Researching the Effectiveness of a Alivis, a Digital Health Application for Borderline Personality Disorder: a Randomized Controlled Trial
Phase: NA
Conditions: Borderline Personality Disorder (BPD)
Sponsor: Gaia AG

 
Clinical investigation plan 
CIP; following ISO 14155:2020 
 
Researching the EffectiVeness of a ALivis, a DIgital health application 
for Borderline Personality Disorder: a randomized controlled trial 
(REVALDI-BPD) 
28.03.2025 
version 5 
 
 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
Table of Contents 
1. General​
6 
1.1 Identification of the clinical investigation plan​
6 
a) Title​
6 
b) Reference number​
6 
c) Version / Date​
6 
d) Summary of the revision history​
6 
e) Version/issue number and reference number​
6 
f) Abbreviations​
7 
1.2 Sponsor​
8 
1.3 Principal investigator, coordinating investigator and investigation site​
8 
a) Name, address, contact details and professional position​
8 
1) principal investigator​
8 
2) coordinating investigator​
8 
b) Name and address of the investigation site​
8 
c) Name and address of external organizations​
8 
1.4 Overall synopsis of the clinical investigation​
9 
1.5 Introduction​
9 
2. Identification and description of the investigational device​
10 
a) Summary description​
10 
b) Manufacturer​
10 
c) Name/number of the model/type, software version and accessories​
10 
d) Description of traceability during and after the clinical investigation​
10 
e) Intended purpose​
10 
f) Populations and indications​
11 
g) Description of the investigational device​
11 
h) Necessary training and experience needed to use the investigational device​
12 
i) Medical or surgical procedures involved in the use of the investigational device​
12 
j) References to the Investigator’s brochure (IB) and IFU.​
13 
3. Justification for the design of the clinical investigation​
13 
a) evaluation of pre-clinical testing/assessment and prior clinical investigations​
13 
b) Clinical data relevant to the proposed clinical investigation​
13 
c) Clinical development stage​
13 
4. Benefits and risks​
13 
a) Anticipated clinical benefits​
13 
b) Anticipated adverse device effects​
14 
c) Risks associated with participation in the clinical investigation​
14 
d) Possible interactions with concomitant medical treatments​
14 
e) Control or mitigation of risks.​
14 
f) Rationale for benefit-risk ratio​
14 
g) Medical justifiability​
14 
5. Objectives and hypotheses​
15 
a) Purpose, claims, effectiveness, safety​
15 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
b) Objectives​
15 
c) Scientific justification and clinical relevance​
15 
d) Primary and secondary hypotheses​
15 
e) Risks and anticipated adverse device effects​
16 
6. Design​
17 
6.1 General​
17 
a) Description of the design type of clinical investigation to be performed​
19 
b) Measures against bias​
20 
c) Primary and secondary endpoints​
20 
d) Methods and timing​
23 
﻿e) Equipment for assessing the clinical investigation variables​
26 
f) Replacement of subjects​
26 
g) Investigation sites​
26 
h) Completion of the clinical investigation​
26 
6.2 Investigational device and comparator​
27 
a) Exposure to the investigational device or comparator​
27 
b) Other medical devices or medication​
27 
c) Number of investigational devices​
27 
6.3 Subjects​
28 
a) Inclusion criteria​
28 
b) Exclusion criteria​
28 
c) Criteria and procedures for subject withdrawal or lost to follow-up​
28 
1) Withdrawal of a subject or stop of use​
28 
2) Tracing of subjects lost to follow-up​
28 
3) Replacement of subjects​
28 
d) Point of enrolment​
28 
e) Point of randomization​
29 
f) Total expected duration​
29 
g) Expected duration for each subject​
29 
h) Number of subjects​
29 
i) Enrolment period​
29 
j) Relationship of investigation population to target population​
29 
k) Vulnerable, pregnant, and breastfeeding population​
29 
6.4 Procedures​
29 
a) Procedures during the clinical investigation​
29 
b) Activities performed by sponsor representatives​
30 
c) Factors compromising outcome or interpretation of results​
30 
d) Methods for addressing these factors​
30 
e) Follow-up period for clinical performance, effectiveness or safety​
30 
f) Specific medical care provided following the clinical investigation​
30 
g) Recommended follow-up for the subjects​
31 
h) Final disposition or potential future use of samples obtained from subjects​
31 
6.5 Monitoring plan​
31 
7. Statistical design and analysis​
32 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
a) Analysis population​
32 
b) Descriptive statistics of baseline data, treatments, safety data​
32 
c) Analytical procedures and measures of precision​
32 
d) Significance level and power​
33 
e) Sample size​
33 
1) Clinical data on outcome variable and effect size​
33 
2) Expected outcomes across treatment groups​
33 
3) Adjustments due to pre-planned interim analyses​
33 
4) Effect size and non-inferiority margin​
33 
5) Randomization allocation ratio​
33 
6) Expected drop-out rate​
33 
f) Procedures to be performed by user and analysis​
34 
g) Pass/fail criteria​
34 
h) Interim analysis and criteria for termination​
34 
i) Management of bias​
34 
j) Management of potential confounding factors​
34 
k) Multiplicity control and adjustment of error probabilities​
34 
l) Subgroups for analysis​
34 
m) Missing, unused or spurious data, including drop-outs​
35 
n) Exploratory analysis and sensitivity analysis​
35 
p) Handling potential imbalance of numbers of subjects across investigation sites​ 35 
q) strategy for pooling data​
35 
r) estimand strategy​
35 
8. Data management​
36 
a) Methods for data entry and collection​
36 
b) CRF tracking, data review, database cleaning, and issuing/resolving data queries​
36 
c) Verification, validation, and securing of electronic clinical data systems​
36 
d) Subject privacy​
36 
e) Database locking and storage​
36 
﻿f) Data retention​
36 
g) Retention period​
37 
h) Other aspects of clinical quality assurance​
37 
9. Amendments to the CIP​
37 
10. Deviations from clinical investigation plan​
37 
a) Statement - deviation from the CIP​
37 
b) Recording, reporting, and analysing CIP deviations​
37 
c) Notification requirements and time frames​
37 
d) Corrective/preventive actions and principal investigator disqualification criteria​
37 
11. Device accountability​
38 
a) Accountability of investigational devices​
38 
b) Safe return of potentially hazardous investigational devices​
38 
12. Statements of compliance​
38 
a) Statement - Declaration of Helsinki​
38 
 
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b) Statement - compliance with ISO 14155:2020 and any regional or national 
regulations​
38 
c) Statement - required approval/favourable opinion from the EC/regulatory authority​
38 
d) Statement - requirements imposed by the EC or regulatory authority​
38 
e) Statement - insurance for subjects​
38 
f) Statement - financing/agreement between sponsor and investigation 
site(s)/investigator(s)​
38 
13. Informed consent process​
39 
a) Informed consent and incentives​
39 
b) Informed consent process - subject unable/emergency treatment​
39 
14. Adverse events, adverse device effects and device deficiencies​
39 
a) Definitions of adverse events and adverse device effects​
39 
b) Definition of device deficiencies​
40 
c) Definitions of serious adverse events and serious adverse device effects​
40 
d) Non-reportable adverse events​
40 
e) Report period of adverse events and device deficiencies​
40 
f) Process for reporting adverse events​
41 
g) Process for reporting device deficiencies​
41 
h) Adverse events, adverse device effects and incidence, mitigation, or treatment​ 41 
i) Emergency contact details for serious adverse events/device effects.​
41 
j) Information regarding the DMC​
42 
15. Vulnerable population​
42 
16. Suspension or premature termination of the investigation​
42 
a) Criteria and arrangements​
42 
b) Criteria for access to and breaking the blinding/masking code​
42 
c) Subject follow-up and continued care​
42 
17. Publication policy​
42 
a) Statement - trial registration​
42 
b) Statement - publicly available results​
42 
c) Statement - conditions/timeframes for publication​
42 
18. Bibliography​
43 
19. Signatures​
47 
 
 
 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
Figure 1| Flow Chart of Trial Design​ ​
​
​
​
​
​
​
  19 
 
Table 1| Chronological Sequence of the Trial​
26 
 
 
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1. General 
1.1 Identification of the clinical investigation plan 
a) Title 
Researching the effectiveness of alivis, a digital health application for Borderline 
Personality Disorder: a randomized controlled trial (REVALDI-BPD) 
b) Reference number 
​This trial will be registered in an international trial registry before the start of 
recruitment. 
c) Version / Date 
​
version 5 / 28.03.2025 
d) Summary of the revision history 
​version 2 (14.08.2023): changes in endpoints, control condition, in- and exclusion 
criteria, and associated procedures. Video instead of telephone interviews. Moreover, 
the description of the program was updated to reflect more clearly which therapeutic 
strategies are used. All changes are marked in yellow.  
version 3 (18.01.2024): change of PI. Telephone instead of video interviews. Details 
on monitoring have been added in section 6.5. All changes are marked in green. 
version 4 (18.07.2024): removal of BPD-CL als secondary endpoint; further 
information on alivis and the development process; updated formulation of primary 
and secondary hypotheses; changes control group from TAU + information material 
to TAU only; further information on the emergency plan for suicidal crises; change of 
responder criteria; updated exclusion criteria; added subgroup analyses; added 
information on the estimand strategy; updated information on funding. All changes 
are marked in pink.  
version 5 (28.03.2025): updated exclusion criterion from “Plans to change treatment 
in the upcoming 6 months after inclusion” to “Plans to change treatment in the 
upcoming 3 months after inclusion”. All changes are marked in orange. 
e) Version/issue number and reference number 
​
version 5 
 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
f) Abbreviations 
​
ACT​
​
​
Acceptance and Commitment Therapy 
​
ANCOVA​
​
Analysis of Covariance 
​
AQoL-8D​
​
Assessment of Quality of Life - 8 Dimensions 
BPD​
​
​
Borderline Personality Disorder  
BSL-23​
​
Borderline Symptoms List-23 
ClinROM​
​
Clinician-reported outcome measure 
DBT​
​
​
Dialectical Behavioral Therapy 
DiGA ​ ​
​
Digital health application 
DSM-V​​
​
Diagnostic and Statistical Manual of Mental Disorders 
GAD-7​​
​
Generalized Anxiety Disorder Assessment 
GDPR​ ​
​
General Data Protection Regulation 
ICMJE​​
​
International Committee of Medical Journal Editors 
ITT​
​
​
intention to treat 
MCID​ ​
​
minimal clinically important difference 
NPS ​ ​
​
Net Promoter Score 
PHQ-9​​
​
Patient Health Questionnaire 
PP​
​
​
per protocol 
PROM​​
​
Patient-reported outcome measure 
PRRC​ ​
​
Person Responsible for Regulatory Compliance 
QMS​ ​
​
Quality Management System 
RCT​
​
​
randomized controlled trial 
SCID-5-PD ​
​
Structured Clinical Interview for DSM-5​
 
ST​
​
​
Schema Therapy 
T0​
​
​
Baseline  
T1 ​
​primary timepoint for analysis of effectiveness; 3 months post 
allocation 
T2​
​
​
6 months post allocation 
T3​
​
​
12 months post allocation 
TAU​
​
​
Treatment as usual 
WAI ​
​
​
Working Alliance Inventory 
WSAS​​
​
Work and Social Assessment Scale 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
ZAN-BPD​
​
Zanarini Rating Scale for Borderline Personality Disorder 
​
​
 
1.2 Sponsor 
GAIA AG, Hans-Henny-Jahnn-Weg 53, 22085 Hamburg 
PD Dr. Gitta Jacob, Antje Riepenhausen, Martina Dietrich, Anja Specht, Louisa Adler 
 
●​ role:​
Patient recruitment, trial management, online-data acquisition,  
telephone interviews, provision of the software, examination and 
evaluation of reports with regard to adverse effects, data analysis 
 
1.3 Principal investigator, coordinating investigator and 
investigation site 
a) Name, address, contact details and professional position 
1) principal investigator 
Prof. Dr. med. Jan Philipp Klein 
Universität zu Lübeck, Zentrum für Integrative Psychiatrie ZiP gGmbH, Ratzeburger 
Allee 160, 23562 Lübeck, philipp.klein@uksh.de 
●​ role: Scientific lead and coordinator, data analysis, monitoring 
 
2) coordinating investigator 
​
Not applicable. 
b) Name and address of the investigation site 
The clinical investigation will be conducted as an online trial without a traditional 
physical investigation site. Study management including patient recruitment will be 
conducted by the sponsor. 
c) Name and address of external organizations 
​
PD Dr. med. Eva Fassbinder 
Zentrum für Integrative Psychiatrie, Campus Kiel, Department of Psychiatry and 
Psychotherapy, Niemannsweg 147, 24105 Kiel, Germany, 
eva.fassbinder@gmail.com 
●​ role: Scientific co-lead and co-coordinator, lead and supervision of data analysis 
PD Dr. med. Eva Fassbinder works on a freelancer basis also for GAIA (the sponsor) 
as an author for the program alivis.  
 
GAIA AG, Hans-Henny-Jahnn-Weg 53, 22085 Hamburg 
PD Dr. Gitta Jacob, Dr. Antje Riepenhausen, Martina Dietrich, Anja Specht, Lea 
Nitzpon, Louisa Adler 
 
●​ role:​
Patient recruitment, trial management, online-data acquisition,  
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
telephone interviews, provision of the software, examination and 
evaluation of reports with regard to adverse effects, data analysis 
 
1.4 Overall synopsis of the clinical investigation 
This randomized controlled trial (RCT) with 470 patients diagnosed with Borderline 
Personality Disorder (BPD) aims to investigate the effectiveness of the unguided 
digital therapeutic alivis for patients with BPD as defined in DSM-5. Inclusion criteria 
are: male, female or non-binary, age 18-65 years, diagnosis of BPD (confirmed by 
SCID-5-PD), borderline severity score (cut-off) of ≥ 1.07 on the Borderline Symptoms 
List 23 (BSL-23), stable treatment (e.g., psychotherapy, medication, no treatment, …) 
for at least 30 days at the time of inclusion, consent to emergency plan for suicidal 
crises, consent to participation, and sufficient German language skills. Exclusion 
criteria are: Plans to change in treatment (e.g., psychotherapy, medication, …) in the 
upcoming 3 months after inclusion, comorbid diagnosis of substance use disorder or 
lifetime diagnosis of psychotic disorder, physical condition that can cause severe 
psychiatric symptoms, acute decompensation of mental health, BMI <15, and prior 
use of the digital intervention priovi.  
Patients will be randomized and allocated to either an intervention group, in which 
they will receive access to alivis in addition to treatment as usual (TAU; n=235), or to 
a control group, in which they will receive access to TAU and publicly available 
information material on BPD (n=235).  
The primary endpoint will be BPD symptoms with three months post-allocation (T1) 
being the primary timepoint for assessment of effectiveness. Six (T2) and twelve (T3) 
months post-allocation will be used as follow-up assessment of endpoints. Secondary 
endpoints will be depressive symptoms, anxiety symptoms, costs caused due to the 
patient’s BPD, social functioning, mental health-related quality of life, specific BPD 
symptoms (on the basis of all nine BPD criteria according to DSM-5), and patient 
activation. For a visualization of the trial design, see figure 1. 
1.5 Introduction 
Borderline Personality Disorder (BPD) is a common, debilitating and costly mental 
disorder which is characterized by an instability in interpersonal relations, behavior, 
and emotions (1–4). Individuals with BPD experience symptoms ranging from frantic 
efforts to avoid abandonment and chaotic relationships, to a distorted self-image, 
feelings of emptiness, emotional dysregulation, dissociation, and intense anger, 
impulsive behaviors, self-harm, and suicidal ideation (3).  
Several effective psychotherapeutic approaches for BPD exist (5,6), including 
dialectical behavior therapy (DBT), schema therapy (ST), and mentalization-based 
treatment. However, fewer than one in four BPD patients have access to 
psychotherapy (7). Digital health applications (DiGAs) can provide evidence-based 
psychotherapies that may help to reduce this treatment gap (8). DiGAs are also 
suitable for patients who prefer to overcome their mental health problems on their 
own or for those who live in areas with low access to psychiatric-psychotherapeutic 
care. This evidently applies to a considerable proportion of those who have a serious 
mental illness but do not seek treatment (9,10). 
 
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To date, a couple of digital health applications for BPD exist, which focus on tools 
from ST or from DBT (11,12). alivis is based primarily on DBT, which is the 
best-evaluated behavioral treatment method for BPD (5,13). DBT is a modular 
treatment program, and alivis makes use of several of these modules: for example, 
skills in emotion regulation, distress tolerance, antidissociative techniques, 
interpersonal effectiveness, and mindfulness are taught. These DBT modules are 
expanded in alivis to include modules on basic needs from ST (14,15), which has a 
good evidence base in BPD (13,16,17), on values work and defusion techniques from 
Acceptance and Commitment Therapy (ACT; 18–20) as well as on fostering 
self-compassion from Mindfulness Self-Compassion Therapy (MSC; 21) adapted to 
the needs of patients with BPD. Similar techniques have been integrated into more 
recent DBT protocols (22,23). The composition of the techniques used in alivis is thus 
based on the latest findings in psychotherapy research as well as on the extensive 
clinical expertise of the development team. Providing such a wide range of strategies 
enhances the chances that the patient will be able to make use of what they are 
offered and eventually profit from the intervention. alivis was developed by clinicians 
and researchers with long-standing expertise in the field of BPD which they have 
incorporated into the development of alivis, and with the involvement of patients 
suffering from BPD.  
The aim of the present RCT is to examine the effectiveness of alivis, a self-guided 
digital intervention for BPD, to decrease symptom severity in BPD patients.  
2. Identification and description of the 
investigational device 
a) Summary description 
Participants allocated to the intervention group will be provided with access to the 
program alivis. alivis is a CE-labeled, interactive online program for patients with 
BPD. alivis is organized in simulated dialogues that enable the patient to learn more 
about their disease and practice relevant skills and competences for managing their 
symptoms and improving their quality of life.  
alivis is a class I medical device according to MDR 2017/745, Annex VIII, Chapter III 
with software safety class A according to IEC 62304. 
b) Manufacturer 
alivis was developed by GAIA AG, an e-health company in Hamburg, Germany, 
specialized on research and development of digital therapeutics. 
c) Name/number of the model/type, software version and accessories 
​
to hand in later 
d) Description of traceability during and after the clinical investigation 
​
to hand in later 
e) Intended purpose 
alivis is intended to provide therapeutic methods and exercises based on 
evidence-based psychological and psychotherapeutic therapies for patients with 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
BPD, to help them manage their BPD symptoms. alivis is intended as a 
self-application for patients 18 years of age or older. alivis is neither intended to 
replace treatment provided by a health care provider nor to provide information which 
is used to make decisions with diagnosis or therapeutic purposes. 
f) Populations and indications 
​
Patients with Borderline Personality Disorder, ICD-10: F60.31 /ICD-11: 6D10. 
g) Description of the investigational device 
alivis is an interactive online program for independent use by users with BPD. It 
focuses on recognized treatment elements from DBT, ST, ACT, and MSC. 
The program alivis is based on proprietary software of the developing company 
(broca®), with access via password-protected and https-encrypted websites. The 
program can be used on conventional web-browsers on desktop PCs, tablets and 
smartphones. Users (patients randomized to the intervention group) receive access 
to the program for 12 months by 12-digit personal codes (vouchers), provided by the 
developer. Data protection and data security will be ensured by compliance with legal 
regulation. After initial registration and consent of general terms and conditions, users 
can log into the program using their email address and personal password at any 
time. The program is set up as an adaptive- and responsive-web-design pulling a 
layout template for a specific device, adapting to dimension and resolution of the 
display used. This results in high flexibility of usage regardless of the available 
hardware. 
An essential element of the program is the presentation of content through simulated 
dialogues (so-called ‘chats’), which are performed by interaction of the user with the 
software acting as a virtual expert. Users navigate through the modules by reading 
short texts and reacting to the information by continuously choosing one or multiple 
predefined options of response. Based on this input, the program subsequently 
adjusts the content. In this process, preferences and needs of the user are matched 
with regard to content and style. This is a form of content tailoring that has been tried 
and tested over many years in other programs of the developing company and, 
importantly, does not involve AI-based chatbots. Brief text passages are 
accompanied by illustrations, audio recordings, worksheets and personalized 
summaries (pdf documents). Users can collect specific techniques, which they found 
particularly helpful, in a personalized toolbox, so that they can access them easily 
when they need them in their daily life. Exercises can be practiced again in a 
‘practice corner’. Moreover, optional daily short text messages (SMS) are sent as 
reminders and to motivate and support users in their daily lives. The program also 
offers a symptom tracking function; that is, users are invited to complete embedded 
questionnaires at regular intervals in order to self-monitor changes over time. 
Moreover, a specific module was created to help users deal with difficult situations 
they encounter in their daily life. Here, the program validates the emotional struggle 
of the user, tries to help them clarify the situation by understanding underlying 
emotions, supports them to use skills they have detected as helpful while using the 
program, proposes new strategies (especially if the user just started the program) or 
reminds them to use their emergency plan in case of a suicidal crisis. 
alivis covers the following therapeutic techniques and content, organized in “chats”. 
Length of chats can be chosen individually by the user.  
 
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●​ Psychoeducation. Psychoeducation covers a variety of issues including BPD 
symptoms, development and maintenance of BPD, normal and BPD-typical 
emotional functioning, the respective treatment strategies and how they are 
supposed to work etc..  
●​ Stress regulation and skills training. Stress regulation with so-called crisis survival 
skills is a central element to DBT and is addressed in detail in specific chats, and 
applied to different life issues throughout the whole program. A specific emphasis in 
this regard is on dissociative symptoms.  
●​ Emotion regulation. Emotional problems are at the core of BPD; thus emotion 
regulation covers both intensive psychoeducation, skills training and techniques to 
detect and regulate emotions in a functional way.  
●​ Mindfulness. Mindfulness is another central part to most third wave therapies 
including DBT. It can be used both as part of stress and emotion regulation, but also 
as a general basis for mental health and psychological well-being.  
●​ Value-based activation. To establish better value-based activation in the patients’ 
lives, alivis discusses their personal values and how to follow them. Throughout the 
whole program, relations between different problems and how to solve them pursuing 
your values are discussed.  
●​ Cognitive techniques. Cognitive techniques are mainly derived from ACT (‘defusion 
skills’) and are supposed to help patients gain a distance from overwhelming 
negative thoughts.  
●​ Social competence. Interpersonal problems are a core problem area in BPD. Social 
competence includes techniques to downregulate oneself in tense social situations, 
healthy and assertive ways of communication in relationships, adequate ways to 
show own personal limits, express one’s needs etc.  
●​ Self-compassion. Self-invalidation, self-criticism and shame are hallmarks of BPD, 
thus techniques to promote self-compassion have been introduced in alivis (as in 
most modern BPD treatments). Psychoeducation, case examples and guided 
practices are provided to help users learn to be kind and understanding rather than 
harshly self-critical, especially when they fail, make mistakes or feel inadequate. 
They learn how to give themselves support and encouragement rather than being 
cold and judgmental when challenges and difficulty arise. 
The control group will receive access to alivis after 12 months. 
Users of alivis can contact the support via study email and telephone numbers or through 
the program itself. Support is offered in case of any questions regarding program usage and 
technical problems. 
 
h) Necessary training and experience needed to use the investigational 
device 
The application of alivis does not require training or any prior experience with the 
program. 
i) Medical or surgical procedures involved in the use of the 
investigational device 
​
Not applicable. 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
j) References to the Investigator’s brochure (IB) and IFU. 
​
Not applicable. 
 
3. Justification for the design of the clinical 
investigation 
a) evaluation of pre-clinical testing/assessment and prior clinical 
investigations 
The device alivissafety and performance of alivis was evaluated and confirmed in 
pilot evaluations according to the requirements applicable to theprocesses of  
development of medical devices (IEC 62366, ISO 13485; MDR Annex I) including 
class I medical devices in a summative evaluation. This includes the verification of 
the functionality and content of alivis as well as evaluation of extensive clinical data 
from post-market surveillance of the technically equivalent devices priovi and 
deprexis. Clinical data from post-market clinical follow-up RCTs is available for the 
equivalent class I medical device priovi.  
b) Clinical data relevant to the proposed clinical investigation 
Several effective psychotherapeutic approaches for BPD exist (5,6). Previously 
published studies demonstrated initial promising effects of digital interventions for 
BPD 
(12), 
but 
so 
far, 
these 
digital 
interventions 
focused 
on 
isolated 
psychotherapeutic approaches (i.e., only ST (24) or only DBT (25)) or on 
psychoeducation (26). alivis represents modern psychotherapy for BPD by combining 
strategies from DBT, ST, ACT, and MSC supplemented with psychoeducation, and 
thus offers the patient a considerably wider spectrum of therapeutic offers than 
previous digital interventions for BPD. The developers of alivis are clinicians and 
researchers with long-standing expertise in the field of BPD which they have 
incorporated into the development of alivis. 
c) Clinical development stage 
﻿Post-Market-Stage 
Due to the CE-label of alivis, the trial will be a post-market clinical follow-up study in 
line with the existing intended purpose. 
4. Benefits and risks 
a) Anticipated clinical benefits 
Since the intervention is designed to improve BPD symptoms, it is possible that the 
severity of BPD symptoms will decrease significantly for the individual study 
participants of the intervention group. Moreover, it is possible that study participants 
will experience further clinical benefits such as reduced symptoms of depression and 
anxiety, as well as increased mental health-related quality of life and ability to work. 
 
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b) Anticipated adverse device effects 
When using alivis, it may happen that not every patient benefits from it. This 
circumstance can potentially lead to feelings of disappointment. Moreover, the 
intervention addresses topics that may evoke temporary emotional distress in rare 
casessome study participants. However, the program is designed in such a way that 
it aims at high inherent safety. First, the program addresses the user in an emphatic, 
affirmative manner throughout. Second, the program regularly offers emotionally 
stabilizing exercises for potentially disturbing topics. Whenever a potentially stressful 
topic is addressed, the user also has the option to skip these sections. All exercises 
can be interrupted or discontinued at any time. 
c) Risks associated with participation in the clinical investigation 
The risk for individual participants can be regarded as very low. The program itself is 
designed with high inherent safety. The exercises can be interrupted or discontinued 
at any time. If persistent emotional distress or pain occurs during or after performing 
the exercises, the program advises seeking medical attention. 
Study procedures cover typical self-report assessments and have little potential to 
have a disturbing effect.  
d) Possible interactions with concomitant medical treatments 
The intervention is tested adjunctively to routine treatment, which provides an 
additional safety layer because participants can access their usual care providers if 
the need arises. The usual routine treatment can be continued without any changes 
or restrictions in both groups. 
e) Control or mitigation of risks. 
Potential adverse events will be recorded and analyzed throughout the trial. At each 
measurement timepoint, participants will be asked for the occurrence of specific 
adverse events, and the negative effects questionnaire (NEQ) is assessed. Moreover, 
users will be instructed to report adverse events via one of multiple channels (email, 
phone or website). All information received directly by the support team at GAIA or by 
the study management team will be reviewed and reports concerning safety-relevant 
issues will be documented and forwarded for assessment and further processing to 
the Person Responsible for Regulatory Compliance (PRRC). If undesirable side 
effects are reported, it will be clarified with the study participant whether further 
examinations or additional treatment is appropriate and the study participant will be 
motivated to make use of them.   
f) Rationale for benefit-risk ratio 
As described above, the risk for individual participants can be regarded as very low. 
Conversely, the benefit of the program is expected to be clinically meaningful. 
Therefore, the benefit-risk ratio is deemed to be positive. 
g) Medical justifiability 
​This study is medically justifiable. 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
5. Objectives and hypotheses 
a) Purpose, claims, effectiveness, safety 
The digital health application alivis aims to narrow the gap between patients’ need for 
effective treatment compared to the services available for patients with BPD. The aim 
of this RCT is to test the effectiveness of alivis in reducing BPD symptom severity. 
Moreover, intervention effects on several secondary endpoints, including depressive 
and anxiety symptoms, mental health-related quality of life, and social functioning will 
be examined. Testing of hypotheses will be performed in a sample of adult patients 
with BPD as defined in DSM-5.  
b) Objectives  
The primary objective of this trial is to evaluate the effectiveness of alivis in addition 
to TAU compared to TAU only. 
c) Scientific justification and clinical relevance 
An effect of Cohen’s d = 0.27 has been observed for a digital intervention for BPD 
that is based on ST only (27). Given that alivis consists of a combination of DBT, ST, 
ACT, and MSC and that participants will be closely guided during the trial, we expect 
the observed effect to be slightly larger and assume an effect size of d = 0.30. In 
order to obtain a power of 0.80, at a two-sided significance level of 0.05, each group 
should have a sample size of 176. Outpatient RCTs for BPD have an average 
dropout rate of approximately 25% (28,29). To compensate for dropouts, we thus aim 
to include and randomize N = 470 (2 X 235) participants with an allocation ratio of 
1:1. 
d) Primary and secondary hypotheses 
The primary hypothesis is that receiving alivis in addition to TAU leads to a better 
reduction of BPD symptoms measured with BSL-23 at T1 (three months after the 
start of the intervention), compared to receiving TAU only. Secondary hypotheses are 
(i) intervention group participants will exhibit a better reduction of depressive 
symptoms at T1, compared to those in the control group; (ii) a better reduction of 
anxiety symptoms, (iii) reduced costs caused due to the participant’s BPD, (iv) higher 
social and work-related functioning, (v) greater mental health-related quality of life, 
(vi) fewer BPD symptoms (regarding all 9 BPD criteria) measured with the Borderline 
Personality Disorder Checklist (BPD-CL), and (vii) higher patient activation compared 
to those in the control group at three months.  
In addition, exploratory moderator analyses will be used to determine whether certain 
baseline variables have an influence on the effectiveness of alivis. The following 
variables will be recorded a priori: currently attending psychotherapy, currently taking 
psychotropic medication, childhood trauma, and BPD symptom severity. 
Let the mean treatment difference be defined as μ (= alivis + TAU minus TAU only). 
For the primary endpoint, the following two-sided hypothesis is planned to be tested. 
●​ BPD symptoms (BSL-23) at T1 
- H0: μ = 0 points against HA: μ ≠ 0 points 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
For the confirmatory secondary endpoints, the following confirmatory one-sided 
hypotheses are planned to be tested. 
●​ Depressive symptoms (PHQ-9) at T1 
- H0: μ = 0 points against HA: μ ≠ 0 points 
●​ Anxiety symptoms (GAD-7) at T1 
- H0: μ = 0 points against HA: μ ≠ 0 points 
●​ Costs (self-compiled cost questionnaire) at T1 
- H0: μ = 0 € against HA: μ ≠ 0 € 
●​ Social functioning (WSAS) at T1 
- H0: μ = 0 points against HA: μ ≠ 0 points 
●​ Health-related quality of life (AQoL-8D) at T1 
- H0: μ = 0 points against HA: μ ≠ 0 points 
●​ Patient activation (PAM-13) at T1 
- H0: μ = 0 points against HA: μ ≠ 0 points 
Operationally, the hypotheses will be evaluated by two-sided tests at the 5% 
significance level. This is equivalent to using a one-sided p-value (nominal α = 0.025) 
and a one-sided 2.5% overall significance level. 
e) Risks and anticipated adverse device effects 
See section 4. b-f. 
 
 
16 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
6. Design 
6.1 General 
This study is a pragmatic, prospective RCT with two arms (30). As alivis already 
holds a CE-marking, this trial will be a post-market clinical follow-up study in line with 
the existing intended purpose. The trial will include a control group which receives 
TAU in addition to publicly available information material on BPD (Links to 
https://borderline-info.de/ 
and 
https://www.borderline-netzwerk.info/), 
and 
an 
intervention group which receives alivis in addition to TAU. The effectiveness of alivis 
will be tested by comparing the effects between both groups at three months (T1; 
primary hypothesis). Although participants will have access to alivis for 12 months in 
total, the relevant content of the intervention should be already covered after three 
months, with the remaining time mainly serving as refreshers and for stabilization 
(27). Therefore, we already expect effects to be present after three months. 
Recruitment of patients will be conducted via online advertisement (e.g., Google Ads 
campaigns). Participants will be routed to a linked study website providing 
information about the trial and details about participation. Using a contact form on the 
website, participants will be able to indicate interest in participation whereupon they 
will receive an email with a link to LimeSurvey, a secure online survey tool. At the 
beginning of the survey, further information about participation will be provided and 
electronic informed consent will be obtained. Participants will be informed about the 
option to receive personal explanation and answers to further questions via 
telephone or email. Moreover, participants will be informed of their right to withdraw 
from the study at any time without negative consequences.  
After electronic informed consent, participants will be asked to fill out an online 
demographic questionnaire followed by the set of questionnaires to collect baseline 
data (T0; see section 6.1.d) for further details). A likely diagnosis of BPD will be 
determined via the Borderline Symptom List-23 (BSL-23). Participants reaching a 
cut-off of ≥ 1.07 will be invited to a telephone interview which will serve to secure the 
diagnosis of BPD (via SCID-5-PD) and assess psychiatric comorbidities, rule out any 
comorbid diagnosis of substance use disorder or psychotic disorder, as well as an 
acute decompensation of mental health symptoms (via Mini-DIPS). Note that 
substance use and psychotic disorders were merely determined as exclusion criteria 
in face of the risk of non-adherence to complete questionnaires, but are not 
considered contraindications for the usage of alivis. In addition, consent to the 
emergency plan for suicidal crises will be obtained. This emergency plan requires 
that participants contact their physician/psychotherapist or the local emergency 
number in case of a suicidal crisis. The plan is established collaboratively with the 
participant at the end of the telephone interview.  If inclusion and exclusion criteria 
are met, participants will be allocated to one of the two study groups by a 
computerized randomization procedure (for details, see section 6.1 b). Participants 
allocated to the intervention group will receive registration information for alivis, 
patients allocated to the control group will be notified receive publicly available 
information 
material 
on 
BPD 
(Links 
to 
https://borderline-info.de/ 
and 
https://www.borderline-netzwerk.info/) and the information that they will receive 
access to alivis in twelve months, if they wish. All of the following measurements are 
carried out exclusively via online questionnaires. After three months (T1; primary 
timepoint for evaluation of effectiveness) participants of both groups will be asked to 
 
17 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
complete an online questionnaire. Although participants receive access to alivis for 
12 months, we expect highest usage of the intervention during the first months, as 
was the case for our intervention priovi (27; as well as still unpublished data from a 
follow-up RCT). Effects of alivis should therefore already be seen after three months. 
Additionally, patients will be surveyed after six and 12 months (T2 and T3; evaluating 
stability of effects). As an incentive, participants will receive a 10€ voucher from 
www.wunschgutschein.de per assessment (T1, T2, and T3; maximum 3×10€ = 30€). 
All participants (from the intervention and control group) will receive this 
compensation if they complete the questionnaires and interview, and, in particular, 
the compensation in the intervention group will not depend on the actual use of alivis.  
Contact to the participants will be established by a study director. Technical and 
content support for the intervention is offered via a central hotline, which is managed 
by a staff member who is not involved in the evaluation of the study. Participants in 
the intervention group will be contacted by email and/or phone if they have not 
redeemed their voucher for access to alivis 7 days after randomization. For a flow 
chart of the trial design, see Figure 1. 
The present RCT is designed to compare alivis in addition to TAU with TAU only. The 
required initial interview to confirm diagnosis of BPD maximizes the probability that 
alivis will be tested in the appropriate intended target group. 
 
 
18 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
 
Figure 1| Flow Chart of Trial Design 
The primary time point for analysis of effectiveness of the intervention will be three months after 
inclusion (T1). Other timepoints of data acquisition: T2 (Follow-up) = six months after inclusion, 
T3 (Follow-up) = 12 months after inclusion.  
 
 
 
a) Description of the design type of clinical investigation to be performed 
 
 
●​ prospective 
●​ randomized (simple randomization; 1:1, in variable blocks of 4, 8, or 16 
participants each) 
●​ two arms 
●​ controlled (against TAU) 
 
19 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
●​ online (no traditional investigation site) 
 
b) Measures against bias 
After successful screening of inclusion and exclusion criteria participants will 
automatically be randomized to one of two study groups (control group or intervention 
group) based on an algorithm.  
c) Primary and secondary endpoints 
Primary Endpoint: ​ Severity of borderline symptoms at T1, assessed via the 
Borderline Symptoms List 23 (BSL-23).  
The BSL-23 is a 23-item PROM with good psychometric 
properties that was validated and tested for reliability in a 
representative German sample (test–retest reliability r = .82, 
p < 0.0001; α = 0.94-0.97; high correlation of total score with 
general psychological burden and depression (53)) to 
assess the typical symptomatology and severity of BPD 
(54). It refers to the last week and has a range from 0 = “not 
at all” to 4 = “very strong”. Its single factor structure was 
optimized to reflect levels and changes in severity of 
BPD-symptomatology based on a mean score (32).  
 
Responders will be defined by a change of borderline 
symptom severity on the BSL-23 total score following both 
conditions: (i) reaching the cut-off of 15% of the range of the 
scale, i.e. improvement of 0.6 points and (ii) a change of 
BSL-23-total score towards a less severe grade from T0 to 
T1. Deteriorators will be defined accordingly by both, (i) 
reaching a deterioration of 0.6 points and (ii) a change of 
BSL-23-total score towards a more severe grade from T0 to 
T1. Non-responders will be defined as no change of the 
borderline severity grade, even if a change of 0.6 points was 
observed. 
The 
BSL-23 
is 
a 
BPD-specific 
PROM 
with 
good 
psychometric properties that was optimized to reflect levels 
and changes in severity of BPD-symptomatology based on a 
mean score (31,32). 
In addition to statistical significance determined by 
ANCOVA, which serves as the primary analysis (see section 
7), a responder analysis will be performed to assess the 
clinical relevance of effects of alivis on the severity of BPD 
symptoms. Responders will be defined by a change of 
borderline symptom severity on the BSL-23 total score 
following both conditions: (i) reaching the psychometric 
criterion of a reliable change index (RCI) (33) and (ii) a 
change of BSL-23-total score towards a less severe grade 
from T0 to T1. Deteriorators will be defined accordingly by 
both, (i) reaching RCI and (ii) a change of BSL-23-total 
score towards a more severe grade from T0 to T1. 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
Non-responders will be defined as no change of the 
borderline severity grade, even if the RCI was reached. 
 
Secondary Endpoints (note that the secondary endpoints are listed in priority order 
for the planned gatekeeping testing strategy, cf. 7.k): ​
 
Depression 
at 
T1, 
assessed 
via 
the 
Patient 
Health 
Questionnaire (PHQ-9) 
The PHQ-9 is the 9-item depression module from the full 
PHQ with comparable sensitivity and specificity, and 
includes the 9 criteria upon which the diagnosis of DSM-IV 
depressive disorders is based. Rating will be done on a 
4-point Likert scale ranging 0 = “not at all” to 3 =  “nearly 
every day”. As a severity measure, scores range from 0 to 
27 and represent: mild (<5), moderate (5-9), moderately 
severe (10-14), and severe depression (≥15). As a 
diagnostic instrument, major depression is diagnosed if 5 or 
more of the 9 depressive symptom criteria have been 
present at least “more than half the days” in the past 2 
weeks, and 1 of the symptoms is depressed mood or 
anhedonia. “Other” depression is diagnosed if 2, 3, or 4 
depressive symptoms have been present at least “more than 
half the days” in the past 2 weeks, and 1 of the symptoms is 
depressed mood or anhedonia (55). According to several 
studies, the German version can be considered reliable 
regarding psychometric standards (34–36). A reduction of  5 
points will be considered as MCID (34). Responders will be 
defined as participants reaching this difference from T0 to 
T1. The proportion of responders between groups will be 
compared using χ² tests. 
The PHQ-9 is a well-established and validated PROM in 
German language (34–36), to assess the 9 criteria upon 
which the diagnosis of DSM-IV depressive disorders is 
based.  
A reduction of  5 points will be considered as minimal 
clinically important difference (MCID) (34). Responders will 
be defined as participants reaching this difference from T0 to 
T1. The proportion of responders between groups will be 
compared using χ² tests. 
 
Anxiety at T1, assessed via the Generalized Anxiety Disorder 
Assessment (GAD-7) 
This self-administered patient questionnaire is used as a 
screening tool and severity measure for generalized anxiety 
disorder (GAD) (37). Studies report good reliability, as well 
as criterion, construct, factorial, and procedural validity 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
(38,39). The GAD-7 is scored on a Likert scale ranging from 
0 = “not at all” via 1 = “several days” and 2 = “more than half 
the days” to 3 = “nearly every day”, yielding a sum score 
ranging from 0-21. Scores of 5, 10, and 15 are taken as the 
cut-off points for mild, moderate and severe anxiety, 
respectively. When used as a screening tool, further 
evaluation is recommended when the score is 10 or greater. 
The GAD-7 is a self-administered patient questionnaire used 
as a screening tool and severity measure for generalized 
anxiety disorder (GAD) (37). Studies report good reliability, 
as well as criterion, construct, factorial, and procedural 
validity (38,39). 
 
Costs caused due to the patient’s BPD 
Costs caused due to BPD will be assessed with a 
self-compiled instrument assessing inpatient and outpatient 
treatment, support from friends, family and professional 
services, contacts with members of the judicial authorities 
and public security, medication, sick leave, and 
physician/therapist visits during work time. 
 
Social Functioning at T1, assessed via the Work and Social 
Adjustment Scale (WSAS).  
The WSAS is a 5-item self-report scale to measure social 
functioning in regard to physical, mental and social health as 
well as age group referenced competence for performance. 
The PROM has good psychometric properties with good 
criterion validity, good sensitivity and strong internal 
consistency (α = 0.89) (40). Individual items address work, 
home management, social leisure, private leisure and 
relationships. Each item is rated on a 9-point Likert scale 
from 0 = “not at all impaired” to 8 = “very severely impaired”. 
The total score has a range of 0-40, with lower scores 
denoting less disability. 
The WSAS is a scale to measure social functioning in regard 
to physical, mental, and social health as well as age 
group-referenced competence for performance. The PROM 
is validated for a representative German sample (40).  
 
Health-Related Quality of Life at T1, assessed via the AQoL-8D 
score on the Assessment of Quality of Life-8 Dimensions 
(AQoL-8D), German version 
The AQoL-8D is a health-related quality-of-life questionnaire 
consisting of 35 items forming eight health dimensions: 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
independent living, happiness, mental health, coping, 
relationships, self worth, pain, senses. Validation of the 
AQoL-8D assessing health-related quality of life showed 
good psychometric properties in a German patient sample, 
including excellent reliability (Cronbach’s α = 0.96) and 
construct validity (strong correlation with the SF-36, r = .81) 
(41). 
The AQol-8D is a self-administered questionnaire to 
measure quality of life in 8 dimensions (independent living, 
happiness, mental health, coping, relationships, self worth, 
pain, senses) which has demonstrated good psychometric 
properties in a German sample (41). 
 
Severity of borderline symptoms at T1, assessed via the 
Borderline Personality Disorder Checklist (BPD-CL).  
The BPD-CL is a DSM-IV based self-report instrument to 
assess BPD symptoms in the previous month (42). 
Importantly, in contrast to the BSL-23, the BPD-CL explicitly 
assesses all nine DSM-5 criteria.  
 
Patient activation at T1, assessed via the Patient Activation 
Measure (PAM-13) 
The PAM13 assesses patients’ active participation in their 
medical care using 13 items (43,44).  Items are answered 
using a Likert scale ranging from 1 = “strongly disagree” to 4 
= “agree strongly”, yielding a total score between 13 and 52.  
The German version of the PAM13, the PAM13-G, is 
validated and demonstrates good psychometric properties, 
including a good internal consistency of Cronbach’s α = 0.84 
(44). An improvement of 4 points on the PAM-13 is 
considered an MCID (56). Therefore, responders will be 
defined as patients who improve by at least 4 points on the 
PAM-13 from T0 to T2. The proportion of responders 
between groups will be compared using χ² tests. 
The PAM-13 is a 13-item instrument assessing patients’ 
active participation in their medical care (43). The German 
version of the PAM-13, the PAM-13-G, is validated and 
demonstrates good psychometric properties (44). 
 
Exploratory Endpoints: Assessments listed in “Secondary endpoints” at T2/T3 
Sociodemographic Variables: 
●​ Age 
●​ Gender 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
●​ Sex 
●​ Education  
●​ Employment Status  
●​ Family Situation 
●​ Language ability 
●​ Ethnicity 
 
Clinical Variables:​
​
 
Assessed at T0 only: 
●​ First diagnosis (date) 
●​ Inclusion diagnosis (BPD) using the respective 
section of the SCID-5-PD interview (45)  
●​ Psychiatric comorbidities (via Mini-DIPS) (46) 
●​ Psychotherapy (past, type) 
Assessed at all timepoints (T0-T3): 
●​ Medications (name of medication, dose, frequency) 
●​ Psychotherapy (current, type) 
●​ Childhood 
trauma 
(via 
Childhood 
Trauma 
Questionnaire (CTQ; 47,48)) 
●​ Number of BPD-related hospitalizations (T0: past 12 
months, T1-T2: past 3 months, T3: past 6 months) 
●​ Number of hospitalizations due to other reasons (T0: 
past 12 months, T1-T2: past 3 months, T3: past 6 
months) 
●​ Number of days in sick leave (past 3 months) 
●​ Number of days in sick pay (past 3 months) 
●​ weight and height (current) 
●​ Use of any other online program for BPD (T0: 
lifetime, T1-T2: past 3 months, T3: past 6 months; 
name) 
 
Treatment satisfaction:​
 
●​ Program Evaluation of the Program  (NPS, Net 
Promoter Score) (49) 
●​ Questionnaire on treatment satisfaction (ZUF-8; 50) 
●​ subjective improvement of BPD symptoms and 
quality of life  
 
Exploratory Variables:​
​
 
●​ Modified version of Working Alliance Inventory WAI-I 
(51) 
 
Usage monitoring (It should be noted that these data reflect only measurable 
engagement with alivis itself and do not capture how long a person has engaged with 
its content outside alivis, e.g. short text messages sent by alivis or PDF-materials 
printed from alivis): 
●​ Number of chats completed 
●​ Number of days active 
●​ Time spent in the program 
 
 
24 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
Safety and usage monitoring: 
●​ Negative Effects Questionnaire (NEQ; (52)) 
●​ Respective user feedback via email, telephone or 
contact form on the alivis trial website 
●​ Suicide attempts (T0-T2: past 3 months, T3: past 6 
months; main safety outcome) 
●​ other life-threatening events (e.g., non-suicidal 
self-injury, drug intoxication, accidents) 
●​ Unplanned and emergency outpatient and inpatient 
treatments (T0-T2: past 3 months, T3: past 6 
months) 
●​ Monitoring of adverse events throughout the trial 
(serious adverse events will be reviewed by a Safety 
Officer/ PRRC) 
●​ Usage 
 
 
d) Methods and timing 
Severity of Borderline Symptoms 
The total score of the Borderline Symptoms List 23 (BSL-23) 
The BSL-23 is a 23-item PROM with good psychometric properties that was 
validated and tested for reliability in a representative German sample (test–retest 
reliability r = .82, p < 0.0001; α = 0.94-0.97; high correlation of total score with 
general psychological burden and depression (53)) to assess the typical 
symptomatology and severity of BPD (54). It refers to the last week and has a 
range from 0 = “not at all” to 4 = “very strong”. Its single factor structure was 
optimized to reflect levels and changes in severity of BPD-symptomatology based 
on a mean score (32).  
 
Responders will be defined by a change of borderline symptom severity on the 
BSL-23 total score following both conditions: (i) reaching the psychometric 
criterion of a reliable change index (RCI) (33) and (ii) a change of BSL-23-total 
score towards a less severe grade from T0 to T1. Deteriorators will be defined 
accordingly by both, (i) reaching RCI and (ii) a change of BSL-23-total score 
towards a more severe grade from T0 to T1. Non-responders will be defined as no 
change of the borderline severity grade, even if the RCI was reached. 
 
Depression 
Total score of Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is the 9-item depression module from the full PHQ with comparable 
sensitivity and specificity, and includes the 9 criteria upon which the diagnosis of 
DSM-IV depressive disorders is based. Rating will be done on a 4-point Likert 
scale ranging 0 = “not at all” to 3 =  “nearly every day”. As a severity measure, 
scores range from 0 to 27 and represent: mild (<5), moderate (5-9), moderately 
severe (10-14), and severe depression (≥15). As a diagnostic instrument, major 
depression is diagnosed if 5 or more of the 9 depressive symptom criteria have 
been present at least “more than half the days” in the past 2 weeks, and 1 of the 
 
25 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
symptoms is depressed mood or anhedonia. “Other” depression is diagnosed if 2, 
3, or 4 depressive symptoms have been present at least “more than half the days” 
in the past 2 weeks, and 1 of the symptoms is depressed mood or anhedonia (55). 
According to several studies, the German version can be considered reliable 
regarding psychometric standards (34–36). A reduction of  5 points will be 
considered as MCID (34). Responders will be defined as participants reaching this 
difference from T0 to T1. The proportion of responders between groups will be 
compared using χ² tests. 
 
Anxiety 
Total score of Generalized Anxiety Disorder Assessment (GAD-7) 
This self-administered patient questionnaire is used as a screening tool and 
severity measure for generalized anxiety disorder (GAD) (37). Studies report good 
reliability, as well as criterion, construct, factorial, and procedural validity (38,39). 
The GAD-7 is scored on a Likert scale ranging from 0 = “not at all” via 1 = “several 
days” and 2 = “more than half the days” to 3 = “nearly every day”, yielding a sum 
score ranging from 0-21. Scores of 5, 10, and 15 are taken as the cut-off points for 
mild, moderate and severe anxiety, respectively. When used as a screening tool, 
further evaluation is recommended when the score is 10 or greater. 
 
Costs caused due to the patient’s BPD 
Assessed with self-compiled questionnaire 
Costs caused due to BPD will be assessed with a self-compiled instrument 
assessing inpatient and outpatient treatment, support from friends, family and 
professional services, contacts with members of the judicial authorities and public 
security, medication, sick leave, and physician/therapist visits during work time. 
 
Social Functioning 
Total score of Work and Social Adjustment Scale (WSAS) - German version 
The WSAS is a 5-item self-report scale to measure social functioning in regard to 
physical, mental and social health as well as age group referenced competence 
for performance. The PROM has good psychometric properties with good criterion 
validity, good sensitivity and strong internal consistency (α = 0.89) (40). Individual 
items address work, home management, social leisure, private leisure and 
relationships. Each item is rated on a 9-point Likert scale from 0 = “not at all 
impaired” to 8 = “very severely impaired”. The total score has a range of 0-40, with 
lower scores denoting less disability. 
 
Health-Related Quality of Life 
Total score of the AQoL-8D - German version 
The AQoL-8D is a health-related quality-of-life questionnaire consisting of 35 items 
forming eight health dimensions: independent living, happiness, mental health, 
coping, relationships, self worth, pain, senses. Validation of the AQoL-8D 
assessing health-related quality of life showed good psychometric properties in a 
German patient sample, including excellent reliability (Cronbach’s α = 0.96) and 
construct validity (strong correlation with the SF-36, r = .81) (41). 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
 
Severity of Borderline Symptoms 
Total score of the Borderline Personality Disorder Checklist (BPD-CL)  
The BPD-CL is a DSM-IV/5 based self-report instrument to assess BPD symptoms 
in the previous month (42). It consists of 47 items that can be grouped according 
to the DSM-IV/5 criteria and that are rated on a 5-point Likert scale from 1 (“not at 
all”) to 5 (“extremely”).The original Dutch version of the BPD-CL has been 
validated in BPD patients and shows very good psychometric properties 
(Chronbach’s α = 0.92). A validation of the German version is currently in press. 
 
Patient Activation 
Total score of the Patient Activation Measure (PAM-13) 
The PAM13 assesses patients’ active participation in their medical care using 13 
items (43,44).  Items are answered using a Likert scale ranging from 1 = “strongly 
disagree” to 4 = “agree strongly”, yielding a total score between 13 and 52.  The 
German version of the PAM13, the PAM13-G, is validated and demonstrates good 
psychometric properties, including a good internal consistency of Cronbach’s α = 
0.84 (44). An improvement of 4 points on the PAM-13 is considered an MCID (56). 
Therefore, responders will be defined as patients who improve by at least 4 points 
on the PAM-13 from T0 to T2. The proportion of responders between groups will 
be compared using χ² tests. 
 
​
Table 1| Chronological Sequence of the Trial 
 
Recruitmen
t 
Allocatio
n 
Post 
Allocation 
Follow-up 
Timepoint 
T0 
T1 
T2, T3 
 
 
 
 
 
Screening 
 
 
 
 
Test of Inclusion Criteria 
x 
 
 
 
Test of Exclusion Criteria 
x 
 
 
 
Sociodemographic Variables 
x 
 
 
 
Clinical Variables 
x 
 
x 
x 
Consent 
x 
 
 
 
Randomization 
 
x 
 
 
Intervention 
 
 
 
 
Intervention group: alivis + TAU 
 
♦ 
♦ 
♦ 
Control group: TAU + publicly 
available information material 
on BPD 
 
 
 
 
Endpoints 
 
 
 
 
BPD 
symptom 
severity 
(BSL-23) 
x 
 
x 
x 
Depression (PHQ-9) 
x 
 
x 
x 
General Anxiety (GAD-7) 
x 
 
x 
x 
Costs questionnaire 
x 
 
x 
x 
Social Functioning (WSAS)  
x 
 
x 
x 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
Health-Related Quality of life 
(AQoL-8D) 
x 
 
x 
x 
BPD 
symptom 
severity 
(BPD-CL) 
x 
 
x 
x  
Patient activation (PAM-13) 
x 
 
x 
x 
Clinical Course 
x 
 
x 
x 
Net Promoter Score (NPS)* 
 
 
x 
x 
Subjective improvement 
 
 
x 
x 
Usage of the Program* 
 
 
x 
x 
Exploratory Variables 
x 
 
x 
x 
Adverse Events (incl. NEQ) 
 
 
x 
x 
 
T0: Before start of Intervention (baseline), T1: 3 months post allocation, Follow-up: T2: 6 months post 
allocation, T3 = 12 months post allocation. Black diamonds indicate access to alivis. *only assessed in 
the intervention group. 
The primary time point for collecting data on the effectiveness of the intervention will 
be 3 months post allocation (T1). Six months post allocation (T2) and 12 months post 
allocation (T3) will be other time points for data collection, which will be treated as 
follow-ups to test the stability of effects. A first analysis is planned after the last 
patient completes T1. The complete data set will be open for analysis after the last 
patient 
completes 
T3. 
Participants 
will 
receive 
a 
10€ 
voucher 
from 
www.wunschgutschein.de as an incentive for participating in T1, T2 and T3 each 
(max. 30€). All participants (from the intervention and control group) will receive this 
compensation if they complete the follow-up questionnaires, and, in particular, the 
compensation in the intervention group will not depend on the actual use of alivis. 
Details of data collection and analysis are summarized in Figure 1 and Table 1. The 
expected total duration of the study for each participant is 14 months (1 month 
pre-assessment, 12 months intervention phase, up to 1 month reminders for the last 
assessment). The expected total duration of the entire study including recruitment is 
estimated at 24 months. 
﻿e) Equipment for assessing the clinical investigation variables 
Equipment is limited to online surveys of participants using a German provider for 
surveys including clinical trials, LimeSurvey. PROMs are listed under 6.1 c-d. 
f) Replacement of subjects 
​
Not applicable. 
g) Investigation sites 
The study is designed as an online trial; there will be no traditional physical 
investigation site(s). See 1.4 b and 6.1 e. 
h) Completion of the clinical investigation 
Data acquisition of the trial will be completed 12 to 13 months after the last patient in 
(up to one month buffer for reminders to complete T3). Complete analyses of the 
dataset will denote completion of the investigation. 
 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
6.2 Investigational device and comparator 
a) Exposure to the investigational device or comparator 
Participants allocated to the intervention group will be provided with access to the 
program alivis, which is to be used additionally to the care provided by their attending 
practitioner. The program can be used on conventional web-browsers on desktop 
PCs, tablets and smartphones. Users (patients randomized to the intervention group) 
receive access to the program for 12 months by 12-digit personal codes (vouchers), 
provided by the developer. After initial registration and consent to the general terms 
and conditions, users can log into the program using their email address and 
personal password at any time. The program is set up as an adaptive- and 
responsive-web-design pulling a layout template for a specific device, adapting to 
dimension and resolution of the display used. This results in high flexibility of usage 
regardless of the available hardware. 
An essential element of the program is the presentation of content through simulated 
dialogues, which are performed by interaction of the user with the software acting as 
a virtual expert. Users navigate through the modules by reading short texts and 
reacting to the information by continuously choosing one or multiple predefined 
options of response. Based on this input, the program subsequently adjusts the 
content. In this process, preferences and needs of the user are matched with regard 
to content and style. Brief text passages are accompanied by illustrations, audio 
recordings, worksheets and personalized summaries (pdf documents). Chats are 
presented in consecutive order and build on previous content. Moreover, optional 
daily short text messages (SMS) are sent as reminders aimed to motivate and 
support users in their daily lives. The program also offers a symptom tracking 
function; that is, users are invited to complete embedded questionnaires at regular 
intervals in order to self-monitor changes over time. Text and graphical feedback are 
provided automatically after users complete the questionnaires embedded in the 
program. Exercises that the user experiences as useful can be saved in a toolbox 
and practiced again in a ‘practice corner’. A crisis module specifically aims at 
supporting users during difficult situations in daily life.  
alivis is provided in addition to the care provided by the participants’ attending 
practitioner (TAU). This may comprise any kind of treatment prescribed or 
recommended by a healthcare professional, including (but not limited to) 
pharmacotherapy, rehabilitation, psychotherapy, etc., as well as no treatment at all.  
Participants in the control condition receive access to only TAU. After 12 months (T3), 
they have the option to receive access to alivis.  
b) Other medical devices or medication 
​Not applicable.  
c) Number of investigational devices 
​No additional investigational device (in addition to alivis) will be used in this trial. 
 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
6.3 Subjects 
a) Inclusion criteria 
●​ male, female, non-binary 
●​ age 18-65 
●​ diagnosis of BPD (telephone interview via SCID-5-PD (45)) 
●​ borderline severity score (cut-off) of ≥ 1.07 on the BSL-23 
●​ Stable treatment (e.g., psychotherapy, medication, no treatment, …) for at least 
30 days at the time of inclusion 
●​ consent to emergency plan for suicidal crises  
●​ consent to participation 
●​ sufficient knowledge of the German language 
b) Exclusion criteria 
●​ Plans to change in treatment (e.g., psychotherapy, medication, …) in the 
upcoming 3 months after inclusion 
●​ Comorbid diagnosis of substance use disorder 
●​ Lifetime diagnosis of psychotic disorder like schizophrenia or schizoaffective 
disorder (except non-transitory paranoid ideas that can be concomitant with BPS 
and in which the ability to test reality is mostly preserved) 
●​ Diagnosis of a physical condition that can cause serious psychiatric symptoms 
●​ Acute decompensation of mental health symptoms, e.g. acute manic state or 
acute suicidality 
●​ BMI <15 
●​ current pychiatric day-care or inpatient treatment 
●​ Prior use of priovi 
 
c) Criteria and procedures for subject withdrawal or lost to follow-up 
1) Withdrawal of a subject or stop of use 
Participants will be informed of their right to withdraw from the study at any time 
without negative consequences. Test subjects will not be included in the clinical trial 
(not randomized) if it was not possible to ascertain baseline variables (T0). There is 
no provision for withdrawal of follow-up examinations.  
2) Tracing of subjects lost to follow-up 
At prespecified points in the course of the study, participants whose response to a 
survey is still outstanding will be reminded by email and/or phone.  
Subsequent replacement of test subjects who evade follow-up examinations is not 
intended. Missing data points will be imputed by applying multiple imputation (cf. 
section 7. m). Possible reasons for being lost to follow-up include but are not limited 
to no further need for a treatment (known as “good enough effect” (57,58)), lack of 
positive effects of the treatment, or loss of interest among control group participants. 
3) Replacement of subjects 
Following standards for RCTs there will be no replacement of participants. 
d) Point of enrolment 
​With randomization and allocation to a study group the participants are enrolled in 
the trial. 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
e) Point of randomization 
After informed consent is obtained, patients interested in participation will be asked to 
fill in an online demographic questionnaire followed by a set of questionnaires to 
collect baseline data (T0). After initial data acquisition and screening for inclusion 
criteria, patients will be asked to take part in an initial telephone interview to conduct 
and determine the diagnosis of BPD, rule out any primary diagnosis of substance use 
disorder or psychotic disorder or acute decompensation of mental health, and to 
obtain consent to the emergency plan for suicidal crises. In case of a positive 
screening process regarding inclusion and exclusion criteria, participants will be 
allocated to a study group by randomization procedure. For further information 
regarding point of time see Table 1. 
f) Total expected duration 
Expected total duration of the entire study including recruitment is estimated as 24 
months. 
g) Expected duration for each subject 
Expected total duration of the study for each participant will be up to 14 months (up to 
1 month pre-assessment, 12 months intervention and follow-up phase, up to 1 month 
reminders for the last assessment). 
h) Number of subjects 
​
N = 470 
i) Enrolment period 
​
The enrollment period is estimated as ten months. 
j) Relationship of investigation population to target population 
The pragmatic RCT design, which evaluates the intervention in a setting in which it is 
also to be used, and the small number of exclusion criteria ensure that the test 
population largely corresponds to the target population of alivis. In addition, the 
required initial clinical interview contributes to the fact that alivis is only tested in the 
intended target group. 
k) Vulnerable, pregnant, and breastfeeding population 
​
Pregnancy or breastfeeding are no contraindications for the use of alivis. 
 
6.4 Procedures 
a) Procedures during the clinical investigation 
Clinical investigation-related procedures will be: 
Screening of inclusion/exclusion criteria and assessment of baseline data via online 
survey and telephone calls using the above itemized PROMs for baseline 
measurement of primary and secondary endpoints, respectively (6.1 c)-d)). The 
baseline assessment will be completed via an online survey on LimeSurvey. 
Specifically, secondary endpoints and sociodemographic / clinical variables will be 
assessed, and a likely diagnosis of BPD will be determined via the BSL-23. 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
Participants reaching a cut-off of ≥ 1.07, are at least 18 years old, do not have any 
physical condition that can cause severe psychiatric symptoms, have not used the 
digital intervention priovi before, and have sufficient knowledge of the German 
language will be invited to schedule an appointment for a telephone call. A telephone 
interview will then serve to secure the diagnosis of BPD (via SCID-5-PD) and assess 
psychiatric comorbidities, rule out any comorbid diagnosis of substance use disorder 
or psychotic disorder, as well as an acute decompensation of mental health 
symptoms (via Mini-DIPS), and obtain consent to the emergency plan for suicidal 
crises.   
All primary and secondary endpoints will be part of the data assessment after 3, 6 
and 12 months as well, assessed via an online survey, see Table 1 for details.  
During the study period, the study team may contact participants to remind them of 
outstanding surveys or to ensure correct technical function of alivis, as appropriate. 
b) Activities performed by sponsor representatives 
•​
Coordination and trial management, online-data acquisition and telephone 
interviews 
•​
Provision of the software 
•​
Development, programming and testing of the survey instruments 
•​
Development of work instructions for the implementation of the measures carried 
out in Figure 1 (including training and monitoring of employees) 
•​
Planning and implementation of patient recruitment 
•​
Regular follow-up meetings (preferably virtual) to monitor project progress 
•​
Examination and evaluation of reports of possible adverse effects 
•​
Data analysis 
c) Factors compromising outcome or interpretation of results 
The outcome of the study may be influenced by a number of confounding factors 
(e.g., age, gender, therapy, etc.). Randomization of participants to the intervention or 
control group ensures approximately equal distribution in both groups, so that any 
differences between groups can be attributed to the intervention. Potential differences 
in baseline values in the outcome variables of interest will be controlled for by 
including them as covariates in analyses of covariance (ANCOVA). 
d) Methods for addressing these factors 
​
See section 6.4 c. 
e) Follow-up period for clinical performance, effectiveness or safety 
The follow-up periods of three months (primary timepoint for assessment of 
effectiveness), six months and 12 months (for stability of effects) have been shown to 
be valid and relevant periods for treatment of BPD-patients with unguided 
internet-based self-management interventions (25,27).  
f) Specific medical care provided following the clinical investigation 
Not applicable. Participants have access to routine care by the attending health care 
professionals over the course of the study. 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
g) Recommended follow-up for the subjects 
​
Not applicable. 
h) Final disposition or potential future use of samples obtained from 
subjects 
​
Not applicable. 
 
6.5 Monitoring plan 
Documented monitoring visits will be conducted before, during (twice) and after the 
trial (close-out visit) by the sponsor to ensure adherence to the study protocol. The 
following items will be monitored during the audits: (i) presence of approval by ethical 
review board, (ii) qualification of investigators, (iii) current status of recruitment and 
participant flow, (iv) adherence to study protocol (e.g., presence of informed consent, 
correct application of inclusion and exclusion criteria, allocation to correct 
intervention, usage of intervention) and (v) correctness of data entries and 
consistency with the source documents. 
 
 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
7. Statistical design and analysis 
All analyses and imputation procedures will be performed using standard statistical 
software such as R (59) or SPSS.  
a) Analysis population 
In line with recommendations of the CONSORT eHealth statement, we will conduct 
both intention-to-treat (ITT) and per-protocol (PP) analyses (60–62). For 
PP-analyses, the dataset will be filtered based on the variable “usage time”. 
Individuals in the intervention group who did not use alivis for at least 4 times on 4 
different days will be excluded from the PP dataset. Additionally, we will exclude 
participants from both groups who reported using other digital health interventions for 
BPD for the relevant follow-up period.   
b) Descriptive statistics of baseline data, treatments, safety data 
Descriptive statistics will include mean value and standard deviation (or median, min, 
max and quartiles as appropriate) for continuous data and absolute numbers and 
percentages for categorical data. These will be presented separately for the 
intervention and control group at baseline. 
c) Analytical procedures and measures of precision 
The Principal Investigator will receive access to all data prior to analysis and will 
remain blinded to group assignment until the end of the analysis of the primary 
outcome and main safety outcome (suicide attempts). 
Analysis of effectiveness of the intervention in addition to TAU vs. TAU will be 
performed by ANCOVA of the primary endpoint and all secondary endpoints (tested 
in sequential order in a gatekeeping testing strategy, see section 7. k), in which the 
posttreatment scores at T1 will be compared between treatment groups (intervention 
group vs. control group), using the baseline scores of the respective outcome as a 
covariate. Treatment effects, i.e., the difference in posttreatment scores, will be 
reported on the original scale, along with the 95%-CI. In addition, Cohen’s d 
(calculated as between-group difference divided by the pooled standard deviation) 
will be used as a standardized effect size to quantify differences in posttreatment 
outcomes. Tests of prolonged treatment effects at  T2 and T3 will be performed 
analogously with baseline as covariate. The ITT analyses will comprise all 
randomized participants, with imputed outcome values as described in section 7. m. 
Analysis of binary or count outcomes (such as medication or number of 
hospitalizations) will be conducted based on non-responder imputed data in the form 
of χ²-tests and Poisson regression, as appropriate, to examine between-group effects 
at T1, and analogously for T2 and T3. 
The primary analysis will be performed as an ITT analysis with multiple imputation 
under ‘missing at random’ (MAR) assumption. In addition, a conservative sensitivity 
analysis based on reference-based multiple imputation (J2R imputation) will be 
calculated (63). 
An exploratory PP analysis will be conducted (61,62). For PP analyses, the dataset 
will be filtered based on the variable “usage time”. Individuals in the intervention 
group who did not use alivis for at least 4 times on 4 different days will be excluded 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
from the PP dataset (62). Additionally, we will exclude participants from both groups 
who reported using other digital health interventions (e.g., DiGAs, apps, online 
programs) for BPD for the relevant follow-up period.  
Measures of accuracy will be p-value [significance level (α) < 0.05] and the 
corresponding 95% confidence interval. 
Moreover, responder analyses will be conducted. Unless a specific MCID is specified 
for an endpoint in section 6.1d), responders will be defined by reaching the cut-off of 
15% of the range of the scale (64). the reliable change index (RCI; 33) will be used to 
identify responders to treatment in patients with complete observations. The RCI is 
calculated as the ratio of the difference between pre- and post-scores of an individual 
participant (numerator) and the standard error of measurement of the difference 
(denominator). RCI scores larger than 1.96 indicate that it is unlikely that the posttest 
score is not reflecting real change (p < .05), thus indicating that the participant is a 
responder (33). If a specific MCID is specified for an endpoint, responder analyses 
will instead be based on that value. Responders will then be defined as participants 
reaching this difference from T0 to T1. Additionally, exploratory responder analyses 
will be conducted for each endpoint, where response is defined as 50% improvement 
since baseline. The proportion of responders between groups will be compared using 
χ² tests. Moreover, the odds ratio will be reported. 
d) Significance level and power  
significance level (α) = 0.05 (two-sided)  
power = 0.80 
e) Sample size 
1) Clinical data on outcome variable and effect size 
An effect of Cohen’s d = 0.27 has been observed for a digital intervention for BPD 
that is  based on ST only (27). Given that alivis consists of a combination of DBT, ST, 
ACT, and MSC and that participants will be closely guided during the trial, we expect 
the observed effect to be slightly larger and assume an effect size of d = 0.30. In 
order to obtain a power of 0.80, at a two-sided significance level of 0.05, each group 
should have a sample size of 176. Outpatient RCTs for BPD have an average 
dropout rate of approximately 25% (28,29). To compensate for dropouts, we thus aim 
to include and randomize N = 470 (2 X 235) participants with an allocation ratio of 
1:1. 
2) Expected outcomes across treatment groups 
​
See 5. d. 
3) Adjustments due to pre-planned interim analyses 
​An interim analysis is planned after three months (T1; primary time point). There will 
be no adjustments.   
4) Effect size and non-inferiority margin 
​
See 7. e 1). 
5) Randomization allocation ratio 
​
1:1, in variable blocks of 4, 8, or 16 participants eachno block randomization, no 
stratification 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
6) Expected drop-out rate 
​25% (28,29). 
f) Procedures to be performed by user and analysis 
​
Not applicable. 
g) Pass/fail criteria 
​
Not applicable. 
h) Interim analysis and criteria for termination 
​Dataset will be open for interim analysis after the last patient completed T1. Results 
of the interim analysis will have no consequences for further study conduct. 
i) Management of bias 
Accompanying clinical variables of the participants are recorded at baseline, 
post-treatment (T1) and follow-up (T2, T3). It is conceivable that differences in e.g., 
the concomitant therapy in both groups in the course of the study could influence the 
study result. The observation period is chosen so that both the intended and 
unexpected effects of the program can be assessed with validity. 
j) Management of potential confounding factors 
The result of the study could be influenced by a number of confounders (e.g., age, 
gender, therapy, etc.). By randomizing the participants to the intervention or control 
group, roughly equal distribution in both groups can be assured, so that possible 
differences between groups can be attributed to the intervention. Additionally, 
potential differences in baseline values in the outcome variables of interest will be 
controlled for by including them as covariates in ANCOVA.  
k) Multiplicity control and adjustment of error probabilities 
No adjustment of the significance level α of 0.05 (two-sided) given that a gatekeeping 
testing strategy will be applied as suggested by the FDA (65). The secondary 
endpoints (listed in section 6.1.c) are listed in priority order for that approach. 
l) Subgroups for analysis 
​The following subgroup analyses are planned: 
a)​ effectiveness of alivis depending on sex (male, female, intersex); 
b)​ effectiveness of alivis depending on gender (male, female, diverse); 
c)​ effectiveness of alivis in patients with concomitant psychotherapy at baseline 
compared to those without; 
d)​ Effectiveness of alivis in patients who take psychotropic medication (ATC codes 
N05, N06) at baseline compared to those who do not; 
e)​ Effectiveness of alivis in patients with changes in treatment (i.e., psychotherapy 
or regular psychotropic medication) between baseline and T1 vs. patients without 
changes in treatment; 
f)​ Effectiveness of alivis in patients with previous diagnosis of BPD vs. in patients 
who were initially diagnosed with BPD as part of the study.  
Results of these subgroup analyses will be visualized as a table and forest plot. 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
 
m) Missing, unused or spurious data, including drop-outs 
In the ITT analysis, missing data points will be imputed using the respective variable 
values at baseline as well as group membership and other sociodemographic and 
clinical variables (such as age, sex, education, employment, family status, 
psychotherapy at baseline, psychotherapy ever). The ITT analysis will be 
implemented following a computationally efficient implementation for bootstrapped 
maximum likelihood multiple imputation (67,68) by von Hippel and Bartlett (2021) 
using the R packages bootImpute (68) and mice (69). In detail, 1,000 bootstrap 
samples of the incomplete dataset will be generated for each outcome variable and 
then the relevant outcome variable will be imputed twice with the mice package with 
default settings (i.e., using predictive mean matching with a pool of 5 candidate 
values) as recommended. 
n) Exploratory analysis and sensitivity analysis 
Exploratory moderator analyses will determine the influence of certain baseline 
variables on the effectiveness of alivis. The following variables will be established a 
priori: currently attending psychotherapy, BPD symptoms (BSL-23), and patient 
activation (PAM-13).  
Reference-based sensitivity analysis (‘jump to reference’ (63,68,70)) will be applied 
following procedures for the ITT-analysis, using an implementation for the R 
programming environment. Assumptions about the structure of missing data points 
will be tested in advance.o) Reporting of deviation(s) from original statistical analysis 
plan 
If there are deviations from the original statistical planning, this deviation will be 
stated in the study register, study report and the publication as well. 
p) Handling potential imbalance of numbers of subjects across 
investigation sites 
​
Not applicable. 
q) Strategy for pooling data 
Not applicable. 
r) Estimand strategy 
​The treatment policy estimand will be used to handle any potential intercurrent 
events. In this study, intercurrent events are defined as the initiation or 
discontinuation 
of 
psychotherapeutic 
or 
psychotropic 
treatment 
and 
the 
discontinuation of alivis usage for any reason in the intervention group. The treatment 
policy estimand evaluates the treatment effect for all randomized patients, 
irrespective of their use of alivis or specific elements of TAU.  
The following estimand strategy attributes are defined: 
●​ Handling of intercurrent events: intercurrent events are ignored and shown in the 
definition of the treatment 
●​ Treatment: alivis + TAU + intercurrent events vs. TAU + intercurrent events 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
●​ Population: defined by inclusion and exclusion criteria; see sections 6.3a) and 
6.3b) 
●​ Variable: primary and secondary endpoints; see section 6.1c) 
●​ Population-level summary: mean difference 
8. Data management 
a) Methods for data entry and collection 
Data is collected using the online-survey provider LimeSurvey. The survey software is 
programmed in such a way that every possible answer (valid answer ranges) is 
predefined. There is a daily backup of the data. The data will be stored in 
pseudonymized form after the study has been completed. Personal data will be 
deleted after the purposes of the study according to the General Data Protection 
Regulation (GDPR). 
b) CRF tracking, data review, database cleaning, and issuing/resolving 
data queries 
​
See section 8. a. 
c) Verification, validation, and securing of electronic clinical data systems 
The development and the operation of the programs of the sponsor including alivis 
are secured according to an ISO 13485 and TÜV-Rheinland certified quality 
management system (QMS). This includes the verification, validation and backup of 
the sponsor’s electronic data systems as well as supplier evaluation and the 
validation of the survey software. 
d) Subject privacy 
The names and contact information of participants will be shared only with the study 
manager. Separation of compromised information will be ensured through the 
procedure described in detail in section 6.1 b. All personnel will be instructed to keep 
patient information confidential. Presentation of data in lectures, seminars, and 
publications will be based solely on the summarized data (anonymized). Electronic 
trial data is later stored under a pseudonym, i.e., only in conjunction with the 
participant ID, without the possibility of tracing back to personal information. All data 
is stored in password-protected directories on secure servers that comply with the 
requirements of the GDPR.   
Subjects are informed that anonymized data may be shared with researchers not 
involved in the current study who submit a relevant research proposal, in order to 
comply with the principles of open science. 
e) Database locking and storage 
The electronic storage of research data is pseudonymized i.e., only linked to a 
participant ID. All recordings are stored in encrypted files and on secure servers of 
the GDPR-compliant provider LimeSurvey and the sponsor. Personal data will only 
be stored for the purposes of the study and will be deleted upon completion of the 
clinical trial or expiry of the intended purpose, respectively. 
 
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﻿f) Data retention 
The electronic storage of research data will be pseudonymized for the purpose of the 
investigation. All recordings are stored in encrypted files and on secure servers of the 
survey provider LimeSurvey and GAIA AG. With completion of the clinical 
investigation and expiration of the purpose of data handling, all data will be 
anonymized and stored on servers of GAIA AG for 10 years. 
g) Retention period 
​
See section 8. f. 
h) Other aspects of clinical quality assurance 
​
See section 6.1 b. 
 
9. Amendments to the CIP 
Changes or additions to the CIP require the approval of the principal investigator and 
the sponsor. Consideration must be given to whether the change(s) in question are 
subject to the requirement to obtain a positive evaluation by the responsible ethics 
committee prior to implementation. In any case, the responsible ethics committee 
must be informed about minor changes (such as a name change) and, if necessary, 
an amendment must be requested. Depending on the nature of the change(s), it must 
also be decided whether relevant documents such as the patient information must be 
adapted accordingly. The study registry will be updated accordingly. 
 
10. Deviations from clinical investigation plan 
a) Statement - deviation from the CIP 
It is hereby declared that the examiner performing the test is not permitted to deviate 
from the test plan during the course, analysis and publication of the data. 
b) Recording, reporting, and analysing CIP deviations 
Significant protocol deviations that have occurred unintentionally in the course of the 
clinical trial and at the same time a) represent a significant reduction in data quality 
and / or b) negatively affect the rights, safety and health of the included patient, will 
be reported to the ethics committee promptly after the protocol deviation becomes 
known. 
c) Notification requirements and time frames 
The following information must be communicated to the ethics committee: 
●​ What was the type of the protocol violation? 
●​ When did the protocol violation occur? 
●​ Who was affected? 
●​ What was / is being done to limit the damage incurred or to avoid repeated 
deviations of the same kind in the future? 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
d) Corrective/preventive actions and principal investigator disqualification 
criteria 
The CIP is the decisive basis for carrying out the clinical trial. All employees involved 
in the study are bound by the protocol. This also applies to the principal investigator. 
 
11. Device accountability 
a) Accountability of investigational devices 
Not applicable (this study represents a post marketing clinical follow up study in 
which alivis is tested in line with the existing Intended Purpose).  
b) Safe return of potentially hazardous investigational devices  
​
Not applicable. 
 
12. Statements of compliance 
a) Statement - Declaration of Helsinki 
This clinical trial complies with the ethical principles of the Helsinki Declaration (WMA 
DECLARATION OF HELSINKI - ETHICAL PRINCIPLES FOR MEDICAL RESEARCH 
INVOLVING HUMAN SUBJECTS). 
b) Statement - compliance with ISO 14155:2020 and any regional or 
national regulations 
Compliance with ISO 14155:2020, the international standard and all regional or 
national regulations is hereby declared for the clinical trial presented. 
c) Statement - required approval/favourable opinion from the 
EC/regulatory authority 
It is hereby declared that the clinical investigation will not begin until the required 
approval/favourable opinion from the EC and regulatory authority have been 
obtained. 
d) Statement - requirements imposed by the EC or regulatory authority 
It is hereby declared that any additional requirements imposed by the EC or 
regulatory authority will be followed. 
e) Statement - insurance for subjects 
There is no test subject insurance. The participants are informed in the information 
sheet (“Probandeninformation”) that there is no test subject insurance for the study 
and that they are using the intervention program at their own risk. 
 
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Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
f) Statement - financing/agreement between sponsor and investigation 
site(s)/investigator(s) 
The PI will apply for funding at the Else Kröner-Fresnius-Stiftung, which has funded 
clinical studies in patients with BPD already in the past. In the case of a negative 
decision, alternative ways for funding may be considered. If no alternative funding 
can be obtained, tThe study described will be financed exclusively from the 
participating institutions' own funds.  
 
13. Informed consent process 
a) Informed consent and incentives 
Recruitment of patients will be conducted via online advertising like Google-Ads 
campaign, and optionally offline recruitment via Flyer, health insurance providers and 
advertisement in print media. Participants will be routed to a linked study website 
providing information about the trial and details about participation. Using a contact 
form on the website, participants can indicate interest in participation whereupon they 
receive an email with a link to LimeSurvey, a secure online survey tool. At the 
beginning of the survey, further information about participation will be provided and 
electronic informed consent will be obtained. Participants will be informed about the 
option to receive personal explanation and answers to further questions via 
telephone or email. Moreover, participants will be informed of their right to withdraw 
from the study at any time without negative consequences. After informed consent is 
obtained, participants will be asked to fill in an online demographic questionnaire 
followed by a set of questionnaires to collect baseline data (T0) and screen for 
inclusion criteria. After informed consent and initial data acquisition, a telephone 
interview is conducted to determine the diagnosis of BPD and rule out any primary 
diagnosis of substance use disorder or psychotic disorder or an acute 
decompensation of mental health. These diagnoses were determined as exclusion 
criteria in face of the risk of non-adherence to complete the questionnaires. However, 
they are not considered contraindications for the usage of alivis. In addition, consent 
to the emergency plan for suicidal crises is obtained.   
Participants will be provided with a 10€ voucher for www.wunschgutschein.de as 
incentive for participation at T1, T2, and T3 (max. 30€). All participants (from the 
intervention and control group) will receive this compensation if they complete the 
follow-up questionnaires, and, in particular, the compensation in the intervention 
group will not depend on the actual use of alivis. 
b) Informed consent process - subject unable/emergency treatment 
​
Not applicable. 
 
41 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
14. Adverse events, adverse device effects and 
device deficiencies 
a) Definitions of adverse events and adverse device effects 
Adverse events (operationalized via unplanned and emergency outpatient and 
inpatient treatments or suicide (attempts), as well as negative side-effects of the 
treatment (NEQ)) are queried at all measurement times. In addition, the intervention 
group has the option of sending information to the program operator using the 
contact form or email. In addition, participants can report adverse events directly to 
the study team by email, telephone, and via the contact form on the alivis trial 
website. The study manager brings together and monitors data from all of the 
channels described. 
b) Definition of device deficiencies 
Since alivis is a web-based application, of which only the current version is available, 
there are no product defects in terms of identity (there is only one software version 
that is shown in the program), quality (no physical product) or durability. GAIA as the 
manufacturer of alivis guarantees program availability averaging 99.5% per year. A 
lower average availability represents a product defect. Further product defects 
represent: malfunction, usage errors, missing or misleading information. 
c) Definitions of serious adverse events and serious adverse device 
effects 
A serious adverse event is any unwanted event that occurs which - directly or 
indirectly - has led, could have led or could lead to the death or serious deterioration 
of the state of health of a test person, a user or another person and was caused by 
the medical device or in which a causal relationship is at least likely. 
d) Non-reportable adverse events 
The 
adverse 
events 
listed 
in 
the 
instructions for use in the chapter 
"Nebenwirkungen": disappointment, distress, dissatisfaction, problems performing 
certain exercises, temporary worsening of symptoms when performing exercises or 
reflecting on your own situation. These are expected adverse events related to 
cognitive behavioral therapy and / or lifestyle changes.  
Upon contact with the study team, these adverse events are recorded, assessed and 
considered as part of the risk management. Additionally, the NEQ is systematically 
assessed at each measurement time point. If the study reveals an unexpected 
frequency with one or more of these undesirable effects, trend reporting is carried out 
(§88 MDR). 
e) Report period of adverse events and device deficiencies 
GAIA reports every serious adverse event immediately after a causal relationship or 
a possible causal relationship has been established between the incident and alivis, 
but no later than 15 days after GAIA has become aware of the incident. There are 
two exceptions to this: 
 
42 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
1. In the event of a serious hazard to public health, notification is made 
immediately, but no later than two days after GAIA has become aware of this 
hazard. 
2. In the event of death or an unforeseen serious deterioration in the state of 
health of a person, notification is made immediately after GAIA has 
established a causal link between the product and the serious incident or as 
soon as GAIA suspects such a connection, but no later than ten days after 
becoming aware of received the serious incident. 
If necessary, in order to ensure a speedy report, GAIA can first transmit a preliminary 
report and this can then be followed by the full report. In the event of uncertainty as to 
whether the incident should be reported after GAIA has received knowledge of a 
possibly reportable event, GAIA will nevertheless submit a report within the 
prescribed period mentioned above. 
f) Process for reporting adverse events 
The reporting or notification of adverse events is carried out to the BfArM using the 
forms provided for this purpose. 
g) Process for reporting device deficiencies 
Product defects are recorded, assessed and documented in accordance with the 
“Feedback & Complaint Handling” procedural instruction explained in more detail 
under sub-item h). 
h) Adverse events, adverse device effects and incidence, mitigation, or 
treatment 
When using the product, it may happen that not every patient benefits from the 
product. This circumstance can potentially lead to feelings of disappointment. It is 
also possible that the use of the program is perceived as stressful and that dealing 
with 
the 
program’s 
content 
feels 
uncomfortable. Not every exercise or 
recommendation is equally suitable for every patient, which can also lead to 
disappointment or even aggravate symptoms.  
If undesirable side effects are reported, it will be clarified with the study participant 
whether further examinations or additional treatment is appropriate and the study 
participant will be motivated to make use of them. For the handling of undesirable 
events that are reported via the program support, a procedural instruction is available 
(Quality Procedure 'Feedback & Complaint Handling'). This regulates procedures for 
dealing with questions, feedback and undesirable events in a timely and content-wise 
manner, and is used in this research project. Regardless of the method of contact 
(phone, email, contact form in the program), messages from study participants are 
collected and processed centrally. 
i) Emergency contact details for serious adverse events/device effects. 
Information on side effects and emergency contacts is provided in the instructions for 
use: 
[…] Es ist möglich, dass nicht jeder Patient von der Programmnutzung profitiert, was unter 
Umständen Gefühle der Enttäuschung auslösen könnte. Wenn die Beschäftigung mit dem 
Programm für Sie zu belastend ist, sollten Sie eine Pause machen, die Programmnutzung 
aussetzen und mit Ihrem Arzt/Psychotherapeuten darüber sprechen. Nicht jede Übung oder 
 
43 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
jede Empfehlung ist für jeden Patienten gleichermaßen geeignet. Wenn Ihnen eine Übung 
oder Empfehlung Schwierigkeiten bereitet, sich unangenehm anfühlt oder Beschwerden 
verursacht/verstärkt, führen Sie diese nicht weiter aus. Wenden Sie sich bei Bedarf an Ihren 
Arzt/Psychotherapeuten. 
Sollten 
im 
Zusammenhang 
mit 
der 
Nutzung 
von 
alivis 
Nebenwirkungen 
auftreten, 
melden 
Sie 
diese 
unverzüglich 
Ihrem 
Arzt 
oder 
Psychotherapeuten oder wenden Sie sich per E-Mail an alivis@broca.io. Weitere 
Kontaktmöglichkeiten finden Sie im Impressum von alivis unter dem Menüpunkt „Hilfe“. 
 
Bei Notfällen (z.B. Krisen, Suizidgefahr, Verschlechterung Ihres Gesundheitszustandes) 
kontaktieren Sie umgehend Ihren behandelnden Arzt/Psychotherapeuten oder wählen Sie 
bitte die für Ihr Land geltenden Notfallnummern von Feuerwehr oder Polizei.  
Hier ein Beispiel: Deutschland: • Notruf allgemein: 112 • Notruf Rettungsdienst: 112 • Polizei: 
110 • Seelsorge: 0800 111 0 111, 0800 111 0 222 
Falls Sie unter den angegebenen Telefonnummern niemanden erreichen oder keine Hilfe 
erfahren, prüfen Sie bitte, ob sich die Telefonnummern geändert haben könnten. […] 
 
Furthermore, in the course of obtaining the declaration of consent, the participants 
are informed that they can contact the study team via email and telephone. 
j) Information regarding the DMC 
​
Not applicable. 
15. Vulnerable population 
​
Not applicable. 
 
16. Suspension or premature termination of the 
investigation 
a) Criteria and arrangements 
If, during the clinical trial, an unacceptable risk, including a serious health hazard, is 
suspected, or if directed to do so by the European Commission or regulatory 
authorities, the sponsor will suspend the trial while the risk is being assessed. The 
sponsor will terminate the trial if the existence of an unacceptable risk that cannot be 
reduced is confirmed. 
b) Criteria for access to and breaking the blinding/masking code 
not applicable. 
c) Subject follow-up and continued care 
There are no special requirements for the follow-up examination of the test subjects 
because, as before, they receive the usual medical care and the risk of adverse 
effects from the intervention alivis or the information documents that participants in 
the control group receive is very small. 
 
 
44 

Study Protocol REVALDI-BPD version 5 (28.03.2025) 
 
17. Publication policy 
a) Statement - trial registration 
The study will be registered in an international trial registry with details of the specific 
primary and secondary endpoints and further details regarding the trial design.  
b) Statement - publicly available results 
The results of the clinical trial are planned to be published in a peer-reviewed journal. 
c) Statement - conditions/timeframes for publication 
After completing the data collection and subsequent analysis of the data set, the 
results of the clinical trial are planned to be published in a peer-reviewed journal 
regardless of whether the null hypothesis is refuted. The authorship is shared 
between those involved in the study according to the current guidelines of the 
International Committee of Medical Journal Editors (ICMJE). The data will be 
published in an aggregated, anonymized form.  
﻿ 
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