Conditions: Type 2 Diabetes Mellitus
Keywords: Diabetes Insulin Glargine Metformin Sitagliptin Diet Excercise Lifestyle
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
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 of sitagliptin, 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 100 patients with recently-diagnosed T2DM. Participants will be randomized to 2 treatment groups: (a) a 12-week course of treatment with sitagliptin, metformin, insulin glargine and lifestyle therapy, or (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 meet criteria for hyperglycemic 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: sitagliptin/metformin - oral administration Behavioral: lifestyle therapy arm 2: Standard glycemic care as informed by the current clinical practice guidelines

Interventions: intervention 1: insulin glargine intervention 2: sitagliptin/metformin intervention 3: lifestyle therapy
Intervention descriptions: intervention 1: Dose is titrated to achieve fasting normoglycemia intervention 2: Dose is titrated to 50/1000 mg bid or maximal tolerated dose intervention 3: Lifestyle intervention includes individualized dietary and exercise advice and frequent visits for goal reinforcement, behavior modification and problem-solving

Protocol document:
Prot_000.pdf: 
 
 
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PROTOCOL 
 
 
 
 
REMIT SITA Trial  
 
An open-label, randomized, parallel design trial to compare  
the efficacy of a sitagliptin-based metabolic intervention  
versus standard diabetes therapy in inducing remission  
of type 2 diabetes. 
 
 
 
 
 
 
 
 
 
 
 
 
December 16, 2015 
 
 
 
 
NCT02623998 
 
 
 
 
 
 
 
 
 


 
 
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REMIT SITA Trial 
 
An open-label, randomized, parallel design trial to compare the efficacy of a 
sitagliptin-based metabolic intervention versus standard diabetes therapy in 
inducing remission of type 2 diabetes. 
 
 
1.0 Hypothesis 
 
In patients with recently-diagnosed T2DM, a 12-week course of sitagliptin, metformin, basal 
insulin glargine and lifestyle approaches will achieve drug-free diabetes remission in a higher 
proportion of patients than standard diabetes therapy at 24 weeks (3 months after the drugs are 
stopped).   
 
 
2.0 Objectives 
 
2.1 Primary: To determine whether the 12-week metabolic intervention with sitagliptin 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: To determine whether the 12-week metabolic intervention with sitagliptin is 
more effective in achieving drug-free diabetes remission than standard diabetes therapy when 
evaluated at 36 weeks and at 64 weeks 
 
2.3 Safety: To determine the rates of severe hypoglycemic episodes in the two treatment groups 
during 64 weeks of follow-up 
 
 
3.0 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 studies1-7 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 highlight the need to characterize strategies 
for metabolic remission of diabetes and to identify the optimal therapies and regimens for 
achieving remission.   
 
We recently finished a peer-reviewed pilot trial of this approach in one centre. People with 
T2DM diagnosed within the prior 3 years were randomized to 3 treatment groups: a) 8-week 
intensive metabolic intervention; b) 16-week intensive metabolic intervention; and c) standard 


 
 
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diabetes therapy.  The intensive metabolic intervention combined lifestyle therapy with basal 
insulin glargine, metformin and acarbose and aimed at achieving normoglycemia on therapy. The 
trial (funded by the Canadian Diabetes Association, Population Health Research Institute and 
local donations) randomized 83 people. The mean (standard deviation) fasting and 2-hour 
capillary glucose levels while on the metabolic intervention were: a) 5.2 (0.5) and 6.2 (0.8) 
mmol/L respectively at 8 weeks; and 4.9 (0.5) and 6.0 (0.7) mmol/L respectively at 16 weeks. As 
follow-up is ongoing, the data cannot yet be analyzed by treatment group. However when the 
treatment and control groups were analyzed together, 28 of 80 participants (35%) who reached 
21 weeks of follow-up achieved a diabetes remission defined as a fasting plasma glucose <7.0 
mmol/L and a 2-hour plasma glucose <11.1 mmol/L on an oral glucose tolerance test (OGTT) 
conducted 4-12 weeks after stopping glucose-lowering medications. These short-term data 
illustrate that metabolic interventions such as the one proposed herein can be successfully 
implemented and have the potential to induce a diabetes remission not requiring glucose-
lowering therapies.  
 
The current multicentre randomized controlled trial will assess the remission-related efficacy of 
an incretin-based regimen in a broader set of patients. It builds on the 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 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. 
 
 
4.0 Design and Participants 
 
This is a multicentre, open-label, randomized controlled trial in 100 patients with early T2DM. 
The trial will have the following inclusion and exclusion criteria:   
 
4.1 Inclusion criteria  
a) men and women 30-80 years of age inclusive; 
b) type 2 diabetes mellitus diagnosed by a physician within 5 years prior to patient enrollment; 
c) anti-diabetic drug regimen (either drug or dose of drug) unchanged during 8 weeks prior to 
screening and randomization;   
d) HbA1C ≤ 9.5% on no hypoglycemic agents or HbA1C ≤ 8.0% on 1 agent or on half-maximal 
doses of 2 agents; 
e) body mass index ≥ 23 kg/m2; 
f) a negative pregnancy test and an agreement to use a reliable method of birth control for the 
duration of the trial in all females with childbearing potential;  
g) ability and willingness to perform self-monitoring of capillary blood glucose (SMBG); 
ability and willingness to self-inject insulin;  
h) provision of informed consent. 
 
 
 


 
 
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4.2 Exclusion criteria  
a) current use of insulin; 
b) history of hypoglycemia unawareness; history of severe hypoglycemia requiring assistance 
within the last 5 years; 
c) renal dysfunction as evidenced by serum creatinine (Cr) ≥ 124 μmol/l;  
d) history of lactic acidosis or diabetic ketoacidosis; 
e) active liver disease or elevated alanine transferase (ALT) levels ≥ 2.5 times upper limit of 
normal at the time of enrollment; 
f) history of pancreatitis; 
g) cardiovascular disease including any of: a) systolic blood pressure > 180 mmHg or diastolic 
blood pressure > 105 mmHg; b) peripheral vascular disease; c) left bundle branch block or 
second or third degree AV block; d) tachyarrhythmias or bradyarrhythmias with uncontrolled 
ventricular rate; e) stenotic valvular heart disease; f) cardiomyopathy; g) history of heart 
failure; h) history of aortic dissection; i) documented history of angina or coronary artery 
disease; j) history of stroke or transient ischemic attack;  
h) history of any disease requiring continuous systemic glucocorticoid treatment;  
i) history of any major illness with a life expectancy of < 3 years; 
j) history of injury or any other condition that significantly limits participant's ability to achieve 
moderate levels of physical activity; 
k) excessive alcohol consumption (>14 alcoholic drinks per week in men and >7 alcoholic 
drinks per week in women); 
l) known hypersensitivity to insulin glargine, metformin, or any DPP-4 inhibitor. 
 
Participants will be randomized to 2 treatment groups: (a) a 12-week course of treatment with 
sitagliptin, 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%, glucose-lowering medications will be discontinued at 12 weeks, and participants 
will be encouraged to continue with lifestyle modifications and regular glucose monitoring.  
Participants who meet criteria for hyperglycemia relapse will receive standard glycemic 
management as informed by the 2013 Canadian Diabetes Association clinical practice 
guidelines8. Participants found to have HbA1C ≥7.3% during week 12 of the trial will also 
receive standard glycemic care. 
 
The primary outcome in this trial will be diabetes remission evaluated at 24 weeks.  Diabetes 
remission is defined as a HbA1C<6.5% off glucose-lowering agents for at least 12 weeks (3 
months).  The primary safety outcome will be the rate of severe hypoglycemic episodes in the 
treatment groups during 64 weeks of follow-up.  Key secondary outcomes will be diabetes 
remission at 36 and 64 weeks (6 and 12 months after stopping glucose-lowering medications).   
 
 
5.0 Procedures 
 
5.1 Screening and Randomization 
After obtaining informed consent at the screening visit, eligibility criteria will be assessed by 
performing an interview, physical examination, laboratory tests and electrocardiogram (ECG) at 
a local research centre. Blood will be drawn for creatinine, ALT, FPG, and HbA1C. A urine 
pregnancy test will be performed in women with childbearing potential. A baseline 


 
 
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electrocardiogram (ECG) will be also performed to assess for any evidence of ischemic heart 
disease or arrhythmia. Fasting blood samples will be collected for storage in participants who 
consent to it (see Section 5.5 and Table 1 for details). Eligible participants will be randomized to 
(i) 12-week intensive treatment with lifestyle, insulin glargine, metformin and sitagliptin and (ii) 
standard diabetes therapy. A randomization schedule will be prepared by an independent 
statistician using a computer-generated random number sequence and it will be stratified by 
centre. Study group allocation will be carried out through an online central system.  
 
5.2. Interventions  
Participants will be randomly allocated to either a sitagliptin-based metabolic intervention 
(comprising an induction phase followed by a maintenance phase), or standard diabetes care.  
 
5.2.1 Sitagliptin-based Metabolic Intervention Group: Induction Phase   
A 12-week metabolic intervention will be used in intervention group participants for induction of 
a normoglycemic state. The intervention will include treatment with basal insulin glargine, 
metformin, lifestyle changes and sitagliptin. The overall goals of the 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 36 of the trial.  At baseline, intervention group participants 
will meet with research staff who will prescribe a personalized low-calorie low-fat diet and a 
moderate-intensity exercise program based on current physical activity patterns and medical 
history.  Lifestyle goals will be reinforced at each study visit. Glucose-lowering agents will be 
titrated gradually to minimize side effects. Sitagliptin/metformin will be started at a dose of 
50/500 mg po (orally) once daily (OD) for 4 days, then increased to 50/500 mg twice daily (bid) 
for 4 days, then 50/850 mg bid for 4 days, then 50/1,000 mg po bid.  Participants will be 
concurrently started on insulin glargine 2 units sc 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). 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 metabolic intervention. All other glucose-lowering 
medications will be discontinued.  
 
At the first study visit, participants will be taught how to self-monitor capillary blood glucose, 
how to recognize and treat hypoglycemia, and how to administer and titrate study medications.  
Participants will be asked to monitor glucose at least twice daily before meals and during 
exercise.  
 
5.2.2 Sitagliptin-based Metabolic Intervention Group: Maintenance Phase with Lifestyle 
Therapy  
Oral glucose-lowering agents will be discontinued after 12 weeks and insulin tapered over a 5-
day period in participants with HbA1C<7.3%.  Participants will be encouraged to continue with 
lifestyle modifications.  Participants will be asked to monitor fasting glucose at least 3 times per 
week and call research staff if they have fasting levels >10 mmol/L.  Participants who have 
fasting glucose levels >10 mmol/L on ≥50% of SMBG readings over 1 week in the absence of an 
acute illness will be considered to have hyperglycemia relapse.  Otherwise, hyperglycemia 
relapse will be defined as (a) a fasting plasma glucose ≥ 7.0 mmol/L or a 2-hour pc plasma 
glucose (PG) ≥ 11.1 mmol/L on the OGTT, or (b) HbA1C ≥ 6.5%.  Participants meeting criteria 


 
 
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for hyperglycemia relapse and all intervention group participants at 64 weeks will return to 
standard glycemic care, which will be provided by participants' regular physician. 
 
5.2.3 Control group  
At the beginning of the trial, a research nurse will meet with standard group participants to 
review self-monitoring of blood glucose, management of hypoglycemia, and the importance of 
healthy diet and regular exercise in diabetes management. Glucose levels in standard group 
participants will be managed by their regular health care provider according to the 2013 CDA 
clinical practice guidelines.  Any approved glucose-lowering medications will be allowed in the 
control group, including biguanides, DPP-4 inhibitors, GLP-1 receptor agonists and insulin. In 
control group participants with HbA1C<7.3%, glucose-lowering agents will be discontinued 
after 12 weeks and insulin will be tapered over a 5-day period.  Participants will be asked to 
monitor fasting glucose at least 3 times per week and call research staff if they have fasting 
levels >10 mmol/L.  Participants meeting criteria for hyperglycemic relapse (see section 5.2.2 for 
definitions) and all participants at 64 weeks will return to standard glycemic care.   
 
5.3 Monitoring 
Research staff will meet with intervention group participants every 1-2 weeks during week 1-12 
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 visit schedule). 
Participants will then be contacted once a month to review glucose readings and screen for 
symptoms of hyperglycemia. Control group participants will be contacted every 1-1.5 months 
during the trial to review glucose readings, medication adherence and side effects. Symptomatic 
and severe hypoglycemic episodes will be documented and reviewed with the treating physician 
promptly. Symptomatic hypoglycemic episode will be defined as an event with clinical symptoms 
consistent with hypoglycemia.  Severe hypoglycemic episode will be defined as an event with 
clinical symptoms consistent with hypoglycemia requiring the assistance of another person to 
treat which is accompanied by either (i) a self-measured or laboratory glucose level of ≤ 2.0 
mmol/L or (ii) a prompt recovery following treatment with carbohydrates or glucagon.  All 
participants will be asked to come back for a final clinic visit at 64 weeks after randomization.   
 
5.4 Duration of Follow-up 
In order to complete recruitment in 12 months, participants will be recruited at 5 Canadian sites.  
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. 
 
5.5 Measurements and Study Outcomes  
HbA1C will be measured locally at baseline and 12, 24, 36, 48 and 64 weeks after randomization 
by a National Glycohemoglobin Standardization Program certified method. Fasting plasma 
glucose will be performed at baseline and at 16 weeks. Standard 75 g OGTT will be performed at 
24 weeks after randomization and participants on glucose-lowering medications will be asked to 
hold them for 48 hours prior to the test unless fasting capillary glucose rises above 12 mmol/l. 
The OGTT will be performed in the morning, after overnight fasting. Blood samples for glucose 
will be drawn at 0 minutes and 120 minutes after administration of the 75 g oral glucose load. 
Fasting blood samples will be collected for storage at baseline and at 16 weeks in participants 
who consent to it.  Genetic markers and analytes related to diabetes remission and/or diabetes 
complications will be measured in the stored samples.  Participants will be asked to hold 


 
 
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glucose-lowering medications for 48 hours prior to these tests unless fasting capillary glucose 
rises above 12 mmol/l.  Physical activity and food frequency questionnaires will be administered 
at baseline and at 12, 24, 36, 48 and 64 weeks.  A quality of life questionnaire will also be 
administered at baseline, 12 and 64 weeks. 
 
5.5.1 Primary Outcomes 
a) The primary outcome in this trial is diabetes remission evaluated at 24 weeks after 
randomization.  Diabetes remission is defined as a HbA1C<6.5% off glucose-lowering 
agents for at least 12 weeks (3 months).  
b) The primary safety outcome will be the rate of severe hypoglycemic episodes during 64 
weeks of follow-up.  
 
5.5.2 Secondary Outcomes  
a) Diabetes remission off glucose-lowering therapy at 36 and 64 weeks after randomization. 
b) Drug-free normal glucose tolerance (NGT) at 24 weeks after randomization. NGT is defined 
as a FPG < 6.1 mmol/l and a 2-hour PG < 7.8 mmol/l on a 75 g OGTT. 
c) Duration of diabetes remission in weeks. 
d) The change in weight, BMI, waist circumference and waist to hip ratio from baseline to 12, 
24, 36 and 64 weeks after randomization.  
 
 
6.0 Statistical Analyses  
 
A detailed statistical analysis plan will be prepared by investigators and analyses will be 
performed by a trained statistician at the Population Health Research Institute.   
 
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 diabetes remission off therapy 24 
weeks after randomization.  Proportion of participants in remission will be compared between 
the intervention group and the control group using a one-sided chi-squared test with α = 0.05 
level of significance. The outcome will be reported as a risk difference in the induction of 
diabetes remission between the intervention group and the control group with 95% confidence 
intervals. 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. Clinical and 
metabolic predictors of the successful induction of diabetes remission at 24, 36 and 64 weeks 
after randomization will be evaluated using logistic regression modeling.  We will evaluate 
whether age, gender, ethnicity, diabetes duration, smoking, family history of diabetes, baseline 
BMI, waist circumference, HbA1C or fasting plasma glucose predict those participants who 
maintain diabetes remission at 24, 36 and 64 weeks after randomization.  
 
 
7.0 Sample Size Considerations 
 
The sample size calculation is based on the estimated proportion of patients achieving diabetes 
remission of p = 0.10 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 < 


 
 
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7.0 mmol/l and HbA1C < 6.2% off therapy after 2 years of follow-up observed in the Dixon et 
al9 trial, after adjusting for the longer duration of diabetes since diagnosis in participants in our 
trial (≤ 5 years versus < 2 years). Assuming a 10% remission rate in controls, a type 1 error of 
5% and a one-sided test, a total sample size of 100 participants (50 per treatment group) is 
estimated to provide 80% power to show an absolute risk increase of >29% in the induction of 
diabetes remission between treatment groups (effect size > 2.9) and 90% power to show an 
absolute risk difference of >34% (effect size > 3.4).   
 
 
 
8.0 Drug Supply 
 
The following supply of sitagliptin/metformin will be provided for each patient: 
Sitagliptin/metformin 50/500 mg po OD for 4 days, then 50/500 mg po bid for 4 days, then 
50/850 mg po bid for 4 days, then 50/1,000 mg po bid for 72 days. Insulin glargine will be 
purchased and dispensed through local pharmacies. 
 
 
9.0 Adverse Events 
 
Information on the following clinical events will be collected in all study participants during the 
trial: 
a) Death (and cause of death as determined by a physician); 
b) Non-fatal coronary disease events (non-fatal myocardial infarction or angina resulting in 
hospitalization or emergency room admission); 
c) Non-fatal cerebrovascular disease events (non-fatal stroke or transient ischemic attack 
diagnosed by a physician); 
d) Heart failure resulting in hospitalization or emergency room admission; 
e) Resuscitated cardiac arrest or life-threatening arrhythmia (including documented or 
presumed ventricular fibrillation, sustained ventricular tachycardia, asystole, or pulseless 
electrical activity); 
f) Cardiogenic shock diagnosed by a physician; 
g) Diabetic ketoacidosis or hyperglycemic hyperosmolar state diagnosed by a physician; 
h) Documented new fractures; 
i) Symptomatic and severe hypoglycemic events; 
j) Hospital admissions or emergency room visits (and reasons for admissions/visits). 
 
Participants will be monitored for adverse events and overdoses from the time of randomization 
until the end of follow-up.  Only those serious adverse events that investigators believe to be 
related to the study drugs will be recorded as serious adverse events.  For non-serious adverse 
events, only those adverse events resulting in a change in dose (including temporary 
withholding) of any of the study medications (insulin glargine, metformin and sitagliptin) will be 
documented on case report forms.   
 
 
10.0 References 
 


 
 
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 1.  Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E. Induction of long-term glycemic 
control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. 
Diabetes Care 1997;20(9):1353-1356. 
 2.  Banerji MA, Chaiken RL, Lebovitz HE. Long-term normoglycemic remission in black 
newly diagnosed NIDDM subjects. Diabetes 1996;45(3):337-341. 
 3.  Li Y, Xu W, Liao Z et al. Induction of long-term glycemic control in newly diagnosed type 
2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care 
2004;27(11):2597-2602. 
 4.  McFarlane SI, Chaiken RL, Hirsch S, Harrington P, Lebovitz HE, Banerji MA. Near-
normoglycaemic remission in African-Americans with Type 2 diabetes mellitus is 
associated with recovery of beta cell function. Diabet Med 2001;18(1):10-16. 
 5.  Park S, Choi SB. Induction of long-term normoglycemia without medication in Korean 
type 2 diabetes patients after continuous subcutaneous insulin infusion therapy. Diabetes 
Metab Res Rev 2003;19(2):124-130. 
 6.  Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 
2 diabetes. Diabetes Care 2004;27(5):1028-1032. 
 7.  Weng J, Li Y, Xu W et al. Effect of intensive insulin therapy on beta-cell function and 
glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre 
randomised parallel-group trial. Lancet 2008;371(9626):1753-1760. 
 8.  Canadian Diabetes Association Clinical Practice Guidelines.  2013. 
https://www.diabetes.ca/clinical-practice-education/clinical-practice-guidelines.  
Ref Type: Online Source 
 9.  Dixon JB, O'Brien PE, Playfair J et al. Adjustable gastric banding and conventional therapy 
for type 2 diabetes: a randomized controlled trial. JAMA 2008;299(3):316-323. 
 
 
 
 
 


 
 
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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 medication 
 
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 
 
Dietary advice 
 
X 
 
I 
 
 
 
 
I 
 
 
 
 
I 
 
 
 
I 
Physical activity advice 
 
X 
 
I 
 
 
 
 
I 
 
 
 
 
I 
 
 
 
I 
Diabetes education 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
Anthropometrics* 
X 
X 
I 
 
I 
 
I 
I 
X 
I 
 
I 
 
X 
Blood pressure 
X 
X 
 
 
 
 
 
 
I 
 
X 
I 
 
 
 
X 
Physical activity and food frequency questionnaires 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting serum for storage** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Cr and urine BhCG*** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Two glucose profiles**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Standard 75 g OGTT***** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return to standard glycemic care if hyperglycemia relapse 
identified 
 
 
 
 
 
 
 
 
 
 
 
BhCG - beta human chorionic gonadotrophin, FPG - fasting plasma glucose, OGTT - oral glucose tolerance test, SMBG - self-monitoring of capillary blood glucose. 
*Anthropometrics will include height and weight at screening visit, and weight, waist circumference, and hip circumference at subsequent visits. 
**Fasting serum sample will be taken for storage at baseline and at 16 weeks. Participants taking glucose-lowering medications will be asked to hold them for 48 hours prior to these tests unless fasting capillary 
glucose rises above 12 mmol/L. 
***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.  
*****Standard 75 g OGTT will be performed in the morning, after overnight fasting. Blood samples for glucose will be drawn at 0 minutes and 120 minutes after administration of the 75 g oral glucose load. The 
OGTT will be performed at 24 weeks after randomization.  Participants taking glucose-lowering medications will be asked to hold them for 48 hours prior to the test unless fasting glucose rises above 12 mmol/L. 


 
 
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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 medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stop diabetes medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic visit 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Telephone follow-up 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
Dietary advice 
 
I 
 
 
 
 
 
 
 
 
 
 
 
 
Physical activity advice 
 
I 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetes education 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
Anthropometrics* 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum Cr and urine BhCG*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1C 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Two glucose profiles**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard 75 g OGTT***** 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Return to standard glycemic care if hyperglycemia relapse identified 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BhCG - beta human chorionic gonadotrophin, FPG - fasting plasma glucose, OGTT - oral glucose tolerance test, SMBG - self-monitoring of capillary blood glucose. 
*Anthropometrics will include height and weight at screening visit, and weight, waist circumference, and hip circumference at subsequent visits. 
**Fasting serum sample will be taken for storage at baseline and at 16 weeks. Participants taking glucose-lowering medications will be asked to hold them for 48 hours prior to these tests unless fasting capillary 
glucose rises above 12 mmol/L. 
***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.  
*****Standard 75 g OGTT will be performed in the morning, after overnight fasting. Blood samples for glucose will be drawn at 0 minutes and 120 minutes after administration of the 75 g oral glucose load. The 
OGTT will be performed at 24 weeks after randomization.  Participants taking glucose-lowering medications will be asked to hold them for 48 hours prior to the test unless fasting glucose rises above 12 mmol/L. 
 

SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
REMIT-Sita 
 
An open-label, randomized, parallel design trial to compare the efficacy of a 
sitagliptin-based metabolic intervention versus standard diabetes therapy in 
inducing remission of type 2 diabetes 
 
 
 
 
NCT02623998 
 
 
 
 
 
Draft  Version 1.1 
Created on 2019-11-26 
 
 
 
 
 
 
Author(s): 
Natalia McInnes, REMIT-Sita, Study Principal Investigator 
Hertzel Gerstein, REMIT-Sita, Study Chair 
Yan Yun Liu, REMIT-Sita, Study Statistician 
 
 


TABLE OF CONTENTS  
LIST OF ABBREVIATIONS ............................................................................................. 3 
1. 
INTRODUCTION ...................................................................................................... 4 
2. 
STUDY OBJECTIVES ............................................................................................... 5 
3. 
POPULATIONS TO BE ANALYZED ...................................................................... 5 
4. 
BASELINE CHARACTERISTICS ............................................................................ 5 
5. 
ADHERENCE ............................................................................................................ 5 
Visit adherence................................................................................................................ 5 
Medication adherence ..................................................................................................... 6 
6. 
STUDY FOLLOW-UP TIME .................................................................................... 6 
7. 
EFFICACY ANALYSES ........................................................................................... 7 
Other Outcomes .............................................................................................................. 8 
8. 
SAFETY ANALYSIS ................................................................................................. 8 
 
 
 
 


LIST OF ABBREVIATIONS 
 
The following abbreviations and special terms are used  
 
 
Abbreviation or 
special term 
Explanation 
 
 
ALT  
BhCG  
bid  
BMI 
BP 
CDA  
CI 
Cr 
ECG 
eGFR 
FPG 
MDRD 
OD 
OGTT 
PA 
pc  
PHRI 
po 
RCT 
RR 
SAE  
sc 
SD 
SGLT2  
SMBG  
T2DM  
WHR 
 
alanine transferase 
beta human chorionic gonadotropin 
twice daily 
body mass index 
Blood Pressure 
Canadian Diabetes Association 
Confidence Interval 
creatinine  
electrocardiogram 
estimated glomerular filtration rate 
fasting plasma glucose 
The Modification of Diet in Renal Disease equation to estimate GFR 
once daily 
Oral Glucose Tolerance Test 
physical activity 
postcibum (postprandial) 
Population Health Research Institute 
taken orally 
randomized controlled trial 
relative risk 
serious adverse event 
taken subcutaneously 
Standard Deviation 
sodium glucose co-transporter 2 
self-monitoring of capillary blood glucose 
type 2 diabetes mellitus 
Waist Hip Ratio 
 
 
 
 
 
 


1. INTRODUCTION 
 
The statistical analysis plan (SAP) specifies the details of the statistical analysis of the 
REMIT-Sita trial described in the Clinical Study Protocol (version 2.0, dated 2015-12-
16).  The SAP is a working document that will be amended as new information becomes 
available.  Appendices may be updated as required during the course of the study. The 
final version of the SAP will be signed off prior to database lock. 
 
REMIT-Sita is a multicentre, open-label, randomized controlled trial in 102 patients with 
recently-diagnosed T2DM. Participants will be randomized to 2 treatment groups: (a) a 
12-week course of treatment with sitagliptin, 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%, glucose-lowering medications will 
be discontinued at 12 weeks, and participants will be encouraged to continue with 
lifestyle modifications and regular glucose monitoring.  Participants who meet criteria for 
hyperglycemia relapse will receive standard glycemic management as informed by the 
2013 Canadian Diabetes Association clinical practice guidelines.  
 
The primary outcome in this trial will be hyperglycemia relapse at or after the 12-week 
visit. The primary safety outcome will be the rate of severe hypoglycemic episodes 
during 64 weeks of follow-up. Key secondary outcomes will be diabetes remission at 24, 
36, 48 and 64 weeks and drug-free normal glucose tolerance at 24 weeks.   
 
Glycemic outcome definitions for this trial are summarized in the following table: 
 
Drug-free normal 
glucose tolerance 
 
Diabetes remission 
Hyperglycemia relapse 
FPG* <6.1 mmol/L 
AND 2-hour plasma 
glucose <7.8 mmol/L 
on OGTT† 
HbA1C <6.5% 
AND no diabetes 
drugs for ≥12 weeks 
AND no relapse 
HbA1C ≥6.5% OR 
FPG* ≥7.0 mmol/L OR 
2-hour postprandial plasma glucose 
≥11.1 mmol/L on OGTT† OR 
Use of diabetes drugs OR  
Capillary glucose ≥10 mmol/L on 
≥50% SMBGs‡ over 1 week 
 
*FPG – fasting plasma glucose 
†OGTT – 75 g oral glucose tolerance test at 24 weeks 
‡SMBG – self-monitoring of blood glucose 


2. STUDY OBJECTIVES 
Primary objective 
To determine whether the 12-week metabolic intervention that includes sitagliptin is 
more efficacious in achieving drug-free remission of type 2 diabetes than standard 
diabetes therapy over 1 year following the 12-week induction period.  
Secondary objective 
To determine whether the 12-week metabolic intervention that includes sitagliptin is 
more efficacious than standard diabetes therapy in achieving diabetes remission when 
evaluated at 24, 36, 48 and 64 weeks after randomization. 
Safety objective 
To determine the rates of severe hypoglycemic episodes in the treatment groups during 
64 weeks of follow-up. 
3. POPULATIONS TO BE ANALYZED  
 
All randomized participants will be included in the treatment groups to which they were 
randomized, regardless of treatments received or duration of trial participation (intention-
to-treat analysis). 
 
4. BASELINE CHARACTERISTICS 
 
Standard methods will be used to provide tabular and graphical summaries as appropriate 
for continuous and categorical variables. Summaries of continuous variables will include 
the number of subjects (N), mean, standard deviation, median, minimum and maximum. 
Frequency distributions (N and %) will be given for categorical data. 
Summary Tables of Baseline characteristics are in Appendix A. 
5. ADHERENCE 
Visit adherence 
Adherence to the visit schedule will be summarized by visit (after randomization) and 
treatment group as follows: 
• total number of participants enrolled in trial (N) 
• frequency and percentage of participants who have completed due visit (or 
provided information by phone or other means) 
• frequency and percentage of participants who have refused visit 
• frequency and percentage of participants who were unable to be contacted for 
visit 
• frequency and percentage of participants who died prior to due visit 


 
Note: participants who died prior to visit X will be excluded for the count of “due” visit 
at visit X+1 and onwards. 
 
Tables are in Appendix A 
Medication adherence 
Adherence with the study medications in the intervention group will be summarized by 
visit (randomization and follow-up), up until the end of the intervention period, in order 
to assess tolerability, as follows: 
• total number of participants enrolled (N) 
• percentage of participants who have completed visit 
• percentage of participants taking each study medication 
• percentage of participants taking all study medications 
Study medication can be stopped without the need for unblinding as it is an open label 
trial.    
 
6. STUDY FOLLOW-UP TIME 
 
Clinic visits for all participants will occur at enrolment (screening and randomization) 
and weeks 6, 12, 24, 36, and 48. Telephone visits will occur at weeks 12.5, 20, 28, 32, 40, 
44, 52, 56, and 60. A final visit will take place at week 64 of follow-up for each 
participant (1 year and 3 months after randomization). All efforts will be made to collect 
complete data for all participants in this study, regardless of their compliance with study 
medications.  
 
In general, missing values within follow up will be treated as ‘missing’ and no attempt 
will be made to impute missing post-randomization values and only observed values will 
be used for analysis.  Diabetes remission and regression status will be imputed as 
indicated in Section 3 of Appendix A and in Appendix B. 
 
Lost to follow-up 
All efforts will be made to collect information about the clinical outcomes for those 
participants who were lost to follow-up.   
 
Missing date information 
When an event date is not known, the site investigator will be asked to provide a best 
estimate as to when the event occurred. Even though the exact date of an event is 
unknown, the investigator often does know some information that would indicate the 
approximate date, such as the first week of a month, in the fall of a year, or the middle of 
a particular year or at least the date when the patient was last seen or contacted. This 
information can be meaningfully incorporated into the estimated date recorded, as this is 
likely to be will be closer to the true date than any produced by an uninformed computer 
program. This estimated date should be the middle date within the period that the event is 
known to have occurred. If the event is known to have occurred in the first week of a 
month, then the date in the middle of that week should be recorded as the estimate. If it 


occurred in the fall of a year, then the middle date in the fall is the appropriate estimate. If 
no information is known then the date in the middle of the plausible time period should 
be given, based on the last contact with the patient prior to the event and the date of 
contact when information about the event was known. This method for date estimation 
has been used in many studies and is recommended by Dubois and Hebert (Dubois & 
Hebert 2001).  
 
Baseline, Time Windows and Calculated Visits 
The randomization visit (Day 0) is the reference for all time-related analyses unless 
otherwise indicated. 
 
It is expected that the study period will include up to 64 weeks of follow-up visits based 
on the REMIT-Sita protocol.   
7. EFFICACY ANALYSES 
Primary Outcome 
The primary outcome in this trial will be hyperglycemia relapse at or after the 12-week 
visit. Time to Relapse analysis will be conducted using a Cox Proportional Hazards 
Model.  Kaplan-Meier curves will be plotted and compared using a log-rank test.  Hazard 
ratio with 95% CI will be obtained form the Cox Proportional Hazards Model.  If 
Proportional Hazard assumption is not held, K-M curves will be compared using 
Wilcoxon test. 
 
Primary Safety Outcome 
Proportion of participants with severe hypoglycemia during 64 weeks of follow-up in 
each treatment group. 
Key Secondary Outcomes at Pre-specified Time Points 
Proportion of participants with diabetes remission will be calculated at 24, 36, 48 and 64 
weeks after randomization.   
 
Drug-free normal glucose tolerance will be calculated based on the oral glucose tolerance 
test at 24 weeks.  This outcome can occur regardless of relapse as participants taking 
glucose-lowering medications were asked to hold them prior to the test. 
 
The primary and secondary analyses will be based on the intention to treat principle, i.e. 
with participants analyzed in the treatment group to which they were randomized. 
Primary safety analysis and all secondary analyses will be exploratory.  Unadjusted 
differences in risk between the treatment groups will be assessed by a generalized linear 
model and presented as relative risk with 95% CI. P value will be presented from Chi-
Square test.  Tests of significance will be 2-sided with Type I error of 5% and no 
adjustment for multiple testing. 
Sensitivity Analysis 


A sensitivity analysis will be conducted where the FPG and OGTT results will not be 
counted when evaluating hyperglycemia relapse.  The following glycemic outcome 
definitions will be used:  
 
Diabetes remission 
Hyperglycemia relapse 
HbA1C <6.5% 
AND no diabetes 
drugs for ≥12 weeks 
AND no relapse 
HbA1C ≥6.5% OR 
Use of diabetes drugs OR  
Capillary glucose ≥10 mmol/L on 
≥50% SMBGs‡ over 1 week 
 
‡SMBG – self-monitoring of blood glucose 
 
Other Outcomes 
For all other analyses comparing treatment groups, significance will be assessed using 
Pearson chi-square test for categorical variables and either two-sample t-test or Wilcoxon 
test for continuous variables. A linear mixed model will be used to explore changes in 
measurements for continuous variables (listed below under #1 and 2) as a repeated 
measurement (MMRM) over time using restricted maximum likelihood. The fixed effects 
used in the MMRM model will be treatment, time, baseline value (only for the outcomes 
that includes change or percent change) and the treatment-by-time interaction term and 
the patient as a random effect. 
 
1. Anthropometric outcomes 
a. Weight 
b. Percent weight loss  
c. Waist circumference 
d. Waist to hip ratio 
 
2. HbA1C 
 
3. Plasma and capillary glucose levels 
 
4. Number and use of specific diabetes medications 
 
5. Physical activity  
 
6. EQ5D  
 
7. Health coaching 
 
All tables are in Appendix A. 
8. SAFETY ANALYSIS 
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 the protocol. The investigators will review safety data for this open trial 


monthly and more formally after the first 50 participants have completed the trial. 
Participant safety will be summarized in a series of tables including reported Serious 
Adverse Events (SAEs), and any serious or non-serious adverse events leading to study 
drug permanent discontinuation.   
 
 
9. REPORTING VARIABLES AND P-VALUES 
All values will be reported to the first decimal place after the decimal point for means and 
standard deviations unless otherwise indicated.  Relative risks and 95% CIs will be 
reported to the fourth decimal place.  Exact p-values to the fourth decimal place after the 
decimal point will be reported or the closest p-value will be stated (e.g. <0.00001).