The Remission Evaluation of Metabolic Interventions in Type 2 diabetes (REMIT) program incorporates a non-surgical-remission-inducing therapeutic approach, pairing health coaching with physician-led pharmacotherapy. This approach has been tested in 5 multi-cite trials (1 pilot, 3 completed and 1 ongoing) and suggests an intensive short-term intervention with passive follow up supports patients in achieving remission. Further research is needed to evaluate the feasibility of the short-term REMIT intervention in real-world settings such as primary care and inform the future rollout of the program in multiple sites across Ontario.

The REMIT-Prime study will evaluate the REMIT short-term metabolic intervention in a primary care setting (Hamilton, Ontario), with the aims of investigating the feasibility and acceptability of the REMIT intervention in primary care settings and understanding the context for implementation. One hundred and eighteen eligible participants from the primary care site will be offered the REMIT intervention or waitlisted as a natural control group. The study protocols will be collaboratively designed and finalized with a primary care team and patient partners to elicit feedback on the adoption and feasibility of the intervention in primary care. Healthcare professionals from the CFFM will also be interviewed and asked to describe their experiences with the intervention. The findings from these interviews will support the rapid translation and rollout of the REMIT program in other interested primary care sites, including in London and Cambridge, Ontario.

Type 2 diabetes (T2D) is a major health problem in Canada, affecting 11 million Canadians. Individuals with diabetes have a greater risk of developing blindness or being hospitalized with cardiovascular disease, end-stage renal disease, and lower limb amputations compared to the general population. Currently, T2D management involves lifestyle modification and glucose-lowering medications in response to rising glucose levels and failing therapeutic regimens. This approach leads to frequent self-blood glucose monitoring (SBGM), clinical appointments, and chronic polypharmacy, all of which are associated with increased risk of adverse effects, non-adherence to medications, and poor quality of life.

Evidence that T2D can be completely or partially reversed is now challenging the traditional approach to its management. Strategies combining dietary interventions, intensive metabolic and pharmacotherapy strategies, or bariatric surgery have been shown to induce diabetes remission. However, extremely low-calorie diets or bariatric surgery is not acceptable to many patients and not scalable for primary care, where diabetes care is primarily delivered.

Over the past 7 years, our investigators of Canadian multidisciplinary health care providers, patient partners, physicians, and researchers have identified and tested non-surgical remission-inducing therapeutic regimens in people with T2D. The Remission Evaluation of Medical Interventions in T2D (REMIT) program comprises 1 pilot study, 3 completed pan-Canadian multicentre (8 sites) trials, and one ongoing trial. For all the trials, the paradigm tested was one of a 3 to 4-month remission-induction period, followed by a 1-year follow-up period to detect relapse. All 5 trials tested the efficacy of an induction period during which normoglycemia was targeted to reduce glucotoxicity with frequent health coaching (focused on self-efficacy, weight reduction, and physical activity), metformin and basal insulin. These trials also included additional metabolic therapy with either: a) dapagliflozin (SGLT2 inhibitor); b) sitagliptin (DPP-4 inhibitor); c) lixisenatide (GLP-1 receptor agonist); or d) liraglutide. In all 5 trials, glucose-lowering drugs were stopped after 3-4 months. Participants with a glycated hemoglobin (A1C) <7.3% were classified as being in possible remission and followed for relapse. Following the pilot study, all 3 completed trials observed a lower hazard of relapse in the intervention group with hazard ratios of 0.60 (95% CI 0.39, 0.95) for the sitagliptin trial, 0.57 (95% CI 0.39, 0.81) for the dapagliflozin trial 0.57 (95% CI 0.40, 0.81) for the lixisenatide trial.

The findings from the previous trials suggest that a short-term intensive intervention with passive follow-up is a viable alternative to achieving remission. Research is needed to test the implementation of an intensive short-term remission approach in real-world settings such as primary care. Therefore, the REMIT-Prime study will use an implementation-effectiveness evaluation approach to assess the REMIT short-term metabolic intervention on the real-world effectiveness and understand implementation barriers and facilitators in primary care settings. This proposed study seeks to simultaneously test the clinical effectiveness and an implementation strategy in one partnering site (Escarpment Health Centre, in Hamilton, Ontario [EHC]), to inform additional implementation sites. Ultimately, the program of REMIT-Prime will inform the future scale, spread and sustainability of the REMIT intervention in primary care.

1.2 What are the principal questions to be addressed?

1.2.1 Primary Research Question: Among patients in primary care settings with T2D diagnosed within the past 5 years, does a 16-week multimodal intensive metabolic program (health coaching for lifestyle changes plus basal insulin, metformin and either an SGLT2 inhibitor, DPP4 inhibitor, or GLP1 receptor agonist titrated to a dose that rapidly achieves normoglycemia) reduce the hazard of diabetes relapse (A1C ≥6.5%) up to 1 year after all drugs are stopped?

1.2.2 Secondary Research Questions: a) Does the REMIT program improve the proportion of patients at 28, 40, 52 and 68 weeks who: i) have relapsed; and ii) achieve and maintain 5% total body weight loss? b) Does the REMIT program improve health-related quality of life (HRQoL), as measured by the European Quality of Life 5 Dimension Scale and Visual Analogue Scale (EQ-5D) at 16, 40 and 68 weeks? and c) Does the effectiveness of the REMIT program depend on baseline participants' demographic variables such as age, sex, gender, ethnicity, diabetes duration or baseline diabetes medications use?

2.0 DESCRIPTION OF POPULATION

2.1 What are the inclusion and exclusion criteria? 2.1.1 Inclusion Criteria: Adults aged 30-80 years with: a) T2D diagnosed ≤ 5 years; b) stable T2D drug regimen in the 8 weeks before consent; c) A1C 6.5-9.5% on no glucose-lowering drugs or 6.5-8.0% on 1-2 glucose-lowering drugs or 6.5-7.5% on basal insulin; d) BMI ≥ 23 kg/m2; e) ability to perform SBMG; f) access to a telephone; and g) ability to read, write, and provide informed consent in English.

2.1.2 Exclusion Criteria: Individuals will be excluded if: a) coaching may not be appropriate (e.g., impaired cognition); b) pregnant (or planning pregnancy) at the time of recruitment; c) cohabiting with a participant in the study (to reduce contamination); c) have an underlying medical condition that may limit one's participation in the study (e.g. history of cardiovascular disease, injury, or contraindication to any study medication (e.g. metformin)); (d) history of bariatric surgery, or planned bariatric surgery in the next 1.5 years; (e) history of any major illness with a life expectancy of < 3 years; (f) history of injury or any other condition that significantly limits participant's ability to achieve moderate levels of physical activity; (g) excessive alcohol intake, acute or chronic; or (h) inability to take the study medications.

Because the safety of the study drugs for a newborn is unknown, participants who intend to become pregnant, are pregnant or are breastfeeding, cannot participate in this study. They must agree to use a reliable form of birth control (either the birth control pill [14 days prior], hormonal injections or implants, an intrauterine device [30 days prior], or a combination of spermicide and condoms) to prevent any pregnancy during the study. Women of childbearing age will be counselled about the possibility of becoming pregnant on these drugs and urine pregnancy tests will be offered at baseline (which is also the final screening visit) and week 12 of the intervention (while on medications). Beyond these timepoints, the participants are not on these medications. If the baseline visit is more than three months from the time the participant starts the trial, then a repeat pregnancy test will be offered. If they become pregnant despite these precautions, they must notify the study team immediately.

2.2 What is the proposed trial sample size and justification for it? The sample size calculation is based on the estimated proportion of patients achieving diabetes remission of 12% in the control group. Assuming ~ 80% follow-up, a total sample size of 118 participants from the primary care site will provide 80% power to show an absolute risk difference of ≥20% (i.e. 68% versus 88%) in diabetes relapse between treatment groups and 90% power to show an absolute risk difference of ≥25%.

3.0 THE PROPOSED STUDY AND OUTCOMES

3.1 What is the proposed study design? The investigators propose an implementation-effectiveness (hybrid type 2) study, where the aim is to simultaneously evaluate the REMIT program in a primary care setting and to understand the context for implementation. This design blends effectiveness and implementation goals (adoption and fidelity) to provide a more rapid translation and valid estimate of real-world effectiveness. The effectiveness component will be a single-site, single-arm study of the effect of the REMIT program on rates of diabetes relapse. The implementation component (embedded within the study) will explore the mechanisms by which the program is delivered (context) and identify potential implementation barriers and facilitators (from the participant and provider perspective) and inform an implementation strategy for additional primary care sites. The implementation component has commenced and is being led by a graduate trainee (Hamilton's Integrated Research Ethics Board - #17376).

Figure 1: REMIT-Prime Study Design

3.2 What is the planned trial intervention, including screening and consent? Pre-screening: All primary care doctors at EHC are aware of the study and have engaged in previous presentations or discussions with the study researchers and health coach to discuss the study and the T2D Remission program. Brochures and posters will be available in the health care provider's offices and the waiting area. Therefore, patients may self-refer, or they can be referred by their primary care provider, by communicating with the health coach.

Screening and Consent: At the initial appointment with the health coach, they will review the study information package and ask if they have any questions. Written consent will be obtained, and confirmation of study eligibility will be determined by the health coach. Consent is sought first to obtain consent to access the electronic medical record (EMR); for example, laboratory confirmation related to A1C value and timing of the latest blood work. Following confirmation of eligibility, study participants will complete all baseline assessments, including demographic questionnaire, quality of life, BMI (height and weight) and A1C.

Eligible participants will either receive the T2D remission program immediately or at the next available appointment (e.g., waitlisted) based on health coach availability. The waitlist group will receive usual care and diabetes educational resources related to healthy eating and increasing physical activity, mimicking real-world waitlist scenarios, while they wait for the program. If participants are waiting for more than 3 months, a recent A1C will be collected and used as a comparator group. The T2D remission program / REMIT program is a 16-week intensive metabolic intervention comprising: i) health coaching to promote behaviour change for diet (caloric reduction of 600 kcal/day) and physical activity (increase intensity for 30 minutes per day); and ii) combination pharmacotherapy aiming for a fasting capillary glucose of 4-5.3 mmol/l. As the intensity of care is a key feature of the REMIT program, those who have started the program will have more frequent interactions during the first 16 weeks than the waitlist care group.

T2D Remission Program:

The Induction Phase - Weeks 1 to 16: Participants who have started the program will have twice-weekly visits (telephone or in-person) for the first 6 weeks and visits every week for the last 10 weeks. At every interaction, a health coach (registered dietitian and certified diabetes educator) will help participants (with the support of a personal workbook that is not meant for data collection or recording of data for study purposes) with: a) tailoring lifestyle changes including a modified diet targeting a weight loss of >5%, and physical activity targeting >150 min of activity/week; b) review of SBGM levels; c) hypoglycemia prevention and treatment; and d) drug titration and adherence. All glucose-lowering drugs except metformin will be stopped when participants begin the program. The regimen will include basal insulin, metformin and a choice of an SGLT-2 inhibitor, DPP-4 inhibitor or GLP-1 receptor agonist, determined by the primary care lead and patient, and all used according to their label. As the REMIT trials with these classes of medications showed a similar effect on the relapse outcome, attention to individualization to patient preferences and needs (e.g. cost, convenience, tolerability) will be paramount. Medications will be titrated, as per the randomized controlled REMIT trial protocols, by the primary care physician, in consultation with the health coach, to achieve fasting capillary glucose levels between 4 and 5.3 mmol/l within 4 - 6 weeks of starting the program..

Observation Follow-up Phase - Weeks 16.5 to 68: After the 16-week induction phase and in-clinic visit, participants will enter a follow-up phase which lasts one year. This phase consists of phone or clinic visits once a month starting at week 20 until week 68, with assessments. Participants will also be asked to contact the site at any time if they note possible relapse of hyperglycemia which is defined as: a) capillary or interstitial glucose values ≥ 10 mmol/L on ≥50% of readings over 1 week in the absence of an acute illness; b) the use of glucose-lowering drugs; or c) a HbA1C level ≥ 7.0% at or after week 28.

Waitlist: While participants wait for the next available health coach appointment, participants on the waitlist will be provided with diabetes educational resources (e.g., physical activity, recipe examples) readily available through the Diabetes Canada website (https://www.diabetes.ca/resources). Waitlist participants will continue to be managed by their usual diabetes care provider, and they will be able to use any approved glucose-lowering medications. If participants are waiting for more than 3 months (>11 weeks), a recent A1C will be collected.

The REMIT-Prime Program will be implemented as follows:

1. Pre-screening by members of the circle of care

2. Call from Patient Care Coordinator to confirm interest in study and schedule an initial appointment with Health Coach (see recruitment and pre-consent scripts)

3. Consent, then final eligibility screening with Health Coach; Baseline assessment

   • If eligible, begin baseline assessment/data collection and first intervention visit (based on capacity)

     -If the health coach is at capacity, the consent, eligibility screening, and baseline data collection will still occur, but the first intervention visit will be scheduled based on the next available slot for the health coach. Baseline data will be re-collected if the first intervention visit is longer than a 3-month wait.

   • Health coach to provide physical activity and diet education and begin initial goal setting and create an action plan

   • Health coach to notify the EHC primary care provider, informing them that their patient is part of the program - internal message through EMR system

   • Under the supervision and direction of Health Coach, the participant will begin study medications

4. Health Coach Calls and Visits: 2x per week (weeks 1 to 6)

   • Weekly clinic visits with phone calls in between with the health coach (contact 2x per week)
   • Health coach continues education and promotion of goal achievement

5. Health Coach Calls and Visits: 1x per week (weeks 6-16)

   • Weekly clinic visits or phone calls with the health coach (contact 1x per week)
   • Health coach continues education and promotion of goal achievement

6. End of intensive remission protocol and outcome measurements (week 16)

   • In-person visit to assess outcome measurements and stop diabetes medication (if within remission criteria)
   • Health coach continues education and promotion of goal achievement
   • Health coach to notify the EHC primary care provider that the patient is still in the program, but beginning a less intensive follow-up period - internal message through EMR system

7. Follow-up Health Coach calls and Visits: 1x per month (weeks 17-67)

   o Monthly clinic visits or phone calls with the health coach (contact 1x per month)

8. End of study and outcome measurements (week 68)

   • In-person visit to assess outcome measurements
   • Health coach to notify the EHC primary care provider, informing them that their patient is finished the study - internal message through EMR system

3.3 What is the proposed frequency and duration of follow-up? Participants will complete assessments at baseline, 16, 28, 40, 52 and 68 weeks after beginning the study. Participants who are waitlisted will repeat their baseline assessments if their wait time is greater than 11 weeks. All assessments will be completed by a trained Health Coach who is also a healthcare professional (Registered Dietitian, and possibly Certified Diabetes Educator) at the primary care site.

3.4 What are the proposed primary and secondary outcome measures? The primary outcome is the relapse of T2D defined as the first occurrence of: a) an HbA1c level ≥ 6.5%; b) SBGM values ≥ 10 mmol/L on ≥50% of readings over 1 week (absent of an acute illness); or c) the use of glucose-lowering drugs. The secondary outcomes include a) proportion of participants relapsed at 28, 40, 52 and 68 weeks; b) weight and body mass index (BMI) as measured at each study visit using baseline height; and c) HRQoL assessed with the EQ-5D (see separate questionnaire). The investigators will collect participant demographic data to describe the population's sex, gender, age, ethnicity, education, diabetes duration and medications, and explore the interaction between primary and secondary outcomes.

Outcome Data Source A1C (or HbA1c) Electronic medical record Weight, height and BMI In person at EHC EQ5D In person; REDCap link to tablet (e.g., ocean) Demographics In person; REDCap Medications In-person and via phone calls

Screening / Baseline Visit(s) Check-in visits (weeks 1-15) Week 16 (end of intensive period) Follow-up week 20 Follow-up weeks 28, 40, 52 Week 68 (end of study) Physical and Clinical Measures Weight X X1 X X X X Height X BMI X X X X X HbA1c X X X X SMBG X X X X X Questionnaires Demographics X Medical History X Quality of Life X X X2 X A REDCap link to the questionnaires will be sent via email ahead of in-person visits to reduce time at the clinics

1. Weight will only be collected at weeks 3, 6, 8, 10, 12, 14 for check-in visits
2. Quality of life measured at week 40 for follow-up period (not weeks 28 or 52)

3.5 How will the outcome measures be measured at follow-up? Outcome measures will be collected at baseline, 16, 28, 40, 52 and 68 weeks. All study assessment visits will occur at EHC in Hamilton. Participants on the waitlist will complete all baseline assessments at the time of consent and again at the initiation of the intervention if it has been longer than 11 weeks since the last A1c.

3.6 What is the planned recruitment strategy and rate? Recruitment strategies that have proven effective from our previous studies completed in Southwestern Ontario include: a) brochures and posters in the primary care office; and b) word of mouth through the primary care doctors and their allied healthcare professionals. Based upon previous recruitment rates of 7-10 participants per month, the investigators anticipate it will take 12 -18 months to recruit 118 participants and 3 years to complete the study.

3.7 What is the likely rate of loss to follow-up? Study participants will be identified, recruited and followed in their primary care setting. Follow-up will be encouraged through the following measures: a) agreement to follow the protocol as one of the eligibility requirements; b) individuals will be contacted if outcome measures are not completed according to the schedule; and c) burdensome laboratory testing is not required, as they will complete study assessments (A1C) as part of their usual diabetes care. Based on the attrition rates from the literature and our trials, the investigators have conservatively estimated a 15-20% loss to follow-up.

4.0 DATA ANALYSIS PLAN All primary and secondary outcomes will be analyzed using the intent-to-treat approach, in which all participants will be included using a single-arm approach for allocation to the T2D Remission Program. Allocation to the T2D remission program will be based on health coach availability, reflecting a real-world implementation approach. The investigators will utilize an instrumental variable (IV) based regression approach to quantify intervention effects on primary and secondary outcomes of interest. Specifically, the team will use intervention availability as an instrumental variable (an exogenous variable) that is related to the intervention but is completely unrelated to the outcomes of interest, except via intervention only. The IV design allows us to identify independent treatment effects even if some or all confounders are unknown or unobserved.

Descriptive statistics will present the data as means, standard deviations (SD), frequencies, and percentages. Baseline characteristics will be compared, and random significant differences will be adjusted for in the sensitivity analysis of the primary outcome. Categorical variables will be compared using an X2 test and continuous variables will be compared using a t-test; all statistical tests will use an α level of 0.05 to indicate significance45. Any individual who withdraws/drops out before the 28, 40, 52, or 68-week visit will be classified as relapsed at that visit. The rates of the primary outcome: the relapse of T2D (from baseline to 28, 40, 52 and 68 weeks) will be compared using Cox regression46 adjusting for duration of diabetes and baseline A1C as independent variables. The effect size will be estimated as a hazard ratio (HR) with 95% confidence intervals. Secondary outcomes: proportions of participants who relapsed at 28, 40, 52 and 68 weeks will be compared by logistic regression with effect size expressed as both odds ratios and risk differences. Differences between groups in changes from baseline to 28, 40, 52 and 68 weeks for weight, BMI, and EQ5D scores will be expressed as mean (95% confidence interval) and assessed using t-tests. In addition, A1C trends over time will be analyzed using a repeated-measures analysis of covariance. Planned subgroup analyses will explore the effect of the intervention by age group (≥, < 55 years), sex, gender, education, diabetes duration (≥, < 2 years) and the number of diabetes medications.

4.1 Safety and Monitoring The REMIT intervention has been studied in 5 pan-Canada trials and delivered by health coaches who comprised regulated and non-regulated health care professionals. In all 5 trials, there were no serious adverse events. Moreover, the REMIT intervention is a multimodal intervention that includes close and frequent contact (approximately every 3 days) with a health coach. For this effectiveness and implementation study, the investigators will emulate the real-world implementation of an evidence-based intervention. Thus, the health coach is a certified diabetes educator and registered dietitian who works as an allied health care professional supporting the Hamilton Family Health Team, which includes EHC. The health coach will obtain prescriptions to initiate medications and support to titrate medications, as part of the REMIT protocol. The lead primary care provider, has reviewed the study protocol and all medications (initiated and titrated) are used as per monograph directions. All participants will be patients of EHC and, therefore, will have access to a primary care provider. If any episodes of severe hypoglycemia (i.e., requiring 3rd party intervention) or adverse events/side effects occur, the health coach will assess and document in the EMR and request an appointment for the participant to meet with their health care provider. Endocrinology consults on a case-by-case situation will be made available as well. The dose of insulin used in this study is at a therapeutic level, not for glycemic management, and thus hypoglycemic events are not common. However, hypoglycemia symptoms are a strong consideration to reduce and/or discontinue insulin and participants will be counselled on these considerations as well as de-prescribed medications that cause side effects during the study period.

Data Safety Monitoring Boards were utilized in the efficacy trials (published and conducted by the Population Health Research Institute, Hamilton, ON) and across 5 randomized controlled trials from hundreds of participants across Canada, there were no safety concerns (e.g., hypoglycemia) or adverse events. To this end, as the study is embedded in the participant's primary care location, is a hybrid type 2 effectiveness-implementation study, and the health coach is working in tandem with their primary care doctor, the T2D remission health coach will have immediate access to the family physician if something is of concern or there is a clinical query.

For this research study, there will be weekly and monthly meetings. Weekly meetings will occur with the immediate implementation team, along with the health coach. They will continue to meet weekly to review study progress, data quality, and participants safety. The review of participant safety will include the following components: adverse events, serious adverse events, hypoglycemia, hyperglycemia, and other incidental concerns that arise, whether directly or indirectly related to the intervention. The study team will meet once a month as needed to evaluate the progress of the study, including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, performance of trial sites, and other factors that can affect study progress and outcomes. Together the investigators will make recommendations and decisions concerning the continuation, modification, or conclusion of the trial. The components for review will include adverse events, serious adverse events, hypoglycemia, hyperglycemia, and other incidental concerns that arise, whether directly or indirectly related to the intervention.

Inclusion Criteria:

Adults aged 30-80 years with:

1. Type 2 diabetes diagnosed ≤ 5 years;
2. stable type 2 diabetes drug regimen in the 8 weeks before consent;
3. glycated hemoglobin HbA1C 6.5-9.5% on no glucose-lowering drugs or 6.5-8.0% on 1-2 glucose-lowering drugs or 6.5-7.5% on basal insulin;
4. Body Mass Index ≥ 23 kg/m2;
5. ability to perform self-blood glucose monitoring or wear a continuous blood glucose monitor;
6. access to a telephone; and
7. ability to read, write, and provide informed consent in English.

Exclusion Criteria: Individuals will be excluded if:

a) coaching may not be appropriate (e.g., impaired cognition); b) pregnant (or planning pregnancy) at the time of recruitment; c) cohabiting with a participant in the study (to reduce contamination); d) have an underlying medical condition that may limit one's participation in the study (e.g. history of cardiovascular disease, injury, or contraindication to any study medication (e.g. metformin)); e) history of bariatric surgery, or planned bariatric surgery in the next 1.5 years; f) history of any major illness with a life expectancy of < 3 years; g) history of injury or any other condition that significantly limits participant's ability to achieve moderate levels of physical activity; h) excessive alcohol intake, acute or chronic; or i) inability to take the study medications.

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Adults living with type 2 diabetes for at least 5 years or less, who are on (maximum) two glucose lowering medications plus basal insulin.