| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 14.1 |
| 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 |
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| 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 compare after 16 weeks of oral double-blind treatment the change from baseline in HbA1c achieved with saxagliptin and placebo.
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| E.2.2 | Secondary objectives of the trial |
To compare after 16 weeks of oral double-blind treatment the effects of saxagliptin versus placebo treatment on:
1) The AUC change from baseline in 2-hour PPG levels, as determined from samples obtained during Mixed Meal Tolerance Test (MMTT).
2) The change from baseline in FPG.
3) The percent of subjects who achieved HbA1c < 7%.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Signed Written Informed Consent
a)Freely given informed consent must be obtained prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the trial. Minor’s parents or legally acceptable representatives must give fully informed written consent. Assent should be obtained according to local regulations and if child is mentally capable.
2)Target Population
a)Male and female patients eligible if 10 years of age, up to 17 years and 32 weeks of age at the time of randomization.
b)Previously diagnosed as having type 2 diabetes prior to study enrollment by WHO/ADA diagnostic criteria for glucose levels (FPG > or = 7.0 mmol/L [126 mg/dL]) or plasma glucose levels 2-hours after 75-gm oral glucose load of > or = 11.1 mmol/L (200 mg/dL) or a casual plasma glucose >200 mg/dL with symptoms. (WHO 1999; WHO 2006; ADA 2010). Subjects must have a diagnosis of type 2 diabetes for a duration of less than two years.
c)HbA1c > or = 7.0% and < or = 10.5% obtained at screening visit, for the study.
d) Body weight > or = 30 kg.
e) BMI > 85th percentile.
3) Age and Reproductive Status
a)Women of childbearing potential (WOCBP) and men must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. See Section 3.3.3 for the definition of WOCBP. The decision for appropriate methods to prevent pregnancy should be determined by discussions between the investigator and the study subject.
b)WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.
c)Women must not be breastfeeding.
d)Sexually active fertile men must use effective birth control if their partners are WOCBP.
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| E.4 | Principal exclusion criteria |
1)Target Disease Exceptions
a)Current use of the following medications for the treatment of diabetes, or use within the specified timeframe prior to screening for the study:
i)Six months: insulin.
ii)Four months: thiazolidinediones.
iii)Two months: any other antidiabetic treatment
iv)Any previous use of DPP4-inhibitor and/or incretin mimetics
b)Current use of prescription or non-prescription weight loss drugs and their use within 3 months of screening.
2)Medical History and Concurrent Diseases
a)Significant co-morbidity that, in the opinion of the investigators would preclude participation in the study
b)Previous diagnosis of monogenic etiology of type 2 diabetes such as MODY (maturity onset of diabetes in youth), genetic disorders with strong associations with insulin resistance/diabetes and/or obesity such as Turner's Syndrome and Prader-Will, or secondary diabetes (steroid use, Cushing's disease, acromegaly) c)Significant cardiovascular history.
d)History of hemoglobinopathies
e)History of unstable or rapidly progressive renal disease.
f)History of alcohol or drug abuse.
g)Psychiatric or cognitive disorder that will, in the opinion of investigators, limit the patient’s ability to comply with the study medications and monitoring.
h)Administration of any other study drug or participation in a clinical research trial within 30 days of planned enrollment to this study (or a longer period if dictated by local regulatory authorities).
i)Any condition, which in the investigator’s opinion may render the subject unable to complete the study or may pose significant risk to the subject.
j)Immunocompromised individuals
k)Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program.
3)Physical and Laboratory Test Findings
a)Fasting plasma glucose (FPG) > 255 mg/dL (14.2 mmol/L) at screening will exclude the patient.
b)Diabetic ketoacidosis (DKA) within 6 months of study entry
c)Abnormal renal function, which is defined as an abnormal creatinine clearance rate as determined by the Schwartz Formula as follows:
eGFR (ml/min/1.73m2) = 0.413 *(height (cms)/serum creatinine (mg/dl):
d)Presence of one or more of the following: antibodies to glutamic acid decarboxylase (GAD), islet cell autoantibody (ICA), protein tyrosine phosphatase-like protein antibodies (IA-2).
e)Active liver disease and/or significant abnormal liver function defined as Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2 times upper limits of normal, and/or serum total bilirubin > 2.0 mg/dL.
f)History of positive serologic evidence of current infectious liver disease including anti-HAV (IgM), HbsAg, or anti-HCV. Patients who may have isolated positive anti HBs may be included.
g)Anemia of any etiology defined as hemoglobin < or = 10.7 g/dL (107 g/L) for females and < or = 11.3 g/dL (113 g/L) for males.
h)An abnormal TSH value at screening will be further evaluated by free T4. Subjects with an abnormal T4 will be excluded.
i)Creatinine kinase (CK) > or = 3 X ULN.
j)Clinically significant (CS) abnormalities in any pre-randomization laboratory analyses or ECG that, in the investigator’s opinion, would preclude randomization.
4)Allergies and Adverse Drug Reaction
a)Subjects who have contraindications to therapy as outlined in the Saxagliptin Investigator Brochure or local metformin package insert.
b)Subjects with known contraindications to DPP-IV therapy.
5)Prohibited Therapies and/or Medications
a)Steroid use exclusions:
i)Excluded: use of oral or parenteral corticosteroids within 3 months
ii)Allowed: inhaled corticosteroids for asthma, and topical corticosteroids if limited to minor surface area.
b)Use of any other antihyperglycemic medication (other than metformin or insulin as applicable for glycemic rescue) after entry into the placebo lead-in period.
c)Prior treatment with saxagliptin.
d)Subjects taking prohibited medication as listed in Section 3.4. Subjects who stop prohibited medication prior to study participation must undergo an appropriate wash out period before visit 1.
e)Diabetes treatment or use of weight loss medications
f)Current treatment with potent CYP3A4/5 inhibitors
6)Sex and Reproductive Status
a)Pregnant, positive serum pregnancy test, planning to become pregnant during the clinical trials, or breastfeeding.
7)Other Exclusion Criteria
a)Prisoners or subjects who are involuntarily incarcerated.
b)Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.
c)Employees of BMS, AstraZeneca (AZ), or their relatives.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change in HbA1c from baseline to Week 16 for all subjects randomized to saxagliptin versus placebo. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analyses at Week 16 of the primary and secondary efficacy endpoints will be based on measurements available at that time point or the last post-baseline measurement prior to the time-point, if no measurement is available at that time point, ie, LOCF. For
subjects who meet the pre-specified rescue criteria, their last post-baseline measurement prior to initiation of rescue medication will be used unless otherwise specified. |
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| E.5.2 | Secondary end point(s) |
• Mean change in 2-hour PPG AUC from baseline to Week 16 (or the last post-baseline measurement prior to Week 16, if no Week 16 assessment is available) in the short-term treatment period.
• Mean change in FPG from baseline to Week 16 (or the last post-baseline measurement prior to Week 16, if no Week 16 assessment is available) in the short-term treatment period.
• Percent of subjects with HbA1c < 7% at Week 16 (or the last post-baseline measurement prior to Week 16, if no Week 16 assessment is available) in the short-term treatment period. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analyses at Week 16 of the primary and secondary efficacy endpoints will be based on measurements available at that time point or the last post-baseline measurement prior to the time-point, if no measurement is available at that time point, ie, LOCF. For
subjects who meet the pre-specified rescue criteria, their last post-baseline measurement prior to initiation of rescue medication will be used unless otherwise specified. |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Belgium |
| Canada |
| India |
| Israel |
| Italy |
| Russian Federation |
| South Africa |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
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| 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
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| Two months after last patient last visit when the locking of the database. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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