Conditions: Type 2 Diabetes Mellitus
Keywords: Diabetes Insulin Glargine Metformin Forxiga Diet Exercise Lifestyle
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 154
Healthy volunteers: no

Brief summary:
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:
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.

Arms:
arm 1: Drug: insulin glargine - sc injection; Drug: metformin, oral administration; Drug: forxiga, oral administration; Behavioral: lifestyle therapy, diet and exercise arm 2: Standard glycemic care as informed by the current clinical practice guidelines

Interventions: intervention 1: insulin glargine intervention 2: metformin intervention 3: Forxiga intervention 4: Lifestyle therapy
Intervention descriptions: intervention 1: Dose is titrated to achieve fasting normoglycemia intervention 2: Dose is titrated to 1 g bid or maximal tolerated dose intervention 3: Dose is titrated to 10 mg po daily or maximal tolerated dose intervention 4: Lifestyle intervention includes individualized dietary and exercise advice and frequent visits for goal reinforcement, behavior modification and problem-solving

Protocol document:
Prot_SAP_000.pdf: 
REMIT-Dapa Protocol 
Version 2.1  July 15, 2015 
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Remission Evaluation of a Metabolic Intervention in  
Type 2 Diabetes (REMIT) with Forxiga 
 
Protocol 
 
Version 2.1       July 15, 2015 
 
 
NCT02561130 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 4 
1. 
INTRODUCTION ................................................................................................... 5 
1.1 
Background and rationale ........................................................................................ 5 
1.2 
Hypothesis and research questions .......................................................................... 5 
1.3 
Benefit/risk and ethical assessment.......................................................................... 6 
2. 
STUDY OBJECTIVES ............................................................................................ 6 
2.1 
Primary objective ..................................................................................................... 6 
2.2 
Secondary objectives ............................................................................................... 6 
2.3 
Safety objective ........................................................................................................ 7 
3. 
STUDY PLAN AND PROCEDURES .................................................................... 7 
3.1 
Overall study design and flow chart ........................................................................ 7 
4. 
SUBJECT SELECTION CRITERIA ...................................................................... 7 
4.1 
Inclusion criteria ...................................................................................................... 7 
4.2 
Exclusion criteria ..................................................................................................... 8 
5. 
STUDY CONDUCT ................................................................................................ 9 
5.1 
Screening and baseline evaluation ........................................................................... 9 
5.2 
Randomization and blinding .................................................................................... 9 
5.2.1 
Procedures for randomization .................................................................................. 9 
5.2.2 
Procedures for handling subjects incorrectly enrolled or randomized ..................... 9 
5.3 
Interventions and monitoring ................................................................................... 9 
5.3.1 
Intensive metabolic intervention (induction phase of the trial) ............................... 9 
5.3.2 
Control group follow-up during the induction phase of the trial ........................... 11 
5.3.3 
Monitoring for hyperglycemia relapse during the maintenance phase of the 
trial ......................................................................................................................... 11 
5.4 
Methodological considerations .............................................................................. 12 
5.4.1 
Planned recruitment ............................................................................................... 12 
5.4.2 
Treatment adherence .............................................................................................. 12 
5.4.3 
Losses to follow-up ................................................................................................ 12 
5.4.4 
Confidentiality and record retention ...................................................................... 13 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 13 
6.1 
Recording of data ................................................................................................... 13 
6.2 
Study outcomes ...................................................................................................... 13 
6.2.1 
Primary and secondary outcomes .......................................................................... 13 


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6.2.2 
Other outcomes ...................................................................................................... 13 
6.2.3 
Stored blood ........................................................................................................... 14 
6.3 
Safety ..................................................................................................................... 14 
6.3.1 
Safety variables ...................................................................................................... 14 
6.3.2 
Definitions of adverse events ................................................................................. 15 
6.3.3 
Documentation and reporting of adverse events, pregnancies and 
overdoses ................................................................................................................ 16 
6.3.4 
Documentation and reporting of pregnancies and overdoses ................................ 16 
6.3.5 
Period of observation ............................................................................................. 17 
7. 
BIOLOGICAL SAMPLING PROCEDURES ....................................................... 17 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 17 
9. 
STUDY MANAGEMENT .................................................................................... 17 
10. 
DATA MANAGEMENT ....................................................................................... 18 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 18 
11.1 
Proposed sample size and justification .................................................................. 18 
11.2 
Statistical analyses ................................................................................................. 18 
12. 
SIGNIFICANCE .................................................................................................... 18 
13. 
APPENDIX A ........................................................................................................ 20 
 
 
 
LIST OF TABLES 
Appendix A: Table 1 - Schedule of visits and assessments in the intervention group (I), 
control group (C), and both groups (X). 
LIST OF FIGURES 
None. 
LIST OF APPENDICES 
None 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
 
 
ALT  
BhCG  
bid  
BMI 
CDA  
Cr 
ECG 
eGFR 
FPG 
MDRD 
OD 
pc  
PHRI 
po 
RCT 
SAE  
sc 
SGLT2  
SMBG  
T2DM  
 
 
 
alanine transferase 
beta human chorionic gonadotrophin 
twice daily 
body mass index 
Canadian Diabetes Association 
creatinine  
electrocardiogram 
estimated glomerular filtration rate 
fasting plasma glucose 
The Modification of Diet in Renal Disease equation to estimate GFR 
once daily 
postcibum (postprandial) 
Population Health Research Institute 
taken orally 
randomized controlled trial 
serious adverse event 
taken subcutaneously 
sodium glucose co-transporter 2 
self-monitoring of capillary blood glucose 
type 2 diabetes mellitus 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
INTRODUCTION 
1.1 
Background and rationale 
The current approach to treating type 2 diabetes mellitus (T2DM) is to add progressively 
higher doses and numbers of glucose-lowering drugs to lifestyle approaches.  People with type 
2 diabetes are therefore taking such drugs from shortly after diagnosis until the end of their 
lives.  A different, novel approach that intensively treats patients with several agents and 
lifestyle approaches for up to 2-4 months, followed by cessation of all drugs, may achieve a 
drug-free metabolic remission that could last for months to years.  Such an approach has not 
been formally tested.  However, a) evidence from small studies suggesting that approximately 
40% of newly diagnosed patients can achieve a remission with short-term intensive treatment 
with insulin; b) a growing list of glucose-lowering drugs with novel mechanisms of action; 
and c) the appeal of remission-induction versus lifelong chronic therapy highlights the need to 
characterize strategies for metabolic remission of diabetes and to identify the optimal 
therapies and regimens for achieving remission.   
 
We have just completed a peer-reviewed pilot trial of this approach at our centre. Eighty three 
people with T2DM diagnosed within the prior 3 years were randomized to 3 treatment groups: 
a) an 8-week intensive metabolic intervention; b) a 16-week intensive metabolic intervention; 
and c) standard diabetes therapy.  The intensive metabolic intervention combined lifestyle 
therapy and basal insulin glargine, metformin and acarbose and aimed at achieving 
normoglycemia on therapy.  We found that an 8-16-week course of therapy was safe and 
feasible and induced remission in up to 40% of people with early T2DM.  These data illustrate 
that metabolic interventions such as the one proposed herein can be successfully implemented 
and have the potential to induce diabetes remission not requiring glucose-lowering therapies.  
The proposed multicentre randomized controlled trial will assess the remission-related 
efficacy of a sodium glucose co-transporter 2 (SGLT2) inhibitor-based regimen in a broader 
set of patients.    
 
1.2 
Hypothesis and research questions 
Hypothesis:  
In patients with early type 2 diabetes, a short-term intensive metabolic intervention 
comprising dapagliflozin (Forxiga), metformin, basal insulin glargine and lifestyle approaches 
will be superior to standard diabetes therapy in achieving sustained diabetes remission.  
 
Primary research question:  
In patients with recently-diagnosed T2DM, does a 12-week course of Forxiga, metformin, 
basal insulin glargine and lifestyle approaches achieve drug-free diabetes remission in a 
higher proportion of patients than standard diabetes therapy at 24 weeks after randomization?  
Diabetes remission is defined as a HbA1C<6.5% off glucose-lowering agents for at least 12 
weeks.   
 
 


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Secondary research questions: 
1) Compared to the control group, does this therapeutic approach achieve drug-free diabetes 
remission in a higher proportion of patients than standard diabetes therapy at 36, 48 and 64 
weeks after randomization?   
2) Compared to the control group, does this therapeutic approach achieve drug-free HbA1C 
<6.0% in a higher proportion of patients than standard diabetes therapy at 24, 36, 48 and 
64 weeks after randomization?   
3) Compared to the control group, does this therapeutic approach achieve drug-free diabetes 
regression in a higher proportion of patients than standard diabetes therapy at 24, 36, 48 
and 64 weeks after randomization?  Diabetes regression is defined as HbA1C 6.5-6.9% off 
glucose-lowering agents for at least 12 weeks. 
4) What HbA1C levels are achieved in the intervention group and the control group at 12, 24, 
36, 48 and 64 weeks after randomization?  
5) What rates of hypoglycemia are observed in the intervention group and the control group 
during 64 weeks of follow-up? 
6) What is the change in weight, body mass index (BMI), waist circumference and waist/hip 
ratio from baseline to 12, 24, 36, 48 and 64 weeks in the intervention group and the 
control group? 
7) Are age, gender, ethnicity, diabetes duration, smoking, family history of diabetes, baseline 
BMI, waist circumference, HbA1C or fasting plasma glucose (FPG) determinants of 
diabetes remission at 24 weeks after randomization?   
 
1.3 
Benefit/risk and ethical assessment 
Participants with type 2 diabetes will be randomly allocated to continue with standard care or 
to receive a 12-week course of intensive lifestyle and glucose-lowering drug therapy which 
includes Forxiga. All participants will be informed that: a) the trial is testing a new short-term 
therapeutic approach to treating type 2 diabetes which could eliminate the need for glucose-
lowering drugs and possibly promote remission; and b) all therapies will be used for their 
approved indications. All participants will also provide written informed consent. 
2. 
STUDY OBJECTIVES    
2.1 
Primary objective 
To determine whether the 12-week metabolic intervention that includes Forxiga is more 
effective in achieving drug-free remission of type 2 diabetes than standard diabetes therapy 
when evaluated at 24 weeks after randomization.  
 
2.2 
Secondary objectives 
To determine whether the 12-week metabolic intervention that includes Forxiga is more 
effective than standard diabetes therapy in achieving diabetes remission and regression when 
evaluated at 36, 48 and 64 weeks after randomization. 


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2.3 
Safety objective 
To determine rates of severe and non-severe hypoglycemic episodes in the treatment groups 
during 64 weeks of follow-up. 
 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
This is a randomized, open-label, 2-arm pilot trial in 152 patients with early T2DM. 
Participants will be randomly assigned to (i) an intensive metabolic intervention of 12 weeks 
in duration, or (ii) standard diabetes therapy, and followed for 64 weeks. In the intervention 
group, the intensive metabolic intervention will combine lifestyle therapy and intensive 
treatment with Forxiga, metformin and insulin glargine. Glucose-lowering medications will 
then be discontinued in all participants with a HbA1C<7.3% on therapy, and participants will 
be encouraged to continue with lifestyle modification and regular home glucose monitoring. 
Participants with HbA1C ≥ 7.3% on therapy during week 12 of the trial or those with HbA1C 
≥ 7.0% at or after the 24-week visit will receive standard glycemic management as informed 
by the 2013 Canadian Diabetes Association clinical practice guidelines. The visit schedule for 
study participants is shown in Table 1 in Appendix A.  
4. 
SUBJECT SELECTION CRITERIA 
The Remission Evaluation of a Metabolic Intervention in Type 2 Diabetes with Forxiga trial 
will be conducted in participants with the following inclusion and exclusion criteria:   
 
4.1 
Inclusion criteria 
1) men and women 30-80 years of age inclusive; 
2) type 2 diabetes mellitus diagnosed by a physician within 8 years prior to patient 
enrollment; 
3) anti-diabetic drug regimen (either drug or dose of drug) unchanged during 8 weeks prior to 
screening and randomization;   
4) HbA1C 6.5-9.5% inclusive on no hypoglycemic agents or HbA1C ≤ 8.0% on up to 2 
glucose-lowering agents; 
5) body mass index ≥ 23 kg/m2; 
6) ability and willingness to perform self-monitoring of capillary blood glucose (SMBG);  
7) ability and willingness to self-inject insulin;  
8) provision of informed consent. 
 
 


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4.2 
Exclusion criteria 
1) current use of insulin therapy; 
2) history of hypoglycemia unawareness, or severe hypoglycemia requiring assistance; 
3) history of end-stage renal disease or renal dysfunction as evidenced by eGFR<60 
mL/min/1.73 m2 by MDRD formula;  
4) history of lactic acidosis or diabetic ketoacidosis; 
5) active liver disease or elevated alanine transferase (ALT) levels ≥ 2.5 times upper limit of 
normal at the time of enrollment; 
6) history of bladder cancer or undiagnosed hematuria; 
7) history of breast cancer;  
8) history of polycythemia;   
9) evidence of volume depletion or hypotension (systolic blood pressure < 90 mmHg);  
10) systolic blood pressure > 180 mmHg or diastolic blood pressure > 105 mmHg; 
11) diagnosed cardiovascular disease (unless cleared for a moderate intensity exercise 
program by a specialist) including: 
a. any history of acute coronary syndrome, hospitalization for unstable angina, 
myocardial infarction, or revascularization with coronary artery bypass grafting or 
percutaneous coronary intervention; 
b. other evidence of coronary artery disease;  
c. peripheral vascular disease, valvular heart disease, cardiomyopathy, aortic 
dissection, tachyarrhythmias, bradyarrhythmias, prior stroke or TIA; 
d. prior hospitalization for heart failure; or 
e. 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).  
12) dependence on oxygen; 
13) history of any disease requiring frequent intermittent or continuous systemic 
glucocorticoid treatment;  
14) history of bariatric surgery, or planned bariatric surgery in the next 1.5 years; 
15) history of any major illness with a life expectancy of < 3 years; 
16) history of injury or any other condition that significantly limits participant’s ability to 
achieve moderate levels of physical activity;  
17) any history of excessive alcohol intake, acute or chronic; 
18) 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; 
19) known hypersensitivity to Forxiga, metformin, or insulin glargine. 


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5. 
STUDY CONDUCT 
5.1 
Screening and baseline evaluation 
At the screening assessment, informed consent will be obtained, and eligibility criteria will be 
assessed by performing an interview and physical examination. Blood will be drawn for 
creatinine, ALT, fasting plasma glucose (FPG), and HbA1C. Fasting serum samples will also 
be taken for storage at the screening visit in participants who agree to it. A urine pregnancy 
test (urine BhCG) will be performed in women with childbearing potential. A baseline 
electrocardiogram (ECG) will also be performed to assess for any evidence of ischemic heart 
disease or arrhythmia. Baseline weight, height, body mass index, waist circumference and hip 
circumference will be obtained in all study participants. Physical activity and food frequency 
questionnaires will also be administered at baseline.   
 
5.2 
Randomization and blinding 
5.2.1 
Procedures for randomization 
Eligible participants will be randomized 1:1 to (i) an intensive metabolic intervention of 12 
weeks in duration, or (ii) standard diabetes therapy. An independent statistician will prepare a 
randomization schedule for each site using a computer-generated random number sequence. 
Concealment of allocation will be ensured by carrying out study group allocation through a 
central online system. In view of the differences in the treatment regimens, duration, and 
glycemic goals in the treatment groups, it will not be possible to blind participants or research 
staff to the intervention. However, the primary and key secondary outcomes of the study are 
based on objective measurements of blood glucose and HbA1C level, and lab personnel will 
be blinded to the treatment group assignment.  
 
5.2.2 
Procedures for handling subjects incorrectly enrolled or randomized  
Participants incorrectly enrolled in the study will be followed till the study end.  They will 
remain in the group they were randomized to.  Participants with contraindications to a specific 
study medication will have that drug discontinued.  Participants incorrectly started in the 
wrong group (i.e. to which they were not allocated) will be switched to the correct treatment 
group. 
 
5.3 
Interventions and monitoring 
5.3.1 
Intensive metabolic intervention (induction phase of the trial)  
An intensive metabolic intervention will be used in intervention group participants for 
induction of a normoglycemic state. It will be 12 weeks in duration and will include intensive 
lifestyle therapy and intensive treatment with Forxiga, metformin and insulin glargine.  
Participants will be asked to discontinue all other glucose-lowering medications. 
 


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5.3.1.1 
Treatment with and handling of Forxiga 
Participants randomized to the intervention group will be started on Forxiga 5 mg po daily for 
4 days and then the dose will be increased to 10 mg po daily. Participants will be continued on 
this dose for 12 weeks. Forxiga will be manufactured and shipped by AstraZeneca. Labels will 
be prepared in accordance with Good Manufacturing Practice and local regulatory guidelines 
for labeling. The drug will be stored at room temperature (15-30°C) in accordance with the 
storage conditions specified on the package label. Creatinine will be checked 2 weeks after 
drug initiation, and then monthly during the intensive metabolic intervention. Forxiga will be 
permanently discontinued if eGFR falls to <60 mL/min/1.73m2. Forxiga contains lactose and 
may cause abdominal discomfort in lactose-intolerant individuals. Forxiga will be temporarily 
stopped or permanently discontinued if a participant develops side effects.  
 
5.3.1.2 
Titration of other glucose-lowering medications 
In drug-naive patients, metformin 500 mg po (orally) once daily (OD) will be administered for 
4 days, then increased to 500 mg po twice daily (bid) for 4 days, then 1,000 mg po bid. 
Patients already on metformin will be continued on it with further titration to maximal 
tolerated doses.  
 
At randomization, participants will be concurrently started on insulin glargine 2-6 units sc 
(subcutaneously) at bedtime, and the dose will be titrated by the participant with guidance 
from the research team aiming to achieve a fasting glucose of 4.0-5.3 mmol/L on self-
monitoring of capillary blood glucose (SMBG). Insulin glargine is chosen in view of the 
previous experience of our center in using this insulin analogue to achieve similar glycemic 
targets in patients with early type 2 diabetes and prediabetes in the ORIGIN trial, a 
multicenter randomized controlled trial with more than 12,500 participants. The overall goal 
will be to finish medication titration by the end of week 2, and to maintain the fasting 
glycemic target of 4.0-5.3 mmol/L for the remaining duration of the intensive metabolic 
intervention. No other glucose-lowering medications apart from insulin glargine, metformin 
and Forxiga will be used in intervention group participants during the intensive metabolic 
intervention. All study drugs will be kept in a secure place under appropriate storage 
conditions. 
 
5.3.1.3 
Intensive lifestyle intervention 
The overall goals of the intensive lifestyle intervention are to achieve and maintain ≥ 150 min 
of moderate physical activity per week by week 12 and ≥ 5% reduction in baseline weight by 
week 24 of the trial. These goals might be modified depending on participant’s baseline 
weight and physical ability. At baseline, participants randomized to the intervention group 
will meet with research staff who will prescribe a personalized low-calorie diet and a 
moderate-intensity exercise program based on participant’s current physical activity patterns 
and cardiovascular history. Participants will be provided with a pedometer as an incentive to 
engage in physical activity. Participants in the intervention group will meet with research 
personnel every 1-2 weeks during the intensive metabolic intervention period for goal 
reinforcement, behaviour modification and problem-solving.  
 


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5.3.1.4 
Monitoring during the induction phase of the trial 
At the first study visit, intervention group participants will be taught how to self-monitor 
capillary blood glucose and how to inject insulin. Participants and their families will also be 
taught how to recognize and treat hypoglycemia. During the intensive metabolic intervention, 
participants will be asked to monitor glucose at least twice daily at varying times, including 
before and 2 hours after meals, and during exercise. Research staff will meet with intervention 
group participants once a week during the first 6 weeks of the trial and will contact them by 
telephone at least once a week between visits to review glucose readings, medication titration, 
medication adherence and side effects (see schedule in Table 1 in Appendix A). Research staff 
will continue to meet with intervention group participants every 2 weeks and will contact 
them by telephone every other week during week 7-12 of the trial. All hypoglycemic episodes 
will be documented and reviewed with an investigator promptly. Glucose-lowering therapy 
will be adjusted accordingly.  
 
5.3.2 
Control group follow-up during the induction phase of the trial 
Participants assigned to the standard diabetes therapy group will meet with research personnel 
at the beginning of the trial who will review self-monitoring of capillary blood glucose, 
management of hypoglycemia, and the importance of healthy diet and regular exercise in 
diabetes management. Control group participants will also be provided with a pedometer as an 
incentive to be active. Glucose levels in standard group participants will be managed by their 
regular diabetes care provider according to the current Canadian Diabetes Association (CDA) 
Clinical Practice guidelines. Any approved glucose-lowering medication will be allowed in 
the control group.  
 
5.3.3 
Monitoring for hyperglycemia relapse during the maintenance phase of the 
trial 
In all participants, HbA1C will be drawn during week 12 of the trial.  At the end of week 12, 
glucose-lowering medications will be discontinued in all participants with a HbA1C <7.3%, 
and insulin will be tapered over a 5-day period. Participants will be encouraged to continue 
with lifestyle modifications and regular home glucose monitoring (i.e. at least 5 fasting 
capillary measures per week). They will meet with research staff every 2-4 months during the 
maintenance phase of the trial to review any challenges in achieving and maintaining exercise 
and weight loss goals. Participants will be assessed by research staff every 1-2 months by 
telephone to review adherence to lifestyle therapy, SMBG readings and to screen for 
symptoms of hyperglycemia.  
 
It is possible that glucose levels may quickly rise after glucose-lowering drugs are stopped in 
some of the participants whose HbA1C is <7.3% on these drugs. This rise may not be detected 
with HbA1C levels due to the well-known time-lag between rising glucose levels and rising 
HbA1C levels.  
 
In light of the above, hyperglycemia relapse will be defined as follows:  
a. a HbA1C ≥ 7.0% at 24, 36, 48 and 64 weeks; or  
b. reinitiation of glucose-lowering drugs; or  


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c. capillary glucose values ≥ 10 mmol/L on ≥50% of SMBG readings over 1 week in 
the absence of an acute illness. 
 
All participants identified to have hyperglycemia relapse will receive standard glycemic 
management according to the judgment of their physician or investigator. Participants found 
to have HbA1C ≥7.3% on therapy during week 12 of the trial will also receive standard 
glycemic management. These participants will continue to be contacted by telephone every 1-
2 months to review SMBG readings, medication adherence and side effects.  
 
5.4 
Methodological considerations 
5.4.1 
Planned recruitment 
A total of 152 participants will be enrolled in this trial. Participants will be recruited at 
approximately 7 Canadian sites. Based on our experience in the pilot trial, we anticipate an 
average recruitment rate of 2 participants per month at each site. Total trial duration is 
estimated to be 2.5 years based on a 3-month start-up period, 12-month recruitment period and 
15-month follow-up period. If recruitment rates fall behind schedule, we will expand the trial 
to additional sites. The trial will be coordinated through the Population Health Research 
Institute which has an extensive experience in conducting multicentre randomized controlled 
trials (RCT) and offers a large pool of experienced research personnel. 
 
5.4.2 
Treatment adherence 
Adherence to intensive lifestyle and glucose-lowering therapy for participants in the 
intervention group will be encouraged during frequent clinic visits and telephone follow-ups. 
It will also be promoted by prompt attention to any side effects of the medications and the 
short, 12-week duration of the intervention period.  
 
Medication adherence will be measured by inspecting medications at each study visit. 
Additionally, two six-point glucose profiles will be collected during the 6th and 12th week after 
randomization. Each six-point glucose profile will include pre-meal and 2-hour post-meal 
SMBG measurements taken on the same day. Adherence to lifestyle advice in both treatment 
groups will be measured by a physical activity questionnaire and food frequency 
questionnaires administered at baseline, 12, 24, 36, 48 and 64 weeks after randomization. 
Anthropometric measurements at study visits will also reflect adherence to the lifestyle 
intervention. 
 
5.4.3 
Losses to follow-up 
Losses to follow-up are expected to be minimal as the study duration is only 64 weeks. The 
investigators will make every effort to contact participants who are lost to follow-up. In order 
to minimize losses to follow-up, participants who do not adhere to the assigned treatment or 
visit schedule will be encouraged to do HbA1C measurements through their regular diabetes 
care provider and will be contacted by telephone to collect key data. Participants who 
withdraw consent will be asked to return any study drugs to the study centre and encouraged 
to return to their regular diabetes care provider for assessment and further care.  


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5.4.4 
Confidentiality and record retention 
Personal information of study participants will be kept in strict confidence. Participants’ 
names will be removed from the data and replaced with identification numbers. The study 
investigator will keep a participant identification list (identification numbers with the 
corresponding participants names) in a secure location. Study data will be stored on a 
computer at the Population Health Research Institute in accordance with local data protection 
laws. The health records related to this study will be kept by each site for up to 25 years after 
the end of the trial. 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
Study variables will be collected at enrollment and during follow-up according to the visit 
schedule (See Table 1 in Appendix A). Study data will be recorded on data collection forms 
and transmitted to the Population Health Research Institute (PHRI).  
 
6.2 
Study outcomes 
6.2.1 
Primary and secondary outcomes 
The primary outcome is drug-free diabetes remission, defined as a HbA1C<6.5% without use 
of glucose-lowering agents for at least 12 weeks. Related outcomes to be analyzed include 
complete diabetes remission, defined as a HbA1C<6.0% without use of glucose-lowering 
agents for at least 12 weeks, and diabetes regression, defined as a HbA1C of 6.5-6.9% without 
use of glucose-lowering agents for at least 12 weeks. 
 
HbA1C will be measured in the local labs at 12, 24, 36, 48 and 64 weeks after randomization, 
during which use of glucose-lowering medications will also be ascertained. FPG will also be 
measured in the local lab at 16 weeks. All FPG levels will be measured approximately 48 
hours after the last dose of any glucose-lowering medication unless fasting capillary glucose 
rises above 12 mmol/L.  
 
6.2.2 
Other outcomes 
Symptomatic and severe hypoglycemic episodes will be measured in both treatment groups. 
Anthropometric measures including height (at the screening visit only), body weight, waist 
and hip circumference will be measured in all participants (see schedule in Appendix A Table 
1). Body mass index will be reported in kg/m2. Waist circumference will be measured around 
the exposed abdomen at the level of the top of the iliac crest at the end of a normal expiration. 
Hip circumference will be measured as the maximal circumference over the buttocks over 
light clothing.   
 


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In addition, 2 six-point glucose profiles will be collected during the 6th and 12th week after 
randomization. Each six-point glucose profile will include pre-meal and 2-hour post-meal 
readings taken on the same day. To standardize this measure, all participants will be provided 
with identical glucometers which will be calibrated regularly. Mean fasting and post-meal 
glucose values will be calculated for each participant from the two glucose profiles.  
 
6.2.3 
Stored blood 
In addition to obtaining fasting serum samples at baseline, fasting serum samples will also be 
taken for storage at 16 weeks in participants who agree to it. They will be shipped and stored 
centrally. Genetic markers and analytes related to diabetes remission may be measured after 
the trial has finished.  
 
6.3 
Safety 
6.3.1 
Safety variables 
Information on the following prespecified safety outcomes will be prospectively collected in 
all study participants during the trial: 
 
1) Death (and cause of death as determined by a physician); 
2) Non-fatal myocardial infarction or angina resulting in hospitalization or emergency room 
admission; 
3) Non-fatal stroke or transient ischemic attack diagnosed by a physician; 
4) Heart failure resulting in hospitalization or emergency room admission; 
5) Resuscitated cardiac arrest or life-threatening arrhythmia (including documented or 
presumed ventricular fibrillation, sustained ventricular tachycardia, asystole, or pulseless 
electrical activity); 
6) Cardiogenic shock diagnosed by a physician; 
7) Diabetic ketoacidosis or hyperglycemic hyperosmolar state diagnosed by a physician; 
8) Documented new fractures; 
9) Newly diagnosed cancers; 
10) Genitourinary infections diagnosed by a physician;  
11) Moderate (eGFR 30-60 mL/min/1.73 m2 by MDRD formula) or severe (eGFR<30 
mL/min/1.73 m2) renal dysfunction; 
12) Symptomatic and severe hypoglycemic events (see below for definitions); 
13) Hospital or emergency room admissions (and reasons for admission). 
 
Participants will be asked to record all hypoglycemic episodes and symptoms in a diary that 
will be provided to them. Moreover, they will be explicitly asked about any episodes of 
symptomatic or severe hypoglycemia during every visit and telephone follow-up. 
Symptomatic hypoglycemia is defined as an event with clinical symptoms consistent with 
hypoglycemia, based on data recorded in the participant’s diary. These will be further 
categorized as confirmed (i.e. with a concomitant home glucose reading ≤ 3.0 mmol/L) or 
unconfirmed. Symptomatic hypoglycemic events and those that result in alteration of any of 
the study drugs will be recorded.  
 


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Severe hypoglycemia 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. Any episode of 
severe hypoglycemia will be recorded and reviewed within one working day. 
 
All safety variables will be recorded on case report forms and supporting documentation will 
be obtained. Information on adverse events and pregnancies will be collected as described in 
Sections 6.3.2-6.3.5. The investigators will review safety data for this open trial monthly and 
more formally after the first 50 patients have completed the trial to determine if any 
modifications to the protocol are indicated.  
 
6.3.2 
Definitions of adverse events 
6.3.2.1 
Adverse events 
An adverse event is any untoward medical occurrence that occurs in a person during the 
period of observation in a clinical study. It does not necessarily have to have a causal 
relationship with any treatment administered as part of that study. An adverse event can 
therefore be any unfavorable and unintended sign, symptom or disease, whether or not it is 
considered related to any medicinal product being taken at the time the event occurs.  
 
6.3.2.2 
Serious adverse events (SAEs) 
A serious adverse event is one that at any dose (including overdose): 
1) results in death; 
2) is life-threatening (i.e. participant was at immediate risk of death at the time of the 
serious adverse event; it does not refer to an adverse event that hypothetically might 
have caused death if it were more severe); 
3) requires inpatient hospitalization or prolongation of existing hospitalization; 
4) results in persistent or significant disability or incapacity (i.e. there is a substantial 
disruption of a person’s ability to carry out normal life functions); 
5) causes a congenital anomaly or birth defect; 
6) is an important medical event (Important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant 
or may require intervention to prevent one of the other outcomes listed in the 
definition above will be also considered serious. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in participant hospitalization, or the 
development of drug dependency or drug abuse. A diagnosis of cancer during the 
course of a treatment will also be considered as medically important.)  
 
6.3.2.3 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe headache). The event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious”, which is 


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based on the outcome or action criteria usually associated with events that pose a threat to life 
or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
 
6.3.3 
Documentation and reporting of adverse events, pregnancies and overdoses 
6.3.3.1 
Documentation and reporting of non-serious adverse events 
Any adverse event resulting in a change in dose (including temporary withholding) of any of 
the study medications (insulin glargine, metformin and Forxiga) will be documented on case 
report forms. Examples of such events could include gastrointestinal complaints or 
genitourinary infections. All changes in the medication dose will be recorded. 
 
6.3.3.2 
Documentation and reporting of serious adverse events (SAEs) 
Whenever an investigator judges an event to be an SAE, he/she will complete an SAE case 
report form within one working day and will notify the PHRI Project Office as well as local 
REB as per REB requirements. All SAEs will be reported by the PHRI to AstraZeneca (± 
Health Canada). If the event meets criteria of (i) serious and (ii) related to insulin glargine, 
metformin or Forxiga and (iii) unexpected, it will be subject to expedited reporting to 
AstraZeneca (± Health Canada).  
 
Every attempt will be made to describe an adverse event in terms of a single diagnosis. If a 
clear diagnosis has been made, individual signs and symptoms will not be recorded. If a clear 
diagnosis cannot be established, each sign and symptom will be recorded individually. It 
should be noted that conditions necessitating surgical procedures may be considered adverse 
events if they satisfy the definitions above. The surgical procedure in question should be 
regarded as a therapeutic intervention rather than as an adverse event. 
 
All participants who are deemed to have had a serious adverse event will be followed to 
determine the outcome. The clinical course of the adverse event will be followed up according 
to accepted standards of medical practice, even after the end of the study, until a satisfactory 
explanation is found or the investigator considers it medically justifiable to terminate follow-
up.  
 
6.3.4 
Documentation and reporting of pregnancies and overdoses 
6.3.4.1 
Pregnancies 
Information on any pregnancies occurring during the study will be collected on specific forms 
and pregnancies will be followed to term. Any confirmed pregnancy will be reported within 1 
working day of knowledge of the event, and study drugs will be stopped in concurrence with 
provision of follow-up medical care. Follow-up forms documenting the pregnancy outcome 
will also be completed. 
 
6.3.4.2 
Overdoses 
Cases in which a “significant overdose” in the judgment of the investigator (for example, an 
overdose leading to severe hypoglycemia) of the study drug (insulin glargine, metformin or 


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Forxiga) was taken (regardless of whether or not any serious adverse event occurred) will also 
be reported on specific case report forms within 1 working day of knowledge of the event. 
 
6.3.5 
Period of observation 
For the purposes of this study, the period of observation for collection of adverse events, 
SAEs, overdoses and any pregnancies extends from the time the participant gives informed 
consent until the end of the study. 
7. 
BIOLOGICAL SAMPLING PROCEDURES 
All bloods done locally will be collected according to local sampling procedures. Procedures 
for collection, shipment and storage of blood samples for future biochemical and genetic 
analyses (collected at baseline and at 16 weeks after randomization) will be detailed in the 
study lab manual. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
The study will be conducted according to Good Clinical Practice Guidelines. Health Canada 
will be approached for the need to get Health Canada approval for this study. Investigators at 
each site will obtain approval of the protocol, informed consent form, advertisement and 
patient materials from local Research Ethics Boards prior to participant recruitment. Any 
changes to the protocol and informed consent form will need to be approved by local Research 
Ethics Boards (± Health Canada).  
9. 
STUDY MANAGEMENT 
Dr. Natalia McInnes (née Yakubovich) and Dr. Hertzel Gerstein will oversee execution of this 
multicentre trial which will be coordinated through the Population Health Research Institute. 
Dr. McInnes is an endocrinologist and Assistant Professor at McMaster University with an 
MSc in Health Research Methodology. She oversaw implementation of the REMIT pilot trial 
with guidance from Dr. Gerstein. Dr. Gerstein is an endocrinologist, epidemiologist and 
clinical trialist who has led many international trials related to diabetes prevention and 
treatment including DREAM, HOPE, ACCORD and ORIGIN. Each participating site will be 
led by a site PI and coordinated by local research staff.  
 
A central research coordinator, biometric programmer and a statistician will assist with study 
implementation. Recruitment, protocol implementation and data collection will be monitored 
centrally by reviewing collected data in a blind manner. 
 


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10. 
DATA MANAGEMENT 
Data management procedures will be outlined in the data management plan. 
 
11. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
11.1 
Proposed sample size and justification  
The sample size calculation is based on the estimated proportion of patients achieving diabetes 
remission of 10% in the control group.  The control group estimate of 10% is based on the 
proportion of patients in the conventional diabetes treatment group of 13% who achieved FPG 
< 7.0 mmol/L and HbA1C < 6.2% off therapy after 2 years of follow-up observed in the 
Dixon et al. trial, after adjusting for the longer duration of diabetes since diagnosis in 
participants in our trial (≤ 8 years versus < 2 years). A total sample size of 152 participants (76 
per treatment group) will provide 80% power to show a risk difference of ≥20% in the 
induction of diabetes remission between treatment groups and 90% power to show a risk 
difference of ≥23%.   
11.2 
Statistical analyses 
All group comparisons will be conducted according to the intention-to-treat principle with 
inclusion of data from all participants according to their treatment group assignment, 
regardless of adherence to therapy. The primary outcome in this study is the proportion of 
patients in the intervention group who achieve drug-free diabetes remission 24 weeks after 
randomization compared to the control group. The treatment groups will be compared using a 
chi-squared test with α = 0.05 level of significance. The outcome will be reported as a risk 
difference in the induction of remission between the intervention group and the control group 
with 95% confidence interval. Any individual who withdraws/drops out prior to the 24, 36, 48 
and 64 week visit will be classified as not having achieved drug-free diabetes remission at that 
point in time. Participants who fail to achieve remission or have hyperglycemia relapse will be 
censored with respect to diabetes remission outcomes. 
 
 
For secondary analyses, a chi-squared test will be used for dichotomous outcomes and a two-
sample t-test (or a non-parametric equivalent) for continuous outcomes. Secondary outcomes 
will be used only for generation of new hypotheses. Clinical and metabolic predictors of the 
successful induction of diabetes remission will be evaluated using logistic regression 
modeling. We do not plan to perform any interim analyses in this trial. 
 
12. 
SIGNIFICANCE 
This trial builds on our ongoing pilot trial and other trials to identify a menu of metabolic 
remission strategies that can then be refined and tailored to individual needs based on future 


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research. Such an approach represents a fresh innovative approach that could turn the therapy 
of type 2 diabetes from a lifelong burden of drugs to either one-time or intermittent remission-
induction courses that may translate into better overall quality of life and health-related 
outcomes.


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13. 
APPENDIX A 
Table 1.  Schedule of visits and assessments in the intervention group (I), control group (C), and both groups (X). 
 
 
Weeks after randomization 
-1 
0 
0.5 
1 
1.5 
2 
2.5 
3 
3.5 
4 
4.5 
5 
5.5 
6 
7 
8 
9 
10 
11 
12 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start study medications 
 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stop diabetes medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinic visit 
X 
X 
 
I 
 
I 
 
I 
 
I 
 
I 
 
X 
 
I 
 
I 
 
X 
Telephone follow-up 
 
 
I 
 
I 
 
I 
 
I 
 
I 
 
I 
 
I 
 
I 
 
I 
 
Adherence to medications and side effects 
 
 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
X 
I 
I 
I 
I 
I 
X 
Review SMBGs 
 
 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
X 
I 
I 
I 
I 
I 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
 
 
 
 
 
I 
 
 
 
 
 
X 
 
I 
 
I 
 
X 
Waist and Hip Circumference 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Blood pressure 
X 
X 
 
I 
 
I 
 
I 
 
I 
 
I 
 
X 
 
I 
 
I 
 
X 
Physical activity and food frequency questionnaires* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting serum for storage** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum ALT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum creatinine 
X 
 
 
 
 
I 
 
 
 
 
 
 
 
I 
 
 
 
I 
 
 
Urine BhCG*** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Two glucose profiles**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Return to standard glycemic care if hyperglycemia 
relapse identified 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE Review and Reporting  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*A quality of life questionnaire will also be administered at -1, 12 and 64 weeks. 
**Fasting serum sample will be taken for storage during the screening visit and at 16 weeks.  
***Urine BhCG will be measured in women with childbearing potential. 
**** Two six-point glucose profiles will be collected on separate days. Each six-point glucose profile will include pre-meal and 2-hour post-meal SMBG 
readings taken on the same day.  


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Weeks after randomization 
12.5 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
Eligibility criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start study medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stop diabetes medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic visit 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Telephone follow-up 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
Adherence to medications and side effects 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review SMBGs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Waist and Hip Circumference 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Blood pressure 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Physical activity and food frequency questionnaires* 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting serum for storage** 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FPG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum ALT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum creatinine 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine BhCG*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1C 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Two glucose profiles**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return to standard glycemic care if hyperglycemia relapse identified 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Review and Reporting  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*A quality of life questionnaire will also be administered at -1, 12 and 64 weeks. 
**Fasting serum sample will be taken for storage during the screening visit and at 16 weeks.  
***Urine BhCG will be measured in women with childbearing potential. 
**** Two six-point glucose profiles will be collected on separate days. Each six-point glucose profile will include pre-meal and 2-hour post-meal SMBG 
readings taken on the same day.