| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012607 |
| E.1.2 | Term | Diabetes mellitus inadequate control |
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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 24 weeks of oral administration of double-blind treatment, the change from baseline in A1C level achieved with each dose of saxagliptin plus metformin IR compared to saxagliptin plus placebo and to metformin IR plus placebo in treatment-na ve subjects with type 2 diabetes who have inadequate glycemic control defined as A1C 61619; 8 but 61603; 12 . |
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| E.2.2 | Secondary objectives of the trial |
| To compare each dose of saxagliptin plus metformin IR versus saxagliptin plus placebo and metformin IR plus placebo after 24 weeks of oral administration of double-blind therapy for the following 1 The change from baseline in fasting plasma glucose FPG . 2 The proportion of subjects achieving a therapeutic glycemic response defined as A1C 7.0 . 3 The proportion of subjects achieving a therapeutic glycemic response defined as A1C 8804; 6.5 . 4 The change from baseline in the area under the curve AUC from 0 to 180 minutes for postprandial glucose PPG response to an oral glucose tolerance test OGTT . 5 The proportion of subjects requiring rescue for failing to achieve pre-specified glycemic targets or discontinuing for lack of efficacy within the 24 week, short-term, double-blind treatment phase. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
| Signed written informed consent 1 Subjects must be willing and able to give written informed consent. Target population 2 Subjects with a diagnosis of type 2 diabetes mellitus. 3 A1C 8805; 8 but 8804; 12 obtained at the screening visit. 4 Fasting C-peptide concentration 8805; 1.0 ng/ml. 5 Subjects will be drug na ve. Drug na ve subjects are defined as subjects who have never received medical treatment for diabetes insulin and/or oral hypoglycemic agents or have received medical treatment for diabetes for less than a total of one month since original diagnosis. In addition, subjects should not have received any antihyperglycemic therapy for more than three consecutive days or a total of seven non-consecutive days during the 8 weeks prior to screening. The exceptions are for women who have received treatment for gestational diabetes during their pregnancy and are no longer receiving therapy or subjects who during a hospitalization received a short course of insulin treatment. 6 Body mass index 8804; 40 kg/m2 . Age and Sex 7 Men and women, ages 18 to 77. Women must be non-nursing and non-pregnant. Women of childbearing potential WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization hysterectomy, bilateral tubal ligation or bilateral oophorectomy or is not postmenopausal defined as amenorrhea 8805; 12 consecutive months; or women on hormone replacement therapy HRT with documented serum follicle stimulating hormone FSH level 35mIU/mL . Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods diaphragm, condoms, spermicides to prevent pregnancy or practicing abstinence or where partner is sterile e.g., vasectomy , should be considered to be of child bearing potential. 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 study medication. |
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| E.4 | Principal exclusion criteria |
| Sex and Reproductive Status 1 WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the study. 2 WOCBP using a prohibited contraceptive method. 3 Women who are pregnant or breastfeeding. 4 Women with a positive pregnancy test on enrollment or prior to study drug administration. Target Disease Exceptions 5 Symptoms of poorly controlled diabetes that would preclude participation in this active-controlled trial including but not limited to marked polyuria and polydipsia with greater than 10 weight loss during the last three months prior to screening or other signs and symptoms. 6 History of diabetic ketoacidosis or hyperosmolar nonketotic coma. 7 Insulin therapy within one year of screening with the exception of insulin therapy during a hospitalization or use in gestational diabetes . Medical History and Concurrent Diseases 8 Significant cardiovascular history defined as a History of myocardial infarction, coronary angioplasty or bypass graft s , valvular disease or repair, unstable angina pectoris, transient ischemic attack, or cerebrovascular accidents within six months prior to entry into the study. or b Congestive heart failure defined as New York Heart Association NYHA stage III and IV see Appendix 2 and/or known left ventricular ejection fraction of 8804; 40 . 9 Chronic or repeated intermittent corticosteroid treatment subjects receiving stable doses of replacement corticosteroid therapy may be enrolled . 10 History of unstable or rapidly progressing renal disease. 11 History of alcohol or drug abuse within the previous one year. 12 Unstable major psychiatric disorders. 13 Immunocompromised individuals such as subjects that have undergone organ transplantation or subjects diagnosed with human immunodeficiency virus. 14 History of hemoglobinopathies sickle cell anemia or thalassemias, sideroblastic anemia . 15 Donation of blood or plasma to a blood bank within three months of screening. 16 Administration of any other investigational drug or participation in a clinical research trial within 30 days of planned enrollment to this study or a longer period of duration if dictated by local regulatory guidelines . 17 Any condition which in the Investigator s opinion may render the subject unable to complete the study or which may pose significant risk to the subject. 18 Physical and Laboratory Test Findings 19 Active liver disease and/or significant abnormal liver function defined as AST 2x ULN and/or ALT 2x ULN and /or serum total bilirubin 2.0 mg/dL. 20 History of positive serologic evidence of current infectious liver disease including anti-HAV IgM , HbsAg, or anti-HCV. Subjects who may have isolated positive anti HBs may be included. 21 Serum creatinine Scr 8805; 1.5 mg/dL 132.6 mol/L for males and 8805; 1.4 mg/dL 123.8 mol/L for females. 22 Creatine Kinase 8805; 3x ULN. 23 Anemia, of any etiology defined as hemoglobin 8804; 12.0 g/dL 120 g/L for men and hemoglobin 8804; 11.0 g/dL 110 g/L for women. 24 Absolute lymphocyte count less than 1000 cells/mm3. 25 Platelet count 140,000 cells/ L. 26 Subjects that have an abnormal TSH value at screening will be further evaluated by free T4. Subjects with an abnormal free T4 will be excluded. Contraindications, Allergies and Adverse Drug Reactions 27 Subjects who have contraindications to therapy as outlined in the Saxagliptin Investigator Brochure, metformin package insert, or pioglitazone package insert. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To compare, after 24 weeks of oral administration of double-blind treatment, the change from baseline in A1C level achieved with saxagliptin plus metformin IR compared to saxagliptin plus placebo and to metformin IR plus placebo in treatment-na ve subjects with type 2 diabetes who have inadequate glycemic control defined as A1C 8805; 8 but 8804; 12 . |
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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 | Information not present in EudraCT |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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