Is MK-0431A XR (fixed-dose combination tablet of sitagliptin and extended-release metformin) more safe and effective than extended release metformin (metformin XR) for the treatment of T2DM in youths failing metformin monotherapy?

Study setting: specialist tertiary care diabetes centres (Diabetic and Endocrinology Units of NHSL, Colombo South Teaching Hospital and Teaching Hospital Kandy)

Consenting participants will be randomized into two arms.

Arm 1: Sitagliptin + Metformin XR fixed-dose combination tablet plus placebo to metformin XR tablet.

Arm 2: Metformin XR tablet plus matching placebo to Sitagliptin + Metformin XR fixed-dose combination tablet.

Dosage:
Arm 1: Sitagliptin / metformin: 50/500 mg, 50/1000 mg two tablets once daily in the morning for 54 weeks

Arm 2: Metformin XR (500 mg, 1000 mg) two tablets once daily in the morning for 54 weeks

Insulin glargine will be used as glycaemic rescue therapy based on American Diabetic Association guidelines

1. Subjects between the age of 10 to 17 years on day of signing informed consent with randomization to occur prior to 18th birthday.
2. Diagnosed Type 2 Diabetes Mellitus (T2DM)
3. Subject has not received treatment with insulin for at least 12 weeks prior to the screening visit
4. Hb A1C ?6.5% and ?10.0% on a stable dose of metformin immediate release or extended release (?1500 mg/day, for ?12 weeks)
5. Participant has a family member or adult closely involved in the daily activities and will participate in the subject's treatment and study protocol (i.e., available for telephone calls, study visits and administration of study medication as needed).
6. Informed consent from parent or guardian

1. Known type 1 diabetes mellitus or documented evidence of positive diabetes auto-antibodies (if performed when patient was diagnosed with diabetes).
2. Known monogenic diabetes, secondary diabetes, or a genetic syndrome or disorder known to affect glucose tolerance other than diabetes.
3. Symptomatic hyperglycemia and/or moderate to large ketonuria requiring immediate initiation of another antihyperglycemic agent. 4.Subject has previously taken a DPP-4 inhibitor or GLP-1 receptor agonist
4. Initiation of chronic treatment with a medication known to cause weight gain OR weight loss
5. Current participation, or has participated within the prior 12 weeks, in a study in which the subject received an investigational compound or used an investigational device or is not willing to refrain from participating in another interventional study.
6. Currently on or likely to require treatment with >14 consecutive days or repeated courses of pharmacologic doses of corticosteroids
7. Undergone a surgical procedure within 4 weeks prior to signing informed consent or has major surgery planned during the study.
8. History of congenital heart disease or cardiovascular disease other than hypertension.
9. Visit 1 systolic or diastolic blood pressure of >95th percentile for age, height percentile and gender and is not considered likely to have values <95th percentile for age, height percentile and gender by Visit 3 with appropriate antihypertensive therapy.
10. History of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C (assessed by medical history), primary biliary cirrhosis, or symptomatic gallbladder disease.
11. Active nephropathy (i.e., nephrotic syndrome or glomerulonephritis). Note: Subjects with diabetic nephropathy will be eligible if they meet all other eligibility criteria.
12. Chronic myopathy, mitochondrial disorder or a progressive neurological or neuromuscular disorder
13. Human immunodeficiency virus (HIV) as assessed by medical history.
14. Clinically important hematological disorder (e.g. aplastic anemia, thrombocytopenia, myeloproliferative or myelodysplastic syndrome).
15. Current treatment for hyperthyroidism or on thyroid hormone therapy and has not been on a stable dose for at least 6 weeks. Note: Subjects under treatment for hypothyroidism with a normal TSH value may participate.
16. Abnormal growth patterns or is being treated with growth hormone.
17. History of malignancy <5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
18. History of idiopathic acute pancreatitis or chronic pancreatitis.
19. Known history of recreational or illicit drug use, or of alcohol abuse or dependence (within the past year).
20. Has donated blood products or has had phlebotomy of >10% of estimated total blood volume within 8 weeks of signing informed consent, or intends to donate blood products or receive blood products within the projected duration of the study.
21. Known pregnancy, positive urine pregnancy test or breast-feeding, or is expecting to conceive or donate eggs during the study, including 14 days following the last dose of study drug.
22. Subject is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study.
23. History or current evidence of any condition, therapy, laboratory abnormality or other circumstance (including hypersensitivity to insulin glargine or unwillingness/inability to initiate and manage insulin therapy) that makes participation not in the subject’s best interest, might interfere with the subject’s participation for the full duration of the study, might confound the results of the study.
24. Inability to swallow study medication (based on witnessed dose).
25. Symptomatic hyperglycemia or moderate to large ketonuria or positive test for ketonemia requiring immediate initiation of antihyperglycemic therapy and in the opinion of the investigator is not considered likely to respond to diet and exercise intervention
26. Clinically significant ECG abnormality which, in the opinion of the investigator, exposes the subject to risk by enrolling in the study
27. Development of a new medical condition, suffered a change in status of an established medical condition, developed a laboratory abnormality, or required a new treatment or medication during the pre-randomization period which meets any previously described study exclusion criterion or which, in the opinion of the investigator, exposes the subject to risk by enrolling in the study
28. Site fasting fingerstick glucose (FFSG) >240 mg/dL (13.3 mmol/L). Note: If the investigator believes that the value does not reflect the subject’s recent glycemic control, then the subject should not be excluded at this time. The current visit should be changed to an Unscheduled Visit and the subject should be rescheduled for Visit 3/ Day 1. If at the rescheduled visit, the subject meets this exclusion criterion, the subject MUST be excluded.