Urtica Comp. Gel for Prevention and Therapy of Radiation Dermatitis (An Interdisciplinary, Interprofessional Phase II Randomized Controlled Trial in Patients With Breast Cancer)
Phase: PHASE2
Conditions: Radiation Dermatitis
Sponsor: University of Bern

Urtica comp. gel for prevention and therapy of radiation dermatitis 
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Urtica comp. gel for prevention and therapy of 
radiation dermatitis     
An interdisciplinary, interprofessional Phase II randomized controlled trial 
in patients with breast cancer 
Urtica comp. zur Vorbeugung und Behandlung von Strahlenerythem 
[Short title: Urtica comp for radiation dermatitis / Urtica comp. gel für Strahlenerythem] 
 
Clinical Study Protocol 
Study Type: 
Clinical trial with Investigational Medicinal Product (IMP)  
Study Categorisation: 
Risk category according to LHR : A 
Study Registration: 
Name of study registry:  clintrial.gov  
[NCT ID not yet assigned]   Unique Protocol ID: 211820931 
 
Applicant (and  Investigator): 
 
 
 
 
Sponsor 
and 
Principal 
Investigator: 
 
 
 
 
Study coordinator 
(/Project Leader): 
 
 
Prof. Dr. med. Ursula Wolf, Universität Bern,  
Institut für Komplementärmedizin,  Fabrikstrasse 8, 3012 Bern 
Phone: +41 (0)31 631 81 40 
Email: ursula.wolf@ikom.unibe.ch 
 
Dr. med. Nicola Cihoric, Inselspital,  
Universitätsklinik für Radio-Onkologie 
Freiburgstr. 4 , Inselspital, Universitätsklinik, 3010 Bern 
Phone:031/632 29 32 
Email: Nikola.cihoric@insel.ch 
 
Dr. med. Gisa Gerstenberg , Universität Bern,  
Institut für Komplementärmedizin, Fabrikstrasse 8, 3012 Bern 
Phone: +41 (0)31 631 81 43 
Email: gisa.gerstenberg@ikom.unibe.ch 
 
Investigational Product: 
Urtica comp.  (swissmedic listed as “Anthroposophic 
Medication without Indication”) 
Protocol Version and Date: 
Version number 1.8 and validity date: 01.Feb.2018 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of the sponsor. The 
information may not - in full or in part - be transmitted, reproduced, published, or disclosed to others 
than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) without prior written 
authorisation from the sponsor except to the extent necessary to obtain informed consent from those 
who will participate in the study. 
 
s wi s s e t h i c s  
Schweizerische Ethikkommissionen für die Forschung am Menschen 
Commissions d’éthique suisses relative à la recherche sur l'être humain 
Commissioni etiche svizzere per la ricerca sull'essere umano 
Swiss Ethics Committees on research involving humans 

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Signature Page(s)  
 
Study number 
Unique Protocol ID: 211820931  [NCT ID not yet assigned]    
 
Study Title 
Urtica comp. gel for prevention and therapy of radiation dermatitis 
An interdisciplinary, interprofessional Phase II randomized controlled 
trial in patients with breast cancer 
 
The Sponsor, Principal-Investigator and trial statistician have approved the protocol version [1.8 (dated 
01.02.2018)], and confirm hereby to conduct the study according to the protocol, current version of the 
World Medical Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable 
and the local legally applicable requirements. 
 
 
 
Sponsor 
and 
Principal 
Investigator: 
Dr. Nikola Cihoric 
 
 
 
Bern,  
Place/Date 
 
Signature 
 
 
Applicant (and Investigator): 
Prof. Dr. Ursula Wolf 
 
 
 
 
 
 
Bern,  
Place/Date 
 
Signature 
 
 
Study Coordinator (Project leader): 
Dr. Gisa Gerstenberg 
 
 
 
Bern 
Place/Date 
 
Signature 
 
 
 
 
 
 

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Table of Contents 
STUDY SYNOPSIS ................................................................................................................................. 7 
STUDY SUMMARY IN LOCAL LANGUAGE .................... FEHLER! TEXTMARKE NICHT DEFINIERT. 
ABBREVIATIONS ................................................................................................................................. 11 
STUDY SCHEDULE .............................................................................................................................. 12 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 13 
1.1 
Sponsor, Sponsor-Investigator .................................................................................................... 14 
1.2 
Principal Investigator(s) ............................................................................................................... 14 
1.3 
Statistician ("Biostatistician") ....................................................................................................... 14 
1.4 
Laboratory ................................................................................................................................... 14 
1.5 
Monitoring institution ................................................................................................................... 14 
1.6 
Data Safety Monitoring Committee ............................................................................................. 14 
1.7 
Any other relevant Committee, Person, Organisation, Institution ............................................... 14 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 15 
2.1 
Study registration ........................................................................................................................ 15 
2.2 
Categorisation of study................................................................................................................ 15 
2.3 
Competent Ethics Committee (CEC) .......................................................................................... 15 
2.4 
Competent Authorities (CA) ........................................................................................................ 16 
2.5 
Ethical Conduct of the Study ....................................................................................................... 16 
2.6 
Declaration of interest ................................................................................................................. 16 
2.7 
Patient Information and Informed Consent ................................................................................. 16 
2.8 
Participant privacy and confidentiality ......................................................................................... 16 
2.9 
Early termination of the study ...................................................................................................... 17 
2.10 Protocol amendments ................................................................................................................. 17 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 18 
3.1 
Background and Rationale .......................................................................................................... 18 
3.2 
Investigational Product (treatment, device) and Indication ......................................................... 19 
3.3 
Preclinical Evidence .................................................................................................................... 19 
3.4 
Clinical Evidence to Date ............................................................................................................ 20 
3.5 
Dose Rationale ............................................................................................................................ 21 
3.6 
Explanation for choice of comparator (or placebo) ..................................................................... 21 
3.7 
Risks / Benefits ............................................................................................................................ 21 
3.8 
Justification of choice of study population ................................................................................... 22 
4. 
STUDY OBJECTIVES ................................................................................................................... 23 
4.1 
Overall Objective ......................................................................................................................... 23 
4.2 
Primary Objective ........................................................................................................................ 23 
4.3 
Secondary Objectives ................................................................................................................. 23 
4.4 
Safety Objectives ........................................................................................................................ 23 
5. 
STUDY OUTCOMES ..................................................................................................................... 24 
5.1 
Primary Outcome ........................................................................................................................ 24 
5.2 
Secondary Outcomes .................................................................................................................. 24 
5.3 
Other Outcomes of Interest ......................................................................................................... 24 
5.4 
Safety Outcomes ......................................................................................................................... 24 

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6. 
STUDY DESIGN ............................................................................................................................ 25 
6.1 
General study design and justification of design ......................................................................... 25 
6.2 
Methods of minimising bias ......................................................................................................... 25 
6.2.1 Randomisation .................................................................................................................... 25 
6.2.2 Blinding procedures ............................................................................................................ 26 
6.2.3 Other methods of minimising bias ....................................................................................... 26 
6.3 
Unblinding Procedures (Code break) .......................................................................................... 26 
7. 
STUDY POPULATION .................................................................................................................. 26 
7.1 
Eligibility criteria ........................................................................................................................... 26 
7.2 
Recruitment and screening ......................................................................................................... 27 
7.3 
Assignment to study groups ........................................................................................................ 27 
7.4 
Criteria for withdrawal / discontinuation of participants ............................................................... 27 
8. 
STUDY INTERVENTION ............................................................................................................... 28 
8.1 
Identity of Investigational Products (treatment / medical device) ................................................ 28 
8.1.1 Experimental Intervention (treatment)................................................................................. 28 
8.1.2 Control Intervention (standard/routine/comparator treatment / medical device) ................ 28 
8.1.3 Packaging, Labelling and Supply (re-supply) ..................................................................... 28 
8.1.4 Storage Conditions.............................................................................................................. 28 
8.2 
Administration of experimental and control interventions ........................................................... 28 
8.2.1 Experimental Intervention ................................................................................................... 28 
8.2.2 Control Intervention ............................................................................................................. 29 
8.3 
Dose modifications ...................................................................................................................... 29 
8.4 
Compliance with study intervention ............................................................................................. 29 
8.5 
Data Collection and Follow-up for withdrawn participants .......................................................... 29 
8.6 
Trial specific preventive measures .............................................................................................. 29 
8.7 
Concomitant Interventions (treatments) ...................................................................................... 29 
8.8 
Study Drug Accountability ........................................................................................................... 29 
8.9 
Return or Destruction of Study Drug / Medical Device ............................................................... 29 
9. 
STUDY ASSESSMENTS ............................................................................................................... 30 
9.1 
Study flow chart / table of study procedures and assessments .................................................. 30 
9.2 
Assessments of outcomes .......................................................................................................... 31 
9.2.1 Assessment of primary outcome ......................................................................................... 31 
9.2.2 Assessment of secondary outcomes .................................................................................. 31 
9.2.3 Assessment of other outcomes of interest .......................................................................... 32 
9.2.4 Assessment of safety outcomes ......................................................................................... 32 
9.2.5 Assessments in participants who prematurely stop the study ............................................ 32 
9.3 
Procedures at each visit .............................................................................................................. 32 
9.3.1 Screening visit (BL -1wk*) ................................................................................................... 32 
9.3.2 Baseline visit* ...................................................................................................................... 32 
9.3.3 Visits during intervention                   (weekly: BL, BL+1wk, BL+2wks, BL+3wks, BL+4wks, 
BL+5wks=EOT*)............................................................................................................................. 32 
9.3.4 Close-out visit / EOT* .......................................................................................................... 32 
9.3.5 Follow-up visit (EOT + 6wks*) ............................................................................................. 33 

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10. SAFETY ......................................................................................................................................... 34 
10.1 Drug studies ................................................................................................................................ 34 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events .. 34 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events ..................... 35 
10.1.3 Follow up of Serious Adverse Events ................................................................................. 36 
11. STATISTICAL METHODS ............................................................................................................. 37 
11.1 Hypothesis ................................................................................................................................... 37 
11.2 Determination of Sample Size ..................................................................................................... 37 
11.3 Statistical criteria of termination of trial ....................................................................................... 37 
11.4 Planned Analyses ........................................................................................................................ 37 
11.4.1 Datasets to be analysed, analysis populations ................................................................... 37 
11.4.2 Primary Analysis ................................................................................................................. 38 
11.4.3 Secondary Analyses ........................................................................................................... 38 
11.4.4 Interim analyses .................................................................................................................. 38 
11.4.5 Safety analysis .................................................................................................................... 38 
11.4.6 Deviation(s) from the original statistical plan ...................................................................... 38 
11.5 Handling of missing data and drop-outs...................................................................................... 38 
12. QUALITY ASSURANCE AND CONTROL .................................................................................... 39 
12.1 Data handling and record keeping / archiving ............................................................................. 39 
12.1.1 Case Report Forms ............................................................................................................. 39 
12.1.2 Specification of source documents ..................................................................................... 39 
12.1.3 Record keeping / archiving ................................................................................................. 39 
12.2 Data management ....................................................................................................................... 39 
12.2.1 Data Management System ................................................................................................. 39 
12.2.2 Data security, access and back-up ..................................................................................... 40 
12.2.3 Analysis and archiving ........................................................................................................ 40 
12.2.4 Electronic and central data validation ................................................................................. 40 
12.3 Monitoring .................................................................................................................................... 40 
12.4 Audits and Inspections ................................................................................................................ 40 
12.5 Confidentiality, Data Protection ................................................................................................... 40 
12.6 Storage of biological material and related health data ................................................................ 41 
13. PUBLICATION AND DISSEMINATION POLICY.......................................................................... 41 
14. FUNDING AND SUPPORT ............................................................................................................ 41 
14.1 Funding ....................................................................................................................................... 41 
14.2 Other Support .............................................................................................................................. 42 
15. INSURANCE .................................................................................................................................. 42 
16. REFERENCES ............................................................................................................................... 43 
17. APPENDICES ................................................................................................................................ 45 
 
 
 

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STUDY SYNOPSIS  
Sponsor and 
Principal Investigator 
Applicant (and 
Investigator) 
Study Coordinator 
(/Project Leader) 
Dr. Nikola Cihoric 
 
Prof. Dr. Ursula Wolf   
 
Dr. Gisa A. Gerstenberg 
Study Title: 
Urtica comp. gel for prevention and therapy of radiation dermatitis 
Short Title / Study ID: 
Urtica comp for radiation dermatitis  
Study ID 211820931 
IRDIS DB 1151 
Protocol Version and 
Date: 
Version 1.8 (date: 01.Feb. 2018)   
Trial registration: 
Provide the name of the study registry and the registration number and 
date (if not registered then indicate the anticipated registry)  
We will register the study on https://clinicaltrials.gov/ 
Study category and 
Rationale 
Clinical drug trial category A 
Urtica comp. gel is a swissmedic listed medication and is traditionally used 
for any kind of burns and skin lesions. This study explores the use for 
radiation dermatitis, for which there is currently only good clinical 
evidence, however so far no studies have been published. 
Thus, a registered drug is used in patients in regular dosing in line with 
medical standards. 
Clinical Phase: 
 
Phase II 
Urtica comp. is according to Swissmedic listed as:  „Zur Zulassung nach 
Artikel 17 Absatz 1 oder 2 KPAV vor dem 1. Oktober 2008 angemeldete 
homöopathische und anthroposophische Präparate ohne Indikation“ 
Background and 
Rationale: 
 
Radiation dermatitis is one of the most common side effects of 
radiotherapy for cancer and affects around 95 % of patients receiving 
radiotherapy [1, 3]. Patients with breast cancer as well as patients with 
head and neck cancer are most frequently affected, due to the higher 
radiation dose to the skin, as compared to other cancer types.  
Radiation dermatitis has a profound impact on the quality of a patient's 
life, due to pain and discomfort. Skin lesions bear a marked risk of 
infection. In addition, all these issues may be the cause of interruption of 
radiation therapy, resulting in inadequate disease treatment [9].  
Despite a plentitude of studies researching local and systemic 
therapeutic approaches, currently no treatment (aside from local steroids 
which bear substantial side-effects [16]) can be explicitly recommended 
[2, 3, 4].  
Thus, further research, especially in therapeutic options with a positive 
side-effect spectrum would be highly beneficial. 
Urtica comp. gel is a Swissmedic registered medication.  
It is e.g. applied in first and second-degree burn and scalding as well as 
sunburn and has been used in over 80 years with an excellent safety 
profile [5]. Positive clinical experience in treating radiation dermatitis with 
Urtica comp. gel suggest studying this therapeutic option in a pilot trial.  
 

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Objective(s): 
Examining the effect of Urtica comp. in prevention and treatment of RD 
in breast cancer patients. 
Outcome(s): 
Primary Endpoints 
Incidence and severity of radiation dermatitis (RD) 
 
Secondary Endpoints 
Percentage requiring no additional therapy for RD (e.g. Flammazine or 
Ialugen plus) 
Percentage of patients RD free at end of therapy 
Percentage of patients with secondary skin infection / need of topical and 
systemic antibiotics  
Patients quality of life / patients evaluation of the treatment  
Study design: 
Prospective pilot study in Breast Cancer patients. 
This randomized pilot study will have an active control group receiving 
the institutional standard skin care “Excipial-Hydrolotion”, and will be 
conducted open label. 
Inclusion / Exclusion 
criteria: 
Inclusion: 
• 
Radiation therapy for Breast Cancer  
• 
Age >= 18 years 
• 
Written informed consent 
Exclusion: 
• 
Ulcerated cancer at beginning of radiation therapy 
• 
Skin lesions in the radiation area before start of radiation therapy 
• 
Known allergies, hypersensitivity or reactions against one of the 
constituents of the investigational product [5]  
• 
Any neurological or psychiatric conditions that, in the evaluation 
of the treating physician, deem the patient incapable to participate 
in the study 
• 
Other clinically significant concomitant disease states (e.g., renal 
failure, hepatic dysfunction, cardiovascular disease, etc.) as 
judged by the PI 
 
The following criteria are exclusion criteria for the conduct of the radiation 
therapy, which is prerequisite for inclusion into the study.  Thus, such 
patients will anyway not meet the inclusion criteria and are explicitly 
excluded from participation: 
• 
Women who are pregnant or breast feeding  
• 
Lack of safe contraception, defined as: Female participants of 
childbearing potential, not using and not willing to continue using 
a medically reliable method of contraception for the entire study 
duration, such as oral, injectable, or implantable contraceptives, 
or intrauterine contraceptive devices, or who are not using any 
other method considered sufficiently reliable by the investigator in 
individual cases. 
• 
Please note that female participants who are surgically sterilised / 
hysterectomised or post-menopausal for longer than 2 years are 
not considered as being of child bearing potential. 
 

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Measurements and 
procedures: 
Population: All eligible patients of the Department of Radiation Oncology. 
Patients will undergo all regularly assigned therapy at the Department of 
Radio- Oncology Inselspital, including the standard skin care “Excipial-
Hydrolotion”. Additionally the patients of the test group will receive the 
study medication Urtica comp. gel. 
Assessment is done at baseline, during the radiation therapy on a weekly 
base, at end-of-therapy and follow-up. The assessment consists of the 
regular clinical assessment conducted as usual during radiation therapy, 
plus  
• 
the Common Toxicity Criteria for Adverse Events (CTCAE) of the 
National Cancer Institute  
• 
a visual analog scale (VAS) where the patient self-assesses the 
skin condition 
• 
the Skindex16, a clinical outcome assessment for skin  (16  
Items)  
• 
the FACIT-TS-G assessing the patients treatment satisfaction at 
the end of therapy 
 
Study Product / 
Intervention:  
The skin care of the study patients will be conducted in line with the 
guidelines of the Department of Radiation Oncology Inselspital:  
„Pflege bei PatientInnen, die bestrahlt werden“ Section 3.2 „Hautpflege 
bei einer Strahlenreaktion“ [4].  
For the patients of the test-group Urtica comp gel is applied three times 
per day locally on the skin as soon as the patient senses “itching, 
tingling” and/or reddening. Otherwise the skincare is exactly as the 
control group in line with the departments general guidelines. 
In case of marked worsening, e.g. epitheliolysis, the patient may receive 
“Flammazine and Ialugen plus” as rescue-care.  
Rescue care: according to the departments therapeutic guidelines 
patients will receive “Flammazine and/or Ialugen plus” as clinically 
indicated at the discretion of the treating physician (usually in cases of 
marked worsening of the skin condition like e.g. epitheliolysis). 
Skin condition is regularly checked before each radiation therapy 
session. 
The study will be conducted, and the study therapy will be administered 
until the radiation treatment, including follow-up, has finished. If the 
radiation dermatitis has ceased and the skin recovered before end of 
study, the patient will finish the study receiving no further cream or lotion 
past the point of recovery.  
 
Control Intervention 
(if applicable): 
Control group receiving the institutional standard skin care “Excipial-
Hydrolotion” – all other therapeutic interventions, assessments and 
rescue-care will be the same in both groups. 
Number of 
Participants with 
Rationale: 
As this is a first pilot study 30 patients with breast cancer will participate.  
(This pilot data will be utilized to test feasibility and calculate the power 
and sample size of a following larger randomized controlled trial). 
Study Duration: 
11 to 15 weeks per patient. 5 Month enrollment time.  
Total study duration: 9 month. 
Screening / Planning CT etc.: one week before therapy start   
treatment duration:  generally a radiation course of 6 weeks 
follow-up: 6 weeks after EOT 

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Study Schedule: 
Month Year of First-Participant-In (planned): December 2017 
Month Year of Last-Participant-Out (planned): August 2018  
Data entry. Data clean and analysis completed: January 2019 
Publication: March 2019  
Investigator(s): 
Prof. Dr. med. Ursula Wolf (Investigator) 
Dr. med. Gisa Gerstenberg  
Universität Bern, Institut für Komplementärmedizin 
Fabrikstrasse 8,  3012 Bern 
 
Dr. med. Nikola Cihoric, Stv. Oberarzt / senior physician, Inselspital, 
Universitätsklinik für Radio-Onkologie (Primary Investigator) 
Susanne Sester, Pflegeexpertin Onkologie, Department DOLS 
Timo Nannen, Study Nurse, Inselspital, Universitätsklinik für Radio-
Onkologie 
Freiburgstr. 4 , Inselspital, Universitätsklinik , 3010 Bern 
Study Centre(s): 
single-centre:  Inselspital, Universitätsklinik für Radio-Onkologie 
Statistical 
Considerations: 
Since this is a pilot study no power analysis will be carried out, but the 
data of the pilot study are utilized for feasibility-assessment and will 
serve as the base for planning an adequately powered RCT.)  
(“Machbarkeitsstudie”) 
 
Calculations will include: 
Incidence and severity of radiation dermatitis  
Percentage of patients developing RD   
Percentage requiring no additional Tx for RD (e.g. Ialugen +) 
Percentage of patients RD free at end of therapy / follow-up 
 
The courses of therapy will be compared with an active control group 
receiving the institutional standard skin care “Excipial-Hydrolotion” (as 
well as with historic standard-courses and the Incidence and 
percentages described in literature.) 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as 
far as applicable) as well as all national legal and regulatory requirements.  
 
 
 

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ABBREVIATIONS 
AE 
Adverse Event  
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
Competent Ethics Committee 
CRF 
Case Report Form  
CTU 
Clinical Trial Unit 
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV) 
CTCAE 
Common terminology criteria for adverse events 
DofH 
Declaration of Helsinki [22] 
DSUR 
Development safety update report 
eCRF 
Electronic Case Report Form 
EOT 
End of Therapy 
FACIT-TS-G 
Functional Assessment of Chronic Illness Therapy  treatment satisfaction  general 
GCP 
Good Clinical Practice  
IB 
Investigator’s Brochure 
Ho 
Null hypothesis 
H1 
Alternative hypothesis 
HFG 
Humanforschungsgesetz (Law on human research) [24] 
HMG 
Heilmittelgesetz [26] 
HRA 
Federal Act on Research involving Human Beings 
ICH 
International Conference on Harmonization [23] 
IMP 
Investigational Medicinal Product 
IIT 
Investigator-initiated Trial 
ISO 
International Organisation for Standardisation [27] 
ITT 
Intention to treat 
KlinV 
Verordnung über klinische Versuche in der Humanforschung (English: ClinO)[25] 
PI 
Principal Investigator  
RD 
Radiation Dermatitis 
RTx 
Radiotherapy 
sAE 
Serious Adverse Event 
SDV 
Source Data Verification  
SOP 
Standard Operating Procedure 
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File  
VAS 
Visual analog scale 
wks 
weeks 
 
 

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STUDY SCHEDULE  
 
 
 
 
 
 
                Visit 
 
Form  
or action 
Screening 
/ Planning 
of RTx* 
Baseline 
(at first 
treatment 
Visit) * 
Visits during intervention 
(Treatment duration 
generally 6 wks * / **)  
EOT / 
close-
out visit 
* 
Follow-
up (EOT 
+ 6wks*) 
Therapeutic 
intervention 
- 
- 
Radiotherapy (all) 
Group A:  Urtica comp. 
Group B:  standard care 
- 
- 
Radomisation 
 
x 
 
 
 
Assessment  
 
 
 
 
 
Eligibility 
x 
 
 
 
 
Informed consent 
 
x 
 
 
 
Med History 
 
x 
 
 
 
Primary Endpoints 
 
 
 
 
 
Extended CTCAE 
(physician)  
- 
x 
At each weekly assessment 
x 
x 
x 
x 
x 
x 
x 
x 
Extended CTCAE 
(nurse) 
- 
x 
If Dr’s score is >= 1.5 
x 
x 
 
 
 
 
 
 
Secondary Endpoints 
 
 
 
 
 
Clinical assessment 
(physician) 
x 
x 
At each weekly assessment 
x 
x 
x 
x 
x 
x 
x 
x 
Skindex 16 Items  
(patient)  
- 
x 
One measurement point at 
mid of therapy 
x 
x 
- 
- 
- 
x 
- 
- 
VAS 
(patient) 
- 
x 
At each weekly assessment 
x 
x 
x 
x 
x 
x 
x 
x 
FACIT-TS-G  
(patient) 
- 
- 
- 
x 
- 
End of Study form 
 
 
 
 
x*** 
 
 
*allowed time frames for each visit: the dates and time frames are aligned with the radiation-therapy 
schedule clinically assigned for the patient. The regular schedule for radiation therapy of breast cancer 
starts with a planning CT and therapy is beginning a week later consisting of a course of six weeks, 5 
weeks of total mamma irradiation and one week of “boost / volume reduction” resulting in a total of 25 
fractions à 2 Gy. Follow-up is conducted 6 weeks (+/- one week) after end of therapy.  In clinical 
experience this timeframe is strictly adhered to in 99% of patients, however should a patient require 
deviation from the schedule, e.g. due to tolerability-issues of the radiation therapy, the deviation as well 
as the reason for it will be recorded in the CRF.  
 
** 6 intervention visits, including the baseline and EOT visit. In detail: BL, BL+1wk, BL+2wks, BL+3wks, 
BL+4wks, BL+5wks=EOT 
 
***at follow-up or whenever the patient ends his/her participation in the study (e.g. in case of drop-out 
at the time of drop-out or as soon as possible after it.) 
 

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1. STUDY ADMINISTRATIVE STRUCTURE  
Applicant (and Investigator): 
Prof. Dr. med. Ursula Wolf, Universität Bern, Institut für Komplementärmedizin,  
Fabrikstrasse 8, 3012 Bern 
Phone: +41 (0)31 631 81 40 
Email: ursula.wolf@ikom.unibe.ch 
 
Initiation and Responsibility of the study; Overseeing and final responsibility for the conduct of the study, 
the data-interpretation and writing of the report. Medical expertise and responsibility for the study drug 
Urtica comp. and related study decisions. 
 
Sponsor and Principal Investigator: 
Dr. Nicola Cihoric, Inselspital, Universitätsklinik für Radio-Onkologie 
Freiburgstr. 4 , Inselspital, Universitätsklinik, 3010 Bern 
Phone:031/632 29 32 
Email: Nikola.cihoric@insel.ch 
 
Responsibility of the study; Overseeing and final responsibility for the conduct of the study, the data-
interpretation and writing of the report. Leading study-physician and researcher at the project site, 
responsible for trial-site related medicinal decisions related to radiation oncology. 
 
Project Leader and Coordinating researcher: 
Dr. med. Gisa Gerstenberg , Universität Bern, Institut für Komplementärmedizin 
Fabrikstrasse 8, 3012 Bern 
Phone: +41 (0)31 631 81 43 
Email: gisa.gerstenberg@ikom.unibe.ch 
 
Initiation and responsibility of the study, designing the study, organizing collection, management, 
analysis, and interpretation of data. Responsible for writing of the report. 
 
Study Nurse: 
Timo Nannen, Study Nurse, Inselspital, Universitätsklinik für Radio-Onkologie 
Freiburgstr. 4, Inselspital, Universitätsklinik, 3010 Bern 
 
Statistician (in conjunction with coordinating researcher): 
Dr. Andreas Limacher, PhD 
Head of Statistics & Methodology 
University of Bern, Department of Clinical Research, CTU Bern, Finkenhubelweg 11, 3012 Bern 
Phone: +41 31 631 35 10 
andreas.limacher@ctu.unibe.ch        www.ctu.unibe.ch 
 
Database (RedCap) Expertise: 
Yves Bochud, Clinical Data Manager 
CTU University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland 
Tel  +41 31 631 56 73 
yves.bochud@ctu.unibe.ch        www.ctu.unibe.ch 
 
Head of responsible institution: 
Prof. Dr. Daniel Aebersold, Radio-Onkologie Tumorzentrum / UCI,  
Freiburgstr. 4 , Inselspital, Universitätsklinik, 3010 Bern 
Phone:031/632 24 31 
Email:Daniel.aebersold@insel.ch 

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1.1 Sponsor 
Dr. med. Nicola Cihoric, Inselspital, Universitätsklinik für Radio-Onkologie 
(Please find Details above in section 1) 
1.2 Principal Investigator  
Dr. med. Nicola Cihoric, Inselspital, Universitätsklinik für Radio-Onkologie 
(Please find Details above in section 1) 
 
1.3 Statistician ("Biostatistician")  
Dr. med. Gisa Gerstenberg (Project Leader and Coordinating researcher) 
and 
Dr. Andreas Limacher, PhD, Head of Statistics & Methodology University of Bern, CTU Bern   
(Please find Details above in section 1) 
 
1.4 Laboratory 
Not applicable.  
 
1.5 Monitoring institution 
Sponsor in combination with the Clinical Trial Unit (CTU) 
The CTU will set up the database REDCap. Otherwise no specific monitoring is required, as the study 
is considered to have a low risk level:  application of the clinically recommended dosage of a Swissmedic 
registered cream, which is already marketed for over 80 years with a very favourable side effect profile 
(see section 3.4). Furthermore no invasive tests or therapy is part of the study.   
However a quality-visit of the CTU (“Qualitätsvisite”) will be considered. 
 
CTU University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland 
Yves Bochud, Clinical Data Manager 
Tel  +41 31 631 56 73;  yves.bochud@ctu.unibe.ch  
www.ctu.unibe.ch 
 
 
1.6 Data Safety Monitoring Committee  
Not applicable.  
 
1.7 Any other relevant Committee, Person, Organisation, Institution  
Not applicable.  
 
 

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2. ETHICAL AND REGULATORY ASPECTS  
Before the study will be conducted, the protocol, the proposed patient information and consent form as 
well as other study-specific documents shall be submitted to the KEK.  
Swissmedic approval will not be applicable as the study is expected to fall into Category A. Any 
amendment to the protocol will be as well be approved (if legally required) by these institutions. 
 
The decision of the CEC and Swissmedic competent authority 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 all required authorities has been received. Any additional 
requirements imposed by the authorities shall be implemented. 
The research project will be carried out in accordance with the research plan and with principles 
enunciated in the current version of the Declaration of Helsinki (DoH) [22]  
 
 
2.1 Study registration  
The study should be registered in a registry listed in the WHO International Clinical Trials Registry 
Platform (ICTRP, http://www.who.int/ictrp/en/). In addition, registration in a national language in the 
Swiss Federal Complementary Database (Portal) is required. 
 
The study is in the process of registration at clinicaltrial.gov  
[NCT ID not yet assigned]   Unique Protocol ID: 211820931 
 
2.2 Categorisation of study  
Klinischer Versuch 
Unterart und Kategorie 
Klinischer Versuch mit Arzneimitteln 
Kategorie A 
 
Clinical drug trial category A 
The Swissmedic listed medication Urtica comp. gel falls into the category of “Anthroposophic Medication 
without Indication”. Urtica comp. gel is traditionally used for any kind of burns and skin lesions. This 
study explores the use for radiation dermatitis, for which there is currently only good clinical evidence, 
however so far no studies have been published. 
Thus, a registered drug is used in patients in accordance with the prescribing information and in regular 
dosing in line with medical standards. 
 
2.3 Competent Ethics Committee (CEC)  
The investigator ensures that approval from an appropriately constituted Competent Ethics Committee 
(CEC), in this case the KEK, is sought for the clinical study.  
 
The reporting within this research project will follow the regular allowed time frame in line with the DoH 
[6] (all changes in the research activity and all unanticipated problems involving risks to humans; 
including in case of planned or premature study end and the final report). No changes are made to the 
protocol without prior Sponsor and 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 

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after study end. Amendments are reported according to chapter 2.10. 
 
2.4 Competent Authorities (CA)  
No Swissmedic approval is required for this category A study.  
 
2.5 Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki [22], the guidelines of Good Clinical Practice (GCP) issued by ICH, 
[23] the Swiss Law and Swiss regulatory authority’s requirements. The CEC and regulatory authorities 
will receive annual safety and interim reports and be informed about study stop/end in agreement with 
local requirements.  
 
2.6 Declaration of interest  
The following statement applies for Prof U. Wolf (Applicant), Dr. N. Cihoric (PI and Sponsor) and Dr. G. 
Gerstenberg (Study Coordinator / Project leader): 
“I have no pecuniary or other personal interest, direct or indirect, in any matter that raises or may raise 
a conflict with my duties in this clinical study.  
In particular not any of the following relevant financial links with the company of the drug Urtica comp. 
or a relevant competitor:   
Employment, Ownership of stocks and shares, Travel and accommodation expenses, Paid consultancy 
or directorship, Paid membership of speakers panels/bureaus and advisory board or acting as an expert 
witness, Being in receipt of a fellowship, equipment, writing, or administrative support.” 
 
2.7 Patient Information and Informed Consent 
The investigators will 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 will 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 
assistance and treatment.  
The participant will be informed that his/her medical records may be examined by authorised individuals 
other than their treating physician. 
All participants for the study will be provided a participant information sheet and a consent form 
describing the study and providing sufficient information for participant to make an informed decision 
about their participation in the study. 
At the Planning meeting for radiation therapy the patient is informed about the study and will be given 
time to consider participation until the baseline assessment when therapy starts (generally about 7 days). 
The patient information sheet and the consent form will be submitted to the CEC and to the competent 
authority (as applicable) to be reviewed and approved. The formal consent of a participant, using the 
approved consent form, will be obtained before the 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. 
 
2.8 Participant privacy and confidentiality  
The investigator will and uphold the principle of the participant's right to privacy and comply with 
applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when presenting 

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the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising subject 
identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator), a competent 
authority (e.g. Swissmedic), or an ethics committee may require direct access to parts of the medical 
records relevant to the study, including participants’ medical history. 
 
2.9 Early termination of the study  
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances, for 
example: 
• 
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  
 
2.10 Protocol amendments 
The Project Leader in conjunction with the Sponsor-Investigator is allowed to amend the protocol or to 
provide suggestions for a protocol amendment. Important protocol modifications (e.g., changes to 
eligibility criteria, outcomes, analyses) will be firstly discussed within this group and then 
communicated to the study-team and relevant parties (e.g., investigators, CEC, competent authorities, 
trial participants, trial registries, journals, regulators). 
 
Substantial amendments are only implemented after approval of the CEC and CA respectively. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-
being of human subjects may proceed without prior approval of the sponsor and the CEC/CA. Such 
deviations shall be documented and reported to the sponsor and the CEC/CA as soon as possible. 
All Non-substantial amendments are communicated to the CA as soon as possible if applicable and to 
the CEC within the Annual Safety Report (ASR).  
 
Sponsor, Principal Investigator, Applicant and Study Coordinator / Project Lead together will consider 
to potentially amend the study after the pilot phase in order to increase patient numbers and / or 
investigate this therapeutic approach in further patient groups.   
 
 
 

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3. BACKGROUND AND RATIONALE  
3.1 Background and Rationale  
Radiation dermatitis is one of the most common side effects of radiotherapy for cancer and affects 
around 95 % of patients receiving radiotherapy [1, 3]. Patients with breast cancer are most frequently 
affected, due to the higher radiation dose to the skin, as compared to other cancer types.  
Radiation dermatitis has a profound impact on the quality of a patient's life, due to pain and discomfort. 
In addition, it may be the cause of interruption of radiation therapy, resulting in inadequate disease 
treatment [9].  
Despite a plentitude of studies researching local and systemic therapeutic approaches, currently no 
treatment (aside from local steroids) can be explicitly recommended [2, 3, 4].  
 
However, topical corticosteroid use may have substantial adverse effects. The most frequent adverse 
effects include atrophy, striae, rosacea, perioral dermatitis, acne, and purpura. Those that occur with 
lower frequency include hypertrichosis, pigmentation alterations, delayed wound healing, exacerbation 
of skin infections, cutaneous tinea and contact sensitization against corticosteroids [14].  
 
Thus, further research, especially in therapeutic options with a positive side-effect spectrum would be 
highly beneficial.  
Positive clinical experience in treating radiation dermatitis with Urtica comp. gel suggest studying this 
therapeutic option in a pilot trial.  
Urtica comp. gel is a Swissmedic registered medication.  
The scope of application of Urtica comp. is an imbalanced, affected process of skin-regeneration, in 
particular when stemming from an overdose of heat or light.  
 
It is applied in first and second-degree burn and scalding, sunburn, allergic and hyperergic (excessive) 
skin conditions (dermatoses), insect bites, abrasions and ulcers.  
Urtica comp. has been used for over 80 years with an excellent safety profile. The only known side 
effects are allergies and overreactions against ingredients, namely Arnica, Thuja or Urtica [5]. 
Also its separate ingredients have been traditionally used in complementary and herbal medicine: Urtica, 
has anti-inflammatory properties [6,7], helps with itching [7] and allergies [8]. Arnica montana has a 
decongestant effect and is soothing to inflammations of the skin by its effect on the capillary of the 
terminal vessels and the interstitial fluids. Calendula officinalis is assumed to support angiogenesis, 
namely the sprouting of arterial capillaries and furthermore the buildup of granulation tissue. Thuja is 
used to prevent keloid, scar proliferation and contractures. Symphytum officinale may regulate the 
body`s fluid processes and has centrally analgesic properties. Argentum colloidae is supposed to 
facilitate the equilibrium between assembly and degradation processes of the skin. Cantharis ex animale 
is used for burns [8]. 
 
So far, no clinical studies with Urtica comp. gel have been published yet.  
Taking all these findings into account, it appears that Urtica comp. gel, based on its composition as well 
as on clinical experience, may well be suited to complement the prevention and therapy of radiation 
dermatitis. Given the fact that no satisfactory standard treatment option exists yet for radiation dermatitis 
along with the excellent safety profile and favorable acceptance of complementary therapeutics among 
patients in oncologic therapy, a pilot trial with Urtica comp. for the prevention and treatment of radiation 
dermatitis appears promising.  
 
 

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3.2 Investigational Product (treatment, device) and Indication  
Urtica comp. is according to Swissmedic listed as:  „Zur Zulassung nach Artikel 17 Absatz 1 oder 2 
KPAV vor dem 1. Oktober 2008 angemeldete homöopathische und anthroposophische Präparate 
ohne Indikation“ 
For details please refer to the separately uploaded attachments BASEC documents section 16 for 
product characteristics:  
16a nonclinical overview and 16b clinical overview, 16c Commission C Monograph, 16d Packet Insert 
(Fachinformation) and 16e Swissmedic “Zulassungsbescheinigung”.  
 
3.3 Preclinical Evidence  
Urtica comp. gelatum in its commercial formulation is used. The colorless gel is also called “Wound and 
Burn Gel” and contains seven active substances: Argentum colloidale Dil. D5, Arnica montana e floribus 
LA 20%, Calendula officinalis e floribus LA 20%, Cantharis ex animale toto Gl Dil. D5, Symphytum 
officinale ex herba LA 20%, Thuja occidentalis e summitatibus LA 20%, Urtica urens ex herba LA 20%. 
All of them were manufactured based on to the methods as described in the German Homeopathic 
Pharmacopoeia (GHP, also known as HAB). 
 
Most of Wound and Burn Gel's active substances are homeopathic dilutions and/or aqueous extracts, 
so there are no pharmacological effects related to dosage or blood concentration. 
For this reason, no further studies, e. g., on bioavailability have been conducted.  
For medicinal products containing potentised substances pharmacologic, pharmacodynamics and 
pharmacokinetic data do not add value for an appropriate use within the anthroposophical therapy. Thus, 
such studies are not being performed. 
 
A review of relevant bibliographic information on the toxicological action of the starting materials of the 
active substances does not reveal evidence for acute or chronic toxicity, genotoxicity, carcinogenity, 
reproductive and developmental toxicity, antigenicity, immunotoxicity or local intolerance of Wound and 
Burn Gel if used according to the recommended route of administration and the given dosage regime. 
Indications of serious drug-associated risks for Wound and Burn Gel have not become apparent. 
The conducted bacterial reverse mutation assay (AMES-test) with Arnica montana e planta tota and 
Thuja occidentalis e summitatibus ferm 33e provide no evidence for genotoxic potential (refer to section 
2.6.6.4 of the preclinical dossier). 
Moreover, all the highest calculated daily maximum doses of the relevant toxic compounds in Wound 
and Burn Gel, Gel, e.g. cantharidin, thujone or pyrrolizidine alkaloids are below mentioned toxicological 
thresholds and recommended average daily dose limits for the intended patient groups. 
The good efficacy, good tolerance and safe use of Wound and Burn Gel, Gel in adults, children and 
infants was confirmed in written surveys (refer to section 2.5.4 and 2.5.5 of the preclinical dossier). 
Wound and Burn Gel, Gel is therefore a safe medication, even for especially sensitive patient groups 
such as children, pregnant women or nursing mothers. However, as a general precaution Wound and 
Burn Gel, Gel, as all medicinal products, should only be used during pregnancy and lactation following 
a consultation with a doctor. 
 
Furthermore, this medicinal product should not be used in case of hypersensitivity to thuja, arnica and/or 
to any other plant of the Compositae family. 
The following side effects are listed in the package leaflet: After using the medicinal product, redness 
and itching at the application site as well as allergic skin reactions may occur which require that the use 
of this medicinal product be discontinued. 
To sum up all, Wound and Burn Gel is a safe medication, even for especially sensitive patient groups 
such as infants, children, pregnant women and nursing mothers when administered according to the 
current package leaflet. 

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3.4 Clinical Evidence to Date  
 
Urtica comp. Gel has been marketed since 1969. It was officially announced in 1978 in Germany and 
registered in Switzerland in 2014. 
  
During the last three years, an average of 86,121 maximal daily doses of Wound and Burn Gel had 
been sold per year. Since its international birth date, 10 individual case safety reports on adverse effects 
have been reported spontaneously to WALA Heilmittel GmbH. 
Analysis of adverse effects:  
The only SE that has occurred with Urtica comp. in over 80 years of clinical practice is allergic 
reaction.  
In average 4.6 adverse events per 100.000 sold packs* have been recorded by Wala GmbH.  
None of them was serious. (No death, no hospitalization, no life-threatening events, no prolongation of 
hospitalization no congenital abnormalities, no resulting disabilities.)   
 
 
Pharmacovigilance data of Urtica comp. by the WALA Heilmittel GmbH: 
 
All adeverse events ever recorded ** 
TOTAL NUMBERS  
(Up to September 2016) 
Application site eczema 
1 
Application site erythema 
5 
Application site hypersensitivity 
1 
Application site pain 
3 
Application site pruritus 
3 
Application site pustules 
1 
Blister 
1 
Burning sensation 
2 
Encapsulation reaction 
1 
Erythema 
1 
Expired product administered 
1 
Hypersensitivity 
1 
Pruritus 
2 
Skin discolouration 
1 
Skin reaction 
3 
 
 
* Sum of all pack sizes in all countries   
 ** Partially more than one symptom per reported side effect has been recorded 
 
 
 
Established international databases (e.g., PubMed, Vigilit), have been thoroughly searched for literature 
data on clinical research (such as human studies, meta-analyses or reviews). 
The evaluation of the data retrieved has revealed no risks to human health as far as Wound and Burn 
Gel and/or its active substances are concerned. No relevant individual case reports have been found, 

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either. As a result, no risk of acute or chronic toxicity, genotoxicity, carcinogenity, reproductive and 
developmental toxicity, antigenicity, immunotoxicity or local incompatibility can be derived from the 
bibliographic data assessed (see clinical overview 2.6.6). 
The medicinal product should, however, not be used in case of hypersensitivity to thuja and/or arnica or 
other plants of the Compositae family. 
Clinical efficacy, safety and compatibility of Wound and Burn Gel even for infants and children have 
been confirmed by several surveys (see clinical overview 2.5.4, 2.5.5). 
The recommendations in the package leaflet concerning Wound and Burn Gel's dosage and method of 
administration are based on therapeutic experience in anthroposophical and homeopathic medicine. 
After using this medicinal product, redness and itching at the site of application and allergy related skin 
reactions may occur which require that the use of this medicinal product be discontinued. 
Comprehensively, Wound and Burn Gel is a very compatible medicinal product, if it is used according 
to the recommendations of the package leaflet. The data presented confirm its favourable benefit-risk-
profile. 
 
 
3.5 Dose Rationale  
The dosing is in line with the general use of this swissmedic listed medication.  
 
3.6 Explanation for choice of comparator (or placebo)  
 
Prospective pilot study with n=15 Breast Cancer patients per study arm. 
This randomized pilot study will have a control group receiving the institutional standard skin care 
“Excipial-Hydrolotion”, and will be conducted open label. (Rescue-care of Ialugen and Flammazine is 
the same for both groups.) 
As currently Excipial-Hydrolotion is the standard skin care in the Department of Radiation Oncology [4] 
this treatment is chosen as the comparator.  
Local steroids, although recommended in some international guidelines [2, 3], are not chosen as 
comparator, as due to their side-effect profile the treatment guideline of the Department of Radiation 
Oncology [4] clearly favors Excipial-Hydrolotion followed by Ialugen and Flammazine for rescue-care as 
required. 
Owing to the fact that this is a pilot-study it is considered suitable to run this pilot open-label for ease of 
conduct. 
 
 
3.7 Risks / Benefits  
 
Risks 
In section 3.4 the so far reported adverse events of Urtica comp. are listed and discussed. 
In order to minimize such rare adverse events further, which have been reported as allergic reactions, 
all patients with a known history of allergies against any of the constituents of Urtica comp. will be 
excluded from participation in the study.  
Patients are, for the whole duration of application of the study drug, regularly checked for adverse 
events.  As no adverse events markedly after the application have been reported during the 80 years 
of Urtica comp. history, no post-trial care aside of the regular follow-up is considered necessary.  
 
Individual Benefits 

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All patients receive the standard skin care “Excipial-Hydrolotion”. Additionally the patients of the test-
group will receive the study medication Urtica comp. gel. It is entirely possible that these patients will 
have no additional benefit due to this therapy.   Although the base assumption for the conduct of this 
study is the clinical observation, that patients benefit from the use of Urtica comp. and it may prevent or 
alleviate the symptoms of radiation dermatitis.  
 
General Benefits 
Tis pilot study will provide a first indication, helping to assess which benefit Urtica comp. may offer in 
the prevention and treatment of radiation dermatitis. Depending on the results of this study, as well as 
potentially following further studies, the future therapy of patients receiving radiation therapy may be 
improved.  
 
Potential threats to the study 
Currently there are no competing trials planned or ongoing. As the study is with 6 month enrolment time 
relatively short, is it considered unlikely that competing studies will be initiated during this time. 
 
 
 
3.8 Justification of choice of study population  
 
No vulnerable participants will be included.  
Study population are patients with breast cancer undergoing radiation therapy. 
• 
Radiation dermatitis is one of the most common side effects of radiotherapy for cancer and 
affects around 95 % of patients receiving radiotherapy [1, 3]. 
• 
Patients with breast cancer are most frequently affected by radiation dermatitis, due to the 
higher radiation dose to the skin, as compared to other cancer types. Furthermore patients 
with breast cancer are traditionally very open towards complementary approaches and highly 
interested in alleviating radiation dermatitis. 
 
 
 

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4. STUDY OBJECTIVES  
4.1 Overall Objective 
To assess, whether Urtica comp. is a viable treatment modality for radiation dermatitis (RD). 
Examining the effect of Urtica comp. in prevention and treatment of RD in breast cancer patients. 
4.2 Primary Objective 
Incidence and severity of radiation dermatitis (RD) 
As compared to the control group.   
4.3 Secondary Objectives 
Percentage requiring no additional therapy for RD (e.g. Flammazine or Ialugen plus) 
Percentage of patients RD free at end of therapy and at follow-up 
Percentage of patients with secondary skin infection / need of topical and systemic antibiotics  
Patient’s assessment of the skin condition / quality of life / patient’s evaluation of the treatment 
As compared to the control group.   
4.4 Safety Objectives 
The following two secondary Objectives are assessing directly the safety of the study drug in comparison 
to the standard skin-care: 
Percentage requiring no additional therapy for RD (e.g. Flammazine or Ialugen plus) 
Percentage of patients with secondary skin infection / need of topical and systemic antibiotics  
 
Furthermore the primary Objective, the occurrence of radiation dermatitis itself could be considered a 
safety-objective, as the study aims to assess also whether prevention of radiation-dermatitis is possible 
by administration of Urtica comp. 
These Objectives will be dealt with in their respective section. 
 
 

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5. STUDY OUTCOMES  
5.1 Primary Outcome 
Primary outcome of the study is the skin condition in the radiation area as measured by the extended 
CTCAE. 
A precise assessment of the skin condition with respect to erythema, scalding etc. as it is done with the 
extended CTCAE (described in section 9.2.1). 
Comparing this assessment between the treatment groups may reveal the effect of Urtica comp. in 
prevention as well as in treatment of RD in breast cancer patients. 
 
5.2 Secondary Outcomes 
Percentage of patients requiring no additional therapy for RD (e.g. Flammazine or Ialugen plus) 
A patient would require the rescue-care of Flammazine or Ialugen plus when, despite the regular 
skincare or study medication, the condition of the skin is worsening. Thus the physicians’ decision to 
utilize the rescue-care marks a point of seriousness of the radiation dermatitis. 
The use of this rescue-care is compared between the two treatment arms. 
“Percentage of patients RD free at end of therapy and at follow-up” is assessed by the Physician scoring 
the extended CTCAE (primary outcome measure). Although it is common, that RD is still persisting at 
EOT, it is nevertheless meaningful to know the proportion of patients being free of RD treated by study 
drug versus comparator, and furthermore follow-up the course 6 weeks after EOT.  
For safety reasons the “Percentage of patients with secondary skin infection / need of topical and 
systemic antibiotics” (which is routinely assessed by the treating physician) shall be compared between 
the two groups.  
 
The Patients perspective is captured  
• 
by the Skindex 16 , which is a questionnaire commonly used for the self-assessment of skin 
conditions. The 16 items are rated on an ordinal scale ranging 0-6. 
• 
by visual analog scales (VAS) are used to assess pain, itching, burning, skin irritation, 
appearance and general quality of life (related to radiation dermatitis).  
• 
By a final evaluation of treatment utilizing a short version of the FACIT-TS-G   
 
5.3 Other Outcomes of Interest 
As this is a pilot study further outcomes might be analysed post-hoc. 
5.4 Safety Outcomes 
Safety outcomes are addressed in primary as well as secondary outcomes, please see above in the 
respective section (extended CTCAE, rescue care and need of antibiotics).   
 

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6. STUDY DESIGN  
6.1 General study design and justification of design  
 
Study design 
The studied treatment, Urtica comp. is compared to the current gold-standard skin care “Excipial-
Hydrolotion” in parallel design. As this is still a comparatively small pilot study with 30 patients in order 
to assess the feasibility of a potential larger trial, we conduct this study pragmatically in an open fashion. 
Generally the framework aimed at would be superiority, however given, that this is a pilot it is at this 
point still of exploratory nature.  
 
Population, Duration and Procedures 
All eligible patients with breast cancer of the Department of Radiation Oncology will be offered 
participation in the study. 1:1 Randomization of the consented patients takes place after the planning 
CT for radiotherapy.  
The radiation therapy is conducted as clinically assigned for the patient, which is generally a course of 
six weeks, 5 weeks of total mamma irradiation and one week of “boost / volume reduction” resulting in 
a total of 25 fractions à 2 Gy. Follow-up assessment takes place at the regular follow-up assignment 
conducted for the radiation therapy 6 weeks after EOT. Thus, all study assessments take place during 
the regular clinical assessments conducted in the Department of Radiation Oncology.  
Patients will undergo all regularly assigned therapy at the Department of Radio- Oncology Inselspital, 
including the standard skin care “Excipial-Hydrolotion”. Additionally the patients of the test-group will 
receive the study medication Urtica comp. gel.  The gel is applied as soon as the patient senses 
“sunburn-like” itching or tingling in the radiation area, even, if the area is not reddened yet. In line with 
the general recommendation, no application is conducted during at least 6 hours before radiation 
therapy. In case of marked worsening, e.g. epitheliolysis, the patient may receive “Flammazine and 
Ialugen plus” as rescue-care.  
Skin condition is regularly checked before each radiation therapy session. In addition to the Baseline 
and end-of-therapy check, a weekly assessment is conducted by the treating physician using the 
Common Toxicity Criteria / Common Terminology Criteria for Adverse Events (CTCAE) of the National 
Cancer Institute. 
Questionnaires are attached under BASEC Document Number 11. 
The study will be conducted, and the study therapy will be administered until the radiation treatment has 
finished and/or until the radiation dermatitis has ceased and the skin recovered or the latest until follow-
up. If a patient wishes to continue to use the cream it can afterwards be obtained during regular clinical 
case outside of the study. 
The reporting of Serious Adverse Events (sAEs) will be conducted in line with the therapeutic standards 
of the Department of Radiation Oncology. 
 
6.2 Methods of minimising bias  
6.2.1 
Randomisation  
Randomization is conducted according to the standard scientific methods as used at the Clinical Trial 
Unit of the University of Bern. 
Allocation will be done via a dedicated website within the clinical trial management system REDCap, 
also containing the electronic case report forms.  
Patients will be stratified by their bodyweight, as the bodyweight is a strong predictive factor for the 
development of radiation dermatitis.   
Only system administrators who are otherwise not involved in the trial will have access to the algorithm 
and stored lists during the recruitment period. Investigators receive the allocation only after registration 

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of a patient. The underlying randomization lists and details of the algorithm will not be disclosed but kept 
securely at CTU Bern. All these measures will help to ensure concealment of allocation. 
 
 
6.2.2 
Blinding procedures  
Not applicable. 
6.2.3 
Other methods of minimising bias  
As the German Version of the CTCAE is not yet fully validated, the English validated Version [16] is 
used alongside the German Translation of “Deutsche Krebsliga” [17] in order to minimise bias. 
For the patients self-assessment a well validated questionnaire, the Skindex16, is used in parallel to the 
not validated, however standardized visual analog scales. (As so far, no suitable standardized self-
assessment specific to Radiation Dermatitis seem to exist).  
 
6.3 Unblinding Procedures (Code break)  
Not applicable. 
 
 
 
 
7. STUDY POPULATION  
Anticipated study population: adult patients attending the department of radiation therapy for Breast 
Cancer and set to start radiation therapy, which is conducted in an outpatient setting. In this pilot study 
no further centers are involved. 
 
7.1 Eligibility criteria  
 
Participants fulfilling all of the following inclusion criteria are eligible for the study: 
• 
Radiation therapy for Breast Cancer  
• 
Age >= 18 years  
• 
Informed Consent as documented by signature (Appendix Informed Consent Form) 
 
 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
• 
Ulcerated cancer at beginning of radiation therapy 
• 
Skin lesions in the radiation area before start of radiation therapy 
• 
Known allergies, hypersensitivity or reactions against one of the constituents of the 
investigational product [5]  
• 
Any neurological or psychiatric conditions that, in the evaluation of the treating physician, 
deem the patient incapable to participate in the study 
• 
Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, 
cardiovascular disease, etc.) as judged by the PI 
 
The following criteria are exclusion criteria for the conduct of the radiation therapy, which is 

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prerequisite for inclusion into the study.  Thus, such patients will anyway not meet the inclusion 
criteria and are explicitly excluded from participation: 
• 
Women who are pregnant or breast feeding  
• 
Lack of safe contraception, defined as: Female participants of childbearing potential, not using 
and not willing to continue using a medically reliable method of contraception for the entire 
study duration, such as oral, injectable, or implantable contraceptives, or intrauterine 
contraceptive devices, or who are not using any other method considered sufficiently reliable 
by the investigator in individual cases. 
• 
Please note that female participants who are surgically sterilised / hysterectomised or post-
menopausal for longer than 2 years are not considered as being of child bearing potential. 
 
 
7.2 Recruitment and screening  
All eligible patients of the Department of Radiation Oncology will be offered participation in the study.  
At the planning CT for radiation therapy the patient is informed about the study by his/her treating 
physician and offered participation. During this time eligibility is assessed by the physician. Until the 
time of baseline-assessment, which is conducted when the radiation therapy starts, the patient has time 
to consider and sign the informed consent. This duration is generally one week. 
No compensation is offered, as any assessment takes place during the regularly scheduled visits for 
radiation therapy and thus patients invest no extra time. 
7.3 Assignment to study groups  
Patient registration/randomization will only be accepted from authorized investigators. 
Prior to registration, the following steps have to be taken: 
• Fill in the patient screening, enrollment and identification list 
• Check the eligibility criteria 
• Obtain signed and dated written informed consent from the patient prior to any protocol-specific 
procedure according to ICH/GCP and local guidelines. 
• The CRFs must be completed at the time of registration 
Registration is done via Internet www.REDCap (https://www.project-redcap.org/). For technical 
difficulties, investigators are recommended to contact data management of CTU Bern 
 
7.4 Criteria for withdrawal / discontinuation of participants  
Patients can anytime withdraw from the study should they wish to do so, their data will be analysed up 
to that timepoint, as laid out in the informed consent document.  
The treating physician can decide at any time to exclude the patient from the study, e.g. in case of 
concerns due to disease progression, change or premature end of the radiation therapy or any kind of 
safety concern. In such case the patient will be followed-up as deemed necessary by the treating 
physician in line with the treatment protocols of the department of radiation therapy. 
 
 
 
 

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8. STUDY INTERVENTION  
8.1 Identity of Investigational Products (treatment / medical device)  
Patients will undergo all regularly assigned therapy at the Department of Radio- Oncology Inselspital, 
including the standard skin care “Excipial-Hydrolotion”. This is the treatment of the comparator group. 
The test group (=study drug group) receives Urtica comp. in addition to the regular treatment.  
Urtica comp is applied as soon as the patients senses itching, tingling or “sunburn-like” sensations or if 
reddening of the skin is discovered, and the use is limited to the affected area. Non affected area is 
continuously cared for with Excipial-Hydrolotion.  
  
8.1.1 
Experimental Intervention (treatment) 
Urtica comp. gelatum in its commercial formulation and packaging is used. The colorless Gel is also 
called “Wound and Burn Gel” and contains seven active substances: Argentum colloidale Dil. D5, Arnica 
montana e floribus LA 20%, Calendula officinalis e floribus LA 20%, Cantharis ex animale toto Gl Dil. 
D5, Symphytum officinale ex herba LA 20%, Thuja occidentalis e summitatibus LA 20%, Urtica urens 
ex herba LA 20%. 
All of them were manufactured based on to the methods as described in the German Homeopathic 
Pharmacopoeia (GHP, also known as HAB). 
Wound and Burn Gel is the only dosage form of Argentum/Urtica comp. 
Urtica comp is applied as soon as the patients senses itching, tingling or “sunburn-like” sensations or if 
reddening of the skin is discovered, and the use is limited to the affected area. Non affected area is 
continuously cared for with Excipial-Hydrolotion.  
 
 
8.1.2 
Control Intervention (standard/routine/comparator treatment / medical device)  
Standard therapy for prevention and treatment of radiation dermatitis is the commercially available 
Excipial Hydrolotion by Galderma Schweiz AG. The lotion is applied directly onto the skin, like a cream.  
1 ml of the lotion contains 20 mg urea. Polihexanid is used for conservation [21].  
 
8.1.3 
Packaging, Labelling and Supply (re-supply)  
Regular commercial packaging is used.  
 
8.1.4 
Storage Conditions  
Regular storage in the medication cabinet of the department.  
 
8.2 Administration of experimental and control interventions  
8.2.1 
Experimental Intervention  
The interventional product, Urtica comp, is applied directly onto the skin, like a cream. It is used as soon 
as the patient senses an itching, tingling or sunburn-like sensation or if reddening of the skin is 
discovered, and is applied onto the affected Area. The application is recommended 2 to 3 times per day, 
in line with the recommended use of the product.  It can be used during the six weeks of radiation 
therapy as well as during the follow-up period (six weeks) if required. Patients are however instructed 
not to use it within 6 hours before radiation therapy, which is the guideline recommendation in the 
Department of Radiation Oncology. 
 

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8.2.2 
Control Intervention 
Excipial Hydrolotion is used as recommended in the patient leaflet [21] and can be used anytime freely 
during the six weeks of radiation therapy as well as during the follow-up period if required. Patients are 
however instructed not to use it within 6 hours before radiation therapy, which is the guideline 
recommendation in the Department of Radiation Oncology. 
8.3 Dose modifications  
Not applicable. 
8.4 Compliance with study intervention  
Clinical practice in the Department has shown that patients with breast cancer are eagerly using the 
recommended cream or lotion in order to prevent and alleviate the symptoms of radiation dermatitis.  
Nevertheless is the use of the study cream and control lotion encouraged and checked at each visit.  
Furthermore is the use check at the end of study, when the left-over products are returned.  
 
8.5 Data Collection and Follow-up for withdrawn participants  
If a patient withdraws from study an attempt should be made to collect the End-of-Study form. Follow-
up is conducted as regularly scheduled for the radiation-therapy follow-up, in case the patient continues 
his/her radiation therapy. Patients who stop in total the therapy at the Department of Radiation Oncology 
will be contacted in order to assess the reason behind the withdrawal and a potential relatedness to 
study procedures.   
Patients dropping out of the trial will be replaced.  
 
8.6 Trial specific preventive measures 
In case of marked worsening of the radiation dermatitis, e.g. epitheliolysis, the patient may receive 
“Flammazine and Ialugen plus” [19, 20] as rescue-care. The use of this medications is recorded in the 
CRF. 
Non-trial specific, however important and specific for the radiation therapy is a pregnancy test at baseline 
and exclusion of pregnant women, women without safe contraception or breastfeeding mothers.  
8.7 Concomitant Interventions (treatments)  
Concomitant antihormonal therapy is permitted and will be recorded in the CRF as it may increase the 
occurrence of radiation dermatitis. Also smoking under therapy (although discouraged) will be recorded 
in the CRF for the same reasons. 
 
8.8 Study Drug Accountability  
The study medication and comparator are marketed and regularly used products. 
According to recommended indication and dosage in this patient group, the comparator cream is 
ordered via the regular ordering.  The Company WALA will provide the study drug for free. Both drugs 
are kept at the Department of Radiation Oncology in the regular medication cupboard.  
 
8.9 Return or Destruction of Study Drug / Medical Device  
The patients are requested to return unused study drug at the end of therapy.  
 

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9. STUDY ASSESSMENTS  
9.1 Study flow chart / table of study procedures and assessments 
 
 
 
 
 
 
 
                Visit 
 
Form  
or action 
Screening 
/ Planning 
of RTx* 
Baseline 
(at first 
treatment 
Visit) * 
Visits during intervention 
(Treatment duration 
generally 6 wks * / **)  
EOT / 
close-
out visit 
* 
Follow-
up (EOT 
+ 6wks*) 
Therapeutic 
intervention 
- 
- 
Radiotherapy (all) 
Group A:  Urtica comp. 
Group B:  standard care 
- 
- 
Radomisation 
 
x 
 
 
 
Assessment  
 
 
 
 
 
Eligibility 
x 
 
 
 
 
Informed consent 
 
x 
 
 
 
Med History 
 
x 
 
 
 
Primary Endpoints 
 
 
 
 
 
Extended CTCAE 
(physician)  
- 
x 
At each weekly assessment 
x 
x 
x 
x 
x 
x 
x 
x 
Extended CTCAE 
(nurse) 
- 
x 
If Dr’s score is >= 1.5 
x 
x 
 
 
 
 
 
 
Secondary Endpoints 
 
 
 
 
 
Clinical assessment 
(physician) 
x 
x 
At each weekly assessment 
x 
x 
x 
x 
x 
x 
x 
x 
Skindex 16 Items  
(patient)  
- 
x 
One measurement point at 
mid of therapy 
x 
x 
- 
- 
- 
x 
- 
- 
VAS 
(patient) 
- 
x 
At each weekly assessment 
x 
x 
x 
x 
x 
x 
x 
x 
FACIT-TS-G  
(patient) 
- 
- 
- 
x 
- 
End of Study form 
 
 
 
 
x*** 
 
 
*allowed time frames for each visit: the dates and time frames are aligned with the radiation-therapy 
schedule clinically assigned for the patient. The regular schedule for radiation therapy of breast cancer 
starts with a planning CT and therapy is beginning a week later consisting of a course of six weeks, 5 
weeks of total mamma irradiation and one week of “boost / volume reduction” resulting in a total of 25 
fractions à 2 Gy. Follow-up is conducted 6 weeks (+/- one week) after end of therapy.  In clinical 
experience this timeframe is strictly adhered to in 99% of patients, however should a patient require 
deviation from the schedule, e.g. due to tolerability-issues of the radiation therapy, the deviation as well 
as the reason for it will be recorded in the CRF.  
 
** 6 intervention visits, including the baseline and EOT visit. In detail: BL, BL+1wk, BL+2wks, BL+3wks, 
BL+4wks, BL+5wks=EOT 
 
***at follow-up or whenever the patient ends his/her participation in the study (e.g. in case of drop-out 
at the time of drop-out or as soon as possible after it.) 
 
 

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9.2 Assessments of outcomes  
9.2.1 
Assessment of primary outcome  
 
Primary Outcome, the skin condition, is measured by the extended CTCAE scoring system (uploaded 
under BASEC section 11) assessing the skin condition with respect to radiation dermatitis. This 
assessment is made by the treating physician and nurse at baseline, at each weekly visit for radiation 
therapy during the treatment course of 6 weeks, at end of therapy and then at follow-up 6 weeks later.  
The physician scores the skin condition on the “extended CTCAE”.  
This scoring system was adapted from the Radiation Treatment Oncology Group (RTOG) and NIH 
Common Toxicity Criteria-Adverse Event (CTCAE) scales for acute radiation skin toxicity, which 
appears to be the most widely used measurement for radiation dermatitis [16]. 
The occurrence and severity of radiation dermatitis is measured using this scoring system, ranging 0.0 
to 5.0 at increments of 0.5.  Half step increments like this have been used in the past e.g. by Ryan et al. 
[15] to capture more precisely the severity of the radiation dermatitis. The score incorporates changes 
in redness, pigment, texture and integrity of the skin. Digital images of portraying the appearance of 
various RDS scores have also been incorporated to complement the verbal descriptions, which are 
containing the text of the standard CTC criteria, version 4.0 [16] as well as the German Translation of 
the CTC Criteria by „Deutsche Krebsliga“ [17]. 
A second rating is conducted by the nurse, in all cases where the physicians score is higher or equal to 
1.5. The scores are combined in a joint score for additional precision.  
 
9.2.2 
Assessment of secondary outcomes 
 
Percentage requiring no additional therapy for RD (e.g. Flammazine or Ialugen plus) 
Percentage of patients RD free at end of therapy and at follow-up 
Percentage of patients with secondary skin infection / need of topical and systemic antibiotics  
Patient’s assessment of the skin condition / quality of life / patient’s evaluation of the treatment 
As compared to the control group.   
 
Secondary Outcomes are measured  
1. by assessing at each visit whether the skin condition requires an additional treatment beyond 
the regular skincare or study medication with Flammazine or Ialugen plus. 
The percentage of the patients requiring such treatment during their radiation therapy is 
compared between the two groups. 
2. by calculating, based on the CTCAE, the Percentage of patients RD free at end of therapy 
and at follow-up and comparison between the two groups. 
3. by assessing secondary skin infection in the radiation field and the need of topical and 
systemic antibiotics. The percentage of the patients requiring such treatment during their 
radiation therapy is compared between the two groups. 
4. The Patients perspective is captured  
• 
by the Skindex 16 , which is a questionnaire commonly used for the self-assessment of skin 
conditions. The 16 items are rated on an ordinal scale ranging 0-6. 
• 
by visual analog scales (VAS) are used to assess pain, itching, burning, skin irritation, 
appearance and general quality of life (related to radiation dermatitis).  
• 
By a final evaluation of treatment utilizing a short version of the FACIT-TS-G (Functional 
Assessment of Chronic Illness Therapy - treatment satisfaction - general). A functional 
assessment of chronic illness therapy (FACIT) measure of satisfaction with treatment for 
chronic illnesses such as cancer and HIV/AIDS.   
The patients’ perspective is compared as well between both treatment groups. 
 

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9.2.3 
Assessment of other outcomes of interest 
No further assessments are planned. 
 
9.2.4 
Assessment of safety outcomes 
9.2.4.1 
Adverse events  
Not applicable for Category A trial.  
9.2.4.2 
Laboratory parameters 
Not applicable. 
9.2.4.3 
Vital signs 
Not applicable. 
9.2.5 
Assessments in participants who prematurely stop the study 
Please refer to section 10 for details  
9.3 Procedures at each visit 
9.3.1 
Screening visit (BL -1wk*) 
The screening visit takes place when the patient comes into the clinic for the planning of his/her radiation 
therapy. At screening visit the patient’s eligibility, medical history and clinical details are assessed. 
(please find a list of all variables per visit as BASEC attachment Nr 05).  The patient receives full 
information about the study. The informed consent document is handed to the patient and he/she can 
consider participation for a week, when the radiation therapy is starting. 
 
9.3.2 
Baseline visit* 
The baseline visit takes place at the start of radiation therapy.  Assessment “A” is conducted.  
“Asessment A”: A clinical assessment is conducted including the assessment of sAEs (please find a list 
of all variables per visit as BASEC attachment Nr 05). The Physician scores the Extended CTCAE. If 
the physician’s score is equal or above 1.5, the Extended CTCAE is also scored by the nurse, who is 
otherwise blind to the scoring content of the physician. The patient fills in the VAS (visual analog scale) 
on his/her skin condition in the radiation area.  
Additionally the patient fills in the Skindex 16. 
Dispense of trial medication.  
 
9.3.3 
Visits during intervention  
 
 
 
 
 
 
 
          
(weekly: BL, BL+1wk, BL+2wks, BL+3wks, BL+4wks, BL+5wks=EOT*) 
The visits take place at the regularly scheduled visits for radiation therapy, which generally take place 
on a weekly base for the duration of six weeks (= 6 times, including the baseline and EOT visit).  
“Assessment A” is conducted (see above). 
 
Additionally the Skindex 16 is filled in by the patient at visit 4. 
 
9.3.4 
Close-out visit / EOT* 
Close-out is conducted at the End Of Therapy, the last and sixth scheduled visit of radiation therapy.   

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“Assessment A” is conducted (see above). 
Additionally the Skindex 16 and the FACIT-TS-G is filled in by the patient. 
 
9.3.5 
Follow-up visit (EOT + 6wks*) 
Follow-up is conducted at the regular follow-up visit of radiation therapy, which is six month after End 
Of Therapy.   
“Assessment A” is conducted (see above). 
Additionally the Skindex 16 is filled in by the patient. 
The End of Study form is completed. 
 
 
* noted timeframes are for general orientation only, the visit schedule will follow exactly the assigned 
visits for radiation therapy. 
 
 
 

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10. SAFETY  
10.1 Drug studies 
In line with the new law on clinical research (ordinance ClinO) the documentation of AEs for Category 
A drug trials is not required and will not be conducted beyond the AEs gathered as outlined in the 
objectives and safety-objectives.  
All serious adverse events (SAEs) are collected, fully investigated and documented in source 
documents and case report forms (CRF) in line with the standards of the Department of Radiation 
Oncology during the entire duration of the study.  
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.  
 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation 
participant administered a pharmaceutical product and which does not necessarily have a causal 
relationship with the study procedure. An AE can therefore be any unfavourable and 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. 
[ICH E6 1.2] 
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
• 
results in death, 
• 
is life-threatening, 
• 
requires in-patient hospitalization or prolongation of existing hospitalisation, 
• 
results in persistent or significant disability/incapacity, or 
• 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in death, or 
require hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the 
other outcomes listed above should also usually be considered serious. [ICH E2A] 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of 
drug dependency or drug abuse.  
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at study 
termination (including safety visit) will be further followed up until recovery or until stabilisation of the 
disease after termination.  
 
Assessment of Causality 
Both Investigator and Sponsor-investigator make a causality assessment of the event to the study drug, 
based on the criteria listed in the ICH E2A guidelines: 
Relationship 
Description 
Definitely(gesichert) 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably (wahrscheinlich) 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly (möglich) 
Temporal relationship 

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Other cause possible 
Unlikely (unwahrscheinlich) 
Any assessable reaction that does not fulfil the above conditions 
Not related (ohne Beziehung) 
Causal relationship can be ruled out 
Can not be assessed (Nicht zu 
beurteilen) 
Impossible to assess or to judge. 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information. [ICH E2A] 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, causality 
and expectedness. If the event is related to the investigational product and is both serious and 
unexpected, it is classified as a SUSAR.  
 
Assessment of Severity 
The grades for severity described in the “Common Terminology Criteria for Adverse Events CTCAE 
Version 4.0” terminology are used.   
 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events  
Reporting of SAEs 
All SAEs must be reported immediately and within a maximum of 24 hours to the Sponsor-Investigator 
of the study, Dr. Nikola Cihoric and must be faxed to the safety desk (++41-(0)31 632 82 63) using the 
SAE reporting form provided by the sponsor-investigator. The Sponsor-Investigator will re-evaluate the 
SAE and return the form to the site. 
SAEs resulting in death are reported to the local Ethics Committee (via local Investigator) within 7 days. 
Exemptions from expedited reporting may be possible if the SAE is a clear result of the underlying 
disease.  
Reporting of SAEs or other safety relevant events to the Marketing Approval Holder (MAH) of the 
drug(s) will be conducted in line with the regular guidelines of Inselspital. 
 
Reporting of SUSARs 
A SUSAR needs to be reported to the local Ethics Committee (local event via local Investigator) within 
7 days, if the event is fatal, or within 15 days (all other events). 
 
Reporting of Safety Signals 
All suspected new risks and relevant new aspects of known adverse reactions that require safety-related 
measures, i.e. so called safety signals, must be reported to the Sponsor-Investigator within 24 hours. 
The Sponsor-Investigator must report the safety signals within 7 days to the local Ethics Committee 
(local event via local Investigator). 
 
Reporting and Handling of Pregnancies 
Pregnancy is an exclusion criterion from the study. However if a pregnancy is diagnosed after the 
accrual (during the treatment or in the follow-up phase), the continuation and discontinuation of the 
pregnancy and the treatment will be discussed with the patient.   

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Any pregnancy during the treatment phase of the study and within 30 days after discontinuation of study 
intervention will be reported to the Sponsor-Investigator within 24 hours. The course and outcome of 
the pregnancy should be followed up carefully, and any abnormal outcome regarding the mother or the 
child should be documented and reported.  
 
Periodic reporting of safety 
Not applicable.  
 
10.1.3 Follow up of Serious Adverse Events 
Patients with any reported ongoing serious Adverse Events at study end will be followed until resolution 
of the event or a stabilized condition of the participant has been achieved. 
 
 
 

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11. STATISTICAL METHODS  
The statistical design is mainly based on the randomized part of the study. 
 
11.1 Hypothesis 
If a Null Hypothesis is tested, state explicitly both Null and Alternative Hypotheses in terms of the 
primary endpoint and justify them in regard of the participant population and dose. The stated 
hypotheses have to be used in the determination of Sample Size. Relate these hypotheses to the 
study objectives. 
 
Descriptive analysis of demographics, disease and treatment features for the whole cohort and each 
treatment arm.  Hypothesis testing: 
o H0: There is no difference between the test arm and the control arm in the incidence and 
severity of radiation dermatitis 
o H1: There is a difference between the treatment arm and the control arm in the incidence and 
severity of radiation dermatitis (favoring the test arm) 
Both, the incidence as well as the severity of radiation dermatitis is highly meaningful to compare 
between the treatment arms in order to examine the effect of Urtica comp. in prevention and treatment 
of RD in breast cancer patients.  
Given, that this is a pilot study to assess feasibility, sample size determination was conducted based on 
practical reasoning and not related to hypothesis testing.  
 
11.2 Determination of Sample Size  
As this is a first pilot study 30 patients with breast cancer will participate.  
Since this is a pilot study no power analysis has been carried out, but the data of this pilot study are 
utilized for feasibility-assessment and will serve as the base for planning further larger and adequately 
powered randomized controlled research ( “Machbarkeitsstudie”). 
 
According to the patient numbers in the department of Radiation Oncology and estimating a 50% 
participation and a 19% drop-out rate the recruitment can be achieved within six month. 
 
11.3 Statistical criteria of termination of trial  
ICH: A description of the "stopping rules" or "discontinuation criteria" for individual participants, parts of 
trial and entire trial. 
Describe the criteria for the termination of the trial or the stopping rules. 
Not applicable. 
11.4 Planned Analyses  
11.4.1 Datasets to be analysed, analysis populations 
The datapoints at baseline and end of therapy are essential for the analysis. Patients for whom one or 
both of this points are missing will thus not be included into the analysis. It can be expected, that 
patients receiving the radiation therapy as scheduled will also follow the process of caring for their 
skin.  
Both groups (test group and comparison group) will be evaluated according to the intention to treat. 
Patients for whom at least baseline and EOT values are available will be part of the analyse, in line 
with their respective group and irrespective of the course of study. 
As this is a pilot study, explorative subgroup analysis may be conducted.   
 

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11.4.2 Primary Analysis 
Incidence and severity of radiation dermatitis throughout the treatment course  will be analysed.  
Both groups (test group and comparison group) will be evaluated according to the intention to treat. 
The statistical comparison between the groups will be carried out by applying a Man-Whitney-U test. 
Timepoint of comparison is at EOT. 
11.4.3 Secondary Analyses 
Calculations for secondary analysis will include: 
Percentage requiring no additional Tx for RD (e.g. Ialugen +).   
Percentage of patients RD free at end of therapy / follow-up.  
Again, the statistical comparisons between the groups will be carried out by applying a Man-Whitney-
U test. 
 
The course of therapy of the group receiving Urtica comp. gel (=test group) will be compared with an 
active control group (comparison group) receiving the institutional standard skin care “Excipial-
Hydrolotion” (as well as with historic standard-courses and the Incidence and percentages described 
in literature.) 
Statistical test will test whether or not the data are normally distributed and dependent on this finding 
the primary and secondary endpoints are compared with parametric testing (such a t-test) or 
nonparametric tests (such as Wilcoxson) between the two groups.  
Timepoint of comparison for the secondary analyses is at EOT as well as at follow-up. 
A p-value ≤ 0.05 will be considered significant. 
 
11.4.4 Interim analyses 
Not applicable. 
11.4.5 Safety analysis 
Safety analysis is integral part of primary and secondary analysis, please see above. 
11.4.6 Deviation(s) from the original statistical plan  
Any deviation from the planned analyses will be justified and reported if required 
11.5 Handling of missing data and drop-outs  
There will be a recruitment of patients until 30 Patient fulfil all the inclusion criteria. The data of dropout 
patients is treated with care and only the already observed data will be used for further analysis. 
 
 
 

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12. QUALITY ASSURANCE AND CONTROL  
REDCap is used as clinical data management system (CDMS). 
Data is recorded at the appointment with the physician and the nurse. Data is managed with the same 
care as it is standardized for every patient consultation. The paper with the data as well as the 
electronic patient reports and the CRF are locked and only authorized personnel has access to the 
data. For further use of the data, the paper version will be entered into REDCap by a co-worker. 
During the process of digitalisation, the data will be coded. The decoded master list is stored save at 
the principle investigator. 
The training of site personnel is conducted in conjunction with the PI, study-coordinator, head nurse 
and study nurse.  
 
12.1 Data handling and record keeping / archiving  
 
12.1.1 Case Report Forms  
An electronic database, REDCap is utilized and set up by the Clinical Trial Unit.  
For each enrolled study participant a CRF is maintained. CRFs must be kept current to reflect subject 
status at each phase during the course of study. Study-related data of the patient will be collected in a 
coded manner. The names of the patients will not be disclosed. A code (unique, consecutive numbered) 
will be attributed to each patient registered.  
Only study personnel trained in monitoring is authorized for CRF entries and it must be assured that 
any authorised person can be identified.  
 
12.1.2 Specification of source documents  
Source data must be available at the site to document the existence of the study participants. Source 
data must include the original documents relating to the study, as well as the medical treatment and 
medical history of the participant. 
The source documents comprise the following: demographic data, visit dates, participation in study 
and Informed Consent Forms, randomisation number, SAEs, AEs of the skin and concomitant 
medication relevant to the study, results of relevant examinations.  
Identification of the data: Data that are recorded in the eCRF in REDCap are uploaded as BASEC 
document 05: “05 CRF Strahlenerythem Variablenliste_Urtica comp.” 
Data evaluated by the physician will be entered from the medical history and data which are evaluated 
by the nurse from the IPDOS system. 
 
12.1.3 Record keeping / archiving  
The study database with all archive tables will be securely stored by CTU Bern for at least 15 years. 
The sponsor also keeps the Trial Master File and interim/final reports for at least 10 years. 
 
12.2 Data management  
REDCap is used as clinical data management system (CDMS). 
12.2.1 Data Management System  
The CRFs in this trial are implemented electronically using a dedicated electronic data capturing (EDC) 
system (REDCap). The EDC system is activated for the trial only after successfully passing a formal 
test procedure. All data entered in the CRFs are stored on a Linux server in a dedicated mySQL 
database. 

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Responsibility for hosting the EDC system and the database lies with CTU Bern. 
 
12.2.2 Data security, access and back-up  
Describe who has access to data, how, where and when – and which backup systems are in place (if 
applicable). 
The server hosting the EDC system and the database is kept in a locked server-room. Only the system 
administrators have direct access to the server and back-up tapes. A role concept with personal 
passwords (site investigator, statistician, monitor, administrator etc.) regulates permission for each user 
to use the system and database as he/she requires. 
All data entered into the CRFs are transferred to the database using Secure Sockets Layer (SSL) 
encryption. Each data point has attributes attached to it identifying the user who entered it with the exact 
time and date. Retrospective alterations of data in the database are recorded in an audit table. Time, 
table, data field and altered value, and the person are recorded (audit trail). 
A multi-level back-up system is implemented. Back-ups of the whole system including the database are 
run internally several times per day and on external tapes once a day. The back-up tapes are stored in 
a secure place in a different building. 
 
12.2.3 Analysis and archiving 
Describe how data are extracted and where they are stored, database status recording, duration and 
place of storage (note MD: the archiving period is different for implantable devices). 
 
At final analysis, data files will be extracted from the database into statistical packages to be analyzed. 
The status of the database at this time is recorded in special archive tables. 
 
12.2.4 Electronic and central data validation  
Data is checked by the EDC system for completeness and plausibility. Furthermore, selected data points 
are cross-checked for plausibility with previously entered data for that participant.  
Before database lock the PI will validate the collected data with his signature. 
 
12.3 Monitoring  
REDCap is used as clinical data management system and is set up by the CTU. Otherwise no specific 
monitoring is required, as the study is considered to have a low risk level:  application of the clinically 
recommended dosage of a Swissmedic registered cream, which is already marketed for over 80 years 
with a very favourable side effect profile (see section 3.4). Furthermore no invasive tests or therapy are 
part of the study.  
 
However a quality-visit of the CTU (“Qualitätsvisite”) will be considered. 
 
12.4 Audits and Inspections  
Not applicable 
 
12.5 Confidentiality, Data Protection  
Data generation, transmission, storage and analysis of health related personal data within this project 
will follow strictly the current Swiss legal requirements for data protection and will be performed 
according to the Ordinance HRO Art. 5. 
Health related personal data captured during this project are strictly confidential and disclosure to third 

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parties is prohibited; coding will safeguard participants' confidentiality. 
Data protection: project data will be handled with uttermost discretion and only be accessible to 
authorised personnel. Direct access to source documents will only be permitted for purposes of audits 
and inspections. 
 
12.6 Storage of biological material and related health data  
Not applicable. 
 
 
13. PUBLICATION AND DISSEMINATION POLICY  
The Trial shall be registered with the ClilnicalTrials.gov Database as well as with the Swiss National 
Clinical Trials Portal (SNCTP). 
The study coordinator / project leader shall have the right of first publication in a peer-reviewed journal: 
Planned is a joint publication with all contributors which is to be organized and prepared by the project 
leader. Authorship is determined in line with scientific practice by contribution of the individuals and 
assuming fulfilment of the roles outlined in the protocol and staff list.  
(Order of Authors: study coordinator / Project leader, Contributor 1, Contributor 2, Contributor 3 to x, 
Sponsor, Applicant. Shared first and last authorship may be applied between coordinator / Project leader, 
Sponsor and Applicant, depending on their contribution to the manuscript.)   
All publications and presentations of results of the study shall be in accordance with accepted scientific 
practice; academic standards and customs.  
 The study coordinator / project leader will submit all manuscripts to the Sponsor for review at least 
twenty (20) days prior to the scheduled submission for publication. The sponsor also has the right to 
provide comments on the manuscript and both parties shall discuss in good faith to incorporate such 
comments in the publication or disclosure.  The sponsor will be co-author of all publications derived from 
the data and additional co-authorship may be attributed to investigators from the centre. 
However in the event that there is no first publication (or reasonable draft publication circulated to all 
involved co-authors) by the project leader within 24 months after termination of the Trial (LPLV), then 
notwithstanding the foregoing, the sponsor may individually propose a publication, provided that the 
proposed publication is first reviewed by the project leader and the applicant of the Department of 
Complementary Medicine or their respective representative. 
 
 
14. FUNDING AND SUPPORT  
 
14.1 Funding  
The project is supported by the division of Anthroposophically extended Medicine (AEM) at the Institute 
of Complementary Medicine of the University of Bern (Prof. Dr. U.Wolf) and the Department of Radiation 
Oncology (Prof. Dr. Aebersold). 
Depending on the results and feasibility of the pilot trial funding for the consecutive and larger RTC will 
be sought.  
 

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14.2 Other Support  
The study medication Urtica comp. will be provided by WALA Heilmittel GmBH, Bad Boll, Germany. 
WALA Heilmittel GmbH has non influence on planning, conduct, data analysis and publishing of the 
study. 
15. INSURANCE  
Not applicable (cat. A study). 
 

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16. REFERENCES  
 
1 Hickok JT et al. Occurrence, severity, and longitudinal course of twelve common symptoms in 1129 
consecutive patients during radiotherapy for cancer.J Pain Symptom Manage. 2005;30(5):433.  
 
2 McQuestion M.  Evidence-based skin care management in radiation therapy: clinical update.Semin 
Oncol Nurs. 2011;27(2):e1.  
 
3 Salvo N et al.  Prophylaxis and management of acute radiation-induced skin reactions: a systematic 
review of the literature. Curr Oncol. 2010 Aug;17(4):94-112.  
 
4 Nursing Guide of the Radiation Oncology Inselspital: „Pflege bei PatientInnen, die bestrahlt werden“ 
Section 3.2 „Hautpflege bei einer Strahlenreaktion“.  
 
5 packet insert uploade das BASEC document 16d or under: 
 https://www.walaarzneimittel.de/de/arzneimittel/wala-wund-und-
brandgel.html https://www.walaarzneimittel.de/files/walaarzneimittel/medicines/beipackzettel/Wund-
und-Brandgel.pdf 
 
6 Stern C. Grosse Brennessel (Urtica dioica). zkm 2015; 1:38-39 
 
7 Glöckler M. (Hrsg.), Anthroposophische Arzneimitteltherapie für Ärzte und Apotheker. einschließl. 5. 
Akt.Lfg. 2014; Wissenschaftliche Verlagsgesellschaft, Stuttgart 2014, ISBN 978-3-8047-3202-5    
 
8 Vogel HH, Wege der Arzneimittelfindung, Band 2, S 868-870 und 249-253 
 
9 Robertson C, Robertson AG, Hendry JH, Roberts SA, Slevin NJ, Duncan WB, MacDougall RH, Kerr 
GR, O'Sullivan B, Keane TJ. Similar decreases in local tumor control are calculated for treatment 
protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers. Int J 
Radiat Oncol Biol Phys. 1998;40(2):319.  
 
11 Meyer F, Fortin A, Wang CS, Liu G, Bairati I: Predictors of severe acute and late toxicities in 
patients with localized head-and-neck cancer treated with radiation therapy. Int J Radiat Oncol Biol 
Phys. 2012 Mar;82(4):1454-62. Epub 2011 Jun 2.  
 
12 Ryan JL:  Ionizing radiation: the good, the bad, and the ugly. J Invest Dermatol. 2012 Mar;132(3 Pt 
2):985-93. Epub 2012 Jan 05.  
 
13 Tejwani A, Wu S, Jia Y, Agulnik M, Millender L, Lacouture ME:  Increased risk of high-grade 
dermatologic toxicities with radiation plus epidermal growth factor receptor inhibitor therapy. Cancer. 
2009;115(6):1286.  
14 Hengge et al.: Adverse effects of topical gluccocorticosteroids. J Am Acad Dermatol, 2006;54:1-15 
15 Ryan JL, Heckler CE, Ling M, et al. Curcumin for radiation dermatitis: A randomized, double-blind, 
placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res 2013; 180:34.   
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998827/figure/F1/ 
 
16 standard CTC criteria, version 4.0, -  https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
 
17 German Translation of the CTC Criteria by „Deutsche Krebsliga“ (  https://eliph.klinikum.uni-
heidelberg.de/pdf/E5.pdf  page 18)    
 
18  Flamazine  packet insert: 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1490937614037.pdf  accessed on 
10.08.2017 11:55h 
 

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19: Flammazine ® Fachinformation: https://compendium.ch/mpro/mnr/21971/html/de accessed on 
10.08.2017 11:50h 
 
20: Ialugen plus ® Fachinformation:  
https://compendium.ch/mpro/mnr/4022/html/de accessed on 10.08.2017 11:50h 
 
21 Excipial Patienteninformation / Beipackzettel:  
 https://compendium.ch/mpub/pnr/23645/html/de 
 
22 Declaration of Helsinki, Version October 2013, 
(http://www.wma.net/en/30publications/10policies/b3/index.html ) 
 
23 International Conference on Harmonization (ICH, 1996) E6 Guideline for Good Clinical Practice. 
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.
pdf) and International Conference on Harmonization (ICH, 1997) E8 Guideline: General 
Considerations for Clinical Trials 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8_Guideli
ne.pdf) 
 
24 Humanforschungsgesetz, HFG Bundesgesetz über die Forschung am Menschen (Bundesgesetz 
über die Forschung am Menschen, HFG) vom 30. September 2011/ Loi fédérale relative à la 
recherche sur l’être humain (loi relative à la recherche sur l’être humain, LRH) du 30 septembre 2011 / 
Legge federale concernente la ricerca sull'essere umano (Legge sulla ricerca umana, LRUm) del 30 
settembre 2011 
http://www.bag.admin.ch/themen/medizin/00701/00702/07558/index.html?lang=de  
 
25 Verordnung über klinische Versuche in der Humanforschung (Verordnung über klinische Versuche, 
KlinV) vom 20. September 2013 / Ordonnance sur les essais cliniques dans le cadre de la recherche 
sur l’être humain (Ordonnance sur les essais cliniques, OClin) du 20 septembre 2013. Ordinanza sulle 
sperimentazioni cliniche nella ricerca umana 
(Ordinanza sulle sperimentazioni cliniche, OSRUm) del 20 settembre 
2013 https://www.admin.ch/opc/de/classified-compilation/20121176/201705010000/810.305.pdf 
 
26 Heilmittelgesetz, HMG Bundesgesetz über Arzneimittel und Medizinprodukte (Heilmittelgesetz, 
HMG) vom 15. Dezember 2000 / Loi fédérale sur les médicaments et les dispositifs médicaux (Loi sur 
les produits thérapeutiques, LPT) du 15 décembre 2000 / Legge federale sui medicamenti e i 
dispositivi medici (Legge sugli agenti terapeutici, LATer)  http://www.admin.ch/ch/d/sr/8/812.21.de.pdf 
 
27 ISO 14155:2011 Clinical investigation of medical devices for human subjects -- Good clinical 
practice www.iso.org 
 
28 WHO, International Clinical Trials Registry Platform (ICTRP) http://www.who.int/ictrp/en/ 
 
 
 
 

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17. APPENDICES 
Table of documents as requested in BASEC and where the information is found, either referring to the 
protocol section or separately provided (uploaded in BASEC under the respective number). 
 
No 
As 
in 
BASEC 
Name of document 
Info 
1 
Cover letter 
Uploaded in BASEC 
2 
Synopsis of study plan 
Not separately required. 
see No 4 page 7ff, section “study Synopsis” 
3 
Participant information sheet 
and informed consent 
German version uploaded in BASEC, French version will be 
translated after approval of the content of the German version. 
4 
Study plan (protocol) 
This document 
4a 
Monitoring plan 
See No 4, p. 16 section 1.5 “monitoring” 
5 
CRF 
Uploaded in BASEC 
6 
Investigators / PIs CV 
Uploaded in BASEC 
7 
Investigators / PIs proof of 
GCP training 
Uploaded in BASEC 
8 
Details 
on 
infrastructure 
suitability 
Not applicable:  Inselspital Radiation Oncology 
9 
Agreements 
Not applicable 
10 
Insurance (optional) 
Not applicable 
11 
Other documents handed to 
study participants 
Uploaded Questionnairs: 
• 
Extended CTCAE (Dr and nurse) 
• 
Skindex (patient) 
• 
VAS (patient) 
• 
FACIT-TS-G (patient) 
12 
Details on compensation 
Not applicable 
13 
Staff list 
Uploaded in BASEC 
14 
Information 
on 
secure 
handling 
of 
biological 
material and personal data 
see No 4: section 12.2, 12.5 and 12.6 for personal data  
biological material: not applicable 
15 
Information on review of this 
proposal by other authorities 
Not applicable 
16 
Product 
information 
as 
approved by Swissmedic 
Uploaded documents: 
16a nonclinical overview and 16b clinical overview  
16c Commission C Monograph  
16d Packet Insert (Fachinformation) 
16e Swissmedic “Zulassungsbescheinigung” 
18 
Proof of labelling 
See No 4, page 31, section 8.1.1: regular commercial product 
is used 
39  
Varia 
Not required.