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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

A 26 Week, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Parallel Group, Phase 3 Trial With a 26 Week Safety Extension Period Evaluating the Safety and Efficacy of Dapagliflozin 5 and 10 mg, and Saxagliptin 2.5 and 5 mg in Pediatric Patients With Type 2 Diabetes Mellitus Who Are Between 10 and Below 18 Years of Age

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03199053
• Other study ID #: D1680C00019
• Secondary ID: 2015-005042-66
• Status: Completed
• Phase: Phase 3
• Start date: October 11, 2017
• Est. completion date: January 3, 2024

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 256
• Est. completion date: January 3, 2024
• Est. primary completion date: February 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Dapagliflozin
Tablets, Oral, 5mg , Once daily Tablets, Oral, 10mg, Once daily
• Saxagliptin
Tablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily
• Placebo
Matching placebo to dapagliflozin 5mg and 10 mg/saxagliptin 2.5 mg and 5 mg, Tablets, oral, Once daily

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Caba
Argentina	Research Site	Ciudad de Buenos Aires
Argentina	Research Site	San Miguel de Tucuman
Argentina	Research Site	San Miguel de Tucumán
Argentina	Research Site	San Miguel de Tucumán
Australia	Research Site	Blacktown
Brazil	Research Site	Brasilia
Brazil	Research Site	Curitiba
Brazil	Research Site	Fortaleza
Brazil	Research Site	Fortaleza
Brazil	Research Site	Passo Fundo
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Ribeirão Preto
Brazil	Research Site	Santa Maria
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Sao Paulo
Canada	Research Site	Montreal	Quebec
Chile	Research Site	Santiago
Colombia	Research Site	Armenia
Colombia	Research Site	Barranquilla
Finland	Research Site	Tampere
India	Research Site	Ahmedabad
India	Research Site	Aurangabad
India	Research Site	Bangalore
India	Research Site	Bikaner
India	Research Site	Chandigarh
India	Research Site	Coimbatore
India	Research Site	Hyderabad
India	Research Site	Kolkata
India	Research Site	Kozhikode
India	Research Site	Nashik
India	Research Site	Pune
India	Research Site	Visakhapatnam
Israel	Research Site	Haifa
Italy	Research Site	Ancona
Italy	Research Site	Napoli
Italy	Research Site	Roma
Korea, Republic of	Research Site	Daejeon-si
Korea, Republic of	Research Site	Incheon
Korea, Republic of	Research Site	Wonju-si
Malaysia	Research Site	George Town
Malaysia	Research Site	Ipoh
Malaysia	Research Site	Johor Bahru
Malaysia	Research Site	Klang
Malaysia	Research Site	Kota Kinabalu
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Kuching
Malaysia	Research Site	Melaka
Malaysia	Research Site	Putrajaya
Malaysia	Research Site	Seremban
Malaysia	Research Site	Seri Manjung
Malaysia	Research Site	Taiping
Mexico	Research Site	Boca del Rio
Mexico	Research Site	Celaya
Mexico	Research Site	Ciudad Madero
Mexico	Research Site	Cuernavaca
Mexico	Research Site	Cuernavaca
Mexico	Research Site	Culiacán
Mexico	Research Site	Durango
Mexico	Research Site	Guadalajara
Mexico	Research Site	Juriquilla
Mexico	Research Site	Merida
Mexico	Research Site	Mexico
Mexico	Research Site	México, D.F.
Mexico	Research Site	Monterrey
Mexico	Research Site	Monterrey
Mexico	Research Site	San Juan del Rio
Mexico	Research Site	Veracruz
Mexico	Research Site	Zapopan
New Zealand	Research Site	Grafton
New Zealand	Research Site	Tauranga
New Zealand	Research Site	Wellington
Philippines	Research Site	Quezon City
Philippines	Research Site	Quezon City
Philippines	Research Site	San Fernando City
Poland	Research Site	Warszawa
Russian Federation	Research Site	Izhevsk
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Ufa
Taiwan	Research Site	Tainan City
Taiwan	Research Site	Taipei
Thailand	Research Site	Bangkok
Thailand	Research Site	Hat Yai
Turkey	Research Site	Aydin
Turkey	Research Site	Bursa
Turkey	Research Site	Eskisehir
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
Turkey	Research Site	Izmir
Turkey	Research Site	Kocaeli
Turkey	Research Site	Kurupelit
Turkey	Research Site	Manisa
Ukraine	Research Site	Dnipro
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Vinnytsia
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Middlesborough
United Kingdom	Research Site	Nottingham
United States	Research Site	Atlanta	Georgia
United States	Research Site	Atlanta	Georgia
United States	Research Site	Charlottesville	Virginia
United States	Research Site	Edinburg	Texas
United States	Research Site	Harlingen	Texas
United States	Research Site	Hialeah	Florida
United States	Research Site	Hialeah	Florida
United States	Research Site	Hollywood	Florida
United States	Research Site	Idaho Falls	Idaho
United States	Research Site	McAllen	Texas
United States	Research Site	Memphis	Tennessee
United States	Research Site	Memphis	Tennessee
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	Neptune	New Jersey
United States	Research Site	New Haven	Connecticut
United States	Research Site	Sacramento	California
United States	Research Site	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Chile,  Colombia,  Finland,  India,  Israel,  Italy,  Korea, Republic of,  Malaysia,  Mexico,  New Zealand,  Philippines,  Poland,  Russian Federation,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dapagliflozin Versus Placebo: 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 multiple imputation washout (MI-WO) within each arm using the data from placebo participants with Week 26 data.	Baseline and Week 26
Primary	Saxagliptin Versus Placebo: 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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (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.	Baseline and Week 26
Secondary	Saxagliptin Versus Placebo: 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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	Low-dose Versus Uptitration to the High Dose: 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.	Baseline and Week 26
Secondary	Low-dose Versus Uptitration to the High Dose: 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.	Baseline and Week 26
Secondary	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.	Baseline and Week 26
Secondary	Saxagliptin 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.	Baseline and Week 26

External Links

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