A 52-week International, Phase 3bTrial with a Blinded 104-week Long - term Extension Period to Evaluate Saxagliptin Co-administered with Dapagliflozin in combination with Metformin Compared to Glimepiride in Combination with Metformin in Patients with Type 2 Diabetes

Phase 1

• Conditions: Inadequately controlled Diabetes Mellitus Type 2.; MedDRA version: 20.0Level: PTClassification code 10067585Term: Type 2 diabetes mellitusSystem Organ Class: 10027433 - Metabolism and nutrition disorders; Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

• Registration Number: EUCTR2014-003721-18-PL
• Lead Sponsor: AstraZeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2015-07-29
• Last Update Posted: 29 April 2020

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 444

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 subj

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified