| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Inadequately controlled Diabetes Mellitus Type 2. |
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| E.1.1.1 | Medical condition in easily understood language |
| Inadequately controlled Diabetes Mellitus Type 2. |
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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 | 20.0 |
| 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 HbA1c achieved with saxagliptin, in co-administration with dapagliflozin, added to current background therapy with metformin, compared to glimepiride added to current background therapy with metformin at Week 52. |
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| E.2.2 | Secondary objectives of the trial |
- Compare the mean change from baseline in total body weight achieved with saxagliptin in co-administration with dapagliflozin, added to current background therapy (CBT) with metformin, compared to glimepiride added to CBT with metformin at W52.
- Compare the proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%, at W52 with saxagliptin in co-administration with dapagliflozin added to CBT with metformin, compared to glimepiride added to CBT with metformin.
- Compare the mean change from baseline in systolic blood pressure (SBP) achieved with saxagliptin in co-administration with dapagliflozin added to CBT with metformin, compared to glimepiride added to CBT with metformin at W52.
- Compare the time to treatment intensification achieved with saxagliptin in co-administration with dapagliflozin added to CBT with metformin, compared to glimepiride added to current CBT during the 52 week double-blind treatment period. Objectives continued in protocol. |
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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) Subjects with T2DM with inadequate glycemic control, defined as a central laboratory HbA1c >= 7.5% and <= 10.5% obtained at the screening visit.
i) Note: The proportion of subject with HbA1c 7.5 % - 8.5 % will be capped at 40%.
ii) Note: At Week -2 (Lead-In), a qualification check will be performed and subjects will be included if their FPG is <= 270 mg/dL. A re-test will be permitted within 7 days if the initial result was > 270mg/dL but < 300mg/dL. 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 be taking the same daily dose of metformin >=1500 mg for at least 8 weeks prior to the enrollment visit and must not take any other antihyperglycemic therapy for more than 14 days (consecutive or not) during 12 weeks prior to screening.
c) BMI 20.0 to 45.0 kg/m2 (inclusive) at the enrollment visit.
d) Subject Re-enrollment: This study permits the re-enrollment of a subject who has been discontinued from the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated). If re-enrolled, the subject must be re-consented.
Inclusion criteria at randomization (Visit 3, based on laboratory results from Visit 2):
a) FPG <= 270 mg/dL (<=15 mmol/L).
For inclusion in the MRI-PDFF sub-study and/or CGM sub-study, subjects must fulfill the following criteria:
a) Provision of informed consent for the MRI-PDFF and/or CGM sub-study.
b) BMI 20.0 to 40.0 kg/m2 (inclusive) at the enrollment visit and upper weight of 140 kg max (MRI-PDFF sub-study only).
If a subject declines to participate in the MRI-PDFF sub-study or CGM sub-study, there will be no consequences for the subject’s participation in the main study. The subject will not be excluded from other aspects of the study described in this Clinical Study Protocol, as long as proper consent is obtained.
3. Age and Reproductive Status
a) Males and females, aged >=18 years old at the time of the 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, and dapagliflozin, and glimepiride plus 5 half-lives of study drugs: saxagliptin, dapagliflozin, and glimepiride (30 days) plu 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 glimepiride 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 continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% per year when used consistently and correctly.
Highly effective contraception methods are outlined in section 3 of the inclusion criteria in the protocol. |
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| E.4 | Principal exclusion criteria |
Target Disease Exceptions
a) Clinical diagnosis of type I DM, known diagnosis of mature onset MODY, secondary DM, or diabetes insipidus.
b) History of diabetic ketoacidosis
2. Medical History and Concurrent Diseases
a) Any of the following cardiovascular/vascular diseases within 3 months of the enrollment:
i) MI
ii) Cardiac surgery or revascularization (CABG/PTCA)
iii) Unstable angina
iv) Unstable CHF
v) TIA or significant cerebrovascular disease
vi) Unstable or previously undiagnosed arrhythmia
vii) CHF, defined as NYHA Class III and IV, unstable or acute CHF and/or known left ventricular EF of <=40%.
Note: eligible patients with CHF, especially those who are on diuretic therapy, should have careful monitoring of their volume status.
b) Renal disease (RD):
i) History of unstable or rapidly progressing RD
ii) Impairment of renal function ( CrCl < 60 mL/min
or serum creatinine >=1.5 mg/dL in males or >= 1.4 mg/dL in females).
iii) 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.
c) Hepatic diseases (HD) :
i) Severe hepatic insufficiency and/or significant abnormal liver function AST> 3x ULN and/or ALT > 3x ULN.
ii) Serum total bilirubin > 2.0 mg/dL.
iii) Severe HD, including chronic active hepatitis. Positive serologic evidence of current infectious liver disease, including subjects who are positive for HBV viral antibody IgM, HBV surface antigen, and HCV antibody.
d) Pancreatic disease
i) History of, or current, acute or chronic pancreatitis.
e) Hematological and oncological disease/conditions:
i) History of hemoglobinopathy, with the exception of sickle cell trait or
thalassemia minor; or chronic or recurrent hemolysis.
ii) Malignancy within 5 years of the screening (with the exception of treated BCC or treated SCC).
iii) History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time.
3. Physical and Laboratory Test Findings
a) Hb <=11.0 g/dL (110 g/L) for men; Hb <=10.0 g/dL (100 g/L) for women.
b) An abnormal TSH value at enrollment will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded. (Please refer to the study protocol for re-test conditions)
c) Any clinically significant abnormality identified on PE, ECG or laboratory tests, which in the judgment of the investigator would compromise the subjects’ safety or successful participation in the study.
4. Allergies and ADR
a) Subjects who have contraindications to therapy as outlined in the saxagliptin and dapagliflozin IBs, the local saxagliptin or dapagliflozin or glimepiride or metformin package insert, including current treatment with potent P450 3A4/5 inhibitors (in countries where dose adjustment would be required by the local saxagliptin label).
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.
c) Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program.
d) Subjects who are taking any prescription or OTC medications for weight loss within 3 months of the screening visit.
e) History of any bariatric surgical procedure, Nissen fundoplication, or other procedures that can affect endogenous GLP-1 levels 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
i) NOTE: Topical 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 (both Sponsor staff and/or staff at the study site).
m) Previous randomization in the present study.
n) Administration of any other investigational drug within 30 days of the screening
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 52 in HbA1c.
A repeated measures analysis (using a MIXED model) will be used to analyze the change from baseline in HbA1c at Week 52 using values prior to rescue/intensification of treatment. 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 (glimepiride) will be tested against saxagliptin/dapagliflozin for the primary endpoint at the alpha = 0.05 level (2-sided). The secondary endpoints (described below) will then be tested sequentially. Each comparison will be tested at the alpha = 0.05 (2-sided) level. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints for analysis for the short-term treatment period include:
- Mean change from baseline in total body weight at Week 52
- Proportion of subjects achieving a therapeutic glycemic response (HbA1c < 7.0 %) at Week 52.
- Mean change from baseline in systolic blood pressure (SBP) at Week 52.
- Time to treatment intensification (addition of insulin or other glucose-lowering agents for rescue therapy or discontinuation for lack of glycemic control) during the 52-week double-blind controlled treatment period.
Secondary endpoints for analysis for the long-term treatment period include:
- Time to treatment intensification (addition of insulin or other glucose-lowering agents for rescue therapy or discontinuation for lack of glycemic control) during the 156-week treatment period.
- Proportion of subjects achieving therapeutic glycemic response (HbA1c < 7.0%) at Week 156. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 52 for secondary endpoints for analysis for the short-term treatment period. Week 156 for secondary endpoints for analysis for the long-term 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 | 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) | 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 |
| Czech Republic |
| Germany |
| Hungary |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Sweden |
| United Kingdom |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 26 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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