Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus (T2DM) Aged 10 to Below 18 Years Old

Phase 3

Completed

Conditions: Diabetes Mellitus, Type 2

Interventions: Drug: Placebo
Drug: Dapagliflozin
Drug: Saxagliptin

Registration Number: NCT03199053

Lead Sponsor: AstraZeneca

Brief Summary: The primary objective of this study is to determine if there will be a greater mean reduction from baseline in glycated hemoglobin (HbA1c) achieved after 26 weeks of oral double-blind add-on therapy of dapagliflozin or saxagliptin compared to placebo in paediatric T2DM patients with HbA1c levels of 6.5 to 10.5% on diet and exercise and metformin, insulin, or metformin plus insulin.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 256

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo arm	Placebo	Oral route. Placebo tablets administered for 52 weeks
Low dose/high dose Dapagliflozin	Dapagliflozin	Oral route. Start with a low dose of Dapagliflozin administered once daily and up titrate to the high dose Dapagliflozin administered once daily if HbA1c \>= 7% at week 12
Low dose Dapagliflozin	Dapagliflozin	Oral route. Start with a low dose of dapagliflozin administered once daily and remain on the low dose regardless of your HbA1c at week 12.
Low dose Saxagliptin	Saxagliptin	Oral route. Start with a low dose of saxagliptin administered once daily and remain on the low dose regardless of your HbA1c at week 12
Low dose/high dose Saxagliptin	Saxagliptin	Oral route. Start with a low dose of saxagliptin administered once daily and up titrate to the high dose if HbA1c \>= 7% at week 12

Primary Outcome Measures

Name	Time	Method
Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on multiple imputation washout (MI-WO) within each arm using the data from placebo participants with Week 26 data.
Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.

Secondary Outcome Measures

Name	Time	Method
Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Dapagliflozin participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Saxagliptin participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Saxagliptin participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26	Baseline and Week 26	A logistic regression model adjusting for sex, age group, background antidiabetes medication and Baseline HbA1c was used. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.
Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in HbA1c at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.
Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Dapagliflozin participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Dapagliflozin participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Saxagliptin participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Saxagliptin participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in FPG at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.
Low-dose/High-dose Versus Placebo (Weighted): Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26	Baseline and Week 26	A weighted logistic regression model adjusting for sex, age group, background antidiabetes medication and Baseline HbA1c was used. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.
Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Dapagliflozin participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Low-dose Versus Placebo (Weighted): Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26	Baseline and Week 26	A weighted logistic regression model adjusting for sex, age group, background antidiabetes medication and Baseline HbA1c was used. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Participants were weighted as follows: participants who had HbA1c \< 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c \>= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c \>= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1.
Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in FPG at Week 26	Baseline and Week 26	Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.
Dapagliflozin Low-dose Versus Uptitration to the High Dose: Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26	Baseline and Week 26	A Fisher's exact test was used and unadjusted difference in percentage of participants and Clopper-Pearson CIs presented using imputed data. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.
Saxagliptin Low-dose Versus Uptitration to the High Dose: Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26	Baseline and Week 26	A Fisher's exact test was used and unadjusted difference in percentage of participants and Clopper-Pearson CIs presented using imputed data. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data.