Diabetic Nephropathy, Proteinuria, Type 2 Diabetes Mellitus
Conditions
Keywords
angiotensin II type I receptor blockers, diabetic nephropathy, end-stage renal disease, renal failure, type 2 diabetes, olmesartan medoxomil
Brief summary
The purpose of the study is to evaluate the effectiveness and safety of olmesartan versus placebo on the progression of diabetic renal disease.
Interventions
DRUGolmesartan medoxomil
Tablets 10, 20, or 40 mg
DRUGPlacebo Tablets
Matching placebo tablets
Sponsors
Daiichi Sankyo Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* clinical diagnosis of diabetic nephropathy in patients with type 2 diabetes * albumin-to-creatinine ratio \>= 300 mg/g creatinine in first morning urinalysis * serum creatinine between 1.0 and 2.5 mg/dL in women and between 1.2 and 2.5 mg/dL in men
Exclusion criteria
* type 1 diabetes * non-diabetic nephropathy * history of myocardial infarction * history of cardiac bypass grafting within 3 months * history of percutaneous coronary intervention (PCI) within 6 months * history of carotid artery or peripheral artery revascularization within 6 months * stroke or transient ischemic attack (TIA) within 1 year * unstable angina pectoris * heart failure of NYHA functional classes III or IV * rapid progression of kidney disease within 3 months * severe orthostatic hypotension * serum potassium level =\<3.5 mEq(mmol)/L or =\>5.5 mEq(mmol)L * history of rapid elevation of the serum creatinine level after starting treatment with AII receptor antagonists or ACE inhibitors * poor glycemic control: HbA1c level =\>11% * history of myocardial infarction (MI) or coronary artery bypass grafting (CABG) within 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Composite Outcomes | Randomization to 5 years | first occurrence of any of the following events: Doubling of serum creatinine level; Death; End stage renal disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Cardiovascular Composite Outcomes | Within 5 years | Number of participants experiencing the first occurence of any of the following: Cardiovascular death; non-fatal stroke; non-fatal myocardial infarction; hospitalization for unstable angina; lower extremity amputation; coronary/carotid/peripheral revascularization. |
| The Change in Proteinuria | Randomization to 5 years | The median percentage change from baseline value in urinary protein:creatinine ratio |
| Reciprocal (1/Serum Creatinine) of Serum Creatinine | Randomization to 5 years | The amount of serum creatinine was determined by blood tests periodically during the study. The amount of creatinine is an indication of kidney function. The reciprocal of serum creatinine is used in an equation to determine the change in kidney function from baseline. The reciprocal of the serum creatinine was monitored to detect kidney function changes over duration of the study. |
Countries
China, Japan
Participant flow
Recruitment details
The study population was defined by the inclusion criteria. This study was carried out at 74 centers in Japan and 3 centers in Hong Kong. After the screening visit, the patients that met inclusion and exclusion criteria were selected to participate in the study. First Patient in: 19 May 2003.
Pre-assignment details
During 6-week screening, patients were treated with placebo and assessed for eligibility. Eligible patients were assigned to 10mg of olmesartan or placebo. 857 were screened; 577 were randomized; 566=the full analysis set (11 who completed were excluded for protocol violations). Data are based on the participants in the full analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Olmesartan Medoxomil Experimental: Olmesartan medoxomil tablets 10mg to 40 mg | 282 |
| Placebo Comparator Matching placebo tablets | 284 |
| Total | 566 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 6 | 5 |
Baseline characteristics
| Characteristic | Olmesartan Medoxomil | Placebo Comparator | Total |
|---|---|---|---|
| Age Continuous | 59.1 years STANDARD_DEVIATION 8.1 | 59.2 years STANDARD_DEVIATION 8.1 | 59.2 years STANDARD_DEVIATION 8.1 |
| Diastolic blood pressure | 77.8 mmHg STANDARD_DEVIATION 10.4 | 77.2 mmHg STANDARD_DEVIATION 10.6 | 77.5 mmHg STANDARD_DEVIATION 10.5 |
| HbA1c | 7.11 Percentage of HbA1c STANDARD_DEVIATION 1.2 | 7.05 Percentage of HbA1c STANDARD_DEVIATION 1.24 | 7.08 Percentage of HbA1c STANDARD_DEVIATION 1.22 |
| Region of Enrollment East Asia | 282 participants | 284 participants | 566 participants |
| Serum creatinine | 1.62 mg/dL STANDARD_DEVIATION 0.32 | 1.62 mg/dL STANDARD_DEVIATION 0.35 | 1.62 mg/dL STANDARD_DEVIATION 0.34 |
| Sex: Female, Male Female | 83 Participants | 92 Participants | 175 Participants |
| Sex: Female, Male Male | 199 Participants | 192 Participants | 391 Participants |
| Systolic Blood Pressure | 141.7 mmHg STANDARD_DEVIATION 17 | 140.8 mmHg STANDARD_DEVIATION 18 | 141.3 mmHg STANDARD_DEVIATION 17.5 |
| Urinary albumin:creatinine ratio | 1.70 g/g | 1.69 g/g | 1.69 g/g |
| Urinary protein: creatinine ratio | 2.19 g/g | 2.05 g/g | 2.12 g/g |
| Use of ACE inhibitors Did not use ACE Inhibitors | 77 participants | 75 participants | 152 participants |
| Use of ACE inhibitors Used ACE Inhibitors | 205 participants | 209 participants | 414 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 264 / 287 | 265 / 288 |
| serious Total, serious adverse events | 147 / 287 | 171 / 288 |
Outcome results
Primary
Renal Composite Outcomes
first occurrence of any of the following events: Doubling of serum creatinine level; Death; End stage renal disease
Time frame: Randomization to 5 years
Population: Full analysis set=566
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olmesartan Medoxomil | Renal Composite Outcomes | 116 participants |
| Placebo Comparator | Renal Composite Outcomes | 129 participants |
Comparison: We planned to collect 400 patients to detect 35% risk reduction for renal outcome in olmesartan group with 80% power at 2-sided .05 alpha level. The Cox regression model was applied to estimate the hazard ratios (HR)between treatment groups with 95% confidence intervals for the renal and cardiovascular composite event rate.p-value: 0.7995% CI: [0.75, 1.24]Regression, Cox
Secondary
Number of Participants Experiencing Cardiovascular Composite Outcomes
Number of participants experiencing the first occurence of any of the following: Cardiovascular death; non-fatal stroke; non-fatal myocardial infarction; hospitalization for unstable angina; lower extremity amputation; coronary/carotid/peripheral revascularization.
Time frame: Within 5 years
Population: Full analysis set=566
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olmesartan Medoxomil | Number of Participants Experiencing Cardiovascular Composite Outcomes | 40 participants |
| Placebo Comparator | Number of Participants Experiencing Cardiovascular Composite Outcomes | 53 participants |
p-value: 0.03995% CI: [0.43, 0.98]Regression, Cox
Secondary
Reciprocal (1/Serum Creatinine) of Serum Creatinine
The amount of serum creatinine was determined by blood tests periodically during the study. The amount of creatinine is an indication of kidney function. The reciprocal of serum creatinine is used in an equation to determine the change in kidney function from baseline. The reciprocal of the serum creatinine was monitored to detect kidney function changes over duration of the study.
Time frame: Randomization to 5 years
Population: Full analysis set=566
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olmesartan Medoxomil | Reciprocal (1/Serum Creatinine) of Serum Creatinine | -0.071 dL/mg/year |
| Placebo Comparator | Reciprocal (1/Serum Creatinine) of Serum Creatinine | -0.089 dL/mg/year |
Secondary
The Change in Proteinuria
The median percentage change from baseline value in urinary protein:creatinine ratio
Time frame: Randomization to 5 years
Population: Full analysis set=566
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olmesartan Medoxomil | The Change in Proteinuria | 144 -week value | -24.9 Median percentage change in ratio |
| Olmesartan Medoxomil | The Change in Proteinuria | 12-week value | -19.5 Median percentage change in ratio |
| Olmesartan Medoxomil | The Change in Proteinuria | 48-week value | -20.0 Median percentage change in ratio |
| Placebo Comparator | The Change in Proteinuria | 48-week value | 6.9 Median percentage change in ratio |
| Placebo Comparator | The Change in Proteinuria | 12-week value | 12.6 Median percentage change in ratio |
| Placebo Comparator | The Change in Proteinuria | 144 -week value | 3.1 Median percentage change in ratio |