Radiotherapy Related Skin Toxicity: Mepitel® Film vs. Standard Care in Patients With Locally Advanced Head-and-Neck Cancer
Phase: NA
Conditions: Head and Neck Neoplasms
Sponsor: University Hospital Schleswig-Holstein

Page 1 of 34 
 
 
RAdiotherapy RElated Skin Toxicity: 
Mepitel® Film vs. Standard Care in Patients with 
locally advanced Head-and-Neck Cancer 
Trial name: RAREST-01 
A multinational, randomized, active-controlled, parallel-group, multicenter trial 
 
Sponsor: 
University Hospital Schleswig-Holstein (UKSH), Campus Lübeck 
 
Coordinating Investigator: 
Prof. Dr. Dirk Rades 
Department of Radiation Oncology 
University of Lübeck 
Ratzeburger Allee 160 
23538 Lübeck 
 
Version 8.0 of 25.06.2019 
 
 
 
 
Confidentiality statement 
The information contained in this protocol are confidential and may not be communicated to 
third parties either in spoken or in written form without the express permission of the trial 
management. This excludes communication of the required information to the ethics 
commission responsible or informing the regulatory authorities. 

Study Protocol: RAREST-01 
 
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Sponsor: 
University Hospital Schleswig-Holstein (UKSH), Campus Lübeck 
Ratzeburger Allee 160, 23538 Lübeck, Germany 
 
 
Coordinating Investigator (contact) 
Prof. Dr. Dirk Rades 
Department of Radiation Oncology 
University of Lübeck  
Ratzeburger Allee 160 
23538 Lübeck, Germany. 
Tel.: +49-(0)451-500-45400 
Fax: +49-(0)451-500-45404 
Email: Rades.Dirk@gmx.net 
 
 
 

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Contents 
SIGNATURE PAGE ................................................................................................................ 6 
1. SYNOPSIS............................................................................................................................. 7 
1.1. ENGLISH .............................................................................................................................. 7 
1.2. GERMAN .............................................................................................................................. 9 
2. FLOW CHART .................................................................................................................. 11 
3. BACKGROUND AND RATIONALE .............................................................................. 12 
4. OBJECTIVES ..................................................................................................................... 13 
5. ENDPOINTS ....................................................................................................................... 13 
5.1. PRIMARY ENDPOINT .......................................................................................................... 13 
5.2. CRITERIA FOR SECONDARY AIMS ..................................................................................... 13 
6. TRIAL DESIGN ................................................................................................................. 13 
6.1 GENERAL TRIAL DESIGN AND DURATION .......................................................................... 13 
6.2 PATIENT SELECTION .......................................................................................................... 14 
6.2.1 GENERAL PREREQUISITES .............................................................................................. 14 
6.2.2 INCLUSION AND EXCLUSION CRITERIA ........................................................................... 14 
6.2.3 TERMINATION CRITERIA FOR INDIVIDUAL PATIENTS .................................................... 15 
6.2.4 DEFINITION OF THE END OF THE TRIAL .......................................................................... 15 
6.2.5 STOPPING RULES............................................................................................................. 15 
6.3 TIMELINE ........................................................................................................................... 15 
7 TREATMENT ..................................................................................................................... 16 
7.1 PATIENT REGISTRATION AND RANDOMIZATION ............................................................... 16 
7.2 TREATMENT ....................................................................................................................... 16 
7.2.1 RADIOTHERAPY .............................................................................................................. 16 
7.2.2. CONCOMITANT CHEMOTHERAPY.................................................................................. 17 
7.2.3. POSSIBLE SIDE EFFECTS OF RADIO(CHEMO)THERAPY .................................................. 17 
7.2.4. ARM A: MEPITEL® FILM ............................................................................................... 17 

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7.2.5. ARM B: STANDARD CARE OF RADIO(CHEMO)THERAPY ............................................... 19 
8. SAFETY MANAGEMENT ............................................................................................... 20 
8.1. DEFINITIONS ...................................................................................................................... 20 
8.1.1. ADVERSE EVENTS ........................................................................................................... 20 
8.1.2 UNEXPECTED ADVERSE EVENTS ..................................................................................... 20 
8.1.3. SERIOUS ADVERSE EVENTS ............................................................................................ 20 
8.2 ASSESSMENT AND DOCUMENTATION OF ADVERSE EVENTS .............................................. 21 
8.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNEXPECTED ADVERSE EVENTS ........... 21 
9. EXAMINATIONS .............................................................................................................. 22 
9.1 OVERVIEW OF EXAMINATIONS .......................................................................................... 22 
9.2 DATA ASSESSMENT AND POTENTIAL PROGNOSIS FACTORS BEFORE THE INITIATION OF 
RADIOTHERAPY ........................................................................................................................ 22 
9.3 EXAMINATIONS WITH RELATION TO PRIMARY AND SECONDARY AIM CRITERIA ............. 22 
9.3.1 RADIATION DERMATITIS ................................................................................................. 22 
9.3.2 ADVERSE EVENTS ........................................................................................................... 22 
9.3.3 QUALITY OF LIFE ............................................................................................................ 22 
9.3.4 PAIN ASSESSMENT ........................................................................................................... 22 
10 STATISTICS ..................................................................................................................... 23 
10.1 SAMPLE SIZE CALCULATION ............................................................................................ 23 
10.2 ANALYSIS SETS................................................................................................................. 23 
10.3. STATISTICAL ANALYSIS ................................................................................................... 24 
11. ETHICAL AND LEGAL PRINCIPLES ........................................................................ 26 
11.1 ETHICS COMMITTEE VOTE ............................................................................................... 26 
11.2 PATIENT INFORMATION AND INFORMED CONSENT ......................................................... 26 
11.3 DECLARATION OF HELSINKI ........................................................................................... 26 
11.4 DATA PROTECTION .......................................................................................................... 26 
11.5 TRIAL REGISTRATION ...................................................................................................... 26 
11.6 PROTOCOL AMENDMENTS ............................................................................................... 27 

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12. DATA MANAGEMENT ................................................................................................. 27 
12.1 PATIENT IDENTIFICATION LIST ........................................................................................ 27 
12.2 DOCUMENTATION SHEET ................................................................................................. 27 
12.3 STORAGE OF TRIAL DOCUMENTS ..................................................................................... 27 
13. QUALITY ASSURANCE ................................................................................................ 28 
13.1 MONITORING.................................................................................................................... 28 
13.2 AUDITS .............................................................................................................................. 28 
13.3 INSPECTIONS .................................................................................................................... 28 
14. DISSEMINATION OF RESULTS AND PUBLICATION POLICY .......................... 29 
15. REFERENCES ................................................................................................................. 30 
APPENDIX I PATIENT INFORMATION ......................................................................... 31 
APPENDIX II INFORMED CONSENT .............................................................................. 32 
APPENDIX III ........................................................................................................................ 33 
APPENDIX IV ........................................................................................................................ 34 
 
 

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SIGNATURE PAGE 
 
RAdiotherapy RElated Skin Toxicity: 
Mepitel® Film vs. Standard Care in Patients with locally advanced Head-and-Neck 
Cancer 
Protocol code:  
RAREST-01  
Version:  
 
8.0 of 25-JUN-2019 
It has been confirmed that the protocol, the case report forms and appendices contain all 
information and regulations necessary for the implementation of the clinical trial, and that the 
trial will be conducted and documented in line with this protocol, abiding by the legal 
regulations and agreements described therein. 
Sponsor of Study 
Name:  
 
University Hospital Schleswig-Holstein, Campus Lübeck 
 
 
 
Represented by Prof. Dr. med. Dirk Rades 
Institution: 
 
Department of Radiation Oncology 
 
 
 
University Hospital Schleswig-Holstein, Campus Lübeck 
Ratzeburger Allee 160 
23538 Lübeck 
 
 
Place, Date 
 
 
 
 
 
 
Signature 
 
Coordinating Investigator 
Name:  
 
Prof. Dr. med. Dirk Rades 
Institution: 
 
Department of Radiation Oncology 
 
 
 
University of Lübeck  
Ratzeburger Allee 160 
23538 Lübeck 
 
 
Place, Date 
 
 
 
 
 
 
Signature 
 
 

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1. Synopsis 
1.1. English 
Trial title 
RAdiotherapy RElated Skin Toxicity: Mepitel® Film vs. Standard 
Care in Patients with locally advanced Head-and-Neck Cancer  
Trial designation 
RAREST-01 
Sponsor 
University Hospital Schleswig-Holstein (UKSH), Campus Lübeck 
Trial manager 
Prof. Dr. Dirk Rades 
Department of Radiation Oncology 
University of Lübeck, Germany  
Trial start 
März 2017 
 
Recruitment period 
24 months 
Type of protocol 
Multinational, randomized, active-controlled, parallel-group, multi-
center trial  
Indication 
Radiotherapy or Radiochemotherapy of Head-and-Neck Cancer 
Objectives 
The primary goal of this randomized trial is to demonstrate that 
Mepitel® Film is superior to Standard Care with respect to prevention 
of 
grade 
≥2 
radiation 
dermatitis 
in 
patients 
receiving 
radio(chemo)therapy for locally advanced SCCHN. 
Primary endpoint 
Rate of patients experiencing grade ≥2 radiation dermatitis (CTCAE 
v4.03) until 50 Gy of radiotherapy 
Secondary aims 
1. Time to grade 2 radiation dermatitis until 50 Gy of radiotherapy 
2. Rate of patients experiencing grade ≥2 radiation dermatitis during 
radio(chemo)therapy 
3. Rate of patients experiencing grade ≥3 skin toxicity during 
radio(chemo)therapy  
4. Adverse Events 
5. Quality of life: Evaluation prior to radiotherapy, at the end of 
radiotherapy weeks 3 + 5, and at 3 weeks following radiotherapy 
6. Pain (radiation fields): Evaluation prior to radiotherapy, during RT 
daily, at the end of radiotherapy weeks 3 + 5, and at 3 weeks 
following radiotherapy 
7. Grade ≥2 dermatitis at 60 Gy and at the end of radiotherapy (EOT) 
Treatment 
Patients will be randomized in a ratio of 1:1 to arm A and arm B: 
Arm A: Treatment with Mepitel® Film, starting at the beginning of 

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radiotherapy. 
Arm B: Treatment with Standard Care, starting at the beginning of 
radiotheraphy. 
In case of grade 2 moist desquamation or any grade 3 radiation 
dermatitis, patients will be treated with local antisepctic agents plus 
fatty cream and absorbing silicon bandage. 
Follow-up: until 3 weeks following radiotherapy 
Number of patients 
168 patients (84 patients per arm) 
Inclusion criteria 
1. Histologically proven locally advanced squamous cell carcinoma of 
the head-and-neck (SCCHN) 
2. Conventionally fractionated (5 x 2 Gy per week) definitive or 
adjuvant radio(chemo)therapy 
3. Age ≥18 years  
4. Written informed consent 
5. Capacity of the patient to contract 
Exclusion criteria 
1. N3 stage (lymph nodes >6 cm) 
2. Distant metastases (M1) 
3. Pregnancy, Lactation 
4. Treatment with EGFR-antibodies (either given or planned) 
5. Expected non-compliance 
Statistics / Sample size 
calculation 
With 80 patients qualifiying for Full Analysis Set in each group, a two-
sided chi-square test with a 5% two-sided significance level will have 
80% power to yield statistical significance if the rate of grade ≥2 
radiation dermatitis in patients receiving standard care for skin toxicity 
is 85% compared to 65% in patients treated with Mepitel® Film.  
Taking into account that 5% of patients will not qualify for Full 
Analysis Set, a total of 168 patients should be randomized.The 
confirmatory evaluation will be performed within the Full Analysis Set, 
which comprises all randomized patients who have started either 
therapy with arm A or with arm B. Cochran-Mantel-Haenszel Chi-
square tests will be used for non-parametric assessment of the overall 
treatment effect, while adjusting for the effects of the stratification 
variables. For sensitity analysis, a logistic regression model for grade 
≥2 radiation dermatitis will be applied including the parameters used 
for stratification. In addition, a model including also additional patient 
characteristics will be fitted. 
To evaluate the tolerance and acceptance of the Mepitel® Film 
treatment after one third of the study an interim analysis will be 
conducted after inclusion of 57 patients. The recruitment will be put on 
hold until the 57 patients have completed the study. Depending on the 
proportion of patients who did not tolerate or accept Mepitel® Film, the 
study will be continued or terminated. Furthermore, the skin toxicity 
between both treatment groups will be compared. 
End of study 
April 2019 (last patient out). 
 

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1.2. German 
Studientitel 
Strahlentherapie-bedingte Hautreaktionen: Mepitel®
Film im 
Vergleich zur Standardbehandlung bei Patienten mit lokal 
fortgeschrittenem Kopf-Hals-Tumor 
Studienkürzel 
RAREST-01 
Sponsor 
Universitätsklinikum Schleswig-Holstein (UKSH), Campus Lübeck 
Studienleiter 
Prof. Dr. Dirk Rades 
Klinik für Strahlentherapie 
Universität zu Lübeck  
Start der Studie 
März 2017 
Rekrutierungs-
zeitraum 
24 Monate 
Studiendesign 
Randomisiert, aktiv-kontrolliert, parallel, multizentrisch 
Indikation 
Strahlentherapie oder Radiochemotherapie bei einem Kopf-Hals-Tumor
Zielsetzung 
Die primäre Fragestellung dieser randomisierten Studie ist der 
Nachweis, dass Mepitel® Film der Standardbehandlung hinsichtlich der 
Vermeidung einer Strahlendermatitis Grad ≥2 bei Patienten, die eine 
Radio(chemo)therapie bei einem lokal fortgeschrittenen SCCHN 
erhalten, überlegen ist. 
Primärer Endpunkt 
Rate der Patienten, bei denen während der Strahlentherapie bis 50 Gy 
eine Dermatitis Grad ≥2 (CTCAE v4.03) auftritt 
Sekundäre Endpunkte 1. Zeit bis zum Auftreten einer Strahlendermatitis Grad 2 bei 
Bestrahlung bis 50 Gy 
2. Rate der Patienten, bei denen während der Radio(chemo)therapie 
eine Strahlendermatitis > Grad 2 auftritt 
3. Rate der Patient, bei denen während der Radio(chemo)therpie eine 
Strahlendermatitis  ≥ Grad 3 auftritt 
4. Nebenwirkungen 
5. Lebensqualität: Bewertung vor Bestrahlung, zum Ende der 
 
Bestrahlungswochen 3 und 5 sowie 3 Wochen nach Bestrahlung 
6. Schmerz (Strahlenfelder): Bewertung vor Bestrahlung, täglich 
während der Strahlentherapie, am Ende der Bestrahlungswochen 3 
und 5 sowie 3 Wochen nach Bestrahlung 
7. Grad ≥2 Dermatitis bei 60 Gy und am Ende der Strahlentherapie 
(EOT) 
Patientenanzahl 
168 Patienten (84 Patienten pro Arm) 
Behandlung 
Patienten werden 1:1 in Arm A oder Arm B randomisiert: 
Arm A: Behandlung mit Mepitel® Film startet mit Beginn der 
Strahlentherapie. 
Arm B: Standardbehandlung startet mit Beginn der Strahlentherapie. 
Bei feuchten Epitheliolysen Grad 2 oder jeglicher Strahlendermatitis 
Grad 3 werden die Patienten lokal mit antiseptischen Mitteln plus einer 

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fetthaltigen Creme und Silikonverband behandelt. 
Follow-up: bis 3 Wochen nach Strahlentherapie 
Einschlusskriterien 
1.    Histologisch gesichertes lokal fortgeschrittenes     
       Plattenepithelkarzinom der Kopf-Hals-Region (SCCHN) 
2.    Konventionell fraktionierte (5 x 2 Gy pro Woche) definitive oder  
       adjuvante Radio(chemo)therapie 
3.    Alter ≥18 Jahre  
4.    Schriftliche Einverständniserklärung 
Ausschlusskriterien 
1.    N3 Stadium (Lymphknoten >6 cm) 
2.    Fernmetastasen (M1) 
3.    Schwangerschaft, Stillzeit 
4.    Behandlung mit EGFR-Antikörpern (auch geplant) 
5.    Zu erwartende Non-Compliance 
Statistik 
/ 
Fallzahl-
kalkulation 
Wenn 80 Patienten pro Gruppe für das Full-Analysis-Set in Frage 
kommen, 
wird 
der 
zweiseitige 
Chi-Quadrat-Text 
bei 
einem 
Signifikanzniveau von 5% eine Power von 80% aufweisen. Wenn die 
Rate an Grad ≥2 Strahlendermatitiden bei Patienten/innen im Standard 
Arm (B) 85% und bei Patienten/innen im experimentellen Arm (A) 
65% beträgt, wird die Überlegenheit als signifikant angesehen. 
Wenn man davon ausgeht, dass sich 5% der Patienten nicht für das 
Full-Analysis-Set qualifizieren, müssen 168 Patienten randomisiert 
werden.Der Wirksamkeitsnachweis wird mit dem Full-Analysis-Set 
durchgeführt, welches alle randomisierten Patienten beinhaltet, die ihre 
Behandlung entweder im Arm A oder Arm B begonnen haben. Der 
Cochran-Mantel-Haenszel 
Chi-Quadrat-Test 
wird 
zum 
nicht-
parametrischen 
Nachweis 
des 
Behandlungseffektes 
verwendet. 
Adjustiert wird nach den Effekten der Stratifizierungsvariablen. 
Für die Sensitivitätsanalyse wird ein logistisches Regressionsmodell für 
die 
Strahlendermatitis 
Grad 
≥2 
angewendet, 
welches 
die 
Stratifizierungparameter berücksichtigt. Zusätzliche wird ein Modell 
verwendet, welches auch an zusätzliche Charakteristika der Patienten 
angepasst ist. 
Um die Toleranz und Akzeptanz des Mepitel® Film Produktes nach 
einem Drittel der Study zu evaluieren wird nach der Behandlung von 
57 Patienten eine Interimsanalyse durchgeführt. Die Rekrutierung wird 
unterbrochen, nachdem die 57 Patienten die Studie beendet haben. Je 
nach dem Anteil der Patienten, die Mepitel® Film nicht toleriert oder 
akzeptiert haben, wird die Studie fortgesetzt oder beendet. Außerdem 
wird die Hauttoxizität zwischen den beiden Behandlungsgruppen 
verglichen. 
Studienende 
April 2019 (last patient out) 
 
 
 

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2. Flow Chart 
 
 
Prior to 
radiotherapy 
During 
Treatment 
(weeks 1, 2, 4)  
  
 During  
Treatment  
(weeks 3 + 5)
Following  
Treatment  
(Last 
day 
of 
treatment [EOT], 
weeks 1 + 3) 
Informed Consent 
X 
 
 
 
Medical History 
X 
 
 
 
Demographic Data 
X  
 
 
 
Concomitant 
Medication 
X 
 
 
 
Patient Characteristics X 
 
 
 
Randomization 
X 
 
 
 
Physical Examination 
X 
X 
X 
X 
Adverse Events, 
Serious Adverse 
Events 
X 
X 
X 
X 
Skin status defined as 
radiation dermatitis 
acording to CTCAE 
v4.03 
 
X 
(daily) 
X 
(daily) 
X 
(daily) 
Quality of Life  
X 
 
X 
X 
(week 3) 
Other Toxicities 
 
X 
X 
X 
Pain score 
X 
X  
(daily) 
X  
(daily) 
X 
(EOT, week 3) 
Radio(chemo)therapy    
(administered as 
planned) 
 
X 
X 
 
 

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3. Background and Rationale 
Locally advanced squamous head-and-neck cancer is a serious malignant disease. In about 
90% of head-and-neck cancers, the histology is squamous cell carcinoma (SCCHN). The vast 
majority of patient with locally advanced SCCHN receive radiotherapy, either as a part of a 
definitive treatment approach, or as an adjuvant treatment following surgery. If radiotherapy 
is administered as definitive treatment, it is usually combined with concurrent cisplatin-based 
chemotherapy [1]. In an adjuvant situation, chemotherapy will be added to radiotherapy in 
case of risk factors, namely microscopically or macroscopically incomplete resection or in 
case of extra-capsular spread of lymph nodes metastases. 
Radiotherapy of locally advanced SCCHN may be associated with severe acute toxicities 
including skin reaction such as erythema or desquamation. Skin toxicity is enhanced if 
concurrent chemotherapy is administered. If the skin toxicity becomes severe (grade ≥3 
according to the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03), it 
may lead to a reduction of the planned chemotherapy dose and to interruptions of 
radiotherapy. Interruptions of radiotherapy have to be reported to be associated with poorer 
treatment outcomes in patients with SCCHN [2,3].       
In order to successfully avoid grade ≥3 skin toxicity, it appears mandatory to avoid or at least 
postpone the development of grade 2 skin toxicity. In previous studies of patients receiving 
radiotherapy or radio(chemo)therapy for locally advanced head-and-neck cancer, rates of 
grade ≥2 skin toxicity ranging between 86% and 92% have been reported, although the 
standard procedures of skin care and protection had been applied [1, 4, 5]. These figures 
demonstrate that the results of standard care need to be improved. 
Three years ago, the results of a systematic inpatient controlled clinical trial were published 
that had investigated the use of an absorbent, self-adhesive dressing (Mepilex® Lite) for skin 
protection in patients irradiated for breast cancer [6]. According to this study the dressings 
were able to significantly reduce the radiation-related skin erythema. Similar dressings 
(Mepilex® Border Sacrum and Mepilex® Heel dressings) have been demonstrated in a 
randomized trial to be effective also in the prevention of sacral and heel pressure ulcers in 
trauma and critically ill patients [7]. In another randomized trial a silver-containing soft 
silicone foam dressing (Mepilex® Ag dressing) was as effective in the treatment of partial-
thickness thermal burns when compared to the standard care (silver sulfadiazine) [8]. In 
addition, the group of patients treated with the Mepilex® Ag dressing demonstrated decreased 
pain and lower costs associated with treatment. More recently, a new dressing (Mepitel® 
Film) has been developed, which is thinner, softer and more comfortable than previous 
dressings. 
The rationale for the present study is to investigate a new option of skin protection in order to 
reduce the rate of grade ≥2 skin toxicity in patients receiving radiotherapy alone or 
radiochemotherapy for locally advanced SCCHN.   
 

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4. Objectives 
The primary goal of this randomized trial is to demonstrate that Mepitel® Film is superior to 
Standard Care with respect to prevent grade ≥2 radiation dermatitis in patients receiving 
radio(chemo)therapy up to 50 Gy for locally advanced SCCHN. 
5. Endpoints 
5.1. Primary endpoint 
The primary aim of this randomized multinational multicenter trial is to investigate the rate of 
patients experiencing grade ≥2 radiation dermatitis (CTCAE v4.03) until 50 Gy of 
radiotherapy.  
Evaluation until 50 Gy of radiotherapy has been selected as the primary endpoint, since up to 
50 Gy, the irradiated volume includes the primary tumor and the bilateral cervical and 
supraclavicular lymph nodes, and, therefore, is almost identical in all patients. After 50 Gy, 
the irradiated volume is much more individual, depending on location and size of the primary 
tumor, involvement of lymph nodes, and the treatment approach (definitive vs. adjuvant).    
5.2. Criteria for secondary aims 
In addition, the following endpoints will be evaluated: 
1. Time to grade 2 radiation dermatitis until 50 Gy of radiotherapy 
2. Rate 
of 
patients 
experiencing 
grade 
≥2 
radiation 
dermatitis 
during 
radio(chemo)therapy 
3. Rate of patients experiencing grade ≥3 skin toxicity during radio(chemo)therapy 
4. Adverse Events 
5. Quality of life: Evaluation prior to radiotherapy, at the end of radiotherapy weeks 3 + 
5, and at 3 weeks following radiotherapy 
6. Pain (radiation fields): Evaluation prior to radiotherapy, during radiotherapy daily at 
the end of radiotherapy weeks 3 + 5, and at 3 weeks following radiotherapy 
7. Rate of patients experiencing a grade ≥2 dermatitis at 60 Gy and at the end of 
radiotherapy (EOT) 
 
 
6. Trial design  
6.1 General trial design and duration 
This is a randomized, active-controlled, parallel-group trial, which will compare the following 
treatments of radiation related skin toxicity in patients with head-and-neck cancer:  
Mepitel® Film (Arm A) vs. Standard Care (Arm B).  

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A total of approximately 4 contributing centers are planned to participate, who aim to include 
an average of 21 patients per year. The recruitment of all 168 patients should be completed 
within 24 months. The follow-up period will be 3 weeks. This equals a total running time for 
the trial of 25 months. 
Stratification will be done using the following prognostic factors: 
1. Tumor site: oropharynx/oral cavity vs. hypopharynx/larynx 
2. Treatment approach: radiochemotherapy vs. radiotherapy alone  
3. Participating site 
In case of uneven distribution to stratification groups, which may result in very small groups 
the strata might be connected for analysis. The decision to merge strata for the analysis will be 
made before data base lock and before the final analysis of the data. 
To evaluate the tolerance and acceptance of the Mepitel® Film treatment after one third of the 
study an interim analysis will be conducted after inclusion of 57 patients. The recruitment will 
be put on hold until the 57 patients have completed the study. Depending on the proportion of 
patients who did not tolerate or accept Mepitel® Film, the study will be continued or 
discontinued. Furthermore, the skin toxicity between both treatment groups will be compared. 
6.2 Patient selection 
This trial will be performed in patients receiving definitive or adjuvant radio(chemo)therapy 
for locally advanced squamous cell carcinoma of the head-and-neck (SCCHN).  
6.2.1 General prerequisites 
Patients must be adequately informed about their diagnosis and about the nature, significance 
and scope of the trial. Patients may only be included after completing the pre-therapy 
clarification and on fulfillment of all inclusion criteria and on non-fulfillment of all exclusion 
criteria.  
6.2.2 Inclusion and exclusion criteria 
Inclusion criteria 
1. Histologically proven locally advanced squamous cell 
carcinoma of the head-and-neck (SCCHN) 
2. Conventionally fractionated (5 x 2 Gy per week) definitive 
or adjuvant radio(chemo)therapy 
3. Age ≥18 years  
4. Written informed consent 
5. Capacity of the patient to contract 
Exclusion criteria 
1. N3 stage (lymph nodes >6 cm) 
2. Distant metastases (M1) 
3. Pregnancy, Lactation 
4. Treatment with EGFR-antibodies (either given or planned) 
5. Expected non-compliance 

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6.2.3 Termination criteria for individual patients 
The patient may terminate participation in the trial at any time and without giving any 
reasons. If the patient agrees, follow up will be performed as planned to receive data even in 
case of termination of participation in the study.  
Otherwise, the reasons for terminating participation in the trial are the same as those for 
individually breaking off treatment with radiotherapy. In the cases, follow up will be 
completed as planned.  
 Serious adverse event, which necessitates termination of treatment 
 Unacceptable toxicities 
 Pregnancy 
Date and reason for termination of treatment must be documented. 
6.2.4 Definition of the end of the trial 
The trial ends after a follow-up for at least 3 weeks following radio(chemo)therapy. 
6.2.5 Stopping Rules 
Individual patients 
Randomized patients have the right to discontinue participation at any time without penalty or 
loss of benefits to which the subject would otherwise be entitled.  
Study site suspension or early termination 
The coordinating principal investigator and ethics committee have the right to suspend or 
terminate a participating site for any of the following possible reasons: Noncompliance to 
obtain patient informed consent; unsatisfactory rate of patient enrollment or compliance to 
eligibility criteria; repeated noncompliance with the investigational plan; inaccurate, 
incomplete, and/or untimely submission of data. 
To evaluate the tolerance and acceptance of the Mepitel® Film treatment after one third of the 
study an interim analysis will be conducted after inclusion of 57 patients. The recruitment will 
be put on hold until the 57 patients have completed the study. Depending on the proportion of 
patients who did not tolerate or accept Mepitel® Film, the study will be continued or 
discontinued. Furthermore, the skin toxicity between both treatment groups will be compared. 
The trial may be stopped prematurely by the principal investigator in case of safety reasons 
that do not appear to be reasonably justified. In case of a prematurely termination of the trial, 
the patient and the ethics committee will be informed promptly. An appropriate further 
therapy and follow-up is assured for the patient. 
6.3 Timeline 
First Patient In 
March 2017 
Last Patient In 
February 2019 

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Last Patient Out  
April 2019 
End of Study 
August 2019 
7 Treatment 
7.1 Patient registration and randomization 
The patients will be assigned two code numbers: the number of the contributing center plus a 
patient ID number, continuously ascending, starting with 001.   
After registration, patients will be randomized in a 1:1 ratio to receive either Mepitel® Film 
(Arm A) or Standard Care (Arm B) for treatment of radiation related skin toxicity.  
A stratified blockrandomization will be performed. The stratification (approximately 4 center, 
2 treatment approaches, 2 tumor sites) will be conducted as described in section 6.1. Further 
details with regard to the randomization will be described in a separate document referred to 
as ”Festlegen der Parameter für die Randomisierung”. 
The randomization will be performed centrally at the ‘Zentrum für Klinische Studien’ (ZKS) 
at the University of Lübeck, Germany via Fax: +49-(0)451-500-50614. The randomization is 
possible from Monday to Thursday 8.00 a.m. to 4.00 p.m., Friday 8.00 a.m. to 2.00 p.m. 
(exclusion: no randomization will be conducted between 24th of December and 1st of January). 
The proceeding is based on standard operating procedures (SOPs) of the ZKS. The fax 
document has to be completed and finally be signed and dated by the investigator. Once the 
randomization is allocated to the patient it cannot be changed. 
7.2 Treatment 
7.2.1 Radiotherapy 
Radiotherapy is administered using conventional fractionation (5 x 2.0 Gy per week).  
In all patients, the initial target volume includes the region of the primary tumor plus bilateral 
cervical and supraclavicular lymph nodes up to 50 Gy.  
Patients treated with adjuvant radiotherapy following complete resection of the primary tumor 
and the involved lymph nodes (R0-resection) receive a radiation boost of 10 Gy (5 x 2.0 Gy 
per week) to the regions of the primary tumor and the involved lymph nodes.  
In case of a microscopically incomplete resection (R1-resection), the boost dose to the 
primary tumor region is 16 Gy.  
In case of extra-capsular spread (ECS) of lymph nodes, the lymph nodes showing ECS 
receive an additional boost of 6 Gy (i.e. a cumulative boost dose of 16 Gy). 
Patients receiving definitive radiotherapy, receive a boost of 10 Gy (5 x 2.0 Gy per week) to 
the primary tumor, the involved lymph nodes, and the lymph node levels adjacent to the 
involved lymph nodes. An additional boost of another 10 Gy (5 x 2.0 Gy per week) is 
administered to the primary tumor and the involved lymph nodes. 
Treatment should be performed as either intensity-modulated radiotherapy (IMRT) or 
volumetric modulated arc theray (VMAT) radiotherapy. 

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The rate of patients experiencing grade ≥2 radiation dermatitis (CTCAE v4.03) until the fifth week 
of therapy (50 Gy) is in focus of this clinical study. In addition to this observation period 
another 2 weeks of radiotherapy (up to 70 Gy) might be performed. This further treatment 
will be conducted in accordance with common treatment guidelines. The treatment of the 
patients > 50 Gy will not be analyzed within this study. The occurrence of adverse events and 
serious adverse events will be documented for the complete duration of radiotherapy. The 
final dose of radiotherapy received by the patient has to be documented in the Case Report 
Form (CRF).  
7.2.2. Concomitant Chemotherapy 
In patients who receive definitive radiochemotherapy, concomitant chemotherapy with two 
courses of cisplatin (20 mg/m2/d1-5 or 25 mg/m2/d1-4), carboplatin (5xAUC 1.0 or 4xAUC 
1.5) or mitomycin C (20 mg/m2/d1) + 5-fluororuracil (1000 mg/m2/d1-5) is administered. 
Cisplatin,carboplatin and mitomycin C/5-fluorouracil are among effective and usedas 
radiosensitizers in the treatment of head-and-neck cancer patients. In this trial commercially 
available cisplatin,carboplatin, mitomycin C and 5-fluorouracil are used. Cisplatin is 
considered the standerad regimen. Carboplatin will be used in case of mild impairment of 
kidney function, and mitomycin C/5-fluorouracil in case of moderately impaired kidney 
function. Cisplatin, carboplatin or mitomycin will be administered after saline hydration as 
intravenous bolus infusion. The saline hyper-hydration will be given according to the 
investigational centre’s routine. All patients treated with cisplatin, carboplatin or mitomycin 
C/5-fluorouracil in addition to radiotherapy must receive adequate anti-emetic therapy prior to 
the administration. It is recommended that a 5HT3 antagonist (e.g. granisetrone) and 
dexamethasone 8 mg i.v. are administered prior to each cycle of treatment. 5-fluororuracil 
(1000 mg/m2/d1-5) will be adimistered as continuous infusion over 120 hours. 
7.2.3. Possible side effects of radio(chemo)therapy 
In addition to skin toxicity, radio(chemo)therapy may be associated with other side effects 
such as mucositis, taste disorders, xerostomia, nausea and vomiting, fatigue, renal 
dysfunction, and pancytopenia. In case of such a grade 3 toxicity according to CTCAE 
criteria, radio(chemo)therapy may be delayed for a maximum of 7 days without 
consequences. If it is delayed for longer than 7 days, the coordinating investigator of the 
clinical trial must be informed. 
7.2.4. Arm A: Mepitel® Film 
At the beginning of radiotherapy Mepitel® Film will be applied to the patient. The treatment 
will be continued until one week after the end of the treatment period or until a patient 
experiences grade ≥2 moist desquamation or grade ≥3 radiation dermatitis. In case of grade 
≥2 moist desquamation or grade ≥3 radiation dermatitis, each day antiseptic agents will be 
administered for wound cleansing followed by administration of silicon or calcium alginate 
bandage. This treatment will be continued until moist desquamation radiation disappears and 
radiaton dermatitis improves to grade 2. 
 
Mepitel® Film is an ultra thin, transparent, breathable soft silicone film dressing.  

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Product description  
Mepitel® Film is a gentle, sterile, transparent, breathable film dressing consisting of 
polyurethane film coated with a Safetac® contact layer. The film dressing is supported with a 
paper frame for ease of application.  
Safetac® Technology  
Safetac® is a patented soft silicone adhesive technology that minimizes pain to patients and 
trauma to wounds. Safetac® technology is less painful because it  
1. tacks gently to dry surfaces, like skin, but not to moist surfaces such as open wounds  
2. moulds to the skin’s pores, covering more skin surface and spreading peel forces on 
removal to prevent skin stripping  
3. seals the wound margins, ensuring exudates do not spread to the surrounding skin and 
minimizing maceration  
Mode of action  
Mepitel® Film provides a flexible, transparent covering to protect the skin or wound from 
microbial contamination, fluid strike through and from other external contamination while 
conforming to surface irregularities and body contours.  
Mepitel® Film maintains a moist environment even though the vapor permeability allows 
excess moisture to pass away from the skin.  
Mepitel® Film provides instant tack adhesion that minimizes the requirement of extra pressure 
in order to fixate well. The product does not leave residues and the adhesion level does not 
increase over time.  
Mepitel® Film is a protective layer that may reduce the shear and friction on the skin and may 
help to prevent skin breakdown.  
Fixation tapes can be fixated on top of the Mepitel® Film product, the Mepitel® Film is then 
used as a protective Landing Zone™ for the fixation tape.  
Mepitel® Film is skin-friendly, non-irritant and non-sensitizing. Mepitel® Film is waterproof.  
Intended Use 
Mepitel® Film is designed for the management for a wide range of superficial wounds such as 
pressure ulcers stage/grade I and II, superficial burns, superficial skin injuries and it may help 
to prevent skin breakdown. Mepitel® Film protects fragile and sensitive skin.  
Mepitel® Film can also be used as a protective cover for open surgical wounds (e.g. 
abdomen), fixate primary dressing as a secondary dressing and be used in combination with 
gels and ointments.  
 

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Instructions for use:  
1.  Clean the application area in accordance with normal procedures.  
Dry the skin/surrounding skin thoroughly.  
Remove the protection film (printed side) and apply the adherent side to the wound and 
smooth Mepitel® Film in place, ensuring a good seal. Do not stretch. The shape of the 
product may not be optimal at difficult to dress areas.  
Mepitel® Film can be repositioned as long as the paper frame is intact. Remove the paper 
frame.  
For best result, Mepitel® Film should overlap the dry surrounding skin by at least 1-2 cm 
for the smaller sizes (sizes up to 10x12 cm) and 5 cm for the larger sizes in order to 
fixate the dressing securely.  
The dressing can be removed without causing skin stripping and pain.  
 
Frequency of change  
Mepitel® Film may be left in place for several days depending on the condition of the skin or 
wound and the surrounding skin, or as indicated by accepted clinical practice.  
Precautions  
Do not use as primary fixation for IV, cannulae, ports, or other infusion and / or life 
sustaining devices.  
 
Mepitel® Film is not a wound contact layer product and does not allow wound exudates to 
pass trough the dressing to a secondary layer.  
 
If more than one product is used and they are overlapped, the vapor permeability goes down; 
this can lead to excess moisture not being allowed to pass away from the skin.  
In case of signs of clinical infection, consult a health care professional for adequate infection 
treatment.  
 
Do not reuse. If reused performance of the product may deteriorate, cross contamination may 
occur.  
 
Do not use if inner package is damaged or opened prior to use. Do not re-sterilize. 
 
7.2.5. Arm B: Standard Care of radio(chemo)therapy  
At the beginning of radiotherapy standard skin care will be applied to the patient. This may 
vary at the participating centers. At the University of Lübeck, it includes two components, 
fatty cream with 2-5% urea (fatty cream alone, if patients do not tolerate urea) and 
mometasone furoate cream. The treatment will be continued until one week after the end of 
the treatment period or until a patient experiences grade ≥2 moist desquamation or grade ≥3 
radiation dermatitis. In case of grade ≥2 moist desquamation or grade ≥3 radiation dermatitis, 
each day antiseptic agents will be administered for wound cleansing followed by 
administration of silicon or calcium alginate bandage. This treatment will be continued until 
moist desquamation radiation disappears and radiaton dermatitis improves to grade 2. 
 

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Cream 
Fatty cream with 2-5% urea is applied to the irradiated skin 3-4 times daily.  
Mometasone furoate cream  
In addition to the fatty cream with 2-5% urea, mometasone furoate cream (solution 0.1%) is 
applied to the irradiated skin once daily. 
Mometasone furoate cream is used in the treatment of inflammatory skin disorders. In terms 
of steroid strength, it is more potent than hydrocortisone, and less potent than dexamethasone. 
It reduces inflammation by causing several effects such as reversing the activation of 
inflammatory proteins, activating the secretion of anti-inflammatory proteins, stabilizing cell 
membranes, and decreasing the influx of inflammatory cells. The exact anti-inflammatory 
mechanism of action is unknown. 
 
8. Safety management 
8.1. Definitions 
8.1.1. Adverse events 
An adverse event is any event experienced by a patient or subject of a clinical trial, which 
does not necessarily have a causal relationship to treatment. An adverse event (AE) can 
therefore be any adverse or inadvertent occurrence (including notable laboratory findings), 
symptom or illness that occurs in the treatment period, no matter whether there is a causal 
relationship or not. Existing illnesses that deteriorate during the trial should be reported as 
adverse events. They may lead to serious adverse events if they fulfill the criteria below.  
Events covered by the documentation for concomitant diseases, the skin status or the radiation 
related acute toxicity grade (CTCAE v4.03) Grade 1 do not have to be additionally 
documented as adverse events. If an additional concomitant disease appears after the start of 
the study an adverse event form has to be completed. 
8.1.2 Unexpected adverse events 
Unexpected adverse events are those whose type, frequency and degree of severity are not 
expected based on current knowledge. 
8.1.3. Serious adverse events 
Serious adverse events are those which fulfill one of the following criteria at any dose level: 
• 
Lethal (resulting in death) event (Note: death is the result, not the event itself) 
• 
Life-threatening event (Note: the term “life-threatening” refers to an event in which the 
patient was in danger of death at the time the event occurred but not to an event that may 
have resulted in death had it been more serious.) 
• 
Patient had to be admitted to hospital or his/her hospital stay had to be extended as a 
result of the event 
• 
Any event leading to permanent or significant disability. 

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• 
Birth defects or malformations 
• 
Any medically significant event or any event necessitating surgery in order to prevent one 
of the abovementioned concomitant illnesses 
Hospitalization should be defined as such that the hospitalization was necessary in order to 
treat the adverse event. Hospital stays as part of the treatment outlined in the protocol or as a 
result of a planned, elective operation are not classed as serious adverse events. Likewise, an 
elective hospitalization to facilitate the trial process does not count as a serious adverse event.  
8.2 Assessment and documentation of adverse events 
The severity of adverse events should be assessed using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. If an adverse 
event occurs which is not described in the CTCAE version 4.03, the five-point scale below 
will be used. 
scale: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening and 5 = fatal. 
The following scale should be used to describe the likelihood that the event was caused by the 
trial treatment:  
1 = certain / definite; 
2 = probable; 
3 = possible; 
4 = unlikely; 
5 = not related; 
6 = not assessable. 
 
8.3 Reporting of serious adverse events and unexpected adverse events 
Serious adverse events and unexpected adverse events must be reported within 24 hours after 
their detection/onset by fax to the address below: 
Prof. Dr. Dirk Rades 
Klinik für Strahlentherapie, Universität zu Lübeck 
Ratzeburger Allee 160; 23538 Lübeck, Germany 
Tel.: +49-(0)451-500-45400  
Fax: +49-(0)451-500-45404 
Email: rades.dirk@gmx.net and dirk.rades@uksh.de 
 

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9. Examinations 
9.1 Overview of examinations 
Refer to the study flow chart in the synopsis for an overview of assessments and examinations 
required at each visit.  
9.2 Data assessment and potential prognosis factors before the initiation of 
radiotherapy 
The following parameters will be recorded at the start of the trial: medical history, 
concomitant diseases, physical examination, complications from head-and-neck surgery, age, 
date of birth, gender, body height and body weight, performance status (ECOG-PS, Appendix 
IV), site of primary tumor (oropharynx, oral cavity, hypopharynx and larynx), TNM-stage, 
AJCC-stage, histology (squamous cell carcinoma), HPV status (negative/positive), histologic 
grading (G1, G2, G3), surgery of primary tumor (no/yes), extent of resection (R0, R1, R2), 
neck dissection (no, unilateral, bilateral), complications of surgery, chemotherapy planned 
(no/yes, type of chemotherapy), Skin Status of the head-and neck region, and Quality of Life 
(EORTC QLQ-C30 Version 3.0 and EORTC QLQ-H&N35).  
9.3 Examinations with relation to primary and secondary aim criteria 
The following parameters will be assessed continuously throughout the course of the trial: 
9.3.1 Radiation dermatitis 
Radiation dermatitis will be assessed daily by two independent observers (specially trained 
nurses, technicians, or physicians), daily during radio(chemo)therapy and up to three weeks 
following radio(chemotherapy) according to CTCAE v4.03 (Appendix III). If the graduation 
of radiation dermatitis varies between the two observers, skin toxicity will be assessed by an 
additional observer. Observers are required to be very experienced in rating skin reactions and 
will additionally undergo a particular briefing prior to the start of this study.  
9.3.2 Adverse Events 
Adverse events, other than radiation dermatitis will be assessed on an ongoing basis according 
to CTCAE v4.03. The documentation is described in section 8.2.  
9.3.3 Quality of life 
Quality of life will be assessed prior to radio(chemo)therapy, at the end of radiotherapy weeks 
3 and 5, as well as three weeks following radio(chemo)therapy using the EORTC QLQ-C30 
Version 3.0 and the EORTC QLQ-H&N35.  
9.3.4 Pain assessment 
Pain (radiation fields) is assessed with a visual analogue scale (self assessment: from 0 = No 
pain; 1 = Mild pain to 10 = Very severe pain). In addition, pain scores will be correlated with 
the grade of skin reactions. 
 

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10 Statistics 
10.1 Sample size calculation 
The primary goal of this randomized trial is to demonstrate that Mepitel® Film is superior to 
Standard Care with respect to prevent grade ≥2 radiation dermatitis in patients receiving 
radio(chemo)therapy up to 50 Gy for locally advanced SCCHN. 
The null hypothesis of equal rates of grade ≥2 skin toxicity is tested against the two-sided 
alternative hypothesis of different rates. Based on this hypothesis system, the sample size 
required for this trial is calculated taking into account the following assumptions: 
• A Chi-square Test will be applied 
• The two-sided significance level is set to 5% 
• In patients treated with radio(chemo)therapy for locally advanced SCCHN, previous 
studies have suggested rates of grade ≥2 skin toxicity of 86-92% if standard skin care 
was administered. 
• Based on these data, a rate of grade ≥2 skin toxicity of 85% can be assumed in the 
reference group (“worst-case”), i.e. in patients receiving standard care for skin 
toxicity.  
• Administration of Mepitel® Film will be considered to be clinically relevant, if the rate 
of grade ≥2 skin toxicity can be reduced to 65%.  
• The power to yield statistical significance if the the difference in rates is in fact 20 
percentage points is set to 80%. 
Based on these assumptions, 80 patients are required per study arm within the Full Analysis 
Set. Taking into account that 5% of patients will not qualify for Full Analysis Set, a total of 
168 patients should be randomized.   
10.2 Analysis Sets 
Full Analysis Set 
The Full Analysis Set includes all randomized patients who have started either therapy with 
arm A or with arm B. The Full Analysis Set will be analyzed according to the Intent-to-Treat 
principle, i.e. patients will be analyzed in their initial group of randomization. 
Per Protocol Set 
The Per Protocol Set will comprise all patients of the Full Analysis Set and will exclude 
patients if any of the following criteria are met: 
• Administration of less than 50 Gy if the reason for discontinuation was any other than 
death or unacceptable toxicity 
• Delay of radiotherapy for more than 7 days prior to reaching 50 Gy 
All patients in the Per Protocol Set will be analyzed within their group of actual treatment 
received. 

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10.3. Statistical analysis  
General Considerations 
All data recorded in the case report forms describing the study population, toxicity and quality 
of life will be analyzed descriptively. Categorical data will be presented in contingency tables 
with frequencies and percentages. Continuous data will be summarized with at least the 
following: frequency (n), median, quartiles, mean, standard deviation (standard error), 
minimum and maximum. Number of patients with protocol deviations during the study and 
listings describing the deviations will be provided. 
In general, chi-square tests will be used to compare percentages in a two-by-two contingency 
table, replaced by Fisher´s exact test if the expected frequency in at least one cell of the 
associated table is less than 5. Stratified two-by-two contingency tables will be analyzed using 
Cochran-Mantel-Haenszel tests. Logistic regression models serve as multivariable methods 
for binary endpoint data. Comparison of ordinal variables between treatment arms will be 
performed using the asymptotic Wilcoxon-Mann-Whitney test, replaced by its exact version 
in case of ordinal categories with small number of categories and/or sparse data within 
categories. Any shift in location of quantitative variables between study groups will be 
performed with Wilcoxon-Mann-Whitney tests as well.  
Time-to-event data will be analyzed by Kaplan-Meier methods, when merely non-informative 
censoring occurs. For statistical comparison, the logrank-test will be provided supplemented 
by multivariate Cox proportional hazards models. 
The data analysis will be performed according to the statistical analysis plan (SAP), and 
which will be finalised prior to database lock and prior to any statistical analysis.  
Primary Endpoint 
The rates of patients experiencing grade ≥2 radiation dermatitis in patients receiving 
radio(chemo)therapy up to 50 Gy will be statistically compared using the Cochran-Mantel-
Haenszel Chi-square test on a two-sided significance level of 5%. This test is the natural non-
parametric extension of the Chi-square test for testing the treatment effect, while adjusting for 
the effects of the stratification variables used for randomization. For further assessment of the 
robustness of the results, a logistic regression model for grade ≥2 radiation dermatitis will be 
applied including the parameters used for stratification. In addition, a model including also 
additional patient characteristics will be fitted. 
The confirmatory evaluation will be performed within the Full Analysis Set, the Per Protocol 
Set serves for further sensitivity analyses.  
Secondary endpoints 
Time to grade 2 radiation dermatitis until 50 Gy of radiotherapy is defined as the time from 
start of radiotherapy to at least grade 2 radiation dermatitis. Patients without grade 2 radiation 
dermatitis will be censored after the date of receiving a total dose of 50 Gy. Rate of grade ≥2 
dermatitis at 60 Gy and at the end of radiotherapy will be evaluated. 
The distribution of the time to grade 2 radiation dermatitis until administration of 50 Gy will 
be described using Kaplan-Meier methods. These analyses will be stratified by treatment arm 
and prognostic risk groups used for randomization. Estimates of median time to grade 2 
radiation dermatitis and estimates of rates for specific time points will be extracted from the 

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Kaplan-Meier analyses together with the associated 95% confidence limits. The treatment 
differences will be tested using a stratified log-rank test, stratified by stratification factors. 
Furthermore, Cox proportional hazards models will be applied to yield adjusted estimates of 
the associated hazard ratios.  
The methods used for statistical analysis of rate of patients experiencing grade ≥2 radiation 
dermatitis during radio(chemo)therapy and rate of patients experiencing grade ≥3 skin toxicity 
during radio(chemo)therapy matches those already described for the primary study endpoint. 
All other adverse events as reported according to CTCAE v4.03 will also be subjected to 
statistical analysis. Adverse event tables will be created. These tables will present the total 
number of patients reporting at least one specific event and the maximum CTCAE grade. 
Thus, patients reporting more than one episode of the same event will be counted only once 
by the worst CTCAE grade per patient. Special tables will be displayed for CTCAE Grade 
III/IV/V adverse events. Additionally, analysis will be restricted to treatment related adverse 
events and treatement related CTCAE Grade III/IV/V events. 
Quality of life will be evaluated using the validated EORTC QLQ-C30 and EORTC QLQ-
H&N35 questionnaires. Data will be scored according to the algorithm described in the 
respective scoring manuals. For all quality of life domains and items, descriptive analyses will 
be presented stratified by visit and treatment arm.  
For descriptive statistical analysis, summary tables will be provided showing measures of 
location and dispersion (minimum, quartiles, median, maximum, mean and standard 
deviation) stratified by visit and treatment arm. Furthermore, individual score items will be 
subjected to statistical analysis. Absolute changes of QoL-scores from baseline will be 
tabulated stratified by treatment group and visit. For graphical illustrations, Box-Whisker 
diagrams will be presented across visits for each treatment group. Nonparametric (exact) 
Wilcoxon-Mann-Whitney tests will be applied for exploratory comparison purposes. 
Additional details of the QoL analysis will be described in the SAP. 
In case of uneven distribution to stratification groups, which may result in very small groups 
the strata might be connected for analysis. The decision to merge strata for the analysis will be 
made before data base lock and before the final analysis of the data. 
Interim analysis 
To evaluate the tolerance and acceptance of the Mepitel® Film treatment after one third of the 
study an interim analysis will be conducted after inclusion of 57 patients. The recruitment will 
be put on hold until the 57 patients have completed the study. Depending on the proportion 
(i.e. ≥ 25%) of patients who did not tolerate or accept Mepitel® Film, the study will be 
continued or discontinued. Furthermore, the skin toxicity between both treatment groups will 
be compared. 
The same procedures will be followed as described for the final analysis of the study. 

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11. Ethical and legal principles 
The examinations to be carried out as part of this trial are all considered standard procedures. 
There are no additional laboratory investigations or X-rays to be done, or any other 
examinations that could be potentially burdensome for the patient.  
11.1 Ethics committee vote 
The trial protocol will be submitted to the ethics committee responsible. The positive vote of 
the ethics committee must be communicated to the trial management along with the names 
and qualifications of the ethics committee members.  
11.2 Patient information and informed consent 
Patient information and informed consent will be submitted along with the trial protocol for 
evaluation by the ethics committee responsible. Before inclusion in the trial, each patient will 
be fully informed about the content and procedure of the trial (Appendix I). 
If the potential trial patient has received the necessary information and if the investigator is 
sure that the patient has understood this information, the patient will be asked to give their 
consent by signature (Appendix II).  
The patient will receive a copy of the patient information and the signed informed consent 
form. The investigator must also inform the patient that he/she has the right to withdraw 
consent to participate in the trial at any time and without having to give any reasons. Patients 
must be informed that the data collected as part of the trial will be documented anonymously 
and will then be forwarded for scientific evaluation. This is also the appropriate point to 
indicate the patient consent to data protection. 
11.3 Declaration of Helsinki  
The trial will be conducted in accordance with the principles laid out in the Declaration of 
Helsinki.  
11.4 Data protection 
Data will be collected in accordance with the regulations set out in the Data Protection Act. 
All findings from the clinical trial will be stored on electronic data storage devices and treated 
with utmost confidentiality. Organization measures have been taken in order to prevent the 
data from being communicated to unauthorized persons. Patients will only be identified via 
their individual patient numbers throughout the entire documentation and evaluation phase 
and their full name will not be used. 
11.5 Trial registration 
The trial will be registered in one of the primary registers accepted by the WHO. The trial will 
not start prior to successful registration. 

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11.6 Protocol amendments 
Amendments to the study protocol may only be implemented if again approved by the 
responsible ethics committee. Only the coordinating principal investigator may carry out such 
changes. However, all co-investigators should contact the coordinating principal investigator 
if modifications seem to be necessary. In case of changes to the study protocol, all 
investigators will be informed after ethics committee approval and the notice has to be 
confirmed. 
12. Data management 
12.1 Patient identification list 
All data relating to patients will be recorded in a pseudonymous way. Each patient will be 
identifiable only by the unique patient number, date of birth and gender. A patient 
identification list will only be kept in the relevant trial centers and will not be forwarded to the 
sponsor.  
12.2 Documentation sheet 
Data collection will be done using the data documentation sheets. 
The data documentation sheets must be filled in using a ballpoint pen. Do not use fountain 
pens or pencils. Corrections must be made as follows: cross the error out once with a straight 
line, enter the correct information next to it and note the date and/or reason for correction. 
Comments must be made if data fields cannot be filled in because of missing information. 
The sheets should be filled in as soon as possible and should be submitted to the checker for 
review, signed, dated and forwarded to the trial management. 
12.3 Storage of trial documents 
The originals of all key trial documents, including the documentation sheets, will be kept at 
the trial headquarters (i.e. the sponsor responsible for the trial) for a minimum of 15 years 
after the final report.  
The principal investigator/head of the trial centre will keep all administrative documents 
(written correspondence with the ethics committee, regulatory authorities, trial management, 
trial headquarters), the patient identification list, the signed informed consent forms, copies of  
the documentation sheets and the general trial documentation (protocol, amendments) for the 
abovementioned period. Original patient data (patient files) must also be kept for the length of 
time stipulated for the trial centers, but not for less than 15 years. 

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13. Quality Assurance 
13.1 Monitoring 
The ZKS Lübeck will conduct clinical on-site monitoring at the German sites according to 
GCP and written standard operating procedures (SOPs) to ensure the patients’ rights and 
safety as well as the reliability of trial results.  
For initiation, trial sites will be visited on-site by a clinical research associate of the ZKS 
Lübeck. During the trial, sites will be visited at regular intervals depending on the rate of 
recruiting and data quality. Informed consent and defined key data will be checked of all 
patients. The medical file of each patient will be screened for adverse and serious adverse 
events. Patients’ questionnaires will be checked for their existence.  
According to SOPs, all trial specific monitoring activities will be defined before starting the 
trial and documented in writing (monitoring manual).  
The Danish sites will be monitored according to the Danish regulations in their own 
responsibility. 
13.2 Audits 
No regular audits are planned. However, to ensure correct execution of the study, audits may 
be conducted if necessary.  
13.3 Inspections 
As the current study is not linked to the German pharmaceutical or medicinal product act, no 
inspections of higher federal authorities are scheduled. 

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14. Dissemination of Results and Publication Policy 
The coordinating principal investigator will work towards comprehensive internal and 
external dissemination of project results and knowledge. Coordinating principal investigator, 
biostatistician and reference centers will create a report according to the CONSORT statement 
regardless of regular or abnormal study termination. 
The scientific results will be published in international, peer-reviewed journals of the highest 
possible quality. In addition, results will be presented at major medical congresses and 
symposia. 
Due to methodological and statistical aspects results will be published only after study 
database closure. All reports and publication related to the study need to be coordinated with 
the biostatistician to avoid misinterpretation of statistical results. Conclusions need to be 
statistically secured and require approval of the statistician.  
The local centers are entitled to use the recorded data for additional scientific exploitation 
under their own name, but not before the main results have been published. There are no 
exceptions to this rule. Any sub-publication requires approval by the coordinating principal 
investigator. For publications of any kind the study acronym RAREST-01 will be used. 

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15. References 
1. 
Rades D, Kronemann S, Meyners T, Bohlen G, Tribius S, Kazic N, Schroeder U, Hakim SG, 
Schild SE, Dunst J. Comparison of four cisplatin-based radiochemotherapy regimens for 
nonmetastatic stage III/IV squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol 
Phys 2011;80:1037-44. 
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Rades D, Stoehr M, Kazic N, Hakim SG, Walz A, Schild SE, Dunst J. Locally advanced stage IV 
squamous cell carcinoma of the head and neck: impact of pre-radiotherapy hemoglobin level and 
interruptions during radiotherapy. Int J Radiat Oncol Biol Phys 2008;70:1108-14.  
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Fesinmeyer MD, Mehta V, Blough D, Tock L, Ramsey SD. Effect of radiotherapy interruptions 
on survival in medicare enrollees with local and regional head-and-neck cancer. Int J Radiat 
Oncol Biol Phys 2010;78:675-81.  
4. 
Rades D, Fehlauer F, Wroblesky J, Albers D, Schild SE, Schmidt R. Prognostic factors in head-
and-neck cancer patients treated with surgery followed by intensity-modulated radiotherapy 
(IMRT), 3D-conformal radiotherapy, or conventional radiotherapy. Oral Oncol 2007;43:535-43. 
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Rades D, Stoehr M, Meyners T, Bohlen G, Nadrowitz R, Dunst J, Schild SE, Wroblewski J, 
Albers D, Schmidt R, Alberti W, Tribius S. Evaluation of prognostic factors and two radiation 
techniques in patients treated with surgery followed by radio(chemo)therapy or definitive 
radio(chemo)therapy for locally advanced head-and-neck cancer. Strahlenther Onkol 
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Diggelmann KV, Zytkovicz AE, Tuaine JM, Bennett NC, Kelly LE, Herst PM. Mepilex Lite 
dressings for the management of radiation-induced erythema: a systematic inpatient controlled 
clinical trial. Br J Radiol 2010;83:971-8. 
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Santamaria N, Gerdtz M, Sage S, McCann J, Freeman A, Vassiliou T, De Vincentis S, Ng AW, 
Manias E, Liu W, Knott J. A randomised controlled trial of the effectiveness of soft silicone 
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critically ill patients: the border trial. Int Wound J 2013, in press. 
8. 
Silverstein P, Heimbach D, Meites H, Latenser B, Mozingo D, Mullins F, Garner W, Turkowski 
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2011;32:617-26. 

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Appendix I Patient Information 
 
Please refer to seperate document ‚Patienteninformation‘. 

Study Protocol: RAREST-01 
 
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Appendix II Informed Consent 
 
Please refer to seperate document ‘Einwilligungserklärung‘.  

Study Protocol: RAREST-01 
 
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Appendix III 
 
Radiation Dermatitis according to CTCAE v4.03 
Grade 1: 
- faint erythema or dry desquamation 
Grade 2:  
- moderate to brisk erythema  
- patchy moist desquamation, mostly confined to skin folds and creases                      
- moderate edema 
Grade 3: 
- moist desquamation in areas other than skin folds and creases 
- bleeding induced by minor trauma or abrasion 
Grade 4: 
- life-threatening consequences 
- skin necrosis or ulceration of full thickness dermis  
- spontaneous bleeding from involved site  
- skin graft indicated 
Grade 5: 
- death 
 

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Appendix IV  
 
Eastern Cooperative Oncology Group (ECOG) – Performance Score 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair 
5 
Dead