Type 2 Diabetes
Conditions
Keywords
Type II Diabetes
Brief summary
The purpose of this study is to assess the 1 month safety and tolerability after multiple oral doses of AZD1656 in patients with Type 2 Diabetes Mellitus Treated with Metformin
Interventions
DRUGAZD1656
Subjects will be treated with tolerable dose twice daily for another 24 days.
DRUGPlacebo
Subjects will be treated with tolerable dose twice daily for another 24 days.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or women of non-childbearing potential (postmenopausal, and/or have undergone hysterectomy and/or bilateral oophorectomy or salpingectomy/ tubal ligation) * Ongoing treatment with metformin on a stable dose of ≥ 1500 mg/day for at least 8 weeks prior to randomisation * HbA1c ≤ 10% at enrolment (HbA1c value according to international Diabetes Control and Complications Trial \[DCCT\] standard)
Exclusion criteria
* History of ischemic heart disease, symptomatic heart failure, stroke, transitory ischemic attack or symptomatic peripheral vascular disease * Clinically significant abnormalities in ECG, clinical chemistry, haematology, or urine analysis results. Positive test for Hepatitis B surface antigen or antibodies to human immunodeficiency virus (HIV) or antibodies to Hepatitis C virus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Systolic Blood Pressure, Change From Baseline to End of Treatment | Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period | — |
| Diastolic Blood Pressure, Change From Baseline to End of Treatment | Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period | — |
| Pulse, Change From Baseline to End of Treatment | Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period | — |
| Weight, Change From Baseline to End of Treatment | Baseline is the day before first dose, end of treatment is last day of treatment | — |
| Clinically Relevant Change of Laboratory Variables | Measured regularly from day before first dose to day after last dose | Number of participants with clinically relevant change of laboratory variables (clinical chemistry, haematology and urinalysis parameters |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| P-Glucose (AUC0-24)/24, Change From Baseline to End of Treatment | Baseline is the day before first dose, end of treatment is last day of treatment | Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent. |
| Area Under the Plasma Concentration vs Time Curve (AUC0-24) of AZD1656 | Measured last day of treatment | Dose-adjusted to a total daily dose of 100 mg due to titrated doses |
| S-C-Peptide (AUC0-24)/24, Change From Baseline to End of Treatment | Baseline is the day before first dose, end of treatment is last day of treatment | Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent. |
| S-Insulin (AUC0-24)/24, Change From Baseline to End of Treatment | Baseline is the day before first dose, end of treatment is last day of treatment | Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent. |
| Maximum Plasma Concentration of AZD1656 | Measured last day of treatment | Dose-adjusted to a morning dose of 50 mg due to titrated doses |
| Time to Reach Maximum Plasma Concentration of AZD1656 | Measured last day of treatment | — |
| Terminal Elimination Half-life of AZD1656 | Measured following the afternoon dose last day of treatment | — |
| Apparent Oral Clearance of AZD1656 | Measured last day of treatment | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental AZD1656 | 19 |
| Placebo Comparator Placebo | 8 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Poor venous access | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Study-specific discontinuation criteria | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Experimental | Placebo Comparator | Total |
|---|---|---|---|
| Age Continuous | 60.2 years | 60.3 years | 60.2 years |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 13 Participants | 3 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 19 | 7 / 8 |
| serious Total, serious adverse events | 1 / 19 | 0 / 8 |
Outcome results
Primary
Clinically Relevant Change of Laboratory Variables
Number of participants with clinically relevant change of laboratory variables (clinical chemistry, haematology and urinalysis parameters
Time frame: Measured regularly from day before first dose to day after last dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental | Clinically Relevant Change of Laboratory Variables | 0 Participants |
| Placebo Comparator | Clinically Relevant Change of Laboratory Variables | 0 Participants |
Primary
Diastolic Blood Pressure, Change From Baseline to End of Treatment
Time frame: Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Diastolic Blood Pressure, Change From Baseline to End of Treatment | -0.2 mmHg | Standard Deviation 6.2 |
| Placebo Comparator | Diastolic Blood Pressure, Change From Baseline to End of Treatment | 2.0 mmHg | Standard Deviation 10.32 |
Primary
Pulse, Change From Baseline to End of Treatment
Time frame: Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Pulse, Change From Baseline to End of Treatment | 2.7 beats/min | Standard Deviation 5.69 |
| Placebo Comparator | Pulse, Change From Baseline to End of Treatment | -1.6 beats/min | Standard Deviation 6.23 |
Primary
Systolic Blood Pressure, Change From Baseline to End of Treatment
Time frame: Baseline is pre-dose first day of dosing, end of treatment is the morning following the treatment period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Systolic Blood Pressure, Change From Baseline to End of Treatment | -0.5 mmHg | Standard Deviation 11.48 |
| Placebo Comparator | Systolic Blood Pressure, Change From Baseline to End of Treatment | 9.2 mmHg | Standard Deviation 10.43 |
Primary
Weight, Change From Baseline to End of Treatment
Time frame: Baseline is the day before first dose, end of treatment is last day of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Weight, Change From Baseline to End of Treatment | 0.2 kg | Standard Deviation 1 |
| Placebo Comparator | Weight, Change From Baseline to End of Treatment | 0.0 kg | Standard Deviation 3.81 |
Secondary
Apparent Oral Clearance of AZD1656
Time frame: Measured last day of treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Experimental | Apparent Oral Clearance of AZD1656 | 9.02 L/h |
Secondary
Area Under the Plasma Concentration vs Time Curve (AUC0-24) of AZD1656
Dose-adjusted to a total daily dose of 100 mg due to titrated doses
Time frame: Measured last day of treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Area Under the Plasma Concentration vs Time Curve (AUC0-24) of AZD1656 | 23.17 umol*h/L | Standard Deviation 7.46 |
Secondary
Maximum Plasma Concentration of AZD1656
Dose-adjusted to a morning dose of 50 mg due to titrated doses
Time frame: Measured last day of treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Maximum Plasma Concentration of AZD1656 | 1.90 umol/L | Standard Deviation 0.99 |
Secondary
P-Glucose (AUC0-24)/24, Change From Baseline to End of Treatment
Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.
Time frame: Baseline is the day before first dose, end of treatment is last day of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Experimental | P-Glucose (AUC0-24)/24, Change From Baseline to End of Treatment | 75.85 Relative ratio in percent |
| Placebo Comparator | P-Glucose (AUC0-24)/24, Change From Baseline to End of Treatment | 99.42 Relative ratio in percent |
Secondary
S-C-Peptide (AUC0-24)/24, Change From Baseline to End of Treatment
Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.
Time frame: Baseline is the day before first dose, end of treatment is last day of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Experimental | S-C-Peptide (AUC0-24)/24, Change From Baseline to End of Treatment | 103.60 Relative ratio in percent |
| Placebo Comparator | S-C-Peptide (AUC0-24)/24, Change From Baseline to End of Treatment | 98.01 Relative ratio in percent |
Secondary
S-Insulin (AUC0-24)/24, Change From Baseline to End of Treatment
Log ratio (End of treatment/Baseline) has been analysed in a mixed-effect ANOVA model, using treatment as fixed effect and log(Baseline) as covariate. Resulting estimates have been back-transformed from the log-scale and then multiplied by 100 to obtain the relative ratio (end of treatment/placebo) in percent.
Time frame: Baseline is the day before first dose, end of treatment is last day of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Experimental | S-Insulin (AUC0-24)/24, Change From Baseline to End of Treatment | 103.81 Relative ratio in percent |
| Placebo Comparator | S-Insulin (AUC0-24)/24, Change From Baseline to End of Treatment | 86.06 Relative ratio in percent |
Secondary
Terminal Elimination Half-life of AZD1656
Time frame: Measured following the afternoon dose last day of treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Experimental | Terminal Elimination Half-life of AZD1656 | 7.07 h |
Secondary
Time to Reach Maximum Plasma Concentration of AZD1656
Time frame: Measured last day of treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Time to Reach Maximum Plasma Concentration of AZD1656 | 0.625 h |