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 3CompletedNCT03199053

AstraZeneca256 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

256

Conditions

Diabetes Mellitus, Type 2

Interventions

DapagliflozinDRUG

Tablets, Oral, 5mg , Once daily Tablets, Oral, 10mg, Once daily

SaxagliptinDRUG

Tablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily

PlaceboDRUG

Matching placebo to dapagliflozin 5mg and 10 mg/saxagliptin 2.5 mg and 5 mg, Tablets, oral, Once daily

Eligibility

Sex: ALLMin age: 10 YearsMax age: 18 Years

Medical Language ↔ Plain English

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

Locations (122)

Outcomes

Primary Outcomes

Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26

Time frame: Baseline and Week 26

Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26

Time frame: Baseline and Week 26

Secondary Outcomes

Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at 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.

Time frame: Baseline and Week 26

Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at 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.

Data from ClinicalTrials.gov

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Research Site

Sacramento, California, United States

Research Site

New Haven, Connecticut, United States

Research Site

Hialeah, Florida, United States

Research Site

Hialeah, Florida, United States

Research Site

Hollywood, Florida, United States

Research Site

Miami, Florida, United States

Research Site

Miami, Florida, United States

Research Site

Miami, Florida, United States

Research Site

Miami Springs, Florida, United States

Research Site

Atlanta, Georgia, United States

...and 112 more locations

Time frame: Baseline and Week 26

Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at 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.

Time frame: Baseline and Week 26

Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at 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.

Time frame: Baseline and Week 26

Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

Time frame: Baseline and Week 26

Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in FPG at Week 26

Time frame: Baseline and Week 26

Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at 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.

Time frame: Baseline and Week 26

Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at 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.

Time frame: Baseline and Week 26

Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at 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.

Time frame: Baseline and Week 26

Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at 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.

Time frame: Baseline and Week 26

Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at 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.

Time frame: Baseline and Week 26

Low-dose/High-dose Versus Placebo (Weighted): Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at 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.

Time frame: Baseline and Week 26

Low-dose Versus Placebo (Weighted): Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at 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.

Time frame: Baseline and Week 26

Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in HbA1c at Week 26

Time frame: Baseline and Week 26

Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in FPG at Week 26

Time frame: Baseline and Week 26

Dapagliflozin Low-dose Versus Uptitration to the High Dose: Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at 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.

Time frame: Baseline and Week 26

Saxagliptin Low-dose Versus Uptitration to the High Dose: Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26

Time frame: Baseline and Week 26