Evaluate Efficacy, Safety and Tolerability of AZD1656 as Add-on Treatment to Metformin in Type 2 Diabetes Mellitus (TD2M) Patients

Study Overview
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Brief Summary
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The primary aim is to evaluate Efficacy, Safety and Tolerability of AZD1656 as Add-on Treatment to Metformin in TD2M Patients

Official Title
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A 4-month, Randomized, Double-blind, Placebo- and Active-Controlled, Multi-centre, Parallel-Group Study, With an Optional 2-month Extension, to Evaluate Efficacy, Safety and Tolerability of AZD1656 as Add-on Treatment to Metformin in Type 2 Diabetes Mellitus Patients

Conditions
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Type II Diabetes Mellitus

Intervention / Treatment
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* Drug: AZD1656
* Drug: Placebo
* Drug: Glipizide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: female of non-childbearing potential Treated with maximally tolerated dose of metformin (≥ 1500mg/day) for at least 10 weeks prior to enrolment. Patients with HbA1c ≥ 7.5 but ≤ 10% at enrolment visit (Visit 1) can enter cohort 1.Patients with HbA1c between >10 % and <12 % can enter the open-label arm with AZD1656 (cohort 2) Exclusion Criteria: Significant cardiovascular event within the last 6 months prior to enrolment or heart failure New York Heart Association (NYHA) class III-IV. Impaired renal function in terms of GFR<60 ml/min, based on Modification of Diet in Renal Disease Study Group (MDRD) calculation. Use of warfarin or amiodarone within 3 months prior to enrolment (screening) and use of potent CYP450 inhibitors, eg, ketoconazole and/or macrolide antibiotics within 14 days before randomisation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>AZD1656 | Drug: AZD1656<br>* Different doses of AZD1656 administered to 5 groups of patients<br>|
| Experimental: 2<br>AZD1656 | Drug: AZD1656<br>* Different doses of AZD1656 administered to 5 groups of patients<br>|
| Experimental: 3<br>AZD1656 | Drug: AZD1656<br>* Different doses of AZD1656 administered to 5 groups of patients<br>|
| Experimental: 4<br>AZD1656 | Drug: AZD1656<br>* Different doses of AZD1656 administered to 5 groups of patients<br>|
| Experimental: 5<br>AZD1656 | Drug: AZD1656<br>* Different doses of AZD1656 administered to 5 groups of patients<br>|
| Placebo Comparator: 6<br> | Drug: Placebo<br>* AZD1656 placebo and glipizide placebo administered to 1 group of patients<br>|
| Active Comparator: 7<br>Glipizide administered to 1 group of patients | Drug: Glipizide<br>* Glipizide administered to 1 group of patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c: Change From Baseline to 4 Month | AZD1656 is analyzed in a ANCOVA model (Glipized and Open Label is Not Included in the model), FAS Prior to Rescue | Baseline to 4th Month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FPG: to Evaluate Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | AZD1656 is analyzed in a ANCOVA model (Glipized and Open Label is Not Included in the model), FAS Prior to Rescue. | baseline to 4 month | 
| SMPG: Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | AZD1656 is analyzed in a ANCOVA model (Glipized and Open Label is Not Included in the model), FAS Prior to Rescue. | baseline to 4 month | 
| OGTT/Plasma Glucose | The relative change in AUC | baseline to 4 month | 
| OGTT/Insulin | The Relative Change in AUC FAS Prior to Rescue | baseline to 4 month | 
| OGTT/C-peptide | The relative change, FAS prior to rescue | baseline to 4 month | 
| OGTT/Pro-insulin/Insulin | The relative change, FAS prior to rescue | baseline to 4 month | 
| HbA1c ≤ 7 | Number of responders ≤ 7, FAS prior to rescue. | baseline to 4 month | 
| HbA1c ≤ 6.5 | Number of Responders ≤ 6.5, FAS Prior to Rescue | baseline to 4 month | 
| LDL-C: Mean Ratio | Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI. | baseline to 4 month | 
| HDL-C: Change From Baseline | Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI. | baseline to 4 month | 
| Total Cholesterol: Change From Baseline | Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI. | baseline to 4 month | 
| Triglycerides: Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| C-reactive Protein: Change From Baseline | Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI | baseline to 4 month | 
| Systolic Blood Pressure, Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Diastolic Blood Pressure, Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Pulse, Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Weight, Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| QTcF; Electorcardiagram Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Haemoglobin; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Leukocytes; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Sodium; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Potassium; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Creatinine; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| ALT; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| AST; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Alkaline Phosphatase; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| Bilirubin; Change From Baseline | Summary statistic of change from baseline | baseline to 4 month | 
| CL/F to Characterise the PK Properties of AZD1656. | The value is calculated using an allometric model (of a patient weighting 75 kg). The value is independent treatment given. | at 4 month | 
| EC50 to Characterise the PD Properties of AZD1656. | The value is model based. The value is independent treatment given. | at 4 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type II Diabetes Mellitus, metformin, glipizide