Type II Diabetes Mellitus
Conditions
Keywords
Type II Diabetes Mellitus, metformin, glipizide
Brief summary
The primary aim is to evaluate Efficacy, Safety and Tolerability of AZD1656 as Add-on Treatment to Metformin in TD2M Patients
Interventions
DRUGAZD1656
Different doses of AZD1656 administered to 5 groups of patients
DRUGPlacebo
AZD1656 placebo and glipizide placebo administered to 1 group of patients
DRUGGlipizide
Glipizide administered to 1 group of patients
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c: Change From Baseline to 4 Month | Baseline to 4th Month | AZD1656 is analyzed in a ANCOVA model (Glipized and Open Label is Not Included in the model), FAS Prior to Rescue |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FPG: to Evaluate Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | 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. |
| SMPG: Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | 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. |
| OGTT/Plasma Glucose | baseline to 4 month | The relative change in AUC |
| OGTT/Insulin | baseline to 4 month | The Relative Change in AUC FAS Prior to Rescue |
| OGTT/C-peptide | baseline to 4 month | The relative change, FAS prior to rescue |
| OGTT/Pro-insulin/Insulin | baseline to 4 month | The relative change, FAS prior to rescue |
| HbA1c ≤ 7 | baseline to 4 month | Number of responders ≤ 7, FAS prior to rescue. |
| HbA1c ≤ 6.5 | baseline to 4 month | Number of Responders ≤ 6.5, FAS Prior to Rescue |
| LDL-C: Mean Ratio | baseline to 4 month | Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI. |
| HDL-C: Change From Baseline | baseline to 4 month | Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI. |
| Total Cholesterol: Change From Baseline | baseline to 4 month | Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI. |
| C-reactive Protein: Change From Baseline | baseline to 4 month | Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI |
| QTcF; Electorcardiagram Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Haemoglobin; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Triglycerides: Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Diastolic Blood Pressure, Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Pulse, Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Weight, Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Leukocytes; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Sodium; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Potassium; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Creatinine; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| ALT; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| AST; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Alkaline Phosphatase; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| Bilirubin; Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
| CL/F to Characterise the PK Properties of AZD1656. | at 4 month | The value is calculated using an allometric model (of a patient weighting 75 kg). The value is independent treatment given. |
| EC50 to Characterise the PD Properties of AZD1656. | at 4 month | The value is model based. The value is independent treatment given. |
| Systolic Blood Pressure, Change From Baseline | baseline to 4 month | Summary statistic of change from baseline |
Countries
Chile, Germany, Hungary, Latvia, Lithuania, Mexico, Peru, Poland, Romania, Sweden, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Higher Dose 20-200 mg AZD1656 add on to metformin, titrated dose | 93 |
| Lower Dose 10-140 mg AZD1656 add on to metformin, titrated dose | 91 |
| 40 mg Fixed Dose 40 mg AZD1656 add on to metformin, fixed dose | 52 |
| 20 mg Fixed Dose 20 mg AZD1656 add on to metformin, fixed dose | 40 |
| Placebo Placebo add on to metformin | 88 |
| Glipizide 5-20 mg Glipizide add on to metformin, titrated dose | 94 |
| Open Label Open label, 20-200 mg AZD1656 add on to metformin, titrated dose | 72 |
| Total | 530 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Extention Period | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Extention Period | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Extention Period | Protocol Violation | 1 | 1 | 1 | 0 | 0 | 0 | 1 |
| Extention Period | Withdrawal by Subject | 2 | 1 | 1 | 0 | 0 | 0 | 0 |
| Main Period | Adverse Event | 5 | 2 | 2 | 1 | 1 | 2 | 1 |
| Main Period | Eligibility Criteria not fullfilled | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
| Main Period | Lost to Follow-up | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Main Period | Protocol Violation | 4 | 4 | 2 | 5 | 2 | 3 | 2 |
| Main Period | Unclasified | 2 | 0 | 1 | 0 | 1 | 3 | 6 |
| Main Period | Withdrawal by Subject | 6 | 5 | 3 | 1 | 6 | 3 | 2 |
Baseline characteristics
| Characteristic | Higher Dose | Lower Dose | 40 mg Fixed Dose | 20 mg Fixed Dose | Placebo | Glipizide | Open Label | Total |
|---|---|---|---|---|---|---|---|---|
| Age Continuous | 57.1 Year | 57.1 Year | 54.4 Year | 57.4 Year | 56.9 Year | 57.1 Year | 53.1 Year | 56 Year |
| Sex: Female, Male Female | 47 Participants | 46 Participants | 22 Participants | 19 Participants | 45 Participants | 46 Participants | 37 Participants | 262 Participants |
| Sex: Female, Male Male | 46 Participants | 45 Participants | 30 Participants | 21 Participants | 43 Participants | 48 Participants | 35 Participants | 268 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 92 | 36 / 90 | 20 / 50 | 10 / 40 | 14 / 87 | 35 / 93 | 9 / 71 |
| serious Total, serious adverse events | 2 / 92 | 1 / 90 | 1 / 50 | 1 / 40 | 2 / 87 | 3 / 93 | 1 / 71 |
Outcome results
Primary
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
Time frame: Baseline to 4th Month
Population: The population is FAS prior to rescue, using the LOCF values (see table 27 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | HbA1c: Change From Baseline to 4 Month | -1.25 Percentage | 95% Confidence Interval -1.14 |
| Lower Dose | HbA1c: Change From Baseline to 4 Month | -1.26 Percentage | 95% Confidence Interval -1.14 |
| 40 mg Fixed Dose | HbA1c: Change From Baseline to 4 Month | -0.67 Percentage | 95% Confidence Interval -0.62 |
| 20 mg Fixed Dose | HbA1c: Change From Baseline to 4 Month | -0.61 Percentage | 95% Confidence Interval -0.6 |
| Placebo | HbA1c: Change From Baseline to 4 Month | -0.45 Percentage | — |
Secondary
Alkaline Phosphatase; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 208 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Alkaline Phosphatase; Change From Baseline | 3.8 IU/L | Standard Deviation 17.5 |
| Lower Dose | Alkaline Phosphatase; Change From Baseline | -1.3 IU/L | Standard Deviation 13.3 |
| 40 mg Fixed Dose | Alkaline Phosphatase; Change From Baseline | 0.0 IU/L | Standard Deviation 13.6 |
| 20 mg Fixed Dose | Alkaline Phosphatase; Change From Baseline | -1.8 IU/L | Standard Deviation 11.9 |
| Placebo | Alkaline Phosphatase; Change From Baseline | -3.4 IU/L | Standard Deviation 11.5 |
| Glipizide | Alkaline Phosphatase; Change From Baseline | -4.2 IU/L | Standard Deviation 16.7 |
| Open Label | Alkaline Phosphatase; Change From Baseline | -11.7 IU/L | Standard Deviation 24.7 |
Secondary
ALT; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 206 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | ALT; Change From Baseline | 2.0 IU/L | Standard Deviation 12 |
| Lower Dose | ALT; Change From Baseline | 1.7 IU/L | Standard Deviation 14.8 |
| 40 mg Fixed Dose | ALT; Change From Baseline | 3.2 IU/L | Standard Deviation 17.7 |
| 20 mg Fixed Dose | ALT; Change From Baseline | -1.8 IU/L | Standard Deviation -1.8 |
| Placebo | ALT; Change From Baseline | -0.4 IU/L | Standard Deviation 11.3 |
| Glipizide | ALT; Change From Baseline | 2.0 IU/L | Standard Deviation 15.3 |
| Open Label | ALT; Change From Baseline | -0.4 IU/L | Standard Deviation 15.5 |
Secondary
AST; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 207 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | AST; Change From Baseline | 2.4 IU/L | Standard Deviation 9.8 |
| Lower Dose | AST; Change From Baseline | 2.0 IU/L | Standard Deviation 11 |
| 40 mg Fixed Dose | AST; Change From Baseline | 2.8 IU/L | Standard Deviation 13.1 |
| 20 mg Fixed Dose | AST; Change From Baseline | -0.6 IU/L | Standard Deviation 8.9 |
| Placebo | AST; Change From Baseline | -0.1 IU/L | Standard Deviation 7.9 |
| Glipizide | AST; Change From Baseline | 2.1 IU/L | Standard Deviation 13.3 |
| Open Label | AST; Change From Baseline | 2.7 IU/L | Standard Deviation 9.6 |
Secondary
Bilirubin; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 209 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Bilirubin; Change From Baseline | -0.02 mg/dL | Standard Deviation 0.17 |
| Lower Dose | Bilirubin; Change From Baseline | -0.06 mg/dL | Standard Deviation 0.21 |
| 40 mg Fixed Dose | Bilirubin; Change From Baseline | 0.02 mg/dL | Standard Deviation 0.13 |
| 20 mg Fixed Dose | Bilirubin; Change From Baseline | -0.05 mg/dL | Standard Deviation 0.2 |
| Placebo | Bilirubin; Change From Baseline | -0.01 mg/dL | Standard Deviation 0.2 |
| Glipizide | Bilirubin; Change From Baseline | -0.07 mg/dL | Standard Deviation 0.2 |
| Open Label | Bilirubin; Change From Baseline | -11.7 mg/dL | Standard Deviation 24.7 |
Secondary
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.
Time frame: at 4 month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | CL/F to Characterise the PK Properties of AZD1656. | 9.29 L/h | Standard Error 3.7 |
| Lower Dose | CL/F to Characterise the PK Properties of AZD1656. | 9.29 L/h | Standard Error 3.7 |
| 40 mg Fixed Dose | CL/F to Characterise the PK Properties of AZD1656. | 9.29 L/h | Standard Error 3.7 |
| 20 mg Fixed Dose | CL/F to Characterise the PK Properties of AZD1656. | 9.29 L/h | Standard Error 3.7 |
| Placebo | CL/F to Characterise the PK Properties of AZD1656. | 9.29 L/h | Standard Error 3.7 |
Secondary
C-reactive Protein: Change From Baseline
Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 234 in CSR)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | C-reactive Protein: Change From Baseline | 0.30 ratio | 95% Confidence Interval 0.88 |
| Lower Dose | C-reactive Protein: Change From Baseline | 0.08 ratio | 95% Confidence Interval 0.86 |
| 40 mg Fixed Dose | C-reactive Protein: Change From Baseline | 0.09 ratio | 95% Confidence Interval 0.99 |
| 20 mg Fixed Dose | C-reactive Protein: Change From Baseline | 0.06 ratio | 95% Confidence Interval 0.74 |
| Placebo | C-reactive Protein: Change From Baseline | -0.02 ratio | 95% Confidence Interval 0.75 |
Secondary
Creatinine; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 211 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Creatinine; Change From Baseline | 0.4 IU/L | Standard Deviation 70.5 |
| Lower Dose | Creatinine; Change From Baseline | -9.9 IU/L | Standard Deviation 87.8 |
| 40 mg Fixed Dose | Creatinine; Change From Baseline | 8.5 IU/L | Standard Deviation 88.7 |
| 20 mg Fixed Dose | Creatinine; Change From Baseline | -8.3 IU/L | Standard Deviation 39.1 |
| Placebo | Creatinine; Change From Baseline | -0.1 IU/L | Standard Deviation 32.2 |
| Glipizide | Creatinine; Change From Baseline | 15.9 IU/L | Standard Deviation 67.1 |
| Open Label | Creatinine; Change From Baseline | -7.3 IU/L | Standard Deviation 47 |
Secondary
Diastolic Blood Pressure, Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 240 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Diastolic Blood Pressure, Change From Baseline | 1.1 mmHg | Standard Deviation 8.6 |
| Lower Dose | Diastolic Blood Pressure, Change From Baseline | 1.4 mmHg | Standard Deviation 8.5 |
| 40 mg Fixed Dose | Diastolic Blood Pressure, Change From Baseline | 1.3 mmHg | Standard Deviation 9.1 |
| 20 mg Fixed Dose | Diastolic Blood Pressure, Change From Baseline | -0.9 mmHg | Standard Deviation 10.8 |
| Placebo | Diastolic Blood Pressure, Change From Baseline | -0.3 mmHg | Standard Deviation 8.5 |
| Glipizide | Diastolic Blood Pressure, Change From Baseline | -0.1 mmHg | Standard Deviation 7.2 |
| Open Label | Diastolic Blood Pressure, Change From Baseline | 0.5 mmHg | Standard Deviation 7.7 |
Secondary
EC50 to Characterise the PD Properties of AZD1656.
The value is model based. The value is independent treatment given.
Time frame: at 4 month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | EC50 to Characterise the PD Properties of AZD1656. | 60.2 nmol/L | Standard Error 14 |
| Lower Dose | EC50 to Characterise the PD Properties of AZD1656. | 60.2 nmol/L | Standard Error 14 |
| 40 mg Fixed Dose | EC50 to Characterise the PD Properties of AZD1656. | 60.1 nmol/L | Standard Error 14 |
| 20 mg Fixed Dose | EC50 to Characterise the PD Properties of AZD1656. | 60.2 nmol/L | Standard Error 14 |
| Placebo | EC50 to Characterise the PD Properties of AZD1656. | 60.2 nmol/L | Standard Error 14 |
Secondary
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.
Time frame: baseline to 4 month
Population: The population is FAS prior to rescue, using the LOCF values (see table 29 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | FPG: to Evaluate Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | -0.818 mmol/L | 95% Confidence Interval -1.373 |
| Lower Dose | FPG: to Evaluate Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | -1.08 mmol/L | 95% Confidence Interval -1.642 |
| 40 mg Fixed Dose | FPG: to Evaluate Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | 0.041 mmol/L | 95% Confidence Interval -0.652 |
| 20 mg Fixed Dose | FPG: to Evaluate Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | 0.024 mmol/L | 95% Confidence Interval -0.737 |
| Placebo | FPG: to Evaluate Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | -0.182 mmol/L | — |
Secondary
Haemoglobin; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: population is safety analysis set regardless of rescue, using the observed cases (see table 197 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Haemoglobin; Change From Baseline | -0.20 g/dL | Standard Deviation 0.68 |
| Lower Dose | Haemoglobin; Change From Baseline | -0.18 g/dL | Standard Deviation 0.62 |
| 40 mg Fixed Dose | Haemoglobin; Change From Baseline | 0.00 g/dL | Standard Deviation 0.63 |
| 20 mg Fixed Dose | Haemoglobin; Change From Baseline | -0.11 g/dL | Standard Deviation 0.69 |
| Placebo | Haemoglobin; Change From Baseline | -0.20 g/dL | Standard Deviation 0.71 |
| Glipizide | Haemoglobin; Change From Baseline | 0.02 g/dL | Standard Deviation 0.69 |
| Open Label | Haemoglobin; Change From Baseline | -0.25 g/dL | Standard Deviation 0.76 |
Secondary
HbA1c ≤ 6.5
Number of Responders ≤ 6.5, FAS Prior to Rescue
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 228 in CSR).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Higher Dose | HbA1c ≤ 6.5 | 35 Participants |
| Lower Dose | HbA1c ≤ 6.5 | 27 Participants |
| 40 mg Fixed Dose | HbA1c ≤ 6.5 | 9 Participants |
| 20 mg Fixed Dose | HbA1c ≤ 6.5 | 4 Participants |
| Placebo | HbA1c ≤ 6.5 | 9 Participants |
| Glipizide | HbA1c ≤ 6.5 | 30 Participants |
| Open Label | HbA1c ≤ 6.5 | 16 Participants |
Secondary
HbA1c ≤ 7
Number of responders ≤ 7, FAS prior to rescue.
Time frame: baseline to 4 month
Population: The population is FAS prior to rescue, using the observed cases (see table 35 in CSR).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Higher Dose | HbA1c ≤ 7 | 43 Participants |
| Lower Dose | HbA1c ≤ 7 | 43 Participants |
| 40 mg Fixed Dose | HbA1c ≤ 7 | 14 Participants |
| 20 mg Fixed Dose | HbA1c ≤ 7 | 11 Participants |
| Placebo | HbA1c ≤ 7 | 16 Participants |
| Glipizide | HbA1c ≤ 7 | 50 Participants |
| Open Label | HbA1c ≤ 7 | 24 Participants |
Secondary
HDL-C: Change From Baseline
Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI.
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 230 in CSR)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | HDL-C: Change From Baseline | 1.06 ratio | 95% Confidence Interval 6.2 |
| Lower Dose | HDL-C: Change From Baseline | 1.06 ratio | 95% Confidence Interval 5.1 |
| 40 mg Fixed Dose | HDL-C: Change From Baseline | 1.05 ratio | 95% Confidence Interval 7.8 |
| 20 mg Fixed Dose | HDL-C: Change From Baseline | 1.03 ratio | 95% Confidence Interval 4.1 |
| Placebo | HDL-C: Change From Baseline | 1.03 ratio | 95% Confidence Interval 5.3 |
Secondary
LDL-C: Mean Ratio
Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI.
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 228 in CSR)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | LDL-C: Mean Ratio | 1.07 ratio | 95% Confidence Interval 29.5 |
| Lower Dose | LDL-C: Mean Ratio | 1.02 ratio | 95% Confidence Interval 20.6 |
| 40 mg Fixed Dose | LDL-C: Mean Ratio | 1.07 ratio | 95% Confidence Interval 38.5 |
| 20 mg Fixed Dose | LDL-C: Mean Ratio | 1.04 ratio | 95% Confidence Interval 23.1 |
| Placebo | LDL-C: Mean Ratio | 1.02 ratio | 95% Confidence Interval 19.3 |
Secondary
Leukocytes; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 198 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Leukocytes; Change From Baseline | 0.39 *10^3 cells/µL | Standard Deviation 1.29 |
| Lower Dose | Leukocytes; Change From Baseline | 0.34 *10^3 cells/µL | Standard Deviation 1.59 |
| 40 mg Fixed Dose | Leukocytes; Change From Baseline | 0.35 *10^3 cells/µL | Standard Deviation 1.41 |
| 20 mg Fixed Dose | Leukocytes; Change From Baseline | -0.15 *10^3 cells/µL | Standard Deviation 1.09 |
| Placebo | Leukocytes; Change From Baseline | -0.8 *10^3 cells/µL | Standard Deviation 1.09 |
| Glipizide | Leukocytes; Change From Baseline | 0.27 *10^3 cells/µL | Standard Deviation 1.43 |
| Open Label | Leukocytes; Change From Baseline | -40 *10^3 cells/µL | Standard Deviation 1.31 |
Secondary
OGTT/C-peptide
The relative change, FAS prior to rescue
Time frame: baseline to 4 month
Population: The population is FAS prior to rescue, using the LOCF values (see table 150 in CSR)The first 50% of patients enrolled in the study were supposed to undertake OGTT, actual number participating was 52%. However, more than 60% of the OGTT patients were excluded from the analyses, as their measurements did not comply with the protocol
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Higher Dose | OGTT/C-peptide | 0.97 ratio |
| Lower Dose | OGTT/C-peptide | 1.11 ratio |
| 40 mg Fixed Dose | OGTT/C-peptide | 0.90 ratio |
| 20 mg Fixed Dose | OGTT/C-peptide | 0.95 ratio |
| Placebo | OGTT/C-peptide | 1.00 ratio |
Secondary
OGTT/Insulin
The Relative Change in AUC FAS Prior to Rescue
Time frame: baseline to 4 month
Population: The population is FAS prior to rescue, using the LOCF values (see table 146 in CSR)The first 50% of patients enrolled in the study were supposed to undertake OGTT, actual number participating was 52%. However, more than 60% of the OGTT patients were excluded from the analyses, as their measurements did not comply with the protocol
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Higher Dose | OGTT/Insulin | 0.81 ratio |
| Lower Dose | OGTT/Insulin | 1.08 ratio |
| 40 mg Fixed Dose | OGTT/Insulin | 0.97 ratio |
| 20 mg Fixed Dose | OGTT/Insulin | 0.90 ratio |
| Placebo | OGTT/Insulin | 0.91 ratio |
Secondary
OGTT/Plasma Glucose
The relative change in AUC
Time frame: baseline to 4 month
Population: The population is FAS prior to rescue, using the LOCF values (see table 142 in CSR)The first 50% of patients enrolled in the study were supposed to undertake OGTT, actual number participating was 52%. However, more than 60% of the OGTT patients were excluded from the analyses, as their measurements did not comply with the protocol
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Higher Dose | OGTT/Plasma Glucose | 0.92 ratio |
| Lower Dose | OGTT/Plasma Glucose | 0.84 ratio |
| 40 mg Fixed Dose | OGTT/Plasma Glucose | 1.02 ratio |
| 20 mg Fixed Dose | OGTT/Plasma Glucose | 0.99 ratio |
| Placebo | OGTT/Plasma Glucose | 0.99 ratio |
Secondary
OGTT/Pro-insulin/Insulin
The relative change, FAS prior to rescue
Time frame: baseline to 4 month
Population: The population is FAS prior to rescue, using the LOCF values (see table 154 in CSR)The first 50% of patients enrolled in the study were supposed to undertake OGTT, actual number participating was 52%. However, more than 60% of the OGTT patients were excluded from the analyses, as their measurements did not comply with the protocol
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Higher Dose | OGTT/Pro-insulin/Insulin | 1.496 Ratio |
| Lower Dose | OGTT/Pro-insulin/Insulin | 1.199 Ratio |
| 40 mg Fixed Dose | OGTT/Pro-insulin/Insulin | 1.248 Ratio |
| 20 mg Fixed Dose | OGTT/Pro-insulin/Insulin | 1.431 Ratio |
| Placebo | OGTT/Pro-insulin/Insulin | 1.185 Ratio |
Secondary
Potassium; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 214 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Potassium; Change From Baseline | 0.02 mEq/L | Standard Deviation 0.45 |
| Lower Dose | Potassium; Change From Baseline | -0.02 mEq/L | Standard Deviation 0.26 |
| 40 mg Fixed Dose | Potassium; Change From Baseline | 0.00 mEq/L | Standard Deviation 0.35 |
| 20 mg Fixed Dose | Potassium; Change From Baseline | -0.01 mEq/L | Standard Deviation 0.29 |
| Placebo | Potassium; Change From Baseline | -0.02 mEq/L | Standard Deviation 0.34 |
| Glipizide | Potassium; Change From Baseline | 0.07 mEq/L | Standard Deviation 0.39 |
| Open Label | Potassium; Change From Baseline | 0.05 mEq/L | Standard Deviation 0.38 |
Secondary
Pulse, Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 236 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Pulse, Change From Baseline | 0.4 Beats/min | Standard Deviation 8.8 |
| Lower Dose | Pulse, Change From Baseline | 1.6 Beats/min | Standard Deviation 7.9 |
| 40 mg Fixed Dose | Pulse, Change From Baseline | 1.3 Beats/min | Standard Deviation 7.9 |
| 20 mg Fixed Dose | Pulse, Change From Baseline | 0.3 Beats/min | Standard Deviation 9.1 |
| Placebo | Pulse, Change From Baseline | -1.1 Beats/min | Standard Deviation 9.4 |
| Glipizide | Pulse, Change From Baseline | -0.4 Beats/min | Standard Deviation 11.6 |
| Open Label | Pulse, Change From Baseline | 1.3 Beats/min | Standard Deviation 8.5 |
Secondary
QTcF; Electorcardiagram Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 258 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | QTcF; Electorcardiagram Change From Baseline | 4.4 msec | Standard Deviation 15.6 |
| Lower Dose | QTcF; Electorcardiagram Change From Baseline | 4.0 msec | Standard Deviation 14.5 |
| 40 mg Fixed Dose | QTcF; Electorcardiagram Change From Baseline | -2.6 msec | Standard Deviation 12.6 |
| 20 mg Fixed Dose | QTcF; Electorcardiagram Change From Baseline | 3.8 msec | Standard Deviation 17.9 |
| Placebo | QTcF; Electorcardiagram Change From Baseline | 2.2 msec | Standard Deviation 13.8 |
| Glipizide | QTcF; Electorcardiagram Change From Baseline | 2.7 msec | Standard Deviation 21.5 |
| Open Label | QTcF; Electorcardiagram Change From Baseline | 1.6 msec | Standard Deviation 16.4 |
Secondary
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.
Time frame: baseline to 4 month
Population: The population is FAS prior to rescue, using the LOCF values (see table 31 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | SMPG: Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | -1.596 mmol/L | 95% Confidence Interval -2.206 |
| Lower Dose | SMPG: Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | -1.557 mmol/L | 95% Confidence Interval -2.155 |
| 40 mg Fixed Dose | SMPG: Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | -0.874 mmol/L | 95% Confidence Interval -1.586 |
| 20 mg Fixed Dose | SMPG: Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | -0.604 mmol/L | 95% Confidence Interval -1.437 |
| Placebo | SMPG: Change From Baseline to 4 Month, Compared With Placebo, FAS Prior to Rescue. | -0.213 mmol/L | — |
Secondary
Sodium; Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 215 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Sodium; Change From Baseline | -0.6 mEq/L | Standard Deviation 2.4 |
| Lower Dose | Sodium; Change From Baseline | -0.7 mEq/L | Standard Deviation 2.4 |
| 40 mg Fixed Dose | Sodium; Change From Baseline | -0.4 mEq/L | Standard Deviation 3 |
| 20 mg Fixed Dose | Sodium; Change From Baseline | -0.1 mEq/L | Standard Deviation 2.6 |
| Placebo | Sodium; Change From Baseline | 0.0 mEq/L | Standard Deviation 2.6 |
| Glipizide | Sodium; Change From Baseline | -0.6 mEq/L | Standard Deviation 3.3 |
| Open Label | Sodium; Change From Baseline | 0.5 mEq/L | Standard Deviation 2.6 |
Secondary
Systolic Blood Pressure, Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 237 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Systolic Blood Pressure, Change From Baseline | -0.4 mmHg | Standard Deviation 12.6 |
| Lower Dose | Systolic Blood Pressure, Change From Baseline | 0.4 mmHg | Standard Deviation 9.9 |
| 40 mg Fixed Dose | Systolic Blood Pressure, Change From Baseline | 5.7 mmHg | Standard Deviation 11.3 |
| 20 mg Fixed Dose | Systolic Blood Pressure, Change From Baseline | 0.1 mmHg | Standard Deviation 12.6 |
| Placebo | Systolic Blood Pressure, Change From Baseline | -0.2 mmHg | Standard Deviation 13.7 |
| Glipizide | Systolic Blood Pressure, Change From Baseline | -1.1 mmHg | Standard Deviation 13.5 |
| Open Label | Systolic Blood Pressure, Change From Baseline | -0.3 mmHg | Standard Deviation 11.7 |
Secondary
Total Cholesterol: Change From Baseline
Geometric mean ratio (safety analysis set, regardless of rescue) and a 95 % CI.
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 232 in CSR)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Total Cholesterol: Change From Baseline | 1.09 ratio | 95% Confidence Interval 36.9 |
| Lower Dose | Total Cholesterol: Change From Baseline | 1.08 ratio | 95% Confidence Interval 60.2 |
| 40 mg Fixed Dose | Total Cholesterol: Change From Baseline | 1.07 ratio | 95% Confidence Interval 41.6 |
| 20 mg Fixed Dose | Total Cholesterol: Change From Baseline | 1.04 ratio | 95% Confidence Interval 25.3 |
| Placebo | Total Cholesterol: Change From Baseline | 1.03 ratio | 95% Confidence Interval 26 |
Secondary
Triglycerides: Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 226 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Triglycerides: Change From Baseline | 40.9 mg/dL | Standard Deviation 115.3 |
| Lower Dose | Triglycerides: Change From Baseline | 38.7 mg/dL | Standard Deviation 99.3 |
| 40 mg Fixed Dose | Triglycerides: Change From Baseline | 19.8 mg/dL | Standard Deviation 185.3 |
| 20 mg Fixed Dose | Triglycerides: Change From Baseline | 4.4 mg/dL | Standard Deviation 49.3 |
| Placebo | Triglycerides: Change From Baseline | 13.7 mg/dL | Standard Deviation 139.4 |
| Glipizide | Triglycerides: Change From Baseline | 18.7 mg/dL | Standard Deviation 152.8 |
| Open Label | Triglycerides: Change From Baseline | 29.8 mg/dL | Standard Deviation 174.3 |
Secondary
Weight, Change From Baseline
Summary statistic of change from baseline
Time frame: baseline to 4 month
Population: The population is safety analysis set regardless of rescue, using the observed cases (see table 244 in CSR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose | Weight, Change From Baseline | -0.3 kg | Standard Deviation 2.5 |
| Lower Dose | Weight, Change From Baseline | -0.6 kg | Standard Deviation 2.9 |
| 40 mg Fixed Dose | Weight, Change From Baseline | -1.2 kg | Standard Deviation 2.7 |
| 20 mg Fixed Dose | Weight, Change From Baseline | -1.4 kg | Standard Deviation 2.3 |
| Placebo | Weight, Change From Baseline | -1.0 kg | Standard Deviation 2.5 |
| Glipizide | Weight, Change From Baseline | 1.0 kg | Standard Deviation 3.4 |
| Open Label | Weight, Change From Baseline | -0.4 kg | Standard Deviation 4.4 |