EFFECT-BACK: Tackling Back Pain - Effects of Exposure Therapy and Cognitive Behavioural Therapy for Chronic Back Pain
Phase: NA
Conditions: Chronic Low Back Pain
Sponsor: University of Kaiserslautern-Landau

Trial Protocol 
 
 
 
„EFFects of Exposure and Cognitive-behavioural Therapy for 
chronic BACK pain („EFFECT-BACK “)” 
 
a randomized controlled psychotherapy study ("two-arm intervention study") 
 
Study acronym:  
 
 
EFFECT-BACK 
Date:  
 
 
 
20.01.2022 
NCT Number: 
 
 
05294081 
 
 

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Content 
1. 
Basic Informations ..............................................................................................................................5 
1.1. Involved persons, institutions and committees .........................................................................................5 
1.2 Signatures .............................................................................................................................................6 
1.3 Declaration of the local study managers ...................................................................................................6 
1.4 Summary ..............................................................................................................................................7 
1.5 Synopsis ...............................................................................................................................................8 
1.6 List of acronyms ................................................................................................................................. 10 
2. 
Background and research question ..................................................................................................... 11 
2.1 Theoretical background ....................................................................................................................... 11 
2.2 Evidence ............................................................................................................................................ 12 
2.3 Research question and justification of the project .................................................................................. 12 
3. 
Study goals and hypothesis ............................................................................................................... 13 
3.1 Primary Outcome: ............................................................................................................................... 13 
3.2 Secondary Outcome: ........................................................................................................................... 14 
3.3 Demography and anamnesis ................................................................................................................ 15 
4. 
Study Design and description ............................................................................................................ 16 
4.1 Study type .......................................................................................................................................... 16 
4.2 Number and type of comparison groups ................................................................................................ 16 
4.3 Allocation .......................................................................................................................................... 16 
4.4 Scope of the study, number of subjects and recruitment ......................................................................... 16 
4.5 Study schedule ................................................................................................................................... 17 
5. 
Selection of patients ......................................................................................................................... 19 
5.1 Inclusion criteria ................................................................................................................................. 19 
5.2 Exclusion criteria ................................................................................................................................ 19 
6. 
Course of study ................................................................................................................................ 20 
6.1 Study Phases ...................................................................................................................................... 21 
6.1.1 Informed Consent ............................................................................................................................ 21 
6.1.2 Randomisation ................................................................................................................................. 21 
6.1.3 Treatment and Aftercare ................................................................................................................... 21 
6.1.4 End of Study Participation ................................................................................................................ 22 

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7. 
Risk and Benefits of the study ........................................................................................................... 23 
7.1 Possible complications and/or risks ...................................................................................................... 23 
7.2 Documentation of side effects .............................................................................................................. 24 
8. 
Biometry ......................................................................................................................................... 24 
8.1 Research hypothesis ............................................................................................................................ 24 
8.2 Primary Estimand ............................................................................................................................... 25 
8.3 Planning the scope of the study (caseload planning) ............................................................................... 25 
8.4 Definition of evaluation collectives ...................................................................................................... 26 
8.5 Statistical methods .............................................................................................................................. 26 
8.5.1 General Methodology ....................................................................................................................... 26 
8.5.2 Analysis of the main objective criterion ............................................................................................. 26 
8.5.3 Analysis of the secondary target criteria ............................................................................................. 27 
8.5.4 Identification of predictive covariates ................................................................................................ 27 
9. 
Data management ............................................................................................................................. 28 
9.1 Patient identification list and pseudonymisation .................................................................................... 28 
9.2 List of responsibilities ......................................................................................................................... 28 
9.3 Data collection ................................................................................................................................... 28 
9.4 Data management ............................................................................................................................... 29 
9.5 Study documents and their storage (archiving) ...................................................................................... 29 
9.6 Video recording .................................................................................................................................. 30 
9.7 Data safety ......................................................................................................................................... 30 
10. 
Quality assurance ......................................................................................................................... 30 
10.1 Standard Operating Procedures .......................................................................................................... 30 
10.2 Control of the study process and data quality ....................................................................................... 30 
10.3 Information on the monitoring programme .......................................................................................... 32 
11. 
Ethics and regulations ................................................................................................................... 32 
11.1 Declaration of Helsinki and Good Clinical Practice .............................................................................. 32 
11.2 Ethics committees ............................................................................................................................. 33 
11.3 Revisions of the study protocol .......................................................................................................... 33 
11.4 Patient insurance ............................................................................................................................... 33 
11.5 Registration ...................................................................................................................................... 33 

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11.6 Funding............................................................................................................................................ 33 
11.7 Final report and publication ............................................................................................................... 34 
References ............................................................................................................................................... 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                          

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1. BASIC INFORMATIONS 
 
1.1. Involved persons, institutions and committees 
 
Director of Studies 
Name:  Prof. Dr. Julia Anna Glombiewski (PI) 
Address: University Koblenz - Landau, Fortstraße 
7, 76829 Landau 
Phone: 06341 280 35 65 
E-Mail: glombiewski@uni-landau.de 
 
 
Biometrician 
Name: Lukas Baumann 
Address: Institute for Medical Biometry, 
Heidelberg University Hospital, Im Neuenheimer 
Feld 130.3, 69120 Heidelberg 
Phone.: 06221 566594 
E-Mail: baumann@imbi.uni-heidelberg.de 
Name: Dr.sc.hum. Anja Sander 
Address: Institute for Medical Biometry, 
Heidelberg University Hospital, Im Neuenheimer 
Feld 130.3, 69120 Heidelberg 
Phone.:  06221 565859 
E-Mail: sander@imbi.uni-heidelberg.de 
 
Study coordination/project management 
Name:  M.Sc. Rabea Vogt 
Address: University Koblenz - Landau, Fortstraße 
7, 76829 Landau 
Phone: 06341 280 356 27 
E-Mail: vogt@uni-landau.de 
 
Monitoring 
 
Centre for Methods, Diagnostics and 
Evaluation, University Koblenz-Landau 
 
 
 
 
 
Datamanagement 
 
Name: Christina Klose 
Address: Institute for Medical Biometry, 
Heidelberg University Hospital, Im Neuenheimer 
Feld 130.3, 69120 Heidelberg 
Phone:  06221 56 5500 
E-Mail: klose@imbi.uni-heidelberg.de 

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1.2 Signatures 
 
 
 
1.3 Declaration of the local study managers 
 
I have read this study protocol and confirm that it contains all the information regarding the 
Clinical Study. I affirm that I will conduct the study in accordance with the protocol and all 
legal requirements. 
The first patient at our center will be enrolled only after all ethical and legal requirements 
have been met. I assure that I will obtain informed consent for study participation from all 
participating patients. 
 
_________________________________________________________________ 
 
Name and signature of local Clinical Project Manager 
 
 
Date 

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1.4 Summary 
 
The overall aim of the present study is to compare two different psychological methods, 
Cognitive Behavioural Therapy (CBT) and Graduated Exposure in vivo (EXP) in the treatment 
of chronic low back pain with regard to effectiveness and improvement in perceived limitation. 
Exploratory research will also be conducted to identify predictors of efficacy for each treatment 
group. This should optimize treatment options and create effective treatment offers for 
subgroups of pain patients.  
Exposure therapy is an effective and economical form of treatment and was shown in a 
previous pilot study to be superior to CBT in reducing perceived limitations of movement. CBT, 
on the other hand, appeared to be more effective in establishing coping strategies. With the 
help of the current study, it should be possible to compare the effectiveness of both treatment 
methods and, in perspective, to identify those patient groups that benefit from exposure 
therapy and thus create a customized treatment program for subgroups of pain patients. 
A total of 380 patients (age: ≥ 18) with chronic back pain and a sufficient degree of impairment 
will be included and analysed in the study. The preparation period for the study is planned to 
be 3 months (March to May 2022), followed by a 20-month recruitment period and the 
treatment phase with a subsequent 6-month follow-up phase (total period 36 months).  
 

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1.5 Synopsis 
 
Study title 
EFFects of Exposure and Cognitive-behavioural Therapy for chronic BACK pain 
(„EFFECT-BACK“) 
Acronym 
EFFECT-BACK 
Director of study 
Prof. Dr. Julia Anna Glombiewski 
Indication/target 
population/disease 
Patients with chronic back pain 
Study design 
Prospective, controlled, multicentre, open-label intervention study with two 
treatment arms (CBT versus EXP); parallel group design with randomized 
allocation; 10-week intervention phase with booster sessions and follow-up (6 
months). 
Aims of the clinical trial  
Overall objective of the project: Improvement and expansion of the treatment offer 
in the treatment of patients with chronic back pain. 
Primary study objective:  
• 
To compare two different psychological methods (Cognitive Behavioural 
Therapy and Graduated Exposure in vivo) in the treatment of chronic 
back pain with regard to effectiveness and improvement in perceived 
limitation. 
Exploratory study objective: 
• 
To identify predictors of effectiveness for each treatment group. The 
variables of movement avoidance and coping will be considered. 
 
Outcomes 
Primary outcome measure: Clinically significant improvement in pain-related 
impairment (measured with the QPBDS) from baseline to 6-month follow-up.  
 
Secondary outcome measures: Pain intensity and experienced impairment 
(adapted scales of the DSF), coping (FESV), BAT-BACK (behavioural test for 
avoidance of movements), depressiveness (HADS), catastrophising (PCS), 
avoidance (PHODA), psych. flexibility (PIPS), fear of pain (PASS-20), absence 
from work, use of the health care system, socio-legal situation (module S, DSF). 
 
 
Recruiting number 
Screening: 494 
randomized: 380  
 
 
 
to be analyzed: 380 
 
 
 
Inclusion criteria 
Chronic back pain (duration > 6 months, pain most days of the week); sufficient 
level of limitation defined by QBPDS ≥15 (Quebec Back Pain Disability Scale, [1]); 
age ≥ 18; patient's written informed consent for study participation. 
Exclusion criteria 
Surgery on the back during the last 6 months or planned back surgery; Medical 
contraindications (red flags); Insufficient knowledge of German (reading and 
language); Pregnancy; Severe alcohol and/or drug addiction; Psychotic 
symptomatology; Parallel psychological treatment; Physical inability to participate 
in the sessions; Parallel participation in another intervention study. 
Interventions/ treatment plan 
10 sessions of psychotherapy: Cognitive Behavioural Therapy or Exposure 
Therapy. 
2 booster sessions 

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Schedule (duration of study) 
Study preparation period (months): 3 
Recruitment period (months): 20 
First enrolled patient to last completed patient (months): 28 
Time for data cleaning and analysis (months): 5 
Duration of the entire studyn(months): 36 
participating (recruitment) 
centres 
planned: n = 5 
University outpatient clinic Landau 
University outpatient clinic Marburg 
University outpatient clinic Mainz 
University Hospital Essen 
University Hospital Heidelberg 
Statistical methods 
Statistical methods to compare the groups for the primary and secondary outcome 
criteria: 
The primary outcome criterion will be analysed using a logistic mixed regression 
model that includes treatment group and baseline QPBDS, HADS, BAT-BACK and 
PHODA fixed effects. In addition, centre-specific random intercepts are specified. 
Missing values are imputed. Similar regression models are used for the exploratory 
analysis of the secondary outcome criteria. 
Methods for additional analyses, such as subgroup analyses and matched 
analyses: 
For the exploratory subgroup analysis, a linear mixed regression model will test 
the interaction between treatment group and baseline BAT-BACK or FESV scores.   
Financing 
Funding for the therapies and funding for the research-linked parts of the project 
is 
provided 
by 
the 
German 
Research 
Foundation 
(Deutsche 
Forschungsgemeinschaft, DFG). 
 
 

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1.6 List of acronyms 
 
CLBP 
Chronic Lower Back Pain 
CBT 
Cognitive behavioural therapy  
EXP 
Exposure Therapy 
RCT 
Randomized Controlled Study 
DSMB 
Data Safety Monitoring Board 
GP 
General Practitioner 
IMBI 
Institute for Medical Biometry  
eCRF 
Electronic Case Report Form  
GCP 
Good Clinical Practice 
SOP 
Standard Operating Procedure  
RBM 
Risk Based Monitoring  
SAB 
Scientific Advisory Board  
 
 
 
 
 
 
 
 
 
 

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2. BACKGROUND AND RESEARCH QUESTION 
The study is a clinical multicentre study and will be conducted in the psychotherapy outpatient 
clinic of the University of Koblenz-Landau and 4 other recruitment centres in Mainz, Marburg, 
Essen and Heidelberg. Prof. Dr. Julia Anna Glombiewski will be the project leader. 
2.1 Theoretical background 
According to a recently published study by the Robert Koch Institute with over 62 000 
participants, one in six men (17.1%) and one in four women (24.4%) in Germany reported 
having suffered from chronic low back pain (CLBP) in the last 12 months [2]. CLBP is a major 
cause of medical costs, absenteeism and disability [3]. Despite apparent advances in medical 
care, the prevalence of CLBP continues to rise [4]. 
According to current guidelines, most of the treatments commonly offered, such as injections 
or surgery, are ineffective; only pharmacotherapy shows small effects but carries a high risk of 
side effects [5].  
Cognitive behavioural therapy (CBT), multidisciplinary approaches with psychological 
treatment components such as CBT and exercise, supported by psychological elements, 
improve pain and condition-related disability in the long term [6, 7]. Disappointingly, however, 
in most studies the effects of multidisciplinary or psychological treatment approaches are small 
to moderate, and in the case of multidisciplinary approaches, do not always justify the high 
costs of inpatient programmes [8, 9]. In outpatient care, specific psychological services in 
addition to pharmacotherapy and physiotherapy are rare. 
EXP treatment for pain is a rarely used psychological treatment that specifically addresses the 
avoidance of physical activity in people with CLBP. In a previous pilot study [10] with 88 
participants, we conducted for the first time a short (10 sessions) and a longer (15 sessions) 
outpatient EXP therapy programme and compared it with a standard 15-session CBT 
programme: 
• 
EXP was more effective than CBT in reducing movement-related impairment. 
• 
EXP-short outperformed EXP-long in efficiency after 10 sessions, meaning that 
individuals improved faster when offered fewer sessions. 
• 
EXP could be safely delivered in the outpatient psychological setting, however CBT 
was more effective than EXP in improving coping strategies.  
A specific behavioural measure, the "BAT-BACK" test, successfully identified participants who 
benefited from EXP in terms of reducing pain-related impairment [11]. Therefore, in the future, 
EXP therapy could be a customised treatment option to achieve better treatment outcomes in 
subgroups of CLBP patients. However, studies with more participants are needed to further 

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clarify whether EXP is successful and for which subgroup of patients. To the best of our 
knowledge, this is the first study aimed at finding out which patient group is more likely to 
benefit from EXP and which from CBT. 
2.2 Evidence 
The effectiveness of CBT-based therapies for chronic low back pain has been investigated in 
several randomised controlled trials (RCTs). The results indicate that the effect sizes are rather 
small and that there are no major differences between the different CBT-based therapies in 
terms of reduction of pain-related impairment [12]. All of these studies have low power due to 
small case numbers and do not provide the opportunity to conduct subgroup analyses.  
 
 
 
 
        
 
 
 
           
 
 
  
There is limited evidence on the efficacy of EXP in CLBP [13]. About ten years ago, the first 
single case studies showed that EXP can reduce impairment and pain-related anxiety in this 
patient group and provided large effect sizes [14, 15].  
Following the case studies, three RCTs published in the same year (all with N< 90), compared 
treatment groups with graduated EXP with a waiting list group and a group undergoing a 
graduated activity programme [16, 17], or with a group of patients in regular medical care [18]. 
These studies found some benefits of EXP, including greater reductions in pain-related anxiety 
and perceived harmfulness of physical activity.  
The pilot study was the first to compare a CBT control group with an EXP group in a 
psychological setting, and the results were promising [10]. One reason for the good effects 
could be the involvement of international treatment experts (e.g. Jeroen de Jong, University 
Hospital Maastricht [18]) and researchers who conducted the previous RCTs and case studies 
and whose experience minimised problems in both treatment and study design. 
2.3 Research question and justification of the project 
We are currently facing the challenge of a widespread disease without being able to offer 
satisfactory treatment options. A comparison of an already established treatment method 
(CBT) with a still less known and used treatment method (EXP) should create starting points 
here. In addition, customized chronic pain treatment specifically to subgroups of pain patients 
could improve care [19, 20].  
In addition, EXP therapy is a promising and cost-effective treatment option that could easily be 
incorporated into multidisciplinary programmes for inpatients or offered by outpatient 
psychotherapists as part of the newly established 12-hour brief psychotherapy. In order to 
validate the preliminary results of the pilot study and to answer open questions, a multicentre 
study with a larger number of participants is planned. 

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The study should also lead to a larger number of therapists trained in EXP therapy in different 
regions in Germany and to an increase in the visibility of our treatment manuals and could lead 
to a more frequent use of EXP for the benefit of the CLBP population. By publishing the results, 
we hope to raise awareness, especially among psychological psychotherapists, that brief, 
manualised, focused treatments may be sufficient to reduce the burden of chronic pain. The 
identification of predictors will help all practitioners involved in the treatment of chronic pain 
(e.g. GPs) to identify those patients who are more likely to benefit from EXP and those who 
are more likely to benefit from CBT. 
3. STUDY GOALS AND HYPOTHESIS 
The overall objective of the project is to improve and expand the range of treatments for 
patients with chronic back pain. 
The scientific study objectives are: 
• 
To compare two different psychological methods (Cognitive Behavioural Therapy and 
Graduated Exposure in vivo) in the treatment of chronic back pain with regard to 
effectiveness and improvement of perceived pain-related impairment. 
• 
To identify predictors of effectiveness for each treatment group. We will look at the 
variables of movement avoidance and coping. 
We expect exposure treatment (EXP) to be more successful than CBT in reducing pain-related 
impairment for chronic back pain. In terms of customised treatment, we expect that.  
a) individuals with higher scores on the behavioural avoidance test "BAT-BACK" will be more 
likely to benefit from EXP than from CBT and that  
b) individuals with lower scores on the Coping Test (FESV) are more likely to benefit from CBT 
than EXP.   
3.1 Primary Outcome:  
Pain-related impairment. Clinically significant improvement between baseline and 6-month 
follow-up survey: Quebec Back Pain Disability Scale (QBPDS, [1]): 
Mandatory outcome measures in pain studies are defined in IMMPACT [22]. We define pain-
related disability as the primary endpoint, which we measure using the QBPDS [1]. We focus 
on clinically significant improvement in impairment (using the Jacobson and Truax (JT) 
method) [23], as this is a more conservative and most meaningful method for patients to 
define a treatment outcome [24].  

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As in the pilot study, to define a reliable and clinically significant improvement in QBPDS [1], 
we will use the test-retest reliability of .92 and the pre-treatment mean from the Kopec et al. 
study [25] (M = 45.6, SD = 15.66). 
Since there are no normative data for the QBPDS [1], we will use Jacobson and Truax's 
"Criterion A", a criterion that relates exclusively to clinical distribution and was already used 
in the pilot study. Criterion A assesses whether a person deviates by more than 2 SD from 
the mean of the "patient" group: 
crit_A = mean (patients) - 2*stdev(patients).  
Based on the pilot study, the cut-off value for criterion A for the QBPDS [1] will be 14. Thus, 
an improvement of 14 or more will be considered clinically significant. 
3.2 Secondary Outcome: 
Absolute changes at post and follow-up: 
• 
Pain-related disability: Quebec Back Pain Disability Scale (QBPDS, [1]).  
• 
Coping: Coping scale from the questionnaire for the assessment of pain processing 
(Fragebogen zur Erfassung der Schmerzverarbeitung, FESV, [26]) at post and follow-
up survey 
• 
Depressiveness: Depression scale from the Anxiety and Depression Scale (HADS, 
[27]) for post and follow-up assessment. 
• 
Catastrophising: Pain Catastrophising (PCS, [28]) for post and follow-up survey 
• 
Avoidance/fear of movement: Photo Series of Daily Activities (PHODA, [29]) for post 
and follow-up survey 
• 
Fear of pain: Pain Anxiety Symptom Scale (PASS-20, [30]) for post and follow-up 
survey 
• 
Behavioural test on avoidance behaviour: Behavioural Avoidance Test - Back Pain 
(BAT-BACK, [31]) for post and follow-up survey 
• 
Psychological flexibility: Psychological Inflexibility in Pain Scale (PIPS, [32]) at post and 
follow-up. 
 
Absolute changes and clinically significant improvement at post and follow-up: 
• 
Pain-related disability: Pain Disability Index (PDI, [33]) at post and follow-up. 
• 
Pain intensity and experienced impairment: adapted 11-item scales from the German 
Pain Questionnaire (Deutscher Schmerzfragebogen, DSF, [34]) for the post and follow-
up survey. 
 

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As with the primary outcome criterion, the Jacobson and Truax (JZ) method [23] will be used. 
Similar to the pilot study, we will use the test-retest reliability of .91 from the study by Grönblad 
et al. [35] and the pre-treatment mean (M = 33.69, SD = 11.59) and normative population data 
(M = 6.8, SD = 11.4) from the study by Mewes et al. [36] to define a reliable and clinically 
significant improvement in PDI [33]. The reliable improvement criterion is set at 9.64 or more 
and the threshold for clinically significant change is set at 10.51 (clinical distribution criterion 
only, criterion "A"). The reliable improvement criterion based on both clinical distribution and 
normative data (criterion "C") is defined as an improvement of 20.13 or more. For the numerical 
pain intensity scale, an improvement of at least 1.5 points (or about 20%) is considered 
clinically significant [37]. 
 
Further: 
• 
Assessment of safety/recording of adverse side effects: After every third hour of 
therapy, patients self-report side effects: Inventory for the Assessment of Negative 
Effects of Psychotherapy (INEP, [36]).  In addition, the therapist fills out a checklist 
after every therapy session to record side effects and/or events that could influence 
the course of therapy. 
3.3 Demography and anamnesis 
• 
Demographic and anamnestic information: Demographic and medical history 
questionnaire with queries on use of the health care system and absences from work 
for the baseline survey, socio-legal situation (module "S" of the DSF [27]) for the 
baseline survey and follow-up. 

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4. STUDY DESIGN AND DESCRIPTION 
 
Figure 1: Study design 
4.1 Study type 
This is a prospective, multicentre, randomized, controlled, open-label, two-arm intervention 
study with a parallel group design. 
4.2 Number and type of comparison groups 
Two parallel groups are formed, the intervention group receives 10 sessions of EXP therapy, 
the control group receives 10 sessions of CBT. 
4.3 Allocation  
The allocation to the therapy methods is randomised. See chapter 6.1.2 
4.4 Scope of the study, number of subjects and recruitment 
This is a multicentre study, the study is being conducted at 5 centres throughout Germany. A 
total of 380 patients will be included, 190 patients per study arm. 
Due to very liberal inclusion and exclusion criteria and based on the data from the pilot study, 
we expect that 77 % of the participants who are screened for eligibility during the preliminary 
examination (V2, see Figure 3 in Section 6 "Examination procedure / visit schedule") will 

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participate in the study. Based on the data from the pilot study [10] and data from pain research, 
we assume a 20% drop-out rate. The number of participants to be recruited for the whole study 
is adjusted for the drop-out rate of 20%. Otherwise, compliance in the pilot study was high with 
minimal missings in all survey instruments.  
Recruitment is done through subsequent working groups: 
Verantwortliche/r 
Institution 
Rekrutierungsziel (n) 
Prof. Dr. Julia Anna 
Glombiewski (Dr. Jens 
Heider) 
University Koblenz- Landau 
Outpatient clinic 
60 
Prof. Dr. Michael Witthöft 
University Mainz 
Outpatient clinic 
60 
Prof. Dr. Winfried Rief (Dr. 
Jenny Riecke) 
University Marburg 
Outpatient clinic 
60 
Prof. Dr. med. Ulrike Bingel University Hospital Essen 
(Multidisciplinary 
Pain 
Centre) 
100 
PD Dr. med. Jens Keßler 
University 
Hospital 
Heidelberg (Multidisciplinary 
Pain Centre) 
100 
Table 1: Recruitment centers 
Recruitment is carried out by directly approaching patients at the respective study centre or 
through self-initiated enquiries by interested persons (e.g. in response to newspaper 
advertising, information flyers in the outpatient clinics or at GPs, etc.). 
4.5 Study schedule 
After approval of the study by the DFG, the first preliminary work has already begun before the 
actual preparation period for the study starts (3 months, planned from March 2022 to May 
2022). This will be followed by a 20-month recruitment period and the treatment phase with a 
subsequent 6-month follow-up phase (total study period: 36 months). 

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2022
1                2                  3                4
2023
1                2                  3               4
2024
1                2                  3               4
2025
1          2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Preparatio
n (incl. 
study 
protocol & 
SOPs & 
sub-
mission of 
the study, 
data 
bank)
Initiation 
of the 
study 
centers
Recruitment: Screening (N = 494) and Inclusion (N = 380)
Randomisation CBT or EXP
Treatment CBT or EXP and Follow-up N = 380
Data cleaning 
and "data 
freeze”
Analysen, 
Publikation der 
Ergebnisse
MS 1
Ethics 
voting & 
initiat-
ion of 
the 
study 
centers
MS 2
Manual-
trainings 
& first
locked-
in 
patient
MS 3
25% of
patients
include
d
MS 4
50 % of
patients
include
d
MS 7
Last 
Follow-
up and 
„data
freeze“
Milestones:
MS 5
75 % of
patients
include
d
MS 6
100 % 
of
patients
include
d
MS 8
First 
publicati
on
Analyses, 
publication of
results
 
Figure 2: Course of study 
After positive screening, the initial examination T0 begins, which is divided into two parts. In 
total, the patients come to 3 visits during the baseline survey, in which the clarification of the 
inclusion and exclusion criteria, detailed information about the study and the informed consent 
of the participants take place. In addition to the collection of demographic data and the 
biographical anamnesis, which includes information on age, gender, nationality, professional 
qualification as well as data on occupational and socio-legal situation, absenteeism and use 
of the health care system, a clinical interview (Mini-DIPS), a series of questionnaires and self-
report scales as well as the BAT-BACK behavioural test are also carried out (see chapters 3.1 
and 3.2).  
Following randomised assignment to one of the treatment methods, the patients receive ten 
sessions of exposure therapy or cognitive-behavioural therapy of 50 minutes each in visits 5 
to 14, which should usually take place weekly. Side effects are recorded after every third 
session. After the end of the treatment phase, the post survey T1 starts with the same surveys 
as at T0, with the exception of the demographic data, the Mini DIPS and the personality 
diagnostics (LPFS-BF and PID5BF+M). A booster session follows in visits 16 and 17. Six 
months after the end of treatment (visit 14), the follow-up survey T2 is carried out with the 
same surveys as at T1; in addition, the socio-legal situation is again queried with the module 
"S" of the DSF. 

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5. SELECTION OF PATIENTS 
A total of 380 patients will be included and analysed in the study.  
5.1 Inclusion criteria 
The following criteria must be present to be included in the study (inclusion criteria): 
• 
Chronic back pain (duration > 6 months, pain most days of the week). 
• 
Sufficient level of limitation, defined via QBPDS ≥15 (Quebec Back Pain Disability 
Scale, [21]). 
• 
Age ≥ 18 years 
• 
Written informed consent of the patient to participate in the study. 
5.2 Exclusion criteria 
If at least one of the following points is present, participation in the study will not take place 
(exclusion criteria): 
• 
Surgery on the back during the last 6 months or planned back surgery 
• 
Medical contraindications (red flags) 
• 
Insufficient knowledge of German (reading and speaking) 
• 
Pregnancy 
• 
Severe alcohol and/or drug addiction 
• 
Psychotic symptoms 
• 
Parallel psychological treatment 
• 
Physical inability to attend sessions 
• 
Parallel participation in another intervention study 
 
 
 
 
 
 
 
 

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6. COURSE OF STUDY 
 
 
 
STUDY SECTION 
 
Enrolment 
Randomisation and 
Baseline 
T0 
Treatment 
Post 
Treatment 
T1 
Booster 
sessions 
Follow 
Up  
T2 
Visit 
V1 
V2 
V3 
V4 
V5 - V14 
V15 
V16 / V17 
V18 
Screening 
X 
X 
 
 
 
 
 
 
Informed consent  
 
X 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
 
X 
 
 
 
 
 
 
Anamnesis and 
demographics 
 
 
 
X 
 
 
 
 
Module „S“ DSF* 
 
X 
 
 
 
 
 
X 
Randomisation 
 
 
 
X 
 
 
 
 
INTERVENTION: 
 
 
 
 
 
 
 
 
CBT 
 
 
 
 
X 
 
X 
 
EXP 
 
 
 
 
X 
 
X 
 
ASSESSMENTS: 
 
 
 
 
 
 
 
 
Accompanying 
treatments 
 
 
 
X 
X 
X 
X 
X 
Pain medication** 
 
 
 
X 
X 
X 
X 
X 
QBPDS 
 
X 
 
 
 
X 
 
X 
Mini DIPS 
 
 
 
X 
 
 
 
 
LPFS-BF und 
PID5BF+M 
 
X 
 
 
 
 
 
 
PDI 
 
 
X 
 
X 
X 
X 
X 
DSF*** 
 
 
X 
 
X 
X 
X 
X 
FESV**** 
 
 
X 
 
 
X 
 
X 
HADS 
 
 
X 
 
 
X 
 
X 
PCS 
 
 
X 
 
 
X 
 
X 
PHODA 
 
 
X 
 
 
X 
 
X 
PASS-20 
 
 
X 
 
 
X 
 
X 
BAT-BACK 
 
 
X 
 
 
X 
 
X 
PIPS 
 
 
X 
 
 
X 
 
X 
WAI-SR 
 
 
 
 
X (V7, V10, V13) 
 
X 
 
REV***** 
 
 
 
 
X (V7-V14) 
 
 
 
INEP 
 
 
 
 
X (V7, V10, V13) 
 
X 
 
Checklist on side 
effects 
 
 
 
 
X (V7, V10, V13) 
 
X 
 
Figure 3: Visit plan 
* Module on the socio-legal situation, absenteeism 
** including adjuvant pain medication (antidepressants) 
*** Adapted scales on pain intensity and experienced impairment 
**** Coping scale 
***** only in EXP condition 
 

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6.1 Study Phases 
6.1.1 Informed Consent 
Each patient is informed about the study in writing and verbally by means of a detailed 
information session between a study staff member and the patient. In particular, the patients 
are informed about the following points: 
- 
the scientific significance of the study and justification of the effort involved 
- 
the duration of the study 
- 
possible stresses and risks associated with specific study procedures 
- 
the possibility of withdrawing from the study at any time and without the expectation of 
negative consequences. 
The patient receives the written patient information and the information on data protection. 
After the information, each patient is given sufficient time and opportunity to clarify open 
questions and to decide on his or her participation.  
Each patient signs and dates his or her consent to participate in the study in writing on the 
consent form. The patient's consent must also explicitly refer to the collection and processing 
of personal data. Therefore, patients are explicitly informed about the purpose and scope of 
the collection and the use of these data, especially health data. 
One copy of the signed consent form (copy or 2nd original) is given to the patient, the other 
remains at the recruitment centre.  
If interested and upon request, the study participants can be included in a mailing list and 
informed about the study results after publication. 
6.1.2 Randomisation 
Randomisation takes place after obtaining informed consent and the baseline survey. Patients 
are randomly assigned to the treatment conditions CBT or EXP in a 1:1 ratio via the centralised 
web-based tool Randomizer (www.randomizer.at). Randomisation will be stratified by centre. 
In order to achieve equally sized groups per stratum, randomisation will be block-wise. Block 
length will be determined by the study biometrician and kept confidential to prevent selection 
bias. 
6.1.3 Treatment and Aftercare 
The treatment phase lasts about 10 weeks. Depending on the therapy condition, the patients 
receive 10 sessions of CBT or EXP, which are followed by the post-survey.  

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Two therapeutic booster sessions take place one and three months after the end of therapy. 
The follow-up survey takes place 6 months after the end of the intervention, which corresponds 
to the usual follow-up period and allows to assess the longer-term impact of the intervention 
and the cost-effectiveness of the treatments. 
Interventions 
Cognitive behavioural therapy and graduated exposure in vivo: these two types of 
treatment are designed to help patients acquire better pain management strategies and thus 
improve well-being and quality of life. They differ in their methodology and focus (e.g. extent 
and type of (physical) exercises and homework), but are both intended to lead to the same 
goal and follow a manualised approach in the study.  
- EXP for pain aims to reduce pain-related impairment by guiding patients to overcome the fear 
of movement and to put weight back on their bodies.  
- CBT encourages patients to develop an adaptive coping style, guides attention-direction and 
problem-solving orientation. 
The treatments are carried out by therapists with different levels of experience in treating pain 
patients, therefore the treatments are supervised every 2-3 sessions (teleconference-based 
group supervision with 4 participants and an experienced supervisor with separate supervision 
groups for each treatment arm). 
Additional treatments 
All (adjuvant) pain medication taken for at least 4 weeks before the first survey will be 
documented and allowed. If participants have just started a new medication, the first survey 
will be delayed by 4 weeks in the baseline measurements until it can be assumed that the 
medication is stable. Participants are asked not to change their medication until the follow-up. 
If a change is necessary, e.g. on the advice of the GP, this will be documented and taken into 
account in the analyses. Participants are asked to refrain from taking medication on 
demand/emergency medication (e.g. taking an additional dose of ibuprofen if the pain gets 
worse), as this could be a safety behaviour that contradicts the basic principle of exposure.  
6.1.4 End of Study Participation 
The regular end of study participation for each participant occurs with the completion of the 
follow-up survey (6-month catamnesis). 
Premature withdrawal of a patient from the study (discontinuation criteria) 
The patient may withdraw consent and discontinue treatment or participation in the study at 
any time and without giving reasons. Treatment discontinuation alone does not lead to study 

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exclusion. The data collected from the patient up to the point of withdrawal will continue to be 
used in the study unless the patient withdraws consent for this as well and requests that his/her 
data be deleted. 
If a patient withdraws his or her consent and drops out of the study, participation is terminated. 
If possible, and if the patient is willing to provide information, an attempt should be made to 
find out the reason for the early termination of the study. The participant is asked to provide 
the reason for discontinuation, but is advised that he or she does not have to do so. It will be 
documented in the study documents and the eCRF that, when and, if applicable, why he or 
she withdrew consent. 
Procedure after (early) withdrawal 
Study participation is voluntary and withdrawal of consent is possible at any time without 
consequences. If necessary, the psychological-psychotherapeutic centres will arrange a 
connection to the psychotherapy outpatient clinics for (further) treatment. The medical centres 
provide counselling on further treatment options and information on psychotherapists in private 
practice. 
7. RISK AND BENEFITS OF THE STUDY 
7.1 Possible complications and/or risks 
Psychological diagnosis and therapy for chronic pain and in general is not associated with 
risks, even though answering personal questions can lead to unpleasant feelings. 
Psychological therapy may occasionally be accompanied by stronger emotions. 
There are no possible impairments or risks for the study participants. The patients will receive 
state-of-the-art outpatient psychotherapy and fill out introduced and standardised 
questionnaires. Both the control group (CBT) and the intervention group (EXP) will receive 
effective treatments. 
There will be no special physical demands on the study participants during the study (no blood 
or saliva sampling, no medication or placebo administration, no invasive measurements). 
Within the framework of the exposure treatment, a short-term increase in pain or muscle 
soreness may occur due to physical stress exercises (e.g. if patients should become physically 
active again after a longer period of inactivity and therefore feel muscle soreness or similar). 
In addition, symptoms of fatigue can occur due to filling out the questionnaires. 
Prof. Dr. Ulrike Bingel will be the medical supervisor of the study and will be involved in 
clarifying red flags of the exposure condition. In the pilot study, patient feedback was obtained 

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and evaluated, and side effects of both therapy conditions were recorded; based on these 
data, no increased risks for the participating patients are to be expected.  
The study is conducted in compliance with the principles of the Declaration of Helsinki, the 
international principles of "good clinical practice" (ICH-GCP) and all applicable laws, e.g. the 
Data Protection Act. A Data Security and Monitoring Body (DSMB) will be established to 
ensure that imbalances between the two intervention groups are identified early.  
Precautions are taken to avoid possible negative effects (see chapters 3.2 and 7.2). 
In the course of therapy and diagnostics, personal and, if necessary, confidential experiences 
and attitudes of the study participants will be asked. All persons involved in the study are 
subject to confidentiality. All data will be collected and analysed pseudonymously. The study 
participants will be fully informed in detail from the beginning about the aims, duration and 
procedure of the study. 
The study participants will receive feedback on the diagnoses, since this is a psychotherapy 
study and this is a prerequisite for a sustainable therapeutic relationship. We expect benefits 
for the patients and the health system, therefore the benefits of the study will outweigh the 
costs and potential risks.   
7.2 Documentation of side effects  
Possible side effects are recorded and documented by means of self-reporting by the patient 
after every third hour of therapy (INEP, see chapter 3.2). In addition, the therapist fills out a 
checklist after every third hour of therapy to record side effects and/or events that could 
influence the course of therapy: 
• 
worsening of physical or psychological symptoms 
• 
Inpatient admission to a somatic, psychiatric hospital  
• 
Rehabilitation therapy 
• 
Therapy interruption (> 4 weeks) 
• 
Stressful events in the private and/or professional environment 
The side effects or events are assessed by the therapist in consultation with the supervisor 
with regard to their severity (mild, moderate, severe) and, if necessary, countermeasures are 
taken in accordance with the study. 
8. BIOMETRY 
8.1 Research hypothesis 
The primary objective of the study is to demonstrate the superiority of EXP over CBT with 
respect to the primary outcome criterion - clinically significant improvement in pain-related 

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impairment (as measured by the QPBDS) from baseline to 6-month follow-up. See Chapter 
3.1 for the definition of clinically significant improvement. 
The following null and alternative hypotheses will be tested: 
H0: pk,CBT = pk,EXP vs. H1: pk,CBT ≠ pk,EXP 
where pk,CBT and pk,EXP denote the probabilities of a clinically significant improvement in 
pain-related impairment in the CBT and EXP groups, respectively, conditional on the baseline 
QPBDS score and the baseline HADS score. 
8.2 Primary Estimand 
The Addendum to the ICH E9 Guideline proposes the Estimands concept as a clear and 
transparent definition of what should be estimated in a study (ICH, 2019). An Estimand is 
composed of the attributes Treatment, Population, Variable, Intercurrent Events and Summary 
Measure. The primary estimand, which corresponds to the primary study objective, is defined 
below: 
Treatment: 10 sessions of manualised Cognitive Behavioural Therapy + two booster sessions 
vs. 10 sessions of manualised Exposure Therapy + 2 booster sessions. 
Population: Defined by the inclusion and exclusion criteria. 
Variable: clinically significant improvement in pain-related distress, as measured by the 
QBPDS, from baseline to 6-month follow-up. See chapter 3.1 for definition of clinically 
significant improvement. 
Intercurrent Events: 
• 
Treatment interruption or discontinuation - treatment policy strategy 
• 
Change of treatment - treatment policy strategy 
• 
Additional medication or treatment - treatment policy strategy 
• 
Death - hypothetical strategy (death not related to treatment) 
Summary Measure: Odds Ratio 
For all secondary questions, the intercurrent events are the same as for the primary estimand. 
Only the attribute variable changes according to the respective endpoint. 
8.3 Planning the scope of the study (caseload planning) 
In our pilot study, a rate of 44% was observed in the CBT group for the primary outcome 
criterion [10]. The short and long EXP groups showed rates of 63.3% and 65.4% respectively. 
However, in the pilot study, 15% of the subjects were excluded because of low levels of pain-
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EXP. For this reason, we assume a conservative rate of 60% responders in the EXP condition. 
Using a two-sided chi-square test to detect this effect at a significance level of 0.05 and a 
power of 80%, 152 patients per group are required. It is expected that using a logistic mixed 
model that includes baseline QBPDS, HADS, BAT-BACK and PHODA scores as fixed effects 
and the centre as a random effect in addition to the treatment group will increase the power of 
the analysis. Based on comparable studies in this research area and the pilot study, we expect 
a drop-out rate of 20%, so that 190 patients per group (380 in total) will be randomised. The 
calculations were performed with PASS 14.0.8. 
8.4 Definition of evaluation collectives 
Full Analysis Set: The Full Analysis Set (FAS) includes all randomised patients. According to 
the intention-to-treat (ITT) principle, all patients are assigned to the group to which they were 
randomised. The FAS is the primary evaluation set for all efficacy outcome criteria. 
Per Protocol Set: The Per Protocol (PP) Set includes all patients in the FAS who completed 
the study without serious protocol violations. Relevant protocol violations that lead to exclusion 
from the PP set are defined in the statistical analysis plan (SAP). Since evaluations in the PP 
Set cannot be interpreted causally, PP analyses play a subordinate role in the interpretation of 
the results and should only be seen as supplementary analyses. 
Safety Set: The Safety Set includes all randomised patients who participated in at least one 
therapy session. The patients are assigned to the group from which they received the majority 
of therapy sessions. 
8.5 Statistical methods 
8.5.1 General Methodology 
The methods of statistical analysis will be described in detail in a statistical analysis plan (SAP), 
which will be prepared promptly after the start of the study. All statistical analyses will be 
conducted using SAS v9.4 software or a later version. 
Demographic and other baseline variables, as well as all other variables, will be summarised 
descriptively for each treatment group. Absolute and relative probabilities will be calculated for 
categorical variables. For continuous variables, mean, standard deviation, minimum, 
maximum, median and 1st and 3rd quartiles are calculated. 
8.5.2 Analysis of the main objective criterion 
The primary target criterion is analysed with a logistic mixed regression model. The primary 
outcome criterion is the dependent variable. Treatment group and baseline values of QPBDS, 
HADS, BAT-BACK and PHODA are considered as fixed effects. In addition, centre-specific 
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chapter 8.3.2 is carried out in the FAS by means of a z-test, which tests whether the regression 
coefficient for the treatment group is different from 0. This test is performed at a two-sided 
significance level of 5%. 
Missing values for the QPBDS (from which the primary target criterion is also derived) and the 
HADS are imputed for each item. The predictive mean matching (PMM) method is used for 
this. The QPBDS (baseline and 6-month follow-up) and the HADS, BAT-BACK and PHODA 
(baseline) are also included in the multiple imputation model, as is the centre as a random 
effect. 
As sensitivity analyses, a pattern mixture model is used instead of the PMM model for 
imputation, and best-case and worst-case scenarios for imputation of missing values are 
considered.  
Supplementary analyses for the primary outcome criterion include analyses in which 
depression, assessed on the basis of a clinical structured interview (binary), is included as a 
covariate in the logistic mixed regression model - instead of the baseline HADS score. In 
addition, a model is calculated in which a change in medication (binary) is included as a 
covariate. It should be noted that the covariate adjustment of logistic regression models 
changes the parameter to be estimated ("non-collapsibility"). The probability parameters refer 
in each case to subgroups of patients who have the same expression of the variable to which 
conditionalization is applied [40]. Since the supplementary analyses conditionalize on other 
covariates, there is therefore a change in the true regression parameter for the treatment 
group.  
8.5.3 Analysis of the secondary target criteria 
Secondary outcomes will be analysed using appropriate mixed regression models, adjusting 
for baseline and HADS baseline. Centre-specific random intercepts are also specified in each 
model. Descriptive p-values and 95% confidence intervals are calculated for the effect of the 
treatment group. 
8.5.4 Identification of predictive covariates 
To identify subgroups of patients who particularly benefit from EXP, a linear mixed regression 
model is calculated in which the QBPDS score at 6-month follow-up is the dependent variable, 
and the treatment group, baseline QBPDS score, baseline HADS score, baseline PHODA 
score, baseline BAT-BACK score, baseline FESV score are the independent variables. In 
addition, interaction terms between the treatment group and the BAT-BACK as well as the 
FESV score are taken into account. Centre-specific random intercepts are also specified. To 
test whether the BAT-BACK or the FESV score are related to the treatment group, it is tested 
whether the respective interaction terms are different from 0. The mixed regression model is 

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also used to estimate individualised treatment effects and to estimate optimal individualised 
treatment rules. 
9. DATA MANAGEMENT 
9.1 Patient identification list and pseudonymisation 
All patient-related data is recorded in pseudonymised form. The identity of the patient cannot 
be deduced from the pseudonym. For the patient identification number, a combination of a 
fixed recruitment centre number (1 = Essen, 2 = Heidelberg, 3 = Landau, 4 = Mainz, 5 = 
Marburg) and a consecutive centre-specific patient number is chosen.  
Each trial centre maintains a coding list in which the patient identification numbers are assigned 
to the names of the participants. The coding list is only accessible to the local trial managers 
and the local study coordinator and is kept in a lockable cabinet and destroyed at the latest 2 
years after the end of the study. As long as the coding list exists, participants can request the 
deletion or destruction of all data collected from them at any time. 
In addition, the participation of the persons concerned in the study is noted in the respective 
patient file. 
9.2 List of responsibilities 
For each recruitment centre, a coding list for study staff and study officers is also filed in the 
study centre folder with, among other things, the name, function in the study, study-related 
activity and staff ID of the responsible persons. The staff ID is also composed of a combination 
of the defined recruitment centre number (1 = Essen, 2 = Heidelberg, 3 = Landau, 4 = Mainz, 
5 = Marburg) and consecutive centre-specific number of the staff members. 
9.3 Data collection 
All information required by the protocol to be collected during the trial must be entered into the 
eCRF by the responsible personnel or designated representative. The responsible staff or 
designated representative should complete the eCRF sections as soon as possible after the 
information is collected, preferably on the same day that the participant appears for an 
examination, treatment or measurement procedure. Any outstanding entries must be 
completed immediately after the T2 follow-up appointment. An explanation should be given for 
any missing data. The completed eCRF must be reviewed and signed by the responsible staff 
member or designated representative. 

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9.4 Data management 
The Institute of Medical Biometry (IMBI) is responsible for data management within the study. 
An efficient infrastructure for electronic data capture and data management will be established. 
The study data will be captured and managed using the REDCap (Research Electronic Data 
Capture [41]) system, a secure, web-based application hosted by the IMBI. Data transfer is 
encrypted using Secure Socket Layer (SSL) technology. The database server is protected by 
a firewall. The system provides an infrastructure for defining user roles and rights. Only 
authorised users can enter or edit data; access is restricted to the data of patients in the 
respective centre. All data changes are logged with a computerised time stamp in an audit trail. 
All data is pseudonymised. To ensure high data quality, rules for data validation are defined in 
a data validation plan. Completeness and plausibility of the data are checked during data entry 
(edit checks) and with the help of validation programmes that generate queries. A tracking 
system for the eCRF data is established to ensure that the data is managed in a timely manner. 
When no further data changes are to be made to the database, the eCRF data is locked. The 
data are finally downloaded and used for statistical analysis. All data management procedures 
are carried out according to IMBI's written standard operating procedures (SOPs), which 
ensure efficient and GCP-compliant (Good Clinical Practice) implementation. At the end of the 
study, the data are converted into different data formats (e.g. csv files) to archive them and 
ensure their reuse. 
9.5 Study documents and their storage (archiving) 
The originals of all essential study documents are retained by the study director for at least ten 
years after the final report has been prepared.  
At each recruitment center, accrued administrative documents (e.g. ethics votes), the patient 
identification list, signed informed consent forms, and general study documentation (study 
protocol, amendments, study forms) will be retained for the above mentioned time, with the 
exception of the patient identification list, which will be destroyed after only 2 years. All records 
must be kept in a secure place and kept confidential. The patient identification list should be 
kept separately from the documentation records, in a lockable cabinet.  
Original study patient records (e.g., medical records) or essential study documents are to be 
retained in accordance with the retention period applicable to recruitment centers, but no less 
than ten years. The recruitment center or the responsible investigator(s) must take precautions 
to prevent the accidental or premature destruction of these documents. 

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9.6 Video recording 
Video recordings are planned to ensure and check the fidelity of the study and for supervision 
purposes. These data will be stored in encrypted form. The video recordings will be deleted 
after completion of the evaluation, but at the latest one year after completion of the last study 
treatment. 
9.7 Data safety 
Extensive measures are taken to protect the data, especially personal data, against access by 
third parties. 
Within the framework of the study, personal data of the test persons (e.g. name, address, 
telephone number), data to answer the research question (pain burden, depressiveness, etc.) 
as well as video recordings for adherence control and supervision are processed.  
The local therapy files and study data are stored in lockable cabinets and are only accessible 
to the respective treating therapists and study staff, who are subject to the legal duty of 
confidentiality.  
In the event of withdrawal of consent to the study by the patient, no further data will be collected 
from the time of withdrawal. The data collected so far will continue to be used and evaluated 
within the study. If a patient only discontinues the study treatment, the data required for the 
study can continue to be collected and used. 
All therapists, supervisors and study assistants are also subject to medical confidentiality. No 
information collected in the course of therapy will be passed on to third parties. 
 
10. 
QUALITY ASSURANCE 
10.1 Standard Operating Procedures 
To ensure adherence to the study protocol and standardised conduct of the study in all 
participating centres, detailed standard operating procedures (SOP) are defined by the study 
management and communicated to all centres. 
10.2 Control of the study process and data quality 
Risk-based monitoring (RBM), which includes clinical site visits if required, is conducted by the 
"Centre for Methods, Diagnostics and Evaluation" at the University of Koblenz-Landau in 
collaboration with central (statistical) monitoring by the IMBI at the University of Heidelberg. 

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Monitoring will follow a study-specific monitoring manual and a risk-based approach to ensure 
protocol compliance, patient safety and data integrity.  
The monitor will conduct and document visits prior to the start of the study. During this first site 
visit, the monitor will review the processes around informed consent, documentation, data 
analysis and administration. All subsequent visits will depend on the feedback the monitor 
receives regularly from the central (statistical) monitoring regarding all target criteria, including 
adverse events, and on feedback from the centres themselves and from the study directors, 
who will store all study processes on an encrypted server. Compliance with the protocol is 
systematically monitored through clinical supervision and evaluation of the treatment videos. 
Inconsistencies are reported to the monitor by the supervisor. 
If one centre's data differs greatly from that of other centres or shows other inconsistencies, 
further site visits are planned. This also happens if unexpected or critical side effects occur, 
compliance with the protocol is not ensured, or dropout rates are above expectations (both 
compared to the pilot study), or if recruitment problems occur. The monitor is given access to 
all study-relevant documents by the principal investigator and other investigators. The 
investigators agree to cooperate fully with the monitor or other third parties. 
Prof. Dr. Ulrike Bingel is the principal investigator of the study and is responsible for ensuring 
the safety of the EXP condition.  
To check and ensure adherence to the manual, the therapy sessions will be videotaped and 
assessed for adherence. The assessment of treatment adherence is based on Leeuw and 
colleagues' method for assessing treatment delivery in clinical trials [42]. Accordingly, manual 
adherence is defined as the presence of at least 70 % of the essential treatment elements. 
Treatment contamination is defined as the presence of at least 10% of the prohibited treatment 
elements. 
Treatment differentiation (i.e. the presence of sufficient differences between the two 
treatments) is considered achieved when more than 90% of the sessions have been correctly 
classified (as EXP or CBT). According to Leeuw and colleagues, each treatment element is 
assigned one of the following categories for each treatment condition: 
(1) essential and specific 
(2) essential but not specific 
(3) compatible but not essential and not unique 
(4) prohibited  

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Elements in category (1) are only allowed in one treatment but not in the other, otherwise the 
treatment may be considered "contaminated".  
Manual compliance is checked at the lead study centre by the study coordinators. 
10.3 Information on the monitoring programme 
Independent Data Safety and Monitoring Board (DSMB): The independent DSMB will monitor 
the progress of the study according to the predefined milestones and make recommendations 
to the study management for stopping, modifying or continuing the study. The principles for 
the DSMB are ethical aspects and safety aspects for the patients. The task of the DSMB is to 
check whether the conduct of the study is still ethically justifiable, whether the safety of the 
patients is guaranteed and whether the conduct of the study is acceptable. To this end, the 
DSMB is regularly informed about compliance with the protocol, patient recruitment and 
observed negative side effects. It consists of a psychologist with practical and scientific 
experience in the field of chronic pain (Dr. Paul Nilges), a medical pain specialist (Prof. Dr. 
Frank Petzke) and a statistician (Prof. Dr. Oliver Christ). The DSMB will be regularly informed 
about all safety aspects of the study and will review the safety data. A meeting or 
teleconference of the board is scheduled every 6 months during the treatment phase.   
Scientific Advisory Board (SAB): The Scientific Advisory Board will provide independent advice 
on scientific, ethical and data protection issues and the dissemination process as appropriate. 
It includes two world-renowned experts on chronic pain and its treatment, Prof. Dr. Steven 
Linton and Prof. Dr. Johan Vlaeyen.   
Clinical expert advisor: Dr. Jeroen de Jong, Maastricht University Hospital, will support the 
exposure treatment arm of the study, e.g. by holding a workshop with Prof. Dr. Julia 
Glombiewski before the start of the recruitment phase, as this is less known and requires more 
expertise in training. 
11. 
ETHICS AND REGULATIONS 
11.1 Declaration of Helsinki and Good Clinical Practice 
The study will be conducted in accordance with the ethical principles and recommendations 
originating in the Declaration of Helsinki and in accordance with the international guidelines on 
"Good Clinical Practice" (ICH-GCP), as applicable. The current version of the Declaration is 
observed in the conduct of the intervention, evaluation and documentation. 
Legal and regulatory requirements are observed, whereby the Medicines Act and the Medical 
Devices Act do not apply. Due to the pilot study, in which we have thoroughly investigated the 
side effects, no increased risks for the participating patients are to be expected. 

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A Data Safety and Monitoring Board (DSMB) will be established to ensure that imbalances 
between the two intervention groups are detected early. We expect benefits to patients and 
the health system, therefore the benefits of the trial will outweigh the costs and potential risks.  
The Clinical Project Manager of each recruitment centre is responsible and ensures that all 
people involved in the study on site are informed about the current study protocol. 
11.2 Ethics committees 
The study protocol is submitted with the required further documents to the responsible lead 
ethics committee of the study director with a request for evaluation. The study can only begin 
after the Ethics Committee has given its approval. 
The Ethics Committees of the participating recruitment centres will receive a copy of the 
positive assessment of the first Ethics Committee and the documents required for granting the 
"second vote" in each case. Each participating trial site will receive copies of the positive 
evaluation of the first Ethics Committee and of its responsible Ethics Committee for the trial 
site folder. 
11.3 Revisions of the study protocol 
The study protocol must be followed. Deviations from the planned examination and treatment 
measures or times must be documented and justified.  
Changes or additions to the study protocol can only be initiated and authorised by the study 
management. The lead ethics committee and the ethics committees of the participating trial 
centres are informed about changes to the study protocol. If necessary, their approval will be 
sought again. Changes requiring evaluation may not be implemented before the decision of 
the ethics committee. 
11.4 Patient insurance 
Accident-route insurance is taken out for all study participants at all centres. 
11.5 Registration 
The study will be registered in the following public register: U.S. NIH ClinicalTrials.gov 
The study coordinator is responsible for the registration in the registry and the maintenance of 
the registry data. 
11.6 Funding 
Funding of the project is provided by the German Research Foundation (DFG). 

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11.7 Final report and publication 
We will communicate the results to the IASP (International Association for the study of pain) 
and its German and European sections as well as to psychological societies such as the 
German Psychological Society. The results will be presented at national and international 
conferences to medical and psychological experts to improve awareness of effective pain 
treatments. We expect interest in the results from the German pension insurance and health 
insurance companies. The treatment manuals, if proven effective, will be offered to the public 
(Open Assess). The results of the study will be reported according to the CONSORT 
statement. Data sharing takes place after publication of the results (OSF repository). 
REFERENCES 
[1] 
Riecke, J., et al., Cross-cultural adaption of the German Quebec Back Pain Disability 
Scale: an exposure-specific measurement for back pain patients. Journal of Pain Research, 
2016. 9: p. 9-15. 
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