Remission Evaluation of a Metabolic Intervention in Type 2 Diabetes With Forxiga

Study Overview
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Brief Summary
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The purpose of the study is to determine whether in patients with early type 2 diabetes, a short-term intensive metabolic intervention comprising Forxiga, metformin, basal insulin glargine and lifestyle approaches will be superior to standard diabetes therapy in achieving sustained diabetes remission.

Detailed Description
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This is a multicentre, open-label, randomized controlled trial in 152 patients with recently-diagnosed T2DM. Participants will be randomized to 2 treatment groups: (a) a 12-week course of treatment with Forxiga, metformin, insulin glargine and lifestyle therapy, and (b) standard diabetes therapy, and followed for a total of 64 weeks (1 year and 3 months). In all participants with HbA1C<7.3% at the 12 week visit, glucose-lowering medications will be discontinued and participants will be encouraged to continue with lifestyle modifications and regular glucose monitoring. Participants with HbA1C ≥ 7.3% at this visit or who experience hyperglycemia relapse after stopping drugs will receive standard glycemic management as informed by the current Canadian Diabetes Association clinical practice guidelines.

Official Title
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Remission Evaluation of a Metabolic Intervention in Type 2 Diabetes With Forxiga

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: insulin glargine
* Drug: metformin
* Drug: Forxiga
* Behavioral: Lifestyle therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: men and women 30-80 years of age inclusive; type 2 diabetes mellitus diagnosed by a physician within 8 years prior to patient enrollment; anti-diabetic drug regimen (either drug or dose of drug) unchanged during 8 weeks prior to screening and randomization; HbA1C 6.5-9.5% inclusive on no hypoglycemic agents or HbA1C ≤ 8.0% on up to 2 glucose-lowering agents; body mass index ≥ 23 kg/m2; ability and willingness to perform self-monitoring of capillary blood glucose (SMBG); ability and willingness to self-inject insulin; provision of informed consent. Exclusion Criteria: current use of insulin therapy; history of hypoglycemia unawareness, or severe hypoglycemia requiring assistance; history of end-stage renal disease or renal dysfunction as evidenced by eGFR<60 mL/min/1.73 m2 by MDRD formula; history of lactic acidosis or diabetic ketoacidosis; active liver disease or elevated alanine transferase (ALT) levels ≥ 2.5 times upper limit of normal at the time of enrollment; history of bladder cancer or undiagnosed hematuria; history of breast cancer; history of polycythemia; evidence of volume depletion or hypotension (systolic blood pressure < 90 mmHg); systolic blood pressure > 180 mmHg or diastolic blood pressure > 105 mmHg; diagnosed cardiovascular disease (unless cleared for a moderate intensity exercise program by a specialist) including: any history of acute coronary syndrome, hospitalization for unstable angina, myocardial infarction, or revascularization with coronary artery bypass grafting or percutaneous coronary intervention; other evidence of coronary artery disease; peripheral vascular disease, valvular heart disease, cardiomyopathy, aortic dissection, tachyarrhythmias, bradyarrhythmias, prior stroke or TIA; prior hospitalization for heart failure; or ECG findings concerning for ischemic heart disease (i.e. pathological Q-waves, ST-segment-T-wave abnormalities in contiguous leads, left anterior hemiblock, left bundle branch block, second or third degree atrioventricular block). dependence on oxygen; history of any disease requiring frequent intermittent or continuous systemic glucocorticoid treatment; history of bariatric surgery, or planned bariatric surgery in the next 1.5 years; history of any major illness with a life expectancy of < 3 years; history of injury or any other condition that significantly limits participant's ability to achieve moderate levels of physical activity; any history of excessive alcohol intake, acute or chronic; currently pregnant, or breastfeeding, or not using a reliable method of birth control for the duration of the trial in all females with childbearing potential; reliable methods of birth control include oral contraceptive (birth control pill), hormonal injection, implant, patch, or vaginal ring, intrauterine device, barrier method (condom and spermicide), tubal ligation, partner vasectomy or abstinence; known hypersensitivity to metformin, Forxiga, or insulin glargine.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Drug: insulin glargine - sc injection; Drug: metformin, oral administration; Drug: forxiga, oral administration; Behavioral: lifestyle therapy, diet and exercise | Drug: insulin glargine<br>* Dose is titrated to achieve fasting normoglycemia<br>* Other names: Lantus;Drug: metformin<br>* Dose is titrated to 1 g bid or maximal tolerated dose<br>Drug: Forxiga<br>* Dose is titrated to 10 mg po daily or maximal tolerated dose<br>* Other names: dapagliflozin;Behavioral: Lifestyle therapy<br>* Lifestyle intervention includes individualized dietary and exercise advice and frequent visits for goal reinforcement, behavior modification and problem-solving<br>* Other names: diet and exercise;|
| No Intervention: Standard Care<br>Standard glycemic care as informed by the current clinical practice guidelines | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Drug-free Diabetes Remission in the Experimental Group Compared to the Control Group | Drug-free diabetes remission is defined as HbA1C < 6.5 % off glucose-lowering agents for at least 12 weeks. | 24 weeks after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Drug-free Diabetes Remission | Drug-free diabetes remission is defined as HbA1C < 6.5 % off glucose-lowering agents for at least 12 weeks. | 64 weeks after randomization | 
| Number of Participants Achieving Drug-free HbA1C < 6.0% | Drug-free complete diabetes remission is defined as HbA1C < 6.0 % off glucose-lowering agents for at least 12 weeks. | 24 weeks after randomization | 
| Number of Participants Achieving Diabetes Relapse Without Overt Hyperglycemia Off Diabetes Drugs | Diabetes relapse without overt hyperglycemia is defined as HbA1C 6.5-6.9% off glucose-lowering agents for at least 12 weeks. | 24 weeks | 
| Glycated Hemoglobin (HbA1C) | Expressed in Diabetes Control and Complications Trial (DCCT) units | 12 weeks after randomization | 
| Number of Participants With Non-severe Symptomatic Hypoglycemic Episodes | Symptomatic hypoglycemic episode is defined as an event with clinical symptoms consistent with hypoglycemia. | During 64 weeks of follow-up | 
| Percentage of Weight Loss From Baseline | (Weight at randomization - weight at 12 weeks)/(weight at randomization) | 12 weeks after randomization | 
| Change in Waist Circumference From Baseline | (Waist circumference at 12 weeks - waist circumference at randomization) | 12 weeks after randomization | 
| Number of Participants With Severe Hypoglycemic Episodes | Severe hypoglycemic episode is defined as an event with clinical symptoms consistent with hypoglycemia in which the participant required the assistance of another person, and one of the following: (i) the event was associated with a documented self-measured or laboratory plasma glucose level </= 2.0 mmol/L or (ii) the event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration. | During 64 weeks of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Insulin, Glargine, Metformin, Forxiga, Diet, Exercise, Lifestyle