Clinical trial NCT03199053: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Keywords: Type 2 Diabetes Mellitus
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-06-26
Enrollment: 256
Sex: ALL
Minimum age (years): 10
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible subjects with HbA1c of 6.5% to 10.5% at screening will be randomized 1:1:1 to receive dapagliflozin 5 mg, saxagliptin 2.5 mg, or placebo. Blinded HbA1c assessment will be performed at Week 12. All subjects with Week 12 HbA1c \< 7% will remain on previously assigned randomized treatment. Subjects taking dapagliflozin with Week 12 HbA1c ≥ 7% will be re-randomized in a 1:1 ratio to continue on the low-dose treatment (dapagliflozin 5 mg) or up titrate to the high-dose treatment (dapagliflozin 10 mg). Subjects taking saxagliptin with Week 12 HbA1c ≥ 7% will be re-randomized in a 1:1 ratio to continue on the low-dose treatment (saxagliptin 2.5 mg) or up-titrate to the high-dose treatment (saxagliptin 5 mg). Subjects taking placebo with Week 12 HbA1c ≥ 7% will continue on placebo treatment. All placebo subjects and all subjects taking saxagliptin or dapagliflozin with HbA1c \< 7% at Week 12 will go through a dummy 2nd randomization process for maintaining the blinding.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26
timeFrame: Baseline and Week 26
measure: Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26
timeFrame: Baseline and Week 26
Secondary outcomes:
measure: Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26
timeFrame: Baseline and Week 26
measure: Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26
timeFrame: Baseline and Week 26
measure: Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26
timeFrame: Baseline and Week 26
measure: Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26
timeFrame: Baseline and Week 26
measure: Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
timeFrame: Baseline and Week 26
measure: Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in FPG at Week 26
timeFrame: Baseline and Week 26
measure: Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26
timeFrame: Baseline and Week 26
measure: Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26
timeFrame: Baseline and Week 26
measure: Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26
timeFrame: Baseline and Week 26
measure: Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26
timeFrame: Baseline and Week 26
measure: Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26
timeFrame: Baseline and Week 26
measure: Low-dose/High-dose Versus Placebo (Weighted): Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26
timeFrame: Baseline and Week 26
measure: Low-dose Versus Placebo (Weighted): Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26
timeFrame: Baseline and Week 26
measure: Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in HbA1c at Week 26
timeFrame: Baseline and Week 26
measure: Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in FPG at Week 26
timeFrame: Baseline and Week 26
measure: Dapagliflozin Low-dose Versus Uptitration to the High Dose: Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26
timeFrame: Baseline and Week 26
measure: Saxagliptin Low-dose Versus Uptitration to the High Dose: Percentage of Participants With Baseline HbA1c ≥ 7% Who Achieved HbA1c < 7% at Week 26
timeFrame: Baseline and Week 26
Other outcomes:
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country: Philippines
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city: London
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city: Middlesborough
country: United Kingdom
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city: Nottingham
country: United Kingdom
facility: Research Site
Study officials:
References: