E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes who have Inadequate Glycemic Control on Metformin Alone |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 the mean change from baseline in glycosylated hemoglobin (HbA1c) achieved with concurrent addition of saxagliptin and dapagliflozin to metformin versus the addition of placebo & saxagliptin to metformin & versus the addition of placebo plus dapagliflozin to metformin after 24 weeks of double-blind treatment. |
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E.2.2 | Secondary objectives of the trial |
To compare the mean change from baseline achieved with concurrent addition of saxagliptin and dapagliflozin to metformin vs. the addition of placebo and saxagliptin to metformin and vs. the addition of placebo plus dapagliflozin to metformin after 24 weeks of double-blind treatment in:
1. 2-hour post prandial glucose from a liquid meal tolerance test (2-h MTT)
2. Fasting plasma glucose (FPG)
• To compare the proportion of subjects achieving therapeutic glycemic response, defined as HbA1c < 7.0%, after 24 weeks of double-blind treatment with concurrent addition of saxagliptin and dapagliflozin to metformin vs. the addition placebo and saxagliptin to metformin and vs. the addition of placebo plus dapagliflozin to metformin.
• To compare the mean change in total body weight achieved with the addition of saxagliptin and dapagliflozin to metformin vs. the addition of placebo and saxagliptin to metformin. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Men and women, aged ≥ 18 years old at time of screening visit
• Subjects with T2DM with inadequate glycemic control defined as central laboratory HbA1c ≥ 8.0 and
≤ 12.0 % at the screening visit.
• Stable metformin therapy for at least 8 weeks prior to screening at a dose ≥ 1500 mg per day
• C-peptide ≥ 1.0 ng/mL (0.34 nmol/L) at screening visit
• BMI ≤ 45.0 kg/m2 at the screening visit |
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E.4 | Principal exclusion criteria |
Moderate or severe impairment of renal function [defined as eGFR <60mL/min/1.73 m2 (estimated by MDRD) or serum creatinine (Scr) ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females]
• Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg Note: Subjects with SBP ≥ 160mmHg and < 180mmHg or a DBP ≥ 100 mmHg and < 110 mmHg will be able to enter the lead-in period, provided their hypertension treatment is adjusted as deemed appropriate by the investigator. These subjects can not be randomized if their blood pressure remains SBP ≥ 160 mmHg or DBP ≥ 100 mmHg measured at Day 1.
• Cardiovascular diseases within 3 months of the screening visit
• Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency, including subjects with ALT and/or AST > 3x ULN and or Total Bilirubin > 2.5xULN.
• Male subjects with microscopic hematuria present at week -6 or -4 AND no common cause that can be confirmed. Male subjects with a confirmed common cause can be randomized with a documented
negative microscopic urinalysis. NOTE: Female subjects with hematuria can be randomized, but should be investigated according to local standards and best clinical practices. (See Appendix 3).
• Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated squamous cell carcinoma)
• Subjects who have contraindications, including but not limited to a history of serious hypersensitivity reaction to saxagliptin, as outlined in the saxagliptin and dapagliflozin Investigator Brochure, the local saxagliptin package insert or the local metformin package insert.
• Administration of any antihyperglycemic therapy, other than metformin, for more than 14 days (consecutive or not) during the 12 weeks prior to screening, as well as exposure to any DPP-4- or SGLT-2 inhibitor is an exclusion criterion.
• Current treatment with potent cytochrome P450 3A4/5 inhibitors (in countries where dose adjustment
would be required by the saxagliptin label).
Randomization Criteria Exclusion:
• FPG >270mg/dl as measured at Week -4
Note: At Week -4 a qualification check will be performed and subjects will be excluded, if their FPG is > 270 mg/dl. A re-test will be permitted within 7 days if the initial result was > 270mg/dl but < 300 mg/dl. Subjects will be excluded if the mean value of the Week -4 result and the re-test result is > 270mg/dl. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Mean change from baseline in HbA1c at Week 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline lead-in period through week 24 treatment period. |
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E.5.2 | Secondary end point(s) |
- Mean change from baseline in 2-hour post-prandial glucose during a liquid meal test (2-h MTT) at Week 24
- Mean change from baseline in fasting plasma glucose (FPG) at Week 24
- Percent of subjects achieving a therapeutic glycaemic response, defined as a HbA1c < 7.0% at Week 24
- Mean change from baseline in body weight at Week 24 with the addition of
saxagliptin and dapagliflozin to metformin vs. the addition of placebo and saxagliptin
to metformin. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline lead-in period through week 24 treatment period. |
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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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 32 |
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 | No |
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 |
Argentina |
Brazil |
Canada |
Germany |
India |
Italy |
Korea, Republic of |
Mexico |
Poland |
Puerto Rico |
Romania |
South Africa |
United States |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 23 |