Design and rationale of the Cardiovascular Health and Text Messaging (CHAT) Study and the CHAT-Diabetes Mellitus (CHAT-DM) Study: two randomised controlled trials of text messaging to improve secondary prevention for coronary heart disease and diabetes

Introduction Mobile health interventions have the potential to promote risk factor management and lifestyle modification, and are a particularly attractive approach for scaling across healthcare systems with limited resources. We are conducting two randomised trials to evaluate the efficacy of text message-based health messages in improving secondary coronary heart disease (CHD) prevention among patients with or without diabetes. Methods and analysis The Cardiovascular Health And Text Messaging (CHAT) Study and the CHAT-Diabetes Mellitus (CHAT-DM) Study are multicentre, single-blind, randomised controlled trials of text messaging versus standard treatment with 6 months of follow-up conducted in 37 hospitals throughout 17 provinces in China. The intervention group receives six text messages per week which target blood pressure control, medication adherence, physical activity, smoking cessation (when appropriate), glucose monitoring and lifestyle recommendations including diet (in CHAT-DM). The text messages were developed based on behavioural change techniques, using models such as the information-motivation-behavioural skills model, goal setting and provision of social support. A total sample size of 800 patients would be adequate for CHAT Study and sample size of 500 patients would be adequate for the CHAT-DM Study. In CHAT, the primary outcome is the change in systolic blood pressure (SBP) at 6 months. Secondary outcomes include a change in proportion of patients achieving a SBP <140 mm Hg, low-density lipoprotein cholesterol (LDL-C), physical activity, medication adherence, body mass index (BMI) and smoking cessation. In CHAT-DM, the primary outcome is the change in glycaemic haemoglobin (HbA1C) at 6 months. Secondary outcomes include a change in the proportion of patients achieving HbA1C<7%, fasting blood glucose, SBP, LDL-C, BMI, physical activity and medication adherence. Ethics and dissemination The central ethics committee at the China National Center for Cardiovascular Disease and the Yale University Institutional Review Board approved the CHAT and CHAT-DM studies. Results will be disseminated via usual scientific forums including peer-reviewed publications. Trial registration number CHAT (NCT02888769) and CHAT-DM (NCT02883842); Pre-results.

The messages were developed using behavior change technique and tailored to a specific Chinese patient population. 4. In contrast to most prior single center text-messaging trials, these two studies are conducted at 37 participating sites spread across a large and geographically diverse country, the results of which may be more generalizable. 5. However, medication adherence and physical activity are measured by self-report, which carries the possibility of recall bias and social desirability bias.

INTRODUCTION
The benefits of secondary prevention strategies for coronary heart disease (CHD) targeting lifestyle modification and risk factor management are well-established worldwide, 1, 2 however adoption of these strategies is suboptimal. 3 Smoking, inactivity and obesity are prevalent among people with established CHD and control of hypertension and diabetes are often suboptimal. Additionally, medication adherence is poor. Prior studies reveal that only one quarter of hospitalized patients do not fill all prescriptions within 120 days of hospital discharge. 4 Furthermore, less than half of patients hospitalized with acute myocardial infarction (AMI) are adherent to evidence-based medications 1 year later, with the greatest gaps in adherence occurring in the first 6 months after treatment initiation. [5][6][7] In lower and middle-income countries (LMICs), including China, which face a growing burden of cardiovascular disease and greater challenges to medication access for secondary prevention, over two-thirds of patients with CHD take no medication. [8][9][10] While high medication costs are influential, 11 there is also limited time for education and consultation regarding lifestyle and medication management during clinic visits, which tend to be very brief. 12,13 Therefore, innovative and cost-effective interventions to enhance adherence are urgently needed.
The pervasiveness of mobile phones to enhance the adoption of secondary prevention strategies for CHD in LMICs provides a promising opportunity.
Mobile phones already serve as a primary, inexpensive and quick form of communication, alerts and reminders. In addition, the number of mobile phone users has grown exponentially in the past decade worldwide, and is projected to reach 4.77 billion by 2017, 14 with nearly 200,000 messages sent every second. 15 As of August 2016, China had the largest number of mobile phone owners in the world, at 1.3 billion. 16 Mobile phones are also used across all geographic regions and income levels. Due to its ubiquity and convenience, mobile phone text messaging has the potential to be a scalable and powerful tool to deliver health information. 17,18 Prior studies of mobile phone text messaging have been conducted to improve glycemic control, 19 hypertension, 20 medication adherence, 21 as well as to promote smoking cessation, 22 and physical activity. 23 These trials have contributed important knowledge, and some, such as TEXT-ME 24 and TExT-MED 25

Study Overview
The CHAT and CHAT-DM studies are multi-center, single-blind, 2-arm, randomized controlled trials of an automated mobile phone text message-based intervention with 6 months of follow-up. Patients were recruited from 37 hospitals across 17 provinces in China ( Figure 1). The enrollment of participants began on August 16, 2016. The two studies were registered at http://www.clinicaltrials.gov (NCT02888769 and NCT02883842) accordingly. All participants provided written informed consent at the initial trial visit.

Study Population
In CHAT, patients were eligible if they had established CHD defined as having a history of AMI and/or percutaneous coronary intervention (PCI), having access to a mobile phone to read and send text messages, and did not have diabetes. In CHAT-DM, patients were eligible if they had a history of documented CHD (as defined in CHAT) and diabetes, and had access to a mobile phone to read and send text messages. In both studies, patients were excluded if they could not read or send text messages, had cognitive or communication disorders, or could not provide informed consent. A 'screening log' of basic demographic information and reasons for not participating in patients deemed ineligible but who declined to participate has been maintained.

Randomization and blinding
Participants were randomly allocated to either the intervention or control arms in a 1:1 ratio using a computerized randomization system. In order to achieve a balance of participants' characteristics in both arms, we employed a stratified randomization approach, based on age, gender, AMI history, education degree and medical insurance type within each study. Researchers, statisticians and clinic staff were blinded to treatment allocation..

Trial intervention
Participants in the intervention groups of the CHAT and CHAT-DM studies receive semi-personalized text messages about CHD risk factor modification for 6 months as well as standard treatment (described below). The control group in both studies receive two thank-you text messages that contain no medical information each month as well as standard treatment. A training session was held by research staff upon enrollment to ensure that all participants were capable of receiving, reading and sending text messages on their mobile phones. Participants were also instructed how to withdraw from the study should they desire, by responding with a specific character.
Researchers could monitor the status of text message delivery, review responses sent by participants and manage withdrawal via a customized software platform. For instance, logs were kept to assess the proportion of text messages successfully delivered, the exact time of messages being sent and the reasons for those that failed to be sent.

Phase 1 Approach to developing text messages
Text messages were originally drafted by members of the research team in Chinese based on current guidelines 28-30 and standards of care pertaining to cardiovascular health and diabetes care. All messages were grounded in behavioral change techniques previously used to develop short health messages, providing information, goal-setting, motivation, social support and stress management advice. 31 Efforts were devoted to selecting the behavioral change techniques most applicable to the Chinese cultural context and compatible with Chinese beliefs and values (Table 1). For example, some text messages applied traditional Chinese aphorisms, chengyu, and catchy rhyme schemes in order to make them more acceptable to patients. As another example, in designing text messages that were motivating, especially in challenging situations, the multidisciplinary group felt that Chinese people tend to prefer more direct and structured counseling instructions rather than indirect  Experts in the fields of cardiology, endocrinology, epidemiology, psychology and behavioral science in the U.S. reviewed them and provided suggestions for further refinement. Finally, Chinese researchers and a linguist reviewed all 550 text messages, further refined the language, and paid special attention to the cultural meaning of all text messages to ensure better understanding among the targeted population (elderly Chinese patients with cardiovascular disease, with and without diabetes). Once feedback from the experts was addressed, the text bank was updated and prepared for user testing.

Phase 3 User testing and pilot study
For user testing, 19 randomly selected text messages from the finalized text bank in the CHAT and CHAT-DM studies were distributed to 39 individuals with CHD (with or without diabetes) for feedback. Likert-type items in a survey were used to assess usefulness and ease of understanding of the text messages. Open-ended questions were asked to obtain suggestions for improvement from participants. In total, 92.4% (582/630) rated the messages as easy to understand and 93.2% (587/630) rated the messages as useful. All 550 text messages were further modified based on feedback from user testing.  Table 2.
Next, the refined text message banks underwent pilot testing to evaluate the efficacy of the message delivery system and quality of the user experience. A customized software program sent messages through a gateway interface, allowing them to be sent to all individuals' mobile phones free of charge and at a bulk-rate cost (0.1 yuan per message, or .01 USD) to the research team.
Participants from the user testing were enrolled in the pilot testing after providing written informed consent (n=33). For the pilot study, messages drawn from the entire text bank were sent to participants. At the end of the 1-month pilot study, 30 participants reported their experience of receiving messages and commented on frequency, timing, content and potential impact of text messages. Minor changes were made to the text message bank following the pilot study based on this feedback.

Frequency and timing of text message delivery
Each participant in the intervention group of the CHAT and CHAT-DM studies receives 6 text messages per week, randomly selected by the software system, across a 6 month timeframe. The messages are sent at one of three random times (9am, 12pm or 4pm), during weekends and weekdays (excluding Monday to give people a break). In the CHAT study, participants receive two general education messages on CHD (one if an active smoker), two blood  F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   13   one general message, one blood pressure related message, one glucose   control message, one lifestyle modification message, one medication   adherence message and one physical activity message per week (Table 3).
Initially, a test message was sent to each participant to ensure that the correct mobile phone number had been recorded and the system was functioning appropriately. All participants received a personalized welcome message, a follow-up reminder and a birthday greeting while enrolled in the study. Most of the text messages were developed to be unidirectional and participants are not anticipated to reply, however bidirectional text messages, checking on medication adherence and blood pressure/glucose level measurements, are sent at weekly intervals to evaluate patient engagement. Throughout the 6-month follow-up, research staff call participants if they do not respond for two consecutive weeks, and only one call is made per patient during the intervention period, so as not to confound the intervention.

Data Collection
Basic and contact information (ID number, address, and phone number), anthropometric data (waist circumference, height and weight), resting blood pressure, heart rate, ambulatory blood pressure, and information on socioeconomic status, risk factor control and current medications were collected at baseline at hospital recruitment sites. Detailed information on patient outcomes (hospitalizations, discharge diagnoses, etc.) was also collected during the survey and hospital records or death certificates obtained  (Table 4).

Data Management
A proprietary software platform was developed by the study IT team for use in sending text messages to participants. The platform is capable of sending tailored and semi-personalized text messages to participants and also recording responses. Additionally, this web-based platform can also serve to monitor project progress, as well as provide management support for hospitals, staff members, equipment and sampling materials. Trained medical staff members fill out pre-designed on-screen case report forms at each site, and data is then securely transmitted to the central server through automatic electronic transfer. To ensure the reliability and validity of the data, continuous checks are run to ensure that data being entered are complete and meet predefined data formats and ranges. The database is regularly backed-up and password protected so that only a limited number of approved staff members can access the data. In order to ensure the confidentiality of all personal

Outcomes
In CHAT study, the primary outcome is the change in systolic blood pressure (SBP) after 6 months. Secondary outcomes include a change in proportion of patients achieving a SBP<140mm Hg, LDL-C, physical activity, medication adherence, body mass index (BMI), and smoking cessation. Exploratory outcomes include the prognosis of the patients at 6 months, such as death, non-fatal myocardial infarction, stroke and any re-hospitalization, as well as health status measured by SAQ and EQ-5D.
In CHAT-DM study, the primary outcome is the change in glycemic hemoglobin (HbA 1C ) as measured by central blood sample. Secondary outcomes include a change in proportion of patients achieving HbA 1C <7%, fasting blood glucose, SBP, LDL-C, BMI, physical activity and medication adherence. Exploratory outcomes include prognosis of patients at 6 months, including death, nonfatal myocardial infarction, stroke and any re-hospitalization, as well as health status (SAQ and EQ-5D).
Blood pressure is measured on the right upper arm after 5 minutes of rest in a seated position using an electronic blood pressure monitor (Omron HEM-7111; Omron Corporation, Dalian, China). Two measurements are taken and the mean value is calculated. If the difference between the two SBP or diastolic blood pressure (DBP) readings is larger than 5 mm Hg, a third measurement is

Statistical Analysis
Intervention evaluation will be carried out on an intention-to-treat (ITT) basis.
Values of analyzed endpoints between intervention group and control group will be compared using Student's t-tests for continuous variables or Chi-square tests for categorical variables according to the analysis plan. Mann-Whitney U tests will be used where continuous data are not normally distributed. The mean level of each risk factor will also be compared between groups in terms of relative risks, 95% CIs and two-sided p values for achieving the guideline level of each risk factor. We will follow prespecified analysis plan and subgroup analysis will be conducted accordingly.
Considering the compliance during the study intervention period, it was estimated that the mean SBP reduction in intervention group would be smaller.
A total sample size of 790 patients was computed to detect a difference in SBP of 3.5mm Hg between two groups. In CHAT-DM study, we assume a mean HbA 1C level of 7.2% [SD, 1.6%] based on data from studies involving similar populations 45, 46 and supposed a 0.5% absolute decrease in HbA 1C across treatment group. A total sample size of 480 patients was estimated to detect a difference in HbA 1C of 0.4% between groups considering the potential compliance during the study. The trial results will be reported in accordance with the SPIRIT checklists.

ETHICS AND DISSEMINATION
The findings of the study will be disseminated by standard scientific forums, including peer-review publications and presentations at conferences. The central ethics committee at the China National Center for Cardiovascular Disease (NCCD) approved the CHAT and CHAT-DM studies. All collaborating hospitals accepted the central ethics approval except for 8, which obtained local approval by internal ethics committees. The Chinese government, which provides financial support, has no role in the design or conduct of the study, the collection, management, analysis, and interpretation of the data; or in the preparation or approval of articles resulting from the studies.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 18

DISCUSSION
The CHAT and CHAT-DM studies aim to assess the efficacy of an innovative solution for improving secondary prevention of CHD by using simple and cost-effective text-messaging technology among patients with known CHD, with or without DM, throughout China. To the best of our knowledge, these two trials are the first to investigate the efficacy of text messages to support management of CHD and DM among a large population in China, and may set a model of such interventions that can be leveraged to improve risk factor management in resource-constrained settings.
The CHAT and CHAT-DM studies have several strengths. Few trials have addressed the role of text messages in managing multiple risk factors in patients with CHD or DM. Targeting multiple risk factors concurrently instead of managing a single risk factor may be more efficient and impactful on disease management as this strategy is more patient-centric than disease-centric, and have a greater likelihood of improving risk factor control and cardiovascular outcomes. 47 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   19 CHAT-DM is 480. It is noteworthy that CHAT is the first study using theory-based text messaging as a method of delivery for CHD patients' behavior change in China. Data from other text messaging intervention studies suggest that text messaging programs achieved better results when message content is theory-based, 49 however, few text messaging studies specified a theoretical rationale. Further, text messages were tailored to a specific Chinese patient population. Studies have found that the majority of Chinese adults prefer learning by following directive rules and guidelines, 50 and practical counseling instructions were provided through text messages to help them better modify health behaviors. Apart from this, the text message language was designed to be plain and easy to memorize, consistent with Chinese cultural features such as aphorism, chengyu and catchy rhyme schemes, making it more acceptable to patients.
The two studies have several additional strengths. In contrast to most prior single center text-messaging trials, these two studies are conducted at 37 participating sites spread across a large and geographically diverse country, the results of which may be more generalizable. Moreover, our research team devoted significant attention to quality data collection, including rigorous on-site monitoring of questionnaire answers, samples collection, and data management. Furthermore, an evaluation of the acceptability and feasibility of our text message-based intervention will provide further important evidence to inform future studies, particularly with regards to optimizing text content, text frequency, and the overall user experience.
Our study also has some potential limitations. First, medication adherence and physical activity are measured by self-report, which carries the possibility of  were proven to help, considering the low marginal cost and anticipated minimal adverse events, even with very modest effects, its benefits would be substantial in a country as large and populous as China.
In conclusion, the CHAT and CHAT-DM studies are multi-center, randomized controlled trials that are being conducted at 37 hospitals in China, and will thoroughly test the efficacy of text-messages to support secondary prevention for CHD and DM in LMICs. The studies targeted high-risk patient populations with a culturally-sensitive, scalable and cost-effective text-message intervention, went through comprehensive data collection and rigorous data       14. Portal TS.
https://www.statista.com/statistics/274774/forecast-of-mobile-phone-users-wor    The person is asked to keep a record of specified behavior(s).
A cold or diarrhea will make your blood sugar levels rise, so monitor your glucose more frequently when you are sick. If you are using insulin, test your blood glucose 6-8 times a day, keep a blood glucose log and share it with your health providers.
Prompt practice Prompt the person to rehearse and repeat the behavior or preparatory behaviors As an old Chinese saying goes, 'It takes more than one cold day for a river to freeze three feet deep; ice in the river takes a long time to melt.' Similarly, cerebrovascular disease requires

General Education (DM) [1x/wk]
Diabetes is not terrible and there are many things you can do to prevent problems from diabetes, such as monitoring blood glucose, watching your diet, keeping fit, and taking pills regularly.

Blood Pressure Control [2x/wk]
Most people do not experience any symptoms of high blood pressure. Do not stop taking blood pressure medication unless directed by your doctor. It is important for patients with hypertension to take medication diligently and to monitor their blood pressure on a regular basis.

Blood Pressure Control [1x/wk]
Home Blood Pressure Monitoring is highly recommended! You can get an accurate picture of your heart health and understand daily changes in blood pressure, which is helpful for doctors to adjust medications for you. Talk to doctors about your concerns and any uncomfortable symptoms after taking pills. Let your doctor help you to find the right medication for you.

Physical Activity [1x/wk]
You can still choose low-intensity exercise even after heart attack, such as walking and Tai Chi, at a slower pace and stick to your exercise plan. Always consult your physician before beginning any exercise program.

Physical Activity [1x/wk]
Try brisk walking -a convenient, safe and cost-effective way of exercising! It's good for your heart and will help control blood glucose.

Smoking Cessation [1x/wk] †
Do you worry about your family having health problems because of your smoking? Quitting is an important choice you can make to benefit your family's health, too.
Secondhand smoke can cause respiratory disease, lung cancer, and heart disease.

Diabetes Management [1x/wk]
See a doctor before you travel. Always carry your diabetes medications and insulin, glucose meter, and strips, so that you can better monitor your glucose. Carry some hard candy and crackers to avoid low sugar. sugar-free biscuits.

Supplementary Materials
Design and rationale of the Cardiovascular Health and Text Messaging (CHAT) Study and CHAT-Diabetes Mellitus (CHAT-DM) Study: two randomized controlled trials of text messaging to improve secondary prevention for coronary heart disease and diabetes Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) _____15______

Randomization and blinding 20
Participants were randomly allocated to either the intervention or control arms 21 in a 1:1 ratio using a computerized randomization system. In order to achieve 22 a balance of participants' characteristics in both arms, we employed a stratified 23  and each text message is less than 70 Chinese characters, which would be 13 equivalent to a 140-160-character message in English. 14

Phase 1 Approach to developing text messages 15
Text messages were originally drafted by members of the research team in 16 Chinese based on current guidelines 30-32 and standards of care pertaining to 17 cardiovascular health and diabetes care. All messages were grounded in 18 behavioral change techniques previously used to develop short health 19 messages, providing information, goal-setting, motivation, social support and 20 stress management advice. 33 In order to strengthening the designing and 21 reporting of theory-based BCT interventions, we took into account the two 22 recent BCT taxonomies by Michie. S, and his colleagues. 34 Chinese cultural context and compatible with Chinese beliefs and values 1 (Table 1). For example, some text messages applied traditional Chinese 2 aphorisms, chengyu, and catchy rhyme schemes in order to make them more 3 acceptable to patients. As another example, in designing text messages that 4 were motivating, especially in challenging situations, the multidisciplinary 5 group felt that Chinese people tend to prefer more direct and structured Experts in the fields of cardiology, endocrinology, epidemiology, psychology 25  12 and behavioral science in the U.S. reviewed them and provided suggestions 1 for further refinement. Finally, Chinese researchers and a linguist reviewed all 2 550 text messages, further refined the language, and paid special attention to 3 the cultural meaning of all text messages to ensure better understanding 4 among the targeted population (elderly Chinese patients with cardiovascular 5 disease, with and without diabetes). Once feedback from the experts was 6 addressed, the text bank was updated and prepared for user testing. 7

Phase 3 User testing and pilot study 8
For user testing, 19 randomly selected text messages from the finalized text 9 bank in the CHAT and CHAT-DM studies were distributed to 39 individuals 10 with CHD (with or without diabetes) for feedback. Likert-type items in a survey 11 were used to assess usefulness and ease of understanding of the text 12 messages. Open-ended questions were asked to obtain suggestions for 13 improvement from participants. In total, 92.4% (582/630) rated the messages 14 as easy to understand and 93.2% (587/630) rated the messages as useful. All 15 550 text messages were further modified based on feedback from user testing. 16 Results of the scores for the message categories in this phase are 17 summarized in Table 2. 18 Next, the refined text message banks underwent pilot testing to evaluate the 19 efficacy of the message delivery system and quality of the user experience. A 20 customized software program sent messages through a gateway interface, 21 allowing them to be sent to all individuals' mobile phones free of charge and at 22 a bulk-rate cost (0.1 yuan per message, or .01 USD) to the research team. 23 Participants from the user testing were enrolled in the pilot testing after 24   (Table 3). 22 Initially, a test message was sent to each participant to ensure that the correct 23 mobile phone number had been recorded and the system was functioning 24     Table 4 at follow-up visit. We conducted on-site 9 monitoring of recruitment, physical measurements, sample collection and 10 document completeness (e.g. informed consent) by trained staff from NCCD to 11 ensure the quality of data collection.    Blood pressure is measured on the right upper arm after 5 minutes of rest in a 1 seated position using an electronic blood pressure monitor (Omron HEM-7111;  2 Omron Corporation, Dalian, China). Two measurements are taken and the 3 mean value is calculated. If the difference between the two SBP or diastolic 4 blood pressure (DBP) readings is larger than 5 mm Hg, a third measurement is 5 done, and the mean value of the last two readings is calculated. HbA 1C is 6 determined using a high-performance liquid chromatography technique with 7 ADAMS TM A 1C HA-8180 (ARKRAY, Inc, Japan). BMI is calculated by dividing patient was re-hospitalized in other hospitals, for example, the study 23 investigators will contact the specific hospital, copy those medical records and 24 transmit them to NCCD as required. 25

Statistical Analysis 2
Intervention evaluation will be carried out on an intention-to-treat (ITT) basis. 3 Values of analyzed parameters at baseline between intervention group and 4 control group will be compared using Student's t-tests for continuous variables 5 or Chi-square tests for categorical variables according to the analysis plan. 6 Mann-Whitney U tests will be used where continuous data are not normally 7 distributed. The primary analysis will employ analysis of covariance (ANCOVA) 8 with baseline values of the analyzed endpoints used as covariates when 9 appropriate. The mean level of each risk factor will also be compared between 10 groups in terms of relative risks, 95% CIs and two-sided p values. We will 11 conduct a pre-specified 2 nd analysis with adjustment for patient characteristics 12 as well as subgroup analyses based on age, sex, education, smoking status 13 and tertiles level of endpoints. 14 All sample size calculations in both studies are for 80% power and 0.05 15 (one-sided) level of significance, allowing for 20% dropout rate during follow up. 16 In the CHAT study, we estimate a mean SBP level of 132mm Hg [SD, 18mm 17 Hg] in the study population according to the report of previous studies, 48 and 18 assume an absolute reduction in SBP of 5 mm Hg at 6 months from baseline. 19 A total sample size of 800 patients would be adequate to detect this difference 20 in SBP between two groups even when considering the potential compliance 21 to the intervention. In the CHAT-DM study, we assume a mean HbA 1C  HbA 1C between two groups even when considering the potential compliance to 2 the intervention. The trial results will be reported in accordance with the 3 SPIRIT checklists. 4

Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained ______7______ Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

______8______
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered _____8-12____ 11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease) ______9______ 11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)

_____14______
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ______9______ Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended ____16-17____ Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) ______7______

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions

_____8-9_____
Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned ______9______ Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions _____8-9_____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how ______9______ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial ____ N/A _____

Methods: Data collection, management, and analysis
Data collection methods 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol ____14-15____ 18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols ____ N/A _____  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  Data management  19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

____15-16____
Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol Methods for any additional analyses (eg, subgroup and adjusted analyses) _____18______ 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) ____ N/A _____

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial ____ N/A _____

Harms 22
Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct _____15______ Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor ____ N/A _____ How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial ____15-16____