| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| 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-naïve subjects with type 2 diabetes
who have inadequate glycemic control defined as A1C ≥ 8% but ≤ 12%. |
|
| E.2.2 | Secondary objectives of the trial |
-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:
1/change from baseline in fasting plasma glucose
2/proportion of subjects achieving a therapeutic glycemic response defined as A1C<7.0%
3/proportion of subjects achieving a therapeutic glycemic response defined as A1C≤6.5%
4/change from baseline in the area under the curve (AUC) from 0 to 180 minutes for postprandial glucose response to an oral glucose tolerance test
5/proportion of subjects requiring rescue for failing to achieve pre-specified
glycemic targets or discontinuing for lack of efficacy within 24 week, short-term,
double-blind phase
-Assess safety and tolerability of each dose of saxagliptin plus metformin IR, saxagliptin plus placebo and metformin IR plus placebo when administered:
1/for up to 24 weeks of short-term double-blind phase
2/in long-term extension phase |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Subjects must be willing and able to give written informed consent.
2) Subjects with a diagnosis of type 2 diabetes mellitus.
3) A1C ≥ 8% but ≤ 12% obtained at the screening visit.
4) Fasting C-peptide concentration ≥ 1.0 ng/ml.
5) Subjects will be drug naïve. Drug naïve 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 ≤ 40 kg/m2.
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 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. |
|
| 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 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.
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).
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 Protocol Appendix 2) and/or known left ventricular ejection fraction of ≤ 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) ≥ 1.5 mg/dL (132.6 µmol/L) for males and ≥ 1.4 mg/dL (123.8µmol/L) for females.
22) Creatine Kinase ≥ 3x ULN.
23) Anemia, of any etiology defined as hemoglobin ≤ 12.0 g/dL (120 g/L) for men andhemoglobin ≤ 11.0 g/dL (110 g/L) for women.
24) Absolute lymphocyte count less than 1000 cells/mm³.
25) Platelet count < 140,000 cells/µL.
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.
27) Subjects who have contraindications to therapy as outlined in the Saxagliptin
Investigator Brochure, metformin package insert, or pioglitazone package insert.
28) History of administration of any antihyperglycemic therapy for a total of one month or for more than three consecutive days or a total of seven non-consecutive days during the eight 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.
29) Use of any other antihyperglycemic medication (other than open-label rescue
pioglitazone) after enrollment (with the exception of insulin therapy during a
hospitalization for other causes).
30) Treatment with potent systemic cytochrome P450 3A4 (CYP 3A4) inhibitors or
inducers such as ketoconazole, fluconazole, itraconazole, miconazole, clotrimazole,
erythromycin, clarithromycin carbamazepine, dexamethasone, phenobarbital,
phenytoin, rifampin, or HIV antivirals such as delavirdine, indinavir, nelfinavir,
ritonavir, saquinavir or nefazodone. Also, subjects should not consume grapefruit or
grapefruit juice one hour before or one hour after taking the study medications during this study.
31) Prior treatment with saxagliptin or any DPP-IV inhibitor.
32) Prisoners or subjects who are compulsorily detained. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
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-naïve subjects with type 2 diabetes who have inadequate glycemic control defined as A1C ≥ 8% but ≤ 12%.
Secondary efficacy endpoints:
To compare 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 ≤ 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.
Primary safety measure:
The incidence of adverse events and of marked abnormalities in clinical laboratory tests. |
|
| 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 | 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) | 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
|
| 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
|
|
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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