Click's Ecological Momentary Assessment (EMA) and Text Message Intervention for Stress Management (FACE STRESS Study)
Phase: NA
Conditions: Stress, Psychological, Loneliness, Covid19, Stress
Sponsor: Click Therapeutics, Inc.

‭Protocol DL-FACE-101 v1.0‬
‭Protocol Title:‬
‭Feasibility and Acceptability of Click’s Ecological momentary assessment (EMA) and text message‬
‭intervention for STRESS management (FACE STRESS study).‬
‭Protocol Number:‬‭DL-FACE-101‬
‭Amendment Number:‬‭N/A‬
‭Device:‬‭N/A‬
‭Study Phase: N/A‬
‭Sponsor Name: Click Therapeutics, Inc‬
‭Legal Registered Address:‬
‭80 White St., 3rd Floor‬
‭New York, NY 10013‬
‭Manufacturer: Click Therapeutics, Inc‬
‭Regulatory Agency Identifier Number(s)‬
‭NCT04907942‬
‭1‬

‭Protocol DL-FACE-101 v1.0‬
‭Sponsor Signatory:‬
‭6/30/2020‬
‭Date‬
‭Medical Monitor Name and Contact Information will be provided separately.‬
‭2‬

‭Protocol DL-FACE-101 v1.0‬
‭Protocol Amendment Summary of Changes Table‬
‭DOCUMENT HISTORY‬
‭Document‬
‭Date‬
‭Original Protocol‬
‭06/25/2020‬
‭Amendment‬
‭N/A‬
‭3‬

‭Protocol DL-FACE-101 v1.0‬
‭Table of Contents‬
‭1. Protocol Summary‬
‭6‬
‭1.1. Synopsis‬
‭6‬
‭1.2. Schema‬
‭8‬
‭1.3. Schedule of Assessments (SoA)‬
‭8‬
‭2. Introduction‬
‭10‬
‭2.1. Study Rationale‬
‭10‬
‭2.2. Background‬
‭10‬
‭2.3. Benefit/Risk Assessment‬
‭12‬
‭3. Objectives and Endpoints‬
‭13‬
‭4. Study Design‬
‭14‬
‭4.1. Overall Design‬
‭14‬
‭4.2. Scientific Rationale for Study Design‬
‭14‬
‭4.2. Justification for Dose‬
‭15‬
‭4.3. End of Study Definition‬
‭15‬
‭5. Study Population‬
‭16‬
‭5.1. Inclusion Criteria‬
‭16‬
‭5.2. Exclusion Criteria‬
‭16‬
‭5.3. Lifestyle Considerations‬
‭16‬
‭5.4. Screen Failures‬
‭16‬
‭5.5. Recruitment‬
‭16‬
‭6. Study Intervention and Concomitant Therapy‬
‭17‬
‭6.1. Study Intervention Administered‬
‭17‬
‭6.2. Preparation/Handling/Storage/Accountability‬
‭17‬
‭6.3. Measures to Minimize Bias: Blinding‬
‭18‬
‭6.4. Study Intervention Compliance‬
‭18‬
‭6.5. Dose Modification‬
‭18‬
‭6.6. Continued Access to Study Intervention after the End of the Study‬
‭18‬
‭6.7. Treatment of Overdose‬
‭18‬
‭6.8. Concomitant Therapy‬
‭18‬
‭7. Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal‬
‭19‬
‭7.1. Discontinuation of Study‬
‭19‬
‭7.2. Participant Discontinuation/Withdrawal from the Study‬
‭19‬
‭7.3. Lost to Follow up‬
‭19‬
‭8. Study Assessments and Procedures‬
‭20‬
‭8.1. Efficacy Assessments‬
‭20‬
‭8.2. Safety Assessments‬
‭22‬
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‭Protocol DL-FACE-101 v1.0‬
‭8.3. Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting‬ ‭23‬
‭8.4. Pharmacokinetics‬
‭27‬
‭8.5. Genetics and/or Pharmacogenomics‬
‭27‬
‭8.6. Biomarkers‬
‭27‬
‭9. Statistical Considerations‬
‭28‬
‭9.1. Statistical Hypotheses‬
‭28‬
‭9.2. Sample Size Determination‬
‭28‬
‭9.3. Analysis Sets‬
‭28‬
‭9.4. Statistical Analyses‬
‭28‬
‭9.5. Interim Analysis‬
‭29‬
‭10. Supporting Documentation and Operational Considerations‬
‭30‬
‭10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations‬
‭30‬
‭10.2. Appendix 2: Clinical Laboratory Tests‬
‭33‬
‭10.3. Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating,‬
‭Follow-up, and Reporting‬
‭34‬
‭10.4. Appendix 4: Contraceptive and Barrier Guidance‬
‭38‬
‭10.5. Appendix 5: AEs, ADEs, SAEs, SADEs, USADEs and Device Complaints and‬
‭Nonconformances: Definitions and Procedures for Recording, Evaluating, Follow-up, and‬
‭Reporting in Device Studies‬
‭39‬
‭Appendix 6: Abbreviations and Definitions‬
‭43‬
‭5‬

‭Protocol DL-FACE-101 v1.0‬
‭1.‬
‭Protocol Summary‬
‭1.1.‬
‭Synopsis‬
‭Protocol Title:‬
‭Feasibility and Acceptability of Click’s EMA and text message intervention for STRESS‬
‭management (FACE STRESS study).‬
‭Rationale:‬
‭The purpose of the proposed study is to explore feasibility, acceptability, and initial efficacy of‬
‭an Ecological Momentary Assessment (EMA) and text message intervention for stress‬
‭management.‬
‭Objectives and Outcomes‬
‭Objectives‬
‭Outcomes‬
‭Primary‬
‭●‬
‭Feasibility of recruitment including‬
‭eligibility rates and acceptance rates‬
‭●‬
‭Feasibility of delivering the‬
‭intervention via text message‬
‭●‬
‭Acceptability of the intervention‬
‭including dropout rates, percentage‬
‭of completed assessments,‬
‭adherence, and estimates of‬
‭satisfaction‬
‭The‬‭main outcome‬‭of the FACE STRESS‬
‭study is to evaluate‬‭feasibility and‬
‭acceptability‬‭of an EMA and EMA plus text‬
‭message intervention. Specifically, we will‬
‭evaluate:‬
‭●‬ ‭number of interested individuals who‬
‭contact Click Therapeutics because‬
‭their interest in  participating in the‬
‭study‬
‭●‬ ‭the number of eligible individuals‬
‭after the initial screening‬
‭●‬ ‭time taken to recruit the sample‬
‭●‬ ‭retention rates‬
‭●‬ ‭the number and percentage of‬
‭participants responding to any EMA‬
‭text over the 3-week study‬
‭●‬ ‭Satisfaction will be measured using‬
‭both open-ended questions and‬
‭likert-scaled questions to examine the‬
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‭Protocol DL-FACE-101 v1.0‬
‭acceptability and utility of the both‬
‭EMA and intervention texts. ‬
‭Secondary‬
‭●‬ ‭Explore indicators of the EMA and‬
‭text message intervention efficacy‬
‭●‬ ‭The effect sizes on reductions in‬
‭perceived stress and other‬
‭psychological symptoms will be‬
‭estimated in the EMA and EMA+‬
‭intervention groups at‬
‭post-intervention, 1, 3 and 6-month‬
‭time-points. ‬
‭Secondary outcomes‬‭will measure:‬
‭●‬ ‭Perceived stress and psychological‬
‭overload‬
‭●‬ ‭symptoms of anxiety and depression‬
‭●‬ ‭symptoms of PTSD‬
‭●‬ ‭positive and negative affects‬
‭●‬ ‭resilience‬
‭●‬ ‭psychological well-being‬
‭Overall Design:‬
‭Brief Summary:‬
‭The purpose of this study is to evaluate feasibility and acceptability of an EMA compared with‬
‭an EMA plus text message intervention in participants with higher-than-average perceived stress.‬
‭Study details include:‬
‭Study Duration: 7 months‬
‭Intervention Duration: 3 weeks‬
‭Number of Participants: 70‬
‭Up to 120 participants will be screened to achieve 70 enrolled to the study (see Section 9.2).‬
‭Groups and Duration: 2 groups (EMA alone or EMA plus text message intervention); 3‬
‭weeks‬
‭Data Monitoring Committee/Data Safety Monitoring Board: N/A‬
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‭Protocol DL-FACE-101 v1.0‬
‭1.2.‬
‭Schema‬
‭N/A‬
‭1.3.‬
‭Schedule of Assessments (SoA)‬
‭CONFIDENTIAL‬
‭8‬
‭Procedure‬
‭Pre-Enroll‬
‭ment‬
‭Day‬
‭1‬
‭Days‬
‭2-4‬
‭Days‬
‭5-25‬
‭Day‬
‭26‬
‭1 Mo.‬
‭Post-Study‬
‭3‬
‭Mos.‬
‭6‬
‭Mos.‬
‭E/D‬‭1‬
‭Telephone‬
‭Contact‬
‭X‬
‭X‬
‭Inclusion and‬
‭Exclusion‬
‭Criteria‬
‭X‬
‭Demography‬
‭X‬
‭Informed‬
‭Consent‬
‭X‬
‭Baseline‬
‭Assessment‬
‭X‬
‭EMA+Interven‬
‭-tion‬
‭X‬
‭Post‬
‭Intervention‬
‭Assessment‬
‭X‬
‭Follow Up‬
‭Assessment‬
‭X‬
‭X‬
‭X‬

‭Protocol DL-FACE-101 v1.0‬
‭CONFIDENTIAL‬
‭9‬
‭Procedure‬
‭Pre-Enroll‬
‭ment‬
‭Day‬
‭1‬
‭Days‬
‭2-4‬
‭Days‬
‭5-25‬
‭Day‬
‭26‬
‭1 Mo.‬
‭Post-Study‬
‭3‬
‭Mos.‬
‭6‬
‭Mos.‬
‭E/D‬‭1‬
‭AE/SAE‬
‭Reporting‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭1.‬
‭Early Discontinuation‬

‭Protocol DL-FACE-101 v1.0‬
‭2.‬
‭Introduction‬
‭Click Therapeutics digital therapeutic software applications are integrated with the unique‬
‭feature of a personalized messaging system. Personalized messages provide the opportunity to‬
‭tailor the intervention to the specific needs of the individual patient. This study will be pivotal‬
‭in addressing the feasibility of adding to Click’s platform a stand-alone text message‬
‭intervention for stress management. Many patients with psychiatric and medical conditions‬
‭suffer with chronic stress which exacerbate course and progression of the disease. A stand-alone‬
‭text message intervention will represent an important feature to add to Click’s platform across‬
‭indications to target patients with high levels of stress.‬
‭2.1.‬
‭Study Rationale‬
‭The overarching goal of Face Stress study is to explore feasibility and acceptability and initial‬
‭efficacy of an EMA and text message intervention for stress management as a digital‬
‭intervention. As the current pandemic has the potential of causing an increase in mental health‬
‭problems in people who will be affected by Covid-19 for various reasons and in-person‬
‭counselling and support are not possible, evaluating the feasibility of using a text messaging‬
‭intervention to manage stress could be the stepping stone to provide support and reach a broader‬
‭population. Based on this premise, our main research questions are: 1) Will it be feasible to‬
‭deliver an EMA and text message intervention for the management of stress?; 2) Will‬
‭participants find the EMA delivery and SMS content acceptable (satisfactory); 3) Efficacy‬
‭question: will the text message intervention result in improved resilience and/or reduced‬
‭psychological distress?‬
‭2.2.‬
‭Background‬
‭The covid-19 pandemic represents an historic event with the potential to cause enormous‬
‭psychological distress both because of the fear of the virus and its health implications, and‬
‭because it requires major life adjustments (i.e. social distancing, isolation, unemployment etc.)‬
‭which pose further strain on people’s mental health. A recent review of the available literature‬
‭reported that in the general population symptoms of distress and self-reported stress (8-28%) are‬
‭common psychological reactions to the COVID-19 pandemic. A survey including 52,730‬
‭participants living in the Wuhan region in China, found that‬‭35% of the respondents experienced‬
‭psychological distress.‬
‭How individuals respond to stressful and traumatic experiences over time have been evaluated in‬
‭longitudinal studies aiming at identifying stress and resilience trajectories. Evidence supports an‬
‭adapting response with‬‭most individuals showing patterns‬‭of resilience and gradual recovery (3).‬
‭However, about 38% of people experiencing traumatic and stressful situations show persistent‬
‭chronic stress or a delayed stress response. Even though these studies have been helpful in‬
‭pointing out that most people are indeed resilient, they present several limitations due to the use‬
‭of‬‭traditional assessment methods. Such measures are‬‭collected infrequently and require‬
‭participants to recall past events, feelings, and states, increasing the likelihood of bias and‬
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‭Protocol DL-FACE-101 v1.0‬
‭limiting the ability to detect points of inﬂection where actual change occurs. Thus,‬‭little is known‬
‭about specific turning points in these trajectories and possible predictors of such turning points in‬
‭both observational and interventional studies‬‭.‬
‭Ecologically valid assessment methods have been developed to address the issues represented by‬
‭the customary recall measures. Ecological Momentary Assessment (EMA) involves measuring‬
‭psychological processes repeatedly in real time as they occur in the natural environment.‬‭EMA‬
‭encompasses diverse assessment techniques including diaries, behavioral observation, and‬
‭self-monitoring. EMA presents the advantage of minimizing recall bias, while improving‬
‭generalizability and ecological validity. It also allows the identification of microprocesses that‬
‭influence behaviors in real-world contexts.‬
‭Several contributions reported that during the 2003 SARS epidemic, individuals who presented‬
‭high levels of stress continued showing stress symptoms longer after the successful containment‬
‭of the disease. A survey conducted on the general population, 4 months after resolution of the‬
‭SARS crisis in Taiwan found that the prevalence of psychiatric morbidity was 11.7%. Lee et al.‬
‭(7) showed that SARS survivors not only had higher stress levels during the outbreak, compared‬
‭with control subjects (PSS-10 scores = 19.8 and 17.9, respectively; P < 0.01), but this also‬
‭persisted 1 year later (PSS-10 scores = 19.9 and 17.3, respectively; P < 0.01). At 1 year, about‬
‭64% of participants scored above the GHQ-12 cut-off suggesting the presence of psychiatric‬
‭morbidity (7). Health care workers had stress levels similar to those of non-health care workers,‬
‭but showed significantly higher stress levels a year later (PSS-10 score = 22.8, compared with‬
‭PSS-10 score = 18.4; P < 0.05) and had higher depression, anxiety, posttraumatic symptoms, and‬
‭GHQ-12 scores (7). Likewise, individuals who had been quarantined, or worked in high-risk‬
‭locations such as SARS wards, or had friends or close relatives who contracted SARS, were 2 to‬
‭3 times more likely to have high PTSD symptoms, than those without these exposures 3 years‬
‭later. In the light of these findings and the knowledge that about 1/3 of individuals affected by‬
‭stressful life events show a chronic or delayed stress trajectory, we can assume that, without‬
‭intervening, millions of survivors in the 216 countries affected will progress to develop‬
‭psychiatric morbidity.‬
‭To overcome the actual challenge of delivering counseling and psychological support in person,‬
‭text messaging interventions could represent a convenient and easy solution to adopt. Text‬
‭message interventions have been widely used to support healthy behavior change such as‬
‭smoking cessation, weight loss and health promotion. Evidence shows that text messaging‬
‭interventions are effective in promoting behavior change. For example, a three-arm randomized‬
‭trial compared self-reported alcohol use three months after emergency department visits, during‬
‭which 765 young adults reported hazardous drinking. The number of self-reported binge‬
‭drinking days decreased from baseline to three months in the real-time feedback group compared‬
‭to text message drinking assessments without feedback or a control condition. A health‬
‭text-messaging program including a range of health topics and information was effective in‬
‭increasing health awareness in college students. Previous research provided evidence that‬‭text‬
‭messages intervention including psychoeducation, reminders, and links to informative materials‬
‭can be effective in improving individuals’ mental health‬‭. For example, a text message‬
‭intervention was found to be effective in improving parental competence and parental distress‬
‭(estimated mean difference, -2.39 points; 95% CI, -4.37 to -0.40 points; P = .02) compared to‬
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‭Protocol DL-FACE-101 v1.0‬
‭controls.‬‭Agyapong et al sent supportive text messages twice a day to a sample of 54 patients‬
‭with depressive symptoms over a 3-month period. During this period, patients in the intervention‬
‭group had significantly lower scores on the Beck Depression Inventory-II than control groups‬
‭(8.5, standard deviation [SD] 8.0 vs. 16.7, SD 10.3,‬‭P‬‭=.003).‬‭In Canada, a supportive text‬
‭message (Text4Mood) program was recently launched to support mental health during‬
‭COVID-19. Within 1 week of the launch of Text4Hope, 32,805 subscribers had signed up to the‬
‭program showing the relevance and timely importance of text messaging intervention.‬
‭2.3.‬
‭Benefit/Risk Assessment‬
‭Some participants may experience discomfort when completing assessments related to their‬
‭stress levels and emotional well-being. Although participation in this study may reduce stress‬
‭and improve emotional well-being, we recognize that individuals experiencing high stress may‬
‭conversely face the risk of symptomatic worsening. Both text message platforms are two-way.‬
‭This will allow for review of the evaluation of content and assessment to determine if‬
‭participants are experiencing a worsening of stress and are in need of further support.‬
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‭Protocol DL-FACE-101 v1.0‬
‭3.‬
‭Objectives and Endpoints‬
‭Objectives‬
‭Outcomes‬
‭Primary‬
‭●‬
‭Feasibility of recruitment‬
‭including eligibility rates and acceptance‬
‭rates‬
‭●‬
‭Feasibility of delivering the‬
‭intervention via text message‬
‭●‬
‭Acceptability of the intervention‬
‭including dropout rates, percentage of‬
‭completed assessments, adherence, and‬
‭estimates of satisfaction‬
‭The‬‭main outcome‬‭of the FACE STRESS‬
‭study is to evaluate‬‭feasibility and‬
‭acceptability‬‭of an EMA and EMA plus text‬
‭message intervention. Specifically, we will‬
‭evaluate:‬
‭●‬ ‭proportion of individuals who will‬
‭contact us because interested to‬
‭participate‬
‭●‬ ‭the number of eligible individuals‬
‭after the initial screening‬
‭●‬ ‭time taken to recruit the sample‬
‭●‬ ‭retention rates‬
‭●‬ ‭the number and percentage of‬
‭participants responding to any EMA‬
‭text over the 3-week study‬
‭●‬ ‭Satisfaction will be measured using‬
‭both open-ended questions and‬
‭likert-scaled questions to examine the‬
‭acceptability and utility of the both‬
‭EMA and intervention texts. ‬
‭Secondary‬
‭●‬ ‭Explore indicators of the EMA and‬
‭text message intervention efficacy‬
‭The effect sizes on reductions in‬
‭perceived stress and other‬
‭psychological symptoms will be‬
‭estimated in the EMA and‬
‭EMA+intervention groups at‬
‭post-intervention, 1, 3 and 6-month‬
‭time-points. ‬
‭Secondary outcomes‬‭will measure:‬
‭●‬ ‭Perceived stress and psychological‬
‭overload‬
‭●‬ ‭symptoms of anxiety and depression‬
‭●‬ ‭symptoms of PTSD‬
‭●‬ ‭positive and negative affects‬
‭●‬ ‭resilience‬
‭●‬ ‭psychological well-being‬
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‭Protocol DL-FACE-101 v1.0‬
‭4.‬
‭Study Design‬
‭4.1.‬
‭Overall Design‬
‭This study is a pilot randomized controlled trial with embedded qualitative research. Eligible‬
‭participants who complete an informed consent form will be randomized to receive 3 weeks of‬
‭EMA or 3 weeks of EMA plus the text message intervention for stress management based on a‬
‭1:1 allocation using random block sizes of 2.‬
‭Eligible participants will sign the consent form online before moving on to complete their‬
‭baseline assessment. All participants will receive a copy of their signed consent form and will be‬
‭provided with the research personnel’s contact details. Participants who do not complete the‬
‭baseline survey within 3 days from enrollment will be excluded from the study. Once their‬
‭baseline is completed, participants will be randomized to receive:‬
‭●‬ ‭Control‬‭: 3 weeks of EMA, consisting of 2‬‭text messages‬‭per day delivered at random‬
‭times during waking hours to prompt participants to complete the survey‬
‭●‬ ‭Intervention‬‭:‬
‭o‬ ‭1 week of EMA, consisting of 2‬‭text messages per day‬‭delivered at random times‬
‭during waking hours to prompt participants to complete the survey‬‭followed by‬
‭o‬ ‭2 additional weeks of EMA in combination with‬‭2 text‬‭messages per day with‬
‭content related to stress management techniques.‬
‭At the end of the 3 weeks, participants in both groups will complete a post-intervention survey‬
‭designed to evaluate participant satisfaction and to gather information for the purposes of‬
‭improving the content of the text-message intervention. Changes in levels of psychological‬
‭distress and well-being from baseline will be also evaluated.‬
‭At 1, 3 and 6-months post intervention, participants will be contacted via text message to‬
‭complete a follow up survey. The follow up survey will include the same information collected at‬
‭baseline with the exclusion of age, race, gender and adverse childhood events.‬
‭Participants from either group will be informed that they can withdraw from the study at any‬
‭time without giving a reason‬‭by replying ‘STOP’‬‭to‬‭any of the messages, or by contacting a‬
‭member of the research team. No further information will be collected from participants who‬
‭withdraw from the study.‬
‭Participants in the control group will be offered the opportunity to receive the intervention after‬
‭the 6 months follow-up period. No data will be collected from this intervention.‬
‭4.2.         Scientific Rationale for Study Design‬
‭This is a research study designed to explore feasibility and acceptability and initial efficacy of an‬
‭EMA and text message intervention for stress management as a digital intervention.‬
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‭Protocol DL-FACE-101 v1.0‬
‭4.2.‬
‭Justification for Dose‬
‭N/A‬
‭4.3.‬
‭End of Study Definition‬
‭The end of trial date is defined as the date at which all subjects have completed all activities‬
‭shown in the Schedule of Assessments, all data has been entered, all data queries have been‬
‭resolved, and the database has been locked.‬
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‭Protocol DL-FACE-101 v1.0‬
‭5.‬
‭Study Population‬
‭70 participants will be randomized to control (n=35) or intervention group (n=35)‬
‭5.1.‬
‭Inclusion Criteria‬
‭Participants are eligible to be included in the study only if all of the following criteria apply:‬
‭1.‬ ‭Age 22 or older‬
‭2.‬ ‭Must reside in an Easter Standard Time or Central Standard Time zone‬
‭3.‬ ‭Able to read and write in English as demonstrated by review and completion of an‬
‭Informed Consent Form‬
‭4.‬ ‭Own an SMS enable smartphone (Android or iPhone OS4)‬
‭5.‬ ‭Scoring >5 on the 4-item Perceived Stress Scale (reflecting higher-than-average‬
‭perceived stress;‬‭15, 16‬‭)‬
‭5.2.‬
‭Exclusion Criteria‬
‭Participants are excluded from the study if any of the following criteria apply:‬
‭1.‬ ‭Reported cognitive impairment and/or psychiatric disorders of the psychotic spectrum‬
‭2.‬ ‭Enrolled in another support study‬
‭3.‬ ‭Currently receiving psychotherapy through telehealth‬
‭4.‬ ‭PHQ-9 score of 20 or greater.‬
‭5.3.‬
‭Lifestyle Considerations‬
‭N/A‬
‭5.4.‬
‭Screen Failures‬
‭Individuals who do not meet the criteria for participation in this study (screen failure) may not be‬
‭rescreened.‬
‭5.5.‬
‭Recruitment‬
‭Between 70 and 120 participants will be recruited by advertisements posted on an internet job‬
‭board, in order to randomize 70 participants.‬‭Participants‬‭who successfully randomize will‬
‭receive incremental incentives in the form of gift cards for a total of $145.‬
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‭Protocol DL-FACE-101 v1.0‬
‭6.‬
‭Study Intervention and Concomitant Therapy‬
‭The study intervention is described below.‬
‭6.1.‬
‭Study Intervention Administered‬
‭Text messages were developed by the principal investigator who is a trained clinical psychologist‬
‭and cognitive behavioral therapist. The development of the text message library followed‬
‭constructs from The Transactional Model of Stress and Coping. This theory provides a‬
‭framework for understanding the process of responding to stress (32‬‭)‬‭. The basic assumption of‬
‭this model is that an individual makes an appraisal of the impact of a stressful event, which‬
‭ultimately impacts his or her outcome (emotional well-being, physical well-being, and behavior).‬
‭Constructs from this theory along with constructs from the Acceptance and Commitment‬
‭Therapy (33) will be incorporated in the text message intervention for stress management. ‬
‭The text message content will include between 150 and 250 characters and will provide along‬
‭with the main component of the stress study, motivational reminders, and call to action. Main‬
‭components of the text message intervention will be: psychoeducation on stress, emotion focused‬
‭(distraction, breathing relaxation, acceptance of negative emotions, and self-support in difficult‬
‭situations) and problem focused coping (Problem-solving, time-management, obtaining‬
‭instrumental social support), 6-step procedure to systematically solve problems, improve‬
‭psychological flexibility and acceptance of uncertainty, noticing and creating moments of‬
‭well-being.‬
‭6.1.1.‬
‭Medical Devices‬
‭N/A‬
‭6.2.‬
‭Preparation/Handling/Storage/Accountability‬
‭Consent and welcome and intervention text messages will be delivered remotely using a‬
‭web-based SMS messaging platform. To send and receive messages, a third-party web-based text‬
‭messaging platform was used as the Internet gateway. Participants’ cell phone numbers will be‬
‭registered in the web-based text messaging platform at baseline. EMA and standard surveys will‬
‭be collected through‬‭SurveyGizmo‬‭, a HIPPA approved‬‭secure survey platform that enables direct‬
‭texting.‬‭The company is GDPR Compliant; data is stored‬‭securely and encrypted in transit, at‬
‭rest, and on all backups to reduce the risk of data security breach. In addition, the company‬
‭leverage‬‭Amazon’s AWS‬‭security features to further‬‭lock down access to data.‬
‭Text message send times and delivery status will be recorded. Participants will be informed that‬
‭this is a one-way message program and not to reply, however record will be kept of any‬
‭incoming messages from participants. A record of the number of times each participant attempts‬
‭to contact the research team and the method of contact (i.e. via phone, email, text message) will‬
‭also be kept.‬
‭17‬

‭Protocol DL-FACE-101 v1.0‬
‭Participants who text-back will be sent an automated text message as follows ‘From FACE‬
‭stress: This is an automated reply. If this is an emergency and you are in need of immediate help‬
‭call 911’. In addition, the content of the message will be reviewed by the research team who will‬
‭determine an appropriate response including:‬
‭●‬ ‭No action required (e.g. text is related to content or acknowledgement)‬
‭●‬ ‭Action required on a study-related problem (e.g. participant reporting a technical problem‬
‭or texting to withdraw from study)‬
‭●‬ ‭Action required on a different problem (e.g. text indicating high distress; response will be‬
‭determined on a case-by-case basis and reviewed by the Principal Investigator and‬
‭Medical Monitor)‬
‭6.3.‬
‭Measures to Minimize Bias: Blinding‬
‭N/A‬
‭6.4.‬
‭Study Intervention Compliance‬
‭Subjects will receive study intervention via text messages.‬
‭Subjects may remain in the trial, even if they are nonadherent with the digital intervention‬
‭treatment.‬
‭A record of the digital intervention administered to each participant will be maintained.‬
‭Intervention start and stop dates will also be recorded.‬
‭6.5.‬
‭Dose Modification‬
‭N/A‬
‭6.6.‬
‭Continued Access to Study Intervention after the End of the Study‬
‭Participants in the control group will be offered the opportunity to receive the intervention at the‬
‭end of the study (after 6 months follow up). No data will be collected from this intervention.‬
‭6.7.‬
‭Treatment of Overdose‬
‭N/A‬
‭6.8.‬
‭Concomitant Therapy‬
‭N/A‬
‭18‬

‭Protocol DL-FACE-101 v1.0‬
‭7.‬
‭Discontinuation of Study Intervention and Participant‬
‭Discontinuation/Withdrawal‬
‭7.1.‬
‭Discontinuation of Study‬
‭If the study intervention is permanently discontinued, any reported AEs/SAEs will be‬
‭collected at the time of discontinuation.‬
‭7.2.‬
‭Participant Discontinuation/Withdrawal from the Study‬
‭●‬
‭A participant may withdraw from the study at any time at his/her own request or‬
‭may be withdrawn at any time at the discretion of the investigator for safety, behavioral, or‬
‭compliance reasons. This is expected to be uncommon.‬
‭●‬
‭If a participant withdraws or is withdrawn from the Study, the sponsor will stop‬
‭collecting new data from the participant, however, the sponsor may retain and continue to‬
‭use any data collected before the participant withdraws or is withdrawn from the study.‬
‭●‬
‭At the time of discontinuation from the study an early discontinuation visit will be‬
‭conducted, as shown in the SoA. See SoA for data to be collected at the time of study‬
‭discontinuation and follow-up and for any further evaluations that need to be completed.‬
‭7.3.‬
‭Lost to Follow up‬
‭A participant will be considered lost to follow-up if he or she repeatedly fails to complete EMA‬
‭and follow up surveys and is unable to be contacted by the study staff.‬
‭The following actions must be taken if a participant fails to complete 2 consecutive days of EMA‬
‭survey:‬
‭●‬
‭The study staff must attempt to contact the participant and address the missed survey‬
‭and whether or not the participant wishes to and/or should continue in the study.‬
‭●‬
‭Before a participant is deemed lost to follow up, the investigator or designee must‬
‭make every effort to regain contact with the participant (where possible, 3 telephone calls‬
‭and, if necessary, an email to the participant’s last known email address). These contact‬
‭attempts should be documented in the participant’s study record.‬
‭●‬
‭Should the participant continue to be unreachable, he/she will be considered to have‬
‭withdrawn from the study.‬
‭19‬

‭Protocol DL-FACE-101 v1.0‬
‭8.‬
‭Study Assessments and Procedures‬
‭●‬
‭Study procedures and their timing are summarized in the SoA. Protocol waivers or‬
‭exemptions are not allowed.‬
‭●‬
‭Outcomes are self-reported by the subject through an electronic system. Study staff‬
‭will review surveys and assessments for completeness.‬
‭●‬
‭Immediate safety concerns will be addressed by the Principal Investigator‬
‭immediately upon occurrence or awareness to determine if the participant should‬
‭continue or discontinue study‬
‭●‬
‭Adherence to the study design requirements, including those specified in the SoA, is‬
‭essential and required for study conduct.‬
‭●‬
‭All screening evaluations must be completed and reviewed to confirm that potential‬
‭participants meet all eligibility criteria. The study coordinator will maintain a‬
‭screening log to record details of all participants screened and to confirm eligibility‬
‭or record reasons for screening failure, as applicable.‬
‭8.1.‬
‭Efficacy Assessments‬
‭Participants will be recruited by advertisements posted on an internet job board. Screening‬
‭assessments will occur remotely via‬‭phone‬‭to evaluate eligibility.‬
‭Planned time points for all efficacy assessments are provided in the SoA.‬
‭●‬ ‭Standard assessment.‬‭Participants will be evaluated at baseline, post-intervention and at‬
‭1, 3 and 6 months follow up.‬
‭o‬ ‭Baseline assessment‬‭will include:‬
‭-‬
‭sociodemographic information‬‭(age, race, gender, employment status,‬
‭annual income, zip code, living situation, health insurance);‬
‭-‬
‭participant’s expectations of the likely success of the intervention and‬
‭self-confidence will be asked with the following questions: “How‬
‭confident are you on the ability of this study to reduce your stress?” “How‬
‭confident are you in your ability to improve your stress?” “By the end of‬
‭the study, how much improvement in your stress symptoms do you think‬
‭will occur?” Answers will be on a likert scale from 1 being not at all to 9‬
‭being very much;‬
‭-‬
‭psychiatric history‬‭(self-reported);‬
‭-‬
‭self-reported information about‬‭general health‬‭(sleep,‬‭drinking habits,‬
‭smoking status, level of physical activity);‬
‭-‬
‭early life events measured by the‬‭Early Childhood‬‭Experiences‬
‭International Questionnaire‬‭(ACE-IN) (20). Due to‬‭their sensitive nature,‬
‭questions about sexual harassment and abuse will be omitted;‬
‭-‬
‭stress will be evaluated using the‬‭Perceived Stress‬‭Scale (PSS-10)‬‭, a‬
‭10-item scale of the degree to which situations in one's life are appraised‬
‭20‬

‭Protocol DL-FACE-101 v1.0‬
‭-‬
‭as stressful and an abbreviated version of the Social Readjustment Rating‬
‭Scale (SRRS) a self-rated questionnaire providing an appraisal of‬‭major‬
‭stressful life events occurred in the previous year‬‭;‬
‭-‬
‭coping skills will be measured using the Brief Cope Questionnaire; ‬
‭-‬
‭symptoms of anxiety and depression measured using respectively the‬
‭GAD-7‬‭and‬‭PHQ-9‬‭;‬
‭-‬
‭presence of PTSD using the‬‭Primary Care PTSD Screen‬‭for DSM-5‬
‭(PC-PTSD-5)‬‭, the Primary Care PTSD Screen for DSM-5‬‭(PC-PTSD-5);‬
‭-‬
‭positive and negative affects assessed using the‬‭Positive‬‭and Negative‬
‭Affect Schedule (PANAS)‬‭;‬
‭-‬
‭uncertainty intolerance will be evaluated using the Intolerance of‬
‭Uncertainty Scale, brief version;‬
‭-‬
‭resilience evaluated using the‬‭Brief Resilience Scale‬‭;‬
‭-‬
‭psychological well-being will be assessed by the‬‭Euthymia‬‭Interview‬‭.‬
‭o‬ ‭Post intervention follow up‬‭will include: ‬
‭-‬
‭the‬‭same information collected at baseline‬‭with the‬‭exclusion of age, race,‬
‭gender and ACE-IN.‬
‭-‬
‭All participants will also receive likert-scaled questions ranked on a scale‬
‭from 1 (completely disagree) to 5 (completely agree) to examine‬
‭acceptability of text messages‬‭. Questions will include items that address‬
‭the acceptability of repeated text messages, what they did with the‬
‭messages (i.e., saved, shared or deleted), the perceived utility of the text‬
‭messages and opinions regarding the intrusiveness, timing and content‬
‭suitability of the text messages.‬
‭-‬
‭Participants in the intervention groups will receive open ended questions‬
‭aimed at evaluating‬‭acceptability of the intervention‬‭and suggestions on‬
‭how to improve the intervention. Specific questions are: “Which text‬
‭message did you like the most? And why?”; “Which text message did you‬
‭like the least? And why?”; “Did any of the text messages lead you to make‬
‭changes in what you might normally do? If so, which text messages were‬
‭these, and how did they influence the way you normally act?”; “What did‬
‭you think about the frequency of the text messages you received?”; “How‬
‭would you suggest we could improve the content and materials so that the‬
‭intervention could be more effective?”.‬
‭-‬
‭Adverse events will be also recorded.‬
‭1, 3 and 6 months follow ups‬‭will include the same‬‭information collected at baseline with the‬
‭exception of age, race, gender ACE-IN and acceptability questions.‬
‭●‬ ‭EMA assessment‬‭. Based on recommendations from the‬‭Science of Behavior Change‬
‭Research Network and Witchers and colleagues on how to evaluate momentary positive‬
‭and negative affects, the following questions will be sent to evaluate momentary‬
‭responses: ‬
‭21‬

‭Protocol DL-FACE-101 v1.0‬
‭1.‬ ‭How stressed do you feel right now?‬
‭2.‬ ‭Did anything stressful occur since the last survey? ‬
‭a.‬ ‭If yes, more questions will be asked to understand the timing and nature of the‬
‭stressor‬
‭.‬
‭How would you describe this stressful event? Please select one of the‬
‭following items. If more than one event happened, please pick the most‬
‭significant event: Argument/conflict/disagreement, financial event,‬
‭home-related event, work-related event, health event or accident, event that‬
‭happened to others, other; ‬
‭i.‬
‭When did this happen?‬
‭2.‬ ‭How overwhelmed do you feel right now? ‬
‭3.‬ ‭How helpless do you feel right now?‬
‭4.‬ ‭How lonely do you feel right now? ‬
‭5.‬ ‭How anxious do you feel right now? ‬
‭6.‬ ‭How guilty do you feel right now? ‬
‭7.‬ ‭How content do you feel right now?  ‬
‭8.‬ ‭How hopeful do you feel right now? ‬
‭Answers will be on a scale from 0 to 10 with 0 being not stressed at all and 10 being‬
‭extremely stressed‬
‭The f‬‭irst EMA survey of the day‬‭will also include‬‭the following question:‬
‭1.‬ ‭How well did you sleep last night? ‬
‭The answer will be rated on a scale 0 to 10, with 0 being not well at all and 10 being‬
‭extremely well.‬
‭The‬‭second EMA survey of the day‬‭will include the‬‭following question:‬
‭2.‬ ‭Hassles are irritants things that annoy or bother you; they can make you upset or‬
‭angry. E‬‭xamples of daily hassles could include concerns‬‭about weight, rising‬
‭prices, home maintenance, too many things to do, misplacing or losing things, and‬
‭physical appearance, or all of the above. Have you had any hassles today?‬
‭The answer will be a YES or NO.‬
‭8.2.‬
‭Safety Assessments‬
‭●‬ ‭AEs and SAEs will be collected at each contact point with the participant, beginning‬
‭when the consent form is signed, and throughout the participants participation in the‬
‭study. Safety events will be reported through an electronic reporting system and‬
‭evaluated by the Principal Investigator.‬
‭●‬ ‭AEs and SAEs that are collected via the text messaging platform will be recorded and‬
‭evaluated. Specifically, adverse events will be reported and categorized with respect to‬
‭22‬

‭Protocol DL-FACE-101 v1.0‬
‭their likely relationship to the intervention (i.e. definitely, possibly, not related). Adverse‬
‭events that might be reasonably related to SMS text messaging include hand or finger‬
‭pain, or involvement in an accident as a result of sending or receiving a text relating to‬
‭the study.‬
‭●‬ ‭Planned time points for all safety assessments are provided in the SoA.‬
‭8.2.1.‬
‭Physical Examinations‬
‭N/A‬
‭8.2.2.‬
‭Vital Signs‬
‭N/A‬
‭8.2.3.‬
‭Electrocardiograms‬
‭N/A‬
‭8.2.4.‬
‭Clinical Safety Laboratory Assessments‬
‭N/A‬
‭8.2.5.‬
‭Pregnancy Testing‬
‭Pregnancy will be self-reported throughout the study. No pregnancy tests will be administered.‬
‭8.3.‬
‭Adverse Events (AEs), Serious Adverse Events (SAEs), and Other‬
‭Safety Reporting‬
‭AEs will be reported by the participant. The investigator and any qualified designees are‬
‭responsible for detecting, documenting, and recording events that meet the definition of an AE or‬
‭SAE and remain responsible for following up AEs that are serious, considered related to the‬
‭study intervention or study procedures, or that caused the participant to discontinue the study‬
‭(see Section 7).‬
‭In the unlikely event of an adverse event resulting from participation in this research study, the‬
‭Click Discovery Lab Standard Operating Procedure will be followed for handling Adverse and‬
‭Serious Adverse Events. The method of recording, evaluating, and assessing causality of AEs‬
‭and SAEs and the procedures for completing and transmitting SAE reports are provided in‬
‭Appendix 3.‬
‭8.3.1.‬
‭Time Period and Frequency for Collecting AE and SAE Information‬
‭All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until‬
‭the 6 months follow-up as specified in the SoA (Section 1.3).‬
‭23‬

‭Protocol DL-FACE-101 v1.0‬
‭All SAEs will be recorded and reported to the investigator immediately. Under no circumstance‬
‭should this exceed 24 hours, as indicated in Appendix 3. The investigator will submit any‬
‭updated SAE data to Designated Click Medical Monitor within 24 hours of it being available.‬
‭8.3.2.‬
‭Method of Detecting AEs and SAEs‬
‭Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and‬
‭non-leading verbal questioning of the participant is the preferred method to inquire about‬
‭AE occurrences.‬
‭Baseline and post treatment screening for depression.‬
‭●‬ ‭Onset of major psychiatric disorders requiring referral to a specialist‬‭. We will use the‬
‭Patient Health Questionnaire-9 (PHQ-9) both at baseline and post treatment to screen for‬
‭depression. The PHQ-9 is a 9-item depression module. 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 two weeks, and 1 of the symptoms is depressed mood or anhedonia.‬
‭If screening positive for major depression, participants will be suggested to refer to their‬
‭primary care physician. Specifically, the following protocol will be activated for‬
‭participants who at baseline score 20 or greater on the PHQ-9 (36)‬
‭1.‬ ‭Participants will be withdrawn from the study and the following message‬
‭will be sent: ‬
‭“Based on most answers most providers would want to talk to you some more‬
‭about your feelings. Have you ever talked to a provider or health care professional‬
‭about these feelings?”‬
‭1.‬ ‭If Yes‬‭, the following texts will be sent:‬
‭“Did the person you talked to about these feelings provide you with any‬
‭suggestions on how to improve your mood?‬
‭1.‬ ‭No ‬
‭2.‬ ‭Yes ‬
‭“Are you undergoing any treatment for your mood such as seeing a‬
‭counselor, psychologist, psychiatrist or taking medications?”‬
‭1.‬ ‭No‬
‭2.‬ ‭Yes ‬
‭If both answers are no‬‭, another text will be sent:‬
‭“Would it be okay if we let your primary care physician know‬
‭about your mood?”‬
‭24‬

‭Protocol DL-FACE-101 v1.0‬
‭1.‬ ‭Yes ---- PCP will be contacted by PI‬
‭2.‬ ‭No‬
‭If No,‬‭the following text will be sent:‬
‭“Okay, that’s fine however we would like to give you some‬
‭information on other places and resources where you can‬
‭find someone to talk about your mood if you don’t want us‬
‭to contact your doctor” We will attach information about‬
‭NYC Well‬
‭(‬‭https://www1.nyc.gov/site/doh/health/health-topics/nyc-w‬
‭ell.page‬‭)‬
‭0.‬ ‭If No, the following texts will be sent:‬
‭“We think it may be a good idea to talk to a healthcare professional about‬
‭these feelings. Would it be okay if we let your primary care physician‬
‭know about your mood?‬
‭1.‬ ‭Yes ---- PCP will be contacted by PI‬
‭2.‬ ‭No‬
‭If No,‬‭the following text will be sent:‬
‭“Okay, that’s fine however we would like to give you some‬
‭information on other places and resources where you can‬
‭find someone to talk about your mood if you don’t want us‬
‭to contact your doctor” We will attach information about‬
‭NYC Well‬
‭(‬‭https://www1.nyc.gov/site/doh/health/health-topics/nyc-w‬
‭ell.page‬‭)‬
‭8.3.3.‬
‭Follow-up of AEs and SAEs‬
‭After the initial AE/SAE report, the investigator is required to proactively follow each participant‬
‭at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event‬
‭is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further‬
‭information on follow-up procedures is provided in Appendix 3.‬
‭25‬

‭Protocol DL-FACE-101 v1.0‬
‭8.3.4.‬
‭Regulatory Reporting Requirements for SAEs‬
‭●‬
‭Prompt notification by the investigator to the sponsor of an SAE is essential so that‬
‭legal obligations and ethical responsibilities towards the safety of participants and the safety‬
‭of a study intervention under clinical investigation are met.‬
‭●‬
‭The sponsor has a legal responsibility to notify both the local regulatory authority‬
‭and other regulatory agencies about the safety of a study intervention under clinical‬
‭investigation. The sponsor will comply with country-specific regulatory requirements‬
‭relating to safety reporting to the regulatory authority, Institutional Review Boards‬
‭(IRB)/Independent Ethics Committees (IEC), and investigators.‬
‭●‬
‭An investigator who receives an investigator safety report describing an SAE or‬
‭other specific safety information (e.g., summary or listing of SAEs) from the sponsor will‬
‭review and file it and will notify the IRB/IEC, if appropriate according to local‬
‭requirements.‬
‭8.3.5.‬
‭Pregnancy‬
‭Pregnancy will be self-reported by the subject. Pregnant females will not be excluded from‬
‭participation‬‭.‬
‭●‬
‭If a pregnancy is reported, the investigator will record pregnancy information on the‬
‭appropriate form and submit it to the sponsor within 24 hours of learning of the female‬
‭participant pregnancy.‬
‭●‬
‭While pregnancy itself is not considered to be an AE or SAE, any pregnancy‬
‭complication or elective termination of a pregnancy for medical reasons will be reported as‬
‭an AE or SAE.‬
‭●‬
‭Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth,‬
‭congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as such.‬
‭●‬
‭Any post-study pregnancy-related SAE considered reasonably related to the study‬
‭intervention by the investigator will be reported to the sponsor as described in Section 8.3.4.‬
‭While the investigator is not obligated to actively seek this information in former study‬
‭participants, he or she may learn of an SAE through spontaneous reporting.‬
‭●‬
‭Any female participant who becomes pregnant while participating in the study may‬
‭continue the study intervention.‬
‭8.3.6.‬
‭Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs‬
‭or SAEs‬
‭N/A‬
‭8.3.7.‬
‭Events of Special Interest‬
‭N/A‬
‭8.3.8.‬
‭Product Quality Complaints and Nonconformances‬
‭N/A‬
‭26‬

‭Protocol DL-FACE-101 v1.0‬
‭8.3.8.1.‬
‭Time Period for Detecting Device Complaints and Nonconformances‬
‭N/A‬
‭8.3.8.2.‬
‭Follow-up of Device Complaints and Nonconformances‬
‭N/A‬
‭8.3.8.3.‬
‭Prompt Reporting of Device Complaints or Nonconformances to Sponsor‬
‭N/A‬
‭8.3.8.4.‬
‭Regulatory Reporting Requirements for Device Complaints and‬
‭Nonconformances‬
‭N/A‬
‭8.4.‬
‭Pharmacokinetics‬
‭N/A‬
‭8.5.‬
‭Genetics and/or Pharmacogenomics‬
‭N/A‬
‭8.6.‬
‭Biomarkers‬
‭N/A‬
‭27‬

‭Protocol DL-FACE-101 v1.0‬
‭9.‬
‭Statistical Considerations‬
‭9.1.‬
‭Statistical Hypotheses‬
‭The primary hypothesis is that the EMA and text message intervention will be feasible and well‬
‭accepted as evaluated by participants completing at least 33% of the surveys and a retention rate‬
‭>= 70%.‬
‭9.2.‬
‭Sample Size Determination‬
‭Based on an expected small to moderate effects size (17) of the text message intervention for‬
‭stress management, a‬‭sample size of 70 participants‬‭(35 participants per arm) will be sufficient to‬
‭establish feasibility for a 80% powered main trial with an 80% upper confidence limit (18).‬
‭About 120 participants will be screened to achieve up to 70 enrolled to the study.‬
‭Note‬‭: “Enrolled” means a participant's, or their legally‬‭acceptable representative’s, agreement to‬
‭participate in a clinical study following completion of the informed consent process and‬
‭screening. Potential participants who are screened for the purpose of determining eligibility for‬
‭the study, but do not participate in the study, are not considered enrolled, unless otherwise‬
‭specified by the protocol.‬
‭9.3.‬
‭Analysis Sets‬
‭The definition for each participant analysis set should be defined at the participant level.‬
‭Optionally, to implement the estimand framework, defined analysis data sets may be included‬
‭here in a separate table that specify the set of data used in the analysis for a given estimand (or‬
‭family of estimands that differ only in endpoint) based on how key intercurrent events will be‬
‭handled for that estimand.‬
‭9.4.‬
‭Statistical Analyses‬
‭Primary outcome.‬‭ ‬
‭●‬ ‭Quantitative analysis‬‭. Feasibility of the intervention‬‭will be reported as descriptive statistics,‬
‭focusing on‬‭number of individuals who contact the‬‭study team with interest in participation;‬
‭the number of eligible individuals after the initial screening; time taken to recruit the sample;‬
‭retention rates;‬‭the rate of EMA survey completion.‬‭Acceptability will be measured as means‬
‭and standard deviations of responses to each item within the satisfaction questionnaire, and‬
‭the proportion of participants giving favorable responses. ‬
‭●‬ ‭Qualitative analysis‬‭. A codebook and coding guidelines‬‭will be developed for analysis of‬
‭qualitative feedback. Two researchers will code all transcripts using‬‭NVivo (version 10, QSR‬
‭International, Inc, Burlington, MA)‬‭and add to the‬‭codebook as needed. Each researcher will‬
‭then independently identify main themes. Results will be compared and discussed until an‬
‭agreement will be reached. Representative samples of feedback from open-ended questions‬
‭will be also used. ‬
‭28‬

‭Protocol DL-FACE-101 v1.0‬
‭Secondary outcomes.‬‭ ‬
‭●‬ ‭Standard responses.‬‭Sociodemographic responses will‬‭be described by mean, standard‬
‭deviation (SD), and range. Mixed-effects models for repeated measure (MMRM) will be‬
‭used to examine change in secondary outcomes, with outcomes examined as change in scores‬
‭between baseline and follow-up. Models will include effects for time, group‬
‭(control/intervention), group x time interactions and baseline values of the outcome variable‬
‭(to control regression to the mean) and other potential confounders. Per Protocol analysis will‬
‭be performed. The per protocol population will include all randomized participants excluding‬
‭those who had protocol violations. A significance level of 0.05 will be used. All analyses will‬
‭be performed using‬‭SPSS for Windows‬‭. ‬
‭●‬ ‭EMA responses.‬‭Variability in momentary responses‬‭will be described by each participant’s‬
‭mean, SD, and range of mean square successive difference (34), which is a measure of‬
‭variability that accounts for the temporal order of responses. Analyses on momentary‬
‭responses will be conducted using Multilevel Modelling (35) because of the hierarchical‬
‭structure of the data (level 1 = measurement time, level 2 = measurement day, level 3 =‬
‭participant) and the aptness for dealing with varying time intervals between assessments and‬
‭missing data. For depicting systematic (i.e. changing with time) or unsystematic (i.e.‬
‭symptom variability) inter- and intraindividual variations in symptom severity and coping‬
‭strategies, intraclass correlation coefficients (ICCs) will be used, while associations of‬
‭symptomatology, coping efficacy and HCC will be analyzed using multilevel correlation and‬
‭regression analyses.‬
‭9.4.1.‬
‭Safety‬‭Analysis‬
‭All AEs will be coded by system organ class and Medical Dictionary for Regulatory Activities‬
‭(MedDRA) preferred team. All AEs will be coded by system organ class and Medical Dictionary‬
‭for Regulatory Activities (MedDRA) preferred term All safety analyses will be made on the‬
‭Safety Population.All safety analyses will be made on the Safety Population.‬
‭9.5.‬
‭Interim Analysis‬
‭N/A‬
‭29‬

‭Protocol DL-FACE-101 v1.0‬
‭10.‬
‭Supporting Documentation and Operational Considerations‬
‭10.1.‬
‭Appendix 1: Regulatory, Ethical, and Study Oversight‬
‭Considerations‬
‭10.1.1.‬
‭Regulatory and Ethical Considerations‬
‭●‬
‭This study will be conducted in accordance with the protocol and with the following:‬
‭o‬ ‭Consensus ethical principles derived from international guidelines including the‬
‭Declaration of Helsinki and Council for International Organizations of Medical‬
‭Sciences (CIOMS) International Ethical Guidelines‬
‭o‬ ‭Applicable ICH Good Clinical Practice (GCP) Guidelines‬
‭o‬ ‭Applicable laws and regulations‬
‭●‬
‭The protocol, protocol amendments, ICF, and other relevant documents (e.g.,‬
‭advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and‬
‭approved by the IRB/IEC before the study is initiated.‬
‭●‬
‭Any amendments to the protocol will require IRB/IEC approval before‬
‭implementation of changes made to the study design, except for changes necessary to‬
‭eliminate an immediate hazard to study participants.‬
‭●‬
‭Protocols and any substantial amendments to the protocol will require IRB/IEC‬
‭approval prior to initiation except for changes necessary to eliminate an immediate hazard to‬
‭study participants.‬
‭●‬
‭The investigator will be responsible for the following:‬
‭o‬ ‭Providing written summaries of the status of the study to the IRB/IEC annually or‬
‭more frequently in accordance with the requirements, policies, and procedures‬
‭established by the IRB/IEC‬
‭o‬ ‭Notifying the IRB/IEC of SAEs or other significant safety findings as required by‬
‭IRB/IEC procedures‬
‭o‬ ‭Providing oversight of the conduct of the study at the site and adherence to‬
‭requirements of 21 CFR, ICH guidelines, the IRB/IEC, and all other applicable local‬
‭regulations.‬
‭10.1.2.‬
‭Informed Consent Process‬
‭●‬
‭Patients who meet the eligibility criteria will be asked to sign an online consent‬
‭form. The consent form will describe the potential risks and benefits of study participation‬
‭as well as the responsibilities of the participants and the investigators.‬
‭●‬
‭Participants must be informed that their participation is voluntary. Participants are‬
‭required to sign a statement of informed consent that meets the requirements of 21 CFR 50,‬
‭local regulations, ICH guidelines, Health Insurance Portability and Accountability Act‬
‭(HIPAA) requirements, where applicable, and the IRB/IEC or study center.‬
‭●‬
‭Participants must be re-consented to the most current version of the ICF(s) during‬
‭their participation in the study.‬
‭●‬
‭A copy of the ICF(s) must be provided to the participant.‬
‭30‬

‭Protocol DL-FACE-101 v1.0‬
‭10.1.3.‬
‭Data Protection‬
‭Study participants will be assigned a unique identifying number (ID). This ID, rather than any‬
‭PII, will be used to label all hard copy and electronic data. Identifiers and study data will be‬
‭saved in separate files, accessible only to study staff.  As a result, the bulk of the data will be‬
‭completely anonymized, including records of screening instruments.‬
‭However, the consent form and documentation of payment will include both the subject’s name‬
‭and ID. As a result, these documents will be stored separately from other records.  All hard copy‬
‭records will be stored in locked cabinets to which only the study investigators will have access.‬
‭All electronic records will be stored on an electronically secure database at Click Therapeutics.‬
‭This database is password protected.‬
‭Data from hard copy records will be entered into Excel and/or SPSS by study staff. Data analysis‬
‭will be conducted in SPSS, and/or Excel. Results will never be reviewed in a manner such that‬
‭individual subjects could be identified.‬
‭10.1.4.‬
‭Patient Privacy‬
‭Protection of Participant Privacy: Privacy in the context of this study includes confidentiality of‬
‭data and personal information and in the handling and reporting of data. The investigator will be‬
‭responsible for ensuring data are stored in a secure area accessible only to study staff. These‬
‭provisions will be monitored periodically. Clinical research may be a stressful experience for‬
‭some patients; therefore, sensitivity in recruitment (i.e., including no coercive strategies) will be‬
‭a high priority.‬
‭HIPPA compliance: All projects will obtain an authorization for the Health Insurance Portability‬
‭and Accountability Act (HIPAA) from the Institutional Review Board (IRB). The authorization‬
‭is to use or disclose protected health information for research that also includes a research‬
‭repository, which will be signed by the participant, with a copy kept in the data management‬
‭system. A copy will also be available to the patient. This authorization will allow the use or‬
‭sharing of private information including information that is given via written questionnaires from‬
‭questions regarding demographic and psychological and medical information.‬
‭Protection of the participant’s privacy and confidentiality: There is a potential risk to the‬
‭participant with regards to possible violation of their privacy. We have taken steps to avoid this‬
‭by making sure that only investigators on the study have access to a protected data file. Both the‬
‭investigator and research coordinator fulfill all requirements of the institution for HIPPA and‬
‭IRB training. As part of the process involved in obtaining written informed consent, all‬
‭participants will be reminded that their responses are confidential and that they may refuse to‬
‭participate in the project or withdraw at any time without explanation, and further, that such‬
‭action will in no way affect their future interactions with their health care provider. Prior to‬
‭inclusion in any data set (internal and external), data will be stripped of all identifying‬
‭information.‬
‭31‬

‭Protocol DL-FACE-101 v1.0‬
‭10.1.4.1.‬ ‭Medical Monitor‬
‭●‬
‭Participant safety will be continuously monitored by the Medical Monitor, which‬
‭includes safety signal detection at any time during the study.‬
‭●‬
‭All safety data collected will be summarized and reviewed by the Medical Monitor‬
‭for agreement of next steps.‬
‭●‬
‭If at any time during the course of the study, the PI judges that risk to subjects‬
‭outweighs the potential benefits, either shall have the discretion and responsibility to‬
‭recommend that the study be terminated.‬
‭●‬
‭Case unblinding may be performed for above reviews if necessary.‬
‭10.1.5.‬
‭Dissemination of Clinical Study Data‬
‭N/A‬
‭10.1.6.‬
‭Data Quality Assurance‬
‭●‬
‭The investigator must permit study-related monitoring, audits, IRB/IEC review, and‬
‭regulatory agency inspections and provide direct access to source data documents.‬
‭●‬
‭The sponsor or designee is responsible for the data management of this study‬
‭including quality checking of the data.‬
‭10.1.7.‬
‭Source Documents‬
‭Source documents are defined as the electronic survey responses. Electronic survey‬
‭responses provide evidence for the existence of the participant and substantiate the‬
‭integrity of the data collected. Source documents for this study will be collected‬
‭electronically and will be maintained by the sponsor.‬
‭10.1.8.‬
‭Study and Site Start and Closure‬
‭N/A.‬
‭10.1.9.‬
‭Publication Policy‬
‭N/A‬
‭32‬

‭Protocol DL-FACE-101 v1.0‬
‭10.2.‬
‭Appendix 2: Clinical Laboratory Tests‬
‭Laboratory tests are not evaluated in this study.‬
‭33‬

‭Protocol DL-FACE-101 v1.0‬
‭10.3.‬
‭Appendix 3: AEs and SAEs: Definitions and Procedures for‬
‭Recording, Evaluating, Follow-up, and Reporting‬
‭10.3.1.‬
‭Definition of AE‬
‭AE Definition‬
‭●‬
‭An AE is any untoward medical occurrence in a clinical study participant,‬
‭temporally associated with the use of study intervention, whether or not considered‬
‭related to the study intervention.‬
‭●‬
‭NOTE: An AE can therefore be any unfavorable and unintended sign (including‬
‭an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally‬
‭associated with the use of study intervention.‬
‭Events Meeting the AE Definition‬
‭●‬
‭Any abnormal laboratory test results (hematology, clinical chemistry, or‬
‭urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs‬
‭measurements), including those that worsen from baseline, considered clinically‬
‭significant in the medical and scientific judgment of the investigator (i.e., not related to‬
‭progression of underlying disease).‬
‭●‬
‭Exacerbation of a chronic or intermittent pre-existing condition including either‬
‭an increase in frequency and/or intensity of the condition.‬
‭●‬
‭New conditions detected or diagnosed after study intervention administration even‬
‭though it may have been present before the start of the study.‬
‭●‬
‭Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention‬
‭interaction.‬
‭●‬
‭Signs, symptoms, or the clinical sequelae of a suspected overdose of either study‬
‭intervention or a concomitant medication. Overdose per se will not be reported as an‬
‭AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming‬
‭intent. Such overdoses should be reported regardless of sequelae.‬
‭●‬
‭The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will‬
‭be reported as AE or SAE if they fulfill the definition of an AE or SAE. “Lack of‬
‭efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE.‬
‭Events‬‭NOT‬‭Meeting the AE Definition‬
‭●‬
‭Any clinically significant abnormal laboratory findings or other abnormal safety‬
‭assessments which are associated with the underlying disease, unless judged by the‬
‭investigator to be more severe than expected for the participant’s condition.‬
‭●‬
‭The disease/disorder being studied or expected progression, signs, or symptoms of‬
‭the disease/disorder being studied, unless more severe than expected for the participant’s‬
‭condition.‬
‭●‬
‭Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that‬
‭leads to the procedure is the AE.‬
‭●‬
‭Situations in which an untoward medical occurrence did not occur (social and/or‬
‭convenience admission to a hospital).‬
‭34‬

‭Protocol DL-FACE-101 v1.0‬
‭●‬
‭Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s)‬
‭present or detected at the start of the study that do not worsen.‬
‭10.3.2.‬
‭Definition of SAE‬
‭An SAE is defined as any serious adverse event that, at any dose:‬
‭a.‬
‭Results in death‬
‭b.‬ ‭Is life-threatening‬
‭The term 'life-threatening' in the definition of 'serious' refers to an event in which the‬
‭participant was at risk of death at the time of the event. It does not refer to an event, which‬
‭hypothetically might have caused death, if it were more severe.‬
‭c.‬
‭Requires inpatient hospitalization or prolongation of existing hospitalization‬
‭●‬
‭In general, hospitalization signifies that the participant has been admitted (usually‬
‭involving at least an overnight stay) at the hospital or emergency ward for observation‬
‭and/or treatment that would not have been appropriate in the physician’s office or‬
‭outpatient setting. Complications that occur during hospitalization are AEs. If a‬
‭complication prolongs hospitalization or fulfills any other serious criteria, the event is‬
‭serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE‬
‭should be considered serious.‬
‭●‬
‭Hospitalization for elective treatment of a pre-existing condition that did not‬
‭worsen from baseline is not considered an AE.‬
‭d.‬ ‭Results in persistent or significant disability/incapacity‬
‭●‬
‭The term disability means a substantial disruption of a person’s ability to conduct‬
‭normal life functions.‬
‭●‬
‭This definition is not intended to include experiences of relatively minor medical‬
‭significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and‬
‭accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life‬
‭functions but do not constitute a substantial disruption.‬
‭e.‬
‭Is a congenital anomaly/birth defect‬
‭f.‬
‭Other situations:‬
‭●‬
‭Medical or scientific judgment should be exercised by the investigator in deciding‬
‭whether SAE reporting is appropriate in other situations such as significant medical‬
‭events that may jeopardize the participant or may require medical or surgical intervention‬
‭to prevent one of the other outcomes listed in the above definition. These events should‬
‭usually be considered serious.‬
‭o‬
‭Examples of such events include invasive or malignant cancers, intensive treatment‬
‭for allergic bronchospasm, blood dyscrasias, convulsions or development of‬
‭intervention dependency or intervention abuse.‬
‭10.3.3.‬
‭Recording and Follow-Up of AE and/or SAE‬
‭AE and SAE Recording‬
‭●‬
‭When an AE/SAE occurs, it is the responsibility of the investigator to review all‬
‭documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports)‬
‭related to the event.‬
‭●‬
‭The investigator will then record all relevant AE/SAE information.‬
‭35‬

‭Protocol DL-FACE-101 v1.0‬
‭●‬
‭It is‬‭not‬‭acceptable for the investigator to send‬‭photocopies of the participant’s‬
‭medical records in lieu of completion of the required form.‬
‭●‬
‭There may be instances when copies of medical records for certain cases are‬
‭requested. In this case, all participant identifiers, with the exception of the participant‬
‭number, will be redacted on the copies of the medical records before submission.‬
‭●‬
‭The investigator will attempt to establish a diagnosis of the event based on signs,‬
‭symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the‬
‭individual signs/symptoms) will be documented as the AE/SAE.‬
‭Assessment of Intensity‬
‭The investigator will make an assessment of intensity for each AE and SAE reported during‬
‭the study and assign it to 1 of the following categories:‬
‭●‬
‭Mild: An event that is easily tolerated by the participant, causing minimal‬
‭discomfort and not interfering with everyday activities.‬
‭●‬
‭Moderate: An event that causes sufficient discomfort to interfere with normal‬
‭everyday activities.‬
‭●‬
‭Severe: An event that prevents normal everyday activities. An AE that is assessed‬
‭as severe should not be confused with an SAE. Severe is a category utilized for rating the‬
‭intensity of an event; and both AEs and SAEs can be assessed as severe.‬
‭An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as‬
‭described in the definition of an SAE, NOT when it is rated as severe.‬
‭Assessment of Causality‬
‭●‬
‭The investigator is obligated to assess the relationship between study intervention‬
‭and each occurrence of each AE/SAE.‬
‭●‬
‭A “reasonable possibility” of a relationship conveys that there are facts, evidence,‬
‭and/or arguments to suggest a causal relationship, rather than a relationship cannot be‬
‭ruled out.‬
‭●‬
‭The investigator will use clinical judgment to determine the relationship.‬
‭●‬
‭Alternative causes, such as underlying disease(s), concomitant therapy, and other‬
‭risk factors, as well as the temporal relationship of the event to study intervention‬
‭administration will be considered and investigated.‬
‭●‬
‭For each AE/SAE, the investigator‬‭must‬‭document in‬‭the medical notes that‬
‭he/she has reviewed the AE/SAE and has provided an assessment of causality.‬
‭●‬
‭There may be situations in which an SAE has occurred and the investigator has‬
‭minimal information to include in the initial report. However, it is very important that the‬
‭investigator always make an assessment of causality for every event before the initial‬
‭transmission of the SAE data.‬
‭●‬
‭The investigator may change his/her opinion of causality in light of follow-up‬
‭information and send an SAE follow-up report with the updated causality assessment.‬
‭●‬
‭The causality assessment is one of the criteria used when determining regulatory‬
‭reporting requirements.‬
‭Follow-up of AEs and SAEs‬
‭36‬

‭Protocol DL-FACE-101 v1.0‬
‭●‬
‭The investigator is obligated to perform or arrange for the conduct of‬
‭supplemental measurements and/or evaluations as medically indicated or as requested by‬
‭[X]‬‭to elucidate the nature and/or causality of the‬‭AE or SAE as fully as possible. This‬
‭may include additional laboratory tests or investigations, histopathological examinations,‬
‭or consultation with other health care professionals.‬
‭●‬
‭New or updated information will be recorded in the originally submitted‬
‭documents.‬
‭●‬
‭The investigator will submit any updated SAE data within 24 hours of receipt of‬
‭the information.‬
‭10.3.4.‬
‭Reporting of SAEs‬
‭SAE Reporting via an Electronic Data Collection Tool‬
‭●‬
‭The primary mechanism for reporting an SAE will be the electronic data‬
‭collection tool.‬
‭●‬
‭If the electronic system is unavailable, then the site will use the paper SAE data‬
‭collection tool (see next section) to report the event within 24 hours.‬
‭●‬
‭The site will enter the SAE data into the electronic system as soon as it becomes‬
‭available.‬
‭●‬
‭After the study is completed at a given site, the electronic data collection tool will‬
‭be taken off-line to prevent the entry of new data or changes to existing data.‬
‭●‬
‭If a site receives a report of a new SAE from a study participant or receives‬
‭updated data on a previously reported SAE after the electronic data collection tool has‬
‭been taken off-line, then the site can report this information on a paper SAE form (see‬
‭next section) or by telephone.‬
‭●‬
‭Contacts for SAE reporting can be found in the Study Reference Manual.‬
‭SAE Reporting via Paper Data Collection Tool‬
‭●‬
‭Email of the SAE paper data collection tool is the preferred method to transmit‬
‭this information.‬
‭●‬
‭In rare circumstances and in the absence of email, notification by telephone is‬
‭acceptable with a copy of the SAE data collection tool sent by overnight mail or courier‬
‭service.‬
‭●‬
‭Initial notification via telephone does not replace the need for the investigator to‬
‭complete and sign the SAE data collection tool within the designated reporting time‬
‭frames.‬
‭●‬
‭Contacts for SAE reporting can be found in the Study Reference Manual.‬
‭37‬

‭Protocol DL-FACE-101 v1.0‬
‭10.4.‬
‭Appendix 4: Contraceptive and Barrier Guidance‬
‭Not applicable.‬
‭38‬

‭Protocol DL-FACE-101 v1.0‬
‭10.5.‬
‭Appendix 5: AEs, ADEs, SAEs, SADEs, USADEs and Device‬
‭Complaints and Nonconformances: Definitions and Procedures for‬
‭Recording, Evaluating, Follow-up, and Reporting in Device Studies‬
‭●‬
‭Both the investigator and the sponsor will comply with all local reporting‬
‭requirements.‬
‭●‬
‭The detection and documentation procedures described in this protocol apply to all‬
‭sponsor devices provided for use in the study. See Section 6.1.1 for the list of sponsor‬
‭devices.‬
‭10.5.1.‬
‭Definition of Device AE and ADE‬
‭Device AE and ADE Definition‬
‭●‬
‭An AE is any untoward medical occurrence in a clinical study participant, users,‬
‭or other persons, temporally associated with the use of study intervention, whether or not‬
‭considered related to the investigational device. An AE can therefore be any unfavorable‬
‭and unintended sign (including an abnormal laboratory finding), symptom, or disease‬
‭(new or exacerbated) temporally associated with the use of an investigational device. This‬
‭definition includes events related to the investigational device or comparator and events‬
‭related to the procedures involved.‬
‭●‬
‭An adverse device effect (ADE) is defined as an AE related to the use of an‬
‭investigational device. This definition includes any AE resulting from insufficient or‬
‭inadequate instructions for use, deployment, implantation, installation, or operation, or‬
‭any malfunction of the investigational device as well as any event resulting from use error‬
‭or from intentional misuse of the investigational device.‬
‭10.5.2.‬
‭Definition of Device SAE, SADE and USADE‬
‭A Device SAE is an any serious adverse event that:‬
‭a.‬ ‭Led to death‬
‭b.‬ ‭Led to serious deterioration in the health of the participant, that either resulted in:‬
‭●‬
‭A life-threatening illness or injury. The term “life-threatening” in the definition of‬
‭“serious” refers to an event in which the participant was at risk of death at the time of the‬
‭event. It does not refer to an event, which hypothetically might have caused death if it‬
‭were more severe.‬
‭●‬
‭A permanent impairment of a body structure or a body function.‬
‭●‬
‭Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing‬
‭condition, or a procedure required by the protocol, without serious deterioration in health,‬
‭is not considered an SAE.‬
‭●‬
‭Medical or surgical intervention to prevent life-threatening illness or injury or‬
‭permanent impairment to a body structure or a body function.‬
‭●‬
‭Chronic disease (MDR 2017/745).‬
‭c.‬ ‭Led to fetal distress, fetal death, or a congenital abnormality or birth defect‬
‭SADE definition‬
‭●‬
‭A SADE is defined as an adverse device effect that has resulted in any of the‬
‭consequences characteristic of an SAE.‬
‭39‬

‭Protocol DL-FACE-101 v1.0‬
‭●‬
‭Any device complaint or nonconformance that might have led to an SAE if‬
‭appropriate action had not been taken, intervention had not occurred, or circumstances‬
‭had been less fortunate.‬
‭Unanticipated SADE (USADE) definition‬
‭●‬
‭An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is‬
‭defined as a serious adverse device effect that by its nature, incidence, severity, or‬
‭outcome has not been identified in the current version of the risk analysis report (see‬
‭Section 2.3).‬
‭10.5.3.‬
‭Recording and Follow-Up of Device AE/SAE/Complaints and Nonconformances‬
‭Device AE, SAE, and Device Complaint and Nonconformance Recording‬
‭●‬
‭When an AE/SAE/device complaint or nonconformance occurs, it is the‬
‭responsibility of the investigator to review all documentation related to the event.‬
‭●‬
‭The investigator will then record all relevant information in the participant’s‬
‭medical records, in accordance with the investigator’s normal clinical practice and on the‬
‭appropriate form.‬
‭●‬
‭It is‬‭not‬‭acceptable for the investigator to send‬‭photocopies of the participant’s‬
‭medical records in lieu of completion of the AE/SAE/complaint and nonconformance‬
‭form.‬
‭●‬
‭There may be instances when copies of medical records for certain cases are‬
‭requested. In this case, all participant identifiers, with the exception of the participant‬
‭number, will be redacted on the copies of the medical records before submission.‬
‭●‬
‭The investigator will attempt to establish a diagnosis of the event based on signs,‬
‭symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the‬
‭individual signs/symptoms) will be documented as the AE/SAE.‬
‭●‬
‭For device complaints and nonconformances, it is very important that the‬
‭investigator describes any corrective or remedial actions taken to prevent recurrence of‬
‭the event.‬
‭o‬ ‭A remedial action is any action other than routine maintenance or servicing of a‬
‭device where such action is necessary to prevent recurrence of a device event. This‬
‭includes any amendment to the device design to prevent recurrence.‬
‭Assessment of Intensity‬
‭The investigator will make an assessment of intensity for each event reported during the study‬
‭and assign it to one of the following categories:‬
‭●‬
‭Mild: An event that is easily tolerated by the participant, causing minimal‬
‭discomfort and not interfering with everyday activities.‬
‭●‬
‭Moderate: An event that causes sufficient discomfort and interferes with normal‬
‭everyday activities.‬
‭●‬
‭Severe: An event that prevents normal everyday activities. An AE that is assessed‬
‭as severe should not be confused with an SAE. “Severe” is a category used for rating the‬
‭intensity of an event; both AEs and SAEs can be assessed as severe.‬
‭●‬
‭An event is defined as ‘serious’ when it meets at least 1 of the predefined‬
‭outcomes as described in the definition of an SAE,‬‭not‬‭when it is rated as severe.‬
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‭Protocol DL-FACE-101 v1.0‬
‭Assessment of Causality‬
‭●‬
‭The investigator is obligated to assess the relationship between study intervention‬
‭and each occurrence of each event.‬
‭●‬
‭A “reasonable possibility” of a relationship conveys that there are facts, evidence,‬
‭and/or arguments to suggest a causal relationship, rather than a relationship, cannot be‬
‭ruled out.‬
‭●‬
‭The investigator will use clinical judgment to determine the relationship.‬
‭●‬
‭Alternative causes, such as underlying disease(s), concomitant therapy, and other‬
‭risk factors, as well as the temporal relationship of the event to study intervention‬
‭administration will be considered and investigated.‬
‭●‬
‭For each event, the investigator‬‭must‬‭document in‬‭the medical notes that he/she‬
‭has reviewed the AE/SAE/device complaint or nonconformance and has provided an‬
‭assessment of causality.‬
‭●‬
‭There may be situations in which an SAE has occurred and the investigator has‬
‭minimal information to include in the initial report. However, it is very important that the‬
‭investigator always make an assessment of causality for every event before the initial‬
‭transmission of the SAE data.‬
‭●‬
‭The investigator may change his/her opinion of causality in light of follow-up‬
‭information and send an SAE follow-up report with the updated causality assessment.‬
‭●‬
‭The causality assessment is one of the criteria used when determining regulatory‬
‭reporting requirements.‬
‭Follow-up of Device AE/SAE/Complaint or Nonconformance‬
‭●‬
‭The investigator is obligated to perform or arrange for the conduct of‬
‭supplemental measurements and/or evaluations as medically indicated or as requested to‬
‭elucidate the nature and/or causality of the event as fully as possible. This may include‬
‭additional laboratory tests or investigations, histopathological examinations, or‬
‭consultation with other health care professionals.‬
‭●‬
‭New or updated information will be recorded in the originally completed form.‬
‭●‬
‭The investigator will submit any updated SAE data within 24 hours of receipt of‬
‭the information.‬
‭10.5.4.‬
‭Reporting of Device AE/SAE/Complaints or Nonconformances‬
‭SAE Reporting via an Electronic Data Collection Tool‬
‭●‬
‭The primary mechanism for reporting an SAE will be the electronic data‬
‭collection tool.‬
‭●‬
‭If the electronic system is unavailable, then the site will use the paper SAE data‬
‭collection tool (see next table) to report the event within 24 hours.‬
‭●‬
‭The site will enter the data into the electronic system as soon as it becomes‬
‭available.‬
‭●‬
‭After the study is completed at a given site, the electronic data collection tool will‬
‭be taken offline to prevent the entry of new data or changes to existing data.‬
‭●‬
‭If a site receives a report of a new event from a study participant or receives‬
‭updated data on a previously reported event after the electronic data collection tool has‬
‭41‬

‭Protocol DL-FACE-101 v1.0‬
‭been taken off-line, then the site can report this information on a paper SAE form (see‬
‭next table) or by telephone.‬
‭●‬
‭Contacts for SAE reporting can be found in the Study Reference Manual.‬
‭Device AE/SAE/Complaint or Nonconformances Reporting via Paper Data Collection‬
‭Tool‬
‭●‬
‭Email transmission of the paper data collection tool is the preferred method to‬
‭transmit this information.‬
‭●‬
‭In rare circumstances and in the absence of email, notification by telephone is‬
‭acceptable with a copy of the paper data collection tool sent by overnight mail or courier‬
‭service.‬
‭●‬
‭Initial notification via telephone does not replace the need for the investigator to‬
‭complete and sign the paper data collection tool within the designated reporting time‬
‭frames.‬
‭●‬
‭Contacts for reporting can be found in the Study Reference Manual.‬
‭10.5.5.‬
‭Reporting of SADEs‬
‭SADE Reporting‬
‭NOTE: There are additional reporting obligations for device nonconformances and complaints‬
‭that are potentially related to SAEs that must fulfill the legal responsibility to notify‬
‭appropriate regulatory authorities and other entities about certain safety information‬
‭relating to devices being used in clinical studies.‬
‭●‬
‭Any device event that is associated with an SAE must be reported to the sponsor‬
‭within 24 hours after the investigator determines that the event meets the definition of a‬
‭device complaint or nonconformance.‬
‭●‬
‭The sponsor will review all device events and determine and document in writing‬
‭whether they could have led to an SAE. These device events will be reported to the‬
‭regulatory authorities and IRBs/IECs as required by national regulations.‬
‭●‬
‭Contacts for SAE reporting can be found in the Study Reference Manual.‬
‭42‬

‭Protocol DL-FACE-101 v1.0‬
‭Appendix 6: Abbreviations and Definitions‬
‭Abbreviation‬
‭Definition‬
‭ADE‬
‭Adverse device effects‬
‭AE‬
‭Adverse event‬
‭CIOMS‬
‭Council for International Organizations of Medical Sciences‬
‭CONSORT‬
‭Consolidated Standards of Reporting Trials‬
‭EMA‬
‭Ecological Momentary Assessment‬
‭GCP‬
‭Good Clinical Practice‬
‭HIPAA‬
‭Health Insurance Portability and Accountability Act‬
‭ICF‬
‭Informed consent form‬
‭ICH‬
‭International Council for Harmonisation‬
‭IEC‬
‭Independent Ethics Committees‬
‭IRB‬
‭Institutional Review Boards‬
‭SADE‬
‭Serious adverse device effect‬
‭SAE‬
‭Serious adverse events‬
‭SoA‬
‭Schedule of Assessments‬
‭USADE‬
‭Unanticipated serious adverse device effect‬
‭43‬