Nephropathy In Type 2 Diabetes and Cardio-renal Events (NID-2)

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetic Nephropathy
• Intervention / Treatment: 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

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).

• Study Type: Interventional
• Enrollment (Actual): 850
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Naples, Italy, I-80131
    • Department of Advanced Medical and Surgical Sciences, Università della Campania "Luigi Vanvitelli", Naples, Italy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care (SoC) therapy; 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; the patients have to be treated according the standard good medical practice by any center
Experimental: Multifactorial Intensified therapy; 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; Therapy for hypertension: - Step 1: irbesartan 300 mg/die and ramipril 10 mg/die; Drug: ramipril; Therapy for hypertension: - Step 1: irbesartan 300 mg/die and ramipril 10 mg/die; Drug: hydrochlorothiazide; 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); Drug: furosemide; 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); Drug: amlodipine; Therapy for hypertension - Step 3: amlodipine up to 10 mg/die; Drug: atenolol; Therapy for hypertension - Step 4: atenolol up to 100 mg/die; Drug: doxazosin; Therapy for hypertension - Step 5: doxazosin up to 4 mg/die; Drug: clonidine; Therapy for hypertension - Step 6: clonidine; Drug: insulin; Therapy for Hyperglycaemia (to achieve HbA1c <7): - insulin; Drug: simvastatin; Therapy for hypercholesterolemia: - for reducing LDL cholesterol < 100 mg/dl: simvastatin up to 80 mg/die; Drug: fibrate; Therapy for hypertriglyceridemia - for reducing triglycerides < 150 mg/dl and/or increasing HDL cholesterol > 40-50 mg/dl: a fibrate; Drug: erythropoietin; Treatment of anaemia: - erythropoietin; Drug: aspirin; Antiplatelet therapy (in all patients without contraindications): - aspirin up to 160 mg/die

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Campania "Luigi Vanvitelli"
• Investigators: Study Director: Ferdinando C Sasso, MD, PhD, Università della Campania "Luigi Vanvitelli", Naples, Italy; Principal Investigator: Roberto Minutolo, MD, MD, Università della Campania "Luigi Vanvitelli", Naples, Italy; Study Chair: Luca De Nicola, MD, MD, Università della Campania "Luigi Vanvitelli", Naples, Italy

Publications and helpful links

General Publications

• Sasso FC, De Nicola L, Carbonara O, Nasti R, Minutolo R, Salvatore T, Conte G, Torella R. Cardiovascular risk factors and disease management in type 2 diabetic patients with diabetic nephropathy. Diabetes Care. 2006 Mar;29(3):498-503. doi: 10.2337/diacare.29.03.06.dc05-1776.
• Minutolo R, Sasso FC, Chiodini P, Cianciaruso B, Carbonara O, Zamboli P, Tirino G, Pota A, Torella R, Conte G, De Nicola L. Management of cardiovascular risk factors in advanced type 2 diabetic nephropathy: a comparative analysis in nephrology, diabetology and primary care settings. J Hypertens. 2006 Aug;24(8):1655-61. doi: 10.1097/01.hjh.0000239303.93872.31.
• Sasso FC, Simeon V, Galiero R, Caturano A, De Nicola L, Chiodini P, Rinaldi L, Salvatore T, Lettieri M, Nevola R, Sardu C, Docimo G, Loffredo G, Marfella R, Adinolfi LE, Minutolo R; NID-2 study group Investigators. The number of risk factors not at target is associated with cardiovascular risk in a type 2 diabetic population with albuminuria in primary cardiovascular prevention. Post-hoc analysis of the NID-2 trial. Cardiovasc Diabetol. 2022 Nov 7;21(1):235. doi: 10.1186/s12933-022-01674-7.
• Sasso FC, Pafundi PC, Simeon V, De Nicola L, Chiodini P, Galiero R, Rinaldi L, Nevola R, Salvatore T, Sardu C, Marfella R, Adinolfi LE, Minutolo R; NID-2 Study Group Investigators. Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease. Cardiovasc Diabetol. 2021 Jul 16;20(1):145. doi: 10.1186/s12933-021-01343-1.
• Sasso FC, Lascar N, Ascione A, Carbonara O, De Nicola L, Minutolo R, Salvatore T, Rizzo MR, Cirillo P, Paolisso G, Marfella R; NID-2 study group. Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy. A multicenter prospective 8 years follow up study. Cardiovasc Diabetol. 2016 Oct 13;15(1):147. doi: 10.1186/s12933-016-0463-9.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2005
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: September 24, 2007
• First Submitted That Met QC Criteria: September 26, 2007
• First Posted (Estimate): September 27, 2007

Study Record Updates

• Last Update Posted (Actual): August 3, 2020
• Last Update Submitted That Met QC Criteria: July 31, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: type 2 diabetes; nephropathy; cardiovascular (CV) events
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Diseases; Diabetic Nephropathies; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Antimetabolites; Protease Inhibitors; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Natriuretic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Hematinics; Angiotensin-Converting Enzyme Inhibitors; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Sodium Chloride Symporter Inhibitors; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Sodium Potassium Chloride Symporter Inhibitors; Aspirin; Amlodipine; Epoetin Alfa; Hydrochlorothiazide; Simvastatin; Furosemide; Clonidine; Ramipril; Irbesartan; Doxazosin; Atenolol
• Other Study ID Numbers: 246813579