Diabetic Nephropathy
Conditions
Keywords
type 2 diabetes, nephropathy, cardiovascular (CV) events
Brief summary
The NID-2 study, a multicentric study (21 centres enrolled), was planned in two phases: Phase 1(observational study, completed in September 2005): after the identification of a type-2 diabetic population with typical Diabetic Nephropathy (DN), to study of the rate of renal and cardiovascular events during a middle term follow-up. Phase 2(interventional study, started in October 2005): after randomization in two groups, a group (intervention group) is treated with an intensive multifactorial intervention whose aim is to reduce morbidity and mortality due to diabetic complications. The other group (control group) continues the conventional therapy . To avoid bias in the treatment in each center, the randomization was performed for centre.
Detailed description
The same patients that completed the first phase of the NID-2 study (observation) were enrolled for the phase 2 of the study (intervention).
Interventions
DRUGSoC therapy
the patients have to be treated according the standard good medical practice by any center
DRUGirbesartan
Therapy for hypertension: \- Step 1: irbesartan 300 mg/die and ramipril 10 mg/die
DRUGramipril
Therapy for hypertension: \- Step 1: irbesartan 300 mg/die and ramipril 10 mg/die
DRUGhydrochlorothiazide
Therapy for hypertension \- Step 2: Diuretic (hydrochlorothiazide 12.5-25 mg/die if serum creatinine \<2 mg/dl, furosemide 25-75 mg/die if serum creatinin ≥2 mg/dl)
DRUGfurosemide
Therapy for hypertension \- Step 2: Diuretic (hydrochlorothiazide 12.5-25 mg/die if serum creatinine \<2 mg/dl, furosemide 25-75 mg/die if serum creatinin ≥2 mg/dl)
DRUGamlodipine
Therapy for hypertension \- Step 3: amlodipine up to 10 mg/die
DRUGatenolol
Therapy for hypertension \- Step 4: atenolol up to 100 mg/die
DRUGdoxazosin
Therapy for hypertension \- Step 5: doxazosin up to 4 mg/die
DRUGclonidine
Therapy for hypertension \- Step 6: clonidine
DRUGinsulin
Therapy for Hyperglycaemia (to achieve HbA1c \<7): \- insulin
DRUGsimvastatin
Therapy for hypercholesterolemia: \- for reducing LDL cholesterol \< 100 mg/dl: simvastatin up to 80 mg/die
DRUGfibrate
Therapy for hypertriglyceridemia \- for reducing triglycerides \< 150 mg/dl and/or increasing HDL cholesterol \> 40-50 mg/dl: a fibrate
DRUGerythropoietin
Treatment of anaemia: \- erythropoietin
DRUGaspirin
Antiplatelet therapy (in all patients without contraindications): \- aspirin up to 160 mg/die
Sponsors
University of Campania Luigi Vanvitelli
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* type 2 diabetic patients * albumin extraction rate (AER= \>30 mg/die (micro- or macro-albuminuric ranges) in at least two determinations in the last six months * diabetic retinopathy * patients followed in the outpatients clinic for at least 12 months
Exclusion criteria
* type 1 diabetic patients * \<40 years old
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Fatal and Non-fatal, Major Adverse Cardiovascular Events (MACEs) | 4 years (in the case the number of events needed by sample size is not reached at the expected 4-year time frame, primary end point will be assessed after the follow-up phase) | number of MACEs in the two groups are reported. In addition, The primary endpoint was analyzed with event curves for the time-to-first event based on Kaplan-Meier analysis. Cox regression model was used to calculate hazard ratio (HR) and 95% Confidence Interval (CI). Due to the cluster randomized study design, a Cox shared-frailty model was fitted. multivariable model was adjusted for selected potential confounders: age, sex, systolic blood pressure (SBP), hemoglobin, estimated glomerular filtration rate (eGFR), albuminuria, HbA1c, total cholesterol and triglycerides (log-scaled) to reduce risk of bias. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved of BP, HbA1c and Total, HDL and LDL Cholesterol Goals at the End of Intervention Phase | 13 years | Achievement of targets at end of intervention was performed applying generalized estimating equation (GEE) models, further adjusting for baseline values as covariate. |
Countries
Italy
Participant flow
Pre-assignment details
Out of patients originally enrolled in our study cohort, 538 patients with negative history of cardiovascular events were considered eligible and 111 further added from three new centers. 189 patients from 10 clinics were excluded prior to randomization due to their refusal to participate, 65 individuals due to change of either center or residence
Participants by arm
| Arm | Count |
|---|---|
| Conventional Therapy Control group patients will continue their usual therapy. During the study such patients could receive all the therapeutic modifications according to the good medical practice of the specialist.
current therapy: the patients have to be treated according the standard good medical practice by any center | 188 |
| Intensified Therapy Intensive multifactorial intervention is performed to achieve goals for the following risk factors: hypertension, hyperglycaemia, lipids, anaemia. New antihypertensive drugs will be added one by one until achievement of BP target (\<130/80 mmHg).
Therapy for Hypertension
1. Step1 - irbesartan 300 mg/die and ramipril 10 mg/die
2. Step 2 (Diuretic) - hydrochlorothiazide 12.5-25 mg/die, if creatinine \<2 mg/dL / furosemide 25-75 mg/die, if creatinine ≥2 mg/dL
3. Step 3 - amlodipine up to 10 mg/die
4. Step 4 - atenolol up to 100 mg/die
5. Step 5 - doxazosin up to 4 mg/die
6. Step 6 - Clonidine
Therapy for Hyperglycaemia (to achieve HbA1c \<7): insulin
Therapy for hypercholesterolemia (to reduce LDL \<100 mg/dl) --\> simvastatin till 80 mg/die
Therapy for hypertriglyceridemia (to reduce triglycerides \<150 mg/dl and/or increase HDL \>40-50 mg/dl) --\> fibrate
Treatment of anaemia: erythropoietin
Antiplatelets (all patients without contraindications): aspirin till 160 mg/die | 207 |
| Total | 395 |
Baseline characteristics
| Characteristic | Intensified Therapy | Total | Conventional Therapy |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 103 Participants | 227 Participants | 124 Participants |
| Age, Categorical Between 18 and 65 years | 104 Participants | 168 Participants | 64 Participants |
| Age, Continuous | 66.1 years STANDARD_DEVIATION 9 | 67.1 years STANDARD_DEVIATION 8.9 | 68.2 years STANDARD_DEVIATION 8.8 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Italy | 207 participants | 395 participants | 188 participants |
| Sex: Female, Male Female | 104 Participants | 209 Participants | 105 Participants |
| Sex: Female, Male Male | 103 Participants | 186 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 103 / 188 | 86 / 207 |
| other Total, other adverse events | 5 / 188 | 8 / 207 |
| serious Total, serious adverse events | 88 / 188 | 69 / 207 |
Outcome results
Primary
Number of Participants With Overall Fatal and Non-fatal, Major Adverse Cardiovascular Events (MACEs)
number of MACEs in the two groups are reported. In addition, The primary endpoint was analyzed with event curves for the time-to-first event based on Kaplan-Meier analysis. Cox regression model was used to calculate hazard ratio (HR) and 95% Confidence Interval (CI). Due to the cluster randomized study design, a Cox shared-frailty model was fitted. multivariable model was adjusted for selected potential confounders: age, sex, systolic blood pressure (SBP), hemoglobin, estimated glomerular filtration rate (eGFR), albuminuria, HbA1c, total cholesterol and triglycerides (log-scaled) to reduce risk of bias.
Time frame: 4 years (in the case the number of events needed by sample size is not reached at the expected 4-year time frame, primary end point will be assessed after the follow-up phase)
Population: number of MACEs reported will be at the end of the whole study period (follow-up) due to the fact that number needed to treat (NNT) at end of intervention was not reached)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Conventional Therapy | Number of Participants With Overall Fatal and Non-fatal, Major Adverse Cardiovascular Events (MACEs) | 146 Participants |
| Intensified Therapy | Number of Participants With Overall Fatal and Non-fatal, Major Adverse Cardiovascular Events (MACEs) | 116 Participants |
p-value: <0.05Regression, Cox
Secondary
Number of Participants Who Achieved of BP, HbA1c and Total, HDL and LDL Cholesterol Goals at the End of Intervention Phase
Achievement of targets at end of intervention was performed applying generalized estimating equation (GEE) models, further adjusting for baseline values as covariate.
Time frame: 13 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Conventional Therapy | Number of Participants Who Achieved of BP, HbA1c and Total, HDL and LDL Cholesterol Goals at the End of Intervention Phase | 150 Participants |
| Intensified Therapy | Number of Participants Who Achieved of BP, HbA1c and Total, HDL and LDL Cholesterol Goals at the End of Intervention Phase | 191 Participants |