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 | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063624 |
E.1.2 | Term | Type II 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 4 weeks of oral administration of double-blind treatment, the change from baseline in 24-hour mean weighted glucose achieved with saxagliptin 5 mg versus placebo as add on treatment to a stable dose of metformin XR ≥ 1500 mg/day. |
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E.2.2 | Secondary objectives of the trial |
1) Change from baseline to Week 4 (Day 28) in 4-hour mean weighted postprandial glucose (after the evening meal). 2) Change from baseline to Week 4 (Day 28) in 2-hour postprandial plasma glucose (PPG, 2-hour after the evening meal). 3) Change from baseline to Week 4 (Day 28) in mean daily glucose (calculated as 7 daily, finger stick glucose measurements (pre-meal, 2-hour post-meal and at bedtime). Mean daily glucose will be calculated based on finger stick glucose measurements collected by the subjects at home in a 3-day period, prior to collection of the 24-h blood samples. 4) Change from baseline to Week 4 (Day 28) in fasting plasma glucose (FPG). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent a) Subjects must be willing and able to give written informed consent. 2) Target Population a) Subjects with a diagnosis of type 2 diabetes mellitus requiring treatment with at least 1500 mg, but not greater than 2550 mg of a stable dose of metformin IR or XR as monotherapy for at least 8 weeks prior to screening are eligible b) A1C ≥ 7% and ≤ 10% obtained at the screening visit. c) Fasting C-peptide concentration ≥ 1.0 ng/ml at the screening visit. d) Body mass index ≤ 40 kg/m2 at the screening visit. 3) Age and Sex a) Men and women, ages 18 to 77 years of age. 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 last dose of investigational product 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. Post menopause is defined as: • Amenorrhea ≥ 12 consecutive months without another cause or • For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL. Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing 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 investigational product. |
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E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study and for up to 4 weeks after the last dose of investigational product. b) WOCBP using a prohibited contraceptive method. c) Women who are pregnant or breastfeeding. d) Women with a positive pregnancy test on enrollment or prior to investigational product administration.
2) Target Disease Exceptions a) Symptoms of poorly controlled diabetes that would preclude participation in this placebo-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. b) History of diabetic ketoacidosis or hyperosmolar nonketotic coma. c) Insulin therapy within one year of screening (with the exception of insulin therapy during a hospitalization or use in gestational diabetes.
3) Medical History and Concurrent Diseases a) Significant cardiovascular history defined as: i) 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 study entry. ii) Congestive heart failure defined as New York Heart Association (NYHA) stage III and IV and/or known left ventricular ejection fraction of ≤ 40%. b) Chronic or repeated intermittent corticosteroid treatment (subjects receiving stable doses of replacement corticosteroid therapy may be enrolled). c) History of unstable or rapidly progressing renal disease. d) History of alcohol or drug abuse within the previous one year. e) Unstable major psychiatric disorders. f) Immunocompromised individuals such as subjects who have undergone organ transplantation or subjects diagnosed with human immunodeficiency virus. g) History of hemoglobinopathies (sickle cell anemia or thalassemias, sideroblastic anemia). h) Donation of blood or plasma to a blood bank within three months of screening. i) Administration of any other investigational drug or participation in a clinical research trial within 30 days of planned enrollment to this study. j) 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.
4) Physical and Laboratory Test Findings a) Active liver disease and/or significant abnormal liver function defined as AST > 2 x ULN and/or ALT > 2x ULN and /or serum total bilirubin > 2.0 mg/dl. b) 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. c) Serum creatinine (Scr) ≥ 1.5 mg/dl (132.6 μmol/L) for males and ≥ 1.4 mg/dl (123.8 μmol/L) for females. d) Creatine Kinase ≥ 3x ULN. e) Anemia, of any etiology defined as hemoglobin ≤ 12.0 g/dL (120 g/L) for men and hemoglobin ≤ 11.0 g/dL (110 g/L) for women. f) Subjects who have an abnormal TSH value at screening will be further evaluated by free T4. Subjects with an abnormal free T4 will be excluded.
5) Allergies and Adverse Drug Reactions a) Subjects who have contraindications to therapy as outlined in the Saxagliptin Investigator Brochure, metformin XR/metformin package insert package insert.
6) Prohibited Therapies and/or Medications a) History of administration of any antihyperglycemic therapy (other than a 1500 mg to 2550 mg maximum daily dose of Metformin IR or XR) during the eight weeks prior to screening. b) Use of any other antihyperglycemic medication (other than a 1500 mg to 2000 mg daily dose of Metformin XR) after enrollment (with the exception of insulin therapy during a hospitalization for other causes). c) Treatment with systemic cytochrome P450 3A4 (CYP 3A4) inducers (see protocol Section 5.5.1). d) Prior treatment with saxagliptin or any DPP IV inhibitor.
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 (eg, infectious disease) illness. |
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E.5 End points |
E.5.1 | Primary end point(s) |
*Primary Endpoint: The primary efficacy variable is the change in 24-hour mean weighted glucose (MWG) from baseline to Week 4.
*Secondary Endpoints: 1) Change from baseline to Week 4 in 4-hour mean weighted postprandial glucose (after the evening meal) 2) Change from baseline to Week 4 (Day 28) in 2-hour postprandial plasma glucose (2-h PPG after the evening meal) 3) Change from baseline to Week 4 (Day 28) in mean daily glucose (calculated as 7 daily, finger stick glucose measurements (pre meal, 2-hour post meal and at bedtime). Mean daily glucose will be calculated based on finger stick glucose measurements collected by the subjects at home in a 3-day period, prior to the collection of 24-h blood samples. 4) Change from baseline to Week 4 (Day 28) in fasting plasma glucose (FPG) using last observation carried forward (LOCF) methodology. |
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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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
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 | 15 |
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 | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |