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

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ClinicalTrials.gov Identifier: NCT03199053
Recruitment Status : Recruiting
First Posted : June 26, 2017
Last Update Posted : December 7, 2018
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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).


Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: Dapagliflozin Drug: Saxagliptin Drug: Placebo Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 243 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Double (Participant, Investigator)
Masking Description: sponsor
Primary Purpose: Treatment
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
Actual Study Start Date : October 11, 2017
Estimated Primary Completion Date : December 20, 2021
Estimated Study Completion Date : December 20, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: Dapagliflozin
Tablets, Oral, 5mg , Once daily Tablets, Oral, 10mg, Once daily
Other Name: Forxiga

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
Drug: Dapagliflozin
Tablets, Oral, 5mg , Once daily Tablets, Oral, 10mg, Once daily
Other Name: Forxiga

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
Drug: Saxagliptin
Tablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily
Other Name: Onglyza

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
Drug: Saxagliptin
Tablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily
Other Name: Onglyza

Placebo Comparator: Placebo arm
Oral route. Placebo tablets administered for 52 weeks
Drug: Placebo
Matching placebo to dapagliflozin 5mg and 10 mg/saxagliptin 2.5 mg and 5 mg, Tablets, oral, Once daily




Primary Outcome Measures :
  1. Change from baseline in HbA1c at Week 26 [ Time Frame: 26 weeks ]
    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.


Secondary Outcome Measures :
  1. Change from baseline in Fasting Plasma Glucose at Week 26 [ Time Frame: 26 weeks ]
    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

  2. Percentage of subjects with baseline HbA1c ≥ 7%, who achieve an HbA1c level < 7.0% at Week 26 [ Time Frame: 26 weeks ]
    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


Other Outcome Measures:
  1. Percentage of subjects who require glycemic rescue medication or discontinue the study medication due to lack of efficacy during the 26-week treatment period [ Time Frame: 26 weeks ]
    To compare the percentage of subjects requiring glycemic rescue medication or discontinuing study medication due to lack of efficacy with dapagliflozin or saxagliptin against the percentage with placebo during 26 weeks of oral double-blind add-on treatment 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.

  2. Change from baseline in HbA1c at Week 52 [ Time Frame: 52 weeks ]
    To assess the mean change from baseline in HbA1c achieved with dapagliflozin therapy versus placebo, and separately, achieved with saxagliptin therapy versus placebo after 52 weeks of oral blinded add-on treatment 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.

  3. Change from baseline in FPG at Week 52 [ Time Frame: 52 weeks ]
    To assess the mean change from baseline in FPG achieved with dapagliflozin therapy versus placebo, and separately, achieved with saxagliptin therapy versus placebo after 52 weeks of oral blinded add-on treatment 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

  4. Percentage of subjects with baseline HbA1c ≥ 7% who achieve an HbA1c level < 7.0% at Week 52 [ Time Frame: 52 weeks ]
    To assess the percentage of subjects with baseline HbA1c ≥ 7% who achieve an HbA1c level < 7.0% after 52 weeks of oral blinded add-on therapy with dapagliflozin versus placebo, or saxagliptin 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   10 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03199053


Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

  Show 178 Study Locations
Sponsors and Collaborators
AstraZeneca

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03199053     History of Changes
Other Study ID Numbers: D1680C00019
2015-005042-66 ( EudraCT Number )
First Posted: June 26, 2017    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:
Type 2 Diabetes Mellitus

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Saxagliptin
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents