Radiation Induced Cystitis Treated With Hyperbaric Oxygen - A Randomized Controlled Trial
Phase: PHASE2
Conditions: Cystitis, Radio Induced
Sponsor: Göteborg University

EudraCT Number: 2012‐001381‐15/RICH‐ART 
 
 
 
Bilaga 2 
 
  
 
Clinical Study Protocol 
 
Study Code: 
RICH-ART 
 
EudraCT No: 
2012-001381-15 
 
Date/version: 
01 May 2014/4 
 
 
 
Radiation Induced Cystits treated with Hyperbaric Oxygen –  
A Randomized controlled Trial 
 
 
 
Principal Investigator: 
 Dr. Nicklas Oscarsson 
Head of Anaesthesiology Department  
The Hyperbaric Unit 
Sahlgrenska University Hospital /Östra 
Smörslottsgatan 1 
416 85 Göteborg 
Tel +46 (0)31-343 43 26  
Fax + 46 (0)31-343 59 32 
 
 
 
Co-investigators: 
Dr. Bernd Mueller, Haukeland Universitetssjukehus, Bergen, Norway 
Dr. Ole Hyldegaard, Rikshospitalet, Copenhagen, Denmark 
Dr. Folke Lind/Mikael Nekludov, Karolinska University Hospital Solna, 
Stockholm, Sweden 
Dr. Lars Spetz, NU-sjukvården, Uddevalla, Sweden 
Dr. Dag Benoni, Blekinge sjukhus, Karlskrona Hospital, Sweden 
Dr. Christer Hammarlund, Helsingborgs lasarett, Sweden 
Dr. Grégoire Mayor, Hôpitaux Universitaires de Genève, Suisse 
Dr. Mika Valtonen, Turku University Hospital, Turku,  
Finland 
 
 
 
Monitor: 
Gothia Forum/CTC 
Sahlgrenska University Hospital /Sahlgrenska 
Gröna Stråket 12 
413 45 Göteborg 
 
 
 
Sponsor: 
Västra Götalandsregionen 
The Hyperbaric Unit 
Dept of Anaesthesiology and Intensive Care 
Sahlgrenska University Hospital /Östra 
416 85 Göteborg  

EudraCT Number: 2012‐001381‐15/RICH‐ART 
 
 
 
Bilaga 2 
 
 
The following Amendment(s) and Administrative Changes have been made to this protocol since the date of preparation: 
Amendment  No. 
 
Date: 
 Administrative Change  No. 
 Date: 
2 Blood samples 
 
2013-01-15   
  
3 Re-screening 
 
2013-03-27   
  
4  
New inclusion criteria added (number 6) – “Radiation 
cystitis is the most probable cause for the patient’s 
symptoms”. 
Genèva added. Updated contact information for 
Copenhagen. Clarification of subject and screening 
number. Instructions for cystoscopy in App E.  
Addition of inclusion criteria number 6. Clarification 
that AE only will be collected during HBOT-period. 
Clarification regarding study-specific blood-test. The 
study’s estimated end-date has been changed (+1y). 
App B, C and D had been updated. App E has been 
added.   
 
2014-05-01   
  
 
 
 
  
  
 

3(67) 
PROTOCOL SYNOPSIS – 1 MAY 2014/4 
Radiation Induced Cystits treated with Hyperbaric Oxygen –  
A Randomized controlled Trial 
 
Principal Investigator  
Dr. Nicklas Oscarsson 
Study centre 
The Hyperbaric Unit 
Sahlgrenska University Hospital /Östra 
Smörslottsgatan 1 
416 85 GÖTEBORG  
Tel +46 (0)31-343 43 26 
Fax + 46 (0)31-343 59 32 
Study period  
Estimated date of first subject enrolled: June 2012 
Estimated date of last subject completed: March 2016 
 
Objectives 
The primary objective of this study is to assess the relief of symptoms after HBO therapy in 
patients with late radiation cystitis by having EPIC symptom estimation scale as primary 
variable.  
The secondary objectives are  
 
To assess health related quality of life before and after HBO therapy having SF-36 as the 
variable  
 
To investigate the mucosa with respect to functionality by assessment of inflammation 
activity, quantification of fibrosis, vascular density and the presence of stems cells having 
biopsies for histological analysis as variables 
 
To assess the severity of radiation injury having the RTOG-scale as variable.   
 
Study design 
This is a prospective, randomized, controlled, parallel-group, multicenter study in Sweden, Norway 
and Denmark to evaluate the effects of hyperbaric oxygen therapy in 80 subjects suffering from radio-

Clinical Study Protocol Synopsis 
Study Code: RICH-ART 
Date: 1 May 2014 
4(67) 
therapy induced cystitis. Study includes 5 visits and has a total duration of approximately 8 months per 
subject including treatment periods. 
 
 
 
 
 
 
 
The control group 
The control group (n=40) will start treatment 6-8 months after randomization (delayed start) otherwise 
following the same protocol 
Intervention 
All 80 subjects will have 40 treatments within 60 days in a mono- or multi-place chamber with 80-90 
minutes of 100% O2 at 2.4-2.5 ATA, each time.  
Outcome variable(s):  
Symptom rating (EPIC), Health-related quality of life (SF36) at baseline (visit 1), visit 3, 4 and 5. 
Cystoscopy with biopsies and RTOG-grading at baseline and at visit 4. 
All patients will be contacted for a post-study long-term follow-up yearly for 5 years regarding 
symptoms and quality of life. 
Safety 
Vital signs and standard clinical chemistry and hematology investigations will be taken before and 
after the study in order to document the health status of the subject. Urologist assessment including, 
cystoscopy and RTOG-grading. Serious adverse events will be recorded 
Statistical methods 
A two-sample t-test with a 5% significance level will be used. For each subject, means of 
measurements from baseline to each of the two measuring points will be calculated. Differences 
between these means for each subject will be used in the comparison of the two groups i.e. between 
group A and the control group B (“delayed start”).  
 
Fisher's exact test and logic regression will be used for comparison of other results in the two treatment 
groups. Jonckheere-Terpstra test will be used for trend analysis.  
Patient-reported outcomes and safety data will be summarized descriptively. 
B 
A 

 
 
TABLE OF CONTENTS 
PAGE
PROTOCOL SYNOPSIS – 1 MAY 2014/4 ............................................................................. 3 
TABLE OF CONTENTS ......................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 8 
1. 
INTRODUCTION ................................................................................................. 10 
1.1 
Background ............................................................................................................ 10 
1.2 
Research hypothesis ............................................................................................... 11 
1.3 
Rationale for conducting this study ....................................................................... 12 
1.4 
Benefit/risk ............................................................................................................. 12 
1.5 
Ethical assessment.................................................................................................. 13 
2. 
STUDY OBJECTIVES AND ENDPOINTS ......................................................... 13 
2.1 
Primary objective ................................................................................................... 13 
2.2 
Secondary objectives .............................................................................................. 13 
2.3 
Primary endpoint .................................................................................................... 13 
2.4 
Secondary endpoints .............................................................................................. 13 
3. 
STUDY DESIGN AND PROCEDURES .............................................................. 14 
3.1 
Overall study design and flow chart ...................................................................... 14 
3.1.1 
Follow-up ............................................................................................................... 17 
3.1.2 
Stopping criteria for continuous hyperbaric oxygen administration ...................... 17 
3.2 
Rationale for study design, doses and control groups ............................................ 17 
4. 
SUBJECT POPULATION ..................................................................................... 17 
4.1 
Inclusion criteria .................................................................................................... 18 
4.2 
Exclusion criteria ................................................................................................... 18 
4.3 
Restrictions during the study .................................................................................. 18 
4.4 
Withdrawal of subjects ........................................................................................... 19 
4.4.1 
Criteria for discontinuation from the study ............................................................ 19 
4.4.2 
Study stop criteria .................................................................................................. 19 
4.5 
Subject enrolment and randomization .................................................................... 19 
4.5.1 
Re-screeing ............................................................................................................. 20 
4.5.2 
Stratification ........................................................................................................... 20 
5. 
TREATMENTS ..................................................................................................... 20 
5.1.1 
Identity of investigational product(s) ..................................................................... 20 
5.1.2 
Doses and treatment regimens ............................................................................... 20 

 
 
5.2 
Concomitant and post-study treatment(s) .............................................................. 21 
5.3 
Treatment compliance ............................................................................................ 21 
5.3.1 
Accountability ........................................................................................................ 22 
6. 
STUDY MEASUREMENTS AND VARIABLES................................................ 22 
6.1 
Screening and demography .................................................................................... 22 
6.1.1 
A post-study follow-up .......................................................................................... 23 
6.2 
Efficacy .................................................................................................................. 23 
6.2.1 
Patient reported outcomes (PRO) .......................................................................... 23 
6.2.1.1 
Procedures for administration of questionnaires .................................................... 23 
6.2.2 
Expanded Prostate cancer Index Composite (EPIC) .............................................. 23 
6.2.3 
Short Form Health Survey 36 (SF-36) ................................................................... 24 
6.2.4 
Radiation Toxicity Grade by Radiation Therapy Oncology Group (RTOG) ........ 24 
6.2.5 
Cystoscopy and Biopsy .......................................................................................... 24 
6.2.5.1 
Immunohistological analysis.................................................................................. 24 
6.3 
Safety ..................................................................................................................... 25 
6.3.1 
Pregnancy ............................................................................................................... 26 
6.3.2 
Recording and reporting of adverse events ............................................................ 26 
6.3.3 
Laboratory safety assessment ................................................................................. 26 
6.3.3.1 
Study-specific blood sample .................................................................................. 27 
7. 
DATA MANAGEMENT ....................................................................................... 27 
7.1 
Recording of data ................................................................................................... 27 
7.2 
Training of study site personnel ............................................................................. 28 
7.3 
Monitoring of the study .......................................................................................... 28 
7.3.1 
Source data ............................................................................................................. 28 
7.4 
Study agreements ................................................................................................... 29 
8. 
STATISTICAL METHODS AND SAMPLE SIZE .............................................. 29 
8.1 
Description of analysis sets .................................................................................... 29 
8.2 
Methods of statistical analyses ............................................................................... 29 
8.3 
Determination of sample size ................................................................................. 30 
9. 
STUDY TIMETABLE ........................................................................................... 30 
9.1 
Definition of end of study ...................................................................................... 31 
10. 
LIST OF REFERENCES ....................................................................................... 31 
 
LIST OF APPENDICES 
Appendix A 
Signatures  
Appendix B 
Additional Safety Information  
Appendix C 
Ethics 

 
 
Appendix D 
Study Management Process 
Appendix E 
Cystoscopy instructions 
Appendix F 
EPIC 
Appendix G 
SF-36 
Appendix H 
Patient information and informed consent 

 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study protocol. 
Abbreviation  
or special term 
Explanation 
AE 
Adverse event (Appendix B) 
CRF 
Case Report Form (electronic/paper) 
CSA 
Clinical Study Agreement 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
GCP 
Good Clinical Practice 
HBO 
Hyperbaric oxygen 
HBOT 
Hyperbaric oxygen therapy 
IC 
Informed Consent 
ICH 
International Conference on Harmonisation 
ISF 
OAE 
Investigator Study File 
Other Significant Adverse Event (Appendix B) 
SAE 
SMF 
Serious adverse event (Appendix B) 
Study Master File 
HRQOL 
Health-related Quality of Life 
 

 
 
STUDY STRUCTURE 
Principle 
Investigator: 
Dr. Nicklas Oscarsson 
The Hyperbaric Unit, Department of 
Anaesthesiology  
Sahlgrenska University Hospital /Östra 
Smörslottsgatan 1 
416 85 Göteborg 
 
Tel: +46 (0)31-343 43 26  
Nicklas.oscarsson@vgregion.se 
 
Co-investigator: 
Dr. Guro Vaagbø / Bernd Mueller  
Seksjon for hyperbarmedisin 
Yrkesmedisinsk avd 
Haukeland Universitetssykehus 
N-5021 Bergen 
 
Tel: +47 55973974 
guro.vaagbo@helse-bergen.no 
  
 
Co-investigator: 
Dr.  Ole Hyldegaard  
Trykkammerenheden 
Department of Anaesthesia, 
Center for Head and Orthopaedics 
Rigshospitalet Copenhagen 
University Hospital, Copenhagen, DK-
2100, Denmark 
 
Tel: +45 3545 3545  
Ole.Hyldegaard@rh.regionh.dk 
 
Co-investigator: 
Dr. Folke Lind,  
Hyperbaric Medicine 
Dept of Anaestesiology,  
Surgical Services and Intensive Care 
Karolinska University Hospital 
SE -17176 Stockholm, Sweden 
 
Tel: +46(0)70-450 77 52 
folke.lind@karolinska.se 
Co-investigator: 
Dr. Lars Spets 
Anestesi och Operationsenheten 
NU-sjukvården 
Lärketorpsvägen 
461 85 Trollhättan 
 
Tel: +46 (0)10 - 473 81 00  
lars.spetz@vgregion.se 
Co-investigator: 
Dr. Grégoire Mayor 
Urology Division 
Geneva University Hospital 
1211 Geneva 14, Suisse 
 
+41(0)79 513 40 54 
gregory.mayor@hcuge.ch 
Co-investigator: 
Dr. Mika Valtonen 
Anaesthesia and Intensive Care,  
Turku University Hospital 
PO Box 52, 20521 Turku 
 
+358 (0)20 313 00 00 
Mika.valtonen@tyks.fi 
 
 

 
 
1. 
INTRODUCTION 
1.1 
Background 
Acute radiation cystitis occurs during or soon after radiation treatment and persists for a short 
period of time. Late radiation cystitis, on the other hand, can develop from 6 months to 20 
years after radiation therapy.  Late radiation cystitis becomes chronic and progressive and 
represents a range of severe and disabling clinical symptoms for which there is as yet no 
recommended standard management (2, 23).  
The chronic phase of radiation cystitis begins approximately 6 months after therapy. However, 
the period between completion of radiotherapy and the manifestation of late toxicity in the 
bladder is extremely variable. Ischemia and fibrosis are the main factors responsible for 
symptoms. The vascular changes include vascular endothelial hyperplasia, vascular occlusion 
and perivascular ﬁbrosis which ultimately cause tissue hypoxia. Normal smooth muscle is 
replaced by ﬁbroblasts. The resulting tissue hypoxia and fibrosis can progress to necrosis and 
fistulation. As the submucosa becomes fibrotic, bladder capacity reduces and vascular 
telangiectasia develop. 
Therefore, clinical presentation can include increased urinary frequency, urgency, pain or 
difficulty on passing urine, incontinence, hematuria, hydronephrosis, pneumaturia and 
fecaluria.  
Bladder tissue examined histologically during the chronic phase of radiation cystitis shows 
non-specific submucosal edema and vasodilatation, hemorrhage, acute and chronic 
inﬂammation and bizarre stromal cells, blood vessels with myointimal thickening  and 
atypical fibroblasts (21). 
Radiation adverse effects appear in about 10-20% of all patients that are exposed for 
radiotherapy in the pelvic region and are severely affecting patents daily life. The frequency of 
delayed radiation toxicity in the bladder is about 5-10%. Therapy is primarily aimed at 
symptoms relief. Surgical options and cystectomy remain when non-surgical interventions fail 
(2). 
Hyperbaric oxygen therapy (HBOT) found early use in the treatment of decompression 
sickness. More recent research has examined the possibility value for other conditions such as 
delayed radiation injury (soft tissue and bony necrosis). 
HBOT involves the inspiration of a high concentration of oxygen under higher than normal 
atmospheric pressure. Typically, a patient breathes 100% oxygen at 2 to 3 atmospheres for 1 

 
 
to 2 hours daily over the course of several weeks. This treatment boosts oxygen levels in 
deoxygenated body tissue. The oxygen transport in soft tissue is significantly increased. More 
importantly, this treatment appears to induce angiogenesis in de-vascularised tissue (3, 4, 10). 
Hyperbar vs normobar oxygen (4) have shown in a rabbit model that hyperbar treatment 
results in marked increased vascularity in previously irradiated tissue.  A few clinical studies 
report the positive healing effects of HBO in patients with chronic radiation cystitis or 
proctitis. 
Recent evidence notes that exposure to HBOT mobilizes stem/progenitor cells from the bone 
marrow by a nitric oxide (NO) -dependent mechanism (25) This mechanism may account for 
the patient cases that suggest recovery of damaged organs and tissues with HBOT.  
HBO therapy is an established treatment for degeneration of blood vessels in the jawbone as a 
result of radiotherapy (osteoradionecrosis). In addition, the loss of osseointegrated implants in 
the maxillofacial bones of these patients could be significantly reduced.  
Further indications for HBO therapy include soft tissue necroses, hemorrhagic cystitis and 
proctitis in tumour patients that have been treated by radiotherapy as part of a multimodality 
approach (7, 9, 10, 11, 18, 19, and 20). The HBO treatment appeared to be safe, effective and 
feasible. 
The present study intends to investigate the effect of HBOT in patients with symptomatic 
radio-therapy induced cystitis. 
1.2 
Research hypothesis  
 HBO therapy can reduce or reverse the change or otherwise limit the damage of the bladder 
function and/or structure, which arose as a result of radiation therapy of cancer in the 
pelvic region organs. 
 The effects of HBOT are associated with relief of symptoms that, at least in part, is related 
to the reduction of the extent of the radiation damage. 
 Vascular density increases, fibrosis prevalence and inflammatory activity are reduced as 
a sign of an improved function of the mucosa. 
 Treatment results of HBOT remains, in whole or in part, during the follow-up (residual 
effect) 

 
 
1.3 
Rationale for conducting this study 
10-20% of all patients receiving radiotherapy to the pelvic region suffer from unwanted side 
effects such as symptoms of bladder and rectum e.g. bleedings, frequent urination, 
incontinence and pain (2, 6, 7, 8). The symptoms are chronic, progressive and often disabling. 
One of the most significant causes of the symptoms of radio therapy is inflammation and 
degeneration of blood vessels in the radiated tissue (1, 8). Hyperbaric oxygen therapy 
involves administration of oxygen at greater than normal atmospheric pressures. A well-
documented effect of HBO treatment is the stimulation of angiogenesis. HBO therapy is an 
established treatment for degeneration of blood vessels in the jaw bone as a result 
of radiotherapy (3, 4, 10) and several publications have shown good efficacy also 
when soft tissue is affected (7, 9, 10).  
If the method of treatment with HBO means a reduction of the radiotherapy side effect it 
is thus an obvious importance for the individual patient. There is also significant potential 
savings for the healthcare and society 
1.4 
Benefit/risk  
Hyperbaric oxygen therapy is a treatment that is associated with low risk (14, 15). Because of 
the encapsulated nature of these chambers patients occasionally become claustrophobic and 
therefore refuse treatment. Patients may also develop difficulty in equalizing ear pressure with 
resultant ear discomfort. Pressure changes can cause a "squeeze" or barotrauma also in the 
tissues surrounding trapped air inside the body e.g. inside paranasal sinuses or trapped 
underneath dental fillings which can give rise to temporally pain. Temporarily changed vision, 
caused by increased fraction in the lens can be perceived which usually resolves in one to two 
months after termination of HBOT.  
 
The risk of oxygen induced seizures increases with increasing exposure time and pressure. In 
the present study the dose is adjusted so that the effect is achieved but the risks of side 
effects are kept to a minimum. In addition some patients will have periodic "air breaks" during 
which they breathe room air to minimize the risk of oxygen toxicity. The use of air-brakes is 
applied according to the protocol of the local centre.  
 
Since placebo treatment in the hyperbaric chamber is extremely difficult to achieve, delayed 
start of the treatment has been chosen in order to create a control group to the group receiving 
treatment without delay. As deterioration of the cystitis is a slow process patients in the 
control group are not expected to be progressing on their symptoms to any great extent. It is 
therefore considered ethical to use “delayed start” as a tool to achieve a control group to 
the treatment group. 

 
 
The safety margins in the dose range, (100% O2 80-90 minutes at 240-250 kPa) are 
considerable. The dose and treatment regimens follow standards and routines. 
1.5 
Ethical assessment 
The study will be conducted in compliance with ICH Good Clinical Practice and applicable 
regulatory requirements and in accordance with the ethical principles in the Declaration of 
Helsinki. For detailed information regarding ethics and regulatory review, informed consent, 
data protection and audits and inspections see Appendix C (Ethics).  
Written approval or favourable opinion must be obtained from the ethics committees 
(IRB/IEC) prior to commencement of the trial. Regulatory authorities will receive the clinical 
trial application (CTA) and required documents. 
The local investigator (LI) will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study. A copy of 
the signed Informed Consent Form is kept by the subject. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary objective 
The primary objective of this study is to assess the relief of symptoms after HBO therapy in 
patients with late radiation cystitis by having EPIC symptom estimation scale as primary 
variable.  
2.2 
Secondary objectives 
 
To investigate the mucosa with respect to functionality by assessment of inflammation 
activity, quantification of fibrosis, vascular density and the presence of stems cells having 
histological analysis from biopsies as variable 
 
To assess the severity of radiation injury having the RTOG-scale as variable  
 
To assess health-related quality of life before and after HBO therapy having SF-36 as the 
variable 
 
2.3 
Primary endpoint 
The primary endpoint of this study is symptom rating after HBO therapy using the self-
administrated EPIC-questionnaire original score as the primary variable at baseline and visit 4.   
2.4 
Secondary endpoints 
 Severity of radiation injury having the RTOG as the variable at baseline and visit 4 

 
 
 Histological analysis of inflammation activity, degree of fibrosis, vascular density and 
the presence of stems cells at baseline and visit 4.  
 Health-related quality of life (SF36) at baseline visit 3, 4 and 5 
 Post-study long-term follow-up follow up with Symptom rating (EPIC) and Health-
related quality of life (SF36) 
3. 
STUDY DESIGN AND PROCEDURES 
3.1 
Overall study design and flow chart 
This is a prospective, randomized, controlled, parallel-group, multicenter study in Sweden, 
Norway and Denmark to evaluate the effects of hyperbaric oxygen therapy in 80 subjects with 
symptomatic radio-therapy induced cystitis.  
All 80 subjects will have 40 treatments within 80 days in a mono- or multi-place chamber 
with 100% O2 at 2.4-2.5 ATA, 80-90 minutes each time. The control group (n=40) will start 
treatment 6-8 months after Group A otherwise following the same protocol. Recruitment will 
continue until 80 subjects have concluded visit 4 according to protocol.  
Subjects will be given full and adequate verbal and written information about the study prior 
to any study procedures. Informed consent will be signed by the patient and the study 
physician. The original IC will be stored at the study site. A copy will be given to the patient. 
Adverse events (AE) including serious adverse events (SAE) will be recorded during the 
HBO-treatment period. Ongoing AE and SAE at the end of the HBO-treatment period will be 
followed up within three months from end of HBO-treatment.  
Any questions or concerns that arise related to the study protocol should be directed to the 
RICH-ART principle investigator. 
Figure 1 and Table 1 show the study overview and activities. 
  
 
 
 
 
Figure 1 
Study overview 
   Visit  
        1     2 
            3 
 
 
          4 
        5 
HBO  

 
 
 
   
 
 
 
 
 
 
 
 
 
          
Table 1 
Study Activities 
Activity 
Visit  
1 
Visit  
2 
Visit  
3  
Visit  
4 
Visit  
5 
 
Screening 
Biopsy 
 
 
 
 
 
Within      
6 weeks 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
Nicotine 
X 
 
 
 
 
 
Weight, height 
X 
 
 
 
 
 
Medical history and smoking 
X 
 
 
 
 
 
Pulse, blood pressure 
X 
 
 
XA 
 
XB 
Physical examination  
X 
 
 
XA 
 
XB 
Blood for laboratory screen 
X 
 
 
XA 
 
XB 
Cystoscopy 
 
X 
 
 
X 
 
Biopsy for histologcal analysis 
 
X 
 
 
X 
 
Incl/excl criteria 
X 
 
 
 
 
 
Randomisation 
X 
 
 
 
 
 
HBO treatment  
 
 
XA 
 
XB 
 
EPIC  
X 
 
 
XA 
X 
XB 
SF36  
X 
 
 
XA 
X 
XB 
Concomitant medication 
X 
 
XA 
XA 
X 
XB 
HBO side effects 
 
 
 
XA 
 
XB 
SAE 
X 
 
XA 
XA 
X 
XB 
XA = Group A onlyXB = Group B only 
 
Visit 1 (screening). All subjects (Group A and B) will undergo a clinical examination 
including demography, medical, surgical and disease history, tobacco use, physical 

 
 
examination, blood pressure, pulse, laboratory blood and urine safety screen and pregnancy 
test (if applicable) within 6 weeks prior to study start. I addition, the disease-specific symptom 
scale (EPIC) and health-related quality of life survey (SF-36) will be completed.  
Cystoscopy including biopsy will be performed by an urologist prior to study start. The 
urologist will also make an assessment of the patient’s medical history and anamnesis in order 
to establish that radiation cystitis is the most probable cause for the patient’s symptoms. At 
this visit, it is advised that a new appointment should be scheduled for the next cystoscopy 
investigation at visit 4. The date of the visit 1 cystoscopy will guide the late treatment start of 
Group B, i.e. 6-8 months later.  
Inclusion and exclusion criteria will be checked. Eligible subjects will be randomized to either 
immediate start of HBO treatment or delayed start. 
Start of screening (Visit 1) is the date patient signs “informed consent”. End of  screening 
(Visit 1) is the date patient is randomized. Time interval between these two should not exceed 
6 weeks. Extra ordinary circumstances might constitute reason to accept a small extension of 
the time frame, but should always be approved by PI, and documented as a “NoteToFile” in 
the CRF. 
Visit 2 - Group A. Patients randomized to Group A will enter the oxygen pressure chamber 
day 1 out of 40 for 80-90 minutes each time. A nurse or another observer will monitor the 
patients and assist with equipment manipulation or emergencies. Patients in a multi-place 
chamber breathe oxygen via a mask or close-fitting plastic hood. Patient in mono-place 
chamber breathe ambient oxygen. Standard routines at each hyperbaric unit will be followed. 
Visit 3 (Group A). After completing treatment, vital signs and medical examinations will be 
carried out. EPIC and SF36 will be completed. Concomitant medication and any side effects 
during treatment period will be recorded in the CRFs. 
At visit 4, approximately 6 months later, all patients (group A and B) will undergo cystoscopy 
including biopsies. All patients will also complete EPIC and SF36. Concomitant medication 
will be recorded. Group B will start the HBO 40-days treatment within 14 days from the 
cystoscopy. Standard routines will be followed. 
Visit 5 (Group B). After completing treatment, vital signs and medical examinations will be 
carried out. EPIC and SF36 will be completed. Concomitant medication and any side effects 
during treatment period will be recorded in the CRFs. 

 
 
3.1.1 
Follow-up 
All patients (Group A and B) will receive HBO treatment within the frame of the clinical 
study. Follow-up of the Group B patients will take place after finalized study. They will be 
contacted by telephone or via mail for completion of EPIC and SF36 after 6-8 months after 
the last study visit. All patients (Group A and B) will be contacted for a post-study long-term follow-
up yearly the first 5 years after last study visit regarding symptoms (EPIC) and quality of life (SF-36). 
3.1.2 
Stopping criteria for continuous hyperbaric oxygen administration 
Stopping criteria for oxygen administration is development of serious side 
effects of hyperbaric oxygen therapy such as more than one oxygen-induced episode of 
generalized seizures, pulmonary barotruma or pronounced deterioration of cardiovascular- or 
respiratory failure.  
3.2 
Rationale for study design, doses and control groups 
The dose is set to 100% O2 at least 80 minutes at least 240kPa. This exposure is considered to 
be sufficient to initiate angioneogenesis. The dose is adjusted so that an effect is achieved, but 
the risks of side effects are kept to a minimum. 
Since placebo treatment in the hyperbaric chamber is extremely difficult to achieve, delayed 
start of the treatment has been chosen in order to create a control group (Group B) to the 
group receiving direct after randomization (Group A). The usual waiting time for treatment 
vary between hospitals but is considered relatively short, which means that patients in this 
group (B) are not expected to be progressing on their symptoms to any great extent.  
Patients in the present study will have had their symptoms for a variety of length. It is 
believed that the longer the changes in the bladder have been, the harder they are to reverse. 
Despite this fact it has been chosen to allocate all patients despite differences in symptom 
history to receive the same treatment per protocol. In the statistical analysis it may be possible 
to make sub-group analysis. 
4. 
SUBJECT POPULATION 
A total of 80 male and female patients, treated according to protocol, between 18 and 80 years 
with clinically verified and symptomatic radio therapy induced cystitis will be included.  
The study population will be identified from hospital oncology and urology clinics at 
participating centers. They can either be referred to the local hypobaric units or to a locally 
assigned coordinator. Subject population should be selected without bias. 

 
 
Investigator must keep a record of subjects who entered pre-study screening but were never 
enrolled (subject screening log). Subjects that do not meet the inclusion/exclusion criteria for 
a study must not be enrolled into the study. 
4.1 
Inclusion criteria 
For inclusion in the study subjects must fulfil the following criteria.  
1. 
Provision of informed consent prior to any study specific procedures 
2. 
Female or male aged 18-80 years 
3. 
Intended curative radiation of the pelvic region as a treatment for cancer 
4. 
End of radiation therapy more than 6 months ago 
5. 
Radiation cystitis with Urological EPIC < 80 
6. 
Radiation cystitis is the most probable cause for the patient’s symptoms 
 
4.2 
Exclusion criteria 
Subjects must not enter the study if any of the following exclusion criteria are fulfilled  
1. 
Patients with major and ongoing bleedings from the bladder (requiring more than 
0.5L blood-transfusion within the last four weeks) 
2. 
Refractory incontinence requiring catheter or surgical intervention 
3. 
Urine bladder capacity < 100ml 
4. 
Fistula in the urine bladder 
5. 
Contraindications for HBO therapy according to the local centres routines 
6. 
Pregnancy 
7. 
Mechanical ventilator support 
8. 
Unable to follow and understand simple commands 
9. 
Not oriented to person, place and time 
 
4.3 
Restrictions during the study 
 
Use effective birth control prior to and during the study (women of childbearing 
potential only) 

 
 
 
Smoking is strongly discouraged, but local routines may be followed and hence it is 
ultimately the LIs decision to ban or allow smoking during the study.   
 
Coffee or drinks with caffeine may be used according to decision by the LI.  
 
4.4 
Withdrawal of subjects 
4.4.1 
Criteria for discontinuation from the study 
Subjects are free to discontinue their participation in the study at any time without prejudice to 
further treatment. Subjects may be discontinued from the study at any time as judged by the 
investigator due to risks to subjects, adverse events and severe non-compliance to protocol. 
Other reasons for discontinuing a subject are incorrect enrolment subjects lost to follow-up, 
new diagnosis of cancer, significant hyperbaric related complications and HBOT for other 
conditions given after enrolment. (See Stopping Criteria section 3.1.1). 
A subject who discontinues will be asked about the reason(s) for discontinuation and the 
presence of any adverse events. If possible, they will be seen and assessed by the investigator. 
Adverse events will be followed up. 
4.4.2 
Study stop criteria 
The Sponsor/Investigator may decide to stop the trial or part of the trial at any time. 
Furthermore, the manufacturers of the study drugs may revoke their products, which may lead 
to the entire study may be interrupted. 
If a trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and ensure appropriate therapy and follow-up. Furthermore, the Investigator should 
promptly inform the Ethics committee and provide a detailed written explanation. The 
regulatory authority should be informed according to national regulations. 
4.5 
Subject enrolment and randomization 
The investigator will obtain signed informed consent from the potential subject before any 
study specific procedures are performed. The investigator will thereafter determine subject 
eligibility. Upon entering the subject into the e-CRF, the subject will be assigned a unique 
screening number, which is used during the screening process. This number is unique 
sequential for all centres.  
Upon randomization a subject number is assigned to the subject by the e-CRF. These numbers 
are strictly sequentially and sequential for each centre with a prefix that identifies the centre. 
Stratification will be made as specified in 4.5.1. If a subject discontinues participation in the 

 
 
study, his/her screening and subject number cannot be reused. Discontinued subjects that 
previously have been randomized into the study are not allowed to re-enter the study.  
Subjects who discontinue from the study or fail treatment according to protocol will, if 
possible, be followed according to protocol (intention to treat). These subjects does not count 
towards the total number of patients included in the study and will hence be replaced. 
Recruitment ends when 80 patients has completed Visit 4 according to protocol.  
This is not a blinded study. The study will use “delayed start” as the control. The analysis of 
EPIC, SF36 and biopsies will be made by persons blinded to the study randomization.  
4.5.1 
 Re-screeing 
Subjects that are screened but have not yet been randomized can be excluded and later re-enter 
the study. This might be the case if some finding during the screening requires intervention 
that prevents the subject to receive HBO. The subject shall be excluded from the study and the 
screening number is blocked. Re-screening must not be made prior to 2 months after 
exclusion. At re-screening the subject shall be entered as a new subject in the e-CRF and a 
“NoteToFile” specifying the previous screening number shall be made.   
4.5.2 
Stratification 
Stratification will be made on the basis of gender, time from radiation to inclusion and 
previous major surgery in the pelvic area. Primary stratification will be made into two groups 
based on gender; male and female. Secondary stratification will be made into two groups 
based on time from last day of radiation therapy to inclusion in RICH-ART; 12 months or less 
and more than 12 months. Tertiary stratification will be made into two groups based on 
previous major surgery to the pelvic region, as defined below; yes or no. 
a. 
Pelvic surgery for malignant disease  
b. 
Surgery on the lower urinary tract for benign disease 
5. 
TREATMENTS 
HBO treatment will be used in the treatment of late radiation cystitis. 
5.1.1 
Identity of investigational product(s)  
100% oxygen (O2)  
5.1.2 
Doses and treatment regimens 
100% oxygen at 240-250 kPa will be delivered to the patents for 80-90 minutes while sitting 
or lying in a hyperbaric oxygen chamber. Patients will receive treatment once every 

 
 
day, except week-ends, for 40 days. Both groups will follow the study protocol, however with 
6-8 months apart (delayed start for Group B).  
The percentage of oxygen being delivered will be checked at start and after the air brake. 
Notes of any discrepancies from study protocol will be made in the CRFs. 
The medical oxygen is obtained from the hospital's gas system. The management and control 
of oxygen comply with the legislation for delivery, storage, labelling, delivery and 
returnable and are specified in local protocols at each hospital. 
5.2 
Concomitant and post-study treatment(s) 
Treatment vital for the patient such as transfusion, diathermy etc. is allowed during the study. 
Other medication, which is considered necessary for the subject’s safety and well-being, may 
be given at the discretion of the investigator. 
All medications must be recorded in the appropriate sections of the case report form (CRF). 
Only one session (30-40 treatments) of HBOT is given for radiation induced cystitis in today’s 
routine care and support for repeated HBOT is lacking. This applies for both responders and 
non-responders. Hence, post-study HBOT will not be offered for this condition. However, if 
an included patient presents with another condition during the follow-up period, where HBOT 
might be considered, the treatment will not be withheld. In this case, the patient will be 
excluded from the post-study follow-up as stated in 4.4.1.  
 
5.3 
Treatment compliance 
When treatment is administered in hospitals, under the supervision of medical staff, there 
is no uncertainty about compliance. The HBO administration (pressure, treatment time, any air 
breaks any other specific conditions) must be recorded in the appropriate sections of the Case 
Report Forms (CRFs). 
The 40 treatments should be given within the framework of 80 days. For longer interruption or 
discontinuation of treatment, patients should not be regarded as treated according 
to protocol but monitoring will continue (intention to treat). However, the patient should 
be considered to be treated as per protocol if at least 30 treatments in the hyperbaric 
chamber have been given within 60 days. 
Any discrepancies from study protocol should be commented upon in CRF.  

 
 
5.3.1 
Accountability 
The study drug (100% O2 at 240-250 kPa for 80-90 minutes) provided for this study will be 
used only as directed in the study protocol and according to standard routines at each 
hyperbaric unit. 
The study personnel will account for oxygen equipment dispensed and returned. 
6. 
STUDY MEASUREMENTS AND VARIABLES  
6.1 
Screening and demography 
Each subject will undergo a pre-entry medical examination 1-6 weeks prior to randomization. 
This will consist of: 
 
Information and signed consent  
 
Demographic data – date of birth, sex 
 
Weight, height (BMI) 
 
Medical history, current medications, nicotine use 
 
Cancer-related history including type and localization of cancer and treatment 
 
Date of radiation tissue injury diagnose  
 
Pulse, systolic and diastolic blood pressure after 5-10 minutes rest in a sitting 
position 
 
Physical examination will include cardiovascular and respiratory systems, general 
appearance, eyes and ears and neurological examination (reflexes). Specification of 
abnormalities must be recorded in the CRFs  
 
Patient self-rating questionnaires: EPIC, Short form (SF)36 
 
Cystoscopy and biopsies 
 
Blood for laboratory screen.  

 
 
6.1.1 
A post-study follow-up 
The group B patients will be contacted via mail or e-mail for completion of EPIC and SF-36 
approximately 6-8 months after visit 5. 
All patients will also be contacted for a post-study long-term follow-up every year during 5 years 
regarding persistent symptom relief and quality of life.  
6.2 
Efficacy 
Efficacy parameters in the study are symptom ratings and health-related quality of life 
measured by EPIC and SF36 as well as cystoscopy including biopsies for histological 
analysis. 
6.2.1 
Patient reported outcomes (PRO) 
6.2.1.1 
Procedures for administration of questionnaires 
Standardization of procedure for administration of the following self-administered 
questionnaires is important. The questionnaires will be filled in at the study site or at home 
according to patient’s and investigator’s discretion. The patients should be allowed to sit alone 
in a reasonable quiet environment to answer the questions. It will be emphasized that patients 
complete the questionnaires prior to clinical measurements stated in the study protocol and 
before meeting a doctor. Questionnaires should be answered by the patient her/himself alone; 
however, the study staff may advise the patients on how to complete the questionnaires, 
however without influencing the patients’ responses. Ensure the patient confidentiality. Study 
staff should check the questionnaires for completeness. E-questionnaires are to prefer. 
Questionnaires will be completed at visit 1 (Group A and B), visit 3 (Group A), visit 4 (Group 
A and B) and visit 5 (Group B) as well as during the follow-up. 
6.2.2 
Expanded Prostate cancer Index Composite (EPIC) 
EPIC was developed to measure health-related quality of life among men with prostate cancer 
(22) modified to enhance sensitivity to therapy effects. It comprises four summary domains; 
urinary, bowel, sexual and hormonal. The urinary domain is divided into two distinct sub 
scales; incontinence and irritative /obstructive subscales. Response options for each item form 
a 5-point Likert scale and scores are transformed to a 0-100 scale with higher scores 
representing better Health Related Quality of Live (HRQOL). 
EPIC has been validated in men with localized prostate cancer who underwent surgery, 
external beam radiation or brachytherapy with or without the use of hormonal adjuvant. EPIC 
is sensitive to change (Appendix F). 

 
 
6.2.3 
Short Form Health Survey 36 (SF-36) 
SF-36 is a self-administered questionnaire and contains 36 items which measure eight 
dimensions: Physical functioning (10 items), Role limitation due to physical health problems 
(4 items), Bodily pain (2 items), General health perceptions (5 items), Vitality (4 items), 
Social functioning (2 items), Role limitations due to emotional problems (3 items) and 
General mental health (5 items). There is an additional single item giving information on 
health change over the past year. Item scores for each dimension are coded, summed and 
transformed to a scale from 0 (worst possible health state measured by the questionnaire) to 
100 (best possible health state). The higher value indicates a better evaluation of health. The 
SF-36 is well documented in terms of reliability and validity in all available language 
versions. In this study the acute version of SF-36 reflecting the last four weeks is used.  
6.2.4 
Radiation Toxicity Grade by Radiation Therapy Oncology Group (RTOG) 
RTOG is an internationally well-established research group in the oncology field. They have 
developed organ specific scales for quantification of both acute and late symptoms after 
radiation. The scale range is from 0 to 5, where 0 is used for normal function and findings and 
5 for death directly related to injuries post radiation. Both subjective and objective findings 
are used when setting the score.   
6.2.5 
Cystoscopy and Biopsy 
Cystoscopy will be carried through according to routines at the hospitals urology department 
at visit 1 and 4. More specific instructions are found in Appendix E “Cystoscopy RICH-
ART”. Subjective symptoms during the last four weeks will be recorded in the CRF. 
Three biopsies will be taken at each cystoscopy. The cold biopsy forceps technique will be 
used. Biopsies will be stored at room temperature in formalin medium during transport to 
Clinical Pathology and Cytology 
Att: Dr. Johan Mölne 
Gula Stråket 8, SU/Sahlgrenska 
413 45 Göteborg  
Samples will be labelled individually with pre-printed labels marked with study code, subject 
number, media, visit number and date.   
Analysis of the biopsies will be made when convenient and no feed-back will routinely be 
given to the urologist. Standard procedures at each centre should be followed if the urologist 
needs the biopsy analysis result in a timely manner i.e. suspects abnormal findings.  
6.2.5.1 
Immunohistological analysis 
All biopsy analysis will be performed by one and the same pathologist and according to 
standard templates and terminology. Analysis of the fibrosis development, vascular changes 
and the inflammatory response will be made. 

 
 
The tissue biopsies will be fixed by immersion into buffered formalin (4%), dehydrated in 
alcohol and embedded in paraffin. Histological 4µm sections will be cut on a microtome to 
glass slides. The following parameters will be determined to assess vascular density, number 
of stem cells and fibrosis: 
Determination of vascular density will be done using immunohistochemical staining for CD31 
and CD34. Stem cells with hematopoietic differentiation (CD34-/low, c-Kit+, Sca-1+) will 
be visualized using immunohistochemisry. Biopsies will be stained with Massong 
trichrome staining and fibrosis manually measured.  In addition, collagen III immunostains 
will be used. Additional analysis may be used in order to further investigate findings of the 
above mentioned.   
6.3 
Safety 
The local investigator is responsible for safety surveillance and for ensuring that procedures 
and expertise are available to handle medical emergencies during the study. The local 
investigator is responsible for ensuring that all staff involved in the study is familiar with the 
content of this section. Serious AEs (SAEs) and discontinuations due to AEs must be collected 
and an assessment of causality of the SAE should be performed. An SAE is an experience that 
at any dose results in any of the following: 
 Death 
 A life-threatening experience 
 In-patient hospitalization or prolongation of existing hospitalisation 
 A persistent or significant disability or incapacity 
 A congenital anomaly or birth defect 
 Important medical events that may not result in death, be life threatening or require 
hospitalisation may be considered an SAE - when based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
The following terms and definitions are used when assessing the relationship between each 
AE/SAE and the relevant trial product(s):  
 Definite – There is no doubt that the incident is related 
 Probably- Good reason and sufficient documentation to assume a causal relationship 
 Possible- A causal relationship is conceivable and cannot be dismissed 
 Unlikely- The event is most likely related to aetiology other than the trial product 
 Unknown/Unclassifiable: a report suggesting an adverse event reaction, which cannot be 
judged because information is insufficient or contradictory and which cannot be 
supplemented of verified. 
 

 
 
For further details on definitions, reporting and guidelines on safety see Appendix B. 
 
Vital signs and standard clinical chemistry and haematology investigations will be taken 
before and after the HBOT in order to document the health status of the subject. Oxygen 
exposure and conditions will be monitored by medical staff. Stopping criteria for oxygen 
administration is development of serious side effects of hyperbaric oxygen therapy such as 
more than one generalized oxygen-induced seizure or pulmonary barotrauma or 
pronounced deterioration of cardiovascular- or respiratory failure.  
A nurse or other observer will be present during HBO treatments monitoring the patients and 
assists with equipment manipulation or emergencies. 
6.3.1 
Pregnancy 
Pregnancy test will be carried out at each visit if applicable. The procedures in case of 
pregnancy are described in Appendix B.  
6.3.2 
Recording and reporting of adverse events 
While this is a study with a registered product within the terms of the regulatory approval, 
serious AEs must be collected, registered in the CRFs and an assessment of causality of the 
SAE should be performed. Also, discontinuations due to AEs will be collected. Non-serious 
AEs will be collected in the present study only during the HBOT-period.   
All SAEs have to be reported, whether or not considered causally related to the investigational 
product.  The investigator is responsible for informing the Ethics Committee and/or the 
Regulatory Authority of the SAE, as per local requirements. The Clinical Study Serious 
Adverse Event Report Form will be used together with other relevant supporting 
documentation (eg. laboratory results, autopsy report) and relevant CRF modules. 
6.3.3 
Laboratory safety assessment 
Blood (20 ml) and urine (10 ml) for laboratory safety screen will be taken at visits 1, 3 (Group 
A) and 5 (Group B). 
Table x 
Laboratory screen 
Clinical Chemistry 
Haematology 
S/P-Creatinine 
B-Haemoglobin (Hb) 
S/P -Bilirubin, total 
B-Leukocytes, total count (LPC) 
S/P -Alkaline phosphatase (ALP) 
B-Leukocytes diff.absolute count: 
S/P -Alanine aminotransferase (ALAT) 
          B-Basofila 
S/P -Aspartate aminotransferase (ASAT) 
          B-Eosinof 
S/P -Albumin 
 

 
 
S/P -Potassium (K) 
          B-Lymfocyter 
S/P -Sodium (Na) 
          B-Monocyter 
S/P -Glucose  
          B Neutrofila 
S/P – C-Reactive Protein (CRP) 
 
 
Study-specific blood samples 
Urine  
3-5 ml blood in EDTA-tube (ethylene diamine 
tetraacetic acid) 
U-Erythrocytes (U-Ery) 
 
U-Albumin (U-Alb) 
 
U-Glucose (U-Glu) 
 
U-pregnancy-test 
 
U-culture (bacterial) 
 
 
The blood samples will be analysed according to routine standards at the Central laboratories 
at each hospital. Valid reference values of all routine analyses will be obtained. Laboratory 
printouts must be dated and signed by the investigator on the day of evaluation and stored in 
the CRFs. Data from the analysis will be transferred into the study database. Laboratory 
values outside the reference limit suspected to be of any clinical significance will be followed-
up and/or repeated as per local investigator discretion.  
6.3.3.1 
Study-specific blood sample 
Approximately 5 ml blood will be drawn to a tube with EDTA (ethylene diamine tetraacetic 
acid).  
 Centrifuge in approximately 3000 rpm (2000 G) for 10 minutes 
 Pipette the plasma into 3 Cryo-tubes 
 Store the tubes in -70 to -80°C  
 
The tubes must me marked individually with subject or screening number, date and visit 
number. The tubes will be sent to Sahlgrenska University Hospital for analysis each year or 
when convenient. Analyses of immunological activity will be made and the results combined 
with findings in the biopsies.   
7. 
DATA MANAGEMENT  
The study monitoring, data handling, essential documents, auditing and inspections, study 
drug handling etc are described in detail in Appendix D. 
7.1 
Recording of data 
Data will be entered in the Web Based Data Capture (WBDC) system at the study site. Data 
entered in the WBDC system will be immediately saved to a central database. When the 

 
 
principal investigator has signed the eCRF electronically as per eCRF instructions, then the 
subject’s data will be locked. The investigator(s) will ensure that all data collected in the study 
will be provided. He/she ensures the accuracy, completeness, legibility and timeliness of the 
data recorded in the appropriate sections of the eCRF and according to any instructions 
provided. There will be paper CRFs in reserve available at each study. 
The local investigator shall ensure that the documentation and medical files of study subjects 
are retained for at least 10 years after the conclusion of the trial. 
7.2 
Training of study site personnel 
The local investigator  at each site will ensure that appropriate training relevant to the study is 
given to all of these staff and that any new information relevant to the performance of this 
study is forwarded to the staff involved. 
The local investigator at each centre will maintain a record of all individuals involved in the 
study (medical, nursing and other staff). 
7.3 
Monitoring of the study 
An independent body will be appointed for monitoring the study. The monitor will be 
appropriately trained and informed about the nature of the study, patient written information, 
GCP and applicable regulatory requirements. Monitor’s qualifications will be documented. 
The monitor will have regular contacts (in person, telephone and/or e-mail) with the study 
sites to verify informed consents of participating subjects, to confirm that facilities remain 
acceptable, that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRF and that therapy accountability is being carried out. The 
study nurse will also ensure source data verification (comparison of the data in the eCRF with 
the hospital/practice and other records at the investigational site).  
7.3.1 
Source data 
All patient source data such as analysis results from the hospital central laboratory, cystoscopy 
reports will be stored at the hospital according to routines. A copy of the eCRF data will be 
archived at the study site.  
The eCRFs serves as the source for demographic data, medical history and physical 
examination Original scorings of patient-reported outcomes (EPIC and SF36) and biopsy 
analysis reports will be defined as source data.  

 
 
7.4 
Study agreements 
All agreements between the Principal Investigator and laboratory or other technical facilities 
in which the measurement or assessment of the study evaluation criteria are performed must 
be in place before any study-related procedures can take place, or subjects be enrolled. 
8. 
STATISTICAL METHODS AND SAMPLE SIZE  
This study evaluates the symptoms before and after terminated HBO therapy and between 
Groups A and B having EPIC symptom estimation scale at baseline and visit 4 as the primary 
variable.  
Secondary variables are RTOG-grading, immunohistological analysis and health-related 
quality of life (SF36). 
All patients will be contacted for a post-study long-term follow-up yearly during 5 years after 
end of treatment regarding symptoms (EPIC) and quality of life (SF36). 
8.1 
Description of analysis sets 
Calculation is based on an Intent-to-Treat (ITT) and Per Protocol (PP) analysis. 
 
All subjects who received at least 1 dose of HBO and for whom post-dose data are available 
will be included in the safety population. Throughout the safety results sections, incorrectly 
treated subjects will be accounted for in the actual treatment group. 
8.2 
Methods of statistical analyses 
The primary endpoint is symptom rating after HBO therapy using the self-administrated 
EPIC-questionnaire original score as the primary variable at baseline and visit 4.   
 
Secondary endpoints: 
 Severity of radiation injury having the RTOG as the variable at baseline and visit 4 
 Histological analysis of inflammation activity, degree of fibrosis, vascular density and the 
presence of stems cells at baseline and visit 4.  
 Health-related quality of life (SF36) at baseline visit 3, 4 and 5 
 Post-study long-term follow-up follow up with Symptom rating (EPIC) and Health-related 
quality of life (SF36). 
 

 
 
A two-sample t-test with a 5% significance level will be used. For each subject, means of 
measurements from baseline to visit 4 will be calculated. Differences between these means for 
each subject will be used in the comparison of the two groups i.e. between group A and the 
control group B (“delayed start”). Nonparametric methods could also be considered.  
Fisher's exact test and logic regression will be used for comparison of other results in the 
two treatment groups. Jonckheere-Terpstra test will be used for trend analysis.  
Other statistical methods might be used in an exploratory fashion but no formal inference will 
be made. Additional sub-analysis will be made in patients with symptoms for more than 30 
months. 
Patient-reported outcomes (EPIC, SF-36): Statistical calculations will be made using data 
obtained from original registrations (questionnaire scores). 
Safety and tolerability data will be summarized descriptively by treatment and presented in 
tabular and/or graphical form. All adverse event data will be listed individually and 
summarized using MedDRA terminology. 
8.3 
Determination of sample size 
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2.  
Using available data from a few similar methodological studies assuming that the symptom 
reduction has a standard deviation of 23 units and that the expected reduction in EPIC exceeds 
that of control group by 15%, a parallel group design with 40 patients in each treatment group 
would have a power exceeding 80% for detecting a statistically difference between the study 
groups in EPIC (using a two-sample t-test with a 5% significance level). 
N=2x(PIxSD/CL)2 ; N=2x(2,8x23/15)2 ; N=37. In order to have a safety margin, N is rounded 
up to 40. In order to secure a statistically sufficient subject population, recruitment will 
continue until 80 subjects are enrolled and have concluded Visit 4 according to protocol.  
 
9. 
STUDY TIMETABLE  
First Subject In: June 2012. Last Subject Last Visit: March 2016  
Final Study Report: December 2016 or within 12 months from end of study. 

 
 
9.1 
Definition of end of study 
The end of the entire study is defined as ”the last visit of the last subject undergoing the trial”. 
The Statistical and Clinical Study Report will be finalized approximately 1 year after last 
analysed sample. 
10. 
LIST OF REFERENCES 
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edition, 2003 p. 575-577 
2. Non-surgical interventions for late radiation cystitis in patients who have received radical 
radiotherapy to the pelvis. Arshi S Denton, Noel Clarke, Jane Maher 
3. The subcellular basis of damage to the human urinary bladder induced by irradiation. 
Antonakopoulos GN, Hicks RM, Berry RJ, J Pathol. 1984 Jun; 143(2):103-16. 
4. Relationship of oxygen dose to angiogenesis induction in irradiated tissue, Marx RE, Ehler 
WJ, Tayapongsak P, Pierce LW, Am J Surg. 1990 Nov;160(5):519-24. 
5. Acute and late complications after radiotherapy for prostate cancer: results of a multicenter 
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Slot A, Tabak H, Mens JW, Lebesque JV, Koper PC, Int J Radiat Oncol Biol Phys. 2005 Mar 
15;61(4):1019-34. 
6. Radiation Cystitis, Peter G. Pavlidakeya and Gregory T. MacLennana, The Journal of 
Urology, Volume 182, Issue 3, September 2009, Pages 1172-1173 
7. Hyperbaric oxygen for the treatment of radiation cystitis and proctitis. Ronald D. Ennis, 
Current Urology Reports, Volume 3, Number 3 / May, 2002 p. 229-231 
8. Eifel PJ, Levenback C, Wharton JT, et al. Time course and incidence of late complications 
in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix. 
Int J Radiat Oncol Biol Phys 1995; 32:1289–1300 
9. Hyperbaric oxygen – an effective tool to treat radiation morbidity in prostate cancer, 
Ramona Mayer, a, Huberta Klemenb, Franz Quehenbergerc, Oliver Sankinb, Elisabeth 
Mayera, Arnulf Hackla and Freyja-Maria Smolle-Juettnerb, Radiotherapy and Oncology, 
Volume 61, Issue 2, November 2001, Pages 151-156 

 
 
10. Marx R. Radiation injury to tissue. In: Kindwall E, Whelan H, editors. Hyperbaric 
medicine practice. 2nd ed., revised. Flagstaff, AZ: Best Publishing; 2004. p. 665–723. 
11. Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and 
controlled double-blind crossover trial with long-term follow-up, Int J Radiat Oncol Biol 
Phys. 2008 Sep 1; 72(1):134-143. Epub 2008 Mar 14 
12. Rubin P, Constine LS, Fajardo LF, et al. Overview: Late effects of normal tissues (LENT) 
scoring system. Int J Radiat Oncol Biol Phys 1995; 31:1041–1042 
13. Wei J, Dunn R, Litwin M, et al. Development and validation of the Expanded Prostate 
Cancer Index Composite (EPIC) for comprehensive assessment of health-related quality of 
life in men with prostate cancer. Urology 2000; 56:899–905 
14. Complications and Side Effects of Hyperbaric Oxygen Therapy, C. Plafki, M.D., P. Peters, 
M.D., M. Almeling, M.D., W. Welslau, M.D., and R. Busch, M.D. Aviat Space Environ Med 
2000; 71:119-24 
15. Hyperbaric oxygen: does it promote growth or recurrence of malignancy? Feldmeier J, 
Carl U, Hartmann K, Sminia P “Undersea & hyperbaric medicine” 2003, vol. 30, no1, pp. 1-
18 (82 ref.) 
17. Socialstyrelsens statistikdatabaser, www.socialstyrelsen.se, VGR, prostatacancer. 
18. Hart GB, Mainous EG: The treatment of radiation necrosis with hyperbaric oxygen. 
Cancer 1976, 37:2580–2585. 
 
19. Williams JA, Clarke D, Dennis WA, et al.: The treatment of 
pelvic soft tissue radiation necrosis with hyperbaric oxygen. Am J Obstet Gynecol 1992, 
167:412–416 
 
20. Weiss JP, Mattei DM, Neville EC, Hanno PM: Primary treatment 
of radiation-induced hemorrhagic cystitis with hyperbaric oxygen: 10-year experience. J Urol 
1994, 151:1514–1517. 
 
21. Chan TY and Epstein JI: Radiation or chemotherapy cystitis with “pseudocarcinomatous” 
features. Am J Surg Pathol 2004; 28: 909 
 

 
 
22. Wei J, Dunn R, Litwin M, et al. Development and validation of the Expanded Prostate 
Cancer Index Composite (EPIC) for comprehensive assessment of health-related quality of 
life in men with prostate cancer. Urology 2000; 56:899–905 
23. Management of radiation cystitis, Shaun G. Smit & Chris F. Heyns, Nature Reviews 
Urology 7, 206-214 (April 2010) 
24. Ronald D. Ennis. Hyperbaric Oxygen for the Treatment of Radiation Cystitis and Proctitis. 
Current Urology Reports 2002, 3:229–231 
25. Stem cell mobilization by hyperbaric oxygen", Stephen R. Thom,1,2 Veena M. Bhopale,1 
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Physiol Heart Circ Physiol 290: H1378–H1386, 2006 
Cochrane Database Syst Rev. 2009 ;(3):CD001773  
 
 

 
 
Study Protocol Appendix B 
 
Study Code: 
RICH-ART 
 
Date: 
01 May 2014 /4 
 
 
 
 
Appendix B - Definitions of Adverse Events and Procedures in case of 
Pregnancy 
 
Definitions: 
 
Adverse Events 
 
Serious Adverse Events 
 
A medical emergency usually constitutes an SAE and is to be reported as such  
Intensity rating 
 
Causal relationship 
 
Action taken 
 
Reporting in CRF 
 
Adverse Events based on signs and symptoms 
 
Final outcome assessment 
 
Reporting of serious adverse events 
 
Further guidance on Serious Adverse Events: 
 
Life threatening 
 
Hospitalisation 
 
Important medical event or medical intervention 
 
A guide to interpreting the causality QUESTION 
 
Other significant Adverse Events 
 
Procedures in case of pregnancy 
 
Maternal exposure 
 
Overdose 
 
 

 
 
DEFINITIONS OF ADVERSE EVENTS AND PROCEDURES IN CASE 
OF PREGNANCY 
It is of the utmost importance that all staff involved in the study is familiar with the content of 
this section. The Local Investigator is responsible for ensuring this.  
Adverse Events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram). In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs  
Serious Adverse Events and suspected unexpected serious adverse reactions (SUSAR) 
It is important to distinguish between Serious Adverse Events (SAEs) and severe adverse 
events (AEs). Severity is a measure of intensity whereas seriousness is defined by the criteria 
listed below. An AE of severe intensity need not necessarily be considered serious. For 
example, nausea which persists for several hours may be considered severe nausea, but not an 
SAE. On the other hand, a stroke which results in only a limited degree of disability may be 
considered a mild stroke but would be a SAE. 
A medical emergency usually constitutes an SAE and is to be reported as such 
A serious adverse event is an AE occurring during any study phase (i.e. run-in, Pre-entry, 
screening, treatment, wash-out), and at any dose of the investigational product, comparator or 
placebo, that fulfils one or more of the following criteria: 
 
results in death 
 
is immediately life-threatening 
 
requires in-patient hospitalisation or prolongation of existing hospitalisation  
 
results in persistent or significant disability or incapacity 
 
is a congenital abnormality or birth defect 
 
is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above.  

 
 
For reporting purposes, any suspected transmission via a medicinal product of an infectious 
agent is also considered an SAE and is reported in an expedited manner. Any organism, virus 
or infectious particle (for example prion protein transmitting Transmissible Spongiform 
Encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. 
Definitions for severity rating 
0. None – No symptoms 
1. Mild - Transient symptoms; awareness of sign or symptom, but easily tolerated. No 
interference with the subject’s daily activities 
2. Moderate - marked symptoms; discomfort sufficient to cause interference with normal 
activities. Moderate interference with the subject’s daily activities 
3. Severe - considerable interference with the subject’s daily activities; unacceptable 
incapacitating Inability to perform normal activities 
N/A 
Not Applicable 
Causal relationship 
The causality of (S)AEs (ie, their relationship to study treatment and/or the investigational 
procedure) will be assessed by the investigator(s), who in completing the relevant case report 
form must answer “yes” or “no” to the question “Do you consider that there is a reasonable 
possibility that the event may have been caused by the drug/the investigational procedure?”  
The following terms and definitions are used when assessing the causal relationship between 
each AE and the relevant trial product(s): 
1. Definite – There is no doubt that the incident is related  
2. Probably- Good reason and sufficient documentation to assume a causal relationship 
3. Possible- A causal relationship is conceivable and cannot be dismissed 
4. Unlikely- The event is most likely related to aetiology other than the trial product 
5. Not related – The event is not related to the trail product 
6. Unknown/Unclassifiable: a report suggesting an adverse event reaction, which cannot be 
judged because information is insufficient or contradictory and which cannot be 
supplemented or verified. 
N/A 
Not Applicable 
 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect will be classified as no reasonable possibility. 
For SAEs causal relationship will also be assessed for additional study drug 
and/or other medication and/or study procedure. Note that for SAEs that could be 
associated with any study procedure the causal relationship is implied as “yes”. 
Action taken: 

 
 
0 
None 
1 
Dose of study drug changed 
2 
Study drug temporarily stopped 
3 
Study drug stopped 
N/A 
Not Applicable 
 
Reporting in the Case report Form  
The following variables will be recorded in the eCRF for each AE; description of the AE, the 
date and time when the AE started and stopped, maximum intensity, whether the AE is serious 
or not, causality rating (yes or no; if yes specify), action taken with regard to investigational 
product, AE caused subject to discontinue study and outcome. 
Adverse Events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open 
question from the study personnel: “Have you had any health problems since the 
previous visit?”, or revealed by observation will be collected and recorded in the 
CRF. When collecting AEs the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms. However, if a diagnosis is 
known and there are other signs or symptoms that are not generally part of the 
diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
Follow-up – Outcome assessment 
Any AEs that are unresolved at the patient’s last AE assessment in the study are 
followed up by the investigator for as long as medically indicated, but without 
further recording in the eCRF. 
The following terms and definitions are used in assessing the final outcome of an AE: 
 
Recovered - The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent. 
 
Recovering - This term is only applicable if the subject has completed the trial or has died 
from another AE. The condition is improving and the subject is expected to recover from 
the event. 
 
Recovered with sequelae - The subject has recovered from the condition, but with lasting 
effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
 
Not recovered - The condition of the subject has not improved and the symptoms are 
unchanged, or the outcome is not known at the time of reporting. 

 
 
 
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered”, “recovering”, “recovered with sequelae” or “not recovered”. An 
AE with fatal outcome must be reported as an SAE. 
 
Unknown - This term is only applicable if the subject is lost to follow-up 
Reporting of serious adverse events 
For studies in countries implementing the EU Clinical Trials Directive, informing Ethics 
Committees and Regulatory Authorities will be performed by the local investigator as needed. 
All Suspected Unexpected Serious Adverse Reactions (SUSARs) have to be reported, whether 
or not considered causally related to the investigational product, or to the study procedure(s). 
The Clinical Study Serious Adverse Event Report Form will be used together with other 
relevant supporting documentation (e.g. ECG, laboratory results, autopsy report) and relevant 
CRF modules. All SUSARs have to be electronically reported to the MPA that will further be 
reported to EMEAs database. 
FURTHER GUIDELINES ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Out-patient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
Examples of such events are: 

 
 
 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 
 
Development of drug dependency or drug abuse 
A guide to interpreting the causality QUESTION 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 
 
Time Course. Exposure to suspect drug. Has the subject actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties? 
 
Dechallenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
 
No alternative cause. The AE cannot be reasonably explained by aetiology such as the 
underlying disease, other drugs, other host or environmental factors. 
 
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? A re-challenge would not normally be recommended or supported. 
 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship? 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE. 
In difficult cases, other factors could be considered such as: 

 
 
 
Is this a recognised feature of overdose of the drug? 
 
Is there a known mechanism? 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this. Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 
 
Other significant Adverse Events 
An expert will identify other significant Adverse Events (OAEs) during the evaluation of 
safety data for the Clinical Study Report. Significant adverse events of particular clinical 
importance, other than SAEs and those AEs leading to discontinuation of the subject from 
study treatment, will be classified as OAEs. Examples of these are marked haematological and 
other laboratory abnormalities, and certain events that lead to intervention (other than those 
already classified as serious), dose reduction or significant additional treatment. For each 
OAE, a narrative will be written and included in the Clinical Study Report.  
Procedures in case of pregnancy 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, normal birth or congenital abnormality) must be followed up and documented 
even if the subject was discontinued from the study. All reports of congenital 
abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. All 
outcomes of pregnancy must be reported to PI on the pregnancy outcomes report form. 
Part I of this form must be completed in full and returned to PI within 30 days. Part II of the 
form must be completed when the outcome of the pregnancy is known. Reports of normal 
outcomes should be sent within 30 days. 
Maternal exposure 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, normal birth or congenital abnormality) must be followed 
up and documented even if the subject was discontinued from the study.  
 
 

 
 
Study Protocol Appendix C 
Study Code: 
RICH-ART 
 
Date: 
01 May 2014 /4 
 
 
 
 
Appendix C - Ethics 
 
Ethics and regulatory review 
 
Subject information and written informed consent form 
 
Subject data protection 
 
Audits and inspections 
 
 
 
 
 
 
 
 

 
 
ETHICS AND REGULATORY REVIEW 
The final study protocol, including the final version of the Written Informed Consent Form 
and other information given to subjects eg, advertisements must be approved or given a 
favourable opinion by an Ethics Committee before enrolment of any subject into the study.  
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
It is the responsibility of the Local Investigator to apply to the Ethics Committee in writing. 
The application document should:  
 
contain the name and address of the Ethics Committee  
 
clearly identify, by title and date, the protocol and other documents submitted for 
review 
 
be dated. 
In addition, the Local Investigator should request the Ethics Committee to provide: 
 
their approval/opinion in a dated document identifying the Local Investigator’s 
application 
 
Ethics Committee composition for the meeting when the approval was given 
 
a statement confirming that the Ethics Committee is organised and operates 
according to GCP and applicable laws and regulations. 
The Local Investigator is responsible for informing the Ethics Committee of any 
modifications and amendments to the protocol as per local requirements. 
Progress reports and notifications of serious and unexpected adverse drug reactions will be 
provided to the Ethics Committee according to local regulations and guidelines 
All correspondence with the Ethics Committee should be filed by the Local Investigator in the 
ISF. 
The Local  Investigator is also responsible for obtaining approvals from scientific bodies if 
necessary for the study. 

 
 
SUBJECT INFORMATION AND WRITTEN INFORMED CONSENT 
(IC) FORM 
The Local Investigator(s) at each centre will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time 
without prejudice to further treatment. The subject should be given the opportunity to ask 
questions and allowed time to consider the information provided.  
The subject’s signed and dated informed consent must be obtained before conducting any 
study-specific procedures.  
The Investigator(s) must store the original, signed Informed Consent Form in the 
Investigator’s Study File. A copy of the signed Informed Consent Form must be given to the 
subject. 
If a protocol amendment requires a change to the Informed Consent Form, the Ethics 
Committee must approve modifications that lead to a revised Informed Consent Form before 
the revised form is used. Any revision in the Informed Consent Form must lead to an updated 
version No. and/or date. 
SUBJECT DATA PROTECTION 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
Extra precautions are taken to preserve confidentiality and prevent genetic or other study data 
being linked to the identity of the subject. In exceptional circumstances, however, certain 
individuals might see both the genetic, other study data and the personal identifiers of a 
subject. For example, in the case of a medical emergency or an investigator might know a 
subject’s identity and also have access to his or her data. Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate. 
AUDITS AND INSPECTIONS 
Authorized representatives of Sponsor (i.e. monitor), a regulatory authority, or an Ethics 
Committee may perform audits or inspections at the centre, including source data verification. 
The purpose of an audit or inspection is to systematically and independently examine all or 
selected study-related activities and documents, to determine whether these activities were 
conducted, and data were recorded, analysed, and accurately reported according to the 
protocol, Good Clinical Practice (GCP), guidelines of the International Conference on 
Harmonisation (ICH), and any applicable regulatory requirements. The “subject information” 
and IC must contain information and approval of the above mentioned.  

 
 
Study Protocol Appendix D 
 
Study Code: 
RICH-ART 
 
Date: 
01 May 2014 /4 
 
 
 
 
Appendix D - Study Management Process 
 
 
Monitoring 
 
Training of study site personnel 
 
Monitoring/Quality control 
 
Data handling 
 
Source data 
 
Data storage 
 
Essential documents 
 
Audits and inspections  
 
Study Drug handling and accountability 
 
Withdrawal of informed consent for donated biological samples 
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
STUDY MANAGEMENT PROCESS 
Monitoring 
Before the study begins, a representative of Sponsor will visit the investigational site to 
 
determine the adequacy of the facilities 
 
discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to study conduct, protocol adherence, and the 
responsibilities of Sponsor or its representatives. 
During the study, a representative of Sponsor will have regular contacts with the 
investigational site. These contacts will include visits to verify informed consent of 
participating subjects, confirm that facilities remain acceptable, that the investigational team is 
adhering to the protocol, that data are being accurately recorded in the Case Report Forms 
(CRFs) and to provide information and support to the investigator and site team. The 
representative will also ensure; that drug accountability is being carried out and source data 
verification (a comparison of the data in the CRF with the hospital/practice and other records 
at the investigational site) is performed. 
A Sponsor representative will be available between visits, should the investigator or the site 
team need information and advice. 
Training of study site personnel 
Before the first subject is entered into the study, the Local Investigator will review and discuss 
the requirements of the Clinical Study Protocol and related documents with the investigational 
staff and also train them in any study specific procedures and systems utilised. 
The local investigator will maintain a record of all individuals involved in the study (medical, 
nursing and other staff). 
Monitoring/Quality control 
An independent body will be appointed for monitoring the study. The monitor will be 
appropriately informed about the study and patient written information. Monitor’s 
qualifications will be documented. 
Monitor will oversee the progress of the clinical trial, and ensure that it is conducted, 
recorded, and reported in accordance with the protocol, GCP and the applicable regulatory 
requirements. 
Data handling 
The investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded in the appropriate sections of the eCRF and according to any instructions provided. 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
When data has been entered, reviewed, edited, monitored and signed, the data is declared 
clean and will be frozen to prevent further editing. Clean File/database lock must be 
documented. The reason for any excluded data will be described in detail in the report. When 
the principal investigator has signed the eCRF then the subject’s data will be locked and 
analysis of data can start. 
Source data 
All patient source data such as analysis results from the hospital central laboratory, readings 
from the PSGs will be stored at the hospital according to routines.  
The eCRF serves as the source for demographic data, medical history and physical 
examination. Other data stored in the eCRF may constitute source data, but this must then be 
documented in the source data file.  
Data storage 
The data collected will be stored in the digital eCRF, without patients name or personal 
identification number but with a code generated by the system. The physician in charge of the 
study and his staff will be responsible for the “code key” with which it is possible to connect 
the data to the patient. All study data and analysis will be filed in the Study Master File 
(SMF). 
Essential documents 
All documents which permit evaluation of the conduct of a clinical study and the quality of 
the data produced should be stored in the Investigator Study File (ISF). Examples of essential 
documents are: Investigators brochure, signed study protocol, information given to the 
subjects, financial aspects of the study, insurance statements, signed agreements, approvals of 
Ethics committee and Regulatory Authorizations, Curriculum Vitae of local and co-
investigators, samples of labels, instructions of handling the study drug(s), other records of 
investigational products, master randomization list, pre-study monitoring report, subject 
screening logs, audit certificate, any revisions, clinical study report. 
Audits and inspections 
Authorised representatives of Sponsor, a regulatory authority, an Ethics Committee may visit 
the centre to perform audits or inspections, including source data verification. The purpose of 
a Sponsor audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analysed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), and any applicable regulatory requirements. The investigator should contact Sponsor 
immediately if contacted by a regulatory agency about an inspection at his or her centre. 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
Study Drug handling and accountability 
The medical oxygen is obtained from the hospital's gas system. The management and control 
of oxygen comply with the legislation for delivery, storage, labelling, delivery and 
returnable and are specified in local protocols at each hospital. 
Withdrawal of informed consent for donated biological samples 
The local investigator keeps full tractability of collected biological samples from the subjects 
while in storage at the centre until shipment and keeps documentation of receipt of arrival. 
If a subject withdraws consent to the use of biological samples donated the samples will be 
disposed or destroyed, if not already analysed and documented. 
Since collection of the biological samples is a voluntary part of the study, the subject may 
continue in the study as long as the primary endpoint variable (EPIC) is obtainable. 
The local investigator ensures that biological samples from that subject, if stored at the study 
site, are immediately identified, disposed/destructed and the action documented and ensures 
the laboratory holding the samples is informed about the withdrawn consent immediately and 
that samples are disposed/destructed and the action documented returned to the study site. 
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
Instructions for cystoscopy and biopsy Appendix E 
 
Study Code: 
2012-001381-15 (RICH-ART ) 
 
Date: 
1 May 2014 
 
 
 
 
Instructions for cystoscopy and biopsy 
 
Copy of the eCRF-form (for reference) 
 
Explanation of the fields 
Cystoscopy 
Preparations 
Measurements 
Biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
COPY OF THE FORM (ENTER DATA IN E-CRF ONLY) 
Date of Cystoscopy  
 
Number of biopsies taken:  
 
 
Any surgery of urine bladder?  
Yes 
No 
Any strictures of urethra?  
Yes 
No 
Digital photography?  
Yes 
No 
Residual urine  
ml  
Bladder max capacity  
ml  
Other clinical findings  
 
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
 
Haematuria  
None 
Microscopic haematuria 
Intermittent macroscopic haematuria 
Frequent macroscopic haematuria 
Transfusion requiring haematuria 
 
Urine bladder – atrophy  
Normal 
Slight epithelial atrophy 
Coherent macroscopic atrophy 
 
Urine bladder – telangectasia  
Normal 
Mild telangiectasia 
Generalized telangiectasia 
Severe telangectasia 
 
Urine bladder – other (more than one option possible)  
Ulceration 
Necrosis 
Perforation 
Fistula 
None of the above 
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
EXPLANATION OF THE FIELDS 
Date of cystoscopy 
The date the cystoscopy was performed. 
Number of biopsies taken 
State the number of biopsies that was sent for analysis. Do not count biopsies taken, but not 
included in the shipment for analysis. Nor biopsies taken for other purpose i.e. for analysis at a 
local laboratory.  
Strive to take three biopsies as described below. If it impossible to take any biopsied or if it is 
only possible to take one or two biopsies, please state the reason in the comment field.  
Any surgery of urine bladder? 
Any previous surgery, including diathermia, should be reported. If “Yes” is marked a 
comment field will be visible where the year and type of surgery should be entered. Separate 
several procedures with a comma. Previous cystoscopy without any intervention is not 
considered surgery and shall not be reported.  
Previous surgery to the prostate gland or the urethra is reported elsewhere in the CRF and 
need not be entered here.  
Any strictures to the urethra? 
Mark “Yes” if any strictures in the urethra are visualized during the examination and specify 
what kind of strictures are seen.  
Digital photography? 
Photography of the urine bladder is NOT mandatory according to protocol. If photos are taken 
and of interest for the study, please mark “Yes” and state why the photo is of interest, what 
area is photographed and where the photos are stored.  
Residual volume and bladder max capacity  
See below for further instructions.  
Other clinical findings 
This field is optional. Any relevant information should be entered here. This includes, but is 
not limited to, findings of previously unknown cancer.  
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
 
Haematuria 
Microscopic haematuria are examined using a urine stick.  
Intermittent macroscopic haematuria is defined as haematuria at a maximum of two times per 
week during the last four weeks.  
Frequent macroscopic haematuria is defined as haematuria more than two times per week 
during the last four weeks.  
Transfusion requiring haematuria is marked if the patient has received transfusions during the 
last four weeks due to haematuria.  
NB! According to the protocol, the patient should be excluded from the study if more than 
500ml blood has been transfused during the last four weeks when examined during screening. 
This is because randomization to Group B for such a patient is considered un-ethical. The 
patient is not excluded if the criterion is fulfilled at visit 4A/B.  
Urine bladder – atrophy/telangiectasia  
Mark ONE option that best describes the WORST findings during the cystoscopy. Further 
explanation to the findings might be given under “Other clinical findings”. 
Urine bladder – other 
Mark ALL options that is valid. Further explanation to the findings might be given under 
“Other clinical findings”.  
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
CYSTOSCOPY  
A cystoscopy is performed at two separate times during the study period regardless of which 
randomization group the patient belongs to.  
The first cystoscopy is done during the screening period. The screening period should not 
exceed six weeks and is calculated from the date when the first examination in the study is 
performed. (This normally is the same date as when the patient signs the Informed Consent.) 
The screening period is ended when the patient either is included in the study i.e. is 
randomized to either group A or B, or is excluded from the study due to findings during the 
screening process that constitutes an exclusion criteria.  
The second cystoscopy is performed at visit 4 (A&B) which should be scheduled six to eight 
months after the inclusion date.  
Preparations and anaesthesia 
The RICH-ART protocol does not state that any special preparations of the patient should be 
made prior to the examination i.e. local procedures are followed for the preparations and 
execution of the cystoscopy.  
Local anaesthesia is preferred over regional (spinal) or general anaesthesia mainly because 
local anaesthesia constitutes less risk for the patient, but also because it is less time consuming 
and requires less resources. However, regional or general anaesthesia may be used according 
to local protocol and patient needs.  
Measurements 
The methods used for measurements may be adjusted to local standard procedures. If other 
methods then the blow described are used, a comment in the CRF should be made. This 
comment should state what alternative method that was used.   
Residual volume  
Residual volume in the protocol and CRF refers to Post Void Residual (PVR) urine volume.  
 Instruct the patient to empty their urine bladder 
Method 1: 
 Measure residual volume by the use of ultrasonic examination – Bladderscan 
Method 2: 
 Insert a catheter or cystoscope and empty the bladder completely. 
 Measure the volume extracted 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
Bladder max capacity 
Bladder max capacity in the protocol and CRF refers to the maximum volume capacity of the 
urine bladder.  
The preferred method to measure is: 
 The patient is under local anaesthesia 
 The urinary bladder is emptied completely  
 Fluid is slowly infused into the urinary bladder via the cystoscope  
 The patient is asked to report when he/she feels a very strong urge to void 
 When the patient reports a very strong urge, the infusion is stopped and the volume 
aspirated and the volume is recorded as bladder max capacity 
Alternative methods must be used if the patient is under regional or general anaesthesia since 
the patient will be unable to feel the urge to void when fluid is infused to the bladder. If this is 
the case, a note must be made in the CRF. This is done by entering “anaesthetic” in the 
comment field.  
The alternative method to measure is:  
 The patient is under regional or general anaesthesia 
 The urine bladder is emptied completely via a cystoscopy instrument 
 Fluid is infused with a standardized pressure i.e. 60-70 cm above the level of the 
bladder 
 Infusion of fluid is allowed until it stops  
 The infused volume is recorded as (anaesthetic) bladder max capacity.  
 
Biopsies 
Biopsies are preferably taken with cold forceps, for instance 5mm, technique in order to affect 
the tissue in the biopsy as little as possible and to minimize the risk of bleeding, fistula 
formation or other complications. If any other technique is used, please make a comment in 
the CRF. 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
The biopsy should at least include the urothelium and some of the underlying lamina propria. 
It is preferred if at least one biopsy includes some part of the muscle layer, but this is not 
always possible.  
In order to maximize the probability for a good quality of the material, three biopsies should 
be taken whenever possible. However, if the urologist deems it impossible to take such a 
number of biopsies or that the quality of the first and/or second biopsy is undisputable, one or 
two biopsies might suffice.  
During screening, biopsies are taken in close proximity to any clinically evident changes in 
the urine bladder. It is recommended that the urologist makes a note of where the biopsies are 
taken during screening. Biopsies taken during visit 4A/B should be in close proximity to the 
previous biopsies, however steering clear of any visible scar tissue. If no evident changes are 
found it is recommended that the three biopsies are taken at the following locations: one 
laterally of each ostium and one in the trigonum area.  
All biopsies are placed in the same sterile plastic tube filled with formalin. The biopsies can 
be stored at room temperature during transport to: 
Clinical Pathology and Cytology 
Att: Dr. Johan Mölne 
Gula Stråket 8, SU/Sahlgrenska 
413 45 Göteborg  
The tubes should be labelled with study code (RICH-ART), subject number, visit number and 
date. 
NB! The biopsies are NOT examined when they arrive to the pathology clinic. They are 
stored for batch analysis by a blinded examiner at a later date. If the urologist suspects 
any pathology that needs to be biopsied and examined promptly, separate biopsies 
should be taken and sent to the local laboratory for analysis.  
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
 
Patient Number:
 
 
Patient's initials: 
 
 
Patient information regarding: 
Hyperbaric treatment of bladder discomfort caused by radiotherapy 
of cancer in the pelvic region 
 
Project 
This is an investigation/study aimed at studying whether oxygen given in a hyperbaric 
chamber may affect symptoms of the bladder that have occurred due to 
radiation therapy of cancer in the pelvic region. The study is administered by the Hyperbaric 
Unit at Sahlgrenska University Hospital/Östra. Several hyperbaric centers in Sweden, Norway 
and Denmark participate in this study. 
 
Background and purpose 
Tissue that has been exposed to radiotherapy can take damage and give rise to a number of 
adverse symptoms. These may debut in close proximity or long time after the radiotherapy has 
been given. Often the symptoms become more pronounced over time. Previous scientific 
studies have shown that oxygen given under pressure in some cases may alleviate the 
symptoms of the radiation injured tissue and may also reverse some microscopic changes. 
 
The purpose of this study is to investigate whether hyperbaric treatment alleviate the 
symptoms that have occurred after radiotherapy of the bladder. We shall also examine the 
appearance of mucous membraine before and after Oxygen Treatment. In this way, we can 
gain in-depth knowledge about the factors influencing the onset and alleviation of symptoms. 
 
How does the study go? 
The first visit takes about 60 minutes. We will ask questions about age, past and current 
illnesses. Health examination and blood tests, urine tests, blood pressure and heart rate are 
taken. We also measure height and weight. A pregnancy test will be carried out where 
appropriate. You can complete the questionnaire on how to experience your quality of life and 
your symptoms. You will also be informed of certain restrictions that will apply during the 
study. It is for example that you must not use hairspray, perfume, greasy ointments, etc. before 
a treatment or bring something flammable into the chamber. 
 
All patients will undergo two cystoscopic examinations with approximately 6-8 months apart. 
These investigations look for changes in the mucous membrane of the bladder and document 
it. In connection with these investigations , tissue samples from the mucous membrane of the 
bladder will be taken. The tissue samples are very small – only a few millimetres. Three tissue 
samples are taken in local anesthesia at each examination.  
 
After the first cystoscopy you will end up in one of two groups. This division takes place 
randomly and can not be affected by you or any of the other. Group A, will be offered 
treatment start as soon as possible. The second group, group B, will be offered treatment 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
initiation after cystoscopy number 2. This means that group B will have to wait 6-8 months 
before receiving treatment.  
 
Treatment days: You come to the clinic for a while before and dress up to comfortable and 
cool cotton clothing. Own underwear can be retained if they are in cotton material. Then you 
get to enter the hyperberic chamber. There is always a nurse nearby throughout the treatment. 
When the door is closed, the pressure slowly increases to a pre-determined treatment 
preassure. You will breathe 100% oxygen in about 90 minutes. In the meantime there is the 
opportunity to watch movies, listen to music or read a book. Finally, the pressure is slowly 
reduced and today's treatment is complete. There is no feeling in the body during treatment. It 
can hit the lid for the ears in the same way as when an airplane lands or a train goes into a 
tunnel. You will undergo one treatment per weekday for 8 weeks, that is to say a total of 40 
treatments. 
 
Once the treatment period is over, you will again have to fill in some questionnaires on how to 
experience your quality of life and your possible symptoms. A shortened health examination 
will then also be performed that includes blood tests. 
 
We will contact you once a year for the next five years and ask you to fill in two 
questionnaires on how to experience your quality of life and your possible symptoms. The 
Study is completed when the 5-year follow-up is completed. 
 
Biobank 
The tissue samples will be examined in a microscope. We will look for the presence of 
inflammation, damaged cells, fibrosis, and the presence of blood vessels.  
One of the blood test tubes is stored together with the tissue sampel in a so-called Biobank 
registered in the Anesthesia section at Sahlgrenska University Hospital, Sahlgrenska, and is 
managed by Biobank manager at the Anaesthesia Clinic. The samples are encoded in such a 
way that they cannot be linked to the individual patient without access to the code key. The 
code key is managed by the research manager and stored in the locked safe. The samples will 
be analysed at the Sahlgrenska University Hospital. No samples will be disclosed to any other 
research group. Saved samples will not be used for other projects without prior review and 
approval by the Regional Ethical Review Board.You may at any time request that samples be 
destroyed in an irreversible manner. 
If the research samples would be relevant for future yet unplanned research, you will be asked 
for consent and new ethics application must be made. 
 
Possible side effects, risks and discomfort 
The risks of oxygen therapy under overpressure are small and we do not have any support atht 
it might lead to an increased risk of relapse in cancer. Some patients may experience 
difficulties in depressurizeing the ears in connection with the pressurization of the chamber. It 
is important to inform the staff of the House if you experience problems with equializayion so 
that they can help you and thus avoid damage to the eardrum. 
Oxygen given under pressure may in very rare cases give rise to transient seizures. The 
seizure is terminated soon after the 100% oxygen dilivery is interrupted. Oxygen can, among 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
other things, give rise to some changes in visual acuity. However, this change nearly almost 
reverse fully. Visual acuity gradually returns to its previous values over the course of someone 
to a few months. When taking tissue samples there is always a small risk of a minor bleeding 
occurring in connection with the small wound that is left behind. The bleeding usually halts by 
itself.  
 
Are there any advantages to participating? 
There is no guarantee that participation in the study will provide any immediate benefits. But 
the purpose of the study is to investigate whether the effect of oxygen therapy under pressure 
can affect the symptom image and you may therefore benefit from the oxygen therapy during 
the treatment period. One advantage of participation may be that you may undergo medical 
examinations and control of your health several times during the study. 
Participation in the study is entirely voluntary. 
You can cancel your participation in the study at any time, without reason and without giving 
reasons, and no one has the right to question your decision. 
 
Processing of personal data (Swedish Personal Data Act SFS 1998:204). 
Participation in the study after consent is documented for the patient. All information from 
patient records are treated with privacy under the Patient Data Act and stored in your 
study file. Study data will be provided with a code that is specific to you. Your name or social 
Security number will therefore not be directly accessible to others. The responsible doctor is 
responsible for the "code key" with which it is possible to link the data to you.  
The “Personuppgiftsombud” of Sahlgrenska University Hospital is responsible for the 
treatment of Personal data. You have the right to request a statement of the information 
recorded about you and get help for any rectification. You can refer to the contact person 
below or to the Hospital representative (see below). 
The study is controlled by an independent auditor, so-called Monitor. They may request 
access to collected material to ensure that the data in the study have been collected correctly. 
The review is subject to the same privacy rules as responsible researchers. 
 
Insurance and compensation 
Being involved in the study does not entail any costs for you. No additional compensation will 
be paid. As always in the in the public healthcare sector, you are covered by the full patient 
insurance. 
 
Results from the study 
The results of the study will be presented in scientific journals and on scientific meetings 
relevant to this type of disease. Results that directly influences healthcare will also be of 
importance for the design of health care policies and guidelines. What is presented, you as a 
patient can take advantage of if desired. You are offered an account of your individual results 
during the planned follow-up. 
 
Consent form 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
This form shall be drawn up in duplicate, of which you retain one. The consent form shall be 
jointly reviewed and signed by you and the physician responsible. 
 
People to contact: If You have questions about the study, you can turn to the principal 
investigator: 
Nicklas Oscarsson , consultant, An-Op-IVA, Sahlgrenska University Hospital 
031-343 40 00 (Sahlgrenska gear) 
 
Other responsible persons: 
Per Aziz, business consultant, anesthesia and 
intensive Care Clinic, SU/ÖPer Lodding, Docent, 
MD, Urol 
KLin. SU/S 
 
Personuppgiftsombud: 
Sahlgrenska University Hospital 
Susan Lindahl 031-343 27 15 
 
Patient Number:
 
 
Patient's initials: 
 
 
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
 
CONSENT FORM 
 
For participation in clinical study, as well as for the saving, use and dispensing of tissue 
samples in biobank prepared for clinical study at the hyperbaric Unit, Sahlgrenska University 
Hospital. 
 
You are hereby asked if you agree to participate in the study of hyperbaric treatment at the 
Bladder discomfort that occurred after radiotherapy for cancer in the pelvic region. You are 
also asked if you agree that tissue samples are taken for storage in Biobank. 
 
The study is approved by the Regional Ethical Review Board in Gothenburg (epn.se). There is 
a registered Biobank (biobanksverige.se) at the Sahlgrenska University Hospital, Sahlgrenska 
Clinic. This consent form has been designed in two copies, of which you retain one copy. 
 
I have received oral and written information about the research project hyperbaric treatment at 
Bladder discomfort that occurred after radiotherapy for cancer in the pelvic region. 
I have had the opportunity to ask questions and get the information I think I need. I am aware 
that participation does not involve any advantages or disadvantages and that my decision 
doesn’t affect other care I receive. I can cancel my participation at any time and without 
justification.  
 
I have received information about how data is handled and encoded. ALL information from 
patient notes and protocols are treated with confidentiality according to the Patient Data Act. 
The study also has a register that been notified to Sahlgrenska University Hospital's 
representative in accordance 
Personal Data Act. 
 
I agree that the tissue samples included in the study are analyzed and stored in a Biobank 
I agree to participate in the study after reading the above. 
 
 ___________________________________  
                          _________________  
Name  
 
 
 
Date 
 
 
Head of research contact, Sahlgrenska University Hospital 
 
  
___________________________________                             _________________ 
Name 
 
 
 
 Date 
  
Project manager for study, specialist Nicklas Oscarsson, anaesthesia and 
Intensive Care Clinic, area 2 Sahlgrenska/Östra. Nicklas.oscarsson@vgregion.se 031-343 40 
00 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
A copy of this signed patient information is given to the patient 
 
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
 
Patientnummer:   
 
Patientens initialer: 
 
 
Patientinformation angående: 
Tryckkammarbehandling vid besvär från urinblåsan som uppkommit efter 
strålbehandling 
av cancer i bäckenregionen 
 
 
Forskningsprojektet  
Detta är en undersökning/studie som syftar till att studera huruvida syrgas givet under  
övertryck i tryckkammare kan påverka symtom från urinblåsan som uppkommit till följd av  
strålbehandling av cancer i bäckenregionen. Studien administreras av Tryckkammarenheten 
på Sahlgrenska Universitetssjukhuset/Östra. Flera tryckkammarcentra i Sverige, Norge och 
Danmark deltar i denna studie.  
 
Bakgrund och syfte  
Vävnad som utsatts för strålbehandling kan ta skada och ge upphov till en rad negativa 
symtom. Dessa kan debutera i nära anslutning eller långt tid efter det att strålbehandlingen 
givits. Ofta  blir symtomen mer uttalade med tiden. Tidigare vetenskapliga studier har visat att 
syrgas som ges under tryck i vissa fall kan mildra symtomen från den strålskadade vävnaden 
och kanske även reversera en del mikroskopiska förändringar. 
 
Syftet med denna studie är att undersöka om tryckkammarbehandling mildrar de symtom som 
har uppkommit efter strålbehandling av urinblåsan. Vi skall även undersöka slemhinnans 
utseende i mikroskop före och efter syrgasbehandling. På så sätt kan vi få fördjupad kunskap 
kring de faktorer som påverkar uppkomsten och lindringen av symtomen.  
 
Hur går studien till? 
Första besöket tar ca 60 minuter. Vi kommer att ställa frågor om ålder, tidigare och nuvarande 
sjukdomar. Hälsoundersökning genomförs och blodprov, urinprov, blodtryck och puls tas. Vi 
mäter också längd och vikt. Ett graviditetstest kommer att göras i förekommande fall. Du får 
fylla i frågeformulär om hur du upplever din livskvalitet och dina symptom. Du blir också 
informerad om vissa restriktioner som kommer gälla under studien. Det är t.ex. att du inte får 
använda hårspray, parfym, feta salvor etc. före en behandling eller ta med dig något 
brandfarligt in i kammaren.  
 
Samtliga patienter kommer att genomgå två cystoskopiundersökningar med ca 6-8 månaders 
mellanrum. Vid dessa undersökningar tittar man efter förändringar i urinblåsans slemhinna 
och dokumenterar det. I samband med dessa undersökningar kommer vävnadsprover från 
urinblåsans slemhinna att tas. Vävnadsproverna är mycket små – endast ett par millimeter. Det 
tas tre vävnadsprov i lokalbedövning vid varje undersökning.  
 
Efter första cystoskopiundersökningen hamnar du i en av två grupper. Denna indelning sker 
slumpmässigt och kan inte påverkas av dig själv eller någon av annan. Den ena gruppen, 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
grupp A, kommer att erbjudas behandlingsstart så snart som möjligt. Den andra gruppen, 
grupp B, kommer att erbjudas behandlingsstart efter andra cystoskopiundersökningen. Det 
betyder att grupp B kommer att få vänta 6-8 månader innan de får sin behandling.  
 
Behandlingsdagarna: Du kommer till kliniken en stund innan och klär om till bekväma och 
svala bomullskläder. Egna underkläder kan behållas om de är i bomullsmaterial. Därefter får 
du gå in i tryckkamaren. Det finns alltid en sjuksköterska i närheten under hela behandlingen. 
När dörren är stängd ökar trycket långsamt till ett förbestämt maxtryck. Du kommer att andas 
100% syrgas i ca 90 minuter. Under tiden finns möjlighet att se på film, lyssna på musik eller 
läsa en bok. Trycket sänks slutligen långsamt och dagens behandling är färdig. Det känns 
inget i kroppen under behandlingen. Det kan slå lock för öronen på samma sätt som när ett 
flygplan landar eller ett tåg åker in i en tunnel. Du kommer att genomgå en behandling per 
vardag i 8 veckor, det vill säga totalt 40 behandlingar. 
 
När behandlingsperioden är över kommer du återigen få fylla i några frågeformulär om hur du 
upplever din livskvalitet och dina eventuella symptom. En förkortad hälsoundersökning 
kommer då även att göras som inkluderar blodprover.  
 
Vi kommer att kontakta dig en gång per år under de kommande fem åren och be dig fylla i två 
frågeformulär om hur du upplever din livskvalitet och dina eventuella symtom. Studien är 
avslutad när 5-års uppföljningen är avklarad.  
 
Biobank  
Vävnadsprovet kommer att undersökas i mikroskop. Man tittar då på förekomst av  
inflammation, skadade celler, bindvävsinlagring, samt förekomst av nybildning av blodkärl.  
Ett av blodprovsrören lagras tillsammans med vävnadsprovet i en så kallad biobank som är 
registrerad på anestesisektionen vid Sahlgrenska Universitetssjukhuset, Sahlgrenska och som 
sköts av biobanksansvarig på anestesikliniken. Proverna är kodade på sådant sätt att de inte 
kan kopplas till enskild patient utan tillgång till kodnyckel. Kodnyckeln sköts av 
forskningsansvarig och förvaras i låst kassaskåp. Proverna kommer att analyseras vid  
Sahlgrenska Universitetssjukhuset. Inga prover kommer att lämnas ut till någon annan  
forskningsgrupp. Du kan när som helst begära att prover destrueras på ett oåterkalleligt sätt.  
Om forskningsprover skulle bli aktuella för framtida ännu ej planerad forskning kommer du 
att tillfrågas för samtycke och ny etikansökan måste göras.  
 
Eventuella biverkningar, risker och obehag  
Riskerna med syrgasbehandling under övertryck är små och leder inte till ökad risk för återfall 
i cancer. En del patienter kan uppleva svårigheter att tryckutjämna öronen i samband med 
trycksättning av kammaren. Det är viktigt att informera personalen vid kammaren om du 
skulle uppleva problem med tryckutjämningen så att de kan hjälpa dig och på så sätt undvika 
att det uppstår skador på trumhinnan.  
Syrgas som ges under tryck kan i mycket sällsynta fall ge upphov till en övergående kramper. 
Dessa bryts så snart syrgastillförseln avbryts. Syrgas kan i bland ge upphov till något 
förändrad synskärpa. Denna förändring består dock nästan aldrig över tid. Synskärpan återgår 
successivt till sina tidigare värden under loppet av någon till några månader. När man tar 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
vävnadsprover finns alltid en liten risk för att det uppstår en mindre blödning i anslutning till 
det milimmeterstora såret som efterlämnas. Blödningen avstannar vanligen av sig självt.  
 
 
Finns det några fördelar med att deltaga?   
Det finns inga garantier för att deltagandet i studien ger några omedelbara fördelar. Men 
avsikten med studien är att undersöka om effekten av syrgasbehandling under tryck kan 
påverka symptombilden och du kan därför komma att ha nytta av syrgasbehandlingen under 
behandlingsperioden. En fördel med deltagandet kan vara att du får genomgå 
läkarundersökningar och kontroll av din hälsa flera gånger under studien. 
Deltagandet i studien är helt och hållet frivillig.  
Du kan när som helst, utan anledning och utan att uppge skäl, avbryta ditt deltagande i studien 
och ingen har rätt att ifrågasätta ditt beslut.  
 
Behandling av personuppgifter (Personuppgiftslagen SFS 1998:204).  
Deltagande i studien efter samtycke dokumenteras i patientjournalen. All information från  
patientanteckningar behandlas med sekretess enligt patientdatalagen och lagras i din  
patientjournal. Studiedata kommer att förses med en kod som är specifik för dig. Ditt namn 
eller personnummer kommer därmed inte vara direkt tillgänglig för andra. Ansvarig läkare 
ansvarar för den ”kodnyckel” med vilken det går att koppla uppgifterna till just dig.  
 
Utförandestyrelsen för Sahlgrenska Universitetssjukhuset är ansvarig för behandlingen av  
personuppgifter. Du har rätt att begära ett utdrag över de uppgifter som registreras om dig  
och få hjälp till eventuell rättelse. Du kan vända dig till nedanstående kontaktperson eller till  
sjukhusets personuppgiftsombud (se nedan).  
 
Försäkring och ersättning  
Att vara med i studien medför inga kostnader för dig. Ingen extra ersättning kommer att utgå. 
Liksom inom sjukvården i övrigt omfattas du av Patientförsäkringen.   
 
Resultat från studien  
Resultaten från studien kommer att presenteras i vetenskapliga tidsskrifter och på  
vetenskapliga möten som är aktuella för denna typ av sjukdom. Resultat som dirket påverkar  
vården kommer också att få betydelse för utformning av vårdprogram och riktlinjer. Det som  
presenteras får du som patient ta del av om så önskas.  
Du erbjuds en redovisning av dina individuella resultat vid den planerade uppföljningen.  
 
Samtyckesformulär  
Detta formulär skall upprättas i två exemplar, varav du behåller det ena. Samtyckesformuläret 
skall gemensamt gås igenom och signeras av dig och ansvarig läkare.  
 
Personer att kontakta: Har du frågor om studien kan du vända dig till:  
Nicklas Oscarsson , specialistläkare, An-Op-IVA, Sahlgrenska Universitetssjukhuset  
031-343 40 00 (Sahlgrenskas växel)  

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
 
Övriga ansvariga personer: 
Sven-Erik Ricksten, professor, överläkare Anetesi- 
och intensivvårdsklinien, SU/S  
 
Heléne Seeman-Lodding, docent, överläkare,  
Anestesi- och intensivvårdskliniken SU/S
Per Arnell, verksamhetsöverläkare, Anestesi- och 
intensivvårdskliniken, SU/Ö 
Per Lodding, docent, överläkare, Urolklin. SU/S 
Jon Kindblom, överläkare, Onkkliniken, SU/S
 
Ansvarig kontakt personuppgiftsombud: 
Clare Melin, Sahlgrenska Sjukhuset 
 Bruna Stråket 21, 413 45 Göteborg 
031- 342 00 00 (växel)  
 
 
Patientnummer:   
 
Patientens initialer: 
 
 
SAMTYCKESFORMULÄR  
 
 För deltagande i klinisk forskningsstudie, samt för sparande, användning och utlämning av 
vävnadsprov i biobank upprättad för klinisk forskningsstudie vid Tryckkammarenheten, 
Sahlgrenska Universitetssjukhuset.  
 
Du blir härmed tillfrågad om du samtycker till att delta i studien om tryckkammarbehandling 
vid  
besvär från urinblåsan som uppkommit efter strålbehandling mot cancer i bäckenregionen. Du 
tillfrågas även om du samtycker till att att vävnadsprov tas för lagring i biobank.  
 
Studien är godkänd av regionala etikprövningsnämnden i Göteborg (epn.se). Vid 
anestesikliniken Sahlgrenska Universitetssjukhuset, Sahlgrenska finns en registrerad biobank, 
(biobanksverige.se). Detta samtyckesformulär har utformats i två exemplar, varav du behåller 
det ena exemplaret.  
 
 Jag har fått muntlig och skriftlig information om forskningsprojektet tryckkammarbehandling 
vid  
besvär från urinblåsan som uppkommit efter strålbehandling mot cancer i bäckenregionen.  
Jag har fått möjlighet att ställa frågor och få den information jag anser att jag behöver. Jag är  
medveten om att ett deltagande inte innebär några fördelar eller nackdelar och att mitt  
ställningstagande inte påverkar den vård jag får. Jag kan när som helst och utan motivering 
avbryta  
mitt deltagande i studien.  
 
 Jag har fått information om hur data hanteras och kodas. All information från 
patientanteckningar  
och protokoll behandlas med sekretess enligt patientdatalagen. Stuiden har också ett register 
som  
anmälts till Sahlgrenska Universitetssjukhusets personuppgiftsombud i enlighet med  
personuppgiftslagen.  
 
Jag samtycker till att vävnadsprov ingående i studien analyseras och lagras i en biobank 
Jag samtycker till att deltaga i studien efter att ha läst ovanstående. 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014 
 
 
  
 
 
___________________________________  
                          _________________  
Namn  
 
 
 
Datum  
 
 
Forskningsansvarig kontaktperson, Sahlgrenska Universitetssjukhuset  
 
  
___________________________________                             _________________  
Namn 
 
 
  
 Datum  
 
  
Projektansvarig för forskningsstudien, Specialistläkare Nicklas Oscarsson, Anestesi- och  
intensivvårdskliniken, Område 2 Sahlgrenska/Östra. Nicklas.oscarsson@vgregion.se 031-343 
40 00  
 
En kopia av denna signerade patientinformation ges till patienten 
 
 

Clinical Study Protocol 
Study Code: RICH-ART 
Date: 1 May 2014