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 |
The primary endpoint is the change in A1C from baseline to Week 12 (or the last post baseline measurement prior to Week 12, if no Week 12 assessment is available). The primary comparison is between the saxagliptin 2.5 mg BID (plus stable background metformin IR) and placebo (plus stable background metformin IR) treatment groups. |
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E.2.2 | Secondary objectives of the trial |
Comparison of saxagliptin 2.5 mg or placebo in combination with metformin IR following 12 weeks of double-blind therapy for the following secondary objectives: 1. The mean change from baseline in FPG. 2. The proportion of subjects who will achieve a therapeutic glycemic response defined as A1C < 7.0%. 3. The proportion of subjects who will achieve a therapeutic glycemic response defined as A1C ≤ 6.5% |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Signed Written Informed Consent 1) Subjects must be willing and able to give written informed consent. 2) Subjects with a diagnosis of type 2 diabetes mellitus. 3) Subjects must be on a stable, BID dosing of at least 1500 mg of metformin IR for ≥ 8 weeks prior to enrollment. 4) Subjects must have a A1C ≥ 7.0% and ≤ 10.0% at screening to be randomized. 5) Subjects must have a fasting C-peptide ≥ 0.8 ng/mL (0.34 nmol/L) at screening. 6) Subjects must have a body mass index ≤ 45.0 kg/m2. 7) Men and women, ages 18 to 78 (inclusive). WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study, and up to 4 weeks after last study drug was taken 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.
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E.4 | Principal exclusion criteria |
1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and up to 4 weeks after the final dose of study drug. 2) Women who are pregnant or breastfeeding. 3) Women with a positive urine HCG pregnancy test at randomization or prior to investigational product administration. 4) Sexually active fertile men not using effective birth control for the entire study period and up to 4 weeks after last study drug was taken if their partners are WOCBP. 5) Symptoms of poorly controlled T2DM including, but not limited to marked polyuria and polydipsia, with a greater than 10% weight loss during the 3 months prior to screening or other signs and symptoms 6) History of diabetic ketoacidosis or hyperosmolar nonketotic coma. 7) Insulin therapy within 1 year of screening (with the exception of insulin therapy during a hospitalization or use in pregnant women with gestational diabetes). 8) Significant cardiovascular history defined as: a) History of myocardial infarction, coronary artery or bypass graft(s), valvular disease or repair, unstable angina pectoris, transient ischemic attack, or cerebral vascular event within 3 months prior to entry into the study or, b) Congestive heart failure defined as New York Heart Association (NYHA) stage III or IV and / or known left ventricular ejection fraction ≤ 40% 9) History of hemoglobinopathies 10) Chronic or repeated intermittent corticosteroid treatment. 11) History of unstable or rapidly progressive renal disease. 12) History of alcohol or drug abuse within 1 year prior to enrollment. 13) Unstable psychiatric disorders. 14) 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). 15) 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. 16) Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program. 17) FPG > 270 mg/dL prior to randomization. 18) Active liver disease and/or significant abnormal liver function (defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 x ULN and/or serum total bilirubin > 2.0 mg/dL). 19) 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. 20) Serum creatinine (Scr) ≥ 1.50 mg/dL (133 μmol/L) for male subjects and ≥ 1.40 mg/dL (124 μmol/L) for female subjects. 21) Anemia of any etiology defined as hemoglobin ≤ 12.0 g/dL (120 g/L) for men and ≤ 11.0 g/dL (110 g/L) for women. 22) Creatinine kinase (CK ) ≥ 3X ULN. 23) Subjects that have an abnormal TSH value at screening will be further evaluated by free T4. Subjects with an abnormal T4 will be excluded. 24) Clinically significant (CS) abnormalities in any pre-randomization laboratory analyses or ECG that, in the Investigator’s opinion, would preclude randomization. 25) Subjects who have contraindications to therapy as outlined in the Saxagliptin Investigator Brochure or local metformin IR package insert. 26) Subjects with known contraindications to DPP-IV therapy. 27) Treatment with potent systemic cytochrome P450 3A4 (CYP3A4) inducers 28) History of administration of any antihyperglycemic therapy (other than metformin IR as applicable) for more than 3 consecutive days or 7 non-consecutive days during the 8 weeks prior to screening. 29) Use of any other antihyperglycemic medication (other than metformin IR as applicable) after entry into the lead-in period (with the exception of insulin therapy during a hospitalization for other causes). 30) Prior treatment with saxagliptin. 31) Use of any prescription weight loss medication within 8 weeks prior to screening. 32) Any history of, or plans for during the course of the clinical trial, weight loss surgery 33) Subjects taking prohibited medication. 34) Prisoners or subjects who are involuntarily incarcerated. 35) Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness. 36) Subjects that do not demonstrate good compliance during the lead-in period with study drug and metformin IR (≥ 80% and ≤ 120%, each) 37) History of malignancy (except subjects who have been disease-free for > 5 years), except if the malignancy was a basal or squamous cell skin carcinoma. Women with a history of cervical dysplasia (CIN2 or higher) should be excluded unless 2 consecutive normal cervical smears have subsequently been recorded prior to enrollment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in A1C level from baseline to Week 12, (or the last post baseline measurement prior to Week 12, if no Week 12 assessment is available) |
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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 | Yes |
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.8.3 |
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 | Information not present in EudraCT |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 | |
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 | 9 |