Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus Aged 10 to Below 18 Years Old

The purpose of this research study is to evaluate the efficacy and safety of the drugs dapagliflozin and saxagliptin in patients with Type 2 Diabetes who are aged 10 to below 18 years old and are currently taking metformin, insulin, or both drugs.

Dapagliflozin and saxagliptin are both approved for use in patients with Type 2 Diabetes aged 18 years or older. Dapagliflozin (alone or in combination with other antidiabetic drugs) is available for use in adults in approximately 40 countries worldwide including the USA and Europe. Saxagliptin (alone or in combination with other antidiabetic drugs) is available for use in adults in approximately 90 countries worldwide. This study will assess how well dapagliflozin and saxagliptin work by finding out how these treatments affect blood glucose (sugar) levels compared to placebo (a pill that contains no active drug), in children and adolescents. Dapagliflozin and saxagliptin are considered investigational products in this study since while they have been approved for use in adults (patients 18 years or older), they haven't been approved for children and adolescents due to lack of clinical studies in this specific population.

Patients with Type 2 Diabetes have higher levels of blood glucose (sugar) than patients who do not have this disease. The high level of sugar in the blood can lead to serious short-term and long-term medical problems. The main goal of treating diabetic patients is to lower blood glucose to a normal level. Lowering and controlling blood glucose help prevent or delay complications of diabetes, such as heart disease, kidney, eye and nerve diseases, and the possibility of amputation.

Dapagliflozin is a drug that helps to reduce blood glucose (sugar) levels by helping the kidneys to remove excess glucose from the blood and excrete it in the urine. It prevents the kidneys from returning glucose from the urine back into the bloodstream.

Saxagliptin increases insulin production when blood glucose levels are high. Insulin is a hormone made by the pancreas that allows the body to use sugar (glucose) from the food that is eaten for energy or to store glucose for future use. Saxagliptin helps to improve blood sugar levels in response to a meal and between meals if blood glucose levels are not lowered effectively. Saxagliptin does not work when the blood glucose is low. Saxagliptin also helps to decrease the amount of sugar made by the body. Together, these processes reduce blood glucose levels and help to control Type 2 Diabetes.

The subject will either receive one of the active study drugs or a placebo (a pill that looks identical but contains inactive drug). This study will be double blind; this means that neither the subject, nor the study doctor will know which treatment the subject will receive.

Which treatment the subject receives is decided by a computer, purely by chance; this is called a "random assignment".

For this study, there will first be a screening phase of up to 6 months if Investigator thinks that some of the screening tests can be repeated, followed by a 2 week lead in phase. Thereafter there will be a 26W short-term treatment phase (W1-26), and a 26 W long-term treatment phase (W27-52). Following this there will be a follow-up telephone call on week 56 and a post study visit at W104. At day 1 visit after the lead in phase the subject will be randomly assigned to receive one of 3 treatments: dapagliflozin 5 mg, saxagliptin 2.5 mg or placebo in a blinded manner. This treatment will continue up to week 14. Then after week 14, and until the end of the study, the subject will be assigned to receive one of the following 5 treatments: dapagliflozin 5 mg, dapagliflozin 10 mg, saxagliptin 2.5 mg, saxagliptin 5 mg or placebo in a blinded manner. The drugs assigned after week 14 will be the same drugs as at Day 1, but some of the groups will receive them at a higher dose.Starting at W32 or W40, i.e., after the end of the primary endpoints, patients with background medication of metformin only, and an HbA1c value < 7.5% at W26 or W32, will undergo a third randomization. Eligible subjects from the treatment arms will undergo the randomized withdrawal of background medication, while eligible patients from the placebo arm will undergo, in addition to randomized withdrawal of background medication a randomized switch to active treatment.

Short- and long-term period study visits can be delayed by a maximum of 11 months in total. If the duration of investigational product administration is longer than 52 (+1) weeks, the safety follow-up period should be shortened such that the complete study duration does not exceed 104 weeks. The W104 visit should not be delayed.If more than 12 weeks elapse between the HbA1c collection at W26 and the third rand at W32, or the HbA1c collection at W32 and the third rand at W40, the subject should not go through this rand as the HbA1c value would no longer be reliable to ascertain eligibility for the third rand

Inclusion Criteria:

• Signed Written Informed Consent
• Target Population
• Previously diagnosed with Type 2 Diabetes Mellitus by World Health Organization/ADA criteria
• HbA1c between 6.5% and 10.5% obtained at screening.
• Currently on diet and exercise and stable dose of at least 1000 mg metformin (IR or XR) for a minimum of 8 weeks, or stable dose of insulin for a minimum of 8 weeks, or a stable combination of at least 1000 mg metformin (IR or XR) and insulin for a minimum of 8 weeks prior to randomization. For those children on insulin, investigators will confirm that attempts at removing insulin from the subject's therapeutic regimen had been previously made but had not been successful.
• Age and Reproductive Status
• Male and female patients eligible if 10 years of age, up to but not including 18 years of age at the time of enrollment/screening. At least 30% of total subjects will be between the ages of 10 and 14 years and at least one third, but no more than two thirds, female subjects.
• Women of childbearing potential must have a negative pregnancy test within 24 hours prior to the start of study drug.
• Women must not be breastfeeding.
• Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs: saxagliptin, and dapagliflozin, plus 5 half-lives of study drugs or 30 days (whichever is longer), plus 30 days (duration of ovulatory cycle) for a total of 60 days post treatment completion.

Exclusion Criteria:

• Target Disease Exceptions
• Presence of Type 1 diabetes, as demonstrated by Preexisting diagnosis of Type 1 diabetes,
• Previous diagnosis of monogenic etiology of Type 2 diabetes
• Diabetes ketoacidosis (DKA) within 6 months of screening
• Current use of the following medications for the treatment of diabetes, or use within the specified timeframe prior to screening for the main study:
• Eight weeks: sulfonylureas, alpha glucosidase inhibitors, metiglinide, oral or injectable incretins or incretin mimetics, other antidiabetes medications not otherwise specified.
• Sixteen weeks: thiazolidinediones, DPP-4 inhibitors (with no reported medication related AEs related to DPP-4 inhibitors), sodium glucose cotransporter-2 (SGLT-2) inhibitors (with no reported medication related AEs related to SGLT-2 inhibitors)
• Initiation or discontinuation of prescription or non-prescription weight loss drugs within 8 weeks of screening. Use of prescription or non-prescription weight loss drugs must be stable during the study.
• Medical History and Concurrent Diseases
• Pregnant, positive serum pregnancy test, planning to become pregnant during the clinical trials, or breastfeeding
• History of unstable or rapidly progressive renal disease
• History of unresolved vesico-ureteral reflux
• History of or current, acute or chronic pancreatitis
• History of hemoglobinopathy, with the exception of sickle cell trait or thalassemia minor; or chronic or recurrent hemolysis
• Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated squamous cell carcinoma)
• Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic corticosteroid taken for > 4 weeks within 3 months prior to the Day 1 visit
• Physical and Laboratory Test Findings
• Abnormal renal function,
• An abnormal thyroid-stimulating hormone (TSH) value at enrollment will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded.
• Hematuria (confirmed by microscopy at screening) with no explanation as judged by the Investigator up to randomization.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2× upper limit of normal (ULN), or clinically significant hepatic disease.
• Serum total bilirubin (TB) > 2x ULN unless exclusively caused by Gilbert's syndrome
• Positive serologic evidence of current infectious liver disease including anti hepatitis A virus (HAV) (IgM), hepatitis B surface antigen (HBsAg), or anti hepatitis C virus (HCV). Patients who have isolated positive anti-hepatitis B surface antibodies may be included.
• Anemia of any etiology
• Volume-depleted subjects.
• Allergies and Adverse Drug Reaction
• Known allergy, sensitivity or contraindication to any study drug or its excipient/vehicle
• Other Exclusion Criteria
• Subject is currently abusing alcohol or other drugs or has done so within the last 6 months prior to the screening visit.
• Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply and Sponsor/designee approval is required.)
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
• Psychiatric or cognitive disorder that will, in the opinion of investigators, limit the subject's ability to comply with the study medications and monitoring.
• Subjects who have contraindications to therapy as outlined in the saxagliptin and dapagliflozin Investigator Brochure or local package inserts.
• Participation and receiving IP in another clinical study during the prior 3 months