Evaluation of Dapagliflozin Taken Twice-daily

Study Overview
=================
Brief Summary
-----------------
This study is being carried out to see if dapagliflozin - administered in a daily dose of 2.5 mg given twice a day or 5 mg twice a day or 10mg once daily - in addition to metformin, is beneficial in diabetes treatment, and if so, how it compares to treatment with metformin alone.

Official Title
-----------------
A 16-week, Multicentre, Randomised, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Safety and Efficacy of Dapagliflozin 2.5 mg BID, 5 mg BID and 10 mg QD Versus Placebo in Patients With Type 2 Diabetes Who Are Inadequately Controlled on Metformin-IR Monotherapy

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: dapagliflozin
* Drug: dapagliflozin
* Drug: dapagliflozin
* Drug: metformin
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of informed consent prior to any study specific procedures Diagnosis of T2DM Current antihyperglycaemic treatment with metformin immediate release formulation monotherapy >/= 1500 mg/day at a stable dose for at least 10 weeks prior to enrolment. Other treatment with OADs within the 10 weeks prior to enrolment is not permitted. HbA1c ≥ 6.7% and ≤10.5%, based on central laboratory values from Screening Visit, and Enrolment Visit 1. Exclusion Criteria: Diagnosis of Type 1 diabetes mellitus, known diagnosis of Maturity Onset Diabetes of the Young (MODY) or secondary causes of diabetes mellitus History of diabetic ketoacidosis Symptoms of poorly controlled diabetes including, but not limited to, marked polyuria, polydipsia, and/or greater than 10% weight loss during the 3 months prior to enrolment FPG >270 mg/dL (>15.0 mmol/L) BMI >45 kg/m2

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 77 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Dapagliflozin 2.5 mg twice-daily plus open-label metformin | Drug: dapagliflozin<br>* 2.5 mg tablet, taken orally, twice daily<br>Drug: metformin<br>* >/= 1500 mg total daily dose, tablets taken orally, twice daily<br>|
| Experimental: 2<br>Dapagliflozin 5.0 mg twice-daily plus open-label metformin | Drug: dapagliflozin<br>* 5 mg tablet taken orally, twice daily<br>Drug: metformin<br>* >/= 1500 mg total daily dose, tablets taken orally, twice daily<br>|
| Experimental: 3<br>Dapagliflozin 10 mg once-daily plus open-label metformin | Drug: dapagliflozin<br>* 10 mg tablet taken orally, once daily<br>Drug: metformin<br>* >/= 1500 mg total daily dose, tablets taken orally, twice daily<br>|
| Placebo Comparator: 4<br>Placebo plus open-label metformin | Drug: metformin<br>* >/= 1500 mg total daily dose, tablets taken orally, twice daily<br>Drug: placebo<br>* placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change in HbA1c Levels | To compare the change from baseline in HbA1c achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Percent Change in Body Weight | To compare the percent change from baseline in body weight achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID, and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. | Baseline to Week 16 | 
| Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 1 | To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 1 week of double-blind treatment. | Baseline to Week 1 | 
| Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. | Baseline to Week 16 | 
| Proportion of Participants With HbA1c<7.0% at Week 16, in Participants Who Had HbA1c ≥7.0% at Baseline. | To compare the adjusted proportions controlling for baseline HbA1c [acc. to Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu] of participants with HbA1c <7.0% achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment, in patients who had HbA1c ≥7.0% at baseline. | Baseline to Week 16 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 2 diabetes, metformin treated, inadequate control, metformin treatment alone