| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
|
| 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 the effects of saxagliptin versus placebo as add-on therapy to insulin (or to insulin combined with metformin) in improving glycemic control (A1C) at 24 weeks (or rescue). |
|
| E.2.2 | Secondary objectives of the trial |
To compare the effects of saxagliptin versus placebo as add-on therapy to insulin (or to insulin combined with metformin) for the following:
• The change from baseline to Week 24 (or rescue) in the postprandial glucose area
under the curve (AUC) from 0 to 180 minutes in response to a meal tolerance test
• The change from baseline to Week 24 (or rescue) in the 120-minute postprandial
plasma glucose (PPG) value in response to a meal tolerance test
• The change in fasting plasma glucose (FPG) from baseline to Week 24 (or rescue)
• The proportion of subjects achieving a therapeutic glycemic response at Week 24 (or rescue), defined as A1C < 7%
• The change in mean total daily insulin dose from baseline to Week 24 |
|
| 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) Subjects must be on a stable dose of insulin (≥ 30 units/day, ≤ 150 units/day) with
≤ 20% variation in total daily dose for ≥ 8 weeks prior to screening, with only
occasional exceptions (≤ one day/week). For example, if the subject is taking
50 units/day of insulin, the total daily doses in the past 8 weeks should not have
exceeded 60 units, or been less than 40 units. However, occasional deviations (≤ one
day/week) during this time period are permitted.
4) Subjects’ insulin type should be intermediate-acting or long-acting (basal) or
pre-mixed (pre-mixed formulation may include short- or rapid-acting insulin as one
component).
5) Among subjects taking metformin, subjects should have been taking the same daily dose of metformin for ≥ 8 weeks prior to screening, if applicable.
6) A1C measured at screening ≥ 7.5% and ≤ 11.0%. Note that A1C will be re-checked
near the end of the lead-in period, at Day -5, and must again be ≥ 7.5% and ≤ 11.0%
for subject to be randomized.
7) Fasting C-peptide ≥ 0.8 ng/mL (≥ 0.26 nmol/L).
8) Body mass index ≤ 45 kg/m²
9) Men and women, ages 18 to 78 (inclusive).
Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout 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. 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. |
|
| 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.
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 investigational
product administration.
5) Symptoms of poorly controlled diabetes that would preclude participation in this 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) Significant cardiovascular history defined as:
a) within six months prior to screening, subject has had history of myocardial
infarction, coronary angioplasty or bypass graft(s), valvular disease or repair,
unstable angina pectoris, transient ischemic attack, or cerebrovascular accident.
b) Congestive heart failure defined as New York Heart Association (NYHA) stage
III and IV (see Appendix 3) and /or known left ventricular ejection fraction of < 40%.
8) Chronic or repeated intermittent corticosteroid treatment (subjects receiving stable doses of replacement corticosteroid (except dexamethasone) therapy may be
enrolled).
9) History of unstable or rapidly progressing renal disease.
10) History of alcohol or drug abuse within the previous year.
11) Unstable major psychiatric disorders.
12) Immunocompromised individuals such as subjects that have undergone organ
transplantation or subjects diagnosed with human immunodeficiency virus.
13) History of hemoglobinopathies (sickle cell anemia or thalassemias, sideroblastic
anemia).
14) Donation of blood or plasma to a blood bank within three months of screening.
15) Administration of any other investigational drug or participation in a clinical research trial within 30 days of entry into Lead-in Period to this study.
16) 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.
17) 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 (34.2 micromoles/L).
18) 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 (ie indicating immunity to hepatitis B infection or previous vaccination) may be
included.
19) Serum creatinine (Scr) ≥ 1.5 mg/dL (132.6 μmol/L) for males and ≥ 1.4 mg/dL
(123.8 μmol/L) for females, or calculated creatinine clearance (by Cockcroft-Gault
equation) < 60 ml/min.
20) Creatine Kinase ≥ 3x ULN.
21) 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.
22) 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.
23) Subjects who have contraindications to therapy as outlined in the Saxagliptin
Investigator Brochure or insulin or metformin (if applicable) package inserts.
24) Subject is using short- or rapid-acting insulin that is not part of a pre-mixed
formulation.
25) History of administration of any antihyperglycemic therapy (other than metformin, if applicable, or insulin) for more than 3 consecutive days or seven non-consecutive days during the eight weeks prior to screening.
26) Use of any other antihyperglycemic medication (other than metformin, if applicable, or insulin) after Entry into the Lead-In Period.
27) Treatment with potent systemic cytochrome P450 3A4 (CYP 3A4) inducers such as
carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin or HIV antivirals
such as delavirdine, indinavir, nelfinavir, ritonavir, saquinavir or nefazadone.
28) Prior treatment with saxagliptin or any DPP-IV inhibitor.
29) Prisoners or subjects who are involuntarily incarcerated.
30) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
*Primary Efficacy Outcome Measures:
The primary efficacy variable is the change in A1C from baseline to Week 24 (or rescue) or the last postbaseline measurement prior to the time-point, if no Week 24 assessment is available.
*Primary Safety Outcome Measures:
The incidence of adverse events and of marked abnormalities in clinical laboratory tests in all subjects throughout the study. |
|
| 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 | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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