Randomized Factorial Trial of Internet-Delivered Psychological Treatment for Cancer Survivors With Clinically Significant Psychiatric Symptoms
Phase: NA
Conditions: Cancer Survivors, Anxiety, Depression
Sponsor: Karolinska Institutet

 
 
 
 
 
 
 
 
 
 
 
Study protocol with rudimentary statistical analysis plan 
 
The original study protocol was approved by the Swedish Ethical Review Authority on August 
16th 2023 on the condition that “in the information for the study participants, the identifier for 
the approval of the Swedish Ethical Review Authority shall be reported (id: 2023-04056-01)”. 
 
 
 
 
 
Internet‐Delivered Psychological Treatment for Cancer Survivors (IN-FACT-1) 
 
ClinicalTrials.gov identifier: NCT06046586 
 
 
 
 
 
 

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Study protocol 
 
Towards an evidence-based Internet‐delivered psychological treatment for 
cancer survivors with clinically significant psychiatric symptoms 
 
A randomized factorial pilot study (IN-FACT-0) and trial (IN-FACT-1) 
 
Summary 
Negative psychological effects of cancer are common, but cancer survivors are rarely offered 
psychological treatment. Most existing treatments have modest effects. Internet-delivered 
treatments have shown some promise, but specific treatment components have not been 
empirically evaluated which means that it is not clear which therapies that should be 
prioritized. In this randomized factorial trial at Karolinska Institutet, Stockholm, Sweden, 400 
cancer survivors with psychiatric symptoms are enrolled in variations on a 10-week therapist-
guided online psychological treatment intended to address the negative psychological long-
term effects of cancer. The aim is to determine the contribution of treatment components to 
the overall effect. Key therapeutic targets include anxiety, depression, the fear of cancer 
recurrence, bodily distress, and existential considerations. The outcome is analyzed using a 
fully factorial statistical model. In secondary analyses, cost-effectiveness and possible 
mediating variables are explored. A factorial pilot study (N=48) is first conducted to inform 
details pertaining to the design of the full-scale trial. We expect the full scale trial to illustrate 
what components that should be prioritized for beneficial outcomes in the treatment of long-
term psychological distress in cancer survivors. 
 
Overview of the field (background) 
 
Need to address the negative psychological long-term effects of cancer 
The long-term effects of cancer on quality of life and other psychological outcomes such as 
anxiety and depression are widely believed to be substantial. Approximately one third of 
cancer survivors report long-term distress related to existential themes, and report difficulty 
moving on with life (1). About 22-87% develop a chronic and significant fear of cancer 
recurrence (2), and approximately 25-38% have been estimated to suffer from clinically 
significant health anxiety (3, 4). This results in increased in health care consumption and a 
substantial long-term reduction in quality of life, including in cancer forms such as breast 
cancer, testicular cancer, and differentiated thyroid cancer where the postoperative long-term 
prognosis is relatively good (3, 5). Patients are often reassured that they suffer from a “good” 
cancer (6), without further clinical intervention, despite findings indicating that depression 
and anxiety are predictive of recurrence and mortality (7). Cancer survivors suffering from 
long-term mood disturbance are rarely offered psychological treatment (8). 
 
Potential benefits of incorporating knowledge from health anxiety research 
A 2019 systematic review and meta-analysis (9) found that the typical effects of existing 
treatments for recurrent fear and anxiety in cancer survivors are relatively small (g=0.33 vs 
rudimentary controls) in comparison to the typical effects of broader modern psychological 
treatments for health anxiety (g=0.54-1.08 vs rudimentary controls) (10). Whereas research on 
the fear of cancer recurrence has developed primarily in recent years, the field of psychiatry 
has seen ca 35 years of research on health anxiety in a broader sense, i.e., a multifaceted trait 
characterized by a fear or preoccupation with having or developing serious health condition 
(11-14). This highlights the potential benefits of making use of lessons learned from the 
broader field of health anxiety for interventions more specifically aimed at cancer survivors. 

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Need for stringent evaluations of treatment components 
Most promising psychological interventions for the negative psychological long-term effects 
of cancer are multicomponent protocols that involve several treatment components such as 
behavioral activation, exposure and response prevention, mindfulness exercises, and self- or 
stress management techniques (15, 16). Randomized controlled trials have usually employed 
rudimentary control conditions. Because treatment components have rarely if ever been 
evaluated against each other, it is yet unclear which components that contribute the most to 
beneficial effects of multicomponent therapies, and how components are best combined. 
 
Factorial experiments enable the evaluation of components 
Randomized trials are commonly referred to as “factorial” if participants are assigned more 
than one property (independent variable) (17). That is, rather than to assign each participant to 
one condition (a, b, or c), participants are assigned a combination of conditions (e.g., a, b, c, 
a+b, a+c, b+c, or a+b+c). A key advantage of a factorial experiment is that the contribution of 
several treatment components, and their combinations, to the effect of an overarching, broad, 
multicomponent treatment can be efficiently evaluated in one and the same clinical trial. 
While modelling the contribution of all treatment components and their interactions in the 
same statistical model, the added effect of a specific component to the average treatment 
effect can be estimated by comparing conditions that included the component to conditions 
where the component was not included. The randomized factorial trial maintains the 
advantage of guarding against confounding, and usually includes a null-component attention 
control reference group, which is similar to a conventional randomized controlled trial. 
 
Potential benefits of the online treatment format 
It is increasingly recognized that therapist-guided Internet-delivered treatments can have large 
mean effects that often approximate those of face-to-face treatment (18, 19). Also, therapist-
guided treatments delivered via the web have shown promise specifically for cancer survivors 
(15, 16, 20). Online therapies typically require less therapist time than face-to-face treatment, 
can be delivered regardless of geographical distances, and also do not require patients to work 
with their therapy during any particular time of the day. The structured online format is ideal 
for researching treatment components and mechanisms, considering that educational content 
can easily be standardized and there is little room for unintended deviations from the protocol. 
 
Summary of background 
In summary, a substantial proportion of cancer survivors experience long-term distress in 
terms of anxiety, depressive symptoms, and existential concerns. Still, access to treatment is 
poor. There have been several attempts at developing psychological treatments, but effects 
have usually been modest. There could be much to learn from the broader field of health 
anxiety. There is also a need for the systematic evaluation of treatment components, for 
example using factorial trial designs. Certain promising treatments have been administered 
online with therapist support. The conventional online format offers advantages in terms of 
scalability and a form factor ideal for the evaluation of treatment components. 
 
Aim of the study 
The overarching aim of this trial is to evaluate the unique contribution of common treatment 
components – (a) behavioral activation, (b) systematic exposure with mindfulness training, 
and (c) self-management techniques – to the overall efficacy of online psychological 
treatment for long-term psychological distress in cancer survivors. More specifically, in a 
fully factorial randomized trial, we aim to assess the incremental effect of adding treatment 

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components on the reduction in depression (PHQ-9) and general anxiety (GAD-7) up to the 
post-treatment assessment, as modeled over 11 weekly measurement points (primary 
outcome; see Table 2). Secondary analyses concern cost-effectiveness and possible mediators 
of the treatment effects. Other key secondary outcomes include effects on the fear of cancer 
recurrence, quality of life, adverse events, and participant satisfaction with the treatment. 
 
Hypotheses: 
 The addition of behavioral activation leads to a larger average reduction in depression. 
 The addition of exposure and mindfulness training leads to a larger average reduction 
in anxiety. 
 All combinations of treatment components are rated as credible and will lead to 
adequate satisfaction, with no statistically significant differences in this regard. 
 The optimal combination of treatment components is cost effective compared to the 
attention control null group. 
 The effect of the behavioral activation component is mediated by an increase in 
behavioral activation, the effect of the exposure and mindfulness training component 
is mediated by a reduction in symptom preoccupation, and the effect of the self-
management component is mediated by increased physical activity and self-efficacy. 
 
A factorial pilot study (N=48) mirroring the design of the full-scale trial is first completed to 
develop content and a credible framework. In the pilot study, we aim to assess the feasibility 
of the online treatment in terms of interest in the study, patient-reported credibility of the 
intervention, adherence to the treatment protocol, satisfaction with the treatment, acceptability 
of the measurement strategy, missing data rates, adverse events, and preliminary efficacy on 
anxiety, depression, the fear of recurrence, and health-related quality of life (Table 1). 
 
Table 1. Key aspects of feasibility assessed within this randomized factorial pilot study. 
Specific aim 
Key outcome 
To assess the feasibility of a 
randomized factorial design 
Experience of study administrators and therapists tasked 
with the assignment and delivery of treatment variants. 
To assess the credibility of the 
treatment as perceived by patients. 
The Credibility/Expectancy scale (C/E scale) (21) 
To assess the adherence to the 
treatment protocol. 
Number of completed modules. 
Number of completed exercises. 
To assess the acceptability of the 
online measurement strategy. 
Number of measurements completed. 
Perceived strain caused by the measurement strategy. 
To assess the patient’s satisfaction 
with the treatment. 
The 8-item Client Satisfaction Questionnaire (CSQ-8) (22) 
Free text item with suggestions for improvement. 
Likert items pertaining to satisfaction with components. 
To assess the rate of adverse events 
and negative experiences 
Adverse events questionnaire used in previous clinical 
trials (e.g., ClinicalTrials.gov: NCT04511286) 
The 20-item Negative Events Questionnaire (NEQ-20) (23) 
To assess preliminary efficacy in 
terms of within-group improvement. 
Efficacy outcomes focusing on general anxiety, depressive 
symptoms, the fear of cancer recurrence, and quality of life 
 
 
 

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Methods 
Design 
This is a randomized factorial trial (N=400; 2x2x2 with a cell size of 50; for the pilot study: 
N=48; 2x2x2 with a cell size of 6) of therapist-guided Internet-delivered psychological 
treatment for cancer survivors with long-term clinically significant anxiety or depression 
despite a good prognosis. Study site is Karolinska Institutet, Stockholm, Sweden. The sample 
size allows for two-sided conventional mean tests of small (d≈0.3) component effects (n=200 
vs. 200) with 80% power of, given an alpha of 5% and up to 14% missing data post-treatment. 
The pilot study will have a feasibility focus, though the sample size will also be sufficient to 
study average within-group effects with 80% power in two-sided tests of moderate effects 
(d≈0.45) on efficacy outcomes measured at two time points, given a 5% alpha and up to 20% 
missing data post-treatment. The study protocol will be reviewed by the Swedish Ethical 
Review Authority and preregistered at ClinicalTrials.gov. All procedures will adhere to the 
declaration of Helsinki and the relevant privacy and data management legislation. 
 
Eligibility criteria 
a) Cancer survivor 0.5-20 years after main therapy. For the pilot study: survivor of breast 
cancer (n=24), testicular cancer (n=12), or thyroid cancer (n=12), 
b) Clinically significant anxiety or depression (PHQ-9≥10, or GAD-7≥8) (24, 25) 
c) At least 18 years old 
d) Resident of Sweden (listed and de facto). For the full trial: Stockholms län, Västra 
Götalands län, or Skåne län. 
e) Sufficient technical knowledge and knowledge of the Swedish language to take part in a 
text-based online treatment 
f) Continuous access to an electronic device that can be used to access the study web platform 
g) Not recurrent thoughts of suicide, as based on clinical judgement aided by the structured 
interview (see below) and the MADRS-S item 9 
h) No severe medical condition (e.g., very poor prognosis, stage IV cancer), severe 
psychiatric disorder (e.g., psychotic disorder, bipolar disorder, or severely debilitating 
substance use disorder, severe depression), or medical treatment (e.g., chemotherapy, 
immunotherapy, radiotherapy) that makes the treatment unfeasible  
i) No other ongoing psychological treatment 
j) Either no continuous psychotropic medication, or continuous psychotropic medication 
stable for the past 4 weeks, and expected to remain so during the intended treatment period 
k) Not planned absence for more than one week of the intended treatment period 
l) Complete pre-treatment assessment and subsequently randomized to a condition 
 
 
 

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Figure 1. Study flowchart 
 
 
Procedure 
 
Recruitment 
The study will be advertised via oncology clinics, patient organizations, and social media. We 
also aim to inform the participants in an ongoing cohort study of thyroid cancer who 
previously, as part of that project, indicated that they were interested in psychological 
treatment (2014/714-31, with a separate amendment that will be submitted for this purpose). 
On the secure study web platform, self-referred individuals are presented with written 
information about participation in the study including data management procedures and their 
right to drop out of the study at any point, and how to get in contact with the research group. 
Applicants provide informed consent via a secure web form. This procedure for obtaining 
informed consent is widespread and has been used in several previous online treatment trials 
(e.g., 2014/1530-31/2, 2020-01740, 2021-01400). After having provided informed consent 
applicants complete a screening battery which includes validated online questionnaires (Table 
2) and standard questions about key demographic and clinical characteristics. Applicants who, 
based on their replies, are subject for immediate exclusion based on criterion a, b, c, d, g, or h 
(see above) are informed of this and referred to routine care services by means of a 
standardized e-mail. The remaining applicants are contacted for a brief psychiatric interview 
with a psychologist or physician working under the supervision of the principal investigator. 
This interview establishes eligibility and is based primarily on the Mini-International 
Neuropsychiatric Interview (26) with a separate module for the assessment of pathological 
health anxiety (Open Science Framework identifier: t3yvz). Information from the interview 
and screening battery is also used to describe the final sample in terms of sociodemographic 
and clinical characteristics. 
 
Information via cohort study, patient 
organizations, oncology clinics, social media 
Informed consent and screening battery 
via the secure online study web platform 
Exclusion based on criterion a, b, c, d, g, or h. 
Referred to routine care. 
Eligibility interview with psychiatric screening 
Exclusion based on at least one criterion. 
Referred to routine care. 
Pre-treatment assessment 
Randomized and thereby included 
Post-treatment assessment 
Follow-up assessments 6 + 12 months after treatment 
10 weeks of Internet-delivered treatment 
 
Either with or without behavioral activation 
 
Either with or without exposure / mindfulness 
 
Either with or without self-management strategies 
Weekly measurements 

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Measurements 
Participants complete validated self-report questionnaires at screening, before treatment, each 
week during treatment, after treatment, and 3 months after treatment. These are administered 
online in Swedish (Table 2). In the pilot study, follow-up will take place 3 months after 
treatment (not at 6 or 12 months).  
 
Table 2. Validated self-report questionnaires administered in the study 
Questionnaire 
Outcome 
Ref 
SN 
PRE 
WK 
PST 
6MFU 
12MFU 
 
 
 
 
 
 
 
 
 
Screening and safety only 
 
 
 
 
 
 
 
 
Alcohol Use Disorders 
Identification Test (AUDIT) 
Alcohol use 
(27) 
x 
 
 
 
 
 
Drug Use Disorders 
Identification Test (DUDIT) 
Drug use 
(28) 
x 
 
 
 
 
 
Hospital Anxiety and 
Depression Scale (HADS) 
General distress 
(29) 
x 
 
 
 
 
 
Montgomery-Åsberg 
Depression Rating Scale item 9  
Suicidal 
ideationa 
(30) 
x 
x 
x 
x 
 
 
Symptom domains and similar 
 
 
 
 
 
 
 
 
36-Item Short Form Health 
Survey (SF-36) 
Health-related 
quality of life 
(31) 
 
x 
 
x 
 
 
7-item general anxiety 
questionnaire (GAD-7) 
General anxiety 
(32) 
x 
xb 
xb 
xb 
xb 
xb 
9-item Patient Health 
Questionnaire (PHQ-9) 
Depression 
symptoms 
(33) 
x 
xb 
xb 
xb 
xb 
xb 
9-item Fear of Cancer 
Recurrence Inventory (FCRI-9) 
Fear of cancer 
recurrence 
(34) 
 
x 
x 
x 
x 
x 
14-item Health Anxiety 
Inventory (HAI-14) 
Health anxiety 
(11) 
 
x 
 
x 
x 
x 
Somatic Symptom Scale 8 
(SSS-8) 
Somatic 
symptom 
burden 
(35) 
 
x 
 
x 
x 
x 
Body Image Scale (BIS) 
Body image 
(36) 
x 
 
 
x 
 
 
12-item WHO Disability 
Assessment Schedule 2.0 
(WD2-12) 
Disability 
(37) 
x 
x 
 
x 
x 
x 
Process and target variables 
 
 
 
 
 
 
 
 
3-item Behavioral Activation 
for Depression Scale – 
Activation (BADS-AC-3) 
Behavioral 
activation 
(38) 
 
x 
x 
x 
x 
x 
Symptom preoccupation scale 
(SYMPS) 
Symptom 
preoccupation 
Not yet 
published 
 
x 
x 
x 
x 
x 
Godin-Shephard Leisure-Time 
Physical Activity Questionnaire 
(GSLTPAQ) 
Physical activity 
(39) 
 
x 
x 
x 
x 
x 
Adapted self-efficacy scale 
Self-efficacy 
(40) 
 
x 
x 
x 
x 
x 
Credibility/Expectancy scale 
(C/E scale) 
Credibility and 
expectancy 
(21) 
 
 
w. 2 
 
 
 
Working Alliance Inventory 
(WAI) 
Relationship 
with the 
therapist 
(41) 
 
 
w. 2 
 
 
 
Explicit evaluation of therapy 
 
 
 
 
 
 
 
 
8-item Client satisfaction 
questionnaire (CSQ-8) 
Satisfaction 
with treamtent 
(22) 
 
 
 
x 
 
 
20-item Negative Effects 
Questionnaire (NEQ-20) 
Negative effects 
of treamtent 
(23) 
 
 
 
x 
 
 
Cost-effectiveness outcomes 
 
 
 
 
 
 
 
 
EuroQol 5D (EQ5D) 
Utility score 
(42) 
 
x 
 
x 
x 
x 
Trimbos questionnaire (TIC-P) 
Resource use 
(43) 
 
x 
 
x 
x 
x 
SN = screening, PRE = pre-treatment, WK = weekly, PST = post-treatment, 6/12MFU = 6/12-months follow-up 
a) Patients with heightened scores are assessed by a clinician, and referred to routine care services if necessary 
b) For the weekly (non-screening) measurements, rephrased to concern the past week. 

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Treatment conditions 
General format of Internet-delivered treatment 
Therapist-guided online treatment is delivered over 10 weeks, which is proven format (18) 
recommended for cancer survivors (20). The patient regularly logs in to the encrypted web 
platform (“BASS”, as provided via the Karolinska Institutet eHealth core facility). Most of the 
treatment content is conveyed via an illustrated text divided into modules, equivalent of book 
chapters. Each modules contains an educational text, homework assignments, and questions 
for reflection. Participants communicate with their therapist via a system reminiscent of 
email, and receive a reply within about two weekdays. Homework exercises are tailored to the 
individual needs of the patient. In total, eight modules are completed at a pace of about one 
module per week. Participants gain access to new models contingent on progress. Therapists 
receive continuous supervision from the principal investigator. 
 
Open access publication of treatment content 
In order to promote transparency and contribute to the research field as well as clinical 
practice, the treatment content from this pilot study will be transferred to the public domain 
and published open access online, tentatively via the Open Science Framework (OSF). 
 
Randomized allocation of treatment components 
The following randomization procedure will be piloted: Each cohort size is a multiplier of the 
number of unique combinations of treatment components (i.e., 8). After completion of the 
pre-treatment assessment, and separately for each cohort, randomization is achieved using a 
true random number service (www.random.org), managed by an individual otherwise not 
involved in the trial. Tentatively, based on the outcome of the 2023 pilot trial and feasibility 
outcomes, interventions will be built using the following components derived from existing 
protocols: (a) behavioral activation with existential themes and emphasis on values (44, 45) 
and relationships, (b) systematic exposure with mindfulness training with a focus on anxiety 
about health and/or death (46), body image, and cancer-related trauma, and (c) an overview of 
self-management techniques in terms of physical exercise, dietary advice, and strategies for 
improved sleep. Fifty patients are randomized to each combination of treatment components: 
a, b, c, a+b, a+c, b+c, a+b+c, and also a null group where support and rudimentary clinical 
information is given to control for the effect of attention from a clinician and enrollment in 
the structured online format, resulting in the total sample size of 400. The point of 
administering all these combinations is to make it possible to model the simple effect (added 
contribution) of each component to the treatment effect, and also all component interactions. 
After the follow-up phase (see below), for ethical reasons, controls are crossed over to the 
a+b+c combination though without therapist support. To the extent that this is found feasible 
in the pilot study, the treatment content for all combinations of components will be developed 
with similar readability (47), interactivity, and picture content. Importantly, even in the null 
group attention control, the treatment will involve support from a clinician, information about 
the negative long-term effects of cancer and will offer participants the possibility of observing 
their own symptoms in a systematic manner. 
 
Partial blinding of study design 
In order for the analysis of treatment components to be valid and helpful in the design of 
future therapies, it is important that the participants remain blinded to the randomized 
factorial design throughout the full measurement period. (Full blinding, i.e., where the patient 
and therapist remain unaware of the treatment condition, is not possible in psychological 
treatment research (48).)  Regardless of condition, participants will be informed that they take 

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part in an Internet-delivered support program for improved mood in the aftermath of cancer. 
At the 12-months follow-up (3 months in the pilot study), a written blinding check will then 
be conducted whereby participants are asked about whether they are aware of which treatment 
variants that are being compared and why. Participants will then be unblinded (debriefed) and 
those in the attention control (see above) will be offered the full material from the full factor 
version of the treatment. 
 
Secondary outcome: registry data on healthcare consumption 
If funding is secured for this secondary outcome, registry data on health care consumption 
will also be collected, pertaining to the 2 years immediately before treatment, and the 2 years 
immediately following treatment. To ensure access to health consumption data, patients will 
be recruited exclusively from Stockholms län, Västra Götalands län, and Skåne län for the full 
trial. This will not be implemented in the pilot study. 
 
Data safety and management 
Throughout the project, data management plans and documentation will be maintained and 
revised in accordance with up-to-date guidelines of Karolinska Institutet. The study web 
platform will employ encrypted traffic and two-factor authentication. Researchers in the 
project have access to study data, which is stored and managed in accordance with European 
Union and Swedish data protection and privacy legislation, and the guidelines of Karolinska 
Institutet. Personal data are exclusively stored in systems classified and provided specifically 
for this purpose by Karolinska Institutet. Study results are reported in a manner that does not 
make it possible to identify individual participants. 
 
Statistical analysis 
The main pre-post efficacy outcomes will be analysed by an individual blinded to treatment 
identity (each component is coded simply as -0.5 vs. 0.5 without labels in the dataset). 
Hierarchical multiple imputation by chained equations will be employed to manage missing 
data, and imputation will be conducted separately for each cell so as to maintain interaction 
effects (49). Efficacy outcomes are analysed using fully factorial linear mixed models, so that 
the simple effects of the components, and also their interactions, can be quantified and tested. 
Health economic analyses will focus on comparing the most potent treatment configuration 
(cells are collapsed if no component shows superiority) to the null group (i.e., rudimentary 
information and support from a clinician only). Mediation analysis will be conducted within a 
structural equation modelling framework, based on parallel process growth models. The pilot 
study will not focus on inferential statistics, but rather the feasibility outcomes (see Table 1). 
 
Ethical considerations 
This randomized factorial trial and the pilot study are conducted in accordance with the 
declaration of Helsinki, current Swedish and European Union privacy and data management 
legislation, and internal guidelines of Karolinska Institutet. The project will be preregistered 
online, and results including the treatment content will be published open access so as to 
ensure transparency and that findings benefit the research field. Applicants will be required to 
provide informed consent in order to be included as participants.  
 
Psychological treatments can induce unwanted effects for example in terms of deterioration or 
an increase in symptoms, disappointment with the quality of treatment, dependency on the 
therapist, stigma associated with enrollment, hopelessness as a consequence of insufficient 
efficacy, or a sense of failure or reduced self-efficacy (50). Based on the existing evidence 
base, the negative effects of therapist-guided Internet-delivered psychological treatments 

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similar to that evaluated here are typically limited (51, 52). In contrast, the beneficial effects 
for example on anxiety are more likely to be at least moderately sized on average. Adverse 
events and participants mood is tightly monitored throughout the intervention. Heightened 
suicidal ideation is automatically flagged and cause for clinical assessment. Participants are 
referred to routine services if necessary. 
 
Personal data including sensitive information about health outcomes, cognitions, and mood 
will be collected, stored, managed as part of the study. This imposes requirements on the 
online treatment format. Applicants and participants are given a personal account to the study 
web platform, access to which requires two-factor authentication. Traffic with the study web 
platform is encrypted. Data are stored on servers classed as secure and suitable for personal 
data by Karolinska Institutet. 
 
Another ethical dilemma relevant to most randomized clinical trial is that of fairness. There is 
reason to suspect that not all variations on the treatment evaluated in this study will eventually 
be found to have equal effects. This said, knowledge about which combinations that will do 
best is so far lacking. This important research question will be addressed by the study, and 
findings can benefit a large number of patients in the population at large. In summary, we 
consider the potential scientific value of the trial combined with the potential gains for 
individual participants to clearly outweigh the expected harms associated with participation. 
 
Research group and previous experience 
The research group has experience of several clinical trials of psychological interventions 
delivered via the Internet, and are well familiar with the patient group and key psychological 
outcomes. The principal investigator, Erland Axelsson, lic. psychologist, PhD, Liljeholmen 
Primary Care Center and Karolinska Institutet has published extensively in the field of 
eHealth and health anxiety in the past 10 years, and has been involved in 14 randomized 
controlled trials of psychological treatment, focusing primarily on distress related to somatic 
symptoms, functional somatic syndromes, chronic stress, anxiety and depression. He has 
certification in good clinical practice (GCP), has led the largest published direct comparison 
of Internet-delivered and face-to-face treatment for any psychiatric condition (52), and has 
experience in evaluating interventions, supervising clinicians, developing research methods, 
and overseeing the management of clinical trials.  
 
The pilot study for this trial will be conducted within the context of the PhD studies of Julia 
Winter, physician (Karolinska Institutet), who will play an active role in the development of 
procedures, in recruitment, and in treatment, under the supervision of CH (main supervisor), 
EA, and LBB. Nils Gasslander, lic. psychologist (Uppsala university), expected to defend his 
thesis around the summer of 2023 will also make substantial contributions to the development 
of procedures, to recruitment and to treatment. Nils has previous experience of online therapy 
for chronic health conditions, and the design and management of randomized clinical trials. 
 
Christel Hedman, lic. physician and PhD at the Department of Molecular Medicine and 
Surgery, KI, and affiliated with research at Karolinska university hospital Solna has extensive 
experience of research on psychological outcomes in cancer survivors with particular 
emphasis on patient’s long-term health-related quality of life in differentiated thyroid cancer. 
 
Linda Björkhem-Bergman, lic. physician and PhD, has extensive experience of palliative care 
and chronic cancer forms, and is an expert in fatigue: one of the most common long-term 

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somatic symptoms in long-term cancer survivors (53). She also has experience of working 
with randomized clinical trials, and developing guidelines for the management of distress. 
 
In summary, the collaboration between EA, CH, and LBB (plus MSc JW, and MSc NG) 
ensures that several perspectives on psychological distress in cancer survivors are represented 
in the research group. EA will lead the project, and continuous meetings will involve all 
researchers. Results will be communicated in open access peer-reviewed journal articles. EA 
also has a broad informal national network in psychotherapy research that will be used to 
spread knowledge about the treatment content and findings of this randomized factorial trial. 
 
Time schedule as of February 2023 
Preparatory work in terms of writing protocols, producing content, and submitting the work 
for ethical review will take place in May-September 2023. We plan to involve patient 
representatives in the treatment drafting process. Hands-on procedures are first evaluated, and 
recruitment is initiated, in September 2023. Recruitment for the pilot trial is complete around 
the end of 2023. The finalization of all routines for the full-scale trial, including the 
recruitment of additional psychologists interested in contributing to the project by serving as 
therapists in exchange for co-authorship, will be completed during the January-June period. 
Recruitment of participants for the full-scale randomized factorial trial will begin in August 
2024. From then on, approximately 80 participants will be recruited each semester until the 
end of 2026. We expect the last 12-month follow-up assessment to be completed in December 
2027. Manuscripts will be submitted for publication throughout 2028 to 2030. 
 
Significance 
This project can lead to substantial societal gains. The population of cancer survivors who 
experience long-term distress is substantial, and access to structured treatment is insufficient. 
Internet-delivered psychological treatment is relatively easy to scale up and disseminate, for 
example in the primary care context, and the development of a free-to-use treatment protocol 
based on rigorous evaluation in clinical trials could potentially have pervasive effects on 
suffering and health care utilization. Though the project will proceed in accordance with this 
research plan, the outcome of the pilot study can also inform the precise design of the full-
sized clinical trial and sufficient amendments will be submitted for ethical review as deemed 
necessary. Experiences from the randomized factorial trial can inform clinical practice in that 
we will arrive at an evidence-based Internet‐delivered psychological treatment for cancer 
survivors with clinically significant psychiatric symptoms. 
 
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