Safety Study Of N-Acetylcysteine (N-ac) For The Prevention Of Contrast Induced Nephropathy (CIN) In Patients With Stage 3 Renal Failure - Full Text View

Sponsored by:	Oregon Health and Science University
Information provided by:	Oregon Health and Science University
ClinicalTrials.gov Identifier:	NCT00575419

Purpose

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.

Condition	Intervention	Phase
Contrast Induced Nephropathy	Drug: N-acetylcysteine	Phase I

MedlinePlus related topics: Kidney Failure

Drug Information available for: Acetylcysteine

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Prevention, Randomized, Single Blind (Subject), Dose Comparison, Parallel Assignment, Safety Study
Official Title:	Dose Escalation Study Of Intravenous 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

Further study details as provided by Oregon Health and Science University:

Primary Outcome Measures:

Toxicity will be graded according to NCI CTCAE version 3.0. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Baseline serum creatinine and calculated creatinine clearance to provide sample size estimates for future studies. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
To estimate the efficacy of NAC in reducing the incidence of CIN. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
To determine NAC pharmacology administered IV or IA. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	60
Study Start Date:	November 2007
Estimated Study Completion Date:	December 2009

Arms	Assigned Interventions
1, IV NAC: Experimental N-acetylcysteine administered intravenously	Drug: N-acetylcysteine 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
2, IA NAC: Experimental N-acetylcysteine administered intra-arterial	Drug: N-acetylcysteine 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

Detailed Description:

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 we 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.

Eligibility

Ages Eligible for Study:	18 Years to 85 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00575419

Contacts

Contact: Edward A Neuwelt, MD	503-494-5626	neuwelte@ohsu.edu
Contact: Nancy A Hedrick, BS	503-494-5626	hedrickn@ohsu.edu

Locations

United States, Oregon
Oregon Health & Science University	Recruiting
Portland, Oregon, United States, 97239
Principal Investigator: Edward A Neuwelt, MD

Sponsors and Collaborators

Oregon Health and Science University

Investigators

Principal Investigator:

Edward A Neuwelt, MD

Oregon Health and Science University

More Information

Responsible Party:	Oregon Health & Science University ( Edward A. Neuwelt, M.D. )
Study ID Numbers:	OHSU-3673
Study First Received:	December 14, 2007
Last Updated:	September 15, 2008
ClinicalTrials.gov Identifier:	NCT00575419
Health Authority:	United States: Food and Drug Administration

Keywords provided by Oregon Health and Science University:

Contrast Induced Nephropathy

Study placed in the following topic categories:

Renal Insufficiency
Urologic Diseases
Acetylcysteine

Kidney Diseases
N-monoacetylcystine
Kidney Failure

Additional relevant MeSH terms:

Anti-Infective Agents
Respiratory System Agents
Antioxidants
Molecular Mechanisms of Pharmacological Action
Therapeutic Uses
Expectorants

Physiological Effects of Drugs
Free Radical Scavengers
Protective Agents
Antiviral Agents
Pharmacologic Actions
Antidotes

ClinicalTrials.gov processed this record on January 16, 2009