Trial Outcomes & Findings for Nephropathy In Type 2 Diabetes and Cardio-renal Events (NCT NCT00535925)

Last Updated: 2020-08-03

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

850 participants

Primary outcome timeframe

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)

Results posted on

2020-08-03

Participant Flow

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

Participant milestones

Participant milestones
Measure	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	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
Overall Study STARTED	188	207
Overall Study COMPLETED	169	199
Overall Study NOT COMPLETED	19	8

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Conventional Therapy n=188 Participants 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	Intensified Therapy n=207 Participants 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	Total n=395 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=188 Participants	0 Participants n=207 Participants	0 Participants n=395 Participants
Age, Categorical Between 18 and 65 years	64 Participants n=188 Participants	104 Participants n=207 Participants	168 Participants n=395 Participants
Age, Categorical >=65 years	124 Participants n=188 Participants	103 Participants n=207 Participants	227 Participants n=395 Participants
Age, Continuous	68.2 years STANDARD_DEVIATION 8.8 • n=188 Participants	66.1 years STANDARD_DEVIATION 9 • n=207 Participants	67.1 years STANDARD_DEVIATION 8.9 • n=395 Participants
Sex: Female, Male Female	105 Participants n=188 Participants	104 Participants n=207 Participants	209 Participants n=395 Participants
Sex: Female, Male Male	83 Participants n=188 Participants	103 Participants n=207 Participants	186 Participants n=395 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Italy	188 participants n=188 Participants	207 participants n=207 Participants	395 participants n=395 Participants

PRIMARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Conventional Therapy n=188 Participants 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	Intensified Therapy n=207 Participants 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
"Number of Participants With Overall Fatal and Non-fatal, Major Adverse Cardiovascular Events (MACEs)"	146 Participants	116 Participants

SECONDARY outcome

Timeframe: 13 years

Achievement of targets at end of intervention was performed applying generalized estimating equation (GEE) models, further adjusting for baseline values as covariate.

Outcome measures

Outcome measures
Measure	Conventional Therapy n=169 Participants 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	Intensified Therapy n=199 Participants 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
"Number of Participants Who Achieved of BP, HbA1c and Total, HDL and LDL Cholesterol Goals at the End of Intervention Phase"	150 Participants	191 Participants

Adverse Events

Conventional Therapy

Serious events: 88 serious events

Other events: 5 other events

Deaths: 103 deaths

Intensified Therapy

Serious events: 69 serious events

Other events: 8 other events

Deaths: 86 deaths

Serious adverse events

Serious adverse events
Measure	Conventional Therapy n=188 participants at risk 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	Intensified Therapy n=207 participants at risk 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
Cardiac disorders Acute Myocardial Infarction	23.4% 44/188 • Number of events 44 • up to 13 years	15.5% 32/207 • Number of events 32 • up to 13 years
Cardiac disorders stroke	14.9% 28/188 • Number of events 28 • up to 13 years	9.2% 19/207 • Number of events 19 • up to 13 years
Cardiac disorders revascularization	6.9% 13/188 • Number of events 13 • up to 13 years	7.7% 16/207 • Number of events 16 • up to 13 years
General disorders major amputation	1.6% 3/188 • Number of events 3 • up to 13 years	0.97% 2/207 • Number of events 2 • up to 13 years

Other adverse events

Other adverse events
Measure	Conventional Therapy n=188 participants at risk 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	Intensified Therapy n=207 participants at risk 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
Metabolism and nutrition disorders Hypoglycemia	0.53% 1/188 • Number of events 1 • up to 13 years	1.4% 3/207 • Number of events 3 • up to 13 years
General disorders Hypotension	1.1% 2/188 • Number of events 2 • up to 13 years	0.97% 2/207 • Number of events 2 • up to 13 years
Renal and urinary disorders End Stage Renal Disease	1.1% 2/188 • Number of events 2 • up to 13 years	1.4% 3/207 • Number of events 3 • up to 13 years

Additional Information

Prof. Ferdinando Carlo Sasso. MD, PhD

University of Campania

Phone: +39-081-5665010

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place