Nephropathy In Type 2 Diabetes and Cardio-renal Events

Study Overview
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Brief Summary
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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
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The same patients that completed the first phase of the NID-2 study (observation) were enrolled for the phase 2 of the study (intervention).

Official Title
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Nephropathy in Type 2 Diabetes: Effects of an Intensive Multifactorial Intervention Trial on Cardio-renal Events.

Conditions
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Diabetic Nephropathy

Intervention / Treatment
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* Drug: SoC therapy
* Drug: irbesartan
* Drug: ramipril
* Drug: hydrochlorothiazide
* Drug: furosemide
* Drug: amlodipine
* Drug: atenolol
* Drug: doxazosin
* Drug: clonidine
* Drug: insulin
* Drug: simvastatin
* Drug: fibrate
* Drug: erythropoietin
* Drug: aspirin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care (SoC) therapy<br>Control group patients will continue their SoC therapy. During the study such patients could receive all the therapeutic modifications according to the good medical practice of the specialist. | Drug: SoC therapy<br>* the patients have to be treated according the standard good medical practice by any center<br>|
| Experimental: Multifactorial Intensified therapy<br>An intensive multifactorial intervention according Scientific Guidelines is performed to achieve the goals for the following risk factors: hypertension, hyperglycaemia, lipids, anaemia. In particular, new antihypertensive drugs will be added one by one until the achievement of blood pressure target (<130/80 mmHg). | Drug: irbesartan<br>* Therapy for hypertension: - Step 1: irbesartan 300 mg/die and ramipril 10 mg/die<br>Drug: ramipril<br>* Therapy for hypertension: - Step 1: irbesartan 300 mg/die and ramipril 10 mg/die<br>Drug: hydrochlorothiazide<br>* 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)<br>Drug: furosemide<br>* 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)<br>Drug: amlodipine<br>* Therapy for hypertension - Step 3: amlodipine up to 10 mg/die<br>Drug: atenolol<br>* Therapy for hypertension - Step 4: atenolol up to 100 mg/die<br>Drug: doxazosin<br>* Therapy for hypertension - Step 5: doxazosin up to 4 mg/die<br>Drug: clonidine<br>* Therapy for hypertension - Step 6: clonidine<br>Drug: insulin<br>* Therapy for Hyperglycaemia (to achieve HbA1c <7): - insulin<br>Drug: simvastatin<br>* Therapy for hypercholesterolemia: - for reducing LDL cholesterol < 100 mg/dl: simvastatin up to 80 mg/die<br>Drug: fibrate<br>* Therapy for hypertriglyceridemia - for reducing triglycerides < 150 mg/dl and/or increasing HDL cholesterol > 40-50 mg/dl: a fibrate<br>Drug: erythropoietin<br>* Treatment of anaemia: - erythropoietin<br>Drug: aspirin<br>* Antiplatelet therapy (in all patients without contraindications): - aspirin up to 160 mg/die<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 13 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 2 diabetes, nephropathy, cardiovascular (CV) events