Safety Study Of N-Acetylcysteine For Prevention Of Contrast Induced Nephropathy In Patients w/Stage 3 Renal Failure

Study Overview
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Brief Summary
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This will be a randomized prospective dose escalation clinical study of N-acetylcysteine (NAC) in patients with stage 3 or worse renal failure (Glomerular Filtration Rate 30-60 ml/min calculated with the Modification of Diet in Renal Disease formula), undergoing a procedure or imaging that requires the administration of contrast media at Oregon Health & Science University or the Portland Veterans Hospital. Subjects will receive NAC 60 minutes prior to the procedure or imaging requiring contrast media. Toxicity will be graded according to NCI Common Toxicity Criteria (CTC) version 3.0. An adult Phase 1 dose escalation study of NAC administered intravenously (IV) and intra-arterially (IA) will be performed. An isotonic nonionic contrast agent will be used in all cases. Contrast Induced Nephropathy (CIN) is defined as an increase in serum creatinine concentration of 25% or more from the subjects baseline value within a 72-hour period after the administration of contrast media. Serum creatinine concentration will be measured at admission, every day during in-patient hospitalization, and at hospital discharge.

Detailed Description
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Radiographic contrast media is being used at an increasing rate for various diagnostic and therapeutic procedures. Renal failure following contrast administration for enhanced imaging has become a serious complication. Patients with underlying renal disorders have an increased incidence of Contrast Induced Nephropathy (CIN). CIN has been reported as the third most common cause of in-hospital renal failure after hypovolemia and post surgical renal insufficiency. Several factors increase the risk of CIN: preexisting renal dysfunction, volume and type of contrast agent employed, and lack of renal prophylaxis. CIN pathogenesis may be due to an injury to the renal cortex and outer medulla resulting from a decrease in blood flow, an osmotic effect, and/or direct toxicity to tubular cells by oxygen free radicals. N-acetylcysteine (NAC) is a cysteine analog and sulfur-containing agent, with strong antioxidant activity, which induces de novo synthesis of glutathione. NAC protection during the evolution of renal failure may be related to the ability to scavenge oxygen free radicals and/or improve endothelium-dependant vasodilation. There is no animal model that directly correlates with CIN, but the investigators have investigated nephrotoxicity and chemoprotection against cisplatin induced nephropathy which has a mechanism of action mediated through the generation of reactive intermediates in an animal model. NAC is potentially protective against cisplatin induced nephrotoxicity when administered at high intravenous (IV) doses (400 mg/kg) and at low intra-arterial (IA) doses (50mg/kg) down the descending aorta. This implies a safe dose-dependent effect of IV NAC and that lower doses can be used IA safely. Objectives: Primary Objective: The primary objective of this study is to establish a maximum tolerated dose of both IV and IA NAC. This maximum tolerated dose will be evaluated primarily for efficacy in a future study. Secondary Objectives: To obtain data on changes from baseline serum creatinine and calculated creatinine clearance to provide sample size estimates for future studies. To estimate the efficacy of NAC in reducing the incidence of CIN. While this study is not adequately powered to address this objective, analyses will be run to assess an increase in serum creatinine concentration of 25% or more from the baseline value within a 48-72 hour period after a procedure or imaging that requires the administration of contrast media as a surrogate for CIN incidence. To determine NAC pharmacology administered IV or IA.

Official Title
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Dose Escalation Study Of I.V. And Intra-Aortic N-Acetylcysteine For The Prevention Of Contrast Induced Nephropathy In Patients With Stage 3 Renal Failure Undergoing Contrast Imaging Studies: A Phase I Trial

Conditions
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Contrast Induced Nephropathy

Intervention / Treatment
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* Drug: N-acetylcysteine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Renal failure, stage 3 or worse Undergoing endovascular procedure with an isotonic, non ionized contrast agent Life expectancy at least 4 weeks from date of registration Platelets greater than or equal to 100,000/mm3 Systolic pressure of greater than 90 mm Hg No contraindications to N-Ac or contrast agent Not at risk for general anesthesia Exclusion Criteria: Acute renal failure Undergoing dialysis Decompensate cardiac failure Pregnant or nursing History of clinically significant reactive airway disease Receiving non-steroidal anti-inflammatory agent within 24 hours of study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1, IV NAC<br>N-acetylcysteine administered intravenously | Drug: N-acetylcysteine<br>* Dose Level 1: 150 mg/kg/day Dose Level 2: 300 mg/kg/day Dose Level 3: 600 mg/kg/day Dose Level 4: 900 mg/kg/day Dose Level 5: 1200 mg/kg/day<br>|
| Experimental: 2, IA NAC<br>N-acetylcysteine administered intra-arterial | Drug: N-acetylcysteine<br>* Dose Level 1: 150 mg/kg/day Dose Level 2: 300 mg/kg/day Dose Level 3: 600 mg/kg/day Dose Level 4: 900 mg/kg/day Dose Level 5: 1200 mg/kg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity will be graded according to NCI CTCAE version 3.0. |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline serum creatinine and calculated creatinine clearance to provide sample size estimates for future studies. |  | 2 years | 
| To estimate the efficacy of NAC in reducing the incidence of CIN. |  | 2 years | 
| To determine NAC pharmacology administered IV or IA. |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Contrast Induced Nephropathy