Effects of Photodynamic Therapy on the Human Inguinal Skin Microbiome to Improve Antiseptic Effect - Pilot 2
Phase: NA
Conditions: Postoperative Wound Infection Deep Incisional Surgical Site, Prosthesis and Implants, Surgical Site Infection, Prosthetic Joint Infection
Sponsor: University of Zurich

 
 
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Clinical Study Protocol 
 
EFFECTS OF PHOTODYNAMIC THERAPY ON THE HUMAN INGUINAL SKIN MICROBIOME TO 
IMPROVE ANTISEPTIC EFFECT – PILOT 2 
 
SHORT TITLE: Effect of photodynamic therapy on skin microbiome (PHOMIC-II) 
Single center study 
 
 
Study Type: 
Health-related intervention  
Study Categorization: 
Other Clinical Trial Category A  
Study Registration: 
Bundesamtes für Gesundheit: www.kofam.ch.  
Fill out after ethical approval 
International trial registry ClinicalTrials.gov 
(clinicaltrials.gov) NCT04618276 
Study Identifier: 
To fill out after ethical approval 
Sponsor study Identifier: PHOMIC-II 
 
Sponsor-Investigator and 
Principal Investigator: 
PD Dr. med. Yvonne Achermann 
University Zurich 
Division of Infectious Diseases and Hospital Hygiene 
Yvonne Achermann, MD 
University Hospital Zurich 
Rämistrasse 100, 8091 Zürich 
Switzerland  
Phone: 044 255 34 02 
E-Mail: yvonne.achermann@usz.ch 
 
Study Intervention: 
Effects of photodynamic treatment on skin microbiome 
Protocol Version and Date: 
V04, 27.11.2020 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of the Division of 
Infectious Diseases of the University Hospital Zurich. The information may not - in full or in part - be 
transmitted, reproduced, published, or disclosed to others than the applicable Independent Ethics 
Committee(s) and Competent Authority(ies) without prior written authorization from Division of 
Infectious Diseases of the University Hospital except to the extent necessary to obtain informed 
consent from those participants who will participate in the study. 
 

 
 
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SIGNATURE PAGE 
Study number 
 
Not yet 
Bundesamtes für Gesundheit: www.kofam.ch. 
International 
trial 
registry 
ClinicalTrials.gov 
(clinicaltrials.gov): NCT04618276 
 
Study Title 
Effects of photodynamic therapy on the human 
inguinal skin microbiome to improve antiseptic 
effect –Pilot 2 
 
 
Sponsor-Investigator (Principal Investigator): 
 
This clinical trial protocol was subject to critical review and has been approved by the Sponsor-
Investigator. The information herein is consistent with 
- 
the current risk/benefit evaluation of the intervention, 
- 
the moral, ethical and scientific principles governing clinical research as set out in the  
  current version of the Declaration of Helsinki, Good Clinical Practice.  
 
 
PD Dr. med. Yvonne Achermann 
 
Zürich, 27.11.2020 
Place/Date 
 
Signature 
 
 
 
 

 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE................................................................................................................2 
STUDY SYNOPSIS ................................................................................................................6 
LIST OF ABBREVIATIONS ....................................................................................................9 
1 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE.............................10 
1.1 
Sponsor, Sponsor-Investigator (Principal Investigator) .......................................10 
1.2 
Study Nurse .......................................................................................................10 
1.3 
Laboratory ..........................................................................................................10 
1.4 
Collaboration ......................................................................................................10 
1.5 
Monitoring Institution ..........................................................................................10 
ETHICAL AND REGULATOR ASPECTS .............................................................................10 
1.6 
Study Registration ..............................................................................................10 
1.7 
Categorization of the Study ................................................................................11 
1.8 
Competent Ethics Committee (CEC) ..................................................................11 
1.9 
Ethical Conduct of the Study ..............................................................................11 
1.10 Declaration of Interest ........................................................................................11 
1.11 Participant Information and Informed Consent....................................................11 
1.12 Participant Privacy and Confidentiality................................................................11 
1.13 Early Termination of the Study ...........................................................................12 
1.14 Protocol Amendments ........................................................................................12 
2 
INTRODUCTION .........................................................................................................12 
2.1 
Background and Rationale .................................................................................12 
2.2 
Study Intervention and Indication .......................................................................14 
2.3 
Clinical Evidence to Date....................................................................................14 
2.4 
Justification of Study Intervention .......................................................................14 
2.5 
Explanation for Choice of Comparator Intervention ............................................14 
2.6 
Risk / Benefits ....................................................................................................14 
2.7 
Study Population ................................................................................................15 
3 
STUDY OBJECTIVES .................................................................................................15 
3.1 
Overall Objective ................................................................................................15 
3.2 
Primary Objective ...............................................................................................16 
3.3 
Secondary Objectives ........................................................................................16 
3.4 
Safety Objectives ...............................................................................................16 
4 
STUDY OUTCOMES ..................................................................................................16 
4.1 
Primary Outcome ...............................................................................................16 
4.2 
Secondary Outcomes .........................................................................................16 
4.3 
Safety Outcomes ................................................................................................16 
5 
STUDY DESIGN AND COURSE OF STUDY ..............................................................16 
5.1 
General Study Design and Justification of the Design ........................................16 
5.2 
Study Duration and Study Schedule ...................................................................17 
5.3 
Methods of Minimizing Bias ................................................................................19 
6 
STUDY POPULATION ................................................................................................19 
6.1 
Eligibility Criteria .................................................................................................19 
6.1.1 Inclusion Criteria .....................................................................................19 

 
 
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6.1.2 Exclusion Criteria ....................................................................................19 
6.2 
Recruitment and Screening ................................................................................20 
6.3 
Criteria for Withdrawal/ Discontinuation of Participants ......................................20 
7 
STUDY INTERVENTION .............................................................................................20 
7.1 
General Information............................................................................................20 
7.1.1 Study Intervention ...................................................................................21 
7.1.2 Control Intervention.................................................................................21 
7.2 
Administration of Study Intervention ...................................................................21 
7.2.1 Study Intervention ...................................................................................21 
7.2.2 Modification of Interventions ...................................................................22 
7.3 
Compliance with Intervention .............................................................................22 
7.4 
Data Collection and Follow-up for Withdrawn Participants..................................22 
7.5 
Concomitant Intervention(s) ...............................................................................22 
8 
STUDY PROCEDURES ..............................................................................................23 
8.1 
Table of Study Procedures and Assessments ....................................................23 
8.2 
Assessments of Outcomes .................................................................................24 
8.2.1 Assessment of Primary Outcome ............................................................24 
8.2.2 Assessment of Secondary Outcomes .....................................................24 
8.2.3 Assessment of Safety Outcomes ............................................................25 
8.2.4 Assessments in Participants who prematurely Stop the Study ................25 
8.3 
Procedures at Each Visit ....................................................................................25 
8.3.1 Screening Visit ........................................................................................25 
8.3.2 Visit 1 = Day 0 of the study .....................................................................25 
8.3.3 Visit 2, 3, 4 (day 1, 3, 5) ..........................................................................26 
9 
SAFETY ......................................................................................................................26 
9.1 
Definitions ..........................................................................................................26 
9.2 
Recording and Assessment of Serious Adverse Events .....................................27 
9.3 
Reporting of Serious Adverse Events .................................................................27 
9.4 
Follow up of (Serious) Adverse Events ...............................................................27 
10 
 
AL METHODS ......................................................................................................................28 
10.1 Hypothesis .........................................................................................................28 
10.2 Determination of Sample Size ............................................................................28 
10.3 Planned Analyses ..............................................................................................28 
10.3.1 Datasets to be Analyzed, Analysis Populations .......................................28 
10.3.2 Primary Analysis .....................................................................................28 
10.3.3 Secondary Analyses ...............................................................................28 
10.3.4 Interim Analyses .....................................................................................28 
10.3.5 Safety Analysis .......................................................................................28 
10.3.6 Deviation(s) from the Original Statistical Plan .........................................28 
10.4 Handling of Missing Data and Drop-Outs ...........................................................28 
11 
ELIGIBILITY OF THE PROJECT SITE(S) ...................................................................28 
12 
DATA QUALITY ASSURANCE AND CONTROL .........................................................29 
12.1 DATA HANDLING AND RECORD KEEPING .....................................................29 
12.1.1 Case Report Forms.................................................................................29 

 
 
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12.1.2 Specification of Source Documents ........................................................30 
12.1.3 Record Keeping / Archiving .....................................................................30 
12.2 Data Management ..............................................................................................30 
12.3 Routine Monitoring .............................................................................................31 
12.4 Audits and Inspections .......................................................................................31 
12.5 Confidentiality, Data Protection ..........................................................................31 
12.6 Storage of Biological Material and Related Health Data .....................................31 
13 
PUBLICATION AND DISSEMINATION POLICY .........................................................31 
14 
FUNDING AND SUPPORT .........................................................................................32 
14.1 Funding ..............................................................................................................32 
14.2 Other Support.....................................................................................................32 
15 
INSURANCE ...............................................................................................................32 
16 
REFERENCES ............................................................................................................33 
17 
APPENDICES .............................................................................................................34 
 
 
 

 
 
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STUDY SYNOPSIS 
Sponsor 
/ 
Sponsor-
Investigator 
PD Dr. med. Yvonne Achermann 
Study Title: 
Effects of photodynamic therapy on the human inguinal 
skin microbiome to improve antiseptic Effect – pilot 2 
Short Title / Study ID: 
Effects of photodynamic therapy on skin microbiome 
(PHOMIC-II) 
Protocol Version and Date: 
v04, 27.11.2020   
Trial registration: 
Bundesamtes für Gesundheit: www.kofam.ch.  
SNCTP 
 
International trial registry ClinicalTrials.gov (clinicaltrials.gov) 
NCT04618276 
Study 
category 
and 
Rationale 
Other clinical study Category A 
Background and Rationale: 
Periprosthetic joint infections are a feared complication after 
orthopedic surgery in particular in our increasing elderly 
population. These infections are usually difficult to treat, 
because microorganisms persist in biofilms on the orthopedic 
implant surface. Therefore, it would be desirable to prevent 
these infections. It is hypothesized that bacteria from the skin 
surface or dermis - such as Staphylococcus aureus, 
coagulase-negative staphylococci, or Cutibacterium sp. - are 
transmitted into the periimplant tissue during surgery. In an 
ongoing interdisciplinary study with the Orthopedic University 
Hospital Balgrist (data in preparation for publication), we see 
that common skin antisepsis preparation is not effective to 
eliminate skin bacteria before surgery because they persist in 
sebaceous or sweat glands. Photodynamic therapy (PDT) has 
recently gained attention in the treatment of acne, a disease 
of the pilosebaceous unit, in which also Cutibacterium acnes 
is implicated. The PDT works here on the one hand through a 
long-lasting destruction of the sebaceous glands, and on the 
other hand due to anti-inflammatory and antimicrobial effects. 
Objective(s): 
The overarching aim of this research project is to prevent 
orthopedic implant-associated infections. This study aims to 
investigate if PDT has an effect on bacterial skin colonization 
in order to improve skin antisepsis strategies for the prevention 
of surgical site infections. 
In a previous pilot study, we investigated if skin antisepsis is 
improved with previous PDT with the photosensitizer-inducing 
prodrug 5% topical methyl aminolevulinate (MAL) on inguinal 
skin in 10 participants. The induced photosensitizer was 
protoporphyrin IX (Pp IX, 635 nm) activated by red light. We 
showed a complete sterilization of colonizing skin bacteria at 
the same day after this treatment However, orthopedic 
surgeons are hesitant to perform an arthroplasty surgery after 
such a treatment due to skin erythema for a few days.  
We are entirely convinced about this novel prevention concept 
but need to identify the photosensitizer with the ideal balance 
of bactericidal effect versus skin irritation. Building upon the 
data we gathered, we will explore PDT with the two 
photosensitizers MAL and Methylene blue with potentially less 
local side-effects (skin erythema). 

 
 
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Outcome(s): 
Primary outcome:  
Effect of photodynamic treatment with the photosensitizers Pp 
IX (MAL) and Methylene blue in combination with surgical 
antisepsis on bacterial skin colonization on the day of 
application and on day 1, 3, and 5 
Secondary outcome:  
Effect of PDT on the skin microbiome using molecular 
techniques. 
Study design: 
Pilot study, open label, single center 
Inclusion / Exclusion criteria: 
Inclusion criteria 
Healthy male and female participants ≥ 18 years who 
• 
volunteer for the pilot study in which a routine 
photodynamic 
treatment 
in 
the 
Department 
of 
Dermatology will be applied and effect of skin colonization 
will be analyzed, and 
• 
an informed consent is signed by the participant (after 
information about the project). 
 
Exclusion criteria 
• 
Pregnant and lacting women 
• 
Participants with inability to follow the procedures of the 
study, e.g. due to language problems, psychological 
disorders, dementia, etc., 
• 
Participants taking antibiotics in the 14 days prior to PDT 
or until follow-up at 21 days 
• 
Participants who received oral retinoid therapy within the 
last 6 months 
• 
Participants who received anti-inflammatory agents as 
NSAR within the 14 days prior and after the PDT 
• 
Participants taking any photosensitizing drugs within 4 
weeks prior to PDT  
• 
Participants who had a history of photosensitivity disorder 
• 
Fitzpatrick’s skin phototype V-VI 
Study Intervention:  
• 
Photosensitizer application, followed by PDT (1x)  
• 
Skin swabs on day 0, 1, 3, and 5 
Group A: use of MAL induced Pp IX photosensitizer 
Group B: use of Methylene blue photosensitizer 
Reference Intervention: 
Skin swabs before and after skin antisepsis in 10 participants 
without PDT from the contralateral side.   
Number of Participants with 
Rationale: 
Aim: 10 volunteers in group A and 10 volunteers in group B 
There will be only descriptive statistics to see if numbers of 
colonizing bacteria are decreased with PDT to plan a clinical 
trial in patients getting a hip joint arthroplasty and previous 
antisepsis. 
Study Duration: 
1 year 
Study Schedule: 
• 
Project start (FPFV): January 2021  
o First participant: January 2021 
o Last participant: June 2021 
• 
Project end (LPLV): December 2021 

 
 
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Investigator(s): 
Yvonne Achermann, MD 
Division of Infectious Diseases and Hospital Hygiene 
University Hospital Zurich 
Rämistrasse 100, 8091 Zürich 
Email: yvonne.achermann@usz.ch 
Tel: 044 255 34 02 
Study Centre(s): 
Single-center  
Statistical Considerations: 
Categorical data will be tested for differences using Fisher’s 
exact or chi-squared tests, as appropriate, whereas 
continuous variables will be tested using Wilcoxon rank sum 
tests. 
GCP Statement: 
This study will be conducted in compliance with the protocol, 
the current version of the Declaration of Helsinki, the ICH-GCP 
as well as all national legal and regulatory requirements.  
 

 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event  
ClinO 
Clinical Trial Ordinance (KlinV) 
CRF 
Case Report Form  
eCRF 
Electronic Case Report Form  
GCP 
Good Clinical Practice  
ICH 
International Council on Harmonization 
ISF 
Investigator Site File  
PI 
Principal Investigator  
SAE 
Serious Adverse Event  
SDV 
Source Data Verification  
SNCTP 
Swiss National Clinical Trial Portal 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File  
PJI 
C. avidum 
CNS 
Sp. 
CEC 
PDT 
MAL 
NSAR 
Pp IX 
Periprosthetic Joint Infection 
Cutibacterium avidum 
Cogulase-negative staphylococci 
Species 
Competent Ethics Committee  
Photodynamic therapy 
Methyl aminolevulinate 
Non-steroidal anti-inflammatory drugs 
Protoporphyrin IX 
 
 

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1 INVESTIGATORS 
AND 
STUDY 
ADMINISTRATIVE 
STRUCTURE  
1.1 Sponsor, Sponsor-Investigator (Principal Investigator) 
Division of Infectious Diseases and Hospital Hygiene 
PD Dr. med. Yvonne Achermann 
University Hospital Zurich 
Rämistrasse 100, 8091 Zürich 
Tel: 044 255 34 02 
Email: yvonne.achermann@usz.ch 
1.2 Study Nurse 
To be determined 
1.3 Laboratory 
Microbiological cultures:  
Institute of Medical Microbiology 
Prof. Dr. med. Reinhard Zbinden 
University Zurich 
Gloriastrasse 30/32, 8006 Zürich 
Tel. +41 44 634 27 00 
Email: rzbinden@imm.uzh.ch 
 
Research fellow: 
Julia Prinz 
University Hospital Zurich 
Rämistrasse 100, 8091 Zürich 
Julia.prinz@usz.ch 
1.4 Collaboration 
Dr. med. Laurence Imhof, Klinik für Dermatologie and Prof. Heinrich Walt (emeritus Professor of 
the University of Zurich, group leader of oral oncology). 
1.5 Monitoring Institution 
Since we only measure microbiological data from skin samples, we think, that intern monitoring 
would be adequate. See chapter 12.3.  
ETHICAL AND REGULATOR ASPECTS 
Before this study will be conducted, the protocol, the proposed participant information and consent 
form as well as other study-specific documents will be submitted to a properly constituted 
Competent Ethics Committee (CEC) in agreement with local legal requirements, for formal 
approval.  
The decision of the CEC concerning the conduct of the study will be made in writing to the 
Sponsor-Investigator before commencement of this study. The clinical study can only begin once 
approval from the CEC has been received. 
1.6 Study Registration 
The study will be registered at the Swiss National Clinical Trials Portal (SNCTP) and in the 
international trial registry ClinicalTrials.gov (clinicaltrials.gov). 

 
 
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1.7 Categorization of the Study 
Category A: The health-related study intervention (PDT) entails only minimal risks and burdens. 
1.8 Competent Ethics Committee (CEC)  
Approval from the appropriate constituted Competent Ethics Committee is sought for the clinical 
trial. The reporting duties and allowed time frame are respected. No substantial amendments 
are made to the protocol without prior CEC approval, except where necessary to eliminate 
apparent immediate hazards to study participants.Premature study end or interruption of the 
study is reported within 15 days. The regular end of the study is reported to the CEC within 90 
days, the final study report shall be submitted within one year after study end. Amendments are 
reported according to chapter 2.9. 
1.9 Ethical Conduct of the Study 
The study will be carried out in accordance with principles enunciated in the current version of the 
Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, and Swiss 
competent authority’s requirements.  
CEC will receive annual safety and interim reports and be informed about non-substantial 
amendments, the course of the study, and the study stop/ end in agreement with local 
requirements. 
1.10 Declaration of Interest  
No conflict of interest 
1.11 Participant Information and Informed Consent 
The investigator must explain to each Participant the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits and any discomfort it 
may entail. Each participant must be informed that the participation in the study is voluntary and 
that he/she may withdraw from the study at any time and that withdrawal of consent will not affect 
his/her subsequent medical treatment.  
The participant must be informed that his/her medical records may be examined by authorized 
individuals other than their treating physician. 
All participants for this study will be provided a participant information sheet and a consent form 
describing this study and providing sufficient information for participants to make an informed 
decision about their participation in this study.   
The participant information sheet and the consent form will be submitted with the protocol for 
review and approval for the study by the CEC. The formal consent of a participant, using the 
approved consent form, must be obtained before that participant is submitted to any study 
procedure.  
The participant should read and consider the statement before signing and dating the informed 
consent form, and should be given a copy of the signed document. The consent form must also 
be signed and dated by the investigator (or his designee) and it will be retained as part of the 
study records. 
1.12 Participant Privacy and Confidentiality 
The investigators are liable to treat the entire information related to the study and the compiled 
data strictly confidentially. Any passing-on of information to persons that are not directly involved 
in the study must be approved by the owner of the information.  
Data generation, transmission, archiving and analysis of personal data within this study, strictly 
follows the current Swiss legal requirements for data protection. Prerequisite is the voluntary 

 
 
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approval of the Participant given by signing the informed consent prior start of participation of the 
clinical trial.  
Individual participant medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Participant’s confidentiality will be further 
ensured by utilizing participant identification code numbers to correspond to treatment data in the 
computer files. 
Such medical information may be given to the participant’s personal physician or to other 
appropriate medical personnel responsible for the participant’s welfare, if the patient has given 
his/her written consent to do so. 
Data generated as a result of this study are to be available for inspection on request by the 
monitors and by the CEC. 
1.13 Early Termination of the Study  
The Sponsor-Investigator may discontinue the study prematurely according to certain 
circumstances: 
• 
ethical concerns, 
• 
insufficient participant recruitment, 
• 
when the safety of the participants is doubtful or at risk, respectively, 
• 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise,  
• 
early evidence of benefit or harm of the experimental intervention  
1.14 Protocol Amendments 
Substantial amendments (significant changes) are only implemented after approval of the CEC. 
 
Significant changes to be authorized by the CEC are the following: 
 
− 
changes affecting the participants’ safety and health, or their rights and obligations;  
− 
changes to the protocol, and in particular changes based on new scientific knowledge 
which concern the trial design, the method of investigation, the endpoints or the form of 
statistical analysis; 
− 
a change of trial site, or conducting the clinical trial at an additional site; or 
− 
a change of sponsor, coordinating investigator or investigator responsible at a trial site. 
 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and 
well-being of human participants may proceed without prior approval of the sponsor and the CEC. 
Such deviations shall be documented and reported to the sponsor and the CEC as soon as 
possible. 
All Non-substantial amendments are communicated to the CEC within the Annual Safety Report 
(ASR). 
2 INTRODUCTION 
2.1 Background and Rationale 
The use of orthopedic implants has been steadily increasing over the last 50 years. Despite 
considerable technical progress, including perioperative skin disinfection and antibiotic 
prophylaxis, implant-associated infections remain a feared complication. Infection rates up to 2% 
after primary joint arthroplasties (Tande and Patel 2014) have been described. National data 
published by Swissnoso – the National Center for Infection Prevention –reported an infection rate 
of 1.2% in hip arthroplasties (Vergleichsbericht 2015/2016). Considering an infection rate of up to 
1.2%, 400 surgeries with primary hip arthroplasty implantation at the Orthopedic Department of 
the Balgrist University Hospital (data of 2015) would result in five periprosthetic joint infections 

 
 
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(PJI) per year, which is medically highly relevant regarding morbidity, mortality and estimated 
costs of 225’000 CHF in total.  
Because bacteria grow and persist in biofilms on the implant surface such infections are difficult 
to eradicate. Definite cure of biofilm infections requires adequate surgical debridement and 
prolonged treatment with an antimicrobial agent resulting in high health-care costs (Tande and 
Patel 2014). Most commonly isolated microorganisms in implant-associated infections are 
staphylococci, streptococci, enterococci, Gram-negative bacteria, and anaerobic bacteria such 
as Cutibacterium acnes/avidum (formerly Propionibacterium acnes/avidum) (Tande and Patel 
2014). 
The majority of implant-associated infections are acquired during surgery. It is hypothesized that 
the same bacteria that colonize the skin surface contaminate the orthopedic implant and cause 
acute or chronic infections (Pulido, Ghanem et al. 2008). Prevention of implant-associated 
infections is key to avoid re-operations and prolonged antibiotic treatment. Current preoperative 
prevention strategies are multifaceted with the focus on skin antisepsis and single shot of an 
antibiotic within 30-60 minutes before surgery (Bratzler, Dellinger et al. 2013, Dumville, McFarlane 
et al. 2015). Preoperative skin antisepsis is performed with alcoholic povidone-iodine (PVI) or 
chlorhexidine gluconate (CHG) prior to implantation as a standard skin preparation (Dumville, 
McFarlane et al. 2013, Berrios-Torres, Umscheid et al. 2017). Povidone iodine oxidizes cell 
constituents and inactivates proteins by iodinating them. Regarding the skin commensal 
Cutibacterium acnes, it could be shown that despite administration of standard preoperative 
prophylaxis before shoulder arthroplasty surgeries, C. acnes could be detected in different sample 
types (in dermis, fascia, synovium, and glenoid tissue of shoulder) of 3 out of 10 patients without 
any signs of infection (Matsen, Russ et al. 2015). There is an increasing number of studies 
reporting the presence of bacteria in deep tissue, which is commonly considered as sterile. A 
recent study by Lee et al. found viable C. acnes in the dermal tissue in seven out of 10 male 
volunteers after surface skin antisepsis (Lee, Pottinger et al. 2014). All these study results have 
led to the assumption that not only the superficial skin bacteria but also bacteria in the dermis 
may find the way to deeper structures and infect an implant.  
We hypothesize that local PDT is able to reduce persistent skin colonizing bacteria through the 
destruction of the sebaceous and sweat glands as well through bactericidal effects and thus 
improve skin antisepsis before surgical incision and implantation of foreign material leading to a 
lower rate of surgical site infections.  
In a previous pilot study, we investigated if skin antisepsis is improved with previous PDT with the 
photosensitizer- inducing prodrug 5% topical methyl aminolevulinate (MAL) on inguinal skin in 10 
participants. The induced photosensitizer was protoporphyrin IX (inducing a photodynamic effect 
with 635 nm light source) and we showed a complete sterilization of colonizing skin bacteria after 
this treatment (Waldmann, Schmid et al. 2020). However, due to skin erythema for a few days 
after PDT, orthopedic surgeons would be hesitant to perform an arthroplasty surgery after this 
treatment. Therefore, we aim to have a PDT with less local side-effects (skin erythema). 
Ondine’s methylene blue based photosensitizer NF-031 is mainly formulated in a primarily 
hydrophilic carrier, and therefore does not penetrate the stratum corneum over short periods of 
time, providing potent surface disinfection. According to the company Ondine, we can expect less 
side effects as with Pp IX. We will also repeat the MAL PDT with day light as a promising light 
source with expected less side effects such as pain and redness (Wiegell, Haedersdal et al. 2008, 
Rubel, Spelman et al. 2014). 
The aim of this pilot study is to evaluate the effect of PDT with the photosensitizer MAL with and 
the photosensitizer Methylene blue on colonizing bacteria immediately before surgical skin 
antisepsis and after it. If we see promising results in this pilot study, we will plan a prospective 
clinical trial in patients undergoing hip arthroplasty surgery.  

 
 
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2.2 Study Intervention and Indication 
Study intervention 
Indication 
PDT  
- 
Photosensitizer in group A: 
MAL 
- 
photosensitizer in group B: 
methylene blue 
- 
Bactericidal effect on skin bacteria (skin 
sterility) 
 
Skin swabs 
- 
Skin scraping method 
- 
Measurement of bacterial growth of colonizing 
bacteria and quantitative bacterial changes 
using molecular methods 
2.3 Clinical Evidence to Date  
PDT has recently gained attention in the treatment of acne, a disease of the pilosebaceous unit, 
in which also C. acnes is implicated. The PDT works here on the one hand through a long lasting 
destruction of the sebaceous glands, and on the other hand due to anti-inflammatory and 
antimicrobial effects (Sakamoto, Lopes et al. 2010). In following studies, photodynamic therapy 
not only validated its efficient activity against bacteria involved in acne such as C. acnes, it 
showed also activity against various other classes of microorganisms (Awad, Tovmasyan et al. 
2016). The mechanism of action of PDT is a photochemical reaction through the generation of 
reactive oxygen species in the presence of oxygen, mainly excited singlet oxygen, by a non-toxic 
photosensitizer reacting with visible light. PDT is routinely performed among others for non-
melanoma skin cancer and therapy-refractory inflammatory dermatoses at the Department of 
Dermatology at the University Hospital Zurich. The treatment enjoys great popularity as it is well 
tolerated, can be repeated arbitrarily often, and gives excellent cosmetic results.  
In a previous pilot study, we investigated if skin antisepsis is improved with previous PDT with the 
photosensitizer- inducing prodrug 5% topical methyl aminolevulinate (MAL) on inguinal skin in 10 
participants. The induced photosensitizer was protoporphyrin IX (inducing a photodynamic effect 
with 635 nm light source) and we showed a complete sterilization of colonizing skin bacteria after 
this treatment (Waldmann, Schmid et al. 2020). However, due to skin erythema for a few days 
after PDT, orthopedic surgeons would be hesitant to perform an arthroplasty surgery after this 
treatment. Therefore, we aim to have a PDT with less local side-effects (skin erythema). 
2.4 Justification of Study Intervention 
PDT enjoys great popularity as it is well tolerated. Therefore, we select this promising treatment 
to investigate an innovative strategy to improve skin antisepsis in a pilot study. If we see that we 
have sterile cultures after PDT and skin antisepsis without side effects, we will plan a larger 
prospective study based on these data. 
2.5 Explanation for Choice of Comparator Intervention 
We will use for our control group without PDT the contralateral groin of the same participants 
(no further participants needed).  
2.6 Risk / Benefits  
In the following, we describe benefits, weakness, opportunities, and risks of this study.  

 
 
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Possible side effects of the PDT are pain in the area of treatment, erythema and edema during 
and after light treatment (Borgia, Giuffrida et al. 2018). These side effects are self-limiting. We 
expect less erythema with day-light PDT and with the photosensitizer Methylene blue than with 
the previously tested MAL induced Pp IX photosensitizer (Waldmann, Schmid et al. 2020). 
Since our study interventions (see above) have minimal risks for participants, it is reasonable to 
conduct this pilot study before starting a larger clinical trial with patients undergoing hip 
arthroplasty surgery. 
2.7 Study Population  
Twenty healthy male and female volunteers’ ≥ 18 years will be recruited for this clinical study. 
The first ten enrolled participants will be allocated to receive MAL (group A), the other ten 
participants will receive Methylene blue (group B). The type of PDT (group A and B) is not 
blinded to both participant and study investigator. The study will be approved by the local ethical 
committee and conducted with a study nurse and a doctoral thesis student (to be determined) 
in collaboration with the Clinic for Dermatology at the University Hospital Zurich, and with the 
Institute of Medical Microbiology at the University of Zurich. An informed consent will be obtained 
from each participant. We will exclude pregnant and lactating women, participants taking 
antibiotics in the 14 days prior to the PDT or until follow-up at 21 days, participants who received 
oral retinoid therapy within the last 6 months, participants who received anti-inflammatory agents 
within the 14 days prior and after the photodynamic treatment, participants taking any 
photosensitizing drugs within 4 weeks prior to the photodynamic treatment, participants who had 
a history of photosensitivity disorder or having a fitzpatrick’s skin phototype V-V (16).  
We will not include vulnerable participants. There will be a financial compensation (value CHF 
50.00) to the participants as in the previous trial (PHOMIC) was asked by the ethical committee. 
3 STUDY OBJECTIVES  
3.1 Overall Objective 
The overarching aim of this research project is to prevent orthopedic implant-associated 
infections. 
Benefits
•Important topic in our society of more elderly patients 
with the increasing need of orthopedic implants
•PDT is a promising method for improving skin anti-
sepsis
•established network with infectious diseases 
specialists (Lead), microbiologists, dermatologists, 
and orthopedic surgeons
Weakness
• not applicable
Opportunities
•Improved skin antisepsis by PDT would change 
routine praxis in orthopedic surgery as well as 
overall in surgery with the consequent reduction in 
morbidity, mortality, and health-care costs
Risks
• Minimal risk (transient erythema and pain) using 
PDT (no long-term sequelae). No inflammation 
seen on histopathology in previous trial

 
 
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3.2 Primary Objective 
In this study we aim to investigate if PDT with MAL or methylene blue has an effect on bacterial 
skin colonization and decreases number of colonizing bacteria to improve skin antisepsis 
strategies for the prevention of surgical site infections. 
In a previous pilot study, we investigated if skin antisepsis can be improved with previous PDT 
with MAL-induced Pp IX on inguinal skin in 10 participants. We showed a complete sterilization 
of colonizing skin bacteria at the same day after this treatment. However, orthopedic surgeons 
are hesitant to perform an arthroplastic surgery after such a treatment due to skin erythema for 
a few days.  
We are entirely convinced about this novel prevention concept but need to identify the optimal 
irradiation source and the photosensitizer with the ideal balance of antibacterial effect versus skin 
irritation. 
3.3 Secondary Objectives 
Effect of PDT on the skin microbiome using molecular techniques. 
3.4 Safety Objectives 
Evaluation of adverse events 
4 STUDY OUTCOMES  
4.1 Primary Outcome 
Effect of PDT with the MAL-induced Pp IX (group A) and Methylene blue (Ondine NF-031) (group 
B) in combination with skin antisepsis on bacterial skin colonization on the day of application and 
on day 0, 1, 3 and 5 
1.1. To quantitatively evaluate bacterial density and species before and after PDT and skin 
antisepsis using culture techniques 
4.2 Secondary Outcomes 
Effect of PDT on the skin microbiome using molecular techniques. 
4.3 Safety Outcomes 
Every PDT is documented as in routine clinics on a standardized protocol in the KISIM database 
(see appendix 1).  
 
Clinical signs and symptoms after PDT as adverse events. We will distinguish between: 
- 
Mild redness and pain as to be expected (yes/no) 
- 
Advanced redness and pain more than expected (yes/no): adverse event.  
o “More than expected” is defined, if patients needs to take more than 1 
painkiller/day 
- 
Other signs and symptoms not expected (yes/no) 
5 STUDY DESIGN AND COURSE OF STUDY 
5.1 General Study Design and Justification of the Design 
This is a pilot study of healthy volunteers, open label, and single center. We will use a parallel 
assignment of Arm A and B without masking (open label). Allocation is non-randomized, we will 
start with group A, followed by group B.  

 
 
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If we see promising results, we will plan a prospective clinical trial in patients undergoing hip 
arthroplasty surgery. 
The intended procedures are PDT on the first day followed by skin swabbing for control of skin 
microbiome of treated area immediately after PDT (day 0) and after 1, 3 and 5 days of PDT to 
analyze how long the effect lasts. 
We think that this study design with healthy volunteers is adequate before starting a clinical trial.  
 
5.2 Study Duration and Study Schedule 
The expected duration of participant’s participation is 6 days from first study visit to the last 
follow-up time to report side effects of photodynamic treatment. The screening visit can be any 
time before but at least 1 week before the first study visit. The study schedule is indicated 
below.  
 
 

 
 
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Figure 1. Flow chart of the study* 
 
 
*Visit 2 must be within 24 hours after photodynamic treatment 
** same participants as in the PDT group but swabs and skin antisepsis on the contralateral leg 
site 
 
At the screening visit, the voluntary participant will be informed and asked for signing the informed 
consent by Dr. Yvonne Achermann. This visit and the last visit will be at the outpatient clinic for 
Infectious Diseases at the University Hospital Zurich. Demographic data (age, sex, current 
medications, and underlying diseases) will be noted.  
Appointments for the photodynamic treatment (day 0) and the control visits (day 1, 3 and 5) will 
be made.  
 
Study schedule:  
Group A (MAL group):  
On day 0, a skin scraping of the groin will be performed and sent for microbiological culture. Then, 
5% topical methyl aminolevulinate (MAL) as the prodrug for the photosensitizer Pp IX will be 
applied (5 x 10cm in the right groin) and the photodynamic process will be started by irradiation 
of the area with day light source. 
Group B (Methylene blue group) 
On day 0, a skin scraping of the groin will be performed and sent for microbiological culture. Then, 
5ml of the 0.01% methylene blue based photosensitizer (NF-031) will be applied for an area of 5 
x 10cm in the right groin of the patient. Immediately after application, the photodynamic process 
will be started by irradiation of the area with 40J/cm2 red light from a 635nm (absorption peak 
670nm) emitting LED during 4 minutes.  
 

 
 
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Immediately after the PDT, skin antisepsis will be performed. Antisepsis of the skin is performed 
with a povidone-iodine/alcohol solution (Betaseptic®, Mundipharma, Limburg, Germany) and 
repeated three times for a total duration of 3 minutes to imitate standard surgical antisepsis before 
a hip arthroplasty surgery. Skin scraping will be repeated after the antisepsis and after 1, 3 and 5 
days for bacterial cultures.  
As a control group, we will take skin swabs before and after skin antisepsis without PDT on the 
contralateral site of all participants. 
 
On day 5 of the study, volunteers will be seen for the last study visit to document any adverse 
effects.  
5.3 Methods of Minimizing Bias  
Excluded bias in our collective 
- 
No selected participants 
- 
Both sexes can be included 
- 
Any age 
Potential bias in our collective: 
- 
Since we will search for healthy volunteers, the microbiome analysis might be slightly 
different to the population undergoing a hip arthroplasty surgery in an orthopedic hospital.  
6 STUDY POPULATION 
Ten healthy male and female volunteers’ ≥ 18 years in each arm will be recruited for this clinical 
study.  
6.1 Eligibility Criteria 
6.1.1 Inclusion Criteria 
Patients fulfilling all of the following inclusion criteria may be enrolled in the study 
Inclusion criteria: 
Healthy male and female participants ≥ 18 years who 
• 
volunteer for the pilot study in which PDT will be applied and effect of skin colonization will 
be analyzed, and 
• 
an informed consent is signed by the participant (after information about the project). 
6.1.2 Exclusion Criteria 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
 
Exclusion criteria: 
• 
Pregnant and lacting women 
• 
Participants inability to follow the procedures of the study, e.g. due to language problems, 
psychological disorders, dementia, etc., 
• 
Participants taking antibiotics in the 14 days prior to PDT or until follow-up at 14 days 
• 
Participants who received oral retinoid therapy within the last 6 months 
• 
Participants who received anti-inflammatory agents as NSAR within the 14 days prior and 
after the PDT 
• 
Photodermatoses Participants taking any photosensitizing drugs within 4 weeks prior to PDT 
• 
Fitzpatrick’s skin phototype V-VI 

 
 
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6.2 Recruitment and Screening 
Volunteers for this pilot study will be recruited by the Division of Infectious Diseases of the 
University Hospital Zurich with a flyer (appendix 2) as a recruitment tool (on pinboard at the 
University Hospital Zurich and the University Hospital Balgrist). Written informed consent will be 
taken under supervision of PD Dr. Y. Achermann.  
The participants will be informed in writing and verbal on: 
• 
The nature, purpose and duration of, and procedure for the research project; 
• 
Their right to withhold or to revoke their consent at any time without giving reasons; 
• 
Their right to receive information at any time in response to further questions relating to the 
research project; 
• 
Their right to be informed of results concerning their health, and their right for such 
information or to designate a person who is to take this decision for them; 
• 
Measures to protect the biological material and the personal data 
 
All participants will have enough time to decide whether to participate or not (at least 1 week).  
The formal consent of a participant will be obtained before the participant is submitted to any 
study procedure. The consent form will be signed and dated by the investigator or his designee 
at the same time as the participant sign. A copy of the signed informed consent will be given to 
the study participant. The form will be retained as part of the study records in the patient file.  
 
There will be a financial compensation (value CHF 50.00) to the participants.  
6.3 Criteria for Withdrawal/ Discontinuation of Participants 
A participant must be withdrawn from the study if 
- 
safety reasons of PDT (other side effects than expected, or more intense known side 
effects).  
- 
Withdrawal of participant informed consent  
Participants who discontinued the study (premature withdrawal) will be follow-up at least once 
after PDT treatment (1 week) to ask for side effects. If no intervention was done, no follow-up is 
needed.  
After withdrawal of consent, the encoded patient samples and data will be analyzed. After 
analysis, the samples and data will be completely anonymised (according to Art. 9 KlinV), 
except if the participant has consented to further use of the samples and data and not 
withdrawn his consent. In this case, the samples and data will be stored as mentioned in 
chapter 12.6." 
7 STUDY INTERVENTION 
7.1 General Information 
The following flowchart shows all steps described in the study plan:  

 
 
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7.1.1 Study Intervention 
Study Intervention(s) (group A and B) 
 
Who 
List of interventions 
PD Dr. med. Yvonne Achermann 
Skin antisepsis, taking swabs, PDT with MAL 
(group A) or Methylene blue (group B) 
* In collaboration with Dr. med. Laurence Imhof from the Department of dermatology and Prof. 
Heinrich Walt (emeritus Professor of the University of Zurich, group leader of oral oncology).    
7.1.2 Control Intervention 
Skin antisepsis without PDT on the contralateral site of the first 10 participants 
7.2 Administration of Study Intervention 
7.2.1 Study Intervention  
Since the clinic of dermatology is located in the circle and not anymore in the main campus of 
the University Hospital of Zurich, the study intervention on day 0 is at the circle.  
The following visits can be done at the main campus at the department of Infectious Diseases. 
Details of study Intervention 
Justification 
1. Inguinal skin scraping before PDT 
Baseline microbiome data 
2. Photosensitizer application, followed by PDT 
(1x)  
Treatment to reduce colonization bacteria 
3. Skin scraping, skin antisepsis in the groin, 
skin scraping after antisepsis 
To measure bacterial colonization after PDT – 
before and after skin antisepsis 

 
 
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7.2.2 Modification of Interventions 
Trial is not modifiable 
7.3 Compliance with Intervention 
There will be no compliance problem of the study participant since the intervention takes place at 
the visits. No intervention by the participant is needed except reporting of adverse effects. 
7.4 Data Collection and Follow-up for Withdrawn Participants  
Not applicable 
7.5 Concomitant Intervention(s) 
Since we only include participants for our analysis who do not take antibiotics or NSAR in the 14 
days prior to the photodynamic treatment or until follow-up at 14 days, we will inform on that issue 
at the screening and at each study visit. We will record it in our eCRF.  
 

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8 STUDY PROCEDURES 
8.1 Table of Study Procedures and Assessments 
 
Study plan: Effects of PDT on the human inguinal skin microbiome to improve antiseptic effect 
 
Study tasks 
Screening 
Intervention Period 
Visit 
Visits 
0 
1 
2 
3 
4 
 
at least -7 
days 
before visit 
1 
0 
1 
(within 
24 
hours) 
3 
5 
1. Participant information and informed 
consent 
√ 
 
 
 
 
2. Inclusion- and exclusion criteria 
√ 
 
 
 
 
3. Demographic data 
√ 
 
 
 
 
4. Inguinal 
skin 
scraping 
before 
photodynamic treatment 
 
√ 
 
 
 
5. Study intervention: PDT  
 
√ 
 
 
 
6. Skin antisepsis in the groin, skin 
scraping before and after antisepsis 
 
√ 
√ 
√ 
√ 
7. (serious) adverse events 
 
√ 
√ 
√ 
√ 
8. End of study information of study 
results 
 
 
  
√ 

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Skin scrapping 
For all skin swabs, we will apply the scratching method using a scalpel as described previously 
(Boni, Kuster et al. 2018) and illustrated below in Figure 2. The swabs will be analyzed for bacterial 
growth. The remaining sample will be immediately frozen at -80C° for later molecular analysis 
such as metagenomics. 
  
Figure 2. Specimen collection in the groin of the hip before disinfection. 
Skin scrapings will be removed with sterile blades and transferred to 
ESwab culture swabs (Copan).  
T, musculus tensor fascia latae; Tr, trochanter  
 
 
Photodynamic treatment 
Group A (MAL group):  
On day 0, a skin scraping of the groin will be performed and sent for 
microbiological culture. Then, 5% topical methyl aminolevulinate (MAL) as the prodrug for the 
photosensitizer Pp IX will be applied under occlusion in the right groin of the patient. After the 
incubation, the PDT will be started by irradiation of the area with day-light.  
Group B (Methylene blue) 
On day 0, a skin scraping of the groin will be performed and sent for microbiological culture. Then, 
5ml of the 0.01% methylene blue based photosensitizer (NF-031) will be applied for an area of 5 
x 10cm in the right groin of the patient. Immediately after application, the PDT will be started by 
irradiation of the area with 40J/cm2 red light from a 635 emitting LED during 4 minutes.  
 
Skin antisepsis 
After PDT, we will perform skin antisepsis as routinely done in clinics three times with a povidone-
iodine/alcohol solution (Betaseptic®, Mundipharma, Limburg, Germany) for a total duration of 3 
minutes to imitate standard surgical antisepsis before a hip arthroplasty surgery.  
8.2 Assessments of Outcomes  
8.2.1 Assessment of Primary Outcome  
What  
When 
How 
Bacterial density and species 
of skin swabs  
Visit 1, 2, 3 and 4 
Skin swab, microbiological 
diagnostic methods (see 
below) 
 
Microbiology 
In short, the patient’s sample swabs will be streaked out onto Columbia sheep blood agar plate 
without antibiotics (bioMérieux, Mary-l’Etoile, France), colistin-nalidixic acid (CNA) blood agar 
(bioMérieux) plate for aerobic cultivation and a Brucella plate (in-house sheep blood agar plates 
with hemin and vitamin K1) for anaerobic cultivation using GENbag (bioMérieux). Final 
identification will be done by matrix-assisted laser desorption ionization-time of flight mass 
spectrometry spectrometry (MALDI-TOF MS) using a Bruker MALDI Biotyper. The amount of 
bacteria will be semiquantitiative described as +, ++, +++ based on growth on agar plates. All 
cultured microorganisms will be stored in skim milk at -80C° for potential subsequent analysis 
by whole genome sequencing for analyzing the secondary outcome.  
8.2.2 Assessment of Secondary Outcomes 
To evaluate the bacterial dynamics on the skin after PDT and skin antisepsis within one week 

 
 
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using PCR technique in collaboration with PD Dr. sc. nat. Philipp Bosshard, Laborleiter FAMH at 
the clinic for dermatology at the University Hospital of Zurich.  
 
What  
When 
How 
Bacterial dynamics 
After termination of all study 
participants 
Real-Time PCR 
8.2.3 Assessment of Safety Outcomes 
8.2.3.1 
Serious Adverse Events  
Recording of serious adverse event (SAE) information time of onset, duration, resolution, action 
to be taken, assessment of intensity, and relationship with study intervention.  
8.2.4 Assessments in Participants who prematurely Stop the Study 
Participants who are withdrawn from the study prematurely due to adverse event, will be followed-
up until adverse-effects disappeared. Follow up may include but is not limited to physical 
examination, laboratory tests, vital signs, telephone calls. Outcomes and resolution of events will 
be recorded in the Case Report Forms. In case of lost to follow up, efforts will be made to contact 
the patient or to ascertain the vital status of the participant. 
8.3 Procedures at Each Visit 
8.3.1 Screening Visit 
Screening visit,– at least -7 days before the study start  
- 
Information of the study and all necessary study visits 
- 
Check for In- and Exclusion criteria 
- 
Enrollment if agree to participate in study 
- 
Enter basic demographic parameters in electronic CRF (age, sex, current medications, and 
underlying diseases) 
- 
Scheduling of all study visits 
Duration: ca. 30 minutes 
Location: Division of Infectious Diseases, University Hospital Zurich 
 
8.3.2 Visit 1 = Day 0 of the study 
Group A (MAL group):  
On day 0 with Dr. Achermann, a skin scraping of the groin will be performed and sent for 
microbiological culture. Then, 5% topical methyl aminolevulinate (MAL) as the as the prodrug for 
the photosensitizer Pp IX will be applied (5 x 10cm in the right groin) and followed by irradiation 
of the area with day light. 
Group B (Methylene blue group) 
On day 0 with Dr. Achermann, a skin scraping of the groin will be performed and sent for 
microbiological culture. Then, 5ml of the 0.01% methylene blue based photosensitizer (NF-031) 
will be applied for an area of 5 x 10cm in the right groin of the patient. Immediately after 
application, the photodynamic process will be started by irradiation of the area with 40J/cm2 red 
light from a 635 emitting LED during 4 minutes.  
 
Immediately after the PDT, skin antisepsis will be performed. Antisepsis of the skin is performed 
with a povidone-iodine/alcohol solution (Betaseptic®, Mundipharma, Limburg, Germany) and 

 
 
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repeated three times for a total duration of 3 minutes to imitate standard surgical antisepsis before 
a hip arthroplasty surgery.  
For all inguinal swabs, we will use the scratching method using a scalpel as already applied in a 
previous study (ethical approval BASEC-Nr 2016-01017). The swabs will be sent to the 
microbiology laboratory of the University of Zurich for bacterial analysis (analysis under 
supervision of Prof. R. Zbinden).  
 
Duration: 1-2 hours 
Location: Clinic for Dermatology (located in the Circle since October 2020), University Hospital 
Zurich 
 
8.3.3 Visit 2, 3, 4 (day 1, 3, 5) 
Skin scraping after skin antisepsis will be repeated 1, 3, and 7 days later and analyzed for bacterial 
cultures.  
In short: 
- 
Inguinal skin scraping 
- 
Skin antisepsis 
- 
Inguinal skin scraping  
- 
Documentation of adverse effects 
Duration: 30 - 60 minutes 
Location: Division of Infectious Diseases, University Hospital Zurich 
9 SAFETY 
During the entire duration of the study, all serious adverse events (SAEs) that may be causally 
related to the study intervention are collected and documented in source documents. Reportable 
events are recorded in the case report form (CRF). Study duration encompassed the time from 
when the participant signs the informed consent until the last protocol-specific procedure has 
been completed, including a safety follow-up period.  
In order to guarantee participants’ safety and health, further adverse events which must be 
documented or reported are to be designated in the protocol or at the request of the responsible 
CEC. 
9.1 Definitions 
Adverse events 
Adverse events (AEs) are defined as any untoward medical occurrence in a patient or clinical 
investigation participant after the intervention and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any favorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
intervention, whether or not related to the intervention. An AE may also consist of a new disease, 
an exacerbation of a pre-existing illness or condition, a recurrence of an intermittent illness or 
condition, a set of related signs or symptoms, or a single sign or symptom. 
 
Serious Adverse Event 
A serious adverse event is defined as any event which: 
• 
requires inpatient treatment not envisaged in the protocol or extends a current 
• 
hospital stay; 
• 
results in permanent or significant incapacity or disability; 
• 
is life-threatening or results in death; or 
• 
causes a congenital anomaly or birth defect. 

 
 
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9.2 Recording and Assessment of Serious Adverse Events 
The investigator has the responsibility for SAE identification, documentation, and assessing the 
causal relationship study intervention. 
All SAEs will be fully documented in the appropriate eCRF. For each SAE, the investigator will 
provide the onset, duration, treatment required, outcome and action taken with regard to the study 
intervention.  
The assessment by the investigator with regard to the study intervention relation is done 
according to the following definitions: 
Unrelated 
• 
The event started in no temporal relationship to the medical 
intervention applied and  
• 
The event can be definitely explained by underlying diseases or other 
situations. 
Related 
 
• 
The event started in a plausible temporal relationship to the medical 
intervention applied and  
• 
The event cannot be definitely explained by underlying diseases or 
other situations. 
9.3 Reporting of Serious Adverse Events 
If, in the course of a clinical trial, serious adverse events occur in participants in Switzerland, and 
it cannot be excluded that the events are attributable to the intervention under investigation, the 
investigator must report these events: 
• 
to the CEC within 15 days. 
 
Safety and protective measures 
If immediate safety and protective measures have to be taken during the conduct of this clinical 
trial, the investigator must notify the CEC of these measures, and of the circumstances 
necessitating them, within 7 days. 
 
Annual Safety Report  
All SAEs will be summed up in the annual safety report (ASR) and submitted to the CEC. ASR 
shall contain:  
- 
A summary of events including severity and causal relationship to the intervention and on 
the safety of participants. 
- 
The accompanying letter provided with the Annual Safety Report should contain a short 
summary of the status of the clinical trial in Switzerland (number of centers open/closed, 
number of patients recruited/recruitment closed, and number of SAEs). 
9.4 Follow up of (Serious) Adverse Events 
Participants terminating the study (either regularly or prematurely) with 
• 
reported ongoing SAE, or 
• 
any ongoing AEs of laboratory values or of vital signs being beyond the alert limit 
will return for a follow-up investigation. This visit will take place up to 30 days after terminating the 
treatment period. Follow-up information on the outcome will be recorded on the respective SAE 
page in the eCRF.  

 
 
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10 STATISTICAL METHODS  
Categorical data will be tested for differences using Fisher’s exact or chi-squared tests, as 
appropriate, whereas continuous variables will be tested using Wilcoxon rank sum tests. 
10.1 Hypothesis 
We hypothesize that PDT improves skin antisepsis by reduction of persistent skin colonizing 
bacteria by its bactericidal effects. 
10.2 Determination of Sample Size  
Aim: 20 volunteers to show the effect of PDT in healthy volunteers.  
10.3 Planned Analyses  
• 
As a pilot study, we plan to do descriptive statistics only.  
• 
Categorical date will be tested for differences using Fisher’s exact or chi-squared tests. 
• 
Continuous variables will be tested using Wilcoxon rank sum tests.  
• 
Data will be analyzed using Stata® version 14.2 (Stata Corporation, College Station, TX). 
Two-tailed P-values <0.05 are considered statistically significant. 
10.3.1 Datasets to be Analyzed, Analysis Populations 
All Study participants that terminated the study (n = max 20 volunteers) 
10.3.2 Primary Analysis 
Descriptive comparisons of microbiological data before and after PDT by Dr. Achermann 
 
10.3.3 Secondary Analyses 
Statistical analysis of microbiological data using whole-genome analysis: will be done by Dr. 
Achermann in collaboration with the Institute of Medical Microbiology and the Clinic for 
Dermatology.  
These analysis will be done after termination of all study participants 
10.3.4 Interim Analyses 
No interim analyses is needed for this small study design. 
 
10.3.5 Safety Analysis 
Analysis of SAE as standard (number of adverse and serious adverse events) 
 
10.3.6 Deviation(s) from the Original Statistical Plan  
Not applicable. 
10.4 Handling of Missing Data and Drop-Outs  
Missing outcome data will be handled as missing. No imputation methods will be used. 
11 ELIGIBILITY OF THE PROJECT SITE(S) 
PD Dr. med. Yvonne Achermann as the project leader is an Infectious Disease attending 
physician with a lot of experience in the field of orthopedic infections working at the University 
Hospital of Zurich. She will be responsible for the study design/protocol, perform skin swabs, PDT 
in collaboration with the Division of dermatology and with the PDT expert Prof. Heinrich Walt. She 
will also analyze microbiological cultures in collaboration with the institute for microbiology (IMM, 

 
 
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with Prof. R. Zbinden). 
Dr. med. Laurence Imhof is the head of Laser Medicine, Photodermatology and Radiation 
Therapy. She has a lot of experience in photodynamic treatment and will therefore advice us in 
any study questions regarding photodynamic treatment as indicated in the study plan. 
PD Dr. med. Yvonne Achermann and Dr. med. Laurence Imhof are trained in Good Clinical 
Practice. 
Prof. Dr. med. Reinhard Zbinden provides the infrastructure for examining the skin swabs.  
12 DATA QUALITY ASSURANCE AND CONTROL 
The Sponsor-Investigator is implementing and maintaining quality assurance and quality control 
systems with written SOPs and Working Instructions to ensure that trials are conducted and data 
are generated, documented (record), and reported in compliance with the protocol, GCP, and 
applicable regulatory requirement(s).  
 
12.1 DATA HANDLING AND RECORD KEEPING 
The study will strictly follow the protocol. If any changes become necessary, they must be laid 
down in an amendment to the protocol. All amendments of the protocol must be signed by the 
Sponsor-Investigator and if essential submitted to CEC.  
12.1.1 Case Report Forms  
The investigators will use electronic case report forms eCRF, one for each enrolled study 
participant, to be filled in with all relevant data pertaining to the participant during the study. All 
participants who either entered the study or were considered not-eligible or were eligible but not 
enrolled into the study additionally have to be documented on a screening log. The investigator 
will document the participation of each study participant on the Enrolment Log.  
For studies with electronic CRF: 
For data and query management, monitoring, reporting and coding an internet-based secure data 
base Redcap® developed in agreement to the Good Clinical Practice (GCP) guidelines will be 
used for this study. It is the responsibility of the investigator to assure that all data in the course 
of the study will be entered completely and correctly in the respective data base. Corrections in 
the eCRF may only be done by the investigator or by other authorized persons. In case of 
corrections the original data entries will be archived in the system and can be made visible. For 
all data entries and corrections date, time of day and person who is performing the entries will be 
generated automatically. 
CRFs/eCRFs will be kept current to reflect participant status at each phase during the course of 
study. Participants must not to be identified in the eCRF by name. Appropriate coded identification 
(e.g. Participant Number) will be used.  
We assure that any authorized person, who may perform data entries and changes in the eCRF, 
can be identified. A list with signatures and initials of all authorized persons will be filed in the 
study site file and the trial master file, respectively. 
The investigators assure to perform a complete and accurate documentation of the participant 
data in the eCRF. All data entered into the eCRF must also be available in the individual 
participant file either as print-outs or as notes taken by either the investigator or another 
responsible person assigned by the investigator.  
Essential documents must be retained for at least 10 years after the regular end or a premature 
termination of the respective study (KlinV Art. 45).  

 
 
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Any patient files and source data will be archived for the longest possible period of time according 
to the feasibility of the investigational site, e.g. hospital, institution or private practice. 
12.1.2 Specification of Source Documents 
The following documents are considered source data, including but not limited to: 
• 
SAE worksheets 
• 
Nurse records, records of clinical coordinators, and  
Source data must be available at the site to document the existence of the study participants and 
substantiate the integrity of study data collected. Source data must include the original documents 
relating to the study, as well as the medical treatment and medical history of the participant. 
The following information (at least but not limited to) should be included in the source documents: 
• 
Demographic data (age, sex) 
• 
Inclusion and Exclusion Criteria details  
• 
Participation in study and signed and dated Informed Consent Forms  
• 
Visit dates  
• 
Microbiological data (identification of bacteria) 
• 
Side effects of PDT (pain, redness) 
• 
SAEs (related) and concomitant medication  
• 
Reason for premature discontinuation  
12.1.3 Record Keeping / Archiving  
All study data will be archived for a minimum of 10 years after study termination or premature 
termination of the clinical trial (at the Division of Infectious Diseases, University Hospital Zurich). 
12.2 Data Management  
All basic demographic data, all microbiological and histopathological results will be manually 
entered in an automatically secured online processing system (REDCap® electronic data 
capture system). The PI will check and validate data on a regular basis for consistency. 
All study data are encrypted in REDCap®. The principal investigator is responsible for data 
collection and will keep the screening log, which guarantees the confidentiality of data by the 
use of participant ID numbers. The participant ID numbers are automatically assigned in 
consecutive ascending form by the REDCap® system. For the purpose of fulfilling their task, the 
principal investigator grants the necessary access authorization in the form of user log-in and 
password to the study staff. Thus, the data cannot be altered in any way by unauthorized 
persons. In the REDCap® system, all relevant processing operations are documented in a user-
specific manner in order to ensure traceability. This is done by means of registration software, 
which records who has edited which data at which time. 
 
All patients have to give their written consent to the project. These informed consents 
documents (IC) will be stored according to ethical regulations. 
 
Health related personal data captured during this project from participants are strictly 
confidential and disclosure to third parties is prohibited; coding will safeguard participants' 
confidentiality. Confidentiality will be ensured by using coded data. The code will be protected 
against unauthorized access and will be stored appropriately. Data will be stored for up to 10 
years after publishing the study as requested by most journals.  
 
• 
Patient’s and microbiological data:  
 

 
 
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o Yvonne Achermann will be responsible for basic characteristics of the volunteers 
of this pilot study. After the last study visit, data will be encoded by the PI and 
safely stored at the Investigator Site File.  
o Clinical and microbiological data will be saved in the electronical database 
Redcap (see above) 
o The collected project data may be subject to inspection by the CEC. 
 
• 
Handling of isolated bacteria of the scrapped skin samples:  
The sub-cultivated bacterial samples will be stored and labeled with an encoded name at 
-80°C at the bacteriology laboratory of the Division of Infectious Diseases and Hospital 
Epidemiology (responsible Yvonne Achermann). The code for the bacterial strains with 
correspondence to patient data will be stored at the Investigator Site File. 
12.3 Routine Monitoring 
Since we only measure microbiological data from skin samples, we think, that an interne 
monitoring would be adequate. This would include:  
- 
Microbiological study part (cultivation procedures) under supervision of Prof. Zbinden. 
Regular control of study result by a microbiologist not involved in the study (to be 
determined) 
- 
Data entry will be done by a doctorand or research associate and by the study nurse by a 
4-eyes control. Control of data entry, informed consents, and SAE will be done by the 
sponsor and by Dominique Braun (attending physician of the Division of Infectious 
Diseases and Hospital Epidemiology) on a regular base (4-eyes principle).  
12.4 Audits and Inspections 
A quality assurance audit/inspection of this study may be conducted by the CEC. The quality 
assurance auditor/inspector will have access to all medical records, the investigator's study 
related files and correspondence, and the informed consent documentation that is relevant to this 
clinical study. 
The investigator will allow the persons being responsible for the audit or the inspection to have 
access to the source data/documents and to answer any questions arising. All involved parties 
will keep the patient data strictly confidential. 
12.5 Confidentiality, Data Protection  
Direct access to source documents will be permitted for purposes of monitoring, audits and 
inspections. 
12.6 Storage of Biological Material and Related Health Data  
Encoded data will be stored for up to 10 years after publishing the study as requested by most 
journals.  
The biological material will be labeled with an encoded name and stored at -80°C at the Division 
of Infectious Diseases and Hospital Epidemiology by the end of the study and destroyed after 
the end of the study. With the second signature in the study informed consent, further use of 
data and the biological material for other research projects is possible. 
 
13 PUBLICATION AND DISSEMINATION POLICY  
After the statistical analysis of this trial the sponsor will make every endeavor to publish the data 
in a medical journal.  
Data of this study can only be published if Reinhard Zbinden, Laurence Imhof and Yvonne 
Achermann agree on the data presentation, analysis, and authors list.  

 
 
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 Commitment for study coordination, ethical protocol, generate microbiological data, 
data entry, study analysis: Division of Infectious Diseases and Hospital Epidemiology, USZ (Dr. 
Achermann) 
 Commitment for PDT application: Clinic for Dermatology, University Hospital of Zurich (Dr. 
Imhof) 
 Commitment for bacterial culture, bacterial identification, storage: Institut of Medical 
Microbiology, UZH (Prof. Zbinden) 
The Principal Investigator will perform the study in accordance with the current protocol version. 
The Principal Investigator will ensure that any investigators and any other staff comply with the 
terms of the Protocol and this agreement. 
14 FUNDING AND SUPPORT  
14.1 Funding  
This study is financed by the sponsor and PI (Yvonne Achermann) 
External funding is provided by the Vontobel foundation. The company Galderma and Ondine 
company will provide the photosensitizers.  
14.2 Other Support  
15 INSURANCE 
Insurance is covered by “Versicherung für klinische Versuche und nichtklinische Versuche“ by 
Zürich Versicherungs-Gesellschaft AG (Policy no.: 14.970.888). 
Any damage developed in relation to study participation is covered by this insurance. So as not 
to forfeit their insurance cover, the participants themselves must strictly follow the instructions of 
the study personnel. Participants must not be involved in any other medical treatment without 
permission of the principal investigator (emergency excluded). Medical emergency treatment 
must be reported immediately to the investigator. The investigator must also be informed instantly, 
in the event of health problems or other damages during or after the course of study treatment. 
The investigator will allow delegates of the insurance company to have access to the source 
data/documents as necessary to clarify a case of damage related to study participation. All 
involved parties will keep the patient data strictly confidential. 
A copy of the insurance certificate will be placed in the Investigator’s Site File. 
 
 

 
 
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16 REFERENCES 
Awad, M. M., A. Tovmasyan, J. D. Craik, I. Batinic-Haberle and L. T. Benov (2016). "Important cellular 
targets for antimicrobial photodynamic therapy." Appl Microbiol Biotechnol 100(17): 7679-7688. 
Berrios-Torres, S. I., C. A. Umscheid, D. W. Bratzler, B. Leas, E. C. Stone, R. R. Kelz, C. E. Reinke, S. 
Morgan, J. S. Solomkin, J. E. Mazuski, E. P. Dellinger, K. M. F. Itani, E. F. Berbari, J. Segreti, J. Parvizi, J. 
Blanchard, G. Allen, J. Kluytmans, R. Donlan, W. P. Schecter and C. Healthcare Infection Control Practices 
Advisory (2017). "Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site 
Infection, 2017." JAMA Surg 152(8): 784-791. 
Boni, L., S. P. Kuster, B. Bartik, R. Zbinden, P. O. Zingg and Y. Achermann (2018). "Association of 
Cutibacterium avidum Colonization in the Groin With Obesity: A Potential Risk Factor for Hip Periprosthetic 
Joint Infection." Clin Infect Dis 67(12): 1878-1882. 
Borgia, F., R. Giuffrida, E. Caradonna, M. Vaccaro, F. Guarneri and S. P. Cannavo (2018). "Early and Late 
Onset Side Effects of Photodynamic Therapy." Biomedicines 6(1). 
Bratzler, D. W., E. P. Dellinger, K. M. Olsen, T. M. Perl, P. G. Auwaerter, M. K. Bolon, D. N. Fish, L. M. 
Napolitano, R. G. Sawyer, D. Slain, J. P. Steinberg, R. A. Weinstein, P. American Society of Health-System, 
A. Infectious Diseases Society of, S. Surgical Infection and A. Society for Healthcare Epidemiology of 
(2013). "Clinical practice guidelines for antimicrobial prophylaxis in surgery." Surg Infect (Larchmt) 14(1): 
73-156. 
Dumville, J. C., E. McFarlane, P. Edwards, A. Lipp and A. Holmes (2013). "Preoperative skin antiseptics 
for preventing surgical wound infections after clean surgery." Cochrane Database Syst Rev(3): CD003949. 
Dumville, J. C., E. McFarlane, P. Edwards, A. Lipp, A. Holmes and Z. Liu (2015). "Preoperative skin 
antiseptics for preventing surgical wound infections after clean surgery." Cochrane Database Syst Rev(4): 
CD003949. 
Lee, M. J., P. S. Pottinger, S. Butler-Wu, R. E. Bumgarner, S. M. Russ and F. A. Matsen, 3rd (2014). 
"Propionibacterium persists in the skin despite standard surgical preparation." J Bone Joint Surg Am 96(17): 
1447-1450. 
Matsen, F. A., 3rd, S. M. Russ, A. Bertelsen, S. Butler-Wu and P. S. Pottinger (2015). "Propionibacterium 
can be isolated from deep cultures obtained at primary arthroplasty despite intravenous antimicrobial 
prophylaxis." J Shoulder Elbow Surg 24(6): 844-847. 
Pulido, L., E. Ghanem, A. Joshi, J. J. Purtill and J. Parvizi (2008). "Periprosthetic joint infection: the 
incidence, timing, and predisposing factors." Clin Orthop Relat Res 466(7): 1710-1715. 
Rubel, D. M., L. Spelman, D. F. Murrell, J. A. See, D. Hewitt, P. Foley, C. Bosc, D. Kerob, N. Kerrouche, 
H. C. Wulf and S. Shumack (2014). "Daylight photodynamic therapy with methyl aminolevulinate cream as 
a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic 
keratosis treatment: a randomized controlled trial." Br J Dermatol 171(5): 1164-1171. 
Sakamoto, F. H., J. D. Lopes and R. R. Anderson (2010). "Photodynamic therapy for acne vulgaris: a critical 
review from basics to clinical practice: part I. Acne vulgaris: when and why consider photodynamic 
therapy?" J Am Acad Dermatol 63(2): 183-193; quiz 193-184. 
Tande, A. J. and R. Patel (2014). "Prosthetic joint infection." Clin Microbiol Rev 27(2): 302-345. 
Waldmann, I., T. Schmid, J. Prinz, B. Muhleisen, R. Zbinden, L. Imhof and Y. Achermann (2020). 
"Photodynamic therapy improves skin antisepsis as a prevention strategy in arthroplasty procedures: A 
pilot study." Photodiagnosis Photodyn Ther: 101941. 
Wiegell, S. R., M. Haedersdal, P. A. Philipsen, P. Eriksen, C. D. Enk and H. C. Wulf (2008). "Continuous 
activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy 
for actinic keratoses; a randomized, controlled, single-blinded study." Br J Dermatol 158(4): 740-746. 
 
 

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17 APPENDICES 
 
Appendix 1: Documentation of PDT (example for MAL PDT) 
 
 

 
 
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Appendix 2. Flyer 
Auswirkungen der Lichttherapie auf Hautbakterien 
 
 
Probandinnen und Probanden gesucht 
 
Für eine wissenschaftliche Studie suchen wir Frauen und Männer mit 
Mindestalter 18 Jahre für die Untersuchung der Hautbakterien vor und 
nach einer Lichttherapie. 
 
Ziel der Studie: Es ist bekannt und natürlich, dass Bakterien die ganze Haut – inklusive 
Schweiss- und Talgdrüsen - kolonisieren. Vor Operationen wird die Haut desinfiziert um diese 
Bakterien abzutöten. Leider ist diese Präventionsmassnahme nicht 100% effektiv. Die Gefahr 
besteht, dass noch vorhandene Bakterien mit dem chirurgischen Schnitt in die Tiefe 
vorgeschleppt werden und dort eine Infektion verursachen können. Aus diesem Grund müssen 
die gegenwärtigen Desinfektionsprozesse hinterfragt und verbessert werden. Mit dieser Studie 
am Universitätsspital Zürich untersuchen wir, ob die Lichttherapie Hautbakterien abtöten. Diese 
Therapie ist auf der Klinik für Dermatologie etabliert, wird gut vertragen und es entstehen keine 
Folgeschäden.  
 
Ablauf: Die Studienteilnahme beinhaltet maximal 5 Termine innerhalb von 2 Wochen. Diese 
finden entweder in der Klinik für Infektionskrankheiten oder der Klinik für Dermatologie statt. Der 
erste Termin dauert ca. 20 Minuten und dient der Studienaufklärung und Abklärung zur 
Teilnahme. Der erste Studientermin dauert bis maximal 2 Stunden und beinhaltet die 
Lichttherapie mit Hautabstrichen vor und nachher. Die zweite, dritte und vierte Studienvisite 
dauert ca. 30 Minuten zur Kontrolle der Hautbakterien und zum Studienabschluss.  
 
 
Alle Daten werden vertraulich behandelt. Für die Versuchspersonen ergibt sich kein direkter 
medizinischer Nutzen. Es gibt eine Entschädigung von CHF 50.00 für die Teilnahme. Alle 
Untersuchungen sind kostenlos.  
 
Wir würden uns freuen, wenn Sie an einer Studienteilnahme interessiert sind. Sie können gerne 
per Email oder telefonisch mit PD Dr. Yvonne Achermann Kontakt aufnehmen: 
 
yvonne.achermann@usz.ch;  
Tel: +41 44 255 34 02 direkt oder übers Sekretariat (044 255 33 22) 
 
 
Bitte nehmen Sie zur Kenntnis, dass ihre Daten bei Zustandekommen eines Kontakts registriert 
werden. Sollten Sie später nicht einer Teilnahme interessiert sein, werden ihre Daten 
unverzüglich gelöscht.  
 
 
 
Dieses Projekt ist organisiert durch:  
PD Dr. med. Yvonne Achermann, Klinik für Infektionskrankheiten, Universitätsspital Zürich  
und Dr. med. Laurence Imhof, Klinik für Dermatologie, Universitätsspital Zürich