| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with documented Type 2 Diabetes Mellitus treated with metformin with inadequate glycemic control. |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| 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 glycated hemoglobin (HbA1c) achieved with saxagliptin in co administration with dapagliflozin added to current background therapy with metformin compared to sitagliptin added to current background therapy with metformin at week 26. |
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| E.2.2 | Secondary objectives of the trial |
• To compare the proportion of patients achieving a therapeutic glycemic response, defined as HbA1c < 7.0%, of double-blind treatment with saxagliptin in co-administration with dapagliflozin added to current background therapy with metformin compared to sitagliptin added to current background therapy with metformin at week 26.
• To compare the mean change from baseline in total body weight achieved with saxagliptin in co administration with dapagliflozin added to current background therapy with metformin compared to sitagliptin added to current background therapy with metformin at week 26.
• To assess the mean change from baseline in Fasting Plasma Glucose (FPG) achieved with saxagliptin in co administration with dapagliflozin added to current background therapy with metformin compared to sitagliptin added to current background therapy with metformin at week 26.
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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 (or designee) must be willing and able to give signed and dated written informed consent.
2. Target Population
a) Patients with T2DM with inadequate glycemic control, defined as a central laboratory HbA1c ≥ 8.0% and ≤ 10.5 % obtained at the screening visit.
i) Note: At Week -2 (Lead-In), a qualification check will be performed and subjects will be inclusive if their FPG is ≤ 270 mg/dl (15 mmol/L). A re-test will be permitted within 7 days if the initial result was > 270mg/dl but < 300mg/dl (16.7 mmol/L). Subjects will be excluded if the mean value of the Week -2 (Lead-In) result and the re-test result is > 270mg/dl.
b) Subjects should have been taking the same daily dose of metformin ≥ 1500 mg for at least 8 weeks prior to the enrollment visit and with no intake of other antihyperglycemic therapy for more than 14 days (consecutive or not) during 12 weeks prior to screening.
c) BMI > 20.0 kg/m2 at the enrollment visit.
3. Inclusion criteria at randomization (visit 3, based on laboratory results from visit 2): a) FPG ≤ 270 mg/dL (≤ 15 mmol/L).
4. Age and Reproductive Status
a) Males and Females, age ≥ 18 years old at time of screening visit.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs: Saxagliptin, Dapagliflozin and Sitagliptin (30 days) plus 30 days (duration of ovulatory cycle) for a total of 60 days post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs: Saxagliptin, Dapagliflozin and Sitagliptin plus 5 half-lives of the study drug (30 days) plus 90 days (duration of sperm turnover) for a total of 120 days post-treatment completion.
f) Azoospermic males and WOCBP who are not continuously heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in protocol. |
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| E.4 | Principal exclusion criteria |
1.Target Disease Exceptions
a) Clinically diagnosed with Type I diabetes, known diagnosis of Maturity Onset Diabetes of Young (MODY), secondary diabetes mellitus or diabetes insipidus.
b) History of diabetic ketoacidosis
2. Medical History and Concurrent Diseases
a) Any of the following CV/Vascular Diseases within 3 months of the enrollment visit: Myocardial infarction, cardiac surgery or revascularization, unstable angina, unstable congestive heart failure, transient ischemic attack or significant cerebrovascular disease, unstable or previously uniagnosed arrhythmia, congestive heart failure or unstable or acute congestive heart failure and/or known left ventricular ejection fraction of ≤ 40%.
b) Renal Disease: History of unstable or rapidly progressing renal disease, impairment of renal function, history of unexplained microscopic or gross hematuria, or microscopic hematuria at screening, confirmed by a follow-up sample at next scheduled visit, where according to the investigator a satisfactory evaluation of hematuria has not been conducted based on guidance in Section 5.3.2. Not applicable as per Protocol Amendment Number 1, hematuria (confirmed by microscopy at screening) with no explanation as judged by the investigator up to randomization. If bladder cancer is identified, subjects are not eligible to participate.
c) Hepatic/GI Diseases: severe hepatic insufficiency and/or significant abnormal liver function, serum total bilirubin (TB) > 2 mg/dL (> 34.2 μmol/L) at the time of screening, history of, or current, acute pancreatitis, severe hepatic disease, including chronic active hepatitis. Positive serologic evidence of current infectious liver disease, including patient's positive for Hepatitis B viral antibody IgM, Hepatitis B surface antigen, and Hepatitis C virus antibody
d) Hematological and Oncological Disease/Conditions: History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or chronic or recurrent hemolysis, history of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time
3.Physical and Laboratory Test Findings at the time of screening
a) Hemoglobin ≤110 g/L for men; hemoglobin ≤ 100 g/L for women
b) Abnormal Free T4
c) Any clinically significant abnormality identified on physical examination, ECG or laboratory tests, which in the judgment of the investigator would compromise the patient’s safety or successful participation in the study
4. Other Exclusion Criteria
a) Subjects who have contraindications to therapy as outlined in the saxagliptin and dapagliflozin Investigator Brochure, the local saxagliptin or dapagliflozin package insert or the local metformin package insert, or the local sitagliptin package insert, including current treatment with potent cytochrome P450 3A4/5 inhibitors
b) Prisoners or subjects who are involuntarily incarcerated
c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
d) Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program
e) History of bariatric surgery or lap-band procedure within 6 months prior to screening
f) Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic corticosteroid taken for > 4 weeks within 3 months prior to the Day 1 visit ( Topical, nasal, or inhaled corticosteroids are allowed)
g) Any unstable endocrine, psychiatric or rheumatic disorders as judged by the Investigator
h) Volume-depleted subjects. Subjects at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics, should carefully monitor their volume status
i) Subject with any condition which, in the judgment of the Investigator, may render the subject unable to complete the study or which may pose a significant risk to the subject or subject suspected or with confirmed poor protocol or medication compliance
j) Subject is currently abusing alcohol or other drugs or has done so within the last 6 months prior to the screening visit
k) Subject is a participating investigator, study coordinator, employee of an investigator or immediate family member of any of the aforementioned.
l) Involvement in the planning and/or conduct of the study (applies to both AstraZeneca/BMS staff and/or staff at the study site)
m) Previous enrollment or randomization in the present study
n) Administration of any other investigational drug within 30 days of the screening visit
o) Clinical conditions or clinically significant abnormalities, in any laboratory value(s) collected after screening and prior to randomization which, in the Investigator’s judgment, should preclude entry into the treatment period |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for analysis is change from baseline to week 26 in HbA1c.
A repeated measures analysis (using a MIXED model) will be used to analyze the change from baseline in HbA1c at Week 26. The model will contain terms for treatment group, baseline measurement, time (each relevant visit), the interaction of treatment and time, and the interaction of baseline value and time. Descriptive statistics as well as adjusted means and 95% confidence intervals will be calculated for the change from baseline in HbA1c as well as for the difference between treatment groups.
The primary endpoint analysis will be repeated using all available values including those after rescue/intensification and also using all available data and including a time varying covariate which indicates rescue status.
The comparator (sitagliptin) will be tested against saxagliptin/dapagliflozin for the primary endpoint at the alpha = 0.05 level (two-sided). The secondary endpoints (described below) will then be tested sequentially. Each comparison will be tested at the alpha = 0.05 (two-sided) level. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The timepoints will be evaluated on specified visits per schedule of assessments.
|
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints for analysis include:
1) Percent of subjects achieving a therapeutic glycemic response (HbA1c < 7 %) at Week 26
2) Mean change from baseline in total body weight at Week 26
3) Mean change from baseline in Fasting Plasma Glucose (FPG) at Week 26 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The timepoints will be evaluated on specified visits per schedule of assessments.
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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 | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 30 |
| 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 |
| Hungary |
| Mexico |
| Poland |
| Romania |
| South Africa |
| United States |
|
| 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
|
| At the end of the study period (Week 52), the sponsor will not continue to supply study drug (saxagliptin or dapagliflozin) to subjects/investigators unless the sponsor chooses to extend the study. The investigator should ensure that the subject receives appropriate standard of care to treat the condition under study. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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