Protocol The Ready to Reduce Risk ( 3 R ) Study for a Group Educational Intervention With Telephone and Text Messaging Support to Improve Medication Adherence for the Primary Prevention of Cardiovascular Disease : Protocol for a Randomized Controlled Trial

Background: Poor adherence to cardiovascular medications is associated with worse clinical outcomes. Evidence for effective education interventions that address medication adherence for the primary prevention of cardiovascular disease is lacking. The Ready to Reduce Risk (3R) study aims to investigate whether a complex intervention, involving group education plus telephone and text messaging follow-up support, can improve medication adherence and reduce cardiovascular risk. Objective: This protocol paper details the design and rationale for the development of the 3R intervention and the study methods used. Methods: This is an open and pragmatic randomized controlled trial with 12 months of follow-up. We recruited participants from primary care and randomly assigned them at a 1:1 frequency, stratified by sex and age, to either a control group (usual care from a general practitioner) or an intervention group involving 2 facilitated group education sessions with telephone and text messaging follow-up support, with a theoretical underpinning and using recognized behavioral change techniques. The primary outcome was medication adherence to statins. The primary measure was an objective, novel, urine-based biochemical measure of medication adherence. We also used the 8-item Morisky Medication Adherence Scale to assess medication adherence. Secondary outcomes were changes in total cholesterol, blood pressure, high-density lipoprotein, total cholesterol to high-density lipoprotein ratio, body mass index, waist to hip ratio, waist circumference, smoking behavior, physical activity, fruit and vegetable intake, patient activation level, quality of life, health status, health and medication beliefs, and overall cardiovascular disease risk score. We also considered process outcomes relating to acceptability and feasibility of the 3R intervention. Results: We recruited 212 participants between May 2015 and March 2017. The 12-month follow-up data collection clinics were completed in April 2018, and data analysis will commence once all study data have been collected and verified. JMIR Res Protoc 2018 | vol. 7 | iss. 11 | e11289 | p.1 http://www.researchprotocols.org/2018/11/e11289/ (page number not for citation purposes) Byrne et al JMIR RESEARCH PROTOCOLS

comparator, care providers, centers, and blinding status (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) ii) 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)

Highly Recommended
iii) Open vs. closed, web-based (self-assessment) vs. face-to-face assessments in abstract: Mention how participants were recruited (online vs. offline), e.g., from an open access website or from a clinic or a closed online user group (closed usergroup trial), and clarify if this was a purely web-based trial, or there were face-to-face components (as part of the intervention or for assessment). Clearly say if outcomes were selfassessed through questionnaires (as common in web-based trials). Note: In traditional offline trials, an open trial (open-label trial) is a type of clinical trial in which both the researchers and participants know which treatment is being administered. To avoid confusion, use "blinded" or "unblinded" to indicated the level of blinding instead of "open", as "open" in web-based trials usually refers to "open access" (i.e. participants can self-enrol) (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) Highly Recommended iv) Results 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) Highly recommended v) 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. Essential viii) Describe mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical framework [6] used to design them (instructional strategy [1], behaviour change techniques, persuasive features, etc., see e.g., [7,8] for terminology). This includes an in-depth description of the content (including where it is coming from and who developed it) [1], "whether [and how] it is tailored to individual circumstances and allows users to track their progress and receive feedback" [6]. This also includes a description of communication delivery channels and -if computer-mediated communication is a component -whether communication was synchronous or asynchronous [6]. It also includes information on presentation strategies [1], including page design principles, average amount of text on pages, presence of hyperlinks to other resources etc. [1].

INTRODUCTION
Essential ix) Describe use parameters (e.g., intended "doses" and optimal timing for use) [1]. Clarify what instructions or recommendations were given to the user, e.g., regarding timing, frequency, heaviness of use [1], if any, or was the intervention used ad libitum.
Highly Recommended x) Clarify the level of human involvement (care providers or health professionals, also technical assistance) in the e-intervention or as cointervention. 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" [6]. 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). Essential xii) Describe any co-interventions (incl. training/support): Clearly state any "interventions that are provided in addition to the targeted eHealth intervention" [1], as ehealth intervention may not be designed as standalone 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.

Essential
Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed i) If outcomes were obtained through online questionnaires, describe if they were validated for online use [6] and apply CHERRIES items to describe how the questionnaires were designed/deployed [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

Highly Recommended ii) Describe whether and how "use" (including intensity of use/dosage) was defined/measured/monitored
No EHEALTH-specific additions here Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions

No EHEALTH-specific additions here
Blinding 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 i) 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).

Essential ii) 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".
Highly Recommended 11b If relevant, description of the similarity of interventions

(this item is usually not relevant for ehealth trials as it refers to similarity of a placebo or sham intervention to a active medication/intervention)
Statistical methods 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 i) 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] [6] for some items to be included in informed consent documents.

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iii) 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)" [1]. (a diagram is  strongly  recommended) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome NPT: The number of care providers or centers performing the intervention in each group and the number of patients treated by each care provider in each center

No EHEALTH-specific additions here
13b For each group, losses and exclusions after randomisation, together with reasons i) 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) [5] or other figures or tables demonstrating usage/dose/engagement.

Recruitment
14a Dates defining the periods of recruitment and follow-up i) Indicate if critical "secular events" [1] fell into the study period, e.g., significant changes in Internet resources available or "changes in computer hardware or Internet delivery resources" [1].

Highly Recommended
14b Why the trial ended or was stopped [early] No EHEALTH-specific additions here

Essential
Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups i) 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.
Essential ii) 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).

Highly Recommended
Outcomes and estimation 17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) i) 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 Highly Recommended metric like a "session" is defined (e.g., timeout after idle time) [1] (report under item 6a).
17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended

No EHEALTH-specific additions here
Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory i) 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).

Highly Recommended
Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) i) 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].

Highly Recommended
ii) Include qualitative feedback from participants or observations from staff/researchers, if available, on strengths and shortcomings of the application, especially if they point to unintended/unexpected effects or uses. This includes (if available) reasons for why people did or did not use the application as intended by the developers.

Highly Recommended
Interpretation/ Principal Findings 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence NPT: In addition, take into account the choice of the comparator, lack of or partial blinding, and unequal expertise of care providers or centers in each group i) Restate study questions and summarize the answers suggested by the data [2], starting with primary outcomes and process outcomes (use).
Essential ii) Highlight unanswered new questions, suggest future research [2]. Highly Recommended * CONSORT = Consolidated Standards of Reporting Trials [10] ** NPT = non pharmacological treatment (CONSORT extension) [11] DISCUSSION Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses i) 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.

Essential
Generalisability 21 Generalisability (external validity, applicability) of the trial findings NPT: External validity of the trial findings according to the intervention, comparators, patients, and care providers or centers involved in the trial i) 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 [2].

Highly Recommended
ii) 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. i) In addition to the usual declaration of interests (financial or otherwise), also state the "relation of the study team towards the system being evaluated" [2], i.e., state if the authors/evaluators are distinct from or identical with the developers/sponsors of the intervention.