| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 10 mg [all doses and regimens combined]) or saxagliptin (2.5 mg or 5 mg [all doses and regimens combined]) 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. |
|
| E.2.2 | Secondary objectives of the trial |
1. Assessments/comparisons of HbA1c, FPG, % of subjects with baseline HbA1c >= 7 % who will achieve target HbA1c of less than 7%" , across the following subgroups of study participants:
- All treated subjects with either dapagliflozin or saxagliptin, independent of dosage, vs placebo(excluding, for this objective only, HbA1c )
- Subjects treated with either drug who achieved HbA1c< 7% at Week 12 + subjects who underwent up-titration at week 12 vs placebo
- Subjects treated with either drug who did not achieved HbA1c < 7% at week 12 and remained at low dose vs subjects who underwent up-titration at week 12
- Subjects treated with either drug who remained at low dose throughout the study vs placebo
2. Additionally, PK and safety objectives will include assessment of drug concentrations and a broad range of adverse events at key time points during the study |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
a) Subjects (or designee) must be willing and able to give signed and dated written informed consent. Minor’s parent(s) or legally acceptable representatives must give fully informed written consent. Assent should be obtained according to local regulations and if child is capable.
2. Target Population
a) Previously diagnosed with T2DM by World Health Organization/ADA criteria
b) HbA1c 6.5% and 10.5% obtained during the 6 month screening period
c) 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 Day 1 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.
d) Subject re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (i.e., subject has not been randomized / has not been treated).
i) If re-enrolled, the subject must be re-consented. All screening procedures will be repeated. Subjects may only be re-screened twice.
3. Age and Reproductive Status
a) Male and female subjects eligible if reached 10 years of age at screening, and , up to but not including 18 years of age at the time of randomization. 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.
b) Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding.
d) 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. |
|
| E.4 | Principal exclusion criteria |
1. Target Disease Exceptions
a) Presence of Type 1 diabetes, as demonstrated by:
• Preexisting diagnosis of Type 1 diabetes,
OR
• Positivity at screening of either antibodies to glutamic acid decarboxylase (GAD) or protein tyrosine phosphatase like protein antibodies (IA-2) AND abnormally low levels of C-peptide. GAD and IA-2 antibody testing will be performed in all screened subjects, C-peptide only in otherwise eligible, antibody-positive subjects. All instances of antibody positive subjects with normal or elevated C-peptide values will be discussed by the Investigator with the study medical monitors and Sponsor’s study director to confirm study eligibility.
b) Previous diagnosis of monogenic etiology of Type 2 diabetes such as maturity onset diabetes of the young (MODY), genetic disorders with strong associations with insulin resistance/diabetes and/or obesity such as Turner’s Syndrome and Prader-Willi, or secondary diabetes (steroid use, Cushing’s disease, acromegaly), secondary diabetes mellitus, or diabetes insipidus
c) Diabetes ketoacidosis within 6 months of screening
d) Current use of the following medications for the treatment of diabetes, or use within the specified timeframe prior to screening for the main study:
i) Eight weeks: sulfonylureas, alpha glucosidase inhibitors, metiglinide, oral or injectable incretins or incretin mimetics, other antidiabetes medications not otherwise specified.
ii) Sixteen weeks: thiazolidinediones, DPP-4 inhibitors (with no reported medication related AEs related to DPP-4 inhibitors), SGLT-2 inhibitors (with no reported medication related AEs related to SGLT-2 inhibitors)
e) 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.
2. Medical History and Concurrent Diseases
a) Pregnant, positive serum pregnancy test, planning to become pregnant during the clinical trials, or breastfeeding
b) History of unstable or rapidly progressive renal disease
c) History of unresolved vesico-ureteral reflux
d) History of or current, acute or chronic pancreatitis
e) History of hemoglobinopathy, with the exception of sickle cell trait or thalassemia minor; or chronic or recurrent hemolysis
f) Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated squamous cell carcinoma)
g) Significant co-morbidity that, in the opinion of the Investigators, will increase the risk to the subject such as immunosuppression, or current treatment for cancer
h) 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
NOTE: inhaled, nasal spray, or topical steroids if limited to minor surface area are allowed.
3. Physical and Laboratory Test Findings
a) Abnormal renal function, which is defined as an estimated glomerular filtration rate (eGFR) calculated by the Schwartz Formula < 80 mL/min/1.73 m2 (1.33 mL/s)16
b) 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.
c) Hematuria (confirmed by microscopy at screening) with no explanation as judged by the Investigator up to randomization.
d) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2× upper limit of normal (ULN), or clinically significant hepatic disease.
e) Serum total bilirubin (TB) 2x ULN unless exclusively caused by Gilbert’s syndrome
f) 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.
g) Anemia of any etiology defined as hemoglobin 10.7 g/dL (107 g/L) for females and 11.3 g/dL (113 g/L) for males. Subjects who are considered to have anemia according to local guidelines should be excluded.
h) Volume-depleted subjects. Subjects at risk for volume depletion due to co existing conditions or concomitant medications, such as loop diuretics, should carefully monitor their volume status.
i) Clinically significant abnormalities in any pre-randomization laboratory analyses or electrocardiogram (ECG) that, in the Investigator’s opinion, would preclude randomization.
4. Allergies and Adverse Drug Reaction
a) Known allergy, sensitivity or contraindication to any study drug or its excipient/vehicle |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in HbA1c at Week 26 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline in FPG at Week 26
• Percentage of subjects with baseline HbA1c ≥ 7% who achieve an HbA1c level < 7.0% at Week 26 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Chile |
| Colombia |
| India |
| Israel |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Philippines |
| Taiwan |
| Thailand |
| United States |
| Finland |
| Poland |
| Romania |
| Italy |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
Print
