................................ 55 
12 
DATA MANAGEMENT ..................................................................................... 56 
12.1 
Data Collection ................................................................................................ 56 
12.2 
Data Correction ............................................................................................... 56 
12.3 
Data Handling .................................................................................................. 56 
12.3.1 
Deviations from the Protocol ............................................................... 56 
12.4 
Data Quality Assurance .................................................................................. 57 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ................................. 58 
13.1 
Study Initiation Activities ............................................................................... 58 
13.2 
Training of Site Staff ....................................................................................... 58 
13.3 
Documentation and Filing .............................................................................. 58 
13.3.1 
eCRF System ....................................................................................... 58 
13.3.2 
List of Patients (patient identification log) .......................................... 58 
13.3.3 
Source Data .......................................................................................... 58 
13.3.4 
Investigator Site File / Regulatory Binder ........................................... 59 
13.4 
Monitoring ....................................................................................................... 59 
13.5 
Audits and Inspections .................................................................................... 59 
14 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ........................... 60 
14.1 
Good Clinical Practice .................................................................................... 60 
14.2 
Informed Consent ............................................................................................ 60 
14.3 
Protocol Approval and Amendment .............................................................. 60 
14.4 
Archiving Study Records ................................................................................ 60 
14.5 
Premature Termination of the Study ............................................................ 61 
14.6 
Confidentiality ................................................................................................. 61 
14.7 
Future Use of Stored Specimens .................................................................... 61 
14.8 
Liability and Insurance ................................................................................... 61 
14.9 
Publication Policy ............................................................................................ 62 
15 
REFERENCE LIST ............................................................................................. 63 
16 
APPENDICES ...................................................................................................... 66 
16.1 
List of Organizations Involved in the Study ................................................. 66 
 
Tables in Text 
Table 1.1: Schedule of Assessments .................................................................................... 9 
Table 6.1: Analysis of Direct Plating Score Response Rate (ITT Population) – Study XF73-
B03 28 


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Table 6.2: Response Rate (SQSA Score = negative/zero) (PD Population; Baseline 
Responders Removed) – Study DMID11-0007 .......................................................... 29 
Table 8.1: Components of 0.2% w/w XF-73 Nasal Gel ..................................................... 34 
Table 8.2: Components of Placebo to Match XF-73 Nasal Gel ......................................... 35 
Table 9.1: Laboratory Parameters ...................................................................................... 44 
 
Figures in Text 
Figure 6.1: 
Study Design ........................................................................................ 26 
 


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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BDRM 
Blinded data review meeting 
BP 
Blood pressure 
B-SIT 
Brief Smell Identification Test™ 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CFU 
Colony forming units 
CHRS 
Cardinal Health Research Service 
CO2 
Carbon Dioxide 
CRA 
Clinical Research Associate 
CSR 
Clinical study report 
DNA 
Deoxyribonucleic acid 
eCRF 
electronic Case report form 
EDC 
Electronic data capture 
ENT 
Ear, Nose and Throat specialist 
FD&C 
Food, Drug & Cosmetic 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
HDPE 
High Density Polyethylene 
HIV 
Human immunodeficiency virus 
HPC 
Hydroxypropyl cellulose 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 


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Abbreviation 
Definition 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IDSA 
Infectious Disease Society of America 
IEC 
Independent Ethics Committee 
IN 
Intranasal 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISF 
Investigational Site File 
ITT 
Intent-to-treat 
JP 
Japanese Pharmacopoeia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum inhibitory concentration 
MRSA 
Methicillin-resistant S. aureus 
MSSA 
Methicillin-sensitive S. aureus 
NF 
National Formulary 
NHSN 
National Healthcare Safety Network 
PCR 
Polymerase chain reaction 
Ph Eur 
European Pharmacopoeia 
PP 
Per-protocol 
QS 
Quantity sufficient 
RNA 
Ribonucleic acid 
S. aureus 
Staphylococcus aureus 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SHEA 
The Society for Healthcare Epidemiology for America 
SIS 
Surgical Infection Society 
SOC 
Standard of care 
SSI 
Surgical site infection 
SUSAR 
Suspected unexpected serious adverse reaction 


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Abbreviation 
Definition 
TBD 
To be determined 
TEAE 
Treatment-emergent adverse event 
US 
United States 
USP 
United States Pharmacopoeia 
WHO 
World Health Organization 
 


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4 
INTRODUCTION 
4.1 
Background 
Staphylococcus aureus (S. aureus) and specially the more antibiotic resistant strain, Methicillin-
Resistant S. aureus (MRSA), is a common causative organism of nosocomial infections in 
hospitals across the world8. It was estimated that 1% of all hospitalized patients in the United 
States (US) suffered from S. aureus infections, equating to nearly 400,000 patients19, at an 
estimated cost of $14.5 billion. Amongst nosocomial infections caused by S. aureus (including 
MRSA), Surgical Site Infections (SSIs) are a major infectious entity and are a cause of 
significant morbidity and mortality22,23. The prevalence of MRSA nosocomial infections in the 
US ranges from 42.6% to 52.0% depending of the site of the nosocomial infection23. The most 
recent data from the National Healthcare Safety Network (NHSN) in the US showed that despite 
recent efforts, 42.6% of all reported S. aureus surgical site infections were due to MRSA23. At 
least 80% of such infections are caused by the patients’ own bacteria9-11. S. aureus can colonize 
several body sites - nose, axillae, groin and throat - although the anterior nares are the preferred 
ecologic niche and are identified as the most frequent site of carriage11-13, with 25 to 35%14 of the 
population being colonized at any given time. S. aureus carriers are at a higher risk of 
staphylococcal infections after invasive medical or surgical procedures than non-carriers, having 
been estimated to be 2 to 10 times more likely to develop surgical-site/intravenous catheter 
infections15-18. Specifically, S. aureus nasal carriage has been identified as a risk factor for the 
development of infections in orthopaedic, thoracic and general surgery as summarized in a 
review by Wertheim et al (2005)11. 
Standard infection control measures, including hand-washing by staff with antiseptic detergents 
or 70% alcohol, ward cleaning, disinfecting equipment, correct handling of clinical waste, etc are 
important for limiting MRSA cross-infection. However, body decolonization procedures 
(typically nasal decolonization and additional body washes) have been adopted or recommended 
for at-risk patients in many settings25. 
In 2010, Bode et al reported the results of a randomized, double-blind, placebo-controlled study 
investigating nasal and body decolonization and concluded that hospital-acquired infections with 
S. aureus could be prevented by initiating decolonization treatment (nasal and body) 
immediately after admission of surgical patients20. In a commentary on this study, Bertrand et al 
also concluded that pre-emptive S. aureus decolonization should be used in surgery with a high 
risk of S. aureus infection such as open-heart surgery and orthopaedic or neurosurgical implant 
procedures9. In their review of published data on decolonization therapy from 2008 to 2010, 
Hebert and Robicsek concluded that decolonization therapy was likely to be an effective tool for 
reducing surgical infection in cardiac and orthopaedic patients21. Kim et al have reported a study 
in 7,019 orthopaedic surgical patients, concluding that a program of identification and 
eradication of both MRSA and methicillin-sensitive S. aureus (MSSA) carriage with intranasal 
mupirocin and chlorhexidine showers can lead to significant reductions in post-operative rates of 
surgical site infection5. 
In February 2013, a consensus involving the Surgical Infection Society (SIS), Infectious Disease 
Society of America (IDSA) and The Society for Healthcare Epidemiology for America (SHEA), 
published guidelines which recommend the use of nasal decolonization of all S. aureus in 
cardiovascular and orthopaedic surgery26. They also discussed the risks in other clean surgeries 
where there was not the level of proof to make a formal recommendation yet. As the only 


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approved agent for nasal decolonization, mupirocin is cited, with caveats over widespread use, 
compliance and awareness of potential resistance. The SIS guidelines26 are likely to increase the 
number of centres employing S. aureus decolonization in the surgeries identified, but this may be 
affected by the limitations of mupirocin in respect of treatment duration, compliance, concerns 
over resistance and logistical difficulties associated with pre-admission screening. 
Despite these recommendations, existing product approvals do not explicitly exemplify the use 
of prophylactic intranasal (IN) antibiotics by surgical patients. In the US, Mupirocin 
(Bactroban®) is indicated for MRSA decolonization during institutional outbreaks; in Europe the 
indication is worded: ‘the elimination of nasal carriage of staphylococci, including MRSA’. In 
fact, S. aureus nasal decolonisation is not universally accepted practice and if practiced it is not 
done in a standard manner, but with a variety of products and dosing regimens for each product 
as none of these are approved for the intended indication. 
Exeporfinium chloride (XF-73) is a dicationic porphyrin derivative having potent bactericidal 
properties with a novel mode of action. XF-73 is being developed as a viscous dermal gel for the 
decolonization of S. aureus in the anterior nares (nasal cavity) to prevent post-operative 
staphylococcal infections.  
XF-73 has been investigated against a panel of 101 Gram-positive and Gram-negative organisms 
selected for susceptibility and cross-resistance testing2. The panel comprised 65 Gram-positive 
isolates (56 aerobic and 9 anaerobic) and 36 Gram-negative isolates (31 aerobic and 
5 anaerobic). XF-73 demonstrated excellent bactericidal activity against all Gram-positive strains 
tested regardless of species, phenotype or genotype, with minimum inhibitory concentrations 
(MICs) of 0.25 to 4 mg/L. The antibacterial activity against Gram-negative species was lower, 
with MICs of 1 mg/L to > 64 mg/L. The study indicated that XF-73 is rapidly bactericidal 
against S. aureus, including methicillin-resistant strains (including USA300) 2 (Study R14). 
Exposure of bacteria to XF-73 resulted in an observed loss of membrane potential within 
1 minute, followed by efflux of small molecular weight molecules, ATP and potassium; 
>99.99% of S. aureus are killed within 5 minutes1. The mode of action is thus focused on the 
bacterial cell membrane. Cell death is not accompanied by lysis of the cells, as observed by 
electron microscopy (Study R39) or resulting in efflux of large molecular weight components 
(DNA, RNA, proteins) 1. 
A multistep study, in which MRSA was passaged 55 times, showed that XF-73 had a very low 
potential for inducing resistance over the 55 passages. The MIC values showed no more than a 
4-fold increase over the starting MIC and the accepted threshold for resistance (≥ 8-fold increase 
in MIC) was not reached3.  
The speed of onset of anti-staphylococcal activity of XF-73 has also been observed during 
clinical studies, in which the level of S. aureus isolated from heavily colonized, stable S. aureus 
carriers was observed to be reduced dramatically after 1 to 3 doses over 1 day. These 
characteristics have supported the targeting of a preferred indication of IN administration to 
prevent post-operative staphylococcal infections. In this setting, the rapidity of action will allow 
for a short treatment course around surgery.  
To date there have been 7 completed clinical studies on XF-73 (5 intranasal and 2 dermal) in 263 
patients, of which 241 received XF-73. In the intranasal (i.n.) studies carried without 
photodymanic therapy, the most common (≥10%) adverse events (AEs) reported with XF-73 gel 
application are headache (11.4%), nasal discomfort (9.0%), and rhinorrhoea (7.8%). Most of the 


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treatment-emergent AEs (TEAEs) associated with nasal gel application from previous studies 
were considered mild to moderate in intensity. Further details can be found in the current version 
of Investigator's Brochure (IB), which contains comprehensive information on the investigational 
product. 
This is a proof-of-concept study which will assess the efficacy and safety of XF-73 in the 
decolonisation of nasal carriers of S. aureus that will undergo a surgical procedure associated 
with risk of post-operative staphylococcal infections.  
4.2 
Rationale 
XF-73 provided as a 2 mg/g nasal gel with 
 is being 
developed for the prevention of post-operative staphylococcal infections. Both microbiological 
and clinical data support the move of XF-73 into this Phase 2 proof-of-concept study to assess 
the safety and microbiological efficacy of XF-73 in reducing the burden of nasal S. aureus before 
surgery in patients who are undergoing procedures at risk of post-operative staphylococcal 
infection, the population for which XF-73 is intended.  
XF-73 possesses anti-bacterial activity in vitro in the 0.5 to 1 mg/L concentration range, against 
S. aureus colonies, including MRSA, as well as for other potentially pathogenic Staphylococci 
spp. This antibacterial activity is rapid and suggests that a short duration of treatment e.g., 24 to 
48 hours will be possible, promoting compliance with the treatment.  
Two Phase 1 studies in human volunteers, who were confirmed nasal carriers of S. aureus, have 
already assessed the safety of XF-73 2 mg/g nasal gel and preliminary efficacy in reducing the 
burden of S. aureus in the nose: study XF-73B03 study with 63 healthy volunteers and study 
DMID11-007 with 56 healthy volunteers. These studies have used different regimens 
concentrations of XF-73 (0.5 mg/g and 2 mg/g) in different regimens (from 1 IN application 
every 12 hours for 2 days to 1 IN application every 8 hours for 1 day and then every 12 hours for 
another 4 days) and have analysed efficacy (burden of nasal S. aureus) in various ways 
(percentage of patients decolonized, evolution of quantitative S. aureus scores and area under the 
curve of quantitative S. aureus scores). Although limited in volunteers’ numbers, both studies 
have shown consistent better responses for the XF-73 2mg/g nasal gel compared to placebo. 
These studies have also allowed to assess the dynamics of nasal burden of S. aureus when 
exposed to XF-73 and inform a dose selection for further development and last but not least, 
these studies have depicted a favourable safety and tolerability profile for XF-73. XF-73 has also 
been assessed for safety up to 5.0 mg/g aqueous solution applied to the shoulder in healthy 
volunteers. These data suggest that XF-73 may also reduce the burden of S. aureus, including 
MRSA, before surgery in patients at risk of post-operative staphylococcal infections.   
In summary, the data from previous studies warrant the move of XF-73 into a further step in its 
development for the prevention of post-operative staphylococcal infections with this Phase 2 
proof-of-concept study where the safety and efficacy of XF-73 to decrease the burden of nasal 
carriage of S. aureus will be studied in actual patients who will undergo a procedure at risk of 
post-operative staphylococcal infections. Please refer to the current IB for further information. 
4.3 
Risk-Benefit Assessment 
The safety of nasal application of XF-73 in concentrations up to 2 mg/g, cumulative doses up to 
13.2 mg and for up to 5 days has already been studied in 172 volunteers. The most common AEs 
reported as related to XF-73 have been nasal discomfort, headache and rhinorrhoea in 17, 14 and 


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14 patients, respectively. These events were mostly mild in intensity, transient and resolved 
spontaneously without sequelae. Post-dose nasal examinations have not revealed erythema or 
increased secretions, so these events seem to be more related with the physical presence and 
sensation of the gel in the nares rather than a physiological interaction with the nasal mucosa; 
though a dose response cannot be fully ruled out.  
Only one suspected unexpected serious adverse reaction (SUSAR), hyposmia, has been reported; 
and has also been the only related serious adverse event so far. This was in study DMID11-007 
and since this report the remaining 21 volunteers were provided a smell test pre- and post- study. 
No signal was detected. 
XF-73 plasma levels have been determined in all studies up to date showing no evidence of 
systemic absorption (assay detection limit 0.2 ng/mL), therefore no systemic toxicity from XF-73 
is expected in this study. Of note, in the studies with XF-73 nasal gel to date, there have been no 
AEs leading to treatment or study discontinuation.  
XF-73 provided as a nasal gel has been shown to be well tolerated in different healthy volunteer 
studies; nevertheless in this Phase 2 study, with patients who will undergo surgery, besides the 
usual safety exams (physical, biochemistry and haematological laboratory tests) a nasal 
examination by an ear nose and throat (ENT) specialist will be performed pre and post-dosing to 
further assess the risks from the contact of XF-73 gel and the nasal mucosa as well as a pre-post-
dosing smell test to address the possible risk of hyposmia as it was seen in study DMID11-007. 
An independent data monitoring committee (IDMC) of experts will be set up which will 
regularly review the safety information from the study as well as the incidence of post-operative 
staphylococcal infections. Should these reach an unexpectedly high level, the IDMC can 
recommend stopping the study. The IDMC charter containing amongst others membership, 
meetings frequency, structure and procedures produced before randomization of the first patient 
will be updated implementing the changes introduced in this version 2.1 of the protocol. 
A benefit cannot be guaranteed, given the early stage of development if XF-73, however it is 
expected that the reduction in nasal burden of S. aureus seen in the healthy volunteers will 
reproduce in patients who participate in this study, which may translate in a reduction in the risk 
of developing post-operative staphylococcal infections. This benefit will be difficult to 
appreciate in this study as the incidence of these infections is low and the number patients to 
enrol very limited. 
In summary, even though a benefit cannot be guaranteed or measured, only expected; the risks 
are limited. Additionally, surveillance measures to reassess benefit-risk during the execution of 
the study such as the nasal examination smell test and an IDMC are in place; so that appropriate 
action can be taken should an unexpected signal arise. The risk-benefit assessment is therefore 
thought to be favourable in this study. 


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5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objective and Endpoint 
Objective 
Endpoint 
To demonstrate the efficacy of a 0.2% XF-73 
nasal gel in reducing the microbiological 
burden of nasal S. aureus measured as change 
in colony forming units (CFU) per mL from 
baseline to immediately prior to surgery in a 
patient population at risk of post-operative 
staphylococcal infection 
• Change in S. aureus log CFU/mL from 
baseline to pre-surgery 
 
5.2 
Secondary Objectives and Endpoint 
Objective 
Endpoint 
To determine the effect of a 0.2% XF-73 nasal 
gel on S. aureus nasal burden from baseline to 
pre-surgery and from baseline to immediately 
post-surgery measured as area under the curve 
(AUC) of S. aureus log CFUs/mL over time. 
• Difference in AUC of S. aureus log 
CFU/mL from baseline to pre-surgery. 
• Difference in AUC of S. aureus log 
CFU/mL from baseline to immediately post-
surgery. 
To determine the efficacy of a 0.2% XF-73 
nasal gel in their effect on S. aureus nasal 
burden measured as CFUs/mL in follow-up 
immediately after surgery, at approximately 
48 hours after surgery and 7 days after surgery. 
• Change in S. aureus log CFU/mL from 
baseline to immediately after surgery 
• Change in S. aureus log CFU/mL from 
baseline to 48 hours after surgery 
• Change in S. aureus log CFU/mL from 
baseline to 7 days after surgery 
To explore the efficacy of XF-73 in reducing 
the burden of S. aureus carriage at the patient 
level. 
• Percentage of patients reaching a specific 
reduction in S. aureus carriage prior to 
surgery, immediately post-surgery and on 
Day 6 ± 24hrs. 
To assess the effect of XF-73 on S. aureus 
nasal carriage in the prevention of post-
operative staphylococcal infections (surgical 
site infections, blood stream infections and 
others) during the 30 days post-surgery 
(90days in the case of a foreign implant).  
• Difference in the incidence of S. aureus 
post-operative infections during the 30-day 
period after surgery (90 days in the case of 
foreign implant) 
To describe the safety and tolerability of 
multiple administrations of a 0.2% XF-73 nasal 
gel in a population of surgical patients at risk 
of post-operative staphylococcal infections. 
• Incidence of TEAEs from the first dose of 
study medication to 7 days post last 
application of study medication 
• Changes in vital signs, safety clinical 


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laboratory assessments, nasal examination, 
and smell identification test. 
 
5.3 
Exploratory Objective and Endpoint 
Objective 
Endpoint 
To describe the use of post-operative anti-
staphylococcal antibiotics, except those 
provided for prophylaxis as local standard of 
care (SOC), during the 30-day post-surgery 
period (90 days in the case of an object 
implant) reported separately. 
• Reason for post-operative prescribed anti 
staphylococcal antibiotic use during the 
30-day post-operative period (90 days in the 
case of an object implant) 
 
 


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6 
OVERALL DESIGN AND PLAN OF THE STUDY 
6.1 
Overview 
This is a Phase 2, multi-centre, randomized, double-blind, parallel, placebo-controlled study of 
multiple applications of a single concentration of XF-73 nasal gel to assess the microbiological 
effect of XF-73 on commensal S. aureus nasal carriage in patients scheduled for surgical 
procedures deemed to be at high risk of post-operative S. aureus infection. The study is divided 
in 4 periods: screening (Days -14 to -1) randomization (Days -10 to -1), treatment (Days -1 and 
0) and follow-up (post-last study dose to Day 30 or Day 90 if an implant is inserted during 
surgery). Day 0 is the calendar day in which surgery takes place. Only patients who test positive 
to S. aureus by a standardized rapid diagnostic test will be enrolled in the study. Approximately 
125 patients will be randomised in a double-blind manner (the investigators and patients are 
blind to the treatment assignment) in a 1:1 ratio to 0.2% w/w XF-73 nasal gel treatment OR 
placebo to match XF-73 nasal gel. 
The study drug, 0.2% w/w XF-73, or matched placebo will be administered 4 times into each 
nostril over 24 hours prior to surgery and then a single application immediately upon closure of 
surgical wound. Additionally, patients may undergo chlorhexidine skin decolonisation ahead of 
surgery and receive perioperative prophylactic systemic antibiotics in accordance with local 
practice. 
In total 7 nasal swabs will be taken: at screening, 3 times prior to surgery (surgery within 
1 hour), post-surgery (right after surgical wound closure), 48 hours post-surgery and 7 days post-
surgery.  
Efficacy will be assessed by S. aureus colonisation from screening to 7 days after surgery as well 
as by incidence of post-operative staphylococcal infections and use of anti-staphylococcal 
antibiotics post-surgery. Safety will be assessed by reported AEs from screening up to Day 6 as 
well as vital signs, physical examination (ENT), clinical laboratory assessments (haematology, 
clinical chemistry, and urinalysis) and Brief-Smell Identification Tests (B-SIT) at different time 
points as reflected in Table 1.1. 
The maximum study duration will be up to 45 or 105 days for each individual (from screening to 
post-study follow-up visit) depending on whether a foreign implant was inserted during surgery.  
An IDMC will be set up which will review the safety information from the study and the 
incidence of post-operative staphylococcal infections. Based on the findings from these 
activities, the IDMC can recommend; 
• Stop the study in case of serious concerns on subject’s safety.   
• Stop the study due to the incidence of post-operative staphylococcal infections. 
• Continue as currently described in the protocol 
• Continue the study with protocol modifications. 
The  IDMC charter containing, amongst other things: membership, meetings frequency, stopping 
criteria, structure and procedures produced before randomization of the first patient will be 
updated implementing the changes introduced in this version 2.1 of the protocol.  
Figure 6.1 presents the study design. 


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Figure 6.1: 
Study Design 
 
 
 


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6.2 
Discussion of Study Design 
This is a Phase 2, randomised, double-blind, parallel, placebo-controlled, study of a 
single concentration of XF-73 nasal gel conducted in surgical patients who are at risk of 
post-operative staphylococcal infections. Patients will be randomised in a double-blind 
manner to either the active or placebo arm on a 1:1 basis. 
6.2.1 Rationale for the Dosage of XF-73 
The dosing regimen to be assessed in this study, four 0.3 mL applications in each naris of 
a 2 mg/g XF-73 
 nasal gel 24 hours before surgery and a 5th application right 
after surgery (a cumulative dose of 6 mg of XF-73), is supported by microbiological and 
clinical data from XF-73 Phase 1 studies. Microbiological data showed that XF-73 has a 
rapid antibacterial activity and suggests that a short duration of treatment may be 
possible, facilitating compliance with this treatment.  
In study XF-73B03, 63 healthy volunteers (safety population) who were nasal persistent 
carriers of S. aureus were randomly assigned to receive XF-73 nasal gel (0.5 mg/gr) or 
XF-73 nasal gel (2.0 mg/gr), both with 
, or placebo in each naris every 12 hours 
for 2 days; 27, 12 and 24 volunteers per group respectively. Burden of S. aureus in the 
naris was measured as semiquantitative S. aureus scores during the 2-day treatment 
period and up to discharge (Day 4) and follow-up (up to Day 6).  
The efficacy data for the treatment period showed consistent better responses for the 
2 XF-73 groups than for placebo in different efficacy measures: eradication rates of 
S. aureus from participants’ noses; semiquantitative S. aureus scores; time to first 
clearance and mean differences in AUC. In many instances these differences were 
statistically significant in favour of XF-73. In the efficacy data at discharge (Day 4), on 
the other hand, only the AUC analysis showed statistically significant differences in 
favour of XF-73 groups for the discharge. No differences between study groups were 
detected during the follow-up period (Days 7 and 14). XF-73 was well tolerated at all 
dose levels used in this study.  
Results for eradication of S. aureus during the treatment period (i.e., after 2 doses to each 
naris in the first 24-hour period and after 4 doses to each naris in the first 48-hour period), 
are described in the Table 6.1 below. In summary, for the XF-73 2.0 mg/g group there 
was a 41.7% (10 out of 24, P = 0.0087) clearance of S. aureus carriage at 24 hours after 
2 doses (total dose 2.4 mg of XF-73) and a 37.5% (9 out of 24, P = 0.0965) clearance of 
S. aureus carriage at 48 hours after 4 doses (total dose 4.8 mg of XF-73) over placebo. 
For the XF-73 0.5 mg/g 
 group the was a 33.3% (4 out of 12, P = 0.0804) 
clearance of S. aureus carriage at 24 hours after 2 doses (total dose 0.6 mg of XF-73) and 
a 50% (6 out of 16, P = 0.0455) clearance of S. aureus carriage at 48 hours after 4 doses 
(total dose 1.2 mg of XF-73) over placebo. 


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Table 6.1: 
Analysis of Direct Plating Score Response Rate (ITT Population) 
– Study XF73-B03 
Time Point 
XF-73 2.0 mg/g 
 
(2d) 
N=24 
XF-73 0.5 mg/g
 
(2d) 
N=12 
Placebo (2d) 
N=24  
Day 2 
102  
(a total of 2.4 mg XF-73) 
41.7%  
7.86 (1.32, 80.65)  
0.0087  
42 
(a total of 0.6 mg XF-73) 
33.3%  
5.50 (0.61, 68.03)  
0.0804  
21 
 
8.3%  
EOT+12h 
92  
(a total of 4.8 mg XF-73) 
37.5%  
3.0 (0.66, 15.63)  
0.0965  
62  
(a total of 1.2 mg XF-73) 
50.0%  
5.0 (0.82, 31.8)  
0.0455  
41  
 
16.7%  
CI=confidence interval; EOT=end of treatment; HPC=hydroxypropyl cellulose 
1 Number of Responders, Response Rate  
2 Number of Responders, (total dose), Response Rate; Comparisons v Placebo - Odds Ratio (Exact 95% 
CI), One-sided Fisher Exact Test p-value using 2.5% significance level. 
 
In addition, the analysis of semi-quantitative S. aureus scores during the treatment period 
also showed a more marked decrease from baseline in the 2 XF-73 treatment groups than 
in the placebo group. This same difference was shown in the analysis of mean differences 
in AUC during the treatment period and it was statistically significant with better 
responses for the XF-73 groups. Moreover, statistical AUC analysis and the change from 
baseline in the reduction in S. aureus semi-quantitative scores there was an apparent dose 
response relationship with the higher 2.0 mg/g XF-73 dosage performing better than the 
0.5 mg/g dosage. 
In conclusion, these data from the study suggest that the highest concentration of XF-73 
(i.e., 2.0 mg/g) should be used to get a maximum response and that an efficient dose 
should be provided right before the point of highest risk for development of post-
operative infections (i.e., right before surgery). 
In the healthy volunteer study DMID11-007, 52 healthy volunteers (safety population) 
who were nasal persistent carriers of S. aureus received XF-73 nasal gel (0.5 mg/gr) 
 
 or XF-73 nasal gel (2.0 mg/gr) 
 or XF-73 nasal gel (0.5 mg/gr) 
 or 
placebo in each naris every 8 hours on Day 1 and every 12 hours Days 2 to 5; this 
provided cumulative doses of XF-73 of 3.3 mg, 13.2 mg and 3.3 mg respectively. 
Thirteen volunteers were randomly assigned to each group. Burden of S. aureus in the 
naris was measured as semiquantitative S. aureus scores during the 5-day treatment 
period and up to discharge (up to Day 6).  
The efficacy data for the treatment period supported the conclusions from study 
XF73-B03. Early in treatment there were important differences in the number of 
volunteers achieving eradication of S. aureus from their nose between placebo and XF-73 




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• There is no approved drug for S. aureus nasal decolonization to prevent post-
operative staphylococcal infections, the indication under study 
• Studies of nasal decolonisation of S. aureus show a significant variability in the 
microbiological measurements and an important placebo effect (up to 50%-60%) 
which supports the need for a placebo to appropriately assess the effect of XF-73.  
• S. aureus nasal decolonisation prior to surgery is not universally accepted practice 
and when practiced it is not done in a standard way, but with considerable 
variation in the products and dosing regimens used of each product; as these 
products are not approved for the intended indication.  
• The study’s primary endpoint is based on microbiological data, not clinical. No 
impact is expected on post-operative staphylococcal infections from the use of 
placebo as their incidence is low and the sample size not enough to detect it.  
• The IDMC will assess the incidence of post-operative staphylococcal infections. 
• Patients will receive skin decontamination prior to surgery and peri-prophylactic 
systemic antibiotics according to SOC at their centre. 


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7 
STUDY POPULATION 
Patients undergoing surgical procedures who are at risk of post-operative S. aureus 
infection due to patient carriage status are eligible to participate in the study. Only 
patients who test positive to S. aureus (MSSA or MRSA) by standardized rapid 
diagnostic test will be enrolled in the study. 
7.1 
Inclusion Criteria 
Individuals who meet all of the following criteria are eligible to participate in the study. 
1. 
Male or female patients between 18 and 75 years of age. 
2. 
Patients who are confirmed nasal S. aureus carriers by polymerase chain 
reaction (PCR) screen assay, and due to undergo surgical procedure. 
3. 
Patients who are willing to provide written informed consent. 
4. 
Patients who are willing and able (as per Investigator judgment) to complete all 
protocol specified visits and assessments. 
5. 
Woman of childbearing potential* with a negative urine pregnancy test 
(sensitive to 25 IU human chorionic gonadotropin [hCG]).  
* Women of childbearing potential are defined as those women between 
menarche and menopause who have not undergone permanent sterilisation. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, 
and bilateral oophorectomy 
 
7.2 
Exclusion Criteria 
Individuals who meet any of the following criteria are not eligible to participate in the 
study. 
1. 
Pregnancy (current) or currently lactating. 
2. 
Uncontrolled acute or chronic illness (as determined by the investigator) in 
addition to those requiring the planned surgical intervention. 
3. 
History of atopy, allergic reactions or hypersensitivity to the study medication 
or its components. 
4. 
Current upper respiratory tract infection, cold or influenza with significant 
nasal symptoms that might impact on the patient’s ability to comply with the 
gel application procedure. 
5. 
History of photosensitivity. 
6. 
Family history of porphyria. 
7. 
Use of intra-nasal topical or systemic antibiotics or anti-infectives within the 
last 4 weeks before screening. (Patients who screen positive for nasal carriage 
of S. aureus and receive topical or systemic antibiotics or anti-infectives which 
are not part of their prophylactic peri-operative SOC between screening and 


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first dose of IMP will be excluded from the study.) The use of intra-nasal 
antibiotics or anti-infectives other than the study medication prior to surgery is 
not allowed. 
8. 
Use of other prescribed or over the counter nasal medication in the last 14 days, 
or oral decongestants in the last 7 days before first administration of study drug. 
9. 
Participation in a clinical trial within the last 12 weeks before first 
administration of study drug. 
10. 
Contemporaneous clinically significant abnormalities in vital signs or 
laboratory analyses reported within 14 days prior to randomization which in the 
opinion of the Investigator would preclude from the safety assessment of the 
medication under study. 
11. 
Nasal polyps or significant anatomical or other nasal abnormality that would 
prevent from appropriate administration of the study treatment or represent an 
excessive risk for the patient’s participation. 
12. 
History of nasal surgery including cauterization. 
13. 
A recent history of frequent epistaxis and/or an episode of epistaxis within 3 
months of the planned surgery. 
14. 
Use of in situ nasal jewellery or existence of open nasal piercings. 
7.3 
Patient Withdrawal 
7.3.1 Reasons for Withdrawal 
Participation is strictly voluntary. Patients must be withdrawn from the study for any of 
the following reasons: 
• 
Withdrawal of informed consent; 
• 
Pregnancy; 
• 
Investigator’s opinion that it is in the best interests of the patient; 
• 
Patient is not willing or able to comply with study requirements 
If a patient withdraws from a trial prematurely, the Investigator must determine the 
primary reason for this and record it in the electronic case report form (eCRF). For 
patients who are lost to follow up, the Investigator should show due diligence by 
documenting in the source documents steps taken to contact the patient. 
7.3.2 Replacement of Patients 
Patients who withdraw or who are prematurely withdrawn from the study having received 
study medication will not be replaced but will be followed-up for safety as far as practical 
for inclusion into the safety dataset. 
7.4 
Patient Identification and Randomization 
At screening, each patient will be given a unique 5-digit number to facilitate anonymous 
identification within the study. The first 2 digits of the number is the centre number (i.e., 


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01, 02, etc.). The following 3 digits will be enrolment order number (i.e., first patient at 
centre number 01 is number 01-001 then 01-002, etc). Once assigned to a patient, a 
patient number will not be re-used. This number will be used throughout the study as the 
subject identifier. 
A randomisation schedule will be prepared by an independent statistician and provided to 
Interactive Response Technology System (IRT) personnel prior to commencement of the 
study. This list will be maintained in the IRT system, under restricted access, until after 
study unblinding occurs. Patients will be randomly allocated in a 1:1 ratio as follows: 
0.2% w/w XF-73 nasal gel treatment OR placebo to match XF-73 nasal gel treatment. 
At randomisation, the IRT will assign an investigational product (IP) pack number. The 
pharmacist or qualified designee will retrieve the appropriate cardboard carton with the 
corresponding number. If a second bottle is needed, e.g. because syringe time to use has 
exceeded 48 hours from preparation, the pharmacist or qualified designee will use the 
IRT system to ascertain the second IP pack number required for the subject. Detailed 
instructions will be provided in the Pharmacy and IRT Manuals. 
7.5 
Stopping and Discontinuation 
An IDMC will be set up which will review the safety information from the study as well 
as the incidence of post-operative staphylococcal infections. Should these reach an 
unexpectedly high level, the IDMC can recommend stopping the study, the decision will 
be communicated to the sponsor as well as investigator sites, competent authorities, and 
ethics committees/IRBs. The IDMC charter containing, amongst other things, 
membership, meetings frequency, stopping criteria, structure and procedures  produced 
before randomization of the first patient will be updated implementing the changes 
introduced in this version 2.1 of the protocol.  






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and an additional 0.3mL dose applied to the contralateral naris. The total volume of study 
drug dispensed on each dose occasion will be 0.6 mL (2 × 0.3 mL equating to 1.2 mg of 
XF-73). Each bottle contains sufficient gel to withdraw 10 × 0.3 mL volumes 
(5 administrations to each nares). The nasal gels are preserved, but care must be taken 
during the opening of the bottle, withdrawal of doses and closing of the bottle to ensure 
the integrity of the product is maintained and not contaminated. If necessary, the syringes 
can be prepared up to 48 hours in advance of dosing. It is expected that doses 1, 2, 3, and 
4 will be prepared at the same time. 
Detailed instructions for the preparation and handling of the syringes from the supplied 
study drug will be provided in the Pharmacy Manual. Detailed instructions for the 
application of the nasal gel to the anterior nares will be provided in the Administration 
Manual. 
8.4 
Packaging, Labelling and Storage 
0.2% w/w XF-73 Nasal Gel and placebo to Match XF-73 Nasal Gel will be provided in 
bottles with screw top caps. Each bottle contains 
s of gel, sufficient to 
allow removal of at least 10 × 0.3 mL of gel as per protocol. The label on each bottle/kit 
does not identify the treatment arm (active or placebo) the nasal gel is assigned to. The 
bottles will be packaged in individual cardboard cartons as part of a patient kit. Each kit 
contains 1 bottle of nasal gel (active or placebo) 1 mL luer slip tip syringes, syringes 
caps, sterile wipes, syringe labels and a zip-lock foil bag in which filled syringes can be 
stored until use. Each bottle/kit will include a pack number which will be allocated to a 
single patient using the IRT system. Study drug will be labelled in accordance with 
applicable regulatory requirements. 
The study drugs must be stored at room temperature, below 25˚C and protected from 
light (by storing in the cardboard carton). The study drug must not be refrigerated or 
frozen. Each bottle and kit containing study drug is labelled with an expiry date. The 
shelf life of the study drug is under constant review based on data availability from 
ongoing stability studies on the batches used in the study and previous batches produced, 
and it is expected to be at least 12 months for each product. Until dispensed, the study 
drug must be stored in a securely locked area, accessible to authorized pharmacy or 
qualified designee personnel only. 
Syringes prepared for the administration of the study drug can be prepared up to 48 hours 
in advance of dosing, in accordance with instruction in the Pharmacy Manual and should 
be stored in the foil zip-lock bag provided until use. It is expected that doses 1, 2, 3, and 4 
will be prepared at the same time. 
Packaging and labelling of study drug will comply with Good Manufacturing Practice 
(GMP), Good Clinical Practice (GCP) rules, and country specific regulatory 
requirements; this information will be available in the local language. 
8.5 
Drug Accountability 
The pharmacist or qualified designee must keep a record of the dates and amounts of 
study drug received, dispensed and left unused at the end of the study. He or she will also 
have responsibility for ensuring the correct pack number is assigned to each patient based 


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on the IRT assignment. The pharmacist or qualified designee is responsible for 
maintaining accurate study drug accountability records throughout the study. 
Each dispensing of study drug will be documented in the Pharmacy File and the time of 
administration should be captured in the eCRF. Any unused prepared syringes will be 
kept in their zip-lock foil bag at pharmacy for accountability and reconciliation. 
The study drug records must be available for inspection by the Sponsor’s representative 
and is subject to inspection by a regulatory agency at any time. Copies of the records will 
be provided to the Sponsor at the end of the study. A Clinical Research Associate (CRA) 
will review the study drug records. Any remaining study drug will be either returned to 
the Sponsor or destroyed at site in accordance with the site’s Standard Operating 
Procedures following final accountability by the CRA. 
8.6 
Compliance 
Patients will be considered compliant if they receive the 5 scheduled applications (4 prior 
to surgery and 1 after surgery) of randomized study drug. 
8.7 
Concomitant Medications 
Any medication the patient takes other than the study drug is considered a concomitant 
medication. All concomitant medications must be recorded in the eCRF. The following 
information must be recorded in the eCRF for each concomitant medication: generic 
name, route of administration, start date, stop date, dosage, and indication. Any changes 
in the dosage or regimen of a concomitant medication must be recorded in the eCRF. 
At randomization, patients will be asked what medications they have taken during the last 
30 days. Changes to concomitant medications will be captured throughout the study and 
follow-up periods. 
The use of intra-nasal antibiotics or anti-infectives other than the study mediation prior to 
surgery is not allowed. 
8.8 
Treatment of Overdose 
There have been no reports of XF-73 overdose or off-target application and under the 
conditions of the study protocols, the possibility has been minimised, as site staff 
administer the product. Please see the Pharmacy and Administration Manual for 
additional information about overdose or off-target application. 


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9 
PARAMETERS AND METHODS OF ASSESSMENT 
9.1 
Microbiological Assessments 
9.1.1 Screening 
Potentially suitable patients who provide written informed consent to nasal swabbing and 
microbiological analysis will be assessed for nasal S. aureus carriage. 
Specimens for detection of S. aureus will be collected using commercial nasal swabs. 
Each specimen will be collected from the anterior naris, and the swab will be immersed 
in the accompanying transport medium container for transfer to the microbiological 
laboratory. PCR will be used for the rapid detection and identification of S. aureus at 
screening. The swab will be processed by a standardized laboratory process using an 
FDA-cleared commercial rapid diagnostic test, the 
 
 to confirm S. aureus and identify whether it is MSSA or 
MRSA. This test will confirm presence or absence of MSSA or MRSA in nasal swab and 
will be used for inclusion in the study.  
Only subjects who are S. aureus positive by the rapid diagnostic test (and meeting other 
criteria) will be enrolled to the study.  
9.1.2 Treatment and Follow-up Periods  
Patients who test positive for S. aureus at screening and provide consent for the main 
study will have nasal swabs taken at the following times 
1. Prior to Dose 1 (22 hours (± 2 hours) prior to surgery; quantitative). 
2. Prior to Dose 3 (6 hours (± 2 hours) prior to surgery; quantitative) 
3. Prior to Dose 4 (Up to 1 hour prior to incision; quantitative) 
4. Prior to Dose 5 (Up to 1 hour post wound closure; quantitative) 
5. 48 hours (± 24 hours) after surgery (quantitative) 
6. 6 days (± 24 hours) after surgery (quantitative) 
 
Swabs will be transferred to the microbiological laboratory and standard microbiology 
culture techniques will be used to quantify the number of bacteria in CFU/mL at each 
timepoint.  
In order to appropriately assess the incidence of post-operative staphylococcal infections 
investigators will take all reasonable efforts to obtain microbiological documentation and 
a bacterial isolate when the suspicion of post-operative infection is raised. This includes 
but is not limited to the collection and culture of exudates, blood, implant or other 
specimens according to the suspected site of infection. Isolates of Staphylococcus spp. 
obtained from these cultures will be kept for further analysis and characterization (e.g., 
genotypic and phenotypic characterization). 
These samples as well as those bacterial isolates obtained from the nasal swabs during the 
study will kept for up to 10 years after the completion of the study for further phenotypic 


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and genotypic analysis and characterization. The details of these tests are not known at 
this time. No subject identifying information will be retained for these samples. The 
Informed Consent Form explains the storage and future use of specimens and subjects 
will be asked to consent for future testing of samples. 
The Sponsor and Sponsor contracted vendors will have access to the samples and will 
perform microbiological work on behalf of the sponsor. Additionally, bacterial isolates 
may be shared with academic researchers. 
As these are bacterial samples, no human genetic testing will be performed. 
9.1.3 Microbiological Specimen Collection and Culture for S. aureus 
The Laboratory Manual of Microbial Procedures will describe the details of collection 
and processing methods for microbiological samples, including type of nasal swab and 
transport tube, microbiological culture methods, and reporting of results. 
9.2 
Efficacy Parameters 
Efficacy will be assessed by measuring CFUs/mL at the time points outlined in the 
Schedule of Assessments (Table 1.1) the incidence of post-operative staphylococcal 
infections as well as use of post-operative anti-staphylococcal antibiotics. 
Any staphylococcal post-operative infections arising between study treatment and up to 
30 or 90 days (if foreign implant) included but not limited to SSI, bloodstream infections, 
catheter-related infections, and implant infections are to be captured as events indicating 
lack of efficacy. These should NOT be captured as safety TEAEs. 
9.3 
Safety Parameters 
Safety will be assessed by incidence of AEs, clinical laboratory parameters, vital signs, 
physical examinations, nasal examination, and the B-SIT. 
9.3.1 Adverse Events 
All AEs, whether identified by the Investigator or the study patient from screening to 
Day 6, will be recorded in the eCRF. Measurement of vital signs and clinical laboratory 
parameters will be performed pre- and post-study and clinically significant values will be 
captured as AEs. For AEs occurring after Day 6, see section 9.3.1.2 of this protocol. 
9.3.1.1 Definitions 
Per ICH, an AE is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavourable or unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. The AE may be any of 
the following: 
• A new illness 


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• An exacerbation of a sign or symptom or the underlying condition or of a 
concomitant illness under treatment 
• Unrelated to participation in the clinical study or an effect of the study medication 
or comparator drug 
• A combination of 1 or more of the above factors 
No causal relationship with the study medication is implied by the use of the term AE. 
Planned or elective surgical or invasive procedures for pre-existing conditions that have 
not worsened are not AEs. However, any complication that occurs during a planned or 
elective surgery is an AE. Conditions leading to unplanned surgical procedures may be 
AEs.  
When an AE occurs after written consent has been obtained but before the first dose of 
study drug, the AE will be considered a non-treatment emergent AE. An AE that occurs 
from the time the patient receives his/her first dose of study drug until his/her last study 
visit will be considered a TEAE regardless of the assessed relationship to the 
administration of the study drug. 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that: 
• Results in death 
• Is life-threatening (Note: the term “life-threatening” refers to any AE that, as it 
occurs, puts the patient at immediate risk of death. It does not refer to an AE that 
hypothetically might have caused death if it were more severe). 
• Requires hospitalization or prolongation of existing hospitalization (not including 
hospitalization for a pre-existing condition that has not increased in severity or 
frequency from the patient’s underlying medical condition prior to entry into the 
study). Hospitalization for an elective procedure, or routinely scheduled treatment for 
a pre-existing condition that has not worsened, is not an SAE. 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is another medically important condition  
 
An important medical event that is not immediately life threatening or will result in death 
or hospitalization, but which may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above, should be reported as “serious” 
as well. 
Medical and scientific judgment should be exercised in deciding whether a case is 
serious. 
“Occurring at any dose” does not imply that the patient is receiving study drug at the time 
of the event.  


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Severity of Adverse Event:  
Refers to the extent to which an AE affects the patient's daily activities. Severity will be 
categorized according to the following criteria: 
Mild: 
The AE does not interfere with the patient’s routine activities. 
Moderate: 
The AE interferes with the patient’s daily routine, but usual routine 
activities can still be carried out. 
Severe: 
The AE results in the inability to perform routine activities. 
The term "severity" is used to describe the intensity of an event. This is not the same as 
"serious". Seriousness, not severity, serves as the guide for defining regulatory reporting 
obligations. The highest severity grade attained should be reported, for AEs with 
divergent severities. 
Causality of Adverse Event:  
Refers to the relationship of the AE to study drug. Causality will be reported according to 
the following criteria: 
Not 
related: 
Adverse events for which a reasonable explanation for an alternative cause 
is considered plausible, e.g., no study drug taken, plausible clinical 
alternative like accidental injury, expected progression of underlying or 
concomitant disease, pharmacologically incompatible temporal relationship, 
or intercurrent illness. 
Related: 
Adverse events for which a reasonably possible clinical and/or 
pharmacological relationship to study drug cannot be excluded, e.g., lacking 
plausible alternatives. 
 
9.3.1.2 Recording Adverse Events 
Patient Enrolment to the First Administration of Study Drug: Non-treatment 
emergent AEs will be recorded from the time when the patient is enrolled into the study 
(date of signature of the screening informed consent) until first administration of study 
drug. These events will be recorded in the medical history section of the eCRF. 
First Administration of Study Drug to Patient's Day 6 visit: Thereafter, all AEs are 
TEAEs and will be recorded until Day 6 visit has been performed.  
After Day 6: Only AEs that meet SAE criteria and are considered related with the study 
medication by the investigator will be recorded after Day 6 through the final follow up 
visit. 
If an AE (serious or not) started during the study but did not end before the final 
follow-up visit, the Investigator should make a reasonable effort to establish the outcome 
and the end date. If this is not possible, the outcome recorded at the final follow-up visit 
will be assumed to be the final outcome. 
If an event stops and later restarts, all the occurrences must be reported. If in a patient the 
same event changes in intensity over time (e.g., diarrhoea starting as mild turns into 


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severe), only the most severe intensity will be recorded. All AEs assessed as related to 
study medication by the Investigator and all SAEs must be followed up until resolution. 
(e.g., value back to baseline value) or stabilization or until final database lock. 
Signs/symptoms should be documented if a definite diagnosis cannot be established. The 
Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. If a diagnosis 
is accompanied by unusual symptoms, both the diagnosis itself and the symptoms will be 
reported. 
After Patient's Last Study Visit: The Investigator records and forwards to the Sponsor 
all SAEs that she or he becomes aware of and she or he considers related to the study 
drug. 
Laboratory values that are outside the normal range and considered clinically 
relevant in the opinion of the Investigator are also defined as AEs. 
If abnormal laboratory values are signs of an AE (e.g., an infection) that has already been 
recorded, the respective abnormal laboratory value does not constitute a separate AE. 
Wherever reasonable the reporting Investigator will use the clinical term rather than the 
laboratory term (e.g., anaemia versus low haemoglobin value). 
9.3.1.3 Responsibilities of the Investigator 
The AE data should be obtained through observation of the patient, from any information 
volunteered by the patient, or through patient questioning. The general type of question 
asked could be similar to: “Do you have any health problems?” or “Have you had any 
health problems since your last clinic visit?” 
All AEs are to be documented/recorded accurately and completely on the AE pages of the 
respective eCRF and in the patient's source data.  
All non-treatment and TEAEs will be recorded through Day 6. 
This is true even if the study drug was not administered according to the study protocol. 
For conditions leading to unplanned surgical procedures the underlying condition, should 
be documented as an AE, but not the procedure. For withdrawals due to AEs these 
should be captured in the CRF. If the AE meets the criteria of an SAE, it should be 
reported to 
 as normal. 
Overdose needs to be captured as an AE in the CRF and reported to 
 
if the AE meets the criteria of an SAE. 
9.3.1.4 Responsibilities of the Sponsor 
For purposes of safety analyses all AEs will be recorded in the clinical database. To 
ensure expedited and periodic notification of authorities, SAEs will also be recorded in 
the drug safety database. 




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Patients that have unresolved AEs, clinically relevant laboratory parameters or SAEs 
after Day 6 (including the Early Termination Visit), should be followed by the 
Investigator until satisfactory resolution (e.g., value back to baseline value) or 
stabilization or until final database lock. If necessary, in order to obtain the additional 
information, the Investigator may request additional physical examinations to be 
completed or additional blood or urine samples to be taken. The assessments measured 
will be determined by the Investigator. All data must be documented in the eCRF. 
Destiny Pharma’s regulatory advisors 
 are 
responsible for fulfilling all sponsor obligations regarding notification of the FDA 
according to applicable regulatory requirements (expedited and periodic reporting, e.g., 
SUSARs, Development Safety Update Report). In addition, 
 will provide 
safety information arising from the authorities of countries other than the US and to 
Investigators according to the current regulations and ensure that the Investigators notify 
their IEC/IRB. 
9.3.2 Pregnancy 
If a female patient or the female partner of a male patient becomes pregnant during the 
study or 30 days after study completion, the patient should notify the Investigator 
immediately, who will report the event to 
. The pregnancy will be 
followed until termination or birth of the baby.  
9.3.3 Laboratory Parameters 
Laboratory references from certified central laboratories will be used. All results of 
laboratory tests will be entered in the study database.  
The tests listed in Table 9.1 will be conducted on samples collected and analysed by 
standard laboratory procedures at the time points designated on the Schedule of 
Assessments (Table 1.1). Tests that are not done must be reported as such on the eCRFs. 
Table 9.1: 
Laboratory Parameters 
Haematology 
 
 
Complete blood count 
including Red blood cell 
(RBC) count 
Haemoglobin 
RBC indices and red cell 
diameter width (RDW) 
Haematocrit, 
White blood cell (WBC) total and 
differential count 
Platelet count 
Clinical Chemistry 
Serum sodium 
(bicarbonate) 
Creatinine 
Alanine aminotransferase 
(ALT) 
Aspartate aminotransferase 
(AST) 
Alkaline phosphatase 
 
Potassium 
Chloride 
Glucose (screening), Glucose; 
Record the time the patient last 
ate for all glucose levels 
Total protein, and Albumin 
Total bilirubin 
 
Carbon dioxide (CO2) 
Blood urea nitrogen (BUN) 
Calcium 
Magnesium 
Phosphate 
Uric Acid 
Urine 


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Table 9.1: 
Laboratory Parameters 
Dipstick with reflex urine microscopic examination may be done at the investigator’s discretion if the 
dipstick test is positive for blood, nitrites, protein, and/or leukocyte esterase.  
Pregnancy Testing (female 
patients only) 
Urine human chorionic gonadotropin (hCG)  
 
All laboratory reports will be reviewed and any values outside the normal range will be 
commented on by the Investigator or qualified designee. The reports will then be signed 
and dated. The laboratory reports will remain with the source documents and the 
Investigator’s comments will be recorded in the eCRF along with the date and time of the 
sample collection.  
9.3.4 Vital Signs 
Vital signs will be measured and recorded at the time points designated on the Schedule 
of Assessments (Table 1.1). All measurements will be recorded on the vital signs eCRF. 
Abnormal test results may be repeated at the discretion of the Investigator and must be 
reported on the corresponding eCRF. When vital signs and/or blood sample collection 
occur at the same time, vital signs should be performed before blood sample collection. 
9.3.5 Physical Examinations 
The Investigator or qualified designee will perform a complete physical examination 
(including nose and nasal passages) at the Randomisation Visit (Table 1.1). Pre-dose 
abnormal findings will be reported on the medical history eCRF. After that, brief, 
symptom-driven physical examinations (including nose and nasal passages) will be done. 
Any adverse change from the baseline physical examination at Randomisation Visit will 
be documented on the AE eCRF (except those occurring prior to first study medication 
application which will be reported in the medical history eCRF).  
A complete physical examination will include inspection of general appearance, skin, 
neck (including thyroid), eyes, ears, nose and nasal passages, throat, heart, lungs, 
abdomen, lymph nodes, extremities, musculoskeletal system, and nervous system.  
9.3.6 Assessment of Nose, Nasal Passages, and Sense of Smell  
9.3.6.1 Nasal Examination by ENT specialist 
Nose and nasal passage examinations will be conducted by an ear nose and throat  (ENT) 
specialist at the time points designated on the Schedule of Assessments (Table 1.1). 
The standard nasal examination will consist of evaluation of both nares and the nasal 
passages for mucosal erythema, oedema, and secretions. Note that the test article is a red, 
viscous gel, and as such, this should be considered during assessments. 
9.3.6.2 Brief Smell Identification Test™ 
In the study, patients are required to complete the B-SIT, also known as the University of 
Pennsylvania B-SIT at the time points designated on the Schedule of Assessments 
(Table 1.1). 


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The B-SIT is self-administered and consists of 1 enveloped-sized booklet containing 
12 “scratch and sniff” odorants. Each odorant strip has a multiple-choice question with 
4 alternative responses. The patient is required to mark one of the 4 alternatives even if 
no smell is perceived. These scores will be recorded in the eCRF. 
A percentile score is established which measures an individual’s olfactory diagnosis. 
Both patients scores will be reviewed by an Investigator. If the patient’s olfactory 
diagnosis at Follow-Up (Day 6) has significantly worsened, this will be recorded as an 
AE and relationship determined.  
 
 


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10 STUDY CONDUCT 
10.1 Observations by Visit 
10.1.1 Screening Visit (Day -14 to Day -1) 
Patients will be asked to sign a screening informed consent form (ICF) prior to 
undergoing nasal swabbing for rapid S. aureus testing. Patients will be given a full 
explanation of the nature of the study and the main study ICF will be provided. As the 
results from the standardized 
 rapid test will take a 
few hours, the patient will have time to become familiar with the main study ICF and 
compose questions if the swab result is positive for S. aureus.  
10.1.2 Randomization Visit (Day -10 to Day -1) 
If the patient is tested S. aureus positive, the following procedures are to be completed 
(Table 1.1): 
• Obtain consent for the main study. Patient’s informed consent to the study will be 
documented before any Randomization Visit study-specific assessments or 
procedures are performed. 
• Verify eligibility (inclusion/exclusion criteria) 
• Record demographic data including sex, age, race, and ethnicity 
• Record medical/surgical history (including any risk factors for S. aureus carriage) 
(Risk factors include: HIV infection, obesity, diabetes, granulomatosis with 
polyangiitis, rheumatoid arthritis, skin and soft tissue infections, recurrent 
furunculosis, atopic dermatitis, smoking, hormonal contraception use, hospital 
workers, haemoglobin in nasal secretions, histocompatibility antigen phenotype 
HLA-DR3, and polymorphisms in genes encoding for the glucocorticoid receptor, 
interleukin-4, C-reactive proteins and complement inhibitor proteins.) Any 
potential AEs related to the screening swab (in the investigator’s judgment) 
should be recorded as medical history.  
• Record previous (4 weeks prior) and current medications 
• Perform a complete physical examination  
• Examination of the nose and nasal passages by an ENT specialist 
• Measure and record vital signs (heart rate and supine blood pressure [BP]) 
• Draw blood for haematology and clinical chemistry  
• Collect urine sample for urinalysis and pregnancy test 
• Record SOC in skin decontamination and peri-operative prophylactic regimen 
• Record AEs 
• -B-SIT 


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• Randomization to study drug after eligibility is verified (may occur from Day - 7 
to Day -1 prior to dose 1) 
10.1.3 Treatment Period (Days -1 to Day 0) 
Patients who meet the entry criteria will undergo the following treatment visits and 
assessments at timepoints designated on the Schedule of Assessments (Table 1.1). All 
assessments should be completed prior to the dose of study drug. Treatment visits will 
normally occur in hospital, however if more convenient for the patient, home visits by 
qualified staff working to an agreed process will be allowed. 
 
It is normally expected that patients will continue as planned to their pre-determined 
surgery time and date after the initial pre-surgical doses of IMP in the previous 24 hours. 
However, in clinical practice surgery can be postponed at any point in the lead up to the 
planned surgery time and date for different reasons and would not be considered a 
protocol deviation. If surgery is delayed, then the following steps should be followed. 
• If the delay to the planned incision timepoint is less than or equal to 48 hours, the 
patient should continue with the remaining doses as per protocol to the new 
timeframe. The remaining IMP must be checked to be within its own 48hr expiry 
window or replaced with a new kit assigned by the IRT system.  
• If the delay to the planned incision timepoint is greater than 48 hours but the 
patient’s new surgery date and time is still within their screening window, then 
existing IMP should be replaced and a new kit assigned to the patient and full 
dosing regimen provided according to the protocol to the new timeframe. 
• If the delay to the planned incision timepoint is greater than 48 hours and the 
patient’s new surgery date and time is outside their screening window, then the 
patient should be withdrawn. If time permits, the patient can be re-screened using 
a new screening number. 
10.1.3.1 First dose visit (Day -1) 
• Verify eligibility (inclusion/exclusion criteria) 
• Randomization to study drug if not completed prior to Day -1 
• Record changes in medical history and concomitant medications from 
randomization visit. 
• Perform a brief symptom-driven physical examination or a complete medical 
examination if it was not performed at randomization visit. 
• Examination of the nose and nasal passages by the ENT specialist (only if not 
performed during randomization visit) before drug application. 
• Nasal swabbing for quantification of S. aureus within 1 hour prior to drug 
application 
• Record SOC in skin decontamination and peri-operative prophylactic regimen 


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• B-SIT before drug application if not performed during randomization visit. 
• Record AEs 
• Record concomitant medications. 
• First application of assigned study drug at 22h ±2h before surgery (estimated 
incision time) 
10.1.3.2 Second dose visit (Day -1) 
• Record SOC in skin decontamination and peri-operative prophylactic regimen 
• Second application of assigned study drug at 14h±2h before surgery (estimated 
incision time) 
• Record AEs  
• Record concomitant medications. 
10.1.3.3 Third dose visit (Day 0) 
• Nasal swabbing for quantification S. aureus within 1 hour prior to drug 
application 
• Record SOC in skin decontamination and peri-operative prophylactic regimen 
• Third application of assigned study drug at 6h±2h before surgery (estimated 
incision time) 
• Record AEs  
• Record concomitant medications. 
10.1.3.4 Fourth dose visit (Day 0)  
• Nasal swabbing for quantification of S. aureus within 1 hour prior to drug 
application 
• Record SOC in skin decontamination and peri-operative prophylactic regimen  
• Application of fourth dose of study medication within one hour before incision 
(e.g. in the operating room). 
• Record number of blood glucose records from time of admission to hospital for 
surgery and how many were over 200 mg/dL. 
• Record number of body temperature measurements from time of admission to 
hospital for surgery and how many were under 35.5o C. 
• Record AEs  
• Record concomitant medications 
10.1.3.5 Fifth dose visit (Day 0) 
• Measure and record vital signs (heart rate and supine BP) 


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• Nasal swabbing for quantification of S. aureus within 1 hour prior to drug 
application 
• Record SOC in skin decontamination and peri-operative prophylactic regimen 
• Application of fifth dose of study medication within 1 hour after closure of 
incision (e.g. in the operating room) 
• Record number of blood glucose records from visit dose 1 and how many were 
over 200 mg/dL. 
• Record number of body temperature measurements from visit dose 1 and how 
many were under 35.5o C.  
• Draw blood for haematology and clinical chemistry after study medication 
application 
• Collect urine sample for urinalysis after study medication application. 
• Record AEs  
• Record concomitant medication 
10.1.4 Follow-up Period  
10.1.4.1 Post-surgical visit (48h ± 24h post closure of surgical incisions) 
• Complete brief symptom-driven physical examination 
• Examination of the nose and nasal passages by the ENT specialist 
• Nasal swabbing for S. aureus 
• Record SOC in skin decontamination and peri-operative prophylactic regimen 
• Measure and record vital signs (heart rate and supine BP) 
• Draw blood for haematology and clinical chemistry 
• Collect urine sample for urinalysis 
• Record concomitant medications 
• Record AEs  
• Record staphylococcal infections and use of antibiotics from visit dose 5. 
10.1.4.2  Follow Up (Day 6 (± 24 hours) 
• Complete brief symptom-driven physical examination (including nose and nasal 
passages) 
• Nasal swabbing for S. aureus 
• Measure and record vital signs (heart rate and supine BP) 
• Draw blood for haematology and clinical chemistry 
• Collect urine for pregnancy test 


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• B-SIT 
• Record concomitant medications. 
• Record AEs 
• Record staphylococcal infections and use of antibiotics 
10.1.4.3 Follow-up (Day 30) 
• Record staphylococcal infections and use of antibiotics 
• Record suspected IP related SAEs, only 
• Record concomitant medications 
10.1.4.4 Follow-up Day 90 (Only if object implant in surgery) 
• Record staphylococcal infections and use of antibiotics 
• Record suspected IP related SAEs, only 
• Record concomitant medications 


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11 STATISTICAL METHODS 
11.1 Disposition of Patients 
The numbers and percentages of patients enrolled, randomized, treated, discontinued with 
associated reasons and completed in the Safety, Intent-to-treat (ITT) and Per-protocol 
(PP) will be tabulated for each treatment group.  
The reasons for patient exclusions from each of the populations of interest will be listed. 
11.2 Protocol Deviations 
Major protocol deviations are compliance issues that have an impact on patient safety or 
the scientific integrity of the study data. All deviations will be evaluated and classified as 
major or minor before database lock and unblinding.  
11.3 Analysis Populations 
11.3.1 All Enrolled Patients  
All enrolled patients include all patients that completed main study informed consent 
(i.e., has a non-missing informed consent date).  
11.3.2 Safety Population 
The Safety Population will consist of all patients who received at least 1 dose of study 
drug. Patients will be presented in the actual treatment group that they received. The 
primary population for the safety analyses will be the Safety population. 
11.3.3 Intent-To-Treat Population 
The ITT Population will consist of all patients who were randomized. 
11.3.4 Modified Intent-To-Treat Population 
The modified ITT Population will consist of all patients who were randomized, received 
at least 1 dose of study drug and have at least 1 post-baseline assessment of S. aureus 
log10 CFU/mL. Patients will be presented in the treatment group that they were randomly 
assigned. 
11.3.5 Microbiological Intent-To-Treat Population 
The microbiological Intent-To-Treat (micro ITT) set will consist of all patients in the 
mITT set who have a log CFU/mL result at baseline greater than 0, i.e. all patients in the 
mITT set with a quantifiable baseline microbiological result. The primary population for 
the efficacy analyses will be the Micro ITT. 
 
 


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11.3.6 Per-protocol Population 
The PP Population will consist of all patients in the micro ITT population without major 
protocol deviations. Supportive efficacy analyses will also be performed on the PP 
population for key endpoints and at key time points, as specified in Section 5. 
11.4 General Considerations 
A Statistical Analysis Plan (SAP) describing the planned final analysis up to Day 6 and 
separately for the 30-day and 90-day follow-up periods and including detail with tables, 
figures and listings templates will be developed as a separate document. 
• Continuous variables will be summarised using the number of patients with 
evaluable data, mean, standard deviation (SD), median, minimum and maximum. 
• Categorical variables will be summarised using the number of observations (n), 
frequency and percentage of patients. All percentages will be presented as one-
decimal point, unless otherwise specified. Percentages equal to 100 will be 
presented as 100% and percentages will not be presented for zero frequencies. 
11.5 Demographics, Baseline Characteristics and Concomitant Medications 
Demographic and baseline characteristic data will be summarised and listed by treatment 
groups by means of descriptive statistics. Further details will be provided in the SAP. 
Concomitant medications will be coded by using the World Health Organisation (WHO) 
Drug Dictionary and will be summarised by treatment group with the number and 
percentage of patients receiving concomitant medication by drug class and preferred drug 
name. A listing of all medications will be produced indicating whether the medication 
was taken prior to, during and/or after treatment. 
11.6 Treatment Compliance 
Treatment exposure will be summarised and listed by treatment group by means of 
descriptive statistics for categorical data (counts and percentages). The number of doses 
taken (range 1 to 5) will be reported for the Safety Population. 
11.7 Efficacy Analyses 
Primary analysis will be on the endpoint of change in log10 CFU from baseline to pre-
surgery using an analysis of covariance (ANCOVA) model including baseline CFU as a 
covariate. A similar analysis will also be performed for the endpoint of change from 
baseline to the post-surgery measurement.  
Secondary efficacy analyses will include; 
• Change in log10 CFU from baseline to post-surgery using an ANCOVA model 
including baseline CFU as a covariate. 
• A log10 AUC for CFUs will also be undertaken utilising data for all time 
points up until the pre-surgery assessment. This analysis of log10 AUC CFUs 
will also including baseline log10 CFU as a covariate. 


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• A log10 AUC for CFUs will also be undertaken utilising data for all time 
points up until the post-surgery assessment. This analysis of log10 AUC CFUs 
will also including baseline log10 CFU as a covariate. 
• Percentage of patients reaching a specific reduction in S. aureus carriage prior 
to surgery, immediately post-surgery and on Day 6 ± 24hrs 
• Proportion of patients with nasal carriage below a set value (value to be 
determined [TBD]) 
• Summary of data for nasal carriage according to SQS along with an analysis 
of proportional odds. 
• Summary of the proportion of patients with a 2-log drop (TBD)  
In addition to the planned analysis in the PP population which requires patients to receive 
4 doses of pre-surgery treatment, and additional sensitivity analysis will be performed 
which will include all patients who receive 3 doses of pre-surgery treatment. 
Analysis of post-operative infections and antibiotic use at Day30 and Day 90 will be 
performed separately to the main analysis period of randomisation Day 0 to follow-up at 
Day 6 and can be reported separately. 
11.8 Safety Analyses 
Safety will be determined by AEs, clinical laboratory parameters, physical examination, 
vital signs, microbiological specimen collection and nasal examination. 
All available data from patients in the Safety Population will be included in the 
assessment of safety and tolerability. All safety and tolerability data will be listed and 
summarised by treatment group using appropriate descriptive statistics. Formal statistical 
comparisons between the different treatment groups will not be conducted. 
All AEs will be coded using the MedDRA terminology. 
Further details will be provided in the SAP. 
11.9 Interim Analyses 
An interim analysis will be performed, depending on recruitment projections, when 
approximately 60% evaluable subjects have been recruited. The aims of this interim 
analysis are to: 
• Review the Safety data generated to date. 
• Review the incidence of post-operative staphylococcal infections. 
• Stop the study in case of serious concerns on subject’s safety 
• Stop the study due to the incidence of post-operative staphylococcal infections. 
The interim analyses will be performed by an independent statistician and will be 
performed using similar methodology to that for the main analysis. This approach will be 
described in further detail in the IDMC SAP.    
All study staff including the Sponsor will remain blinded until the end of the study.  


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Full details of these analyses and the role of the IDMC will be provided in the new 
version of the IDMC charter implementing the changes introduced in this version 2.1 of 
the protocol. 
11.10 Determination of Sample Size 
Individual CFU data is presented in the study of Verhoeven 201227 in the absence of 
treatment. As the primary population for the efficacy analysis is the micro-ITT, those 
values with zero CFU have been excluded and the resulting data have been converted to 
the log10 CFU scale. The SD of these values has been used as the estimate of variability 
for an analysis of change from baseline whilst including baseline log10 CFU as a 
covariate. As a result, a trial including 80 evaluable patients (40 per arm) would have a 
greater than 90% power to detect a true treatment effect of a 2 log10 CFU difference and 
an 90% power to detect a true treatment effect of a 1.5 log10 CFU difference between XF-
73 and placebo, assuming 2-sided alpha=0.05, a between patient SD of 2 log10 CFUs 
taken from the Verhoeven study.  
We estimate that approximately 125 patients will need to be recruited in order to have 
around 80 patients with a burden S. aureus nasal carriage which will allow for the 
detection of an effect of XF-73 nasal gel. 


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12 DATA MANAGEMENT 
12.1 Data Collection 
The trained Investigator site staff will enter the data required by the protocol into the 
eCRFs from source documents (e.g., medical records and study-specific data capture 
tools as needed) directly into the study database on a central server. All information in the 
eCRFs must be traceable to these source documents. Data recorded directly into the 
eCRFs will be defined before study start and the eCRFs will be considered the source 
data. Clinical Research Associates and a Data Manager will review eCRFs entered by 
investigational staff for completeness and accuracy. Automatic quality programs check 
for data discrepancies in the eCRFs and the resulting queries will be notified to the 
investigational site using an electronic data query process within the electronic data 
capture (EDC) system. Designated Investigator site staff are required to respond to 
queries and make any necessary changes to the data. Details of the data correction 
process will be specified in the Data Management Plan.  
A validated, electronic database will be employed from the EDC system. An audit trail of 
all changes to this database, including the date, reason for the data change and who made 
the change, will be maintained within the same database. The audit trail will be part of 
the archived data at the end of the study. 
The complete data management process (data capture, data entry, data validation, checks 
on plausibility, query handling, data editing after entry, coding, data base closure, etc.) 
will be defined in advance within a data handling plan/ data management plan together 
with a description of the personnel responsible for data entry. 
12.2 Data Correction 
Automatic and manual queries will be defined according to the data validation plan. 
These queries will be generated by the Destiny’s data management provider 
 
 and sent through the EDC system for clarification. Corrections will be entered 
directly into the system. This procedure will be repeated until all queries are resolved. All 
query forms will be linked to the eCRF in the EDC system. 
12.3 Data Handling 
The final data will be transferred to the SAS-system for data analyses in accordance with 
the SAP. The MedDRA dictionary will be used for coding of AEs and concomitant 
diseases. Concomitant medication will be coded using the WHO Drug Dictionary 
A(natomical) T (herapeutical C(hemical) code. 
12.3.1 Deviations from the Protocol 
Deviations from the protocol will be judged during the study and/or when an individual 
patient’s eCRF is completed (monitored).  
Before unblinding the data, a blinded data review meeting (BDRM) will take place where 
protocol deviations will be classified (major/minor protocol deviations) for statistical 
analysis. 


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12.4 Data Quality Assurance 
Destiny Pharma will conduct a site visit to verify the qualifications of each Investigator, 
inspect the site facilities, and inform the Investigator of responsibilities and the 
procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded on the eCRFs for this study must be consistent with 
the patients’ source documentation (i.e., medical records). 


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13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 Study Initiation Activities 
The Investigator(s) are informed about study objectives and methods, the inclusion and 
exclusion criteria, the time-schedule, and study procedures at a Pre-Study Visit by the 
monitor (if necessary), an Investigators’ meeting, and during the Site Initiation Visit by 
the monitor. 
13.2 Training of Site Staff 
The Investigator will ensure that everyone assisting with the clinical study is adequately 
informed about the protocol, the investigational product(s), and their study-related duties 
and functions. Furthermore, the Investigator will maintain a list of qualified persons to 
whom the Investigator has delegated study-related duties. 
13.3 Documentation and Filing 
13.3.1 eCRF System 
All data recorded according to this study protocol must be documented in an eCRF. The 
Investigator and persons authorized by the Investigator will be instructed about how to 
complete the eCRF. Entries in the eCRF must only be made by the Investigator or 
persons authorized by the Investigator. A list of all persons who are allowed to make 
entries in the eCRF must be available in each study site. 
The Investigator must verify that all data entries in the eCRF are accurate and correct. 
Entries will be checked against appropriate source documentation by the monitor. 
13.3.2 List of Patients (patient identification log) 
The Investigator will keep a confidential list of names of all patients participating in the 
study, so that the patients' records can be identified if necessary.  
In addition, the Investigator will keep a list of all patients screened on a screening log to 
document identification of patients who entered pre-study screening. If someone is not 
eligible to participate in the study, a reason must be provided. 
13.3.3 Source Data 
Per ICH, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
study necessary for the reconstruction and evaluation of the study. Source data are 
contained in source documents which comprise clinical documentation, data, and records 
(e.g., hospital records, clinical and office charts, laboratory notes, memoranda, patients' 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, 
x-rays, patient files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical study). 


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13.3.4 Investigator Site File / Regulatory Binder 
Before site initiation 
 will provide an ISF/ Regulatory Binder to each site. 
The ISF will include essential documents as defined by the ICH GCP guideline and 
applicable local requirements. 
The Investigator will be responsible for the update and maintenance of the ISF, which 
will be reviewed periodically by the monitor(s). These documents will be reviewed 
during an audit by the Sponsor or an inspection by the Regulatory Authorities. 
All study-related documents are to be archived and stored according to legal 
requirements. 
Prior to destruction of study-related documents, the Investigator will contact the Sponsor 
for approval and conformation. 
13.4 Monitoring 
The CRA is responsible for checking the quality of data and ensuring that the 
investigative site is adhering to the study protocol. Additionally, the CRA ensures that the 
site is following the legal and ethical requirements as stated in local laws and the 
principles of GCP. 
The interval between monitoring visits will depend on the recruitment rate and the 
complexity of the study. 
Source data verification is an essential part of the monitoring process and the Investigator 
must grant direct access to the patient’s source data. 
The extent and nature of monitoring will be described in detail in the monitoring plan. 
13.5 Audits and Inspections 
Audits will be performed according to the corresponding audit program. The Sponsor’s 
Quality Assurance Department may visit the investigative site to audit the performance of 
the study, as well as all study documents. Audits may also be performed by contract 
auditors who will be instructed about the timing and extent of the audits. In the event of 
an audit at the investigational site, the monitor will usually accompany the auditor(s).  
Inspections by Regulatory Authority representatives and IECs/IRBs are possible at any 
time, even after the end of study. The Investigator is to notify the Sponsor immediately of 
any such inspection. The Investigator and institution will permit study-related 
monitoring, audits, reviews by the IEC/IRB and/or Regulatory Authorities and will allow 
direct access to source data and source documents for monitoring, audits, and inspections. 


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14 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
14.1 Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the GCP guidelines of the ICH, and of the current 
version of the Declaration of Helsinki (Brazil 2013). The study also will be carried out in 
keeping with local legal requirements.  
14.2 Informed Consent 
Before each patient is admitted to the study, a pre-screening nasal swab informed consent 
will be obtained from the patient (or his/her legally authorized representative) according 
to the regulatory and legal requirements of the participating country (i.e., the Declaration 
of Helsinki, ICH GCP, US Code of Federal Regulations for Protection of Human Patients 
(21 Code Federal Regulation [CFR] 50.25 (a) and (b), CFR 50.27, and CFR Part 56, 
Subpart A), and other applicable local regulations). If the patient is S. aureus positive, 
he/she will be asked to sign the main ICF. This consent form must be dated and retained 
by the Investigator as part of the study records. The Investigator will not undertake any 
investigation specifically required only for the clinical study until valid consent has been 
obtained. The terms of the consent and when it was obtained must also be documented in 
the eCRF. 
If a protocol amendment is required, the ICF may need to be revised to reflect the 
changes to the protocol. If the consent form is revised, it must be reviewed and approved 
by the appropriate IEC/IRB and signed by all patients subsequently enrolled in the study 
as well as those currently enrolled in the study. 
14.3 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local legal 
requirements. The Sponsor must ensure that all ethical and legal requirements have been 
met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be 
written, receive approval from the appropriate personnel, and receive 
IRB/IEC/Competent Authority approval prior to implementation (if appropriate).  
Administrative changes (not affecting the patient benefit/risk ratio) may be made without 
the need for a formal amendment. All amendments will be distributed to all protocol 
recipients, with appropriate instructions. 
14.4 Archiving Study Records 
According to ICH guidelines, essential documents should be retained for a minimum of 
2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. However, these documents should be retained for a longer period 
if required by the applicable legal requirements. 


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14.5 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or 
events that suggest a possible hazard to patients if the study continues, the study may be 
terminated after appropriate consultation between the relevant parties. The study may 
also be terminated early at the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study; 
• Failure to enrol patients at an acceptable rate; 
• A decision on the part of the Sponsor to suspend or discontinue development of the 
drug. 
14.6 Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior 
written approval from the Sponsor. 
The anonymity of participating patients must be maintained. Patients will be identified on 
eCRFs and other documents submitted to 
 by their patient number, initials 
and/or birth date, not by name. Documents not to be submitted to Pharm-Olam that 
identify the patient (e.g., the signed ICF) must be maintained in confidence by the 
Investigator.  
14.7 Future Use of Stored Specimens 
In order to appropriately assess the incidence of post-operative staphylococcal infections 
investigators will take all reasonable efforts to obtain microbiological documentation and 
a bacterial isolate when the suspicion of a staphylococcal post-operative infection is 
raised. This includes but is not limited to the collection and culture of exudates, blood, 
implant or other specimens according to the suspected site of infection.  
The Sponsor is planning to store these samples as well as those bacterial isolates obtained 
from the nasal swabs after the completion of the study for up to 10 years for further 
analysis and characterization. The details of these tests are not known at this time. No 
subject identifying information will be retained for these samples. The Informed Consent 
Form explains the storage and future use of specimens and subjects will be asked to 
consent for future testing of samples. 
14.8 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance 
with all local legal requirements. The civil liability of the Investigator, the persons 
instructed by him and the hospital, practice or institute in which they are employed and 
the liability of the Sponsor with respect to financial loss due to personal injury and other 
damage that may arise as a result of the carrying out of this study are governed by the 
applicable law. 


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The Sponsor will arrange for patients participating in this study to be insured against 
financial loss due to personal injury caused by the pharmaceutical products being tested 
or by medical steps taken in the course of the study. 
14.9 Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study 
for the purposes of national and international registration, publication and information for 
medical and pharmaceutical professionals. If necessary, the authorities will be notified of 
the Investigator's name, address, qualifications and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the Sponsor in advance. 


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15 REFERENCE LIST 
1. 
Ooi N, Miller K, Hobbs J, Rhys-Williams W, Love W, Chopra I. XF-73, a novel 
antistaphylococcal membrane-active agent with rapid bactericidal activity. The 
Journal of antimicrobial chemotherapy 2009;64:735-40. 
2. 
Farrell DJ, Robbins M, Rhys-Williams W, Love WG. In vitro activity of XF-73, a 
novel antibacterial agent, against antibiotic-sensitive and -resistant Gram-positive 
and Gram-negative bacterial species. International journal of antimicrobial 
agents 2010;35:531-6. 
3. 
Farrell DJ, Robbins M, Rhys-Williams W, Love WG. Investigation of the 
potential for mutational resistance to XF-73, retapamulin, mupirocin, fusidic acid, 
daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus 
isolates during a 55-passage study. Antimicrobial agents and chemotherapy 
2011;55:1177-81. 
4.  
Holtfreter S, Grumann D, Balau V, et al. Molecular Epidemiology of 
Staphylococcus aureus in the General Population in Northeast Germany: Results 
of the Study of Health in Pomerania (SHIP-TREND-0). Journal of clinical 
microbiology 2016; 54:2774-85. 
5.  
Kim DH, Spencer M, Davidson SM, et al. Institutional pre-screening for detection 
and eradication of methicillin-resistant Staphylococcus aureus in patients 
undergoing elective orthopaedic surgery. The Journal of bone and joint surgery 
American volume 2010; 92:1820-6. 
6.  
Mendy A, Vieira ER, Albatineh AN, Gasana J. Staphylococcus aureus 
Colonization and Long-Term Risk for Death, United States. Emerging infectious 
diseases 2016; 22:1966-9. 
7.  
Sporer SM, Rogers T, Abella L. Methicillin-Resistant and Methicillin-Sensitive 
Staphylococcus aureus Screening and Decolonization to Reduce Surgical Site 
Infection in Elective Total Joint Arthroplasty. The Journal of arthroplasty 2016; 
31:144-7. 
8.  
Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG, Jr. Staphylococcus 
aureus infections: epidemiology, pathophysiology, clinical manifestations, and 
management. Clinical microbiology reviews 2015; 28:603-61. 
9.  
Bertrand X, Slekovec C, Talon D. Use of mupirocin-chlorhexidine treatment to 
prevent Staphylococcus aureus surgical-site infections. Future microbiology 
2010; 5:701-3. 
10.  
von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a 
source of Staphylococcus aureus bacteremia. Study Group. The New England 
journal of medicine 2001; 344:11-6. 
11.  
Wertheim HF, Melles DC, Vos MC, et al. The role of nasal carriage in 
Staphylococcus aureus infections. The Lancet Infectious diseases 2005; 5:751-62. 
12.  
Williams RE. Healthy carriage of Staphylococcus aureus: its prevalence and 
importance. Bacteriological reviews 1963;27:56-71. 


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13.  
Sollid JU, Furberg AS, Hanssen AM, Johannessen M. Staphylococcus aureus: 
determinants of human carriage. Infection, genetics and evolution: journal of 
molecular epidemiology and evolutionary genetics in infectious diseases 
2014;21:531-41. 
14.  
VandenBergh MF, Yzerman EP, van Belkum A, Boelens HA, Sijmons M, 
Verbrugh HA. Follow-up of Staphylococcus aureus nasal carriage after 8 years: 
redefining the persistent carrier state. Journal of clinical microbiology 1999; 
37:3133-40. 
15.  
Kluytmans JA, Wertheim HF. Nasal carriage of Staphylococcus aureus and 
prevention of nosocomial infections. Infection 2005; 33:3-8. 
16.  
Perl TM, Golub JE. New approaches to reduce Staphylococcus aureus nosocomial 
infection rates: treating S. aureus nasal carriage. The Annals of pharmacotherapy 
1998; 32: S7-16. 
17.  
Wenzel RP, Perl TM. The significance of nasal carriage of Staphylococcus aureus 
and the incidence of postoperative wound infection. The Journal of hospital 
infection 1995; 31:13-24. 
18.  
Wertheim HF, Vos MC, Ott A, et al. Risk and outcome of nosocomial 
Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet 
(London, England) 2004; 364:703-5. 
19.  
Suaya JA, Mera RM, Cassidy A, O'Hara P, Amrine-Madsen H, Burstin S, Miller 
LG. Incidence and cost of hospitalizations associated with Staphylococcus aureus 
skin and soft tissue infections in the United States from 2001 through 2009. BMC 
infectious diseases 2014; 14:296. 
20.  
Bode LG, Kluytmans JA, Wertheim HF, et al. Preventing surgical-site infections 
in nasal carriers of Staphylococcus aureus. The New England journal of medicine 
2010; 362:9-17. 
21.  
Hebert C, Robicsek A. Decolonization therapy in infection control. Current 
opinion in infectious diseases 2010; 23:340-5. 
22.  
Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of 
health care-associated infections. The New England journal of medicine 2014;3 
70:1198-208. 
23.  
Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Kallen AJ, Edwards JR, 
Sievert DM. Antimicrobial-Resistant Pathogens Associated With Healthcare-
Associated Infections: Summary of Data Reported to the National Healthcare 
Safety Network at the Centers for Disease Control and Prevention, 2011-2014. 
Infection control and hospital epidemiology 2016; 37:1288-301. 
24.  
ECDC. Annual Epidemiological Report for 2014 - Antimicrobial Resistance 
(EARS-Net), 2018. 
25.  
Calfee DP, Salgado CD, Milstone AM, et al. Strategies to prevent methicillin-
resistant Staphylococcus aureus transmission and infection in acute care hospitals: 
2014 update. Infection control and hospital epidemiology 2014; 
35 Suppl 2:S108-32. 


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26.  
Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for 
antimicrobial prophylaxis in surgery. American journal of health-system 
pharmacy: AJHP: official. 
27. 
Verhoeven PO, Grattard F, Carricajo A, Lucht F, Cazorla C, Garraud O, Pozzetto 
B, Berthelot P. An algorithm based on one or two nasal samples is accurate to 
identify persistent nasal carriers of Staphylococcus aureus. Clin Microbiol Infect. 
2012 Jun;18(6):551-7. doi: 10.1111/j.1469-0691.2011.03611.x. 
 


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16 APPENDICES 
16.1 List of Organizations Involved in the Study 
Sponsor 
Destiny Pharma plc 
Sussex Innovation Centre 
Science Park Square,  
Falmer 
Brighton, BN1 9SB 
UK 
Chief Medical Monitor 
 
Contract Research 
Organization 
 
 
  
 
 
Safety Reporting 
 
 
 
 
 
 
 
 
 
  
Data Management, Statistics 
and Medical Writing 
 
 
 
 
 
 
 
Central Laboratory 
 
Blood samples, Nasal Swabs and Bacterial Isolate 
storage: 
 
 
 
 
 
 
 
 


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Nasal Swabs, post-operative infection sample 
processing and bacterial isolate storage: 
 
 
 
 
 
  
 
IP Supply & IRT 
 
  
  
  
  
 
Regulatory Unblinding 
Service 
  
  
  
 
  
 

SAP_001.pdf: 
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A Phase 2 Study to Assess the Effect of a Repeated Dose 
of Exeporfinium Chloride (XF-73) Nasal Gel on the 
Microbiological Burden of Commensal Staphylococcus 
aureus Nasal Carriage in Surgical Patients at Risk of 
Post-Operative Staphylococcal Infections 
Destiny Pharma Study No: XF-73B07 
 Study No:  DMA18003 
Statistical Analysis Plan 
Version: 3.0 
Date: 8th February 2021 
For 
– Lead Statistician
For Destiny Pharma plc 
NCT03915470


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Modification History 
 
Version Change History 
Reason 
Date 
1.0 
First Version 
N/A 
16SEP2019 
2.0 
• 
Section 3: Updated sample size 
section following protocol amendment. 
• 
Section 5: Removed text relating to 
interim analysis of efficacy data – only 
safety data was considered per 
Protocol Amendment 2.1 (dated 
04JUN2020). 
• 
Section 6.4: Removed modified ITT 
from list of analysis sets (and 
throughout SAP) – no longer required 
for the analysis. 
• 
Section 6.4: Added microbiological 
ITT as the primary population for the 
efficacy analyses per Protocol 
Amendment 2.1 (dated 04JUN2020). 
• 
Section 6.11.1: Added details of new 
table – change from baseline by 
baseline CFU category and new plot - 
change in S. aureus log CFU/mL from 
baseline versus observed baseline S. 
aureus log CFU/mL scatterplot. 
• 
Minor clarifications to SAP text 
throughout. 
All updates resulting from 
the changes in Protocol 
V2.1 (dated 04JUN20) 
17SEP2020 


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3.0 
• 
Section 6: New section for Follow-Up 
Review and re-numbered subsequent 
sections accordingly. 
• 
Section 7.3: updated to specify that 
study day will be calculated relevant 
to Day -1. 
• 
Section 7.4: added details to clarify 
process for reviewing protocol 
deviations leading to exclusion from 
the PPS. 
• 
Added MedDRA version that will be 
used to the relevant sections (v23.1) 
• 
Section 7.8.3: Added summary of 
number of patients receiving peri-
operative prophylaxis interventions by 
the time at which they were recorded. 
• 
Sections 7.11.2.1 and 7.11.2.2: Added 
details of how missing data will be 
handled in the calculation of AUC. 
• 
Section 7.11.2.4: Added details of 2 
new summary tables to support the 
figures for patients reaching a specific 
reduction in S. aureus carriage. 
• 
Section 7.11.2.6: Changed from Semi-
quantitative scale to semi-quantitative 
categorization. 
• 
Section 7.11.3.1: Added that duration 
of post-operative staphylococcal 
antibiotics will be summarized. 
• 
Section 7.11.3.1: Added new plot of 
the individual patient data for S. 
aureus log10 CFU/mL over time. 
• 
Section 7.14: Text added to clarify 
how major protocol deviations leading 
to exclusion from the PPS are 
handled compared to the definition of 
major protocol deviations in the study 
protocol. 
• 
Other minor clarifications to SAP text. 
All updates to provide 
clarification on current 
analyses or to provide 
additional supportive 
summaries. 
05FEB2021 
 
 


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Contents 
 
1 
INTRODUCTION ............................................................................................................................. 6 
2 
STUDY OBJECTIVES AND DESIGN ............................................................................................. 6 
2.1 
Study Objectives ......................................................................................................................... 6 
2.2 
Study Endpoints .......................................................................................................................... 7 
2.3 
Study Design ............................................................................................................................... 7 
2.4 
Visit Structure .............................................................................................................................. 8 
3 
Sample Size .................................................................................................................................... 8 
4 
Randomisation ................................................................................................................................ 9 
5 
IDMC Safety review ........................................................................................................................ 9 
6 
Follow-Up Review ........................................................................................................................... 9 
7 
Analysis Plan ................................................................................................................................. 10 
7.1 
General ..................................................................................................................................... 10 
7.2 
Blinded Data Review Meeting ................................................................................................... 10 
7.3 
General Derivations .................................................................................................................. 10 
7.4 
Analysis Sets ............................................................................................................................ 11 
7.5 
Data presentations .................................................................................................................... 12 
7.6 
Disposition of patients ............................................................................................................... 13 
7.7 
Protocol Deviations ................................................................................................................... 13 
7.8 
Background and Demographic Characteristics ........................................................................ 13 
7.8.1 
Demography .......................................................................................................................... 13 
7.8.2 
Medical History ...................................................................................................................... 14 
7.8.3 
Surgery .................................................................................................................................. 14 
7.9 
Prior, Concomitant and Follow-up Period Medications............................................................. 14 
7.10 
Administration of Study Drug and Exposure ............................................................................. 15 
7.11 
EFFICACY EVALUATION ........................................................................................................ 15 
7.11.1 
Primary Endpoint ................................................................................................................... 16 
7.11.2 
Secondary Endpoints ............................................................................................................. 17 
7.11.3 
Exploratory Endpoints ............................................................................................................ 20 
7.12 
Multiplicity ................................................................................................................................. 20 
7.13 
SAFETY EVALUATION ............................................................................................................ 21 
7.13.1 
Adverse Events ...................................................................................................................... 21 
7.13.2 
Clinical Laboratory Evaluation ............................................................................................... 22 
7.13.3 
Vital Signs .............................................................................................................................. 23 
7.13.4 
Physical Examination ............................................................................................................. 23 
7.13.5 
Pregnancy Test ...................................................................................................................... 23 
7.13.6 
Nasal Examination ................................................................................................................. 23 
7.13.7 
Brief Smell Identification TestTM (B-SIT) ................................................................................ 23 
7.14 
Changes from the Protocol Planned Analysis .......................................................................... 24 
7.15 
References ................................................................................................................................ 24 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AIC 
Akaike Information Criterion 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Curve 
BDRM 
Blinded Data Review Meeting 
BMI 
Body Mass Index 
B-SIT 
Brief Smell Identification Test 
CFU 
Colony Forming Units 
CI 
Confidence Interval 
CRF 
Case Report Form 
ENR 
Enrolled Set 
ENT 
Ear, Nose and Throat 
IDMC 
Independent Data Monitoring Committee 
ITT 
Intent-to-treat   
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model for Repeated Measures 
PPS 
Per Protocol Set 
PT 
Preferred Term 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SQS 
Semi-Quantitative Scale 
S. aureus  
Staphylococcus aureus 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
WHO Drug World Health Organization Drug Dictionary 
XF-73 
Exeporfinium Chloride 
 
 


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1 INTRODUCTION 
This document details the statistical analysis of the data that will be performed for the 
Destiny Pharma study: A Phase 2 Study to Assess the Effect of a Repeated Dose of 
Exeporfinium Chloride (XF-73) Nasal Gel on the Microbiological Burden of 
Commensal Staphylococcus aureus Nasal Carriage in Surgical Patients at Risk of 
Post-Operative Staphylococcal Infections. 
The proposed analysis is based on the contents of the Final Version (Version 2.1) of 
the protocol (dated 04 June 2020). In the event of future amendments to the protocol, 
this statistical analysis plan (SAP) may be modified to account for changes relevant to 
the statistical analysis.  
The table, listing and figure (TLF) shells are supplied in a separate document. 
2 STUDY OBJECTIVES AND DESIGN 
2.1 Study Objectives 
The primary objective of the study is to demonstrate the efficacy of a 0.2% XF-73 nasal 
gel in reducing the microbiological burden of nasal Staphylococcus aureus (S. aureus) 
measured as change in colony forming units (CFU) per mL from baseline to 
immediately prior to surgery in a patient population at risk of post-operative 
staphylococcal infection. 
The secondary objectives of the study are to: 
• Determine the effect of a 0.2% XF-73 nasal gel on S. aureus nasal burden from 
baseline to pre-surgery and from baseline to immediately post-surgery 
measured as area under the curve (AUC) of S. aureus log CFUs/mL over time. 
• Determine the efficacy of a 0.2% XF-73 nasal gel in their effect on S. aureus 
nasal burden measured as CFUs/mL in follow-up immediately after surgery, at 
approximately 48 hours after surgery and 7 days after surgery. 
• Explore the efficacy of XF-73 in reducing the burden of S. aureus carriage at 
the patient level. 
• Assess the effect of XF-73 on S. aureus nasal carriage in the prevention of 
postoperative staphylococcal infections (surgical site infections, blood stream 
infections and others) during the 30 days post-surgery (90 days in the case of 
a foreign implant). 
• Describe the safety and tolerability of multiple administrations of a 0.2% XF-73 
nasal gel in a population of surgical patients at risk of post-operative 
staphylococcal infections. 
The exploratory objective of the study is to describe the use of post-operative 
anti-staphylococcal antibiotics, except those provided for prophylaxis as local standard 
of care, during the 30-day post-surgery period (90 days in the case of an object 
implant) reported separately. 


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2.2 Study Endpoints 
The primary endpoint of the study is the change in S. aureus log CFU/mL from baseline 
to pre-surgery.  
The secondary endpoints are: 
• Difference in AUC of S. aureus log CFU/mL from baseline to pre-surgery. 
• Difference in AUC of S. aureus log CFU/mL from baseline to immediately 
post-surgery. 
• Change in S. aureus log CFU/mL from baseline to immediately after surgery. 
• Change in S. aureus log CFU/mL from baseline to 48 hours after surgery. 
• Change in S. aureus log CFU/mL from baseline to 7 days after surgery. 
• Percentage of patients reaching a specific reduction in S. aureus carriage prior 
to surgery, immediately post-surgery and on Day 6 ± 24hrs. 
• Difference in the incidence of S. aureus post-operative infections during the 
30-day period after surgery (90 days in the case of foreign implant). 
• Incidence of Treatment Emergent Adverse Events (TEAEs) from the first dose 
of study medication to 7 days post last application of study medication. 
• Changes in vital signs, safety clinical laboratory assessments, nasal 
examination and smell identification test. 
The 
exploratory 
endpoint 
is 
the 
reason 
for 
post-operative 
prescribed 
anti-staphylococcal antibiotic use during the 30-day post-operative period (90 days in 
the case of an object implant).  
2.3 Study Design  
This is a Phase 2, multi-center, randomized, double-blind, parallel, placebo-controlled 
study of multiple applications of a single concentration of XF-73 nasal gel to assess 
the microbiological effect of XF-73 on commensal S. aureus nasal carriage in patients 
scheduled for surgical procedures deemed to be at high risk of post-operative 
S. aureus infection.  
The study is divided in 4 periods: screening (Days -14 to -3), randomization (Days -10 
to -1), treatment (Days -1 and 0) and follow-up (Day 1 to Day 30 or Day 90 if an implant 
is inserted during surgery). Day 0 is the calendar day in which surgery takes place. 
Only patients who test positive to S. aureus by a centrally performed rapid diagnostic 
test will be enrolled in the study.  The maximum study duration will be 45 or 105 days 
for each individual (from screening to post-study follow-up visit) depending on whether 
a foreign implant was inserted during surgery. 
Approximately 125 patients will be randomized in a double-blind manner (the 
investigators and patients are blind to the treatment assignment) in a 1:1 ratio to 0.2% 
w/w XF-73 nasal gel treatment OR placebo to match XF-73 nasal gel. Patients are 
planned to be recruited from approximately 10 sites in the USA, 10 sites in Georgia 
and 4 sites in Serbia. The randomization scheme will be stratified by site. 
The study drug, 0.2% w/w XF-73 nasal gel, or matched placebo will be administered 
4 times into each nostril over 24 hours prior to surgery and then a single application 


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immediately upon closure of surgical wound. Additionally, patients may undergo 
chlorhexidine skin decolonization ahead of surgery and receive perioperative 
prophylactic systemic antibiotics in accordance with local practice. 
Seven nasal swabs will be collected: one at screening, three pre-surgery (between 
24 hours and 1 hour prior to surgery) and three post-surgery (immediately after 
incision closure, 48 hours after surgery and 7 days after surgery). 
2.4 Visit Structure 
The visit structure and scheduled assessments are detailed Section 10, and Table 1.1 
of the protocol.  A diagrammatic explanation of the swab and treatment times can be 
found in Figure 6.1 of the protocol and is included below. 
 
 
3 SAMPLE SIZE 
Individual CFU data is presented in the study of Verhoeven 20121 in the absence of 
treatment. As the primary population for the efficacy analysis is the microbiological 
Intent-to-Treat (micro-ITT) set, those values with zero CFU have been excluded and 
the resulting data have been converted to the log10 CFU scale. The standard deviation 
(SD) of these values has been used as the estimate of variability for an analysis of 
change from baseline whilst including baseline log10 CFU as a covariate. As a result, 
a trial including 80 evaluable patients (40 per arm) would have a greater than 90% 
power to detect a true treatment effect of a 2 log10 CFU and an 90% power to detect 
a true treatment effect of a 1.5 log10 CFU difference between XF-73 and placebo, 
assuming 2-sided alpha=0.05 and a between patient SD of 2 log10 CFUs taken from 
the Verhoeven study. 
It is estimated that approximately 125 patients will need to be recruited in order to have 
80 patients with a burden S. aureus nasal carriage which will allow for the detection of 
a microbiological effect of XF-73 nasal gel. 


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4 RANDOMISATION 
Patients will be randomly allocated in a 1:1 ratio as follows: 0.2% w/w XF-73 nasal gel 
treatment OR placebo to match XF-73 nasal gel treatment prior to dosing. 
A randomization scheme will be prepared where patients will be stratified by site. 
Treatment packs will be prepared according to the random code, numbered for 
sequential allocation to eligible study patients. 
5 IDMC SAFETY REVIEW 
An interim analysis will be performed, depending on recruitment projections, when 
approximately 60% of evaluable patients have been recruited. The interim analysis 
will: 
• 
Review the Safety data generated to date. 
• 
Review the incidence of post-operative staphylococcal infections. 
• 
Stop the study in case of serious concerns on patient’s safety. 
• 
Stop the study due to the incidence of post-operative staphylococcal infections. 
All study staff including the Sponsor will remain blinded until the end of the study. 
Full details of the objectives, timing, analyses and the role of the Independent Data 
Monitoring Committee (IDMC) will be provided in the IDMC charter and IDMC SAP.  
The IDMC safety review has been completed. The meeting took place on 5th August 
2020 and it was agreed that the study should continue without modification. 
6 FOLLOW-UP REVIEW 
The main analysis of primary and secondary endpoints will be performed once the 
last patient has completed their Day 6 visit. Following this, there will be a review of 
relevant, longer term data, as part of the secondary and exploratory objectives, once 
the last patient has reached their 30 or 90-day follow-up visit depending on whether 
the patient had a foreign implant inserted or not. TFLs to be included in the follow-up 
analysis will be indicated in the TFL Shells document and will include the following 
data: 
• Concomitant Medications 
• Adverse Events 
• Staphylococcal infections 
• Use of post-operative staphylococcal antibiotics 
 


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7 ANALYSIS PLAN 
7.1 General 
Summary statistics for continuous variables will consist of number of non-missing 
observations (n), mean, standard deviation (SD), minimum, median, maximum, 25th 
and 75th percentiles unless specified otherwise. The precision of these variables is 
defined in the table, figure and listing shells document.  
For categorical variables the number and percentage of patients in each category will 
be presented, based on the number of non-missing observations apart from 
disposition of patients, protocol deviations, background and demographic 
characteristics, prior and concomitant medications/procedures and adverse events 
where the percentage will be based on the number of patients in the analysis set.  
All statistical tests will be performed using a two-tailed 5% overall significance level, 
unless otherwise stated.  The null hypothesis at all times will be that the 0.2% w/w 
XF-73 nasal gel and the placebo are equivalent.  All comparisons between the 
treatments will be reported with 95% confidence intervals for the difference. 
7.2 Blinded Data Review Meeting  
The Sponsor may convene a blinded data review meeting (BDRM) after the data has 
been cleaned and before the study is unblinded. This will be performed using blinded 
data taken directly from the database (i.e. TLF outputs will not be created). 
The BDRM will make decisions that will include but will not be limited to assessment 
of protocol deviations, population assignment and if changes are required to the SAP. 
If required, after the BDRM and prior to database lock, a new version of the SAP will 
be issued. 
7.3 General Derivations 
This section provides details of general derivations. Derivations specific to the 
parameter of interest are detailed within the specific SAP section.  
• Definition of study day 
Throughout this SAP any references to “Day XX” refer to the pre-specified visits 
defined in the protocol (where Day 0 is the calendar day in which surgery takes place).   
Data listings will additionally present study day. Study day will be calculated relative 
to the first date of administration of study drug (Study Day -1).   
• Definition of baseline 
Baseline is defined as the last non-missing value (including scheduled and 
unscheduled assessments) prior to the patient receiving study drug. 
• Incomplete dates 
For calculation purposes, incomplete dates will be completed using worst case. 
Further details are detailed in the relevant sections as required.   
• Non-numeric values recorded in numeric field 


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In the case where a variable is recorded as “>x”, “≥x”, “<x” or “≤x” rather than an exact 
number, then for analysis purposes a value of x will be taken. Where a range of values 
is quoted the midpoint of the range will be taken.  
• Methods for handling withdrawals and missing data 
In general, data will not be imputed.  Where imputation may be deemed appropriate, 
information is detailed in the analysis descriptions. 
7.4 Analysis Sets 
The Enrolled Set (ENR) includes all patients who completed main study informed 
consent. 
The Safety Analysis Set (SAF) consists of all patients who received at least one dose 
of study drug. Patients will be presented in the actual treatment group that they 
received. The primary population for the safety analyses will be the SAF set. 
The Intent-To-Treat (ITT) set consists of all patients who were randomized.   Patients 
will be presented in the treatment group they were randomly assigned to. 
The microbiological Intent-to-Treat (micro ITT) set includes all patients who were 
randomized, received at least one dose of study drug, have at least one post-baseline 
assessment of S. aureus log10 CFU/mL and have a log CFU/mL result at baseline 
greater than 0. The primary population for the efficacy analyses will be the micro ITT. 
Patients will be presented in the treatment group that they were randomly assigned to. 
The Per-Protocol Set (PPS) will be a subset of the micro ITT set consisting of those 
patients who do not have major protocol deviations considered to have a serious 
impact on the efficacy results. Patients will be presented in the actual treatment group 
that they received. Supportive efficacy analyses will also be performed on the PPS for 
key endpoints and at key time points. 
All protocol deviations will be assessed and documented on a case-by-case basis by 
Destiny Pharma at the following intervals: monthly, prior to interim analysis, prior to 
database lock at Day 6 and prior to final data base lock. The protocol deviations will 
be classified as major or minor deviations.  All major deviations will be reviewed prior 
to database lock, whilst blinded, to identify those considered to have a serious impact 
on the efficacy results, leading to exclusion from the PPS.  Some categories of major 
protocol deviations that might be considered as having a serious impact on the efficacy 
results include but are not limited to: 
• 
Patients failing specific eligibility criteria. 
• 
Any patients with treatment administration errors. 
• 
Taking inadmissible concomitant medication. 
• 
Significant non-compliance with timing of study visits. 
• 
Non-compliance of study drug administration. Patients will be considered compliant 
if they receive 5 scheduled applications (4 prior to surgery and 1 after surgery) of 
randomized study drug during the appropriate dosing windows.  
This is a non-exhaustive list and additional protocol deviations other than those 
specified above may be identified.  Protocol deviations leading to exclusion from the 
PPS, will be referred to as ‘important’ protocol deviations in the statistical outputs and 


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will be finalized at the population assignment meeting ahead of database lock and 
unblind. 
The definitions for the SAF, ITT, and micro ITT analysis sets are sufficient to determine 
the patients included within these analysis sets and so do not require listing and 
agreeing prior to breaking the blind. The list of subjects included in the PPS will be 
agreed as far as possible prior to database lock and unblinding. 
Actual study drug received will be determined using a kit list report obtained from 
 and provided to 
 once the blind has been broken. The report will be 
reconciled with the site records to confirm the correct kit was administered to each 
patient.  
7.5 Data presentations 
The data will be summarized in tabular form by treatment group apart from disposition 
of patients, protocol deviations and background and demographic data which will be 
summarized by treatment group and overall patients. Patients will not be presented 
for each site/country separately in the summaries unless otherwise specified. 
Similarly, patients will not be presented for each country separately in the listings. 
Treatment group labels will be “0.2% w/w XF-73 Nasal Gel” and “Placebo XF-73 Nasal 
Gel” and presented in this order.  
Visits and time points will be presented throughout as follows: 
Case Report Form (CRF) 
Visit Name 
Time point 
SAP and TLF Terminology 
Randomisation  
(Day -14 to Day -1) 
- 
Randomization 
Treatment Period  
(Day -1 to Day 0) 
First dose nasal swab 
Third dose nasal swab 
Fourth dose nasal swab 
Fifth dose nasal swab 
Baseline 
Prior to third dose 
Immediately prior to surgery 
Within 1 hour of incision closure 
48h post wound closure 
- 
48 hours after surgery 
Follow up (Day 6) 
- 
6 days after surgery 
Follow up (Day 30) 
- 
30 days after surgery 
Follow up (Day 90) 
- 
90 days after surgery 
Only scheduled post-baseline assessments will be tabulated, post-baseline 
repeat/unscheduled assessments will not be tabulated although they will be listed and 
in particular all clinically significant values will be noted. 
Eligibility, consent, completion/withdrawal and analysis set listings will be based on 
the enrolled set, safety listings will be based on the SAF set, and all other listings will 
be based on the ITT set. 
Listings will be sorted by treatment, patient number and date/time of assessment. 
Graphical presentations of the data will also be provided where appropriate. 


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Analysis sets will be summarized using the enrolled set. Study completion/withdrawal 
will be summarized using the ITT set. Background and demographic characteristics 
will be summarized using the ITT set. The primary efficacy endpoint will be 
summarized using the micro ITT set and the PPS. Selected secondary endpoints may 
be summarized using the micro ITT set and the PPS but generally will be based on 
the micro ITT set only. Prior and concomitant medications, administration of study drug 
and exposure and safety will be summarized using the SAF set. 
7.6 Disposition of patients 
The number and percentage of all patients enrolled, included in the SAF set, ITT set, 
micro ITT set and PPS, who completed the study and prematurely discontinued the 
study and study duration will be summarized.  The number and percentage of patients 
will be summarized by their reasons for withdrawal from the study. In addition, the 
table will include the number of patients screened and the number who failed at least 
one inclusion or exclusion criteria. These patients will be summarized by the inclusion 
criteria failed. Note that patients failing screening due to a negative polymerase chain 
reaction (PCR) result for MSSA/MRSA carriage are not entered into the database. 
Therefore, a separate list of these subjects will be obtained from the interactive 
randomization technology system (
) and will be included in an appendix to the 
CSR.  
For patients with a positive PCR result, eligibility for each of the analysis sets along 
with reasons for exclusion will be listed. Study completion/withdrawal data will be 
listed. Eligibility for the study, together with the details of any failed criteria will also be 
listed.  
Study duration will be derived as (date of study completion or the date of early study 
withdrawal - date of first administration of study drug) +1. 
7.7 Protocol Deviations 
Destiny Pharma will review the individual deviations at the following intervals: monthly, 
prior to interim analysis, prior to database lock at Day 6 and prior to final data base 
lock.  The review of protocol deviations will be performed whilst blinded to randomized 
treatment. See Section 7.4 for further details. 
The number and percentage of patients with at least one important protocol deviation 
will be summarized. The number of patients with each important protocol deviation will 
be summarized for each important deviation category. Important protocol deviations 
are major protocol deviations considered to impact the evaluation of efficacy and lead 
to exclusion from the PPS. 
Details of all important protocol deviations will be listed. 
7.8 Background and Demographic Characteristics 
7.8.1 Demography 
Demographic characteristics (age, sex, ethnic origin and race) and body 
measurements (height, weight and body mass index (BMI)) collected at screening 
(Randomization Day -14 to Day -1) will be summarized. The number of patients within 
each country and within each site will also be summarized. 
BMI is calculated as (weight (kg)/height (m)²). 


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All patient demographic data including the country where the site is based will be listed.  
Country will be determined from the site list relevant at the time of data extraction.  
Informed consent data will be listed. 
7.8.2 Medical History 
Medical history events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary version 23.1. This was updated to address the 
introduction of COVID-19 specific terms. The version used will be indicated in the data 
summaries and listings.  The number and percentage of patients will be presented for 
ongoing conditions and previous conditions separately by system organ class (SOC), 
and preferred term (PT), where SOC and PT will be presented in decreasing frequency 
of the total number of patients with medical history events. Ear, nose and throat (ENT), 
Peri-operative and Other events will be presented in separate tables. All events will be 
listed. 
7.8.3 Surgery 
Summaries will be provided of the number of patients receiving surgery and whether 
this surgery involved a foreign implant. The number of patients receiving any peri-
operative prophylaxis interventions and the type of intervention will also be 
summarized. This summary will be further broken down by the time at which peri-
operative prophylaxis interventions were recorded – randomization, treatment period 
(Day -1 to Day 0) and 48 hours after surgery. 
Measurements for blood glucose and body temperature will be taken between hospital 
admission and Dose 5. They will be entered in to the CRF under two separate 
collection periods (hospital admission to Dose 4 and Dose 1 to Dose 5). The collection 
period of interest for the listings and summaries will be Dose 1 to Dose 5. 
For each patient, the percentage of blood glucose measurements over 200 mg/dL will 
be calculated as: 
100 ∗
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑚𝑒𝑛𝑡𝑠 𝑜𝑣𝑒𝑟 200 𝑚𝑔/𝑑𝐿
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑚𝑒𝑛𝑡𝑠 𝑡𝑎𝑘𝑒𝑛 𝑏𝑒𝑡𝑤𝑒𝑒𝑛 𝐷𝑜𝑠𝑒 1 𝑎𝑛𝑑 𝐷𝑜𝑠𝑒 5  
A similar calculation will be performed for the number of body temperature 
measurements under 35.5°c for each patient. The percentage of blood glucose 
measurements over 200 mg/dL and the percentage of body temperature 
measurements under 35.5°c will be summarized for each treatment group.  
Data relating to the planned surgery (date, time and procedure), performed surgical 
procedure (date and time of incision, date and time of wound closure, whether the 
procedure involved a foreign implant), blood glucose and body temperature 
measurements (number of measurements taken between admission and Dose 4 and 
between dose 1 and dose 5 and the number of measurements over 200 mg/dL or 
under 35.5°c as applicable in the two periods) and the peri-operative prophylaxis 
interventions carried out will be listed.   
7.9 Prior, Concomitant and Follow-up Period Medications 
Medications will be coded using the World Health Organization Drug dictionary (WHO 
Drug) version 23.1.  The version used will be indicated in the data summaries and 
listings.  


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Prior medications are defined as those that started and ended prior to the first 
administration of study drug. Medications that are either ongoing at the first 
administration of study drug, or started after time of first administration and on or 
before a patients’ Day 6 visit will be deemed to be concomitant medications. If 
medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  Follow-up period medications are 
defined as those that started after a patient’s Day 6 visit.  
The number and percentage of patients taking concomitant medications will be 
summarized by medication class and standardized medication name, where 
medication class and standardized medication name will be presented in decreasing 
frequency of the total number of patients with medications. In summary tables, patients 
taking multiple medications in the same medication class or having the same 
standardized medication recorded multiple times in the study will be counted only once 
for that specific medication class and standardized medication name. Additional 
concomitant medications tables will also be summarized for patients with Peri-
operative 
Prophylaxis 
Interventions 
and 
for 
patients 
with 
Post-operative 
Staphylococcal Antibiotics. These will be identified using the classification recorded in 
the CRF (those with ‘Indication category’ = Peri-operative prophylaxis or ‘Indication 
category’ = Post-operative anti-staphylococcal antibiotic). A medical review will be 
performed on an ongoing basis to ensure that indication categories are assigned 
correctly in the CRF.  
Medication data will be listed, where medications will be flagged as prior, concomitant 
or follow-up period medications. 
7.10 Administration of Study Drug and Exposure 
Treatment exposure will be summarized by treatment group and will include the total 
number of patients and percentage of patients with each number of doses applied. 
Compliance will also be included in the summary table where a compliant subject is 
defined as having received all 5 doses of study drug all within the acceptable dosing 
windows.  
Acceptable dosing windows for each dose are as follows: 
• First dose: 22 hours ±2 hours before estimated incision time. 
• Second dose: 14 hours ±2 hours before estimated incision time. 
• Third dose: 6 hours ±2 hours before estimated incision time. 
• Fourth dose: Within 1 hour before incision time. 
• Fifth dose: Within 1 hour of incision closure time. 
Details of the doses applied including the total number of doses applied will be listed. 
7.11 EFFICACY EVALUATION 
One average S. aureus CFU/mL value will be supplied for each patient at each swab 
collection time point. These data will be supplied on the original scale and will be log-
transformed for analysis as appropriate. In the event that a S. aureus CFU/mL value 
is 0 (or no S. aureus has been detected), the value will be replaced with the next lowest 
meaningful value (1 CFU/mL) to enable the log transformation to be applied. Values 
between 0 and 1 CFU/mL are not expected. 


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For all efficacy endpoints the analyses will be performed on the micro ITT set. The 
primary efficacy endpoint will be repeated in the PPS.  
For all analyses the baseline value is defined as the swab collected prior to the first 
dose of study drug at approximately 24 hours prior to surgery. 
The null hypothesis is that there is no difference between the treatment means for the 
primary endpoint. The alternative hypothesis is that there is a difference between the 
two treatment means (0.2% w/w XF-73 Nasal Gel - Placebo XF-73 Nasal Gel). 
Denoting θ1 and θ2 as the mean of the response variable for each treatment group 
respectively, the hypotheses can alternatively be expressed as: 
 
H0: θ1 = θ2 vs. H1: θ1 ≠ θ2 
 
where H0 is the null hypotheses and H1 is the alternative hypothesis.  
The null hypothesis of no difference in mean change between treatment groups will 
be assessed from the analysis of the primary endpoint. The null hypothesis will be 
rejected in favour of the alternative hypothesis should the probability of the test 
statistic, derived from observed data occurring if the null hypothesis were true (α), be 
less than 5% (or in other words, the two-sided p-value shows p<0.05). 
7.11.1 Primary Endpoint 
The primary endpoint of the study is the change in S. aureus log10 CFU/mL from 
baseline to immediately prior to surgery.  
The baseline value is defined as the swab collected prior to the first dose of study drug 
at approximately 24 hours prior to surgery.  The immediately prior to surgery value is 
defined as the pre-surgery swab collected up to 1 hour prior to surgery which is 
obtained following three doses of study drug and prior to the fourth dose of study drug.  
Primary Analysis 
The change in S. aureus log10 CFU/mL from baseline to immediately prior to surgery 
will be analyzed using an analysis of covariance (ANCOVA). The model will be fitted 
with the change in S. aureus log10 CFU/mL from baseline to immediately prior to 
surgery as the dependent variable and treatment group and country as fixed effects. 
The baseline S. aureus log10 CFU/mL value will be included as a covariate.  
Adjusted Least square means (LS Means) for the placebo and 0.2% w/w XF-73 
treatment groups estimated by the model will be presented, together with the 
associated standard errors (SE).  The adjusted LS Mean, SE and 95% CI and 
two-sided p-value of the treatment difference will also be presented.  All estimates 
provided by the ANCOVA model will be presented on the log10 scale.  
The assumption is that the log10 CFU data are normally distributed. This assumption 
will be assessed using a Shapiro-Wilks’ test alongside a visual inspection of the 
residual plots. If this assessment indicates a departure from log-normality, additional 
data transformations or a non-parametric analysis will be considered for further 
analysis post-hoc, as appropriate. 
Sensitivity Analysis 
In addition to the planned analysis in the PPS which requires patients to receive at 
least 4 doses of pre-surgery treatment, a sensitivity analysis will be performed which 


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will include all patients who receive at least 3 doses of pre-surgery treatment to confirm 
the main analysis conclusions.  
A Mixed Model for Repeated Measures (MMRM) using all available data will be fitted 
in order to estimate the change from baseline to immediately prior to surgery. Further 
details on the model fitted can be found in Section 6.11.2.3 of this SAP. 
Where conclusions resulting from these analyses provide substantive differences in 
the conclusions drawn, imputation methods may be used and additional analyses may 
also be considered for key secondary endpoints.  
Summaries 
Descriptive statistics including the geometric mean and geometric co-efficient of 
variation will be presented for all observed S. aureus CFU/mL values for each 
pre-surgery and post-surgery swab collected (baseline, prior to the third dose of study 
drug, immediately prior to surgery, within 1 hour of incision closure, 48 hours after 
surgery and 6 days after surgery). The change from baseline values will also be 
presented and summarized by CFU category. For both the observed and the change 
from baseline, descriptive statistics for the log-transformed values will also be 
presented (geometric mean and co-efficient of variation will not be presented as these 
are not relevant for log transformed data).  
Box and whisker plots will be presented for each treatment group for the change from 
baseline in S. aureus log10 CFU/mL over time. The change in S. aureus log CFU/mL 
from baseline versus observed baseline S. aureus log CFU/mL will also be presented 
in a scatterplot. 
The observed S. aureus CFU/mL and log10 CFU/mL values will be listed. 
7.11.2 Secondary Endpoints 
7.11.2.1 
AUC of S. aureus from baseline to pre-surgery 
An AUC of S. aureus CFU/mL will be calculated using the values collected at baseline, 
prior to the third dose of study drug and immediately prior to surgery.  Data on the 
original scale will be used to determine the AUC. The AUC will be calculated using the 
trapezoidal method and will be log10-transformed for analysis.  
The formula for the trapezoidal method is below: 
 
Baseline 
Prior to the third dose 
Immediately prior to surgery 
Time 
t1 
t2 
t3 
Response 
a 
b 
c 
 
AUC = (t2- t1)(a+b) + (t3-t2)(b+c) 
 
2 
 
2 
AUC will only be calculated where a patient has non-missing results at both the 
baseline and immediately prior to surgery time points. An ANCOVA model will be fitted 
and presented as described in Section 6.11.1 where the baseline S. aureus log10 
CFU/mL value will be included as the covariate and treatment group and site as fixed 
effects. If there is evidence that there is a departure from the assumptions of normality 
alternative transformations such as AUC of log10 S. aureus CFU/mL will be considered.  


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7.11.2.2 
AUC of S. aureus from baseline to post-surgery 
An AUC of S. aureus CFU/mL including values at all timepoints from baseline to within 
1 hour of incision closure will be calculated.  This AUC will include the following time 
points: at baseline, prior to the third dose, immediately prior to surgery and within 
1 hour of incision closure. The AUC will be calculated as described in section 6.11.2.1 
using the trapezoidal method where the equation will be expanded to include the 
appropriate post-surgery time point as: 
AUC = (t2- t1)(a+b) + (t3-t2)(b+c) + … + (tn- tn-1)(rn-1+rn) 
 
2  
      2  
 
      2  
where tn and rn are the time and the response at the post-surgery timepoint 
respectively. The AUC will be log10-transformed for analysis. AUC will only be 
calculated where a patient has non-missing results at all of the following time points: 
baseline, immediately prior to surgery and within 1 hour of incision closure. 
An ANCOVA model will be fitted and presented as described in Section 6.11.1 where 
the baseline S. aureus log10 CFU/mL value will be included as the covariate and 
treatment group and site as fixed effects.  
Summaries 
Descriptive statistics will be presented for the pre-surgery AUC and the post-surgery 
AUC.  
Box and whisker plots will be presented for each treatment group for the AUC of S. 
aureus log10 CFU/mL over time.  
The calculated AUC values will be listed on both the observed and log10 scale. 
7.11.2.3 
Change in S. aureus log10 CFU/mL from baseline to post-surgery 
The change in S. aureus log10 CFU/mL between baseline and post-surgery will be 
assessed at each of the post-surgery time points (within 1 hour of incision closure, 
48 hours after surgery and 6 days after surgery) using an MMRM with visit, treatment 
group, site and the treatment group by visit interaction as fixed effects, and the 
baseline S. aureus log10 CFU/mL value as a covariate. F-tests from PROC MIXED will 
be based on Kenward-Roger’s adjusted degrees of freedom. The model will include 
data from all pre and post-surgery visits. 
To select the best model, the following variance/covariance matrix structures for the 
repeated visits within a subject will be assessed: Compound symmetry, 1st order 
autoregressive, Toeplitz and unstructured. The variance/covariance matrix structure 
that results in the smallest Akaike information criterion (AIC), indicating the best model 
fit will be selected. 
Results from the MMRM, for the estimate of the effect of each post-surgery time point, 
will be presented as described in Section 6.11.1.  Results from the MMRM, for 
immediately prior to surgery will also be presented as a sensitivity analysis for the 
primary analysis (see section 6.11.1). 
7.11.2.4 
Patients Reaching a Specific Reduction in S. aureus Carriage 
For each patient, the log10 CFU/mL S. aureus values obtained prior to third dose, 
immediately prior to surgery, within 1 hour of incision closure, 48 hours after surgery 
and 6 days after surgery will each be subtracted from their baseline log10 CFU/mL S. 


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aureus value to determine the reduction in their log10 CFU/mL S. aureus nasal 
carriage. 
A plot of the proportion of patients with a range of specific reductions in log10 CFU/mL 
S. aureus nasal carriage from baseline will be presented for each treatment group for 
each time point of interest.  Cut-offs in intervals of 0.5 log10 CFU/mL will be considered 
in the first instance, but other intervals will be considered as appropriate.  The plot will 
present the percentage of patients with a reduction greater than or equal to the cut-off. 
Treatment groups will be represented by different symbols and line style.  The 
reductions at the time-points of interest will be presented on separate plots. A 
supporting table containing the proportion of patients with a range of specific 
reductions in log10 CFU/mL S. aureus nasal carriage presented by treatment group 
and time point will also be produced. 
7.11.2.5 
Proportion of patients with nasal carriage below a specific cut-off 
The proportion of patients with a nasal carriage of log10 CFU/mL S. aureus considered 
in intervals of 0.5 will be presented using methods described in section 6.11.2.4, 
presenting the percentage of patients below the cut-off.  Alternative intervals will be 
used as appropriate. 
7.11.2.6 
Nasal carriage according to semi-quantitative categorization  
A semi-quantitative categorization will be used to categorize S. aureus. nasal carriage. 
The categories are: 
S. aureus nasal carriage (CFU/mL) 
Semi-Quantitative Scale Category 
0 
Negative 
1-10 
0 
>10-100 
1 
>100-1,000 
2 
>1,000-10,000 
3 
>10,000-100,000 
4 
> 100,000 
5 
The category for each S. aureus nasal carriage value at all time points will be listed.  
7.11.2.7 
Proportion of patients with a 2-log drop in S. aureus 
A 2-log drop in log10 CFU/mL S. aureus is defined as a value which is 100 times smaller 
than their baseline S. aureus value. The 2-log drop in S. aureus will be determined 
from the values obtained from prior to the third dose through to 6 days after surgery.   
The percentage of patients with a 2-log drop in log10 CFU/mL S. aureus will be 
summarized.  
A flag will be added to the listing of S. aureus data to indicate patients identified as 
having a 2-log drop in S. aureus nasal carriage. 
7.11.2.8 
Difference in S. aureus Post-operative Infections 
The number of patients experiencing post-operative infections will be calculated from 
study treatment to 30 days after surgery (or 90 days after surgery in the case of an 
object implant). Post-operative infections (as recorded on the ‘Post-Operative 


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Infection’ CRF page) include, but are not limited to, surgical site infection, bloodstream 
infections, catheter-related infections and implant infections. Descriptive statistics for 
the number of post-surgery days per patient will also be presented. For patients who 
have not reached 30 days after surgery at the time of analysis (or 90 days after surgery 
in the case of an object implant), the number of post-surgery days per patient will be 
calculated as (date of early study withdrawal – date of surgery) + 1. The number and 
percentage of subjects not reaching 30 days (or 90 days in the case of an object 
implant) will also be presented. 
The number and percentage of patients with post-operative infections will be 
presented for each treatment group together with the severity of these infections and 
the bacterial strains identified.  
All post-operative infection data will be listed.  
7.11.3 Exploratory Endpoints 
7.11.3.1 
Post-operative Antibiotic Use 
The reason for post-operative prescribed anti-staphylococcal antibiotic use during the 
30-day post-operative period (90 days in the case of an object implant) will be 
summarized by treatment group. 
The reason for the post-operative antibiotic use will be obtained from the indication 
field of the concomitant medication page of the CRF. A medical review will be 
performed on an ongoing basis to ensure that indication field in the CRF is correct. 
The number and percentage of patients within each category will be presented in a 
summary table and categories assigned will be included in the medication listing. 
Duration of post-operative staphylococcal antibiotics will also be summarized. Where 
a patient took more than one post-operative staphylococcal antibiotic medication, the 
total duration of all post-operative staphylococcal medications taken by the patient will 
be summarized. 
7.11.3.2 
Change in S. aureus log CFU/mL following surgery 
The change in S. aureus log10 CFU/mL from within 1 hour of incision closure will be 
described graphically to identify any rebound effects.  
A plot of the mean S. aureus log10 CFU/mL with error bars will be presented over time 
for each treatment group. The plot will display both treatment groups on the same 
graph. Each pre-surgery and post-surgery time point (baseline, prior to the third dose 
of study drug, immediately prior to surgery, within 1 hour of incision closure, 48 hours 
after surgery and 6 days after surgery) will be included to provide a complete depiction 
of the S. aureus log10 CFU/mL values over time. 
Additionally, a plot of the individual patient data for S. aureus log10 CFU/mL will be 
presented over time. A separate plot will be produced for each treatment group with 
each patient represented by a separate line on the same plot. Each pre-surgery and 
post-surgery time point (baseline, prior to third dose, immediately prior to surgery, 
within 1 hour of incision closure, 48 hours after surgery and 6 days after surgery) will 
be included. 
7.12 Multiplicity 
All secondary endpoints will be considered as descriptive evidence of efficacy and will 
be analyzed without any procedures to account for multiple comparisons. 


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7.13 SAFETY EVALUATION 
The safety and tolerability of 0.2% w/w XF-73 will be assessed based on adverse 
events, nasal examinations, brief smell identification test and safety evaluations 
including clinical laboratory evaluations and vital signs. 
7.13.1 Adverse Events 
Adverse events (AEs) will be coded using the MedDRA dictionary version 23.1. The 
version used will be indicated in the data summaries and listings.  
AEs will be collected between screening and 6 days after surgery.  
An AE occurring after written screening consent has been obtained but before the first 
dose of study drug, the AE will be considered a non-treatment emergent AE. These 
events will be reported in the medical history summaries.  
A TEAE is defined as an AE that occurs from the time the patient receives their first 
dose of the study drug until the patient’s Day 6 visit, or for serious AEs (SAEs) 
considered related to study drug, until the final follow-up visit. Note only AEs meeting 
the serious SAE criteria and considered related to study drug will be recorded between 
the Day 6 visit and the final follow up visit (Day 30 or Day 90 in the case of an object 
implant).  
If a subject discontinues treatment but has an AE occurring from the time of first dose 
and on or prior to Day 6 (Date of first dose (Day 0) + 6 days) then this will be considered 
a TEAE. Any AE occurring after Day 6 for a discontinued subject will not be considered 
treatment-emergent unless it meets the SAE criteria.  
If adverse event dates are incomplete and it is not clear whether the adverse event 
was treatment-emergent, it will be assumed to be treatment-emergent. If the TEAE 
has a missing relationship it is assumed to be related to the study drug for analysis 
purposes.  
A summary table will present the following:  
• TEAEs (number of events and number of patients).  
• Serious TEAEs (number of events and number of patients).  
• Serious study drug-related TEAEs (number of events and number of patients). 
• TEAEs by severity (mild/moderate/severe) (number of events and number of 
patients). 
• TEAEs by relationship to study drug category (Not related/Related) (number of 
events and number of patients).  
• TEAEs leading to withdrawal of study drug (number of patients only).  
• Study drug-related TEAEs leading to withdrawal of study drug (number of 
patients only). 
• TEAEs leading to death (number of patients only). 
In the above summaries, if a patient experienced more than one TEAE, the patient will 
be counted once using the most related event for the “by relationship to study drug” 
and “study drug-related” summaries and at the worst severity for the “by severity” 
summary. 


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The following tables will be presented for events and patients: 
1. TEAEs by System Organ Class (SOC) and Preferred Term (PT). 
2. TEAEs by SOC and PT –ENT flagged events (as indicated on the ‘Adverse 
Events’ CRF page). 
3. TEAEs by PT. 
4. TEAEs by SOC, PT and severity. 
5. TEAEs by SOC, PT and relationship to study drug. 
For all of the above, SOC and PT will be presented in decreasing frequency of the 
total number of patients in the 0.2% XF-73 nasal gel treatment group with TEAEs. 
Further details of the above five tables are given below: 
1. If a patient experienced more than one TEAE, the patient will be counted once 
for each SOC and once for each PT.   
2. If a patient experienced more than one ENT TEAE, the patient will be counted 
once for each SOC and once for each PT. 
3. If a patient experienced more than one TEAE, the patient will be counted once 
for each PT. 
4. If a patient experienced more than one TEAE, the patient will be counted once 
for each SOC and once for each PT at the worst severity. 
5. If a patient experienced more than one TEAE, the patient will be counted once 
for each SOC and once for each PT using the most related event. 
Adverse event data will be listed in full and this will also include a treatment emergent 
flag, an ENT finding flag, the time of onset and cessation of event relative to first dosing 
of study drug and duration of AE. 
7.13.2 Clinical Laboratory Evaluation 
Observed values and change from baseline in hematology, biochemistry and 
urinalysis assessments will be summarized over time. If the test results are reported 
in categorical format, the results will be summarized by patient counts and percentage 
for each category. 
Each hematology and biochemistry parameter will be classed as low, normal, high or 
missing based on the reference ranges. Shift tables in relation to the normal range 
from baseline over time will be presented.  
Hematology, biochemistry and urinalysis data will be listed separately including 
change from baseline, reference ranges flagging all out of range values and their 
clinical significance. 
Scatterplots of key hematology parameters (Hemoglobin, White blood cell count, 
Neutrophils count, Lymphocyte count and Platelets) and key biochemistry parameters 
(Creatinine, Alanine aminotransferase, Aspartate aminotransferase, Total bilirubin and 
Alkaline phosphatase) will be produced, with measured value appearing on the y-axis 
and time (days since first administration of study drug) on the x-axis.  The relevant 
reference range will be overlaid on the plot as a reference line. Parameters will be 
presented in the same order as the CRF. 


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Listings of clinically significant hematology, biochemistry and urinalysis laboratory 
measurements recorded throughout the study will be provided. 
7.13.3 Vital Signs 
Vital sign observed values and change from baseline by parameter will be summarized 
over time. 
Parameters will be presented in the same order as the CRF. 
All vital sign data will be listed including change from baseline and flags for substantial 
changes from baseline and reference ranges flagging all out of range values. 
7.13.4 Physical Examination 
Details of timings of physical examinations will be listed.  
7.13.5 Pregnancy Test 
Pregnancy test details will be listed. 
7.13.6 Nasal Examination 
Nasal examinations will be carried out by an ear nose and throat (ENT) specialist at 
Baseline and 48 hours after surgery. 
The number of patients with a clinically significant nasal examination will be 
summarized at each time point by treatment group. 
All data from the nasal examinations will be listed. 
7.13.7 Brief Smell Identification TestTM (B-SIT) 
The Brief Smell Identification Test (B-SIT) is a measure of olfactory function which is 
self-administered in a ‘scratch and sniff’ format. An accompanying questionnaire has 
4 possible options for each of the 12 odorants tested. If the patient does not perceive 
an odor a response must still be entered.  
A patient scores 1 point for every correctly identified scent and the overall score is 
derived as the total correct scents identified out of 12, with higher scores indicating a 
better olfactory performance.  
The percentile rank of the score is determined using the B-SIT interpretation matrix 
which is divided into age groups and differs between the sexes. This percentile rank 
is then used by the investigator to attribute the patient to one of the following three 
categories: abnormal relative to age, deficit relative to younger persons and normal.  
The data will be presented as collected on the CRF.  If the score is so low that the 
percentile rank is not quantifiable the percentile and the category will both be entered 
as ‘below percentile rank’.    
B-SIT data will be summarized using shift tables, in relation to the normal category, 
from baseline over time.  
A medical review will be performed on an ongoing basis in the CRF to identify medical 
history and adverse events linked to subjective impact on smell. The baseline B-SIT 
score will be compared to any smell related medical history events (those with ‘Was 
this medical history an ENT finding?’ = Yes) and the Day 6 B-SIT score will be 
compared to any smell related TEAEs (those with ‘Was this event an ENT finding?’ = 
Yes). 


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All B-SIT data will be listed including change from baseline for the B-SIT score.  
7.14 Changes from the Protocol Planned Analysis 
For the analysis of the change in log10 CFU from baseline to post-surgery an MMRM 
model has been chosen in favor of the ANCOVA specified in protocol section 11.7.  
The AUC of S. aureus from baseline to pre-surgery will be calculated using values on 
the original scale and will then be log10-transformed, as opposed to calculating the 
AUC on the log10-transformed values as described in protocol section 11.7.  
The proportional odds model described in protocol section 11.7 for the nasal carriage 
according to SQS has been removed. Summary statistics are deemed to be sufficient.  
Any reference to the modified Intent-to-Treat (mITT) set has been removed from the 
SAP as analysis will no longer be performed in this population. 
The major protocol deviations leading to exclusion from the PPS has been clarified in 
Section 7.4. Major protocol deviations are defined more broadly in the protocol, so 
include deviations which are important to report, but would not impact the evaluation 
of efficacy. Therefore, the SAP has made clear that only those major protocol 
deviations considered to impact the evaluation of efficacy (i.e. deemed important) will 
be excluded from the PPS. 
7.15 References 
1. Verhoeven PO, Grattard F, Carricajo A, Lucht F, Cazorla C, Garraud O, 
Pozzetto B, Berthelot P. An algorithm based on one or two nasal samples is 
accurate to identify persistent nasal carriers of Staphylococcus aureus. Clin 
Microbiol Infect. 2012 Jun;18(6):551-7. doi: 10.1111/j.1469-
0691.2011.03611.x.