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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03199053




Registration number
NCT03199053
Ethics application status
Date submitted
22/06/2017
Date registered
26/06/2017
Date last updated
28/06/2019

Titles & IDs
Public title
Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus Aged 10 to Below 18 Years Old
Scientific 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
Secondary ID [1] 0 0
2015-005042-66
Secondary ID [2] 0 0
D1680C00019
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes Mellitus, Type 2 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Dapagliflozin
Treatment: Drugs - Saxagliptin
Treatment: Drugs - Placebo

Experimental: Low dose 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.

Experimental: Low dose/high dose 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

Experimental: Low dose 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

Experimental: Low dose/high dose 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

Placebo Comparator: Placebo arm - Oral route. Placebo tablets administered for 52 weeks


Treatment: Drugs: Dapagliflozin
Tablets, Oral, 5mg , Once daily Tablets, Oral, 10mg, Once daily

Treatment: Drugs: Saxagliptin
Tablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily

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

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change from baseline in HbA1c at Week 26 - To determine if there will be a greater mean reduction from baseline in HbA1c achieved after 26 weeks of oral double-blind add-on therapy of dapagliflozin 5 mg or saxagliptin 2.5 mg (with titration to the high-dose for those who do not achieve the glycemic target of HbA1c < 7% at 12 weeks) compared to placebo in pediatric T2DM subjects with HbA1c levels of 6.5 to 10.5% on diet and exercise and metformin (IR or XR), insulin, or metformin (IR or XR) plus insulin.
Timepoint [1] 0 0
26 weeks
Secondary outcome [1] 0 0
Change from baseline in Fasting Plasma Glucose at Week 26 - To determine if there will be a greater mean reduction from baseline in Fasting Plasma Glucose (FPG) achieved after 26 weeks of oral double-blind add-on therapy of dapagliflozin 5 mg or saxagliptin 2.5 mg (with titration to the high-dose for those who do not achieve the glycemic target of HbA1c <7% at 12 weeks) compared to placebo in pediatric T2DM subjects with HbA1c of 6.5 to 10.5% on diet and exercise and metformin (IR or XR), insulin, or metformin (IR or XR) plus insulin
Timepoint [1] 0 0
26 weeks
Secondary outcome [2] 0 0
Percentage of subjects with baseline HbA1c = 7%, who achieve an HbA1c level < 7.0% at Week 26 - To compare the percentage of subjects with baseline HbA1c = 7% who achieve an HbA1c level < 7.0% after 26 weeks of oral double-blind add-on therapy of dapagliflozin 5 mg or saxagliptin 2.5 mg (with titration to the high-dose for those who do not achieve the glycemic target of HbA1c <7% at 12 weeks) versus placebo in pediatric T2DM subjects with HbA1c of 6.5 to 10.5% on diet and exercise and metformin (IR or XR), insulin, or metformin (IR or XR) plus insulin
Timepoint [2] 0 0
26 weeks

Eligibility
Key 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.
Minimum age
10 Years
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Blacktown
Recruitment hospital [2] 0 0
Research Site - Nedlands
Recruitment postcode(s) [1] 0 0
2148 - Blacktown
Recruitment postcode(s) [2] 0 0
6009 - Nedlands
Recruitment outside Australia
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Sumy
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Birmingham
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Middlesbrough
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Nottingham

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
AstraZeneca
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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. 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.

Dapagliflozin (alone or in combination with other antidiabetic drugs) has been shown to be
effective in lowering blood glucose in adults with Type 2 Diabetes and is available for use
in adults (patients 18 years or older) in approximately 40 countries worldwide including the
USA and Europe. Dapagliflozin has not yet been studied in children (pediatric patients).

Saxagliptin (alone or in combination with other antidiabetic drugs) has been shown to be
effective in lowering blood glucose in adults with Type 2 Diabetes and is available for use
in adults (patients 18 years or older) in approximately 90 countries worldwide. Saxagliptin
also has not yet been studied in children (pediatric patients).

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 weeks, followed by a 2 week
lead in phase. Thereafter there will be a 26 week short-term treatment phase (week 1-week
26), and a 26 week long-term treatment phase (week 27-week 52). Following this there will be
a follow-up telephone call on week 56 and a post study visit at week 104.

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.

After completion of the 26-week short-term phase, the subject will enter a 26 week long-term
phase. The same treatment that the subject had been assigned to at week 14 visit will be
continued. This long-term phase is primarily designed to provide additional information on
how well dapagliflozin and saxagliptin are tolerated.

Following the treatment phases, there will be a follow-up telephone call at week 56.

The subject will be asked to visit the clinic at week 104 again for a final evaluation of the
physical development (based on the stage of puberty).
Trial website
https://clinicaltrials.gov/show/NCT03199053
Trial related presentations / publications
Public notes

Contacts
Principal investigator
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AstraZeneca Clinical Study Information Center
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information.center@astrazeneca.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03199053