Limbix Spark: A CBT-based Mobile Intervention as First Line Treatment for Adolescent Depression During COVID-19
Phase: NA
Conditions: Depression
Sponsor: Limbix Health, Inc.

A CBT-based mobile intervention as first line treatment for adolescent depressive symptoms during COVID-19
Protocol Version Number: 7.0
04/21/2021
NCT: 04524598
Sponsor:
Limbix Health Inc.
548 Market St
PMB 91609
San Francisco, CA 94104-5401
Investigators:
Dr. Jessica Lake, PI
Dr. Aarthi Padmanabhan, Sub-I
Dr. Jeffery Gold, Sub-I
Virtual Study Contact Number:
888-546-2495 ext. 1

1.
Purpose of the Study and Background
1.1 Purpose of the Study
The primary aim of the proposed research is to evaluate the effectiveness of a self-guided, CBT-based mobile
app intervention (Limbix Spark) compared to an educational control condition for the treatment of teens with
depressive symptoms under the supervision of a healthcare provider during the COVID-19 pandemic.
This aim will be accomplished by evaluating:
●
Statistically significant change in pre to post treatment depressive symptoms (as measured by PHQ-8)
between Limbix Spark and web-based educational control condition as a primary outcome
●
Secondary outcomes of remission rates (PHQ-8 score <10), intervention safety based on participant
(and parent, where applicable) clinical concerns, anxiety symptoms, and global functioning, as well as
retention rates, program adherence, and usability ratings
1.2 Background
1.2.1 Adolescent depression is a major public health concern
Depression, the most common mental health disorder among adolescents and young adults, is a critical health
problem within the US, ranking 4th in global burden of disease1,2. Annual incidence of a major depressive
episode among adolescents is ~3.2 million, affecting 13.3% of teenagers and increasing to 26% when
including mild depressive symptoms3. Rates of adolescent depression are rising sharply, with a 63% increase
over the past 5 years4. There has also been a 56% increase in adolescent suicides in the last decade, making
suicide the #2 cause of death amongst teens5-7. These alarming trends highlight an urgency to develop
effective and accessible treatments for affected adolescents4. Adolescent depression has far-reaching
consequences including impairments in academic and work performance and social and family relationships,
substance abuse, and exacerbation of other health conditions8-15. Affected youth are also at a higher risk for
developing a range of other mental health disorders, as well as for unemployment and physical health
problems in adulthood16-19. Adolescent depression places significant economic burdens on the US healthcare
system20, with higher medical costs than those for almost any other mental health condition21. Lastly,
depression is a pervasive disorder22,23, with lifetime recurrence rates of ~70%24,25, and a $210B societal burden
annually as a whole, thus targeting this problem in adolescence, the typical time of initial onset, is critical for
improving future outcomes. The proposed study is significant as it will target a critical public health concern,
the urgency of which is now magnified by a global pandemic and mandated social distancing26-28, that impacts
a significant proportion of the population and is presently a leading cause of global disability in youth29.
1.2.2 Effective care for adolescents with depression is limited
Adolescents with depression constitute a large group with significant unmet clinical needs. Despite high
prevalence rates of depression among adolescents, very few seek treatment and they are more prone to
discontinue or reject psychotherapy, due to concerns over privacy and/or stigma30,31. In addition, access to
effective mental health care is often limited32-34. Demand for mental health professionals has outstripped
supply, particularly in rural areas, a problem that is predicted to intensify over the next 10 years35-38. Waitlists for
mental health providers are often at least 2-6 months long and represent one of the most substantial barriers to
receiving care39-44. Consequently, 60-80% of adolescents with depression do not receive appropriate or timely
treatment45,46. Mandated social distancing practices implemented during the COVID19 pandemic are expected
to magnify the already significant challenges47,48. Digital intervention is a solution that is needed immediately.
Primary care visits provide a unique opportunity to identify adolescents with depression and direct them
towards appropriate treatment. Primary care physicians often serve as a gateway for mental health treatments

as official American Academy of Pediatrics guidelines recommend annual depression screening of adolescents
in primary care49. However, many primary care providers lack adequate time and training to provide effective
psychotherapy-based treatment and approved options for pharmaceutical treatments within adolescent
populations are limited, have limited effectiveness50-52 and may pose safety concerns in youth, including side
effects in 10-25% of users53,54.  50% of adolescents decline antidepressant use and only about a third of youth
adhere to prescribed antidepressant therapy after it has been initiated in a pediatric setting55,56. These
significant barriers highlight a critical need and opportunity for new and effective treatment options for
adolescent depression that can be prescribed by primary care providers. An evidence-based, self-guided
psychotherapy delivered via a prescription product and overseen by a pediatrician can be a promising adjunct
to standard of care with few anticipated side effects and can overcome existing limitations in access to mental
health care, adherence, and safety.
1.2.3 Digital Cognitive Behavioral Therapy Interventions for Adolescent Depression
Accumulating evidence highlights the efficacy of digital health interventions for mental illness, providing
cost-effective, convenient, and accessible means of treatment57-59. Digital treatments via mobile applications
hold particular promise for adolescent mental illness, as youth increasingly report high levels of smartphone
use60 and enjoy using novel technologies57. Digital interventions can be completed at home, allowing patients
to practice implementation of clinical recommendations61 and increasing accessibility of on-demand resources.
Critically, such interventions can serve as a first line of defense for treatment, reducing57 high economic costs
associated with traditional in-person psychotherapies and wait times to access clinically-validated treatment.
Digital health interventions can also be less stigmatizing, leading to higher rates of engagement and
self-disclosure62-65. Mobile applications allow for delivery of interactive content, information collection,
self-report, and remote patient monitoring, which can be harnessed to personalize and enhance treatment and
to intervene appropriately. The recent COVID-19 global pandemic66,67 has further underscored the urgency for
safe, accessible, and effective digital alternatives to standard mental health treatments68,69. This need is critical
for the adolescent population who are especially vulnerable to depression and suicidality following
environmental stressors, trauma, and social isolation48,70-75.
Cognitive-behavioral therapy (CBT) is effective in the prevention and treatment of depression in children and
adolescents76-80 and a recommended form of treatment by the American Academy of Pediatrics 81. Digital forms
of CBT76,77,79,80,82, have been shown to be effective in the treatment of anxiety and depression in youth83.
Behavioral Activation (BA)84-87, a core CBT skill, seeks to 1) increase engagement with adaptive and
contextually relevant activities that induce feelings of mastery or pleasure, 2) advance an individual’s personal
goals using a combination of motivational strategies, reward-seeking, natural reinforcers, and self-monitoring,
and 3) reduce harmful and avoidant behaviors that often manifest during depressive episodes84,85,87,88.
Adolescents may be especially vulnerable to reward-related deficits due to immaturities in reward processing
neural systems89,90, impacting their ability to both experience reward and overcome avoidance. BA can also be
helpful in treating symptoms that especially impact adolescents with depression, including withdrawal from
social activities, inactivity, and avoidance91. BA-specific therapy offers a promising approach for treating
depression in adolescents92-94. Given that BA is necessarily individually paced, self-driven, and self-monitored,
it can be easily delivered digitally, which may be appealing to depressed youth who have limited access to or
interest in traditional care. In contrast, cognitive aspects of CBT require therapist input to challenge the
patient’s thinking, which is challenging to implement in a digital format. Moreover, cognitive aspects of CBT
may be especially challenging for adolescents due to developmental immaturities, for those with learning
disabilities, comorbid neurodevelopmental disorders or delays, or as a consequence of their depression91.
Recent evidence suggests that behavioral aspects of CBT are equally effective as cognitive approaches in

reducing depressive symptoms in youth and may mechanistically drive symptomatic reduction in CBT80,95,96. A
digital BA program for adolescent depression represents an exciting new direction for treatment83,97,98. We
hypothesize that the quantity and quality of behavioral activations completed by adolescents may
mechanistically explain symptom improvement in response to a digital behavioral activation focused digital
intervention.
Despite reported benefits and preliminary efficacy of digital CBT in clinical research, the rigor of previous
research is problematic as studies have suffered from small sample sizes and widespread adoption of and
adherence to such interventions in clinical practice is limited99. Treatments developed in research settings are
incongruous with those developed for commercial use, with the former lacking engaging content and
accessibility and the latter lacking an adequate evidence base. To our knowledge, there are no commercially
available interventions nor prescription digital therapeutics specific to adolescent depression. We hypothesize
that leveraging engaging mobile technologies will enhance treatment engagement and adherence, mediating
clinical effectiveness, and ultimately reducing costs and wait times for mental health treatment for patients,
closing a significant treatment gap in the care of adolescents with depression.
2.
Criteria for Subject Selection
2.1 Number of Subjects
A convenience sample of participants will be recruited via online advertising, social media, word of mouth,
flyering, and recommendations by doctors, schools, and other youth and/or health-focused organizations.
Limbix may also work with participant recruitment companies, such as TrialFacts and Dynata. Healthcare
providers involved in identifying potential study participants may be compensated for recruitment efforts (based
on hourly effort and not on number of referrals or enrolled participants).  A total of 60 participants will be
recruited in Phase I, and a minimum of 120 participants with PHQ-8 ≥ 10 will be recruited in Phase II.A
statistically powered Phase III study will be designed following completion of Phase II.
Preliminary power calculations revealed that a sample size of 175 will achieve 80% power to detect a
moderate effect size (Cohen’s d=0.5) between Limbix Spark and active control at a significance level of 0.05
for a two-tailed t-test with an estimated 27% attrition rate100. A moderate effect size is expected based on
previous digital interventions with active controls for depression101-102 and evidence of superior efficacy for
CBT-based interventions102. An effect size will be calculated at the end of Phase II and may inform power
calculations in determining sample size for Phase III.
2.2 Gender of Subjects
Given prevalence rates of depression by gender, we expect to recruit at least 50% female participants but no
gender quotas will be set for enrollment. Based on the predominant recruitment of females in Phase I,
recruitment efforts in Phase II may be taken to ensure a more balanced gender representation.
2.3 Age of Subjects
13-21 years old.
Adolescent depression is on the rise, which can have deleterious effects on healthy transitioning to adulthood,
with prevalence rates highest within this age range. The age group selected is expected to have the capacity to
complete a self-guided treatment program.

2.4 Racial and Ethnic Origin
A convenience sampling approach will be taken without firm quotas for enrollment based on racial or ethnic
characteristics. Recruitment efforts may be taken in Phase II to ensure adequate representation of
underrepresented racial and ethinic minority groups.
2.5 Inclusion Criteria
Phase I
1.
Between the ages of 13 and 21
2.
Self-reported symptoms of depression
3.
Will be residing in the USA for the duration of the 5-week study
4.
Under the care of a US-based primary care and/or licensed mental healthcare provider and willing and
able to provide the name and contact information of the provider during consent appointment
5.
English fluency and literacy of adolescent and consenting legal guardian if under 18
6.
Access to a smartphone (iPhone 5s or later or running Android 4.4 KitKat or later) and regular internet
access
7.
Willing to provide informed e-consent/assent and have legal guardian willing to provide informed
e-consent if under 18
Phase II
1.
Between the ages of 13 and 21
2.
Self-reported symptoms of depression
3.
Stable for at least two months on any treatment (including medication or psychotherapy) for a mental
health disorder
4.
Will be residing in the USA for the duration of the up to 12-week study
5.
Under the care of a US-based primary care and/or licensed mental healthcare provider and willing and
able to provide the name and contact information of the provider during consent appointment
6.
English fluency and literacy of adolescent and consenting legal guardian if under 18
7.
Access to a smartphone (iPhone 6s or later and running iOS 13.0 or later or running Android 4.4 KitKat
or later) and regular internet access
8.
Willing to provide informed e-consent/assent and have legal guardian willing to provide informed
e-consent if under 18 (unless minor is legally emancipated or financially independent under relevant
state laws)
2.6 Exclusion Criteria
Phase I
1.
Self-reported lifetime suicide attempt or active self-harm or active suicidal ideation with intent
2.
Have a diagnosis by a clinician of bipolar disorder, substance use disorder, or any psychotic disorder
including schizophrenia
3.
Incapable of understanding or completing study procedures and digital intervention as determined by
participant, patient/legal guardian, healthcare provider, or clinical research team
Phase II
1.
Self-reported lifetime suicide attempt or active self-harm or active suicidal ideation with intent

2.
Have a diagnosis by a clinician of bipolar disorder, substance use disorder, or any psychotic disorder
including schizophrenia
3.
Incapable of understanding or completing study procedures and digital intervention as determined by
participant, patient/legal guardian, healthcare provider, or clinical research team
4.
Previously participated in user testing or clinical testing of Limbix Spark
2.7 Vulnerable Subjects
Adolescents between the ages of 13-21 will be included in this research as the program to be evaluated is
specifically designed to treat adolescents with symptoms of depression. Assent will be obtained from all
children under 18 for study enrollment unless legally emancipated or financially independent in accordance
with CA state regulations and regulations of the state in which the minor resides.
3. Methods and Procedures
3.1 Procedure
Participants will be recruited via online advertising, social media, word of mouth, flyering, and
recommendations by doctors, schools, and other youth- and/or health-focused organizations. Potential
participants will be directed to a web-based landing page where they will read a description of the research
procedures, review study eligibility criteria, and indicate whether they are eligible and interested in
participation. Potential participants will use an online calendar to schedule a virtual consent appointment with a
study coordinator.
The virtual consent process will involve a video conference call during which the study coordinator will describe
the research procedures, give the participant and their legal guardian (if required) time to review the consent
form, and answer any questions they may have in accordance with good clinical practice (GCP) and human
subjects research guidelines. Potential participants will be told that their participation is voluntary, that they are
free to discontinue participation at any time, and that all information will be kept confidential with the exception
of 1) mandatory limits to confidentiality and 2) safety concerns for participants or others. Participants will be
told that they are free to refuse to answer any question during study interviews or questionnaires and that they
can discontinue participation in the research at any time for any reason. All potential risks or discomforts will be
explicitly listed and explained. Participants will be asked to notify the research team if changes to their
treatment for depression or another mental health condition changes during the course of the study in order to
determine if it is in the best interest of the participant to continue in this research. During consent, participants
and their legal guardian (if required) will be asked to indicate whether they’d be interested in participating in a
post-intervention interview about their experience with the program. Participants will also be asked to indicate
whether or not they’d be willing to be contacted regarding future research opportunities. After all questions
concerning any aspect of the study have been fully answered by study staff, a Part 11 compliant, electronic
signature will be obtained from the participant or their legal guardian (if required) to document consent.
Documentation of the assent of a minor will also be obtained. Participants or their legal guardian will be
required to display a valid form of identification to verify identity. If the participant will turn 18 during the time
period in which the participant will be engaging in research activities, and required consent from a legal
guardian at the time of enrollment, a follow up consent appointment will be scheduled with the participant for
them to consent as an adult of legal consenting age to continuing their participation in the study. If such
consent cannot be obtained within a reasonable time frame, participation in the study will be terminated.
Emancipated minors and/or minors who are financially independent will be allowed to provide informed
consent without a legal guardian in accordance with federal guidelines, CA state regulations, and regulations of
the state in which the minor resides.

After consent, the study coordinator will ask participants and their legal guardian (if required) to verbally
confirm study eligibility. If eligibility is not confirmed, participants will be informed that they are ineligible for
participation and will be directed to a list of mental health resources available on the Limbix website. If eligibility
is confirmed, the study coordinator will create subject accounts for participants and parents (if required) with
usernames (participant/legal guardian email addresses) and temporary passwords. Mobile phone numbers and
email addresses will be collected at this time from participants and their legal guardian, if required, and entered
into a secure researcher portal. Provider name and contact information will also be collected. Date of birth will
also be collected to confirm the participant’s age and determine whether 17 year old participants will reach the
age of majority during their participation in the study. Lastly, the participant’s home address and emergency
contact will be collected in case an emergency arises during the study and the participant cannot be reached
via phone If this is the case, an additional consent appointment will be scheduled for after the participant turns
18, before the completion of their participation in the study. The research coordinator will generate emails to be
sent to participants and their legal guardian, if required, to reset their account passwords. Upon account
creation, participants will be randomized to either the Limbix Spark condition or the educational control
condition (see descriptions below).
The research coordinator will direct participants and parents to a 21 CFR Part 11 compliant web portal where
they will log in with their account credentials and complete baseline self-report assessments (see Assessments
below). The research coordinator will send an email to the participant and their legal guardian (if required) with
a safety plan document and instructions for completing and using this safety plan document should it be
necessary. A reminder email to complete the safety plan will be sent to participants and their legal guardian if
required) 3 days later. The study coordinator will remain on the video call as participants and their legal
guardian (if required) complete self-report assessments. After the study coordinator confirms that the
assessments have been completed, the study coordinator will text or email the participant a link to download
the study mobile app from the app store and will instruct them on how to download the Limbix mobile app.
Participants will sign in using their login credentials, will undergo onboarding and be prompted to complete a
baseline PHQ-8 in the mobile app. Completion of this initial PHQ-8 will be required for study participation to
allow safety monitoring of symptom deterioration. Based on the randomization procedure, participants will have
access to either the Limbix Spark intervention or the educational active control condition. The study coordinator
will provide instructions on using the program to which the participant was assigned, answer any questions and
end the video call.
Both mobile programs (Limbix Spark and educational control) will be fully self-guided, completed by
participants at home. Each program is designed to be completed over 5 weeks but users may progress
through the program at their own pace. The Limbix Spark program progresses linearly, i.e., a task must be
completed before a participant can progress to the next task. Content for a given week is not expected to take
more than 60 minutes to complete. All participants will be prompted to complete a weekly PHQ-8 and clinical
concerns questionnaire in the mobile app. Automated app notification reminders to complete these
questionnaires will be sent. If users have not opened the app in 3 days, an automated app notification
encouraging participants to use the app will be sent. An automated reminder notification will be sent 7 days
before the end of the intervention period to remind participants that the intervention period will be ending in 7
days.

The legal guardian of participants under 18 will be emailed links to complete a parent-reported participant
symptom check weekly. If they have not completed the questionnaire, they will be sent a reminder email 6 days
later to remind them that the questionnaire is due the next day.
After the 5 week intervention period, participants and their legal guardian (if required) will be emailed links to
complete post-intervention self-report assessments via secure web portal. Participants and their legal guardian
(if required) will receive automated email reminders to complete the post-intervention assessments after 6 days
if they have not completed the assessments. If participants or their legal guardian do not complete the
post-intervention assessments within a week the research coordinator may reach out to participants or legal
guardians via phone or email to encourage them to complete these assessments.
There will be two phases of this study. Phase I will evaluate feasibility of a minimum viable product (MVP)
version of the Limbix Spark mobile app (Version 1) within the context of a real world deployment. After
feasibility is established, Phase II will be initiated during which a primary outcome of effectiveness of the Limbix
Spark app will be evaluated. At the commencement of Phase II, an updated version of Spark (Version 2) will be
implemented. In order to quickly support teens during COVID-19 with an engaging and efficacious digital
treatment, one additional app update is planned (Version 3) during Phase II. Recruitment for Phases I and II
may not be powered to detect statistically significant differences between Spark and the educational control
condition. Participants in Phase I will be randomized using a 1:1 ratio. Participants in Phase II will be
randomized using a block randomization approach to ensure equal group sizes. Block size will range in
multiples of 2 from 4-12 and be randomly generated to prevent guessing of allocation and eliminate bias.
In Phase I if the participant does not complete the post-intervention assessments within 4 weeks from the end
of the intervention period they will be considered lost to follow up. If a participant chooses to withdraw from the
study at any point or  is deemed lost to follow up or dropped from the study during the intervention period (5
weeks), access to the web portal and mobile app will be restricted at that time. Otherwise, access to the mobile
app will be restricted at the end of the 5-week intervention period and access to the web portal will be restricted
after post-intervention assessments have been completed or the participant is deemed lost to follow up (4
weeks after intervention period). Participants will be compensated $25 in the form of an electronic gift card or
cash transfer for completing the post-intervention assessments regardless of adherence to their assigned
intervention. Gift cards will be emailed to participants.
In Phase II, for participants randomized to the treatment arm, if the participant does not complete the
post-intervention assessments within 2 weeks from the end of the intervention period they will be considered
lost to follow up. If a participant chooses to withdraw from the study at any point or the participant is deemed
lost to follow up or is dropped from the study during the intervention period (5 weeks), access to the web portal
and mobile app will be restricted at that time, otherwise access to the mobile app will be restricted at the end of
the intervention period and access to the web portal will be restricted after post-intervention assessments have
been completed or the participant is deemed lost to follow up (2 weeks after intervention period).
Participants randomized to the control arm will have two weeks to complete the post-intervention assessments.
Once the post-intervention assessments have been completed or 2 weeks have passed, whichever occurs
first, participants in the control arm will be granted access to the treatment condition (Limbix Spark) for 5
weeks. After access to Limbix Spark for 5 weeks, participants will have two weeks to complete another set of
post-intervention assessments. If a participant chooses to withdraw from the study or the participant is deemed
lost to follow up during the control app intervention period or Limbix Spark app intervention period (5 weeks

each), access to the web portal and mobile app will be restricted at that time. Otherwise, access to the mobile
app will be restricted at the end of each intervention period and access to the web portal will be restricted after
the second set of post-intervention assessments have been completed or the participant is deemed lost to
follow up (2 weeks after Limbix Spark intervention period).
In Phase II, if participants report a change in their treatment for a mental health disorder while enrolled in the
study, they may be withdrawn from the study.
In Phase II, all participants will be compensated $25 in the form of an electronic gift card for completing the
baseline assessments and $25 for completing each set of post-intervention assessments regardless of
adherence to intervention (1 set of post-intervention assessments will be completed if assigned to the
treatment arm and 2 sets of post-intervention assessments will be completed if assigned to the control arm-- 1
after completing the control app and another after subsequently completing the Limbix Spark app.) Gift cards
will be emailed to participants.
If participants indicated during the consent process that they would be interested in participating in a
post-intervention feedback interview, a research coordinator may contact participants and their legal guardian
(if under 18) to set up this interview to be conducted over video conferencing. Participants who were
randomized to the control condition may be contacted to complete these interviews following completion of the
control arm, prior to starting the treatment condition. Participants and their legal guardian will be asked,
separately, to answer questions about their experience with the program and provide feedback that may help
improve the product for future users. These interviews may be audio-recorded with permission. These
interviews are expected to take 1 hour, and participants and parent/legal guardians who participate will be
compensated $25/hr. Reimbursement will be prorated for interviews lasting less than 1 hour. For participants
randomized to the control arm in Phase II, this interview will occur after completion of the Limbix Spark
intervention period.
All relevant FDA requirements for the conduct of clinical trials will be followed, including registration on
clinicaltrials.gov.
3.2 Description of the Limbix Spark Program
The Limbix Spark program is a 5 week program divided into levels intended to be completed weekly. A
character called ‘Limbot’ is used as a guide. Limbot encourages the user in completing the behavioral
activation program and provides personal examples of how he/she has undertaken behavioral activation
therapy. Participants are instructed to complete a weekly Patient Health Questionnaire (PHQ)-8 assessment
and participant symptom check in the mobile app. Tasks in the mobile app progress in a linear fashion-- i.e.,
each task must be completed to progress to the next task. Certain on-demand resources can be accessed in
the app at any time, including emergency resources for patients experiencing thoughts of suicide or self-harm.
3.2.1 Release Version 1 (Phase I)
In Limbix Spark Version 1, the level system is framed around the idea that the app is teaching a skill
(behavioral activation) and as participants progress through the program, they are building this skill and
becoming more of an expert at it. The different levels are:
●
Level 1 (Learning): Complete the learning part of the app
●
Level 2 (Growing): Complete two activations

●
Level 3 (Doing): Complete 3 activations
●
Level 4 (Practicing): Complete 4 activations
●
Level 5 (Mastering): Complete 5 activations
UI Architecture
●
Tabs
○
Home tab. The default screen the participant lands on when opening the app.
■
Shows participant current level and progress through it.
■
Shows participant the next action they need to take and provides direct access to that
action (e.g. direct link to the next learning task or to review an activity).
■
Has crisis resources
■
Gives users the opportunity to provide product feedback.
○
Learning tab. Contains the 6 learning activities that are done during the program
■
Spark Overview
■
Mood & behavior 1 & 2
■
Breaking the cycle
■
Identify your values
■
Intro to activity scheduling
○
Activities tab.
■
View upcoming activities
●
See and edit scheduled activities
●
See and access activities that need review
■
View past activities
●
Activity scheduling button
○
A floating button that is available on any screen and allows the participant to schedule a new
activity
Program Flow
●
Level 1: Learning tasks
○
Onboarding.
■
Choose a Limbot
■
Enter name
■
View a walkthrough tutorial of the app interface.
■
Learn about weekly levels
●
Level 1 (Learning): Learning part of the app
●
Level 2 (Growing): Complete two activations
●
Level 3 (Doing): Complete 3 activations
●
Level 4 (Practicing): Complete 4 activations
●
Level 5 (Mastering): Complete 5 activations
○
Overview
■
Description of the program and how it works.
○
Mood and behavior 1 & 2
■
Learn the BA model of depression, focusing on the relationship between mood and
behavior, and how that leads to a downward cycle of depression.  The participant
identifies common feelings and associated avoidance behaviors.
○
Breaking the cycle

■
Learn how to break the downward spiral of depression by changing behavior
○
Identify values
■
Complete values clarification task and learn that choosing activities that align with values
helps activities to be more effective in treating depression.
○
Intro to activity scheduling.
■
Participant is taught how to schedule activities using the activity scheduling button and
tab.
■
View walkthrough tutorial of the Activities tab
■
See messaging that Level 1 is completed, Limbot acknowledgement and celebration!
■
Review next level’s goals, and see a reminder about trying to advance one level per
week
●
Level 2 through 5: Activity scheduling
○
Schedule activities and review them
■
Participant schedules activity based on values.
■
Participant reflects on activity.
○
With each level they complete, they receive Limbot acknowledgement and a celebration. They
then learn about their next goal.
■
If they complete level 5 before the 5 week study is done, participant is encouraged to
continue scheduling activities in the app until the study ends.
3.2.2 Release Version 2 (Phase II)
Release version 2 expands on version 1 with the addition of new features and content based on product
feedback from participants in a recently completed feasibility study of a Spark prototype. Minor modifications
may also be made based on feedback from participants who received version 1.
Features/content to be added:
●
Interactive psychoeducation focusing on the TRAP (trigger/response/avoidance pattern) and TRAC
(trigger/response/alternative coping) model of depression and how it relates to behavior activation.
●
A mood tracking feature that enables users to practice recognizing the relationship between their mood
and their behavior. The feature will accomplish this by prompting users to log activities that they have
done and how those activities made them feel. Users will also learn the concept of ‘up activities’ (those
that improve their mood) and ‘down activities’ (those that worsen their mood) and will apply this concept
by categorizing their logged activities as either ‘up’ or ‘down’.
●
The activity scheduling feature from version 1 will be enhanced by enabling users to ‘favorite’ their ‘up’
activities, and subsequently schedule favorited activities as behavioral activations. For example, if a
user categorized ‘riding my bike’ an up activity, then that activity can be favorited and easily scheduled
as a behavioral activation.
●
Two new tabs in the user interface.  A highlights tab that enables users to view summaries of their
mood logs, up activities, favorites, and completed activities and associated values. A ‘My Logs’ tab has
also been added that enables users to browse their mood-activity logs and behavioral activations by
date.
●
3.2.3 Release Version 3 (Phase II)

Release version 3 will further expand on version 2 with additional features and content based on product
feedback from participants in a recently completed feasibility study of a Spark prototype. Minor modifications
may also be made based on feedback from participants who received version 1 or version 2.
Features/content to be added:
●
Animations and visual aids to further reinforce psychoeducational content and improve engagement.
●
Problem-solving educational content,  including how to apply the COPE (Clarity, Options, Perform,
Evaluate) problem-solving framework. After learning the framework, users will be guided through an
interactive process of applying this framework to overcome obstacles they may encounter when they
complete scheduled activities.
●
Mindfulness educational content and exercises, including application of mindfulness to mood-activity
tracking and scheduled activities to enable users to better notice the relationship between mood and
behaviors.
●
Relapse prevention education and exercises, including development of a personalized relapse
prevention plan. Users will be taught about the possibility of relapse, including potential triggers and
early warning signs, and will then identify actions they can take if relapse occurs, including the
application of skills that they learned throughout the rest of the program.
3.3 Description of the educational control
3.3.1 Description of educational control for Phase I
The control mobile application will consist of 5 weeks of psychoeducational content with no active CBT or BA
components. Consistent with FDA recommendations, the educational control will be similar to the Limbix Spark
program in program duration (5 weeks), amount of content, modality of information delivery (mobile app) and
design interface. The educational control will largely be based on the content of the NIMH Teenage Depression
e-book (https://www.nimh.nih.gov/health/publications/teen-depression/index.shtml). This content will be
supplemented with additional content from publicly available government-sponsored websites. Participants will
be instructed to complete a weekly Patient Health Questionnaire (PHQ)-8 assessment and participant
symptom check in the mobile app.
Program Flow:
●
Lesson 1: What is Depression?
○
Description of what depression is, why you can’t just “snap out” of it, and what causes
depression
○
Additional reading links are provided
●
Lesson 2: What are the signs and symptoms of depression?
○
Describes signs and symptoms of depression and addresses the fact that depression may affect
different people in different ways
○
Additional reading links provided
●
Lesson 3: How do doctors treat depression?
○
Describes psychotherapy and antidepressants
○
Additional reading links provided
●
Lesson 4: What else can I do to stay healthy?
○
Describes other activities/healthy habits teens can try to say healthy as they give treatment time
to work
○
Additional readings links provided
●
Lesson 5: How do I get help?

○
Related resources and links provided
○
3.3.2 Description of educational control for Phase II
The control mobile application will consist of 5 weeks of psychoeducational content with no active CBT or BA
components. Consistent with FDA recommendations, the educational control will be similar to the Limbix Spark
program in program duration (5 weeks), amount of content, modality of information delivery (mobile app) and
design interface. The educational control will consist of age-appropriate educational material on the
neurobiology of depression. Market research in teens indicated equivalent expectations of treatment benefit for
this program when compared to Limbix Spark. Participants will be instructed to complete a weekly Patient
Health Questionnaire (PHQ)-8 assessment and participant symptom check in the mobile app.
Program Flow:
●
Lesson 1: Understanding behavior
○
Introduction to program
○
The brain and behavior
○
Studying the brain
○
The teenage brain
●
Lesson 2: Exploring the brain
○
Depression in the brain
○
Brain structure
○
Brain function
○
Depression in teens
●
Lesson 3: Mastering Messengers
○
Messages in the brains
○
Neurotransmitters
○
Messengers in depression
○
Teens and transmitters
●
Lesson 4: Riding the Wave
○
Hormones and behavior
○
Hormones in depression
○
Puberty & the brain
○
Puberty & depression
●
Lesson 5: People & personality
○
What are genes?
○
Personality
○
Big 5
○
Big 5 interactive task
○
Genes & depression
3.4 Assessments
Baseline and post-intervention assessments for participants and parents (if under 18) will be completed via a
secure web portal. Weekly participant assessments will be completed in the mobile app. Weekly parent
assessments will be completed via secure web portal.

Schedule of Assessments:
Baseline
Weekly during
study
Post-intervention
Patient Health Questionnaire
(PHQ-8)
X
X
X
Baseline Questionnaire- Participant
X
Baseline Questionnaire- Parent
X
Brief Resilience Scale
X
Generalized Anxiety Disorder
(GAD-7)
X
X
PROMIS Pediatric Global Health
Scale
X
X
PROMIS Parent Proxy Global Health
Scale
X
X
Mood and Feelings Questionnaire
(Short Parent Version)
X
X
Participant Symptom Check-
Participant
X
Participant Symptom Check- Parent
X
Post Program Questionnaire-
Participant
X
Post Program Questionnaire- Parent
X
System Usability Scale
X
User Engagement Scale
X
Description of Assessments
●
The Patient Health Questionnaire (PHQ-8) is an 8-item self-report measure for screening for
depression and for establishing depression severity. The PHQ-8 has been demonstrated to have high
sensitivity and specificity in both adolescents and young adults. Clinically significant improvement is
defined as a reduction in assessment score >= 5. Post-intervention scores < 10 are defined as
remission.
●
Baseline Questionnaire- Participant and Parent: Contains demographic, clinical history questions,
and questions related to the impact of COVID-19.
●
The Brief Resilience Scale is a 6 item self-report measure for assessing the ability to “bounce back” or
recover from stress. It has been shown to be reliable and to measure a unitary construct.
●
7 item Generalized Anxiety Disorder scale (GAD-7). The GAD-7 is a brief 7-item assessment for
generalized anxiety disorder with satisfactory sensitivity and specificity. We will evaluate changes in
anxiety symptoms given the high comorbidity between anxiety and depression.

●
PROMIS Pediatric Global Health Scale and PROMIS Parent Proxy Global Health Scale: The
PROMIS Pediatric and Parent Proxy Global 7+2 are 9-item measures that produce essentially a
unidimensional measure of global health perception/well-being.
●
Mood and Feelings Questionnaire Short Parent version (MFQ-PS). The MFQ-PS consists of a
series of 13 descriptive phrases regarding how the subject has been feeling or acting recently and is a
screening tool for depression in children and young people.
●
Participant Symptom Check- Participant & Parent. Assesses parent and participant reported clinical
concerns, severity level, and relationship of the clinical concern to the intervention.
●
Post-Program Questionnaire- Participant and Parent. Contains questions about changes in
treatment and questions about COVID19
●
System Usability Scale (SUS). Provides a “quick and dirty”, reliable tool for measuring the usability of
systems. It consists of a 10 item questionnaire with five response options for respondents; from
Strongly agree to Strongly disagree. The SUS has become an industry standard, with references in
over 1300 articles and publications. It is a very easy scale to administer to participants, can be used on
small sample sizes with reliable results, and is valid – it can effectively differentiate between usable and
unusable systems.
●
User Engagement Scale- Short Form (UES-SF). A statistically reliable measure of self-reported user
engagement. The form has 12 items and uses a 5 point Likert scale.
4. Data Analysis and Data Monitoring
4.1 Primary Outcome
Phase I
●
Primary outcome measures will include feasibility data including: % of potential participants eligible to
participate, % of eligible participants willing to participate, adherence to program (% of enrolled
participants completing all sessions by post-treatment), participant satisfaction with the program, and
clinical concern rates.
Phase II
●
Between-subjects treatment-related change in depressive symptoms from baseline to 5-weeks as
measured by PHQ-8 for those with baseline PHQ-8 ≥10.
4.2 Secondary Outcomes/Analyses
Phase I
●
Between-subjects treatment-related change in depressive symptoms as measured by PHQ-8 for those
with baseline PHQ-8 ≥ 5
●
Remission rates based on PHQ-8 < 10 (sub-analysis for those with baseline PHQ-8 ≥10)
●
Between-subjects treatment-related change in participant-rated anxiety symptoms and global
functioning as measured by GAD-7 and PROMIS Pediatric Global Health Scale
●
Between-subjects treatment-related change in parent-reported depressive symptoms and global
functioning as measured by MFQ, and PROMIS Parent Proxy Global Health Scale
●
Average treatment-related usability (SUS) and engagement (UES-SF) ratings
●
Treatment-related program adherence and engagement based on mobile app analytics
Phase II

●
Remission rates based on PHQ-8 < 10
●
Between-group treatment-related differences in participant-rated anxiety symptoms and global
functioning as measured by GAD-7 and PROMIS Pediatric Global Health Scale
●
Between-group treatment-related differences in parent-reported depressive symptoms and global
functioning as measured by MFQ, and PROMIS Parent Proxy Global Health Scale
●
Average treatment-related usability (SUS) and engagement (UES-SF) ratings
●
Between-group treatment-related differences in clinical concernt rates and serious clinical concerns
●
Between-group treatment-related differences in program adherence and engagement based on
behavioral and mobile app analytics
●
4.3 Tertiary/Exploratory Analyses
Phase I
●
Exploratory analysis of moderating effects of demographic, clinical, COVID19-specific, and engagement
factors on the relationship between treatment status and change in PHQ-8.
Phase II
●
Exploratory analysis of moderating effects of demographic, clinical, COVID19-specific, resilience (BRS),
and engagement factors on the relationship between treatment status and change in PHQ-8.
●
Within-group (control group only) treatment-related change in depressive symptoms measured by the
PHQ-8.
●
Within-group (control group only) treatment related change in participant-rated anxiety symptoms and
global functioning as measured by GAD-7 and PROMIS Pediatric Global Health Scale.
●
Within-group (control group only) treatment related change in parent-reported depressive symptoms
and global functioning as measured by MFQ, and PROMIS Parent Proxy Global Health Scale.
●
Within-group (control group only) treatment-related differences in usability (SUS) and engagement
(UES-SF) ratings.
●
Within-group (control group only) treatment-related differences in clinical concern rates and serious
clinical concerns.
●
Within-group (control group only) treatment-related differences in program adherence and engagement
based on behavioral and mobile app analytics.
●
Between-group differences between Spark versions on clinical outcomes (PHQ-8, GAD-7, PROMIS,
MFQ), program adherence, usability (SUS) and engagement (UES-SF).
●
Factor analysis to investigate whether clusters of symptoms as indicated by PHQ-8 items are
differentially impacted by Spark
4.4 Data Analysis
Phase I
The purpose of Phase I is to evaluate the feasibility of the self-guided Limbix Spark program. Feasibility
outcome measures for conducting an RWE fully remote trial of a novel digital treatment for adolescent
depression will include enrollment feasibility (i.e., proportion of recruited participants ineligible to participate
and/or who decline to enroll), intervention tolerability (i.e., proportion of enrolled participants who discontinue
intervention, are lost to follow-up, or experience clinical concerns), and adherence (i.e., proportion of modules
completed). Self-report assessments will be collected at pre and post program time points. Weekly PHQ-8
assessments will also be collected during the 5-week intervention as well as at pre and post time points.

Self-reports of clinical concerns will be collected weekly from both the participant and legal guardian (where
required) during the 5-week intervention. Patient feedback on ease of use, satisfaction with technology and
content, expressed willingness to continue use, and enjoyment will be assessed via questionnaires and a
qualitative interview following the intervention.  Adherence will be tracked via the mobile app, which will log the
time and duration of sessions and user activities.
As per recommendations for pilot studies, formal hypothesis testing will not be prioritized in data analysis103.
The sample size and planned data analysis, which will rely on qualitative and confidence interval approaches,
are appropriate to accomplish the stated objectives of this trial phase. Confidence intervals will be calculated
for each outcome measure using varying levels of confidence to evaluate preliminary evidence of effectiveness
and feasibility103. Feasibility and acceptability of the intervention will also be qualitatively evaluated based on
post-intervention interviews with patients. Post-intervention participant interviews are expected to demonstrate
that the intervention was feasible for participants to integrate into their daily routine, easy to use, and deemed
acceptable and efficacious for helping participants live well with their depression symptoms.
Means, variability, and effect sizes for primary and  secondary outcomes will be calculated. A confidence
interval approach, using multiple levels of confidence to evaluate the strength of preliminary evidence of
efficacy measured by the PHQ-8, will be taken to evaluate whether the mean treatment difference is above
zero and whether confidence intervals include a clinically important difference for outcomes. Clinical
significance for changes in depressive symptoms will be considered a 5-point reduction in PHQ-8 scores and a
post-intervention PHQ-8 score of ≤ 9. For all other measures, clinical significance will be defined as a
standardized effect size between 0.3 and 0.5. The time course of weekly PHQ-8 scores  will be plotted to
assess trends in change over time.
Lastly, we will assess treatment adherence and usability by evaluating program completion and daily mobile
app usage , and evaluating means and variability in self-reported usability and engagement using the SUS and
UES in the treatment group.
Phase II
The main purpose of Phase II is to evaluate the effectiveness of the Limbix Spark program relative to an
educational control condition. All analyses will be restricted to those participants with PHQ-8 ≥ 10 unless
otherwise indicated. Data from participants who reported a change in their medication or treatment for a mental
health disorder that occurred during the study may be excluded from primary analysis. The core analysis
strategy in this project is longitudinal mixed effects modeling, where we fully utilize the repeatedly measured
primary and secondary outcomes and maximum likelihood estimation will be applied104.
Data across versions 2 and 3  will be pooled and statistical analyses conducted with the combined dataset may
be computed with version included as a covariate. Statistical analyses may also be conducted separately for
versions 2 and 3 cohorts. All analyses will be completed in line with the intent-to-treat (ITT) principle, where all
participants will be included in the analyses according to their assigned study arm at baseline, regardless of
adherence to study protocol. Modern per protocol analyses will also be conducted to estimate treatment effects
for participants who adhered to the protocol105,106,107. All analysis results will be two-tailed, with a significance
level at 0.05 and 95% confidence intervals.
All measures will be analyzed using mixed effects modeling, followed by generalized estimating equations to
account for irregularly spaced measurements108, fully utilizing all repeated measures and all available data.
Missing data will be imputed using multiple imputation and likelihood-based analyses. Case analysis or single

imputation methods may also be used and a specific approach for imputation will be selected based on key
attributes of the obtained data, including % missing and whether data are missing at random109. Sensitivity
analyses will be conducted to determine if data are missing at random. In these analyses, allowing for random
intercepts and slopes, the change (slope) will be the key dependent variable and the randomization status will
be the key independent variable. The results of these analyses can be easily converted to group or treatment
differences at post assessments. In our mixed effects modeling, all variables will be analyzed as continuous
with the exception of clinical concerns (occurrence/non-occurrence), which will be treated as a repeatedly
measured binary outcome.
As an exploratory investigation, multiple variables will be investigated as possible moderators of
treatment effects on depressive symptoms (PHQ-8). For example, we may evaluate medication status,
symptom severity, age, sex, COVID19 specific factors, and aspects of program engagement (e.g., time to
complete program, duration of use) as potential moderators. For this investigation, we will employ the
MacArthur framework for moderator analysis,110,111 following the eligibility and analytical criteria for determining
moderators. To maximize power, moderator analyses will also be conducted using mixed effects modeling.
Exploratory analyses using mixed effects modeling will also be conducted to evaluate whether successive
program updates (between versions 2 and 3 of Limbix Spark) result in statistically significant differences on
primary and secondary outcome measures, including depressive symptoms, global functioning, and treatment
adherence, usability, and engagement.
Content analysis of post-study interviews will be conducted. Data will be codified to identify themes with an
emphasis on engagement, usability, comprehension, therapeutic alliance, and overall impact of treatment. Key
insights will be drawn from themes and contextualized with quantitative user session data.
Lastly, we will assess treatment adherence by evaluating treatment-related differences in  rates of program
completion and daily mobile app usage using independent samples (between treatment and control groups) or
paired (within the educational control group)  t-tests. We will also assess treatment-related differences in
self-reported usability and engagement using the SUS and UES scales descriptively by comparing means and
variability between groups and within group (control group only)
Statistical analyses for the primary outcome variable and between group differences in rates of clinical
concerns rates will be conducted when N=60 (~30/grp) and N=120 (~60/grp) participants have completed
Phase II. If no statistical differences are detected in the primary outcome variable, possible moderators of
treatment status on the primary outcome may be evaluated, including age, concurrent treatment, and PHQ-8
score at baseline. Results of the interim analyses may be used to adjust recruitment targets for the remainder
of the trial.
An effect size will be calculated for the primary outcome and may be used to determine sample size for a
Phase III trial.
4.5 Data Monitoring
This is a low risk research study.

A clinical concern is defined here as any negative experience or symptom reported by participant or parent in
the Participant Symptom Check Questionnaire, in freeform text, spontaneously reported, or clinically significant
deterioration of symptoms, whether or not thought to be associated with participation in the study.
Clinical concerns will be categorized as follows:
0- Not a clinical concern: Research team determined that triggering event was not a clinical concern
1- Mild clinical concern: Research team determined that triggering event doesn’t require clinician input and will
continue to monitor participant’s responses
2- Moderate clinical concern: Research team determined that triggering event requires clinician input. Clinician
determined that research team should continue to monitor participant’s responses but that no follow-up was
needed.
3- Elevated clinical concern: Research team determined that triggering event requires clinician input. Clinician
determined follow-up was indicated and confirmed participant safety (participant did not endorse intent to self
harm) via email or phone communication with participant or their parent/guardian or their provider.
4- Significant clinical concern: Research team determined that triggering event requires clinician input.
Clinician determined that follow-up was indicated and after follow-up with participant, parent/guardian, or
provider determined that participant should be withdrawn from study (e.g. due to suicide attempt, self-harm or
self-harm attempt, suicidal ideation with intent, reported hospitalization for self-harm or suicide attempt while
enrolled in study).
All adverse device effects and complaints will be recorded (whether anticipated or unanticipated). The project
PI and study clinician will determine whether it is in the participant’s best interest to remain in the study after
any clinical concern.
Anticipated serious clinical concerns, given the study population, include depressive symptoms as defined in
the DSM-V, suicidal ideation, active self-harm, clinically significant deterioration in depressive symptoms,
suicide attempts, and suicide.
This study may be stopped prior to its completion if: 1) study recruitment or retention is too low for the study to
provide meaningful results; 2) new information becomes available during the trial that necessitates stopping
the trial; 3) other situations occur that might warrant stopping the trial. Given that the trial intervention is
relatively safe and updates to the mobile app are planned a priori, the trial will not be stopped prior to
implementation of Spark version 3 for lack of demonstrated efficacy. The trial may be stopped early if PIs, in
collaboration with study clinician and DSMB, determine from interim analyses during implementation of version
3 that the Spark app is not efficacious or if there are safety concerns. The trial will be stopped early if PIs, in
collaboration with the study clinician, find that the harm to study participants outweighs the benefit of the
scientific evidence to be accrued by continuing the trial at any time.
Unanticipated adverse device effects (UADE, as defined in 21 CFR 812.3, also referred to as “Unanticipated
Problems”): Any serious adverse effect on health or safety or any life-threatening problem or death caused by,
or associated with, a device, if that, effect, problem, or death was not previously identified in nature, severity, or

degree of incidence in the investigational plan or application; OR Any other unanticipated serious problem
associated with a device that relates to the rights, safety, or welfare of subjects.
UADEs must meet all of the following criteria:
●
Serious
●
Associated with the device under investigation
●
Unexpected
●
Likely to require a significant change to study protocol (i.e., serious clinical concern occurring with a
frequency or severity that changes such as modification of safety monitoring protocol or revision of
inclusion/exclusion criteria would be required)
PIs will report unanticipated adverse device effects to the IRB and DSMB within 10 working days. Limbix will
immediately conduct an evaluation of any reported unanticipated adverse device effect and will report such
effects to the FDA within 10 working days. If it is determined that an unanticipated adverse device effect
presents an unreasonable risk to subjects, the investigation or parts of the investigation presenting that risk will
be terminated as soon as possible. Termination shall occur not later than 5 working days after the sponsor
makes this determination and not later than 15 working days after the sponsor first received notice of the effect.
Limbix will not resume a terminated investigation without IRB approval and, if the investigation was terminated
under paragraph (b)(2) of 21 CFR 812.46, FDA approval.
Limbix will submit to FDA a copy of any report by an investigator under paragraph (a)(5) of section 21 CFR
812.150 of use of a device without obtaining informed consent, within 5 working days of receipt of notice of
such use.
Per 21 CFR 56.108(b)(1) and 21 CFR 812.150(a)(1), PIs will report any unanticipated problem involving risk to
human subjects or others to the IRB.
4.5.1 Study Staff Responsibilities
Data monitoring will be conducted by the research coordinator and overseen by project PIs. In the course of
data collection and monitoring, study coordinators will follow an internal safety protocol and alert a study PI or
study clinician of any clinical concerns that occur during baseline or post study interview sessions sessions, in
freeform text, email/text/phone correspondence, in weekly PHQ scores, and the weekly participant symptom
check.
The PIs in consultation with study clinicians will be responsible for monitoring participant safety during the
study. The PIs and study clinicians will review relevant assessments, free-responses, and reports from study
staff to assess whether it is appropriate for the participant to continue study participation and whether further
action to ensure the safety and wellbeing of the participant is warranted. If warranted, the study clinician will
reach out to the participant and parent (if under 18) to confirm safety. Because this study is low risk, the study
clinicians will not be on call 24/7.
The study clinicians are licensed medical providers and have experience in the assessment of mood and
anxiety symptoms, in directing the treatment of such symptoms, and in addressing possible adverse reactions
during clinical trials. The study clinicians will assess the benefits and risks of the protocol on an ongoing basis
and will be available to the study team  for questions regarding inclusion/exclusion criteria, protocol conduct,
and safety. The study clinicians will review and evaluate information relevant to the safety of this study before

the implementation of the protocol and will recommend alterations to the study design based on review of
subject safety trends.
PIs will review all data collection materials on an ongoing basis for data completeness and accuracy as well as
protocol adherence. Protocol deviations and violations will be reported in accordance with IRB and FDA
guidelines. In this study, a protocol violation includes but is not limited to enrollment of an ineligible participant
and failure to obtain informed consent. A protocol deviation includes but is not limited to minor deviations from
protocol that do not impact safety or efficacy and failure to keep IRB approval up to date.
4.5.2 Data Safety Monitoring Board
We will assemble a formal Data and Safety Monitoring Board (DSMB) for Phase II of this study to ensure that
the safety of study subjects is protected and that the scientific goals of the study are being met. The
assessment of feasibility in Phase I will help to determine what safety parameters are required for Phase II.
The team assembled for the DSMB will have relevant and complementary expertise in adolescent psychiatry,
clinical trial design, digital health, and statistics. Importantly, none of these individuals will be involved in any
other capacity with this study or have any potential conflicts of interest in study- related outcomes.
The DSMB will review and evaluate information relevant to the safety of this study before the implementation of
the protocol. Activities of the DSMB will include:
1.
Reviewing the study protocol at the start of the study and any proposed amendments related to
changes in study design, safety monitoring, or analytic plan.
2.
Recommending alterations to the study design
3.
Approving the study before commencement
4.
Performing expedited monitoring of unexpected adverse device effects at the time of their occurrence
and providing recommendations accordingly
5.
Performing quarterly review of  all clinical concerns
6.
Performing ongoing quarterly review of study progress.
7.
Reviewing any data that may reflect differences in safety between treatment groups
8.
Determining whether study procedures should be changed or the study should be halted for reasons
related to the safety of study subjects
9.
Performing quarterly review of the completeness and validity of data to be used for analysis of safety
and efficacy.
DSMB will convene by video- or teleconference prior to the start of the study and then quarterly through the
study period. The Study PIs will be responsible for providing the study protocol to the DSMB prior to the initial
meeting.   At the initial meeting, the study PIs will meet with the DSMB to review the research protocol,
informed consent documents, and plans for data safety and monitoring. The DSMB will review the protocol,
discuss with the study team, discuss amongst themselves, and then make recommendations -if any- for
modification of the protocol to the study team. The study team will record the recommendations and provide a
written document to the DSMB following the meeting for approval and sign off.
The DSMB will then meet on a quarterly basis to assess study progress, data quality, participant recruitment,
accrual, and retention, participant risks versus benefits, any breaches of confidentiality, clinical concerns, any
interim results of safety and efficacy, and the ethics of this trial. Additional meetings may be convened when

deemed necessary.The study PIs will be responsible for providing a report to the DSMB prior to the meeting
with all of the necessary information as outlined above.
The DSMB will provide verbal recommendations during the quarterly meetings related to continuation,
termination, or other modifications of the trial and sign off on a written report following the meeting. The DSMB
may also conduct independent analysis of the data. The Study PIs will be responsible for providing all data
necessary to the DSMB to conduct this analysis. Unexpected serious device effects will be reported to the
DSMB within 10 business days.
The IRB will receive a summary report of safety findings on an annual basis from the DSMB. This data and
safety review as well as an assessment of protocol compliance and data quality will facilitate the early
detection of safety signals and will maximize the likelihood of continued appropriateness of the research and
protection of human subjects. The review will also ensure that participants who experience and report clinical
concerns are provided with proper and, if necessary, ongoing attention. Any recommendations to improve
patient safety, protocol adherence, or data quality will also be included.
5. Data Storage and Confidentiality
Ethical guidelines for clinical research will be followed. All information obtained will be kept strictly confidential
except as required by law and as otherwise indicated in this protocol and informed consent forms. We will
comply with all mandated reporting rules. All researchers must demonstrate through training and testing
up-to-date understanding of and commitment to follow all the guidelines and rules related to HIPAA, human
subjects research, and good clinical practice that apply to this research.
Special care will be taken to prevent unauthorized access to data files. Limbix owned computers on which data
files will be accessed will have password-protection. All study participants will be assigned participant ID
numbers upon enrollment in the study and all subsequent data processing will be completed by reference to
these numbers. The file linking participant ID number to personal identifying information, post-study interview
audio recordings, and case report forms are stored on Google Drive with a business agreement in place
protecting those files. Only research staff who require access for study-related activities have permissions to
view and/or edit these files.
Signed electronic consent forms will be stored through HelloSign Part 11 compliant services.
The data generated by the Spark mobile client or web portal (used for baseline and post-intervention
assessments for participants and parents) will be stored in an Aptible PostgreSQL database, which is backed
up daily to geographically separate regions and encrypted at rest. After the study, the data will continue to be
stored in said database. In the event that we need to decommission the database, we will move the data to
cold storage in either Google Cloud Platform or Amazon Web Services (AWS) for the remaining length of time
required to comply with GCP and will configure those buckets to be encrypted at rest as well. An anonymized
copy of a portion of the study data will be synced daily to Google Cloud Platform for easier analysis. This copy
of the data will have sensitive fields such as email, phone number, and first name removed and still require a
valid Limbix employee login for access.
Access to the database requires SSH login to Aptible ephemeral containers that generate logs every time an
employee logs in. Accounts on Aptible are limited on a need basis and employees are assigned to roles based

on the level of access they need to the system. The roles with access to the database are Account Owners
and Enclave Owners only.
There will be a researcher portal where Limbix research staff can view aggregate and individual participant
data of accounts that are enrolled in the study. Accounts on the researcher portal have access to study data
limited by roles. The roles with access to study data are System Admin, Study Admin (PIs), Study Operator,
and Read-only. All content on the researcher portal will require valid login credentials with password protection.
Data generated by the Spark mobile client or web portal will also be visible through an admin portal. Accounts
on the admin portal will be limited to employees that need access in order to run and maintain technical
infrastructure. All access to the admin portal will require valid login credentials with password as well as a
one-time MFA password.
Anonymous usage data (such as button clicks and screen navigation) generated by the Spark mobile client will
be aggregated using Google Analytics. All access to this data will require a valid Limbix employee login for
access.
The Spark mobile application will also require valid login credentials with password protection to access
individual account information. If the mobile app does not communicate with the server for 30 days, the user
will be signed out of their account automatically and have to re-login to access their data in the mobile
application. After participants have completed study participation, they will be marked as completed by a
research staff member via the researcher portal and access to the mobile application will be restricted.
Only the study coordinator or PIs will directly contact study participants via phone or email per the study
protocol to answer study-related questions. Text and email communication is encrypted in transit but
unencrypted when being sent or received. Other research staff may interact with participants to troubleshoot
software issues that may arise. Study clinicians may contact participants and/or parents (if under 18) if safety
concerns arise.
The research coordinator will recommend that participants complete research-related activities including the
virtual consent process in a private location. The research coordinator will conduct all research-related
activities in a private room where individuals beyond the research investigators and staff cannot overhear the
conversation. Participants are expected to complete the self-guided Spark program at a location of their
choice.
No data with subject identifiers will be released, and all data obtained will be stored and maintained in a secure
manner. All publications or reports of data will be anonymous in relation to subject identification. Protected
health information will be disclosed to other professionals treating the patient only upon written authorization of
the patient. Data will be stored in a confidential manner after the research is completed in accordance with
GCP. The PI will retain responsibility for ensuring that data are maintained in a secure manner.
De-identified data or a limited data set may be shared for future research by Sponsor after a data use
agreement is signed, where appropriate.
6. Transition from Research Participation
N/A

7. Risk/Benefit Assessment
7.1 Risk Category
Minimal risk
7.2 Potential Risk
Psychological risks: Some personal questions about life experiences or mood may bring up uncomfortable
feelings.
Loss of confidentiality: As this study involves the use of identifiable, personal information, there is a chance
that a loss of confidentiality will occur though steps to mitigate this risk have been taken as described below.
7.3 Protection Against Risk
To minimize psychological risks, participants will be instructed that they can choose not to answer any question
in any assessment and can discontinue their participation at any time. As the mobile app progresses in a linear
fashion, questions in the mobile program must be answered to progress to the next task. During consent,
participants will be informed that if they do not wish to answer a question in the mobile app they may
discontinue their participation at any time. Patient responses to assessments completed weekly will be
monitored as well as free response answers to questions delivered via the mobile app. This will enable
detection of deterioration in clinical status. If such deterioration occurs, research staff will immediately contact
the PI/study clinician. Participation will be terminated if clinical evidence indicates that continuing would not be
in the best interest of the subject as determined by study PI in consultation with a study clinician. Weekly
symptom reporting will also help the research team to identify any psychological or physical health
consequences of study participation and, in consultation with study clinicians, determine the best way to
mitigate further risks to participant health.
To minimize risks to privacy and/or confidentiality, only personnel with training in protecting private information
about human subjects will have access to study data. Special care will be taken to prevent unauthorized
access to data files.
Computers on which data files will be accessed will have password-protected access. All study participants will
be assigned code numbers on entry to the study and all subsequent data processing will be completed by
reference to these numbers. Special care will be taken to prevent unauthorized access to the data file
connecting participant identity to subject numbers.
All publications or reports of data will be anonymous in relation to subject identification. Protected health
information will be disclosed to other professionals treating the patient only upon written authorization of the
patient. PIs will retain responsibility for ensuring that files are maintained in a secure manner during and after
study.
Study personnel will ensure that no individuals outside the research team can overhear conversations during
the virtual consent process. Participants in the study will be expected to complete mobile interventions at a
location of their own discretion with respect to privacy and confidentiality.

Although every reasonable effort has been taken, confidentiality during Internet and phone-based
communication procedures cannot be guaranteed and it is possible that additional information beyond that
collected for research purposes may be captured and used by others not associated with this study.
Any data shared in the future will be stripped of all identifying information and protected health information or a
limited data set may be shared with a data use agreement, when applicable.
7.4 Potential Benefits to the Subjects
No direct benefits can be guaranteed by participating in this research protocol. As participants in the treatment
arm will receive a mobile program designed to be therapeutic they may experience direct benefits from
participation in terms of reduced symptoms of depression, as well as potential reductions in comorbid anxiety
symptoms, and improvements in mood, and/or functional outcomes. Participants in the control arm will receive
educational information about depression, including information on healthy habits and wellbeing which may
also result in direct benefits from participation in terms of reduced symptoms of depression, as well as potential
reductions in comorbid anxiety symptoms, and improvements in mood, and/or functional outcomes.
Participants may also directly benefit from participating in the proposed research because of the knowledge
obtained. Assessments and procedures completed during the study may provide participants with an
opportunity to reflect on their thoughts, feelings, and behaviors which may be valuable in helping individuals
better understand their own emotional functioning. These benefits outweigh the minimal risks associated with
this trial.
Participants will have the opportunity to provide feedback about the intervention to help improve the program
for future users. This ability to help others may also have therapeutic benefits for participants.
7.5 Alternatives to Participation
Prospective participants who decline to enroll in this study are free to consider alternatives, including seeking
treatment. Standard of care treatment for adolescent depression typically includes psychotherapy with or
without antidepressants, depending on clinically determined variables. Mental health resources will be shared
with potential participants who decline to participate in this study but are treatment-seeking. However,
alternative treatments are not promised or guaranteed.
8. Subject Identification, Recruitment and Consent/Assent
8.1 Method of Subject Identification and Recruitment
Participants will be recruited via online advertising, social media, word of mouth, flyers, and recommendations
by doctors, schools, and other youth and health focused organizations. Providers may be compensated for
recruitment efforts (based on hourly effort and not on number of referrals or enrolled participants). Online ads
will be targeted to adolescents ages 13-21 or to the parents of adolescents nationwide. Study ads will direct
potential participants to a study landing page. The study landing page will provide a basic overview of the study
and will ask interested participants to confirm their eligibility based on provided eligibility criteria and set up a
virtual consent appointment with a research coordinator. Interested potential participants under 18, when
required, will be instructed that they will need a legal guardian to attend the virtual consent appointment.
Flyers and advertisements (provided as attachments) may also be posted online on Craigslist, Facebook, and
other websites.

8.2 Process of Consent
Any trained member of the research team will be authorized to obtain informed consent.
Prior to participation, e-consent will be obtained for all participants over 18. For participants under 18,
e-consent from a legal guardian and documented assent from participants will be obtained.
The consent process will be completed virtually via videoconferencing. To ensure participant privacy, the
research staff member conducting the consent process will ensure that no one outside of the research team
can overhear the consent process from their end and will recommend that the potential participant join the
videoconference from a private location.
The researcher will explain the study, review the consent form, take time to answer any questions, provide time
for decision-making and request an electronic signature.
The session will emphasize:
1) This is a research study testing an investigational medical device intended as a treatment for depression
2) Possible (minimal) risks and benefits of participation,
3) Participants can elect not to respond to any question(s) they are not comfortable answering
4) Participants can choose to end their participation at any time for any reason
5) All information will be kept confidential with the exception of certain information we must report for legal or
ethical reasons including suspected child abuse or neglect, suspected elder abuse or neglect, or intent to harm
oneself or others.
The consent and assent process will be considered complete only if the adolescent (and legal guardian if the
participant is under 18) report comfort with and comprehension of all study procedures. The session will
proceed only if informed consent is obtained.
After all questions concerning any aspect of the study have been fully answered by study staff, a Part 11
compliant, electronic signature (via HelloSign) will be obtained from the participant or their legal guardian (if
under 18) to document consent. Documentation of the assent of a minor will also be obtained. Participants or
their legal guardian will be required to display a valid form of identification to verify identity. Participants will be
provided with a link to access and download a copy of the signed consent form at any time. Signed electronic
consent forms will be stored through HelloSign Part 11 compliant services.
If a minor will become of legal consenting age during their participation in the study they will be required to set
up an e-consent appointment at that time and consent to continuing their participation.
8.3 Subject Capacity
The study will not enroll participants who are unable to consent or whose legal guardians are unable to
consent on their behalf (if potential participants are under 18). Discussions between potential participants
and research staff member about study requirements during the consent process will disclose any obvious
comprehension problems or physical limitations that would prohibit participation. Cognitive and physical
limitations that would preclude participation are included as part of study eligibility criteria.
8.4 Subject/Representative Comprehension

All participants will receive a verbal explanation, in terms suited to their comprehension, of the purpose,
procedures and potential risks of the study and of their rights as research participants. Participants and their
legal guardian will be given ample time and opportunity to carefully review the consent forms and ask
questions regarding this study to study staff, family, friends, and/or doctors prior to signing. After expression of
understanding, the participants, legal guardian, and research staff member will electronically sign the consent
form. Understanding will be confirmed by asking specific questions to patients and their legal guardians to
evaluate comprehension.
8.5 Debriefing Procedures
No information will be purposefully withheld from participants or their legal guardians.
8.6 Consent Forms
The following informed consent forms are being submitted with this protocol:
1. Informed Consent
8.7 Documentation of Consent
A Part 11 compliant, electronic signature (via HelloSign) will be obtained from the participant or their legal
guardian (if under 18) to document consent. Documentation of the assent of a minor will also be obtained.
Participants or their legal guardian will be required to display a valid form of identification to verify identity.
Participants will be provided with a link to access and download a copy of the signed consent form at any time.
Signed electronic consent forms will be stored through HelloSign Part 11 compliant services.
8.8 Costs to the Subject
Participants are expected to provide payment for clinical care that is not part of this research protocol (e.g.,
hospitalization costs) through standard health care payment procedures. Participants will have no costs
associated with research participation. Limbix will pay for all procedures associated with the study or
necessary study-related follow-up.
8.9 Payment for Participation
Participants will be compensated $25 for completing the post-intervention assessments regardless of program
adherence. Participants and legal guardians who complete post-intervention user interviews will each be
compensated $25. In Phase II, all participants will also be compensated $25 for completing baseline
assessments and participants randomized to the control arm can earn an additional $25 for completing a
second set of post-intervention assessments after they are provided access to Limbix Spark. Payment will be
issued in the form of a gift card upon the completion of the compensated research activity (i.e., completion of
assessments or user interview).
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