Safety of Dual Blockage of Rennin-angiotensin System in Patients With Advanced Renal Insufficiency

Study Overview
=================
Brief Summary
-----------------
The primary aim of the present study is to assess the safety of combined treatment of benazepril (an ACE inhibitor) or losartan (an ARB) in non-diabetic patients with advanced renal insufficiency.

Detailed Description
-----------------
Interruption of the renin-angiotensin systerm (RAS) with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) slows the progression of chronic renal insufficiency in the presence or absence of diabetes. Even for advanced chronic renal insufficiency (stage 4 CKD), ACE inhibitors and ARBs can still provide renoprotection. Some clinical studies showed that dual RAS blockage seemed to enhance the antiproteinuric effect compared with single-agent ACE inhibitor or ARB and then improve renal survival. However, in the only one randomized controlled trial investigating the renoprotection of combined ACE inhibitor and ARB for mild or moderate chronic renal insufficiency (the mean creatinine value is 2.9mg/dl), the incidence of hyperkalemia was increased in combination therapy compared with monotherapy. Although increase of hyperkalemia was not statistical significant, it suggested that combination treatment of ACEI and ARB might increase the incidence of hyperkalemia in patients with advanced renal insufficiency. However, it is still undetermined whether combination treatment of ACE inhibitor and ARB is safe as an ACE inhibitor or ARB monotherapy in advanced non-diabetic chronic renal insufficiency (stage 4 CKD). The primary aim of the present study is to assess the safety of combined treatment of benazepril (an ACE inhibitor) or losartan (an ARB) in non-diabetic patients with advanced renal insufficiency.

Official Title
-----------------
Safety of Dual Blockage of Rennin-angiotensin System in Patients With Advanced Renal Insufficiency

Conditions
-----------------
Renal Insufficiency, Chronic

Intervention / Treatment
-----------------
* Drug: Benazepril
* Drug: Losartan
* Drug: Benazepril+Losartan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Serum creatinine concentration of 3.0 to 5.0 mg per deciliter (265 to 442 µmol/L) Creatinine clearance of 15 to 30 ml per minute per 1.73m2, with variations of less than 30 percent in the three months before screening evaluation non-diabetic renal disease Persistent heavier proteinuria (defined by urinary protein excretion of more than 0.3g per day for three or more months without evidence of urinary tract infection or overt heart failure [a New York Heart Association class of Ⅲ or Ⅳ]) had not received ACE inhibitors or ARBs for at least two weeks before screening Exclusion Criteria: No history of allergic reaction to drugs, especially ACE inhibitors and/or ARBs Hyper-or hypokalemia (serum potassium concentration 5.6 mmol per liter or more，or 3.5 mmol per liter or less) Malignant hypertension (blood pressure >180/120 mm Hg) or blood pressure <110mm Hg without antihypertensive treatment Treatment with drugs affecting serum potassium such as diuretic, β2 receptor blocker et al. Treatment with corticosteroids, non-steroidal anti-inflammatory drugs, or immunosuppressive drugs, especially ciclosporin A Myocardial infarction or cerebrovascular accident in the year preceding the trial Nephrotic syndrome (albuminaemia less than 25 g/L) Renovascular disease or connective-tissue disease Obstructive uropathy Immediate need for dialysis Pregnancy or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Benazepril group | Drug: Benazepril<br>* 20 mg per day<br>* Other names: Lotensin;|
| Active Comparator: 2<br>Losartan group | Drug: Losartan<br>* 100 mg per day<br>* Other names: Cozaar;|
| Active Comparator: 3<br>Benazepril+Losartan group | Drug: Benazepril+Losartan<br>* combination treatment of 10 mg benazepril and 50 mg losartan per day<br>* Other names: Lotensin+Cozaar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with increase in serum potassium ≥6.0 mmol/L. |  | Every 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with serum creatinine increase >30% |  | Every 4 weeks | 
| The proportion of patients with drug-related cough |  | Every 4 weeks | 
| The proportion of patients with hopotension (systolic blood pressure <110 mmHg despite withdrawal of all additional antihypertensive medication) |  | Every 4 weeks | 
| The proportion of patients with non-fatal cardiovascular events |  | Every 4 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Renal insufficiency, Benazepril, Losartan, combination treatment, Safety