Comparing Online and On-Site Cognitive Behavior Therapy in Major Depressive Disorder: Protocol for a Noninferiority Randomized Controlled Trial

Background The incidence of mental health disorders in Canada is increasing with costs of CAD $51 billion (US $40 billion) per year. Depression is the most prevalent cause of disability while cognitive behavioral therapy (CBT) is the best validated behavioral depression treatment. CBT, when combined with mindfulness meditation (CBT-M), has strong evidence for increased efficacy. While randomized controlled trials (RCTs) have demonstrated online CBT-M efficacy, comparisons with in-office delivery are lacking. Objective The aim of this research is to assess whether online group CBT-M (with standard psychiatric care) is non-inferior in efficacy and more cost-effective than office-based, on-site group CBT-M at post-intervention and 6-months follow-up in major depressive disorder. The study will also assess whether digitally recorded data (ie, online workbooks completed, Fitbit step count, and online text messages) predict depression symptom reduction in online participants. Methods This single-center, two-arm, noninferiority RCT employs assessor-blinded and self-report outcomes and economic evaluation. The research site is the Centre for Addiction and Mental Health (Toronto), a research-based psychiatry institution where participants will be identified from service wait lists and through contacts with other Toronto clinics. Inclusion criteria are as follows: (1) aged 18-60 years, any ethnicity; (2) Beck Depression Inventory-II (BDI-II) of mild severity (score ≥14) with no upper severity limit; (3) Mini-International Neuropsychiatric Interview-confirmed, psychiatric major depressive disorder diagnosis; (4) fluent in English. All patients are diagnosed by staff psychiatrists. Exclusion criteria are as follows: (1) receipt of weekly structured psychotherapy; (2) observation of Diagnostic and Statistical Manual of Mental Disorders (5th Edition) criteria for severe alcohol or substance use disorder (in past 3 months), borderline personality disorder, schizophrenia (or other primary psychotic disorder), bipolar disorder, or obsessive-compulsive disorder; (3) clinically significant suicidal ideation (imminent intent or attempted suicide in the past 6 months); and (4) treatment-resistant depression. All participants receive standard psychiatric care, experimental participants receive online group CBT-M, and controls receive standard care in-office group CBT-M. The online group program (in collaboration with NexJ Health, Inc) combines smartphone and computer-accessed workbooks with mental health phone counselling (16 hours in 16 weeks) that coordinates software interactions (eg, secure text messaging and Fitbit-tracked walking). The primary outcome is BDI-II, and secondary outcomes are anxiety (Beck Anxiety Inventory), depression (ie, Quick Inventory of Depressive Symptomatology and 17-item Hamilton Depression Rating Scale), mindfulness (Five-Facet Mindfulness Questionnaire), quality of life (European Quality of Life Five Dimension), and pain (Brief Pain Inventory). Results Based on prior studies with the BDI-II and 80% power to reject an inferiority hypothesis with a 1-sided type I error rate of 5%, a sample of 78 per group is adequate to detect small-to-medium–effect sizes. Conclusions This study assesses online CBT-M efficacy and noninferiority in relation to in-person CBT, and the cost-effectiveness of both interventions. Trial Registration ClinicalTrials.gov NCT04825535; https://www.clinicaltrials.gov/ct2/show/NCT04825535 International Registered Report Identifier (IRRID) DERR1-10.2196/29726


1a-i) Identify the mode of delivery in the title
Identify the mode of delivery. Preferably use "web-based" and/or "mobile" and/or "electronic game" in the title. Avoid ambiguous terms like "online", "virtual", "interactive". Use "Internet-based" only if Intervention includes non-web-based Internet components (e.g. email), use "computer-based" or "electronic" only if offline products are used. Use "virtual" only in the context of "virtual reality" (3-D worlds). Use "online" only in the context of "online support groups". Complement or substitute product names with broader terms for the class of products (such as "mobile" or "smart phone" instead of "iphone"), especially if the application runs on different platforms.
Does your paper address subitem 1a-i? * Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Recent research has focused on online CBT (including internet-delivered or telephonebased interventions) as a means of delivering cost-effective treatment to populations that are not able to access high-quality psychotherapy services provided in traditional in-office environments. The structured and goal-directed modules of CBT are well-suited to online delivery, and numerous randomized controlled trials (RCTs) have indicated that internetdelivered CBT is highly effective in symptom reduction and depression remission7-9. In recent years, CBT has been integrated with mindfulness meditation following strong evidence for the increased efficacy when CBT and mindfulness meditation are combined10. While other trials support online CBT and mindfulness efficacy vs. wait list controls11-20, no prior trial has compared the efficacy and the cost-effectiveness of online group CBT-M vs. standard office-based group CBT-M." "The present study has 3 aims: (1) to evaluate whether online group CBT-M plus standard psychiatric care is non-inferior in efficacy to office-based group CBT-M plus standard care as measured by Beck Depression Inventory-II (BDI-II) score in the treatment of adults with major depressive disorder (MDD); (2) to evaluate whether online group CBT-M is more costeffective than office-based group CBT-M at post-intervention and 6 months post-intervention follow-up; (3) to assess, within the online group CBT-M intervention group, whether digitally recorded adherence data (i.e. online workbooks completed, Fitbit tracked steps, online text messages exchanged, phone sessions completed) predict outcome benefits as indicated by changed BDI-II score." "Online Intervention: The online group CBT-M program combines software-based workbooks with phone-based Navigator-Coaching that coordinates software interactions (e.g. secure text messaging, Fitbit tracked walking, food monitoring via photography). Each participant is loaned a Fitbit-HR Charge 3, which assesses physical steps and 24-hour heart rate, averaged in 5 second intervals. Intervention content builds on two online RCTs with students6-9, and an RCT with adults with Type 2 Diabetes11-13 (where significant mental health and blood glucose benefits resulted). The content contains 24 workbook chapters on multiple topics derived from focus group study (e.g. Living By Your Truths, Overcoming Wired-ness and Tired-ness, Mindfulness and Relationships, Loss and Grief, and Resilience, Befriending Ourselves, Befriending Your Body with Exercise, Body Image, Intimacy, Forgiveness, Overcoming Procrastination, Dealing with Negative Moods, Stress Resilience, Reducing Performance Anxiety, Cultivating Inspiration), addressed in sequences mutually agreed on by participants and Navigator-Coaches.
The online CBT-M groups address structured tasks that elevate mood and decrease anxiety. Depressive social withdrawals are identified, and reactive withdrawals reflected on while corrective emotional experiences are elicited, structured and supported. Healthy internet interactions are reinforced by the online program content (24 workbooks, 56 videos), with priorities guided by participant interests. While internet-based contacts, generally, can offer distracting 'escapes' (e.g. Netflix movies, video game playing), they can also be productive, socially engaging events (e g TED Talks CBT discussion mindfulness instructions) where subitem not at all important 1 2 3 4 5 essential socially engaging events (e.g. TED Talks, CBT discussion, mindfulness instructions) where role-modeling coordinates with learning. Group members stimulate and reinforce health practice adoptions (exercise, CBT, mindfulness, sleep hygiene, diet, text-message encouragement) and transformations from distractive media fixations to the positive learning and enjoyment. Online contacts integrate with face-to-face professional and familial contacts, and social intimacy development. Group online CBT-M tasks emphasize applying CBT-mindfulness methods in accord with content themes: de-catastrophizing; overcoming perfectionism; sound sleep for increased vitality; self befriending; courage development; forgiveness; interpersonal mindfulness; and autonomous generosity. This progression coordinates physical and cognitive changes that integrate interpersonal contacts with self-management. The tracking of walking exercise and heart rate (HR) on 24hour basis captures HR elevations that reflect episodes of anxiety and negative affect (elevated HR with minimal movement). There is selective sharing of Fitbit bio-behavioural data with designated staff and group members. Reduced HR often accompanies mindfulness practice while mildly elevated HR is closely associated with walking (i.e., movement-affected HR). Self-modification goals involve improving autonomic nervous system balance through appropriate exercise, improved sleep hygiene and restorative sleep41." "

1a-ii) Non-web-based components or important co-interventions in title
Mention non-web-based components or important co-interventions in title, if any (e.g., "with telephone support").

Clear selection
Does your paper address subitem 1a-ii?
Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The non-web-based CBT component is delivered in the standard, empirically supported "person-to-person" format and does not require elaboration. subitem not at all important 1 2 3 4 5 essential 1a-iii) Primary condition or target group in the title Mention primary condition or target group in the title, if any (e.g., "for children with Type I Diabetes") Example: A Web-based and Mobile Intervention with Telephone Support for Children with Type I Diabetes: Randomized Controlled Trial

Clear selection
Does your paper address subitem 1a-iii? * Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The title clearly indicates the primary condition, "Major Depressive Disorder".

1b-i) Key features/functionalities/components of the intervention and comparator in the METHODS section of the ABSTRACT
Mention key features/functionalities/components of the intervention and comparator in the abstract. If possible, also mention theories and principles used for designing the site. Keep in mind the needs of systematic reviewers and indexers by including important synonyms. (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it) Clear selection Does your paper address subitem 1b-i? * Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "All participants receive standard psychiatric care (1 pharmacotherapy focused visit/month with a psychiatrist of 15-30 minute duration). Experimental participants additionally receive online group CBT-M or while control participants receive standard care in-office group CBT-M. The online group CBT-M program (in collaboration with NexJ Health, Inc.) combines exposure to smartphone and computer accessed workbooks with phone-based mental health counselling (16 hours in 16 weeks) that coordinates with ongoing software interactions (e.g. secure text messaging, Fitbit tracked walking). Each participant is loaned a Fitbit-HR Charge 3 to assess physical activity as measured by daily step count. "

1b-ii) Level of human involvement in the METHODS section of the ABSTRACT
Clarify the level of human involvement in the abstract, e.g., use phrases like "fully automated" vs. "therapist/nurse/care provider/physician-assisted" (mention number and expertise of providers involved, if any). (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it)

Clear selection
Does your paper address subitem 1b-ii?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Intervention modality is clearly explained in the abstract; all interventions are human-tohuman.

Clear selection
Does your paper address subitem 1b-iii?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The assessment format is clearly explained; self-report assessments are delivered through REDCap and the HDRS-24 is administered by a trained, blinded assessor-rater.
1b-iv) RESULTS section in abstract must contain use data Report number of participants enrolled/assessed in each group, the use/uptake of the intervention (e.g., attrition/adherence metrics, use over time, number of logins etc.), in addition to primary/secondary outcomes. (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it)

INTRODUCTION 2a) In INTRODUCTION: Scientific background and explanation of rationale
Does your paper address subitem 1b-iv?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is a protocol paper and recruitment has not yet taken place. Target participant enrolment numbers are included.

1b-v) CONCLUSIONS/DISCUSSION in abstract for negative trials
Conclusions/Discussions in abstract for negative trials: Discuss the primary outcome -if the trial is negative (primary outcome not changed), and the intervention was not used, discuss whether negative results are attributable to lack of uptake and discuss reasons. (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it)

Clear selection
Does your paper address subitem 1b-v?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This paper is a protocol paper and thus there are no results provided in the conclusion/discussion. Does your paper address subitem 2a-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Mental health disorders are Canada's most costly chronic health problem for both health systems and patients, and they are increasing in incidence. The current economic costs of mental health are estimated at $51 billion annually, with $42.3 billion in direct costs to the Canadian healthcare system1. Depression is a commonly diagnosed mental health disorder, representing the most prevalent cause of disability worldwide2. Cognitive Behavioural Therapy (CBT) is the best validated psychotherapy for the treatment of depression, with decades of research demonstrating its efficacy3. Despite its demonstrated efficacy, many individuals are not able to access adequate CBT treatment due to the limitations of face-toface delivery. Improving access to CBT services is crucial to overcome the treatment barriers-including geographic distance, cost, time, and perceived stigma-that currently prevent access to necessary mental health care for individuals with depression4-6. Recent research has focused on online CBT (including internet-delivered or telephone-based interventions) as a means of delivering cost-effective treatment to populations that are not able to access high-quality psychotherapy services provided in traditional in-office environments. The structured and goal-directed modules of CBT are well-suited to online delivery, and numerous randomized controlled trials (RCTs) have indicated that internetdelivered CBT is highly effective in symptom reduction and depression remission7-9. In recent years, CBT has been integrated with mindfulness meditation following strong evidence for the increased efficacy when CBT and mindfulness meditation are combined10. While other trials support online CBT and mindfulness efficacy vs. wait list controls11-20, no prior trial has compared the efficacy and the cost-effectiveness of online group CBT-M vs. standard office-based group CBT-M.
Previous non-inferiority RCTs have indicated that guided online CBT can be at least as effective as in-person CBT for the treatment of depression, but these studies are limited by the use of small, non-clinical samples and do not include cost-effectiveness comparisons 21-23. Research is now required with a large and adequate sample size and in-depth cost comparisons to fully establish non-inferiority and cost-effectiveness." Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Mental health disorders are Canada's most costly chronic health problem for both health systems and patients, and they are increasing in incidence. The current economic costs of mental health are estimated at $51 billion annually, with $42.3 billion in direct costs to the Canadian healthcare system1. Depression is a commonly diagnosed mental health disorder, representing the most prevalent cause of disability worldwide2. Cognitive Behavioural Therapy (CBT) is the best validated psychotherapy for the treatment of depression, with decades of research demonstrating its efficacy3. Despite its demonstrated efficacy, many individuals are not able to access adequate CBT treatment due to the limitations of face-toface delivery. Improving access to CBT services is crucial to overcome the treatment barriers-including geographic distance, cost, time, and perceived stigma-that currently prevent access to necessary mental health care for individuals with depression4-6. Recent research has focused on online CBT (including internet-delivered or telephone-based interventions) as a means of delivering cost-effective treatment to populations that are not able to access high-quality psychotherapy services provided in traditional in-office environments. The structured and goal-directed modules of CBT are well-suited to online delivery, and numerous randomized controlled trials (RCTs) have indicated that internetdelivered CBT is highly effective in symptom reduction and depression remission7-9. In recent years, CBT has been integrated with mindfulness meditation following strong evidence for the increased efficacy when CBT and mindfulness meditation are combined10. While other trials support online CBT and mindfulness efficacy vs. wait list controls11-20, no prior trial has compared the efficacy and the cost-effectiveness of online group CBT-M vs. standard office-based group CBT-M.
Previous non-inferiority RCTs have indicated that guided online CBT can be at least as effective as in-person CBT for the treatment of depression, but these studies are limited by the use of small, non-clinical samples and do not include cost-effectiveness comparisons 21-23. Research is now required with a large and adequate sample size and in-depth cost comparisons to fully establish non-inferiority and cost-effectiveness." METHODS 3a) Description of trial design (such as parallel, factorial) including allocation ratio Does your paper address CONSORT subitem 2b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Online group CBT-M will be non-inferior to standard, office-based group CBT in the treatment of MDD (as indicated by BDI-II score change) when online and office-based treatment groups are compared, using both intention-to-treat (ITT) and per protocol analyses (PP). Online group CBT-MM will be more cost-effective than standard, office-based group CBT, as measured by cumulative costs and quality-adjusted life-years (QALYs) calculated in the cost utility analysis. Within the online group CBT-M intervention participant group, digitally recorded adherence data will predict outcome benefits (BDI-II change).
Adherence over time will be compared within each participant using a generalized estimating equation (GEE) logistic regression model with an AR1 correlation structure." https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS64RdfIAFvmrTSkZQL2-3O8O9hrL5Sw/viewform?hl=en_US&formkey=dGlKd2Z2Q1lNS… 20/65 3b) Important changes to methods after trial commencement (such as eligibility criteria), with reasons Does your paper address CONSORT subitem 3a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Participants will be identified from wait-lists within Centre for Addiction and Mental Health (CAMH General Adult Psychiatry and Health Systems Division which services thousands of MDD patients annually. Participants may also be identified though contacts with other Toronto outpatient clinics. Potentially eligible participants will be identified by a Research Coordinator who will explore interest with the participant, and if interest is expressed, the Research Coordinator will review and explain the study. Eligibility screening and written consent will be undertaken in person prior to randomization. The study biostatistician (GT) will perform electronic randomization with study IDs blindly assigned to intervention (online group CBT-M plus standard psychiatric care) and control (office-based group CBT-M plus standard psychiatric care) groups. The Study ID information with the respective group allocation will be transferred onto cards placed in opaque, individual, sealed envelopes. After a participant completes baseline questionnaires, the Research Coordinator will open the next envelope in sequence to determine group allocation and Study ID. Based off of the results of previous successful RCTs including our own conducted at the same study site, we will recruit 100 participants per group or 200 overall (total N = 200). One-sided type 1 error rate is set at 5%. We chose a margin of 3 and a correlation of 0.70, giving a sample size of 78 per group in 2 groups, allowing for a drop-out rate of 20%. This sample is more than adequate for detection of small to medium effect sizes." Does your paper address CONSORT subitem 3b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study No, as this is a protocol paper and the trial has not yet started.

Clear selection
Does your paper address subitem 3b-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer Does your paper address CONSORT subitem 4a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Inclusion Criteria The inclusion criteria are: (1) individuals 18-60 years of age; (2) Beck Depression Inventory-II of at least mild severity (BDI-II score ≥ 14) with no upper severity limit37; (3) MINI-confirmed diagnosis of MDD38; (4) fluent in English. All participants are diagnosed by a CAMH staff psychiatrist with diagnosis confirmed via MINI International Neuropsychiatric Interview (MINI)38, administered at the screening visit.

Exclusion Criteria
The exclusion criteria are: (1) individuals currently receiving weekly structured psychotherapy; (2) individuals who meet DSM-V criteria for severe alcohol/substance use disorder (in the past 3 months), borderline personality disorder, schizophrenia or any other primary psychotic disorder, bipolar disorder or obsessive-compulsive disorder; (3) individuals who manifest clinically significant suicidal ideation defined as imminent intent or attempted suicide (in the past 6 months); (4) individuals who are judged to have treatment resistant depression (TRD), as defined by failure in at least two trials of antidepressant medications and/or a course of psychotherapy during the current depressive episode38-40."

4a-i) Computer / Internet literacy
Computer / Internet literacy is often an implicit "de facto" eligibility criterion -this should be explicitly clarified.

Clear selection
Does your paper address subitem 4a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer subitem not at all important 1 2 3 4 5 essential 4a-ii) Open vs. closed, web-based vs. face-to-face assessments: Open vs. closed, web-based vs. face-to-face assessments: Mention how participants were recruited (online vs. offline), e.g., from an open access website or from a clinic, and clarify if this was a purely webbased trial, or there were face-to-face components (as part of the intervention or for assessment), i.e., to what degree got the study team to know the participant. In online-only trials, clarify if participants were quasi-anonymous and whether having multiple identities was possible or whether technical or logistical measures (e.g., cookies, email confirmation, phone calls) were used to detect/prevent these.

Clear selection
Does your paper address subitem 4a-ii? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Participants will be identified from wait-lists within Centre for Addiction and Mental Health (CAMH General Adult Psychiatry and Health Systems Division which services thousands of MDD patients annually. Participants may also be identified though contacts with other Toronto outpatient clinics. Potentially eligible participants will be identified by a Research Coordinator who will explore interest with the participant, and if interest is expressed, the Research Coordinator will review and explain the study. Eligibility screening and written consent will be undertaken in person prior to randomization. The study biostatistician (GT) will perform electronic randomization with study IDs blindly assigned to intervention (online group CBT-M plus standard psychiatric care) and control (office-based group CBT-M plus standard psychiatric care) groups. The Study ID information with the respective group allocation will be transferred onto cards placed in opaque, individual, sealed envelopes. After a participant completes baseline questionnaires, the Research Coordinator will open the next envelope in sequence to determine group allocation and Study ID. Based off of the results of previous successful RCTs including our own conducted at the same study site, we will recruit 100 participants per group or 200 overall (total N = 200). One-sided type 1 error rate is set at 5%. We chose a margin of 3 and a correlation of 0.70, giving a sample size of 78 per group in 2 groups, allowing for a drop-out rate of 20%. This sample is more than adequate for detection of small to medium effect sizes." https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS64RdfIAFvmrTSkZQL2-3O8O9hrL5Sw/viewform?hl=en_US&formkey=dGlKd2Z2Q1lNS… 24/65 subitem not at all important 1 2 3 4 5 essential 4a-iii) Information giving during recruitment Information given during recruitment. Specify how participants were briefed for recruitment and in the informed consent procedures (e.g., publish the informed consent documentation as appendix, see also item X26), as this information may have an effect on user self-selection, user expectation and may also bias results.
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Patients who are deemed suitable to participate in research will be asked by their Attending Physician/Clinician for verbal consent to receive more information about the research project. The first point of contact for flagged patients will be their Attending Physician/Clinician. The patient's Attending Physician/Clinician will obtain verbal consent to contact the them with more information about the Research Project. If the patient declines, the CLEARR Coordinator will document the REB number and that the participant did not consent to receiving further information about the research study. The patients who provide verbal consent will be introduced to the Research Coordinator (who will also be the CLEARR Coordinator) to receive more information about the Research Project. If the patient provides verbal consent to be contacted about the Research Project, they will be approached by the CLEARR Coordinator to receive more information about the Research Project. Prior to obtaining informed consent, no Authorized Research Personnel other than the CLEARR Coordinator will have access to additional PHI. The Research Coordinator will provide further information and if the patient is interested in potentially participating, a screening visit will be scheduled. Prior to any screening taking place, the Research Coordinator will receive written consent from the participant. Participants will sign read the attached information sheet and discuss any questions with the Research Coordinator, then sign informed consent form (provided in this application).

COVID-19 Amendment to Consent
For the duration of the time that CAMH is limiting on-site non-essential research visits, consent for study participation will be obtained remotely. The guidelines informing the remote consent process are CAMH SOP GR 106, the CAMH Ethical Considerations for Remote Consent document, the CAMH Research Guidelines for Virtual Participant Sessions, and the CAMH SOP HSR 201 -Documentation Requirements for Human Subject Research.
The steps to obtaining remote consent that will be followed are as follows: 1. Participant is provided with an overview of the study, and options for receiving the informed consent form (ICF) and conducting the consent discussion Prospective participants will be contacted using the Initial Telephone Contact Script provided by REB and tailored to reflect the specific details of this study. The telephone script that will be used is attached to this REB Amendment (document titled Initial Telephone Contact Script -Gratzer REB #087/2020). Prior to the consent discussion, participants will be provided with the REB-approved ICF to assist in the consent discussion. The updated ICF that reflects the COVID-19 REB Amendments being made is attached to this REB Amendment application. The ICF will be provided to participants via their preferred method for receiving the consent material (email or by mail). Participants will give verbal consent to receive the ICF via mail or email in the initial telephone call made to participants by the Research Coordinator A second appointment will be made based on participant availability https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS64RdfIAFvmrTSkZQL2-3O8O9hrL5Sw/viewform?hl=en_US&formkey=dGlKd2Z2Q1lNS… 26/65 Research Coordinator. A second appointment will be made based on participant availability to discuss the ICF, ensuring adequate time for the participant to receive the ICF and read it over in detail. Participants will be provided with as much time as they need to review the consent form both prior to and during the appointment when consent is obtained.
2. Consent discussion will occur via CAMH-approved teleconference (via Webex) or telephone The consent discussion will occur via teleconference, using Webex, or telephone if the participant is not comfortable using Webex. If the participant consents to receiving information regarding Webex over email, an email will be sent to participants with a meeting invite using the email template included in this REB Amendment application (document titled Email Template for Participant Contact -Gratzer REB #087/2020). Remote visits, including the consent visit, will occur in accordance with the CAH Research Guidelines for Virtual Participant Sessions. Research participant identification will occur at the beginning of the consent visit via showing the research personnel conducting the visit governmentissued photo ID (via Webex) during the first encounter with the research personnel. If the consent visit is occurring over the phone at the participants preference, participant identity will be confirmed using double identifiers (full name and date of birth). Research personnel will document their verification of research participant identity in a paper copy of the Participant Contact Information and Identification Form (provided in CAMH SOP GR 106), which will be transferred onto CAMH property by research personnel as feasible. All participant questions will be answered and time will be taken to fully address the entirety of the ICF as would be done if the consent process was occurring in person. The research personnel conducting the consent visit will confirm that the individual has the ICF with them and can follow along during the discussion, pausing during the consent discussion to ask if the prospective participant wants to further discuss or review any information, answer questions throughout the consent discussion to gauge engagement and comprehension, and to support participants in their use of technological platforms including explaining how participants can complete the consent process in lay terms.

Informed consent is documented
Informed consent will be documented, as per the CAMH guidelines on Ethical Considerations for Remote Consent. Research personnel will confirm that the participant has the technical capability to print the ICF in order to sign it. Participants will sign the ICF using wet ink and the participant will send a scanned copy or photograph of the signed ICF back to the research personnel via email. When the ICF is received by research personnel, it will be signed by the team member conducting the consent discussion and dated. Participants will be sent a pre-paid envelope to return the original hard-copy ICF to CAMH. It will be documented on the paper copy of the Participant Contact Information and Identification Form that consent has been obtained.
4. Participant is provided with completed, fully signed ICF Participants will be provided with a completed, fully signed ICF via email or regular mail, depending on their preference. Paper Participant Records will document that the participant has been provided with the fully signed ICF and these records will be transported to CAMH when on-site activity resumes as per SOP GR 106. Does your paper address CONSORT subitem 4b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study All data is collected from participants in Toronto, Ontario, Canada.

4b-i) Report if outcomes were (self-)assessed through online questionnaires
Clearly report if outcomes were (self-)assessed through online questionnaires (as common in web-based trials) or otherwise.

Clear selection
Does your paper address subitem 4b-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Self-report assessments are administered to participants via REDCap. subitem not at all important 1 2 3 4 5 essential Does your paper address subitem 5-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The software used was developed by NexJ Health, Inc.
"Licences for and use of the smartphone app, NexJ Connected Wellness (NCW), are provided for this trial free-of-charge by NexJ Health, Inc. (Toronto, Ontario). The platform is cloud-based and hosted on IBM Cloud's Tier 4 data centers in Toronto and Montreal. IBM Cloud maintains an industry-leading array of security and privacy certifications, including SOC 1, 2, and 3, as well as the ISO 27000 family of certifications. By hosting on IBM Cloud, NexJ Health benefits from extremely high system uptime, fault tolerance, and security controls. As part of NexJ's extensive security processes and controls, 24/7 monitoring is conducted, which includes annual third-party penetration testing. All data is encrypted at rest and in transit, and no patient information is stored on the patient's device. The summary Privacy Impact Analysis is provided upon request. Privacy Policy and Terms of Use are also provided on request. See Appendices A1 and A2 for the Privacy Policy and Terms of Use."

5-ii) Describe the history/development process
Describe the history/development process of the application and previous formative evaluations (e.g., focus groups, usability testing), as these will have an impact on adoption/use rates and help with interpreting results.

Clear selection
Does your paper address subitem 5-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer

5-iii) Revisions and updating
Revisions and updating. Clearly mention the date and/or version number of the application/intervention (and comparator, if applicable) evaluated, or describe whether the intervention underwent major changes during the evaluation process, or whether the development and/or content was "frozen" during the trial.
Describe dynamic components such as news feeds or changing content which may have an impact on the replicability of the intervention (for unexpected events see item 3b).

Clear selection
Does your paper address subitem 5-iii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study There have been no revisions of the intervention.

5-iv) Quality assurance methods
Provide information on quality assurance methods to ensure accuracy and quality of information provided [1], if applicable. Does your paper address subitem 5-iv?

Clear selection
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer 5-v) Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing flowcharts of the algorithms used Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing flowcharts of the algorithms used. Replicability (i.e., other researchers should in principle be able to replicate the study) is a hallmark of scientific reporting.

Clear selection
Does your paper address subitem 5-v?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer

5-vi) Digital preservation
Digital preservation: Provide the URL of the application, but as the intervention is likely to change or disappear over the course of the years; also make sure the intervention is archived (Internet Archive, webcitation.org, and/or publishing the source code or screenshots/videos alongside the article). As pages behind login screens cannot be archived, consider creating demo pages which are accessible without login.

Clear selection
Does your paper address subitem 5-vi?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer

5-vii) Access
Access: Describe how participants accessed the application, in what setting/context, if they had to pay (or were paid) or not, whether they had to be a member of specific group. If known, describe how participants obtained "access to the platform and Internet" [1]. To ensure access for editors/reviewers/readers, consider to provide a "backdoor" login account or demo mode for reviewers/readers to explore the application (also important for archiving purposes, see vi). Does your paper address subitem 5-viii? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Interventions Online Intervention: The online group CBT-M program combines software-based workbooks with phone-based Navigator-Coaching that coordinates software interactions (e.g. secure text messaging, Fitbit tracked walking, food monitoring via photography). Each participant is loaned a Fitbit-HR Charge 3, which assesses physical steps and 24-hour heart rate, averaged in 5 second intervals. Intervention content builds on two online RCTs with students6-9, and an RCT with adults with Type 2 Diabetes11-13 (where significant mental health and blood glucose benefits resulted The online CBT-M groups address structured tasks that elevate mood and decrease anxiety. Depressive social withdrawals are identified, and reactive withdrawals reflected on while corrective emotional experiences are elicited, structured and supported. Healthy internet interactions are reinforced by the online program content (24 workbooks, 56 videos), with priorities guided by participant interests. While internet-based contacts, generally, can offer distracting 'escapes' (e.g. Netflix movies, video game playing), they can also be productive, socially engaging events (e.g. TED Talks, CBT discussion, mindfulness instructions) where role-modeling coordinates with learning. Group members stimulate and reinforce health practice adoptions (exercise, CBT, mindfulness, sleep hygiene, diet, text-message encouragement) and transformations from distractive media fixations to the positive learning and enjoyment. Online contacts integrate with face-to-face professional and familial contacts, and social intimacy development. Group online CBT-M tasks emphasize applying CBT-mindfulness methods in accord with content themes: de-catastrophizing; overcoming perfectionism; sound sleep for increased vitality; self befriending; courage development; forgiveness; interpersonal mindfulness; and autonomous generosity. This progression coordinates physical and cognitive changes that integrate interpersonal contacts with self-management. The tracking of walking exercise and heart rate (HR) on 24hour basis captures HR elevations that reflect episodes of anxiety and negative affect (elevated HR with minimal movement). There is selective sharing of Fitbit bio-behavioural data with designated staff and group members. Reduced HR often accompanies mindfulness practice while mildly elevated HR is closely associated with walking (i.e., movement-affected HR). Self-modification goals involve improving autonomic nervous system balance through appropriate exercise, improved sleep hygiene and restorative sleep41.

Clear selection
Office-Based Intervention: the on-site, usual-care CBT group follows the structure of the Mind Over Mood workbook (MOM, Guilford Press) in reviewing CBT concepts and procedures A series of work sheets assist participants in differentiating moods and in subitem not at all important 1 2 3 4 5 essential procedures. A series of work sheets assist participants in differentiating moods, and in differentiating moods from thoughts and situational influences, leading to modifications of thinking, behaviour, emotion and mood.
Difficulties with cognitive change are assumed to be associated with self-acceptance deficits and negative mood dominance. Increased self-acceptance is linked with mindfulness experiences, which involve 'more focusing on the present moment' and on nonjudgmental acceptance of ongoing experience. Mindful breathing awareness is described in content on 'balanced deep breathing' and in tension releases achieved via Progressive Muscle Relaxation practice.
An emphasized structure is the automatic thought record (ATM) by which negative, disturbing thoughts are identified, and attention directed to alternate thoughts judged clearer and less distorted. These transitions are more difficult when immersions in negative moods diminish the confidence in finding a 'better' thought. Accordingly, self-efficacy is an important goal, emphasized in exchanges of support between group members and in enhanced experiences of self-acceptance.
Behavioural activations (BA) are structured for the development of increased awareness and observations of how self-control resources elicit gratifying activities. On the basis of BA practices, cognitive restructuring (CR) strategies utilize the ATM or experiential approximations."

5-ix) Describe use parameters
Describe use parameters (e.g., intended "doses" and optimal timing for use). Clarify what instructions or recommendations were given to the user, e.g., regarding timing, frequency, heaviness of use, if any, or was the intervention used ad libitum.

Clear selection
Does your paper address subitem 5-ix?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer

5-x) Clarify the level of human involvement
Clarify the level of human involvement (care providers or health professionals, also technical assistance) in the e-intervention or as co-intervention (detail number and expertise of professionals involved, if any, as well as "type of assistance offered, the timing and frequency of the support, how it is initiated, and the medium by which the assistance is delivered". It may be necessary to distinguish between the level of human involvement required for the trial, and the level of human involvement required for a routine application outside of a RCT setting (discuss under item 21 -generalizability).

Clear selection
Does your paper address subitem 5-x?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Interventions: All participants receive standard psychiatric care (1 pharmacotherapy focused visit/month with a psychiatrist of 15-30 minute duration). Experimental participants additionally receive online group CBT-M or while control participants receive standard care in-office group CBT-M. The online group CBT-M program (in collaboration with NexJ Health, Inc.) combines exposure to smartphone and computer accessed workbooks with phone-based mental health counselling (16 hours in 16 weeks) that coordinates with ongoing software interactions (e.g. secure text messaging, Fitbit tracked walking). Each participant is loaned a Fitbit-HR Charge 3 to assess physical activity as measured by daily step count."

5-xi) Report any prompts/reminders used
Report any prompts/reminders used: Clarify if there were prompts (letters, emails, phone calls, SMS) to use the application, what triggered them, frequency etc. It may be necessary to distinguish between the level of prompts/reminders required for the trial, and the level of prompts/reminders for a routine application outside of a RCT setting (discuss under item 21 -generalizability).

Clear selection
Does your paper address subitem 5-xi? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Prompts are not used, and not incorporated into the intervention structure.

5-xii) Describe any co-interventions (incl. training/support)
Describe any co-interventions (incl. training/support): Clearly state any interventions that are provided in addition to the targeted eHealth intervention, as ehealth intervention may not be designed as stand-alone intervention. This includes training sessions and support [1]. It may be necessary to distinguish between the level of training required for the trial, and the level of training for a routine application outside of a RCT setting (discuss under item 21 -generalizability. Does your paper address subitem 5-xii? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study There are no co-interventions provided.

Clear selection
Does your paper address CONSORT subitem 6a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study 7b) When applicable, explanation of any interim analyses and stopping guidelines 8a) Method used to generate the random allocation sequence NPT: When applicable, how care providers were allocated to each trial group Does your paper address subitem 7a-i?
Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Based off of the results of previous successful RCTs including our own conducted at the same study site, we will recruit 100 participants per group or 200 overall (total N = 200). One-sided type 1 error rate is set at 5%. We chose a margin of 3 and a correlation of 0.70, giving a sample size of 78 per group in 2 groups, allowing for a drop-out rate of 20%. This sample is more than adequate for detection of small to medium effect sizes." Does your paper address CONSORT subitem 7b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The study has not started thus this is not applicable.
Does your paper address CONSORT subitem 8a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The study has not started thus this is not applicable. 8b) Type of randomisation; details of any restriction (such as blocking and block size) 9) Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned 10) Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions Does your paper address CONSORT subitem 8b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "The study biostatistician (GT) will perform electronic randomization with study IDs blindly assigned to intervention (online group CBT-M plus standard psychiatric care) and control (office-based group CBT-M plus standard psychiatric care) groups. The Study ID information with the respective group allocation will be transferred onto cards placed in opaque, individual, sealed envelopes. After a participant completes baseline questionnaires, the Research Coordinator will open the next envelope in sequence to determine group allocation and Study ID." Does your paper address CONSORT subitem 9? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "The study biostatistician (GT) will perform electronic randomization with study IDs blindly assigned to intervention (online group CBT-M plus standard psychiatric care) and control (office-based group CBT-M plus standard psychiatric care) groups. The Study ID information with the respective group allocation will be transferred onto cards placed in opaque, individual, sealed envelopes. After a participant completes baseline questionnaires, the Research Coordinator will open the next envelope in sequence to determine group allocation and Study ID." 11a) If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how NPT: Whether or not administering co-interventions were blinded to group assignment subitem not at all important 1 2 3 4 5 essential Does your paper address CONSORT subitem 10? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "The study biostatistician (GT) will perform electronic randomization with study IDs blindly assigned to intervention (online group CBT-M plus standard psychiatric care) and control (office-based group CBT-M plus standard psychiatric care) groups. The Study ID information with the respective group allocation will be transferred onto cards placed in opaque, individual, sealed envelopes. After a participant completes baseline questionnaires, the Research Coordinator will open the next envelope in sequence to determine group allocation and Study ID." 11a-i) Specify who was blinded, and who wasn't Specify who was blinded, and who wasn't. Usually, in web-based trials it is not possible to blind the participants [1, 3] (this should be clearly acknowledged), but it may be possible to blind outcome assessors, those doing data analysis or those administering co-interventions (if any).

Clear selection
Does your paper address subitem 11a-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The HDRS-24 blinded assessor rater is blinded to participant group assignment. Other research team members are not blinded. 12a) Statistical methods used to compare groups for primary and secondary outcomes NPT: When applicable, details of whether and how the clustering by care providers or centers was addressed 11a-ii) Discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator" Informed consent procedures (4a-ii) can create biases and certain expectations -discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator".

Clear selection
Does your paper address subitem 11a-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Both interventions are of interest.
Does your paper address CONSORT subitem 11b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The similarities of interventions is discussed in the paragraphs labeled "Interventions" https://docs.google.com/forms/d/e/1FAIpQLSfZBSUp1bwOc_OimqcS64RdfIAFvmrTSkZQL2-3O8O9hrL5Sw/viewform?hl=en_US&formkey=dGlKd2Z2Q1lNS… 45/65 Does your paper address CONSORT subitem 12a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "The primary analysis will be a Bayesian analysis of covariance (ANCOVA), with change in BDI-II between baseline and 16 weeks as the outcome and two covariates, the baseline score and the intervention group variable, coded as O (for online), and I (for in-office). We refer to the parameter of interest as ∆, the (baseline-adjusted) difference between the two groups in the change in BDI-II from baseline to 16 weeks, coded such that ∆ < 0 means that the on-line group has a smaller decrease in the level of depression over the course of the study. Then, if ∆ > -3, the improvement in the on-line group is at most 3 points worse than the improvement in the in-office group and the online group is non-inferior to the in-office group. Using non-informative priors for all study parameters in the ANCOVA model, we will compute and plot the full posterior distribution of ∆, presenting the lower 95% credible interval for ∆, and then calculating the posterior probability that ∆ > -3, i.e., the probability (after observing the study data) that on-line CBT is non-inferior, according to our definition. One advantage of a Bayesian approach is that it allows the assigning of posterior probabilities of non-inferiority at other margins, notably other margins near 3 may have equal levels of evidentiary support. For example, without a penalty for multiple testing, we can compute the probability that ∆ > -2 or ∆ > -4. Another advantage of the Bayesian approach is that it involves a more useful presentation of results than a simple confidence interval or p-value. Finally, the outputs of the Bayesian model can be used as probabilistic inputs for the economic analysis. Since this is a non-inferiority approach, the primary analysis will be per protocol, which in the presence of intervention non-adherence is more conservative than intention-to-treat (i.e., less likely to conclude groups are similar when they are not). Three secondary analyses of the primary outcome will be conducted. First, we will make the above between-group comparison of the changes in BDI-II scores from baseline to each follow-up time point. Secondly, we will perform an intention-to-treat analysis, including outcomes on participants who were non-adherent to their program (standard care CBT vs. CBT online) using established cut-offs. Finally, to assess for sensitivity to random imbalance in baseline characteristic, the following covariates will be added to the ANCOVA model: age, baseline anxiety (BAI), baseline depression (HDRS-24), baseline pain, and baseline mindfulness. If more than 5% of participants included in the per protocol are missing outcome data, that analysis will use multiple imputation within the Bayesian model with full baseline covariate data used to impute missing outcomes. In a second approach, we will assume missing follow-up data are missing not-at-random and replace missing values by values randomly sampled from the upper half (high BDI-II) of their predictive distribution. This represents the assumption that those who have no follow-up BDI-II all have values lower than the median predicted by their baseline characteristics. This will be repeated within the intention-to-treat analysis, where missing outcome data will be more common. subitem not at all important 1 2 3 4 5 essential (EQ-5D). While non-inferiority margins per outcome are non-existent, we will present probabilities for a range of margins based on fractions of the minimally clinical important difference (MCID) for these scales (where available) or fractions of a standard deviation. All primary and secondary outcomes will be analyzed as continuous variables, with outcomes modelled as normal, t, rescaled beta, log-normal or gamma distributions, whichever is most appropriate."

Secondary Outcomes
12a-i) Imputation techniques to deal with attrition / missing values Imputation techniques to deal with attrition / missing values: Not all participants will use the intervention/comparator as intended and attrition is typically high in ehealth trials. Specify how participants who did not use the application or dropped out from the trial were treated in the statistical analysis (a complete case analysis is strongly discouraged, and simple imputation techniques such as LOCF may also be problematic [4]).

Clear selection
Does your paper address subitem 12a-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Missing Data Missing data may occur when participants miss an assessment or outcome measure but continue study participation or because participants drop out prematurely. In the first case, regression-based imputation at the individual patient level will be used to impute the missing outcome(s). In the second case, imputing data using bottom quintile scores of responders will be used as a worst-case sensitivity analysis46, 47. Loss to follow-up is unavoidable in MDD studies and can reflect poor intervention response. It was a relevant comparison variable in the recently completed RCT where loss to follow-up in the intervention arm was 10%, compared to 60% in the standard psychiatry control arm17,18. While differences may be more modest in the proposed trial (e.g. 40% in group in-office CBT versus 10% in group online CBT) they will be carefully monitored and, as previously mentioned, represented in the cost-effectiveness and intention-to-treat analyses." Does your paper address CONSORT subitem 12b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "Cost-effectiveness We will conduct a full economic evaluation following the design of a cost-utility analysis conducted from a societal and healthcare consumer/payer's perspective. We will adopt the following time horizons: within-trial (4 and 10 months) and the lifetime of the trial cohort. A within-trial cost utility analysis will focus only on interventions directly evaluated in the trial54. We will estimate costs for: i) the interventions; ii) physician services; iii) emergency department visits and hospitalizations; iv) outpatient diagnostic tests; v) drugs, including drug unrelated to major depressive disorder; vi) home care; vii) long-term care; viii) out-ofpocket costs; and ix) productivity costs. The intervention will be cost-estimated by estimating the value of time of those administering the intervention, facility-use costs, and device/equipment costs, amortized over an appropriate period. Resource utilization, out-ofpocket costs, and productivity costs will be estimated using a patient cost diary. We will assess health outcome data in QALYs using the EQ-5D at each time point48-51. Cumulative costs and QALYs will be estimated and compared in order to calculate the incremental cost utility ratio, and incremental net health benefit. We will plot the cost-effectiveness acceptability curves and confidence ellipses to demonstrate variability in a trial sample and illustrate probability of online CBT-M being cost-effective compared with standard CBT program at a range of willingness to pay thresholds."

X26-i) Comment on ethics committee approval
Clear selection

Clear selection
Does your paper address subitem X26-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer

X26-iii) Safety and security procedures
Safety and security procedures, incl. privacy considerations, and any steps taken to reduce the likelihood or detection of harm (e.g., education and training, availability of a hotline) Clear selection  13b) For each group, losses and exclusions after randomisation, together with reasons Does your paper address subitem X26-iii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study

Your answer
Does your paper address CONSORT subitem 13a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study N/A shown in a CONSORT flow diagram) * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Not applicable -results have not been obtained as this is a protocol paper.

13b-i) Attrition diagram
Strongly recommended: An attrition diagram (e.g., proportion of participants still logging in or using the intervention/comparator in each group plotted over time, similar to a survival curve) or other figures or tables demonstrating usage/dose/engagement.

Clear selection
Does your paper address subitem 13b-i?
Copy and paste relevant sections from the manuscript or cite the figure number if applicable (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer 14b) Why the trial ended or was stopped (early) Does your paper address CONSORT subitem 14a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study "The present study has 3 aims: (1) to evaluate whether online group CBT-M plus standard psychiatric care is non-inferior in efficacy to office-based group CBT-M plus standard care as measured by Beck Depression Inventory-II (BDI-II) score in the treatment of adults with major depressive disorder (MDD); (2) to evaluate whether online group CBT-M is more costeffective than office-based group CBT-M at post-intervention and 6 months post-intervention follow-up; (3) to assess, within the online group CBT-M intervention group, whether digitally recorded adherence data (i.e. online workbooks completed, Fitbit tracked steps, online text messages exchanged, phone sessions completed) predict outcome benefits as indicated by changed BDI-II score."

14a-i) Indicate if critical "secular events" fell into the study period
Indicate if critical "secular events" fell into the study period, e.g., significant changes in Internet resources available or "changes in computer hardware or Internet delivery resources"

Clear selection
Does your paper address subitem 14a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer Does your paper address CONSORT subitem 14b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.
Does your paper address CONSORT subitem 15? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

15-i) Report demographics associated with digital divide issues
In ehealth trials it is particularly important to report demographics associated with digital divide issues, such as age, education, gender, social-economic status, computer/Internet/ehealth literacy of the participants, if known. Does your paper address subitem 15-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

16-i) Report multiple "denominators" and provide definitions
Report multiple "denominators" and provide definitions: Report N's (and effect sizes) "across a range of study participation [and use] thresholds" [1], e.g., N exposed, N consented, N used more than x times, N used more than y weeks, N participants "used" the intervention/comparator at specific pre-defined time points of interest (in absolute and relative numbers per group). Always clearly define "use" of the intervention.

Clear selection
Does your paper address subitem 16-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

16-ii) Primary analysis should be intent-to-treat
Primary analysis should be intent-to-treat, secondary analyses could include comparing only "users", with the appropriate caveats that this is no longer a randomized sample (see 18-i).

Clear selection
Does your paper address subitem 16-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study

Your answer
Does your paper address CONSORT subitem 17a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study subitem not at all important 1 2 3 4 5 essential 17b) For binary outcomes, presentation of both absolute and relative effect sizes is recommended 18) Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory 17a-i) Presentation of process outcomes such as metrics of use and intensity of use In addition to primary/secondary (clinical) outcomes, the presentation of process outcomes such as metrics of use and intensity of use (dose, exposure) and their operational definitions is critical. This does not only refer to metrics of attrition (13-b) (often a binary variable), but also to more continuous exposure metrics such as "average session length". These must be accompanied by a technical description how a metric like a "session" is defined (e.g., timeout after idle time) [1] (report under item 6a).

Clear selection
Does your paper address subitem 17a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study

Your answer
Does your paper address CONSORT subitem 17b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Does your paper address CONSORT subitem 18? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

18-i) Subgroup analysis of comparing only users
A subgroup analysis of comparing only users is not uncommon in ehealth trials, but if done, it must be stressed that this is a self-selected sample and no longer an unbiased sample from a randomized trial (see 16-iii).

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Does your paper address subitem 18-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer Does your paper address CONSORT subitem 19? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is addressed in the consent discussion where informed consent is obtained prior to study participation. Please see above.

19-i) Include privacy breaches, technical problems
Include privacy breaches, technical problems. This does not only include physical "harm" to participants, but also incidents such as perceived or real privacy breaches [1], technical problems, and other unexpected/unintended incidents. "Unintended effects" also includes unintended positive effects [2].

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Does your paper address subitem 19-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Your answer 22-i) Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use) Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use).

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Does your paper address subitem 22-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

22-ii) Highlight unanswered new questions, suggest future research
Highlight unanswered new questions, suggest future research.

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Does your paper address subitem 22-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

20-i) Typical limitations in ehealth trials
Typical limitations in ehealth trials: Participants in ehealth trials are rarely blinded. Ehealth trials often look at a multiplicity of outcomes, increasing risk for a Type I error. Discuss biases due to non-use of the intervention/usability issues, biases through informed consent procedures, unexpected events.

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Does your paper address subitem 20-i? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

21-i) Generalizability to other populations
Generalizability to other populations: In particular, discuss generalizability to a general Internet population, outside of a RCT setting, and general patient population, including applicability of the study results for other organizations

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Does your paper address subitem 21-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

21-ii) Discuss if there were elements in the RCT that would be different in a routine application setting
Discuss if there were elements in the RCT that would be different in a routine application setting (e.g., prompts/reminders, more human involvement, training sessions or other co-interventions) and what impact the omission of these elements could have on use, adoption, or outcomes if the intervention is applied outside of a RCT setting. Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study This is not applicable as this is a protocol paper and this information is not yet available.

Clear selection
Does your paper address CONSORT subitem 23? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study ClinicalTrials.gov Identifier: NCT04825535 Does your paper address CONSORT subitem 24? * Cite a Multimedia Appendix, other reference, or copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study Not available for public access

About the CONSORT EHEALTH checklist
Does your paper address CONSORT subitem 25? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study The study is funded by the Canadian Institute of Health Research (CIHR).

X27-i) State the relation of the study team towards the system being evaluated
In addition to the usual declaration of interests (financial or otherwise), also state the relation of the study team towards the system being evaluated, i.e., state if the authors/evaluators are distinct from or identical with the developers/sponsors of the intervention.

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Does your paper address subitem X27-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briefly explain why the item is not applicable/relevant for your study As a result of using this checklist, did you make changes in your manuscript? * What were the most important changes you made as a result of using this checklist?

Your answer
How much time did you spend on going through the checklist INCLUDING making changes in your manuscript * Around five hours were spent.
As a result of using this checklist, do you think your manuscript has improved? * STOP -Save this form as PDF before you click submit To generate a record that you filled in this form, we recommend to generate a PDF of this page (on a Mac, simply select "print" and then select "print as PDF") before you submit it.
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