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Effectiveness and cost-effectiveness of a lifestyle modification programme in the prevention and treatment of subclinical, mild and moderate depression in primary care: a randomised clinical trial protocol

Introduction Major depression is a highly prevalent pathology that is currently the second most common cause of disease-induced disability in our society. The onset and continuation of depression may be related to a wide variety of biological and psychosocial factors, many of which are linked to different lifestyle aspects. Therefore, health systems must design and implement health promotion and lifestyle modification programmes (LMPs), taking into account personal factors and facilitators. The main objective of this protocol is to analyse the clinical effectiveness, cost-effectiveness and cost utility of an LMP and an LMP with information and communication technologies (ICTs) as adjunctive treatment for depression in primary care patients. The secondary objectives are to analyse the clinical effectiveness in the subgroup that presents comorbidity and to analyse the correlation between personal factors on health behaviour and lifestyle patterns. Methods and analysis A randomised, multicenter pragmatic clinical trial with three parallel groups consisting of primary healthcare patients suffering from subclinical, mild or moderate depression. The following interventions will be used: (1) Usual antidepressant treatment with psychological advice and/or psychotropic drugs prescribed by the general practitioner (treatment as usual (TAU)). (2) TAU+LMP. A programme to be imparted in six weekly 90-minute group sessions, intended to improve the following aspects: behavioural activation+daily physical activity+adherence to the Mediterranean diet pattern+sleep hygiene+careful exposure to sunlight. (3) TAU+LMP+ICTs: healthy lifestyle recommendations (TAU+LMP)+monitoring using ICTs (a wearable smartwatch). The primary outcome will be the depressive symptomatology and the secondary outcomes will be the quality of life, the use of health and social resources, personal factors on health behaviour, social support, lifestyle patterns and chronic comorbid pathology. Data will be collected before and after the intervention, with 6-month and 12-month follow-ups. Ethics and dissemination This study has been approved by the Clinical Research Ethics Committee of Aragón (approval number: C.P.-C.I. PI18/286) and the Research Ethics Committee of the Balearic Islands (IB3950/19 PI). Data distribution will be anonymous. Results will be disseminated via conferences and papers published in peer-reviewed, open-access journals. Trial registration number ClinicalTrials.gov Registry (NCT03951350).

1. My main concern is that many items in the SPIRIT checklist are not currently addressed in the manuscript text. In my opinion it is not sufficient to write "NA" as a response to checklist items; each one should be explicitly addressed in text. Where the item is not applicable, the authors should explain why this is the case. For example, why is there no statement of the role of the funder? Why is there no steering committee or data monitoring committee? It is fine for the investigators to have no plans to discontinue or modify interventions, or to improve adherence, or promote participant retention, but this should be stated in the protocol. The authors may wish to review other published protocols for guidance here. 2. Where the authors indicate they have addressed SPIRIT checklist items these are often not described in enough detail; in particular, please review items relating to allocation, masking, data collection, and statistical methods. Where can a full statistical analysis plan be found? Other items have not been addressed at all; for example as far as I can tell there is no information on data management. 3. There seem to be a lot of outcome measures and some are quite lengthy; have the researchers considered the burden on participants and potential for assessment fatigue and associated drop out? 4. The title and study objectives make reference to subclinical, mild, and moderate depression. Are the researchers planning on analyzing the intervention's effectiveness in each of these severity subgroups? 5. At present the manuscript finishes quite abruptly and would benefit from at least a short concluding paragraph. Again, consider reviewing recently published protocols for ideas. Specific comments 6. P5, line 37: There don't seem to be any study objectives that justify the inclusion of two different intervention groups. Are the authors expecting these groups to differ? If so, how? If not, what is the rationale for including them both? 7. P5, line 18: The study design does not specify that this is a randomised controlled trial although it seems to be; consider revising. 8. P5, line 55: How is "perfect" understanding of Spanish assessed? Even native speakers could be argued not to have perfect understanding of a language as there are inevitably words we misuse or haven't come across before! 9. P5, line 57: The diseases listed here specifically affect the brain, conditions affecting other parts of the central nervous system (i.e., spine) presumably don't interfere with eligibility? Consider rephrasing. 10. P6, line 31: what are the eligibility criteria for study sites? How are PHCs selected? (Also just a minor comment, the acronym PHC already includes 'centre' so saying 'PHC centre' is redundant) 11. P6, line 48: As above, please include more detail on randomization and blinding. What ratio are patients allocated to trial arms? What is the size of the blocks? How are they generated? How is the allocation sequence generated and concealed? How are patients informed of their allocation? If GPs are not blinded to allocation, what is the potential for contamination and how is this being addressed? 12. P6-7: As above, please include more detail on concomitant care, discontinuation/modification criteria (if none, please state), and adherence monitoring/promotion (if none, please state). 13. P7, line 5 and 30: review session descriptions for repeated text ("benefits of engaging in regular physical activity. Benefits of regular physical activity") 14. P567, line 56: As above, please include more detail on data collection methods. How are questionnaires administered at follow-up? 15. P8, line 35: Is data on chronic disease collected at every timepoint? Is it reasonable to expect a difference in these measures in a short space of time? 16. P10, line 49: analysis plan to "compare the two groups" is confusing given there are three, and relates to earlier comment about ensuring all three groups are addressed in the study objectives. 17. P10, line 54: makes reference to "the main hypothesis" but no hypotheses have been stated. 18. P10, line 57: will the models also adjust for clustering of participants within PHCs?
19. P11, line 5: Secondary variables listed here include QoL, chronic disease, and health perception. It is not clear what third variable is, or how other secondary outcomes will be analysed (social support, use of health services, personal factors). Further, are all these outcomes continuous? Are any strategies being employed to account for the large number of comparisons planned? How will missing data be handled? 20. P11, line 6: This is the only reference to analysis of the two intervention groups on adherence to lifestyle modification requirements. Is this the only analysis comparing these groups (are there no plans to compare clinical effectiveness)? How is adherence defined? (Is it continuous? Binary?

REVIEWER
Fermin Mayoral Hospital Regional University of malaga REVIEW RETURNED 31-Mar-2020

GENERAL COMMENTS
In terms of economic analysys in adition to estimating costeffectiveness it would be highly appreciated to calculate incremental cost-utility ratios (ICUR) of intervention from the healthcare or social perspective. To minimize the bias resulting from non-randomization, a propensity score-based method should be used.

Baptiste Leurent
London School of Hygiene and Tropical Medicine, UK REVIEW RETURNED 03-Jul-2020

GENERAL COMMENTS
Please find my specific comments below: Sample size (page 7): Some information is missing to reproduce the sample size, such as the BDI standard deviation. Please add an appendix with the details of the sample size calculation (including formula and all parameters).
Randomization (page 7): Please specify block size Outcomes (page 8-11): I was not sure to follow the outcomes measurement schedule. When is "immediately after the intervention"? Will this be for participants in the control arm as well (when?). Are all of the outcomes listed measure at each of the 4 time points? If not, please specify (a table presenting the measurement schedule may  help).
What additional data are collected at baseline (e.g. socio-demographics…)? The MINI is mentioned, is it at baseline only?
Please clarify (here or in the statistical analysis section) the list of secondary outcomes to be compared between arms. The list provided here differs from the one in the statistical analysis paragraph (see comment below). You may need to distinguish the "measurements" (data collected), and the list of primary/secondary "outcomes", which will be formally compared between group. For example, I was not clear if you are planning to compare "comorbidity" and "social support"? Do you expect the intervention to affect these outcomes? Or are these additional data?
Statistical analysis (page 10): Note that CONSORT are guidelines for reporting, not for the analysis.
I am not very familiar with RM ANOVA, but I do not see reason to use it as opposed to a (repeated-measure) linear regression, which you mention later. I would strongly advise against RM ANOVA if it either i) does not allow to adjust for covariates ii) does not allow to estimate the treatment effect (estimate mean difference between arms and confidence interval), or iii) does not allow for missing data (exclude any participant with some missing data). If any of these limitations apply, please consider a using a linear regression for your primary analysis. How will you compare the arms exactly? Will you compare arms 2 (LMP) and 3 (LMP+ICT) to TAU as two separate analyses? Or will you also compare 2 vs. 3, or conduct an "overall" test? I would consider a "sensitivity analysis" comparing arms 2 + 3 combined vs. TAU, which could explore the effect of LMP with more power Similarly for the time-points, you may want to clarify what comparison you are planning to conduct. Will you assume a different treatment effect at each time point (and if so, how will you test for an "overall treatment effect"?), or a single treatment effect over all the follow-ups? Or are you planning to consider one of the time-point (e.g. 6 month) as "primary"? Please remind the time-points at which BDI will be measured.
Please clarify the list of secondary outcomes. What EQ5D measure (see comment below)? What is "effectiveness in chronic diseases"? What is/are "self perception"? (All the outcomes listed as "Personal factors on health behaviour"?). Are you not planning to compare any other outcomes? What about the lifestyle measures ?
In the abstract, you mention "analysis of the effectiveness of the intervention in comorbid chronic pathology". Do you mean a subgroup analysis (of treatment effect in the comorbid subgroup)? It should be mentioned in the statsitical analysis.
Cost-effectiveness analysis (page 11): Why are you focussing on 6 months? Are you not collecting data up to 12 months? Again, why only looking at EQ-5D at 6 months? It is also collected "post-intervention" and at 12 months?
Page 11 it is mentioned an "Analysis of the correlation and the weight of personal factors in the completion of the LMP". Is this part of the cost-effectiveness analysis? If not, please add another header. This section was not clear. What are the "Personal factors", and "completion of the LMP"? Do you mean you are planning to look at the baseline characteristics associated to attending the LMP sessions? This is quite a different analysis (not randomised and not related to the effectiveness of the intervention), and should probably be presented separately, as an additional analysis of interest.
What does "an analysis will be carried out of correlations between personal factors and compliance variables, primary and secondary outcome variable" means exactly? Please leave your comments for the authors below Thank you for the opportunity to review this protocol of a trial examining whether a lifestyle modification program delivered via 6 weekly group sessions can improve depression relative to usual primary care, and whether it can do so cost-effectively. The intervention has the potential to provide a useful adjunct to existing models of care and could feasibly be delivered in routine settings. However I do not consider the manuscript in its current form to be suitable for publication, for reasons outlined below. Please note that the page numbers in the SPIRIT checklist did not correspond to those in the combined PDF I downloaded from the journal website; I suspect this is a function of the uploading process. Page numbers below refer to those in the combined PDF. I do not consider myself to have sufficient expertise in economic evaluations to comment on the planned economic analysis so defer to other reviewers on this section of the manuscript. Thank you very much for your thorough review. We are very glad for your comments and feedback. We agree with you, there is a mismatch between the pages of the main manuscript and the pages of the final PDF generated automatically by the platform. This is an inconvenience because we do not know the real pages until we upload all the documents and the final PDF is generated.

VERSION 1 -AUTHOR RESPONSE
General comments 1. My main concern is that many items in the SPIRIT checklist are not currently addressed in the manuscript text. In my opinion it is not sufficient to write "NA" as a response to checklist items; each one should be explicitly addressed in text. Where the item is not applicable, the authors should explain why this is the case. For example, why is there no statement of the role of the funder? Why is there no steering committee or data monitoring committee? It is fine for the investigators to have no plans to discontinue or modify interventions, or to improve adherence, or promote participant retention, but this should be stated in the protocol. The authors may wish to review other published protocols for guidance here. Thank you. Due to the limit of words, we had omitted some information. However, we have added these sentences following your advises and SPIRIT checklist: -The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funding body will audit trial conduct.
-Data collection and monitoring: One RA will collect the data and another will perform entry and coding of the identified data. All RA managing the data will be blinded to participant allocation, as well as the RA conducting the outcome assessments and data analysis. All information collected will be treated in accordance with the provisions of current legislation on personal data protection. The study will not have a formal data monitoring committee since adverse intervention events have not been reported. Any serious unexpected adverse events or outcomes will be discussed by the trial management committee (identical to the authors of this protocol). There are no plans to discontinue or modify interventions, or to improve adherence or promote participant retention. The trial management committee will monitor recruitment, treatment and attrition rates and any concerns related to the study. Reasons for dropping out will be also registered. Concomitant care is permitted and registered as long as it is not one of the exclusion criteria. Group-specific processes will be taken into account and will be evaluated and informed, in accordance with recommendations of the "Mechanisms of Action in Group-based Interventions"(MAGI) framework (38).
-We also have changed the SPIRIT checklist.
2. Where the authors indicate they have addressed SPIRIT checklist items these are often not described in enough detail; in particular, please review items relating to allocation, masking, data collection, and statistical methods. Where can a full statistical analysis plan be found? Other items have not been addressed at all; for example, as far as I can tell there is no information on data management. Thank you. We have added the information as you can read in the previous comment. We have also changed the following paragraph: "Randomization, allocation and masking of study groups: Once baseline data is collected, the participants will be randomized. An independent statistician will perform the individual randomization using a computer-generated random number sequence that employs blocked randomization. The randomization will be carried out using blocks of patients from the Zaragoza and Mallorca PHCs. Since three PHCs in Zaragoza and three PHCs in Mallorca will participate, the 31 participants to be recruited from each PHCs will be randomized, so that 62 patients are randomized into each of the three arms ( Figure 1). Given the nature of the interventions, participants will not be blind to their allocation. An RA will phone them to explain their assigned intervention and where they should go and when. The RA will request that participants not inform other researchers of their allocation." We also added more information about data management and statistical analysis in the first paragraph of the "Data analysis plan" section: "Analysis of the outcomes at baseline: standard deviation for quantitative variables) will be performed. Then, correlation analysis will be carried out between the questionnaires that evaluate personal factors on health behavior (Self-Efficacy Scale, PAM, SOC-13, HLS-EUQ16 and IPS), social support (MOS-SS) and depression (BDI-II). We will also analyze the correlation between personal factors on health behavior and the questionnaires assessing lifestyle patterns (IPAQ-SF, MEDAS and PSQI). Finally, we will analyze the relation of lifestyle patterns and social support with depression. Inferential statistical analysis will be carried out using the Chi-square test for qualitative variables, and Student's t-test or one-way ANOVA test to assess the potential relationship between qualitative and quantitative variables. Data collection and statistical analysis will be performed using Excel software, SPSS software (version 25.0) (68) and the R statistical software environment (version 3.6.2) (69).." 3. There seem to be a lot of outcome measures and some are quite lengthy; have the researchers considered the burden on participants and potential for assessment fatigue and associated drop out? Thank you. We have been considering the balance between obtaining the necessary information and the high burden of questionnaires or being shorter in the evaluations. That is why we decide to use the short version of every questionnaire. Moreover, they are going to be administrated by high qualified personnel to promote engagement. However, if it is observed in the development of the research that it may be a limitation in the study, it will be reflected as such in the article of the results.
4. The title and study objectives make reference to subclinical, mild, and moderate depression. Are the researchers planning on analyzing the intervention's effectiveness in each of these severity subgroups? Thank you. Although that is not one of our objectives, we will consider performing a subgroup analysis, as long as the size of the subgroups is viable. We have eliminated the distinction of the different levels of depression in the objective paragraph: "The main objective of this protocol is to analyze the clinical effectiveness, cost-effectiveness and cost-utility of a Lifestyle Modification Program and a Lifestyle Modification Program with ICTs as adjunctive treatment for depression in primary care patients. The secondary objectives are to analyze the clinical effectiveness in the subgroup that presents comorbidity and to analyze the correlation between personal factors on health behavior and lifestyle patterns." 5. At present the manuscript finishes quite abruptly and would benefit from at least a short concluding paragraph. Again, consider reviewing recently published protocols for ideas. Thank you for your suggestion, we agree. We have added the following conclusion paragraph as suggested by the reviewer: "Depression is a significant cause of morbidity having low detection and treatment rates in primary care (75,76). Only 9% of all depressed primary care patients receive adequate treatment, and only 6% achieve remission, making depression an important management issue in primary care (77). An effective treatment for depression that can be implemented in PHCs is brief psychotherapy (6 to 8 sessions programs), which have the advantage of being performed by either mental health professionals or trained non-mental health providers (78). In this case, the promotion of healthy lifestyles will be used to address depressive symptoms, as it has shown efficacy in a number of studies (20-31). To ensure treatment adherence, facilitators should be used, such as the use of ICTs and the group format. They provide monitoring and social support, respectively (33). Organizing group therapies in PHCs generates a range of organizational benefits, in relation to efficient use of facilities, high therapist-to patient ratios and potential reductions to treatment waittimes (79). Moreover, participants are just as likely to engage in group treatment as individual work and the benefits are also maintained over time (80). The strengths of this study include the design, a randomized controlled and the wide range of outcome measures. It will provide a wealth of information on the interplay between depression, personal factors on health behavior and lifestyles. Study limitations include the possible attrition of participants due to session scheduling or participant refusal to participate in a group intervention or do the complete follow-ups (81). However, the possible reasons for attrition and other issues will be registered regarding MAGI framework (38). Therefore, the creation of a 6-session group program addressing lifestyle modifications (plus testing the monitoring with ICTs by adding a smartwatch to one of the intervention group) appears to be a good choice for depression treatment. The long-term aim of this study is to establish intervention for patients with depression, making it accessible in their PHCs, effective and cost-effective." Specific comments 6. P5, line 37: There don't seem to be any study objectives that justify the inclusion of two different intervention groups. Are the authors expecting these groups to differ? If so, how? If not, what is the rationale for including them both? Thank you. The reason for carrying out two intervention groups, without and with monitoring through ICTs, derives from the results of our previous articles, in which some results showed the need of monitoring patients. We want to observe the differences that occur when monitoring or not the participants. Thus, we changed the main objective to the following: "The main objective of this protocol is to analyze the clinical effectiveness, cost-effectiveness and cost-utility of a Lifestyle Modification Program and a Lifestyle Modification Program with ICTs as adjunctive treatment for depression in primary care patients. The secondary objectives are to analyze the clinical effectiveness in the subgroup that presents comorbidity and to analyze the correlation between personal factors on health behavior and lifestyle patterns." 7. P5, line 18: The study design does not specify that this is a randomised controlled trial although it seems to be; consider revising. Thank you, we agree with the comment. We have changed the sentence that describe the study design to this one: "Multicenter pragmatic randomized controlled trial in 3 parallel groups".
8. P5, line 55: How is "perfect" understanding of Spanish assessed? Even native speakers could be argued not to have perfect understanding of a language as there are inevitably words we misuse or haven't come across before! Thank you. We agree with you so we have eliminated the word "perfect".
9. P5, line 57: The diseases listed here specifically affect the brain, conditions affecting other parts of the central nervous system (i.e., spine) presumably don't interfere with eligibility? Consider rephrasing. We have changed "CNS" to "brain": "Exclusion criteria will be: suffering from another disease that affects the brain (organic brain pathology or having suffered a traumatic brain injury of any severity, dementia)".
10. P6, line 31: what are the eligibility criteria for study sites? How are PHCs selected? (Also just a minor comment, the acronym PHC already includes 'centre' so saying 'PHC centre' is redundant) First, we have eliminated the word "centre" after PHC. We added this sentence in the "recruitment" paragraph: "Most representative PHCs in the area will be invited, based on size, urban or rural area and PHCs with a different socio-demographic profile will be selected".
11. P6, line 48: As above, please include more detail on randomization and blinding. What ratio are patients allocated to trial arms? What is the size of the blocks? How are they generated? How is the allocation sequence generated and concealed? How are patients informed of their allocation? If GPs are not blinded to allocation, what is the potential for contamination and how is this being addressed? Thank you for your comment. GPs will be blinded to allocation. As we have indicated in comment 2, we have added this paragraph: "Randomization, allocation and masking of study groups: Once baseline data is collected, the participants will be randomized. An independent statistician will perform the individual randomization using a computer-generated random number sequence that employs blocked randomization. The randomization will be carried out using blocks of patients from the Zaragoza and Mallorca PHCs. Since three PHCs in Zaragoza and three PHCs in Mallorca will participate, the 31 participants to be recruited from each PHCs will be randomized, so that 62 patients are randomized into each of the three arms (Figure 1). Given the nature of the interventions, participants will not be blind to their allocation. An RA will phone them to explain their assigned intervention and where they should go and when. The RA will request that participants not inform other researchers of their allocation".
12. P6-7: As above, please include more detail on concomitant care, discontinuation/modification criteria (if none, please state), and adherence monitoring/promotion (if none, please state). Thank you. As we have indicated in comment 1, we have added this sentence in "data collection and monitoring" paragraph: "There are no plans to discontinue or modify interventions, or to improve adherence or promote participant retention. The trial management committee will monitor recruitment, treatment and attrition rates and any concerns related to the study. Reasons for dropping out will be also registered. Concomitant care is permitted and registered as long as it is not one of the exclusion criteria".
13. P7, line 5 and 30: review session descriptions for repeated text ("benefits of engaging in regular physical activity. Benefits of regular physical activity") Thank you. We have eliminated the sentence "Benefits of regular physical activity". We have rewritten both sentences because due to mention "to engaged" and then "doing a regular activity" as two separated concepts. But we have agreed that maybe it seems too repetitive.
14. P567, line 56: As above, please include more detail on data collection methods. How are questionnaires administered at follow-up? Thank you. To administer the questionnaires at follow-up, we will meet the patients at their PHC. The post-intervention questionnaires will be administered in a period of 2 to 7 days after the last intervention session. The questionnaires at six months, will be administered in the sixth and twelfth month after the last session of the intervention, with a margin of ± two weeks to administer to all patients. We have created Table 1 with all of this information. Also, we added the information in the "outcomes and measures" section: "We will collect patient data using the questionnaires administered in baseline, immediately after the intervention (in a period of 2 to 7 days after the last intervention session) and at 6 and 12-month follow-up after the last intervention session (with a margin of ± two weeks). A blinded RA will phone each patient of the three arms and establish an appointment in their PHC to administrate the questionnaire". We added also this information in the flowchart (Figure 1). 15. P8, line 35: Is data on chronic disease collected at every timepoint? Is it reasonable to expect a difference in these measures in a short space of time? Thank you. We agree with your comment. Now, in table 1, we specify the measurement points. We will collect all the primary and secondary outcomes at the four measurement points. With the exception of chronic disease data, which will not be collected immediately after the intervention because no significant changes are expected.
16. P10, line 49: analysis plan to "compare the two groups" is confusing given there are three, and relates to earlier comment about ensuring all three groups are addressed in the study objectives. Thank you. We have changed the objectives and we change the word "two" for "three".
17. P10, line 54: makes reference to "the main hypothesis" but no hypotheses have been stated. Thank you. We have changed "To confirm the main hypothesis" to "To analyze the clinical effectiveness".
18. P10, line 57: will the models also adjust for clustering of participants within PHCs?
Thank you. The socio-demographic characteristics of each participant will be included in the questionnaires. So, they will be analyzed by participant data and not of each PHC. It is not expected to do a specific analysis by PHC. However, if it is observed in the development of the research that it may be a limitation in the study, it will be reflected as such in the article of the results.
19. P11, line 5: Secondary variables listed here include QoL, chronic disease, and health perception. It is not clear what third variable is, or how other secondary outcomes will be analysed (social support, use of health services, personal factors). Further, are all these outcomes continuous? Are any strategies being employed to account for the large number of comparisons planned? How will missing data be handled? Thank you. For a better understanding, we have changed "quality of life, effectiveness in chronic diseases, health perception" to the following sentence: "personal factors on health behavior and assessment of lifestyle". Also, we have explained in the beginning of the "data analysis plan" section that personal factors on health behavior are Self-Efficacy Scale, PAM, SOC-13, HLS-EUQ16 and IPS; and that the questionnaires that assess lifestyle patterns are IPAQ-SF, MEDAS and PSQI.
We have rewritten this paragraph: "Clinical effectiveness analysis: The report of the results will follow a pre-specified plan, based on the CONSORT guidelines (70) in order to compare the three groups using an intention-to-treat analysis (ITT) and Multiple Imputation technique (MI) for handling missing data. Initially a descriptive comparison (proportions, means or medians) will be carried out between groups for prognostic variables in order to establish their baseline comparability after randomization.
To analyze the clinical effectiveness, a repeated-measure linear regression will be conducted, including all evaluations over time. For this purpose, the main variable, BDI-II score, will be used as a continuous variable. The models will include adjustments for the baseline value of the BDI-II and for any other variable that would have shown differences in the baseline measurement. Possible Group per Time interactions will be examined using linear regression. Similar analyses will be carried out using the secondary outcomes (personal factors on health behavior and assessment of lifestyle). To counteract the problem of multiple comparisons we will use Bonferroni correction. Comparisons will also be made between the LMP and LMP + ICTs groups regarding adherence to lifestyle modification requirements. Adherence will be considered as a good or beneficial score on the questionnaires assessing lifestyle patterns (IPAQ-SF, MEDAS and PSQI). In addition, we will compare the LMP and combined LMP+ICTs groups, assuming that they are comparable to each other and the two groups have significant results. A binary variable regarding comorbidity will be created (comorbidity yes/no). We will determine if the effectiveness of the intervention differs in the subgroup presenting comorbidity and if the pathology improves. Statistical analyses will be selected based on subsample size (parametric or nonparametric tests). As for the time-point in which we administrate the follow-up questionnaires, we will consider the first follow up assessment (in a period of 2 to 7 days after the last session of the intervention) as the more relevant. We expect to find an immediate effect in the LMP and LMP+ICTs groups after attending group intervention, due to the potential social support received. In the 6 and 12-month follow-up, we expect a beneficial change in the questionnaires assessing lifestyle, reflecting a long-lasting effect." 20. P11, line 6: This is the only reference to analysis of the two intervention groups on adherence to lifestyle modification requirements. Is this the only analysis comparing these groups (are there no plans to compare clinical effectiveness)? How is adherence defined? (Is it continuous? Binary? Thank you. We will compare the LMP and LMP+ICTs groups separately. As we have now stated in the objectives: "The main objective of this protocol is to analyze the clinical effectiveness, cost-effectiveness and cost-utility of a Lifestyle Modification Program and a Lifestyle Modification Program with ICTs as adjunctive treatment for depression in primary care patient". We have also added in the "clinical effectiveness analysis" section this sentence: "In addition, we will compare the LMP and combined LMP+ICTs groups, assuming that they are comparable to each other and the two groups have significant results". "Adherence will be considered as a good or beneficial score on the questionnaires assessing lifestyle patterns (IPAQ-SF, MEDAS and PSQI)". So, it will be continuous.

Reviewer: 2
Reviewer Name Fermin Mayoral Institution and Country Hospital Regional University of malaga Please state any competing interests or state 'None declared': None declared Please leave your comments for the authors below In terms of economic analysys in adition to estimating cost-effectiveness it would be highly appreciated to calculate incremental cost-utility ratios (ICUR) of intervention from the healthcare or social perspective. To minimize the bias resulting from non-randomization, a propensity score-based method should be used.
Thank you very much for your comment, we consider it very useful. For a better understanding, we have changed the paragraph to this one: "Cost-effectiveness and cost-utility analysis: The effectiveness of the interventions will be estimated using the difference between the BDI-II baseline score and the score at the 6 and 12-month followups, and utility will be estimated using QALYs at the 6 and 12-month follow-ups. QALYs will be calculated based on these scores using the Spanish EQ-5D tariffs (71). Along with the EQ-5D utility scores, scores recorded on the EQ VAS will also be used as an outcome for the analysis. Cost effectiveness will be explored through the calculation of incremental cost-effectiveness ratios (ICERs) for the active intervention groups (LMP and LMP+ICTs) using the TAU group as the control. ICER is defined as the ratio between incremental costs and incremental effectiveness. In this way, cost utility will be explored by calculating incremental cost-utility ratios (ICURs), which are defined as the ratio between incremental costs and incremental utilities measured on QALYs. QALYs gained in each evaluation are approximated using the area under-the-curve technique (72). Total costs will be calculated by adding direct and indirect costs. Direct costs will be calculated by adding the costs derived from the medication and the use of health services and clinical tests. The medication costs will be calculated by determining the price per milligram during the study period according to the Vademecum of the last year of study, including value-added tax (VAT). The total cost of drug treatment will be calculated by multiplying the price per milligram by the daily dose in milligrams and the number of days the treatment is received. Costs derived from the use of health services will be calculated considering the data from the Oblikue database (73). Indirect costs will be calculated based on the sick leave days and multiplying them by the Spanish minimum daily wage during the study period, 2019-2020. We assume that data will be missing at random (MAR). Only patients with both cost and relevant outcome data at the 6 and 12-month follow-ups will be included in the cost-effectiveness and costutility analyses. Notwithstanding this, sensitivity analysis imputing missing 6 and 12-month data will test the robustness of cost-effectiveness and cost-utility results. The imputations will be performed using the "mice" package (74) Sample size (page 7): Some information is missing to reproduce the sample size, such as the BDI standard deviation. Please add an appendix with the details of the sample size calculation (including formula and all parameters). Thank you. We have added the formula and all parameters in the supplementary file 2. The SD was already in the text: "we found that the average BDI score at the beginning of the study was 24.5 points (SD 9.8)".
Randomization (page 7): Please specify block size Thank you. We have added more information in this paragraph, including the block size: "Randomization, allocation and masking of study groups: Once baseline data is collected, the participants will be randomized. An independent statistician will perform the individual randomization using a computer-generated random number sequence that employs blocked randomization. The randomization will be carried out using blocks of patients from the Zaragoza and Mallorca PHCs. Since three PHCs in Zaragoza and three PHCs in Mallorca will participate, the 31 participants to be recruited from each PHCs will be randomized, so that 62 patients are randomized into each of the three arms (Figure 1). Given the nature of the interventions, participants will not be blind to their allocation. An RA will phone them to explain their assigned intervention and where they should go and when. The RA will request that participants not inform other researchers of their allocation".
Outcomes (page 8-11): I was not sure to follow the outcomes measurement schedule. When is "immediately after the intervention"? Will this be for participants in the control arm as well (when?). Are all of the outcomes listed measure at each of the 4 time points? If not, please specify (a table presenting the measurement schedule may help). Thank you. We created Table 1 with all of that information. Also, we added the information in the "outcomes and measures" section: "We will collect patient data using the questionnaires administered in baseline, immediately after the intervention (in a period of 2 to 7 days after the last intervention session) and at 6 six and 12-month follow-up after the last intervention session (with a margin of ± two weeks) (see Table 1). A blinded RA will phone each patient of the three arms and set up an appointment in their PHC for questionnaire administration. Study outcomes and measures are summarized in Table 1." What additional data are collected at baseline (e.g. socio-demographics…)? The MINI is mentioned, is it at baseline only? Thank you. We added this paragraph: "Sociodemographic and social data: We will gender, age, marital status, education, occupation, economical level. These data will be collected through an ad hoc questionnaire." And also, we also added the complete information in Table 1.
Please clarify (here or in the statistical analysis section) the list of secondary outcomes to be compared between arms. The list provided here differs from the one in the statistical analysis paragraph (see comment below). You may need to distinguish the "measurements" (data collected), and the list of primary/secondary "outcomes", which will be formally compared between group. For example, I was not clear if you are planning to compare "comorbidity" and "social support"? Do you expect the intervention to affect these outcomes? Or are these additional data?
Statistical analysis (page 10): Note that CONSORT are guidelines for reporting, not for the analysis. Thank you. We changed it to this sentence: "The report of the results will follow a pre-specified plan, based on the CONSORT guidelines (70)". I am not very familiar with RM ANOVA, but I do not see reason to use it as opposed to a (repeatedmeasure) linear regression, which you mention later. I would strongly advise against RM ANOVA if it either i) does not allow to adjust for covariates ii) does not allow to estimate the treatment effect (estimate mean difference between arms and confidence interval), or iii) does not allow for missing data (exclude any participant with some missing data). If any of these limitations apply, please consider a using a linear regression for your primary analysis. Thank you for your comment. We have rewritten this paragraph: "Clinical effectiveness analysis: The report of the results will follow a pre-specified plan, based on the CONSORT guidelines (70) in order to compare the three groups using an intention-to-treat analysis (ITT) and Multiple Imputation technique (MI) for handling missing data. Initially a descriptive comparison (proportions, means or medians) will be carried out between groups for prognostic variables in order to establish their baseline comparability after randomization. To analyze the clinical effectiveness, a repeated-measure linear regression will be conducted, including all evaluations over time. For this purpose, the main variable, BDI-II score, will be used as a continuous variable. The models will include adjustments for the baseline value of the BDI-II and for any other variable that would have shown differences in the baseline measurement. Possible Group per Time interactions will be examined using linear regression. Similar analyses will be carried out using the secondary outcomes (personal factors on health behavior and assessment of lifestyle). To counteract the problem of multiple comparisons we will use Bonferroni correction. Comparisons will also be made between the LMP and LMP + ICTs groups regarding adherence to lifestyle modification requirements. Adherence will be considered as a good or beneficial score on the questionnaires assessing lifestyle patterns (IPAQ-SF, MEDAS and PSQI). In addition, we will compare the LMP and combined LMP+ICTs groups, assuming that they are comparable to each other and the two groups have significant results. A binary variable regarding comorbidity will be created (comorbidity yes/no). We will determine if the effectiveness of the intervention differs in the subgroup presenting comorbidity and if the pathology improves. Statistical analyses will be selected based on subsample size (parametric or nonparametric tests). As for the time-point in which we administrate the follow-up questionnaires, we will consider the first follow up assessment (in a period of 2 to 7 days after the last session of the intervention) as the more relevant. We expect to find an immediate effect in the LMP and LMP+ICTs groups after attending group intervention, due to the potential social support received. In the 6 and 12-month follow-up, we expect a beneficial change in the questionnaires assessing lifestyle, reflecting a long-lasting effect." Missing data: Methods such as Last/Worst-Observations Carried Forward are widely discouraged (see for example Lachin 2015 https://doi.org/10.1177/1740774515602688). Please consider conducting the primary analysis under "Missing at Random" assumption (e.g. using repeated-measure linear regression), and conducting sensitivity analysis with different missing data assumptions (WOCF could be one, or consider better alternatives, see for example Cro et al. 2020Cro et al. (https://doi.org/10.1002). Thank you for your comment. In addition to the answer in the previous comment, we added this explanation in the "Cost-effectiveness and cost-utility analysis" section: "We assume that data will be missing at random (MAR). Only patients with both cost and relevant outcome data at the 6 and 12month follow-ups will be included in the cost-effectiveness and cost-utility analyses. Notwithstanding this, sensitivity analysis imputing missing 6 and 12-month data will test the robustness of costeffectiveness and cost-utility results. The imputations will be performed using the "mice" package (74), freely available in cran-R (69). " How will you compare the arms exactly? Will you compare arms 2 (LMP) and 3 (LMP+ICT) to TAU as two separate analyses? Or will you also compare 2 vs. 3, or conduct an "overall" test? I would consider a "sensitivity analysis" comparing arms 2 + 3 combined vs. TAU, which could explore the effect of LMP with more power We will compare the LMP and LMP+ICTs groups separately. As we now stated in the objectives: "The main objective of this protocol is to analyze the clinical effectiveness, cost-effectiveness and costutility of a Lifestyle Modification Program and a Lifestyle Modification Program with ICTs as adjunctive treatment for depression in primary care patients. The secondary objectives are to analyze the clinical effectiveness in the subgroup that presents comorbidity and to analyze the correlation between personal factors on health behavior and lifestyle patterns". Also, we have added in the "Clinical effectiveness analysis" section: "In addition, we will compare the LMP and combined LMP+ICTs groups, assuming that they are comparable to each other and the two groups have significant results." Similarly for the time-points, you may want to clarify what comparison you are planning to conduct. Will you assume a different treatment effect at each time point (and if so, how will you test for an "overall treatment effect"?), or a single treatment effect over all the follow-ups? Or are you planning to consider one of the time-point (e.g. 6 month) as "primary"? Please remind the time-points at which BDI will be measured. Thank you. We added this paragraph: "As for the time-point in which we administrate the follow-up questionnaires, we will consider the first follow up assessment (in a period of 2 to 7 days after the last session of the intervention) as the more relevant. We expect to find an immediate effect in the LMP and LMP+ICTs groups after attending group intervention, due to the potential social support received. In the 6 and 12-month follow-up, we expect a beneficial change in the questionnaires assessing lifestyle, reflecting a long-lasting effect." In Table 1 now is stated that BDI-II is going to be administrated at baseline and in the follow-up sessions.
Please clarify the list of secondary outcomes. What EQ5D measure (see comment below)? What is "effectiveness in chronic diseases"? What is/are "self perception"? (All the outcomes listed as "Personal factors on health behaviour"?). Are you not planning to compare any other outcomes? What about the lifestyle measures? Thank you. We changed "quality of life, effectiveness in chronic diseases, health perception" to this: "personal factors on health behavior and assessment of lifestyle". We explain in the beginning of the "data analysis plan" section that personal factors on health behavior are Self-Efficacy Scale, PAM, SOC, HLS-EUQ16 and IPS; and that the questionnaires that assess lifestyle patterns are IPAQ-SF, MEDAS and PSQI. As we stated in previous comment, we have rewritten this paragraph: "Clinical effectiveness analysis".
In the abstract, you mention "analysis of the effectiveness of the intervention in comorbid chronic pathology". Do you mean a subgroup analysis (of treatment effect in the comorbid subgroup)? It should be mentioned in the statsitical analysis. Thank you. We added this sentence in the "data analysis plan" paragraph: "A binary variable regarding comorbidity will be created (comorbidity yes/no). We will determine if the effectiveness of the intervention differs in the subgroup presenting comorbidity and if the pathology improves. Statistical analyses will be selected based on subsample size (parametric or non-parametric tests)".
Cost-effectiveness analysis (page 11): Why are you focussing on 6 months? Are you not collecting data up to 12 months? Please clarify which EQ-5D measure you will use: the questions (and if so, how converted to utility), or the VAS? What is a "multivariate gamma regression with logarithmic transformation."? Are you planning to logtransform the cost variable? This is not usually recommended ( Again, why only looking at EQ-5D at 6 months? It is also collected "post-intervention" and at 12 months? Thank you. We have rewritten this paragraph: "Cost-effectiveness and cost-utility analysis: The effectiveness of the interventions will be estimated using the difference between the BDI-II baseline score and the score at the 6 and 12-month followups, and utility will be estimated using QALYs at the 6 and 12-month follow-ups. QALYs will be calculated based on these scores using the Spanish EQ-5D tariffs (71). Along with the EQ-5D utility scores, scores recorded on the EQ VAS will also be used as an outcome for the analysis. Cost effectiveness will be explored through the calculation of incremental cost-effectiveness ratios (ICERs) for the active intervention groups (LMP and LMP+ICTs) using the TAU group as the control. ICER is defined as the ratio between incremental costs and incremental effectiveness. In this way, cost utility will be explored by calculating incremental cost-utility ratios (ICURs), which are defined as the ratio between incremental costs and incremental utilities measured on QALYs. QALYs gained in each evaluation are approximated using the area under-the-curve technique (72). Total costs will be calculated by adding direct and indirect costs. Direct costs will be calculated by adding the costs derived from the medication and the use of health services and clinical tests. The medication costs will be calculated by determining the price per milligram during the study period according to the Vademecum of the last year of study, including value-added tax (VAT). The total cost of drug treatment will be calculated by multiplying the price per milligram by the daily dose in milligrams and the number of days the treatment is received. Costs derived from the use of health services will be calculated considering the data from the Oblikue database (73). Indirect costs will be calculated based on the sick leave days and multiplying them by the Spanish minimum daily wage during the study period, 2019-2020. We assume that data will be missing at random (MAR). Only patients with both cost and relevant outcome data at the 6 and 12-month follow-ups will be included in the cost-effectiveness and costutility analyses. Notwithstanding this, sensitivity analysis imputing missing 6 and 12-month data will test the robustness of cost-effectiveness and cost-utility results. The imputations will be performed using the "mice" package (74), freely available in cran-R (69)." Page 11 it is mentioned an "Analysis of the correlation and the weight of personal factors in the completion of the LMP". Is this part of the cost-effectiveness analysis? If not, please add another header. This section was not clear. What are the "Personal factors", and "completion of the LMP"? Do you mean you are planning to look at the baseline characteristics associated to attending the LMP sessions? This is quite a different analysis (not randomised and not related to the effectiveness of the intervention), and should probably be presented separately, as an additional analysis of interest. What does "an analysis will be carried out of correlations between personal factors and compliance variables, primary and secondary outcome variable" means exactly? Thank you. We have added another header and change the position and content of the paragraph by the following: "Analysis of the outcomes at baseline: First, descriptive analyses of all the variables (proportions for qualitative variables; means and standard deviation for quantitative variables) will be performed. Then, correlation analysis will be carried out between the questionnaires that evaluate personal factors on health behavior (Self-Efficacy Scale, PAM, SOC-13, HLS-EUQ16 and IPS), social support (MOS-SS) and depression (BDI-II). We will also analyze the correlation between personal factors on health behavior and the questionnaires assessing lifestyle patterns (IPAQ-SF, MEDAS and PSQI). Finally, we will analyze the relation of lifestyle patterns and social support with depression. Inferential statistical analysis will be carried out using the Chi-square test for qualitative variables, and Student's t-test or one-way ANOVA test to assess the potential relationship between qualitative and quantitative variables. Data collection and statistical analysis will be performed using Excel software, SPSS software (version 25.0) (68) and the R statistical software environment (version 3.6.2) (69). "

REVIEWER
Baptiste Leurent London School of Hygiene and Tropical Medicine, UK REVIEW RETURNED 14-Sep-2020

GENERAL COMMENTS
Thank you for sending this revised manuscript, and for satisfactorily addressing most of my earlier comments.
I have only a couple of minor comments remaining: Sample size: Thank you for providing the additional information, and sorry to have missed the SD. I am not very clear why you assumed a variance of 136 (SD=11.7) in the sample size formula when you mention a SD of 9.8 in the text? I am not too concerned about this inconsistency, as the sample size calculation seems sensible overall. I am however concerned that you have not inflated your sample size to take into account of the drop-out. You mention up-to 20% drop-out, why did you not inflate your sample size to take this into account? I am concerned that the trial may be underpowered to achieved its stated objective, but understand it is now too late to change this. You may want to consider rewording or move the "drop-out" sentence, which currently seems to imply it was taken into account in the sample size.
Randomization: I still cannot see the size of the randomization blocks. E.g. are they blocks of size 3, 6, 12,…?
The sentence "The randomization will be carried out using blocks of patients from the Zaragoza and Mallorca PHCs" is confusing. Did you mean you stratified the randomisation (used different lists)? If so, specify this and indicate at which level (region or centre?) If not (used a single randomisation list), should probably remove this sentence.
Thank you for your other modifications to the text. The measurement schedule and the statistical analysis is now much clearer.
A few parts are still not perfectly clear to me (list of secondary outcomes, handling of missing data, cost-effectiveness analysis, etc.), but these can be clarified in your future analysis plan.
VERSION 2 -AUTHOR RESPONSE Thank you for sending this revised manuscript, and for satisfactorily addressing most of my earlier comments.
-Thank you very much for your thorough review. We are very glad for your comments and feedback.
I have only a couple of minor comments remaining: Sample size: Thank you for providing the additional information, and sorry to have missed the SD. I am not very clear why you assumed a variance of 136 (SD=11.7) in the sample size formula when you mention a SD of 9.8 in the text? I am not too concerned about this inconsistency, as the sample size calculation seems sensible overall.
I am however concerned that you have not inflated your sample size to take into account of the dropout. You mention up-to 20% drop-out, why did you not inflate your sample size to take this into account? I am concerned that the trial may be underpowered to achieved its stated objective, but understand it is now too late to change this. You may want to consider rewording or move the "dropout" sentence, which currently seems to imply it was taken into account in the sample size.
-Thank you. We have changed SD in the supplementary file 2 and we also have taken into account the 20% drop-out. It was a mistake. We have recalculated the sample size. And now the paragraph is the following:

Sample size
Scientific evidence suggests that a 17% reduction in the BDI-II (34) is considered clinically relevant (36). In a previous study conducted by our team with psychiatric outpatients, we found that the average BDI score at the beginning of the study was 24.5 points (SD 9.8) (22), so we consider that a reduction of at least 4.8 points would have clinical significance and would benefit the patient. Accepting an α risk of 0.05 and a β risk of 0.20 in a bilateral contrast, 44 subjects will be required for each group. With an estimated withdrawal rate of 20%, the sample size will require approximately 53 patients in each group. The total sample required is 159 subjects. A formula based on the Snedecor's F distribution (37) has been used (see supplementary file 2). It is estimated that approximately 50% of these patients will present some physical or mental comorbidity (12).

Randomization:
I still cannot see the size of the randomization blocks. E.g. are they blocks of size 3, 6, 12,…?
The sentence "The randomization will be carried out using blocks of patients from the Zaragoza and Mallorca PHCs" is confusing. Did you mean you stratified the randomisation (used different lists)? If so, specify this and indicate at which level (region or centre?) If not (used a single randomisation list), should probably remove this sentence.
-Thank you very much for this comment. We have reworded the word "block". Now, the paragraph is the following: Once baseline data is collected, the participants will be randomized. An independent statistician will perform the individual randomization using a computer-generated random number sequence. The randomization will be carried out using a list of patients from Zaragoza and Mallorca (Figure 1).

REVIEWER
Baptiste Leurent London School of Hygiene and Tropical Medicine REVIEW RETURNED 10-Nov-2020

GENERAL COMMENTS
Thank you for your clarifications, I do not have any further comments on the manuscript.