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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.
The same patients that completed the first phase of the NID-2 study (observation) were enrolled for the phase 2 of the study (intervention).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard of Care (SoC) therapy | Active Comparator | 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. |
|
| Multifactorial Intensified therapy | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| SoC therapy | Drug | the patients have to be treated according the standard good medical practice by any center |
|
| 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) |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ferdinando C Sasso, MD, PhD | Università della Campania "Luigi Vanvitelli", Naples, Italy | Study Director |
| Roberto Minutolo, MD, MD | Università della Campania "Luigi Vanvitelli", Naples, Italy | Principal Investigator |
| Luca De Nicola, MD, MD | Università della Campania "Luigi Vanvitelli", Naples, Italy | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Advanced Medical and Surgical Sciences, Università della Campania "Luigi Vanvitelli", Naples, Italy | Naples | I-80131 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16505495 | Background | 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. | |
| 16877970 | Background | 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. |
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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
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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
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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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) | Posted | Count of Participants | Participants | 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) |
|
up to 13 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute Myocardial Infarction | Cardiac disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypoglycemia | Metabolism and nutrition disorders | Systematic Assessment | if fasting glycemia <= 70 mg/dL |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Ferdinando Carlo Sasso. MD, PhD | University of Campania | +39-081-5665010 | ferdinandocarlo.sasso@unicampania.it |
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| ID | Term |
|---|---|
| D003928 | Diabetic Nephropathies |
| D003924 | Diabetes Mellitus, Type 2 |
| D007674 | Kidney Diseases |
| ID | Term |
|---|---|
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D000077405 | Irbesartan |
| D017257 | Ramipril |
| D006852 | Hydrochlorothiazide |
| D005665 | Furosemide |
| D017311 | Amlodipine |
| D001262 | Atenolol |
| D017292 | Doxazosin |
| D003000 | Clonidine |
| D007328 | Insulin |
| D019821 | Simvastatin |
| D058607 | Fibric Acids |
| D004921 | Erythropoietin |
| D001241 | Aspirin |
| ID | Term |
|---|---|
| D001713 | Biphenyl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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| irbesartan | Drug | Therapy for hypertension: - Step 1: irbesartan 300 mg/die and ramipril 10 mg/die |
|
| ramipril | Drug | Therapy for hypertension: - Step 1: irbesartan 300 mg/die and ramipril 10 mg/die |
|
| hydrochlorothiazide | Drug | 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) |
|
| furosemide | Drug | 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) |
|
| amlodipine | Drug | Therapy for hypertension - Step 3: amlodipine up to 10 mg/die |
|
| atenolol | Drug | Therapy for hypertension - Step 4: atenolol up to 100 mg/die |
|
| doxazosin | Drug | Therapy for hypertension - Step 5: doxazosin up to 4 mg/die |
|
| clonidine | Drug | Therapy for hypertension - Step 6: clonidine |
|
| insulin | Drug | Therapy for Hyperglycaemia (to achieve HbA1c <7): - insulin |
|
| simvastatin | Drug | Therapy for hypercholesterolemia: - for reducing LDL cholesterol < 100 mg/dl: simvastatin up to 80 mg/die |
|
| fibrate | Drug | Therapy for hypertriglyceridemia - for reducing triglycerides < 150 mg/dl and/or increasing HDL cholesterol > 40-50 mg/dl: a fibrate |
|
| erythropoietin | Drug | Treatment of anaemia: - erythropoietin |
|
| aspirin | Drug | Antiplatelet therapy (in all patients without contraindications): - aspirin up to 160 mg/die |
|
| 36344978 | Derived | 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. |
| 34271948 | Derived | 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. |
| 27733159 | Derived | 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. |
| 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
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 |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | number and percentage | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 | 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 |
| OG001 | 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
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 |
|
|
|
| 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. | Posted | Count of Participants | Participants | 13 years |
|
|
|
| 103 |
| 188 |
| 88 |
| 188 |
| 5 |
| 188 |
| EG001 | 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
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 | 86 | 207 | 69 | 207 | 8 | 207 |
| stroke | Cardiac disorders | Systematic Assessment |
|
| revascularization | Cardiac disorders | Systematic Assessment |
|
| major amputation | General disorders | Systematic Assessment |
|
|
| Hypotension | General disorders | Systematic Assessment | if systolic blood pressure <= 100 mmHg |
|
| End Stage Renal Disease | Renal and urinary disorders | Systematic Assessment | if eGFR (CKD-EPI) < 15 ml/min |
|
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| D052801 | Male Urogenital Diseases |
| D048909 | Diabetes Complications |
| D003920 | Diabetes Mellitus |
| D004700 | Endocrine System Diseases |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D013141 | Spiro Compounds |
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D002740 | Chlorothiazide |
| D001581 | Benzothiadiazines |
| D013449 | Sulfonamides |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D049971 | Thiazides |
| D013424 | Sulfanilamides |
| D000577 | Amides |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| D004095 | Dihydropyridines |
| D011725 | Pyridines |
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D020005 | Propanols |
| D011224 | Prazosin |
| D011799 | Quinazolines |
| D048288 | Imidazolines |
| D007093 | Imidazoles |
| D011384 | Proinsulin |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008148 | Lovastatin |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D058610 | Isobutyrates |
| D002087 | Butyrates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D010647 | Phenyl Ethers |
| D004987 | Ethers |
| D010636 | Phenols |
| D003115 | Colony-Stimulating Factors |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D016298 | Hematopoietic Cell Growth Factors |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |