A Randomized, Controlled, Parallel-group Clinical Investigation Evaluating the Impact of Digital Cognitive Behavioural Therapy on Psychological Symptom Burden in Adults Diagnosed With Pulmonary Fibrosis
Phase: NA
Conditions: Pulmonary Fibrosis, Anxiety
Sponsor: Vicore Pharma AB

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Clinical Investigation Plan 
 
 
Number: 
VP-dCBT-PF-101 
Title: 
A randomised, controlled, parallel-group clinical investigation 
evaluating the impact of digital cognitive behavioural therapy on 
psychological symptom burden in adults diagnosed with pulmonary 
fibrosis 
Brief Title: 
Controlled investigation to evaluate impact of dCBT in adult subjects 
with PF  
Acronym: 
COMPANION 
Device: 
digital Cognitive Behavioural Therapy in Pulmonary Fibrosis (dCBT-
PF) 
Version: 
5.0 
Sponsor: 
Vicore Pharma AB 
Kronhusgatan 11 
SE-411 05 Gothenburg, Sweden 
 
 
 
 
This document is the property of Sponsor. No unpublished information contained herein may be 
disclosed without prior written approval from Sponsor. 

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Table of Contents 
 
 
Table of Contents ...........................................................................................................................2 
1. 
Summary..........................................................................................................................5 
1.1. 
Synopsis ............................................................................................................................5 
1.2. 
Schema ..............................................................................................................................9 
1.3. 
Schedule of Activities (SoA) ..........................................................................................10 
2. 
Introduction ...................................................................................................................13 
2.1. 
Rationale for Clinical Investigation ................................................................................13 
2.2. 
Background .....................................................................................................................13 
2.3. 
Benefit/Risk Assessment ................................................................................................16 
2.3.1. 
Risk Assessment .............................................................................................................16 
2.3.2. 
Benefit Assessment .........................................................................................................16 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................17 
3. 
Objectives, Endpoints, and Estimands .......................................................................18 
4. 
Investigation Design ......................................................................................................21 
4.1. 
Overall Design ................................................................................................................21 
4.2. 
Scientific Rationale for Design of Clinical Investigation ...............................................21 
4.3. 
End of Clinical Investigation Definition .........................................................................22 
5. 
Investigation Population ..............................................................................................23 
5.1. 
Eligibility criteria for the Part 1, pilot phase ..................................................................23 
5.1.1. 
Inclusion criteria (Part 1, pilot) .......................................................................................23 
5.1.2. 
Exclusion criteria (Part 1, pilot) ......................................................................................23 
5.2. 
Eligibility criteria for the Part 2, pivotal phase ...............................................................24 
5.2.1. 
Inclusion criteria (Part 2, pivotal) ...................................................................................24 
5.2.2. 
Exclusion criteria (Part 2, pivotal) ..................................................................................24 
5.3. 
Lifestyle Considerations .................................................................................................24 
5.4. 
Screen Failures ................................................................................................................25 
5.5. 
Subject reimbursement ...................................................................................................25 
6. 
Investigational Medical Device ....................................................................................26 
6.1. 
Description of Medical Device .......................................................................................26 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................27 
6.3. 
Measures to Minimize Bias: Randomization ..................................................................28 
6.4. 
Investigational Device Compliance ................................................................................28 
6.5. 
Continued Access to the Investigational Device after End of the 
Clinical Investigation ......................................................................................................28 
6.6. 
Prior and Concomitant Therapy ......................................................................................29 
7. 
Discontinuation of Investigational Medical Device and 
Subject Discontinuation/Withdrawal ..........................................................................30 
7.1. 
Discontinuation of Investigational Medical Device treatment .......................................30 
7.1.1. 
Temporary Discontinuation ............................................................................................30 

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7.2. 
Subject Discontinuation/Withdrawal from the Clinical 
Investigation....................................................................................................................30 
7.3. 
Lost to Follow up ............................................................................................................30 
8. 
Clinical Investigation Assessments and Procedures ..................................................32 
8.1. 
Pre-screening and Screening/Baseline Assessments ......................................................32 
8.1.1. 
Pre-screening assessment ................................................................................................32 
8.1.2. 
Screening/Baseline assessments .....................................................................................32 
8.2. 
Efficacy Assessments .....................................................................................................34 
8.2.1. 
General Anxiety Disorder-7 ............................................................................................34 
8.2.2. 
Kings brief interstitial lung disease questionnaire ..........................................................35 
8.2.3. 
37 
8.2.4. 
38 
8.2.5. 
Hamilton anxiety rating scale .........................................................................................40 
8.2.6. 
41 
8.2.7. 
Video interview to evaluate functionality (applicable for pilot 
phase only) ......................................................................................................................42 
8.3. 
Safety Assessments .........................................................................................................42 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ........................................................................................................................42 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................43 
8.4.2. 
Method of Detecting AEs, ADEs SAEs, and SADEs .....................................................43 
8.4.3. 
Follow-up of AEs, ADEs SAEs, and SADEs .................................................................43 
8.4.4. 
Regulatory Reporting Requirements for reportable events ............................................43 
8.5. 
Reporting of Device deficiencies ....................................................................................44 
8.6. 
 ..............................................................44 
9. 
Statistical Considerations .............................................................................................45 
9.1. 
Statistical Hypotheses .....................................................................................................45 
9.1.1. 
Multiplicity Adjustment ..................................................................................................45 
9.2. 
Analysis Sets ...................................................................................................................45 
9.3. 
Statistical Analyses .........................................................................................................45 
9.3.1. 
General Considerations ...................................................................................................45 
9.3.2. 
Primary Endpoint/Estimand Analysis .............................................................................46 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................46 
9.3.4. 
Safety Analyses ...............................................................................................................47 
9.3.5. 
Other Analyses ................................................................................................................47 
9.4. 
Sample Size Re-estimation .............................................................................................48 
9.5. 
Sample Size Determination ............................................................................................48 
10. 
Supporting Documentation and Operational Considerations ..................................49 
10.1. 
Appendix 1: Regulatory, Ethical, and Clinical investigation 
Oversight Considerations ................................................................................................49 
10.1.1. Regulatory and Ethical Considerations ...........................................................................49 
10.1.2. Financial Disclosure........................................................................................................49 
10.1.3. Informed Consent Process ..............................................................................................49 
10.1.4. Data Protection................................................................................................................50 

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10.1.5. Committees Structure......................................................................................................50 
10.1.6. Dissemination of Clinical Investigation Data .................................................................50 
10.1.7. Data Quality Assurance ..................................................................................................50 
10.1.8. Source Documents ..........................................................................................................52 
10.1.9. Clinical Investigation and Site Start and Closure ...........................................................52 
10.1.10. Publication Policy ...........................................................................................................53 
10.2. 
Appendix 2: AEs, ADEs, SAEs and SADEs: Definitions ..............................................54 
10.2.1. Definition of AE .............................................................................................................54 
10.2.2. Definition of ADE (Adverse Device Effect) ..................................................................54 
10.2.3. Definition of SAE (Serious Adverse Event) ...................................................................55 
10.2.4. Definition and categorization of SADEs (Serious Adverse 
Device Effects)................................................................................................................55 
10.2.5. Recording and follow-up on of AE, ADEs, SAEs or SADEs ........................................56 
10.2.6. Device deficiencies .........................................................................................................57 
10.3. 
Appendix 3: Organisation ...............................................................................................58 
10.4. 
Appendix 4: Abbreviations .............................................................................................59 
11. 
Amendment History .....................................................................................................61 
12. 
References ......................................................................................................................67 
13. 
Sponsor and Coordinating Investigator Signatures ..................................................71 
 
 

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Primary Estimand:  
The change from baseline to Week 9 in GAD-7 scores, assessed for the intention-to-treat 
population with treatment as randomised, independent of treatment withdrawal or major 
deviations according to the treatment policy, with withdrawals from the clinical investigation 
prior to Week 9 not possible to follow-up being imputed using multiple imputation including 
their last known assessment. The difference between treatments with 95% confidence intervals 
from analysis of covariance analysis (ANCOVA) adjusting for stratification will be estimated. 
Key Secondary Estimands:  
The change from baseline to Week 9 in each of HAM-A, K-BILD psychological and K-BILD 
total scores, assessed for the intention-to-treat population with treatment as randomised, 
independent of treatment withdrawal or major deviations according to the treatment policy, with 
withdrawals from the clinical investigation prior to Week 9 not possible to follow-up being 
imputed using multiple imputation including their last known assessment. The difference 
between treatments with 95% confidence intervals from ANCOVA adjusting for stratification 
will be estimated. 
Overall Design: 
This investigation consists of two parts;  
• Part 1 is the pilot phase of the clinical investigation with the key purpose of testing the 
functionality of dCBT-PF.  
• Part 2 is the pivotal phase of the clinical investigation with the key purpose of evaluating the 
efficacy of dCBT-PF versus a control on patient-reported psychological symptom burden in 
patients with PF. 
Part 1 – pilot investigation: 
Part 1 is a single-arm, 4-week, open clinical investigation. Part 1 will enroll 10-20 subjects with 
IPF. All subjects will receive dCBT-PF. 
 
 
  
Prior to initiation of part 2, an update to the dCBT-PF will be performed, based on the provided 
feedback during part 1 of the investigation.  
Part 2 – pivotal investigation: 
Part 2 part is a 9-week, randomised, assessor-blind, controlled, parallel-group clinical 
investigation with a 3-week follow-up period evaluating the impact of dCBT-PF on 
psychological symptom burden in adults with PF. Recruitment for Part 2 will continue until end 
July 2023, or when  a maximum of 250 subjects with PF have been enrolled, whatever comes 
first. Subjects will be 1:1 to dCBT-PF or an open-label waitlist control group. Subjects in the 

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control group will receive access to dCBT-PF treatment after the follow-up visit at Week 12 (see 
Section 6.5). 
Randomization will be stratified by anxiety severity based on the GAD-7 score at baseline:  
• Mild:  
5-9 points 
• Moderate:  10-14 points 
• Severe:  
>15 points 
Approximately 400 subjects with PF are expected to be screened to achieve 250 enrolled and 
randomly assigned subjects. 
All assessments will be conducted remotely via telehealth or phone calls i.e., no in-person visits. 
Individual subject participation in the clinical investigation from time of randomisation is 
expected to be approximately 12 weeks. 
The primary endpoint is the change from baseline in anxiety symptom severity assessed by 
GAD-7 at Week 9. The key secondary endpoints are change from baseline in HAM-A, K-BILD 
psychological domain score and K-BILD total score at Week 9. Type 1 errors will be controlled 
using a fixed sequential testing hierarchy. 
1.2. 
Schema 
 
 
Eligibility will be determined at pre-screening (V0) and baseline (V1), and eligible subjects will 
be randomised to either dCBT-PF or a waitlist control group. GAD-7 and K-BILD 
questionnaires will be completed at baseline, every 3rd week during the treatment period and at 
the end of the 3-week follow-up period. 
 
 
 

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2. 
Introduction 
dCBT-PF is a digital cognitive behavioral therapy (dCBT) that has been developed to help 
address the psychological impact of living with PF, specifically symptoms of anxiety.  
2.1. 
Rationale for Clinical Investigation 
PF is comprised of a wide range of serious and debilitating fibrosing ILDs. Up to 60% of patients 
suffering from PF have been shown to experience anxiety, which may significantly impact their 
quality of life (Coelho et al., 2010). Although cognitive behavioral therapy (CBT) is 
recommended as a first-line treatment for anxiety disorder (Powers, 2015), patients with PF may 
face barriers in accessing CBT, including difficulties/risks of travel to hospital, the costs of in-
person therapy and stigma issue.  
dCBT-PF is a dCBT developed to address the psychological impact of living with PF, 
specifically anxiety symptoms. dCBT-PF is available as an app-based treatment and does not 
require visits to a psychologist. 
The main purpose of this investigation is to evaluate the effectiveness of dCBT-PF on patient-
reported psychological symptom burden in adult patients diagnosed with PF. 
2.2. 
Background 
PF and anxiety 
The term interstitial lung disease (ILD) refers to a large and heterogeneous group of parenchymal 
lung disorders (Cottin et al., 2019) characterized by damage to the lung tissue caused by various 
degrees of fibrosis and/or inflammation. The primary site of injury is the interstitium, i.e. the 
space between the alveolar epithelium and the capillary endothelium (American Thoracic & 
European Respiratory, 2002), (European Respiratory, n.d.). There are more than 300 ILDs with 
similar symptoms of breathlessness, usually caused by inhibition of oxygen exchange in the 
alveoli. Approximately 65% of patients are affected by an ILD of unknown cause, which include 
idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonias (IIP), ILDs 
associated with connective tissue disorders such as rheumatoid arthritis (RA), systemic sclerosis 
(SSc) (Kaul et al., 2021; Nili et al., 2022) and sarcoidosis. Known casuses for ILD include 
pneumoconiosis (asbestosis, silicosis), hypersensitivity pneumonitis and post-infectious ILD 
(European Respiratory, n.d.). The distribution of ILDs shows large variation geographically, but 
studies in North America has generally shown IPF and ILD related to connective tissue disorder 
to be the most common ILD subtypes (Kaul et al., 2021). IPF is associated with progressive 
pulmonary fibrosis, but patients diagnosed with other ILDs are also at risk of developing 
progressive pulmonary fibrosis, often with a phenotype not dissimilar to IPF (Cottin et al., 2019). 
Although the underlying disease may in some cases be managed by medication, the development 
of progressive pulmonary fibrosis implies a non-remitting course of disease, associated with an 
increasing risk of morbidity and mortality. 
The prognosis of IPF is poor, with an estimated life expectancy of 3-5 years after diagnosis 
which is shorter than many malignancies (Vancheri et al., 2010). The prognosis for the other 
diseases leading to PF varies, and it is often difficult to predict whether the course of disease will 

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be either stable, slowly declining or rapidly progressing with a poor prognosis (Wang et al., 
2022). 
The age- and sex-adjusted prevalence of fibrosing ILD per 100,000 in the US population has 
been estimated at approximately 117.82, of which 70.30 were assessed to have chronic fibrosing 
ILD with a progressive phenotype (Olson et al., 2021).  
Specifically looking at IPF, there are approximately 3 million people worldwide living with the 
disease. Debilitating symptoms typically appear between the ages of 50 and 70 years and, while 
the disease is most common in men, the number of cases in women is increasing (Olson et al., 
2018). With PF related to connective tissue disorder or sarcoidosis, disease onset is usually 
earlier in life (30-50), and affects women as often as men. 
The knowledge of being diagnosed with a fibrosing ILD, i.e. PF, comes as a shock to many 
patients as there is often no identified cause and patients may feel they lose control of living the 
way they want. They may fear they will no longer be able to fulfill their role in life, whether that 
be as a parent, spouse, or grandparent. In the case of IPF, this is often at a time in life when 
patients are slowing down to enjoy retirement. People with PF learn that daily activities may 
have to change - normal routines like taking walks or travel must be adjusted around the 
debilitating respiratory symptoms of the disease, as well as the use of oxygen tanks and tubes, 
safety measures for protection against COVID-19, and perhaps a persistent and embarrassing 
cough. This has a negative impact on mental health, particularly in patients experiencing a 
noticeable deterioration in physical symptoms. Several studies have reported that symptoms of 
depression and anxiety are common in patients with PF. In various ILD populations, the 
prevalence of anxiety has been reported as 21-60% and no significant association between the 
type of underlying ILD and anxiety was shown (Coelho et al., 2010; Glaspole et al., 2017; 
Holland et al., 2014; Lee et al., 2017). The prevalence of anxiety has been shown to be 
associated with a decreased health-related quality of life (Lee et al., 2017).  
As part of market research, Vicore Pharma has performed a large number of interviews with IPF 
and other PF patients in the US. Interviews have revealed that these patients tend to isolate when 
they have fear of infection or doubts about the safety of an activity. An episode of shortness of 
breath can be experienced as suffocation, leading to a less self-assured state and increased 
isolation, and resulting in a vicious cycle.  
Another piece of the Vicore Pharma market research analysis showed that 102 of 161 patients 
with IPF (63% (Vicore, 2021) and 35 of 56 patients with PF (63%) experienced anxiety as 
defined as a score of 5 or more on the Generalized Anxiety Disorder 7 item scale (GAD-7) 
(Vicore, 2021).  
Despite these profound impacts of the diagnosis on mental health, the usual standard of care for 
IPF in the US does not include referral to a psychologist (Raghu et al., 2015). There is a high 
unmet medical need to appropriately adress these mental aspects, including anxiety, that are 
experienced by patients with PF.  
Rationale for the use of a digital therapeutic in PF  
The dCBT-PF product is a digital cognitive behavioral therapy (dCBT) developed to reduce 
symptoms of anxiety in patients suffering from PF and, thus, address the unmet medical need in 
this specific patient population.  

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The practice of CBT was first developed in the 1960s. CBT is a psychosocial intervention 
focusing on the reworking of a patient’s behaviors and thinking patterns (Driessen & Hollon, 
2010). CBT is a recommended first-line treatment for anxiety disorders according to 
international guidelines (Powers, 2015).  
The dCBT-PF is also incorporating acceptance and commitment therapy (ACT), an empirically 
based psychological intervention based on CBT. ACT focuses to a greater degree on acceptance 
and mindfulness strategies for behavior change (Gloster, 2020). 
ACT is a form of clinical behavioural analysis developed in the 1980’ties (Hayes et al., 2013). A 
meta-analysis showed that ACT is efficacious for all conditions that were examined, including 
anxiety, depression, substance use, pain, and transdiagnostic groups. Results also showed that 
ACT was generally superior to inactive controls (e.g. waitlist, placebo), treatment as usual, and 
most active intervention conditions (Gloster, 2020). 
Digital therapeutics (DTx) are software-as-a-medical-device products. Several DTx products are 
on the market in the US, for patients with depression, anxiety, type 1 and type 2 diabetes, 
substance abuse disorders, chronic pain, irritable bowel syndrome, attention deficit hyperactivity 
disorder, insomnia, and post-traumatic stress disorder. 
Treatment of anxiety is the intended use of several of these software-as-medical-device products. 
Daylight, a CBT DTx product has demonstrated reduced symptoms of anxiety compared with a 
waitlist control (Carl et al., 2020). Ensemble is another example of a CBT-based digital therapy 
for anxiety or depression. Deprexis, a digital CBT for treating mild to severe depression, was 
also recently launched on the market in the US (Zwerenz et al., 2017).  
The potential benefits of using CBT in the management of anxiety in patients with PF has 
recently been highlighted (Wijsenbeek et al., 2019).  
Patients with PF are often susceptible to lung infections and may experience poor clinical 
outcomes after respiratory infections compared to the general population, as has been shown for 
IPF (Naqvi et al., 2021). In other ILDs, e.g. connective tissue associated ILD, treatment with 
immunosuppressive medications may contribute to the risk of infection and negative outcomes 
(Molina-Molina et al., 2022), (Naqvi et al., 2021). Patients with severe PF are often not highly 
mobile and may carry oxygen tanks and are hesitant to have frequent visits to a hospital. This 
combined with an overall lack of access to psychologists, coupled with a pandemic associated 
fear of in-person clinic visits, enhances a need for digital alternatives to traditional CBT in 
patients with PF.  
The dCBT-PF product is developed to reduce symptoms of anxiety in patients diagnosed with PF 
and address the unmet medical need in this specific patient popoulation.  
Initially, the dCBT-PF product was intended for patients with IPF to support the population 
targeted in Vicore Pharma’s ongoing drug development program, but in the months leading up to 
the final product, through patient interviews and discussions with expert pulmonologists, in 
addition to a suggestion by FDA at a pre-submission meeting on March 21, 2022, Vicore Pharma 
and Alex Therapeutics decided to expand the availability of the product to all patients with PF, 
including IPF.   
 

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2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Potential Residual 
Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk  
Mitigation Strategy  
(Control Measure) 
dCBT-PF 
Negative wellbeing / 
distress (ADE or 
ASADE)  
 
Negative wellbeing /distress 
have been observed in patients 
after initiation of CBT 
Eligibility criteria to safeguard 
that population will exclude 
patients at high risk for negative 
impact on wellbeing/distress (i.e., 
patients with a history of hospital 
admissions due to suicidal 
behavior or attempts (self-
reported) or patients with a 
diagnosis of major depressive 
disorder (self-reported) 
Questions will be asked to 
enquire about any potential 
adverse events, and depending on 
the response, the appropriate 
action will be taken to ensure that 
the well-being of the subject is 
safeguarded (including reporting 
and follow-up of any AEs and 
ADEs) 
The dCBT-PF will include 
disclaimers to encourage subjects 
to contact their PCP or National 
suicide hotline, if there is a need 
for professional support 
No other residual risks are anticipated to cause ADEs. 
2.3.2. 
Benefit Assessment 
Studies have reported that symptoms of anxiety are common in patients with PF. Studies have 
indicated the proportion of patients with anxiety in broad ILD populations may be as high as 
60% (Coelho et al., 2010; Glaspole et al., 2017; Holland et al., 2014; Lee et al., 2017) 
CBT is a recommended first-line treatment for anxiety disorders (Powers, 2015). Despite the 
potential benefits of treatment, patients with PF face barriers in accessing CBT, including 
difficulties/risks of travel to hospital. Studies have shown that patients with chronic lung diseases 
including IPF have poor clinical outcomes with COVID-19 disease (Gerayeli et al., 2021; Naqvi 
et al., 2021). As a result of the COVID-19 pandemic, pulmonologists have reported that patients 

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with PF have been less willing to visit hospital clinics or have face to face consultations with a 
psychologist or therapist. A digital solution for treatment of anxiety will make it possible for PF 
patients to receive CBT without any travelling or visits to a hospital clinic or a psychologist.  
Subject’s randomised to active therapy (dCBT-PF) may see an improvement in anxiety and 
quality of life. The CBT based digital therapeutics have long lasting benefits after end of therapy 
(Carl et al., 2020). 
All subjects will receive online consultations with the site staff and will contribute to the 
development of a new therapy specifically developed for PF patients with anxiety. 
2.3.3. 
Overall Benefit Risk Conclusion 
The overall benefit risk balance is considered positive. This is based on the consideration that 
none, or a limited number of, ADEs are expected using dCBT, the virtual nature of the clinical 
investigation and potential benefits in treating anxiety with dCBT. 

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• Change from baseline in QoL assessed by 
Brunnsviken Brief Quality of life scale 
(BBQ) at Week 9 
 
 
Primary Estimand:  
The change from baseline to Week 9 in GAD-7 scores, assessed for the intention-to-treat 
population with treatment as randomised, independent of treatment withdrawal or major 
deviations according to the treatment policy, with withdrawals from the clinical investigation 
prior to Week 9 not possible to follow-up being imputed using multiple imputation including 
their last known assessment. The difference between treatments with 95% confidence intervals 
from ANCOVA adjusting for stratification will be estimated. 
Key Secondary Estimands:  
The change from baseline to Week 9 in each of the HAM-A, K-BILD psychological and K-
BILD total scores, assessed for the intention-to-treat population with treatment as randomised, 
independent of treatment withdrawal or major deviations according to the treatment policy, with 
withdrawals from the clinical investigation prior to Week 9 not possible to follow-up being 
imputed using multiple imputation including their last known assessment. The difference 
between treatments with 95% confidence intervals from ANCOVA adjusting for stratification 
will be estimated. 

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4. 
Investigation Design 
4.1. 
Overall Design 
This investigation consists of two parts;  
Part 1:  
• A pilot investigation with the purpose of testing the functionality of the developed dCBT-PF.  
• This is a single-arm, 4-week, open investigation that will enroll 10-20 subjects with IPF. All 
subjects will receive dCBT-PF. 
Prior to initiation of part 2, an update to the dCBT-PF will be performed, based on the provided 
feedback during part 1. 
Part 2: 
• A pivotal investigation with the purpose of evaluating the efficacy of dCBT-PF versus a 
control group on patient-reported psychological symptom burden in subjects with PF. 
• A 9-week, randomised, assessor-blind, controlled, parallel-group clinical investigation 
evaluating the impact of dCBT-PF on psychological symptom burden in adults with PF. 
Recruitment for Part 2 will continue until end July 2023, or when a maximum of 250 subjects 
with PF have been enrolled, whatever comes first. Subjects will be randomised 1:1 to dCBT-
PF or an open-label control group.  
• Randomization will be stratified by anxiety severity (GAD-7 score 5-9, 10-14 or >15 points) 
at baseline. 
4.2. 
Scientific Rationale for Design of Clinical Investigation 
The proposed clinical investigation design is based on the guidance provided by FDA, EMA and 
the international organization for standardization (ISO) (EU, 2017; FDA, 1996; ISO, 2020) and 
recently conducted DTx clinical investigations utilizing dCBT as a treatment of anxiety or 
depression (Carl et al., 2020; Gu et al., 2020).  
Parts 1 and 2 of the investigation will enroll IPF and PF subjects, respectively, with a GAD-7 
score of ≥ 5, defined as mild to severe anxiety. PF patients, including IPF, are considered to have 
a level of anxiety appropriate for dCBT-PF treatment as it maps to psychological norms of a 
treatable level (Spitzer et al., 2006). Studies suggest that anxiety and depression significantly 
influence quality of life in patients with PF (Lee et al., 2017).  
Part 1 will recruit patients with self-reported IPF. 
Part 2 will recruit patients with self-reported PF, who have radiological findings of PF 
(interstitial changes) on a CT scan report, as confirmed by the PI. Historical CT scans, not older 
than 5 years, are used for this assessment. As most cases of PF are irreversible (Yu & Tang, 
2022), this time span is considered acceptable.  
dCBT-PF is not recommended for patients with active drug or alcohol addiction, history of 
suicidal behaviour, major depressive disorder, manic or psychotic disorders, and these patients 
will thus be excluded from the clinical investigation. 

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The overall aim of part 1 is to collect user feed-back on the functionality of the dCBT-PF from 
IPF patients with anxiety.  
Part 2 will use the GAD-7 questionnaire to assess the primary endpoint. The GAD-7 
questionnaire is considered responsive to evaluate the level of generalized anxiety disorder. The 
GAD-7 questionnaire has been used to assess effect on anxiety symptom severity in recently 
conducted CBT DTx investigations (Carl et al., 2020). 
The planned dCBT-PF treatment duration is 9 weeks with an intended daily use of 10 minutes. 
Traditional CBT conducted via sessions with a psychologist, or a psychotherapist can vary 
considerably in length and duration, with sessions lasting between 30 to 60 minutes and 
treatment containing 5 to 20 sessions (NHS, 2019). The dCBT-PF consist of 7 interventional 
CBT modules (Therapy modules) and 3 non-interventional modules (PF Essentials). A target 
treatment duration of 9 weeks in the pivotal part of the clinical investigation is considered 
justifiable based on both traditional and digital CBT experience.   
To minimize bias, the clinical investigation will have a randomised, assessor-blind, controlled 
design. Subjects will be randomised 1:1 to dCBT-PF or an open-label waitlist control group and 
the randomization will be stratified by self-reported anxiety severity based on GAD-7 score to 
ensure an equal distribution in both groups (active and control).  
Implementation of a placebo-app (sham) would not provide sufficient blinding and was 
considered to create substantial bias in the design of the clinical investigation. A clinician-
reported outcome, HAM-A, assessed by a blinded clinician, is implemented to support the 
primary endpoint. 
The proportion of PF patients with mild to moderate anxiety (scoring 5-14 on a 0-21 scale) may 
be as high as 60% in patients with PF (Coelho et al., 2010; Glaspole et al., 2017; Holland et al., 
2014; Lee et al., 2017). Although live sessions with a psychotherapist providing traditional CBT 
could be effective for PF patients, psychological therapy or other mental health interventions are 
not part of standard of care in patients with PF (Raghu et al., 2015).  
4.3. 
End of Clinical Investigation Definition 
End of clinical investigation is defined as the date of the last visit of the last subject. A subject is 
considered to have completed the clinical investigation if he/she has completed the Week 12 visit 
(follow-up). 

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5. 
Investigation Population 
Part 1 of this clinical investigation will enroll adult subjects with IPF and mild to severe anxiety 
(i.e., a GAD-7 score ≥5). 
Part 2 will enroll adult subjects with PF and mild to severe anxiety (i.e., GAD-7 score ≥5). 
Prospective approval of deviations to recruitment and enrollment criteria, also known as waivers 
or exemptions, is not permitted. 
5.1. 
Eligibility criteria for the Part 1, pilot phase 
Subjects are eligible to be included in the investigation only if the following criteria are fulfilled: 
5.1.1. 
Inclusion criteria (Part 1, pilot) 
1. Age ≥22 years at the time of signing the informed consent 
2. Self-reported IPF diagnosis 
3. A GAD-7 composite score of ≥5 at baseline (Visit 1) 
4. If currently on prescribed medication for depression/anxiety, a stable dose for at least 4 
weeks prior to baseline (Visit 1) 
5. Capable of using a mobile device (compatible with dCBT-IPF) and common applications, 
in the judgement of the investigator or designee, and has an appropriate mobile or tablet 
device 
6. Written informed consent, consistent with Good Clinical Practice and local laws, obtained 
before the initiation of any procedures related to the clinical investigation 
7. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this clinical 
investigation plan (CIP) 
5.1.2. 
Exclusion criteria (Part 1, pilot) 
1. Manic disorders, psychotic disorders, suicidal ideation, schizophrenia, self-harm, or 
alcohol/drug abuse during the past 6 months prior to baseline (Visit 1) as judged by the 
investigator or designee 
2. Cognitive impairment e.g., dementia preventing engagement with dCBT-IPF as judged by 
the investigator or designee 
3. Verbal and/or written communication problems limiting ability to engage with dCBT-IPF as 
judged by the investigator or designee 
4. Inability to comply with investigation procedures, due to severe medical conditions or 
otherwise as judged by the investigator or designee 
5. Life expectancy of less than 6 months as determined by the need for palliative care as 
judged by the investigator or designee 
6. Currently receiving CBT  

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5.2. 
Eligibility criteria for the Part 2, pivotal phase 
Subjects are eligible to be included in the investigation only if the following criteria are fulfilled: 
5.2.1. 
Inclusion criteria (Part 2, pivotal) 
1. Age ≥22 years at the time of signing the informed consent 
2. Self-reported PF diagnosis  
3. A GAD-7 composite score of ≥5 at pre-screening and baseline (Visit 1) 
4. If currently on prescribed medication for depression/anxiety, a stable dose for at least 4 
weeks prior to baseline (Visit 1) 
5. CT (Computed Tomography) within 5 years prior to baseline (Visit 1) with signs of 
pulmonary fibrosis (interstitial changes), as judged by the investigator or designee  
6. Capable of using a mobile device (compatible with dCBT-PF) and common applications, in 
the judgement of the investigator or designee, and has an appropriate mobile or tablet device 
7. Written informed consent, consistent with Good Clinical Practice and local laws, obtained 
before the initiation of any procedures related to the clinical investigation 
8. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this clinical 
investigation plan (CIP) 
5.2.2. 
Exclusion criteria (Part 2, pivotal) 
1. Self-reported manic disorders, psychotic disorders, schizophrenia, or alcohol/drug abuse 
during the past 6 months prior to baseline (Visit 1), as judged by the investigator or designee 
2. Self-reported history of hospital admissions due to suicidal behavior or attempts, as judged 
by the investigator or designee 
3. Self-reported previous or current diagnosis of major depressive disorder, as judged by the 
investigator or designee 
4. Verbal and/or written communication problems limiting ability to engage with dCBT-PF as 
judged by the investigator or designee 
5. Inability to comply with investigation procedures, due to e.g. cognitive impairment or 
severe medical conditions as judged by the investigator or designee 
6. Currently receiving CBT  
7. Participation in the pilot phase of the clinical investigation 
 
5.3. 
Lifestyle Considerations 
There are no lifestyle considerations in the investigation. 

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5.4. 
Screen Failures 
A screen failure occurs when a subject who consents to participating in the clinical investigation 
is not subsequently randomly assigned to dCBT-PF or the control group.  
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure subjects to meet the Consolidated Standards of Reporting Trials publishing requirements. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAEs.  
Re-prescreening/re-screening is allowed for the following screen failure reasons -  
• Inclusion criterion 4: If stable dose is confirmed 
• Inclusion criterion 5: If a CT scan report becomes available 
• Inclusion criterion 6: If the subject obtains an appropriate mobile or tablet device 
• Exclusion criterion 2: Subjects who pre-screen failed due to PHQ-9 question 9 under CIP 
V4.0, and were otherwise eligible, can be re-prescreened. 
• Exclusion criterion 3: Subjects who pre-screen failed due to PHQ-9 composite score 
under CIP V4.0, and were otherwise eligible, can be re-prescreened. 
• Exclusion criterion 6: If no longer receiving CBT 
 
For subjects that will be re-(pre)screened all assessments will be redone. The subject ID under 
which the subject was previously re-(pre)screened will be recorded as part of the clinical 
database. 
 
5.5. 
Subject reimbursement 
For the pilot and pivotal phases, subjects will receive $100.00 and $250.00, respectively, as 
compensation at the completion of their participation in the investigation. 

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6. 
Investigational Medical Device 
The investigational device is the dCBT-PF. dCBT-PF will be used by the subject according to 
the CIP.  
Note - For the pilot phase, the investigational device was referred to as dCBT-IPF, as it was 
initially intended to IPF patients only. In the months leading up to the final product, through 
patient interviews and discussions with expert pulmonologists, in addition to a suggestion by 
FDA at a pre-submission meeting on March 21, 2022, Vicore Pharma and Alex Therapeutics 
decided to expand the availability of the product to patients with PF. This change was 
implemented prior to initiating the pivotal phase and is reflected in the CIP version 4.0. 
Consequently, throughout the CIP the investigational device name is changed to dCBT-PF. 
6.1. 
Description of Medical Device 
In part 1 (pilot investigation) each subject will receive dCBT-PF.    
In part 2 (pivotal investigation) each subject will be randomised to receive treatment with dCBT-
PF or be allocated to the control group.  
The dCBT-PF device is a stand-alone digital CBT intervention, used without clinician 
supervision, delivered as a mobile phone or tablet (Android or iOS) application. 
Subjects will, prior to use, receive instructions on how to download and use the dCBT-PF.  
The dCBT consists of 7 interventional CBT modules (therapy modules) and 3 non-interventional 
modules (IPF essentials). The therapy modules are CBT or ACT-based digital therapy. The IPF 
essentials are educational material related to IPF. The therapy modules take 9 weeks to complete 
if used as intended. An overview of the modules is presented in Table 3. During the intervention 
period, the subjects will be instructed to use the dCBT-PF for approximately 10 minutes per day 
for an estimated time of 4 weeks in the pilot investigation and 9 weeks in the pivotal 
investigation.  
Subjects assigned to dCBT-PF therapy in part 1 (pilot investigation) will use 4 of the modules.  
In part 2 (pivotal investigation) the subjects will complete all modules. This intervention 
corresponds to approximately 14 face-to-face sessions with traditional CBT. The therapy 
modules of the dCBT-PF focus on psychoeducation and introduces concepts and ideas from CBT 
and ACT through text, video, and audio. 
 
The IPF essential modules focus on educational 
aspects for IPF patients. 
Table 3 Therapy modules  
Module 
Content 
1 Intro and 
motivations 
 
 (Barlow, 2014; Harris, 2019; Miller, 2013). 
2. Why am I 
feeling like this? 
Psychoeducation 
 
 
 (Barlow, 2011; Barlow, 2002, 2014; Harris, 

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2019; Howard & Dupont, 2014; Livermore et al., 2015; Miller, 2013; 
Ramnerö, 2008).  
3. Why am I acting 
like I do? 
 
 
 
 
 (Barlow, 2011; Barlow, 2014; Harris, 2019; Ramnerö, 2008)  
4. What’s 
important in my 
life? 
 
 (Barlow, 2011; 
Barlow, 2014; Harris, 2019; Hayes, 2012; Ramnerö, 2008). 
5. Living my life 
fully 
 
 
 
 
(Barlow, 2011; Barlow, 2002, 2014; 
Harris, 2019; Hayes, 2012).(Barlow, 2011; Barlow, 2002, 2014; Harris, 
2019; Hayes, 2012) 
6. Handling 
difficult thoughts 
and feelings 
 
 
 (Harris, 2019; Hayes, 2012). 
7. Sustainable 
change 
 
 
 (Barlow, 2011; Barlow, 2002, 2014). 
Table 4 IPF essentials modules 
1. Living with IPF 
 
 
2. Caring for 
myself 
. 
3. Physical activity 
.  
6.2. 
Preparation, Handling, Storage, and Accountability 
 
Subjects randomised to the dCBT-PF will receive a unique product code. This product code 
gives access to the dCBT-PF. Subjects will download an app and use the dCBT-PF on their own 
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Subjects will receive instructions on how to download the dCBT-PF app from written 
instructions and/or via a virtual onboarding session with the site staff. 
Access to the dCBT-PF will be revoked after the subject has completed the clinical investigation. 
The number of days the dCBT-PF has been accessed, the time spent, and the number of modules 
completed will be logged in the dCBT-PF system and will be transferred to the database for the 
clinical investigation.   
6.3. 
Measures to Minimize Bias: Randomization 
This is a randomised, assessor-blind, controlled, parallel-group, clinical investigation. Subjects, 
care providers, investigators, sponsor, and CRO/vendor staff know if the subject is randomised to 
dCBT-PF or the control group. The control group is implemented to serve as a baseline for 
determining the effectiveness of the intervention. The control group will not receive any 
treatment but will follow the same assessment as the group randomised to dCBT-PF. Subjects in 
the control group will receive access to dCBT-PF treatment after the follow-up visit at Week 12 
(see Section 6.5). 
The clinician assessing rating anxiety based on the HAM-A questionnaire will be blinded to 
treatment to reduce reporter bias.  
Randomization will be stratified by: Anxiety severity (GAD-7 score 5-9, 10-14 or >15 points) at 
baseline to prevent imbalance in anxiety level between the dCBT-PF and control group. 
6.4. 
Investigational Device Compliance 
Subjects randomised to the dCBT-PF will receive access to the dCBT-PF app. Adherence to the 
dCBT-PF will be measured in terms of the number of days the dCBT-PF app is accessed, time 
spent, and the number of modules completed during the treatment period. 
Adherence to the dCBT-PF will be assessed by a weekly compliance report prepared by Alex 
Therapeutics. The reports will indicate the compliance adherence by color coding. If compliance 
is less than expected, the site staff should discuss the reason and educate the subject to comply 
with the investigation. Intervention start and stop dates will also be recorded in the dCBT-PF 
database and will be transferred to the database for the clinical investigation. 
6.5. 
Continued Access to the Investigational Device after End of the 
Clinical Investigation 
Subjects allocated to the control group will receive access to the dCBT-PF when their 
participation in the investigation is completed, i.e., after the end of the 3-week follow-up period.  
Access for the control group will be provided under an Exclusive Release of the product, 
following the FDA medical device enforcement discretion guidelines i.e., outside of the scope of 
this CIP. Obtaining subject consent, as well providing instructions for getting access to the 
dCBT-PF treatment, will be performed under this CIP, to allow for the GAD-7 data, collected 
through the dCBT-PF by Alex Therapeutics, the Legal Manufacturer of the product, to be used 
for quality control purposes and for the patient’s own insight. The data collected will be 
anonymized.  

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6.6. 
Prior and Concomitant Therapy 
Concomitant therapy is defined as any therapy (including over-the-counter, prescription 
medicines, oxygen supplementation, recreational drugs, vitamins, treatment from a psychologist 
or psychiatrist and/or herbal supplements) or other specific categories of interest that the subject 
is receiving or continues at the time of enrollment or receives after start of treatment with the 
dCBT-PF. 
All concomitant therapy taken according to the subject at baseline (Visit 1) should be recorded. 
In addition, relevant prior therapy taken up to 4 weeks prior to baseline (Visit 1) should be 
recorded. Relevant prior therapy is defined as antifibrotic treatment, psychological therapy 
including counseling, antidepressants, or anti-anxiety treatments. Other relevant prior therapy 
can be reported at investigator’s discretion. 
Concomitant therapy and prior therapy must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 

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7. 
Discontinuation of Investigational Medical Device and Subject 
Discontinuation/Withdrawal 
Discontinuation of the clinical investigation is detailed in Appendix 1 (see Section 10.1). 
7.1. 
Discontinuation of Investigational Medical Device treatment  
A subject should be discontinued from the dCBT-PF if, in the opinion of the investigator it is 
medically necessary or if it is the wish of the subject. 
If treatment with dCBT-PF is discontinued, the investigator or designee should make all efforts 
to ensure that the subject will remain in the clinical investigation and ensure that the subject 
attends the remaining visits. 
7.1.1. 
Temporary Discontinuation 
There are no specific criteria for temporary discontinuation of dCBT-PF treatment. If a 
temporary discontinuation is required according to the investigator’s judgement, the stop and 
start date and reason for a temporary discontinuation should be reported in the case report form 
(CRF). If the subject is still within the treatment period of the clinical investigation when a 
temporary discontinuation is no longer required, treatment with the dCBT-PF can be restarted. 
7.2. 
Subject Discontinuation/Withdrawal from the Clinical Investigation 
• A subject may withdraw from the clinical investigation at any time at his/her own request 
i.e., withdrawal of consent. 
• Subjects expressing significant new or worsened negative wellbeing or distress during the 
study will be withdrawn from the clinical investigation (cf. separately IRB approved 
‘Suicide Ideation Process’). 
• The subject will be permanently discontinued from using the dCBT-PF at the time of 
withdrawal from the clinical investigation. 
• If the subject withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
7.3. 
Lost to Follow up 
A subject will be considered lost to follow-up if he/she repeatedly fails to call in for required 
visits and is unable to be contacted by the clinical investigational site. 
The following actions must be taken if a subject fails to call in for a required clinical 
investigation visit or complete the questionnaire: 
• The site must attempt to contact the subject and reschedule the missed assessments as 
soon as possible, counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the 
clinical investigation. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, at least 3 telephone calls 

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plus additional methods such as SMS/email). These contact attempts should be 
documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the clinical investigation. 

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8. 
Clinical Investigation Assessments and Procedures 
• Clinical investigation procedures and their timing are summarized in the SoA. Procedures 
will be performed via telehealth or phone calls. 
• Waivers or exemptions are not allowed. 
• Adherence to the clinical investigation design requirements, including those specified in 
the SoA, is essential and required for conduct of the clinical investigation. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. 
8.1. 
Pre-screening and Screening/Baseline Assessments 
Planned timepoints for all pre-screening and screening/baseline assessments are provided in the 
SoA. 
8.1.1. 
Pre-screening assessment 
Eligibility at pre-screening will be assessed by GAD-7 and patient reported medical information. 
Upon registering at the investigation landing page, subjects will be prompted to complete the 
prescreen GAD-7 questionnaires. Subjects are required to have a GAD-7 composite score of ≥5 
at both pre-screening and baseline to be eligible. If the GAD-7 composite score at pre-screening 
is <5, no further assessments will be performed. 
Subjects will be asked for additional self-reported information relevant to assess eligibility. 
If the subject is confirmed eligible per pre-screening assessments, the consent form for support 
with medical records (CT scan, cf. Section 8.1.3) can be obtained. 
The information collected at the pre-screening assessment is done prior to obtaining informed 
consent, and the data obtained will consequently not be included in the clinical database. It will 
only be used for the purpose of assessing eligibility criteria. 
8.1.2. 
Screening/Baseline assessments 
Subjects confirmed eligible based on the pre-screening assessments will be requested to provide 
a CT scan report confirming their PF diagnosis or provide their physician information in order 
for Curebase to request the report on their behalf. Once received, a video call with the site 
staff/Clinical Research Coordinator (CRC) will take place to obtain consent and conduct the 
baseline visit procedures. The Principal Investigator (PI) will then evaluate eligibility after 
informed consent has been obtained and baseline visit has been completed. 
8.1.2.1. 
Demographics 
Demographic and baseline characteristics will be obtained. The following information will be 
collected:  
• Age 
• Race and ethnicity 
• Sex 

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8.1.2.2. 
Medical History  
All current medical conditions and relevant previous medical conditions should be recorded. 
For the pilot phase, subjects can be included based on self-reported IPF diagnosis. If available, 
medical history information may also be recorded for the pilot phase. 
For the pivotal phase, the following information is required:  
• PF diagnosis confirmation (self-reported) 
• Date of PF diagnosis (self-reported, approximate/incomplete date is accepted if not 
known) 
• CT report (no more than 5 years old). A non-high-resolution CT may be sufficient to 
confirm the diagnosis. Inclusion criteria 5 will always be assessed based on investigator 
judgement and should the CT scan report not be sufficient to confirm the diagnosis, an 
HRCT scan report can be requested to confirm eligibility.  
• Other relevant diseases reported by the subject. 
 
 

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8.2. 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA. 
8.2.1. 
General Anxiety Disorder-7  
Anxiety severity will be assessed by GAD-7 by the subject using an electronic diary on their own 
smartphone, tablet device or computer. 
The GAD-7 questionnaire includes the following questions (paper version displayed): 
 
The response scores of the first 7 questions are added to create a composite score (range 0-21), 
with higher scores indicating a higher level of anxiety.  
Composite scores of ≤4, 5-9, 10-14, and ≥15 represent minimal, mild, moderate, and severe 
anxiety, respectively.  
 
 

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8.2.2. 
Kings brief interstitial lung disease questionnaire 
PF HRQoL will be assessed by K-BILD by the subject using an electronic diary on their own 
smartphone, tablet device or computer. 
The K-BILD questionnaire includes the following questions (paper version displayed): 
 

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Scores will be calculated for each domain (breathlessness and activities, chest symptoms and 
psychological) and for the total questionnaire. The K-BILD domain and total scores ranges are 0-
100; 100 represents the best health status.  
 
 
 
 
 

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8.2.5. 
Hamilton anxiety rating scale 
The HAM-A scale will be used to assess clinician-rated signs and symptoms of anxiety. Ratings 
will be performed by clinician-based interviews with the subject. The clinician will be 
independent to the site staff conducting the investigation and blinded to the subject’s treatment 
assignment. The subject will be instructed not to mention their investigational treatment during 
the interviews. A structured interview guide for the HAM-A scale (SIGH-A; past week recall) 
will be used to complete the assessments. 
HAM-A will be completed no more than 2 days after the subject has completed the patient-
reported questionnaires. The HAM-A will be completed electronically; the paper version is 
displayed below. 
 
 
HAM-A is a 14-item questionnaire rating the intensity of psychic and somatic anxiety on a 5-
point severity scale. Each item ranging from 0 (not present) to 4 (very severe) will be summed up 
to give a total possible score of 0 to 56, where lower scores indicate less anxiety. 

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8.2.7. 
Video interview to evaluate functionality (applicable for pilot phase only) 
In the pilot phase, subjects will be interviewed by delegated Alex Therapeutics staff following a 
separate semi-structured interview guide. Topics can include:  
1. Is the product helpful?  
a. What new learnings have the product provided? 
b. Has the product led to any real change in everyday life? 
c. Has it affected your overall anxiety and mood? 
2. Is the product intuitive?  
a. Was the product able to instinctively understand your mood? 
3. Is the product engaging?  
a. Do people stay for the whole program? 
b. Where do people drop-off? 
c. Where is motivation lacking? 
d. Is there any particular content that is hard to understand and/or bothersome 
4. Is it specific enough to IPF patients?  
a. Do IPF patients recognize themselves in content and examples? 
b. Is there something that is not addressed? 
Video interviews will be transcribed, and outcomes will be summarized in a separate report.  
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (see Section 1.3). 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions and reporting requirements for AEs, ADEs, SAEs, and SADEs can be found in 
Appendix 2 (see Section 10.2). 
AEs will be reported by the subject and will be classified as AEs, ADEs, SAEs, and SADEs 
according to the definitions provided in Section 10.2. ADEs and SADEs can only occur in the 
dCBT-PF group as there are no intervention in the control group. All ADEs, SAEs and SADEs 
should be reported in the CRF. Aes, not fulfilling the definition of an ADE, SAE, and SADE, 
should only be reported if they are related to a psychological disorder or a procedure of the 
clinical investigation. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE, ADE, SAE, or SADE. They further remain 
responsible for following up on AEs, ADEs, SAEs, or SADEs. 

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8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
AEs, ADEs, SAEs and SADEs will be collected from signing of the ICF at baseline (V1) and 
until Week 4 (pilot phase) or Week 12 (pivotal phase), respectively, at the timepoints specified in 
the SoA (see Section 1.3). Aes, ADEs, SAEs and SADEs are followed until they have reached a 
final outcome or the subject’s participation in the clinical investigation ends, whichever comes 
first.  
All SAEs and SADEs will be recorded and reported to the sponsor immediately and under no 
circumstance should this exceed 24 hours after SAE / SADE awareness. The investigator or 
designee will submit any updated SAE/SADE data to the sponsor within 48 hours of it being 
available. For all reportable events, the sponsor will adhere to local reporting timelines. 
Information on relevant AEs, ADEs, SAEs, and SADEs must be entered in the CRF. 
Investigators are not obligated to actively seek information on AEs, ADEs, SAEs, or SADEs 
after conclusion of the clinical investigation participation. However, if the investigator learns of 
any SAE or SADE, including a death, at any time after a subject has been discharged from the 
clinical investigation, and he/she considers the event to be reasonably related to the intervention 
or participation in the clinical investigation, the investigator must promptly notify the sponsor 
regardless of the time that has elapsed (post-clinical investigation events). 
8.4.2. 
Method of Detecting AEs, ADEs SAEs, and SADEs 
Care will be taken not to introduce bias when detecting AEs, ADEs, SAEs, and/or SADEs. 
Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire 
about AE occurrences. 
8.4.3. 
Follow-up of AEs, ADEs SAEs, and SADEs 
After the initial AE/ADE/SAE/SADE report, the investigator is required to proactively follow 
each subject at subsequent visits/contacts. All SAEs and SADEs will be followed until 
resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up (see 
Section 7.3).  
8.4.4. 
Regulatory Reporting Requirements for reportable events 
• Prompt notification – within 24 hours of SAE/SADE awareness – by the investigator to 
the sponsor of a SAE/SADE is essential so that legal obligations and ethical 
responsibilities towards the safety of subjects and the safety of the IMP under clinical 
investigation are met. 
• The sponsor has a legal responsibility to notify relevant regulatory authorities about the 
safety of the intervention under clinical investigation. The sponsor will comply with 
country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, institutional review board (IRB)s, and investigators. 
• An investigator who receives an investigator safety report describing a SAE/SADE or 
other specific safety information (e.g., summary or listing of SAEs/SADEs) from the 
sponsor will review and then file it in the investigator site file and will notify the IRB, if 
appropriate according to local requirements. 

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8.5. 
Reporting of Device deficiencies  
The definition for device deficiencies can be found in Section 10.2.6. Device deficiencies will be 
collected from start of dCBT-PF use and until Week 4 (pilot phase) or Week 9 (pivotal phase). 
Device deficiencies will be reported by the subject or the site.  
Device deficiencies can only occur in the dCBT-PF group. 
Device deficiency that might have led to a serious adverse event if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate must be 
reported to the sponsor within 24 hours of device deficiency awareness. The sponsor will report 
this type of device deficiencies to the regulatory authority, if required, institutional review board 
(IRB)s, and investigators. This will be according to national legislation. 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 

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9. 
Statistical Considerations 
The statistical analysis plan will be finalized prior to enrolling the first subject in the pivotal 
phase of the clinical investigation, and it will include a more technical and detailed description of 
the statistical analyses described in this section. This section is a summary of the planned 
statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
9.1. 
Statistical Hypotheses 
The aim of this clinical investigation is to show superiority of dCBT-PF over a control group 
regarding selected efficacy measures. The null hypothesis to be tested for each endpoint will be 
that there is no difference between dCBT-PF and control, against the alternative hypothesis that 
dCBT-PF is better than control. All tests will be done using 2-sided alternatives. 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
9.2. 
Analysis Sets 
For the purposes of analysis, the following analysis set has been defined: 
Subject Analysis Set 
Description 
Intention to treat (ITT) 
analysis set 
All randomised subjects. Subjects will be included in the analyses 
according to the intervention they were randomised to. 
Safety set 
All enrolled subjects. Subjects will be analyzed according to the 
actual intervention received, dCBT-PF or control. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
All tests will be 2-sided at a 5% significance level. 

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Baseline will be defined as the last non-missing assessment obtained prior to randomization. 
Stratification will be done based on baseline disease severity defined as the total score on the 
GAD-7 questionnaire (GAD-7 score 5-9, 10-14 or ≥15 points) at baseline (Visit 1). 
The actual stratification will be used as factors in the statistical analysis, subjects included in 
wrong stratum at randomization will be moved to their correct strata belonging in the analyses. 
Continuous variables will be summarized using (arithmetic) means, standard deviation (SD), 
median, minimum, and maximum value, categorical variables will be summarized using numbers 
and percentages. 
The ITT analysis set is used for the main analysis of all endpoints related to the efficacy 
objectives. Sensitivity analyses related to efficacy objectives will be described in the SAP. The 
safety analysis set is used to analyze the endpoints and assessments related to safety. 
All data regarding subject characteristics, efficacy and safety will be listed. 
9.3.2. 
Primary Endpoint/Estimand Analysis 
The primary endpoint, change from baseline in patient-reported anxiety symptom severity 
assessed by GAD-7 at Week 9, will be compared between treatment groups using an ANCOVA 
model with treatment and strata (baseline anxiety severity) as factors, the baseline GAD-7 score 
as covariate and the baseline by strata interaction. 
The adjusted mean difference between groups will be given together with 95% confidence 
intervals and associated 2-sided p-value.  
Withdrawals prior to Week 9 not possible to follow-up will be imputed using multiple 
imputation taking subjects baseline characteristics, treatment, and post-treatment GAD-7 scores 
into account. 
The ITT analysis set will be used for the main analysis of the primary endpoint. Sensitivity 
analyses will be performed with alternative methods for imputation (for instance using the 
average of the opposite treatment group as base) and a tipping point analysis will also be 
performed investigating the impact on the treatment effect by successive shifts introduced in the 
imputation for the active group. Sensitivity analysis will be described in the SAP. In all analyses 
subjects will be included as randomised. All collected data post-intervention will be used to 
assess the endpoint. 
9.3.3. 
Secondary Endpoints Analysis 
The ITT analysis set will be used for the main analysis of key secondary and exploratory 
endpoints. Subjects will be included in analyses as randomised. All collected data post-
intervention will be used to assess the endpoints. The key secondary endpoints are: 
• Change from baseline in clinician-reported anxiety symptom severity as assessed by Hamilton 
anxiety rating scale (HAM-A) at Week 9 
• Change from baseline in HRQoL assessed by K-BILD psychological domain score at Week 9 
• Change from baseline in HRQoL assessed by K-BILD total score at Week 9 

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The key secondary endpoints will be tested in a pre-specified hierarchical order following the 
test of the primary endpoint. Other exploratory endpoints will be tested independently without 
adjustment for multiple tests. 
The key secondary endpoints, change from baseline in HAM-A, K-BILD psychological domain 
and total scores at Week 9, will be compared between treatment groups using an ANCOVA 
model with treatment and strata (baseline anxiety severity) as factors and the baseline score as 
covariate. 
Withdrawals from the clinical investigation prior to Week 9 not possible to follow-up will be 
imputed using multiple imputation taking subjects baseline characteristics, treatment, and post-
treatment scores into account. 
Other continuous endpoints assessed at baseline and post-intervention will be compared using 
similar ANCOVA models as for the primary (with interaction; GAD-7 based endpoints) or key 
secondary endpoints (without interaction) with treatment effect expressed as difference in mean 
scores. PGIC scores will be compared using a similar ANOVA model omitting the covariate.  
Endpoints assessing proportion of subjects (binary outcome) will be compared using logistic 
regression models adjusting for treatment and strata (baseline anxiety severity) as factors. 
Categorical endpoints will be summarized by category and compared using the chi2-test. 
9.3.4. 
Safety Analyses 
Safety analysis will be based on the safety set. 
AEs will be analyzed using quantitative and qualitative measures. AEs will be summarized by 
treatment group for all AEs, ADEs, SAEs, SADEs (unanticipated SADE (USADE), or 
anticipated SADE (ASADE)), deaths, AEs leading to discontinuation of dCBT-PF or to 
withdrawal from investigation, and device deficiencies. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class and 
preferred term for each treatment group. ADEs and SADEs only applies to the dCBT-PF therapy 
group. 
9.3.5. 
Other Analyses 
The subject flow including total number of screened subjects, number of randomised subjects, 
completers, withdrawn subjects (including reason for withdrawal) and subjects included in each 
of the analysis sets will be summarized by group and for the total. 
Health care utilisation will be summarized by type of health care utilisation and by treatment 
group. 
The number of subjects with major deviations will be summarized by category of violation and 
by treatment group. 
Adherence to the device will be summarized using descriptive statistics for the subjects 
randomised to dCBT-PF. 
Demographic and baseline characteristics will be summarized using descriptive statistics for 
each treatment group and for the total number of randomised subjects. Medical history will be 
coded using MedDRA and summarized by system organ class and preferred term for each 
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investigational medical device independent and stopped at latest at randomization. Concomitant 
therapy will denote medications started prior to but continuing after randomization or 
medications with a start date at or after the randomization date. Prior and concomitant therapy 
will be summarized separately by Anatomical Therapeutic Chemical levels 2 and 4. 
Subgroup analyses of the primary and key secondary endpoints will be made to assess 
consistency of the intervention effect across at least the following subgroups: 
• Age group: <65 vs ≥65 years 
• Sex: female vs male 
• Baseline disease severity (GAD-7 score at baseline: 5-9, 10-14, ≥15) 
If the number of subjects is too small (less than 10%) within a subgroup, then the subgroup 
categories may be redefined prior to data analysis. Further details on the statistical analysis will 
be provided in a statistical analysis plan. 
Answers to functionality interview of the DTx will be evaluated using qualitative methods and 
will be reported separately. 
9.4. 
Sample Size Re-estimation 
No sample size re-estimation will be made as a result of the data collected in the pilot part of the 
investigation.  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Clinical investigation 
Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This clinical investigation will be conducted in accordance with the CIP and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
international ethical guidelines. 
• Applicable FDA, ISO and GCP guidelines. 
• Applicable laws and regulations. 
The CIP, substantial amendments, ICF and other relevant documents (e.g., subject facing 
material and advertisements) will be submitted to an IRB and reviewed and approved by the IRB 
before the clinical investigation is initiated. 
Any amendments to the CIP will require IRB approval before implementation of changes except 
for changes necessary to eliminate an immediate hazard to subjects. 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the clinical investigation to the IRB 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB. 
o Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures. 
o Providing oversight of the conduct of the clinical investigation at the site and 
adherence to requirements of 21 CFR (part 812), ISO 14155, medical device 
regulation (MDR), the IRB and all other applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the clinical investigation and 
for 1 year after completion of the clinical investigation. 
10.1.3. 
Informed Consent Process 
The investigator or his/her representative will via the telehealth system explain the nature of the 
clinical investigation, including the risks and benefits, to the subject and answer all questions 
regarding the clinical investigation.  
Subjects must be informed that their participation is voluntary. Subjects will be required to sign a 
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14155, MDR, data privacy, and data protection requirements, where applicable, and the IRB or 
site. 
Subjects must be reconsented, as applicable, to the most current version of the ICF(s) during 
their participation in the clinical investigation. 
A copy of the signed ICF(s) must be provided to the subject.  
10.1.4. 
Data Protection 
Subjects will be assigned a unique identifier by the sponsor. Any subject records or datasets that 
are transferred to the sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal clinical investigation-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject who will be required to give consent for their data to be used as 
described in the informed consent. 
The subject must be informed that his/her medical records may be directly examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
10.1.5.1. Data Monitoring Committee 
An independent data monitoring committee (DMC) will be established to provide oversight of 
the pivotal phase of the investigation.  
The functions and responsibilities of the DMC will be described in a DMC charter.  
Throughout the duration of the investigation, the DMC will evaluate all SADEs on an ongoing 
basis. In addition, the DMC will meet at least once during the investigation (timepoint(s) to be 
defined in the charter) to review safety and efficacy data to oversee the safety of the 
investigation, subjects, and the scientific validity and integrity of data collected as part of the 
investigation.  
The DMC will provide appropriate written recommendations to the Sponsor regarding 
investigation continuation and/or investigational plan modifications.  
Any safety related DMC recommendations that may result in investigational plan changes or to 
the management of subjects in the investigation will be reported to the IRB. 
10.1.6. 
Dissemination of Clinical Investigation Data 
Information about the clinical investigation will be posted on the US National Institutes of 
Health’s website www.clinicaltrials.gov prior to the first subject entering the pivotal phase of the 
clinical investigation. 
10.1.7. 
Data Quality Assurance 
All subject data relating to the clinical investigation will be collected at the virtual site in one 
central clinical system. Data will be entered by the subjects in an electronic patient reported 

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outcome (ePRO) system or by the site staff. An overview of the data flow is provided in Figure 
1. 
• The clinical system will have the following functionalities: 
o Pre-screening system 
o Telehealth system  
o eConsent  
o ePRO system 
o Randomisation (IRT) 
o Site assessments EDC system 
o Source documentation  
• Information on use of the dCBT-PF will be collected in the dCBT-PF database and 
will be transferred to the clinical investigation database 
• Medical records (CT report) confirming the PF diagnosis will uploaded in the source 
documentation system (not applicable for the pilot part of the investigation). 
 
Figure 1: Data flow  
  
• The investigator must permit clinical investigation-related monitoring, audits, IRB 
review, and regulatory agency inspections.  
• Monitoring details describing strategy, including definition of critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management 

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and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
• The sponsor or designee is responsible for the data management of this clinical 
investigation, including quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this clinical 
investigation must be retained by the investigator for 10 years after completion of the 
clinical investigation or after the last device is sold, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may 
be transferred to another location or party without written notification to the sponsor. 
10.1.8. 
Source Documents 
• Source documents is in this clinical investigation considered prior medical records, 
including the documentation for the diagnosis of PF (CT report), used to enter relevant 
medical history details (not applicable for the pilot part of the investigation). 
• Majority of the clinical data in this clinical investigation will be entered directly into the 
CRF and no source data verification will be performed.  
• Data reported entered in the site assessment CRF system that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained.  
• Definition of what constitutes source data, and its origin can be found in the monitoring 
plan. 
10.1.9. 
Clinical Investigation and Site Start and Closure 
First Act of Recruitment 
The clinical investigation start date is the date on which the clinical investigation will be open for 
recruitment of subjects. 
The first act of recruitment is the first site open and will be the clinical investigation start date. 
Clinical investigation/Site Termination 
The sponsor or designee reserves the right to close the clinical investigation site or terminate the 
clinical investigation at any time for any reason at the sole discretion of the sponsor. Clinical 
investigation sites will be closed upon clinical investigation completion. A clinical investigation 
site is considered closed when all required documents and have been collected and a clinical 
investigation-site closure visit has been performed. 
The investigator may initiate clinical investigation-site closure at any time, provided there is 
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Reasons for the early closure of a clinical investigation site by the sponsor or investigator may 
include but are not limited to: 
For clinical investigation termination: 
• Discontinuation of further device development. 
For site termination: 
• Failure of the investigator to comply with the CIP, the requirements of the IRB or local 
health authorities, the sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by 
the investigator. 
• Total number of subjects included earlier than expected. 
If the clinical investigation is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IRBs, the regulatory authorities, and any contract research 
organization(s) used in the clinical investigation of the reason for termination or suspension, as 
specified by the applicable regulatory requirements. The investigator shall promptly inform the 
subject and should assure appropriate subject therapy and/or follow-up. 
10.1.10. 
Publication Policy 
• The primary publication should be published by the sponsor prior to any other 
investigator-initiated publications, manuscripts, abstracts, or presentations. 
• The results of this clinical investigation may be published or presented at scientific 
meetings. If this is foreseen, the investigator agrees to submit all manuscripts or abstracts 
to the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
• The sponsor will comply with the requirements for publication of clinical investigation 
results. In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 

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10.3. 
Appendix 3: Organisation 
 
Clinical Research Organization  
 
Curebase Inc.  
340 S. Lemon Ave 3356 
Walnut, CA 91789 
USA 
 
Roles and responsibilities:  
• Project management 
• eClinical software including EDC, eSource, eConsent, ePRO, telehealth and 
randomization systems 
• Digital clinical investigation services including IRB submissions, remote monitoring, 
data management, vendor management, safety event management, data standardization, 
statistical analyses, and eTMF management 
• Clinical site services 
 
Device manufacturer 
 
Alex Therapeutics  
Upplandsgatan 7 
111 23 Stockholm 
Sweden 
 
Roles and responsibilities:  
• Legal dCBT-PF device manufacturer 
• Administration and hosting of dCBT-PF database  
 
 

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10.4. 
Appendix 4: Abbreviations 
ACT 
Acceptance & Commitment Therapy 
AE 
Adverse event 
ADE 
Adverse device effect 
ALAT 
Latin American Thoracic Association 
ANCOVA 
Analysis of covariance analysis 
ASADE 
Anticipated serious adverse device effect 
ATS 
American thoracic society 
 
  
CBT 
Cognitive behavioral therapy 
CIP 
Clinical investigation plan  
CRC 
Clinical Research Coordinator 
CRF 
Case report form 
CT 
Computed Tomography 
dCBT 
Digital cognitive behavioral therapy 
dCBT-IPF 
Digital cognitive behavioural therapy in idiopathic pulmonary 
fibrosis (DTx name applicable for the pilot phase) 
dCBT-PF 
Digital cognitive behavioural therapy in pulmonary fibrosis 
Dtx 
Digital therapeutics 
ePRO 
Electronic patient reported outcomes 
 
 
ERS 
European respiratory society 
FVC 
Forced vital capacity 
GAD-7 
7-item generalized anxiety disorder questionnaire 
GCP 
Good clinical practice 

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HAM-A 
Hamilton anxiety rating scale 
HRCT 
High-Resolution Computed Tomography 
 
 
ICF  
Informed consent form 
IRB 
institutional review board 
IPF  
Idiopathic pulmonary fibrosis 
ISO 
International organization for standardization 
ITT 
Intention to treat 
JRS  
Japanese respiratory society 
K-BILD 
King’s brief interstitial lung disease questionniare 
MDR 
Medical device regulation 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCP 
Primary Care Provider 
 
 
 
 
 
 
PI 
Principal Investigator 
SAE  
Serious adverse event 
SADE 
Serious adverse device effect 
SoA 
Schedule of activities 
SD 
Standard deviation 
USADE 
Unanticipated serious adverse device effect 

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11. 
Amendment History  
Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Description of Change 
Rationale for changes 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Document 
Description of Change 
Rationale for changes Applicable for sections 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Adjustment for the 
assessment for the pivotal 
phase. 
To reflect the above 
listed changes and ensure 
a better operational flow. 
1.2, 8.1, 8.1.1., 8.1.2.2, 8.2.2 

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Text for sample size 
determination updated 
after FDA advise. 
Section
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Document 
Description of 
Change 
Rationale for changes 
Applicable for sections 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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13. 
Sponsor and Coordinating Investigator Signatures  
 
Vicore Pharma 
 
Medical Expert and Sponsor  
Medical Monitor : 
 
 
________________________ 
 
 
Chief Medical Officer,    
 
Signature and date 
 
 
 
 
 
 
 
 
VP, Clinical Development:  
________________________ 
    
 
Signature and date 
 
 
 
 
 
 
 
 
Statistical Expert: 
 
 
________________________ 
 
 
.   
 
Signature and date 
 
 
 
 
 
 
 
 
Coordinating 
Investigator:  
 
 
________________________ 
 
 
,                    Signature and date                       
 
  
,  
  
USA