Safety Study Of N-Acetylcysteine For Prevention Of Contrast Induced Nephropathy In Patients w/Stage 3 Renal Failure
| Status: | Completed |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease, Nephrology |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - 85 |
| Updated: | 4/2/2016 |
| Start Date: | November 2007 |
| End Date: | December 2015 |
| Contact: | Edward A Neuwelt, MD |
| Email: | neuwelte@ohsu.edu |
| Phone: | 503-494-5626 |
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
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.
(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.
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:
1. To obtain data on changes from baseline serum creatinine and calculated creatinine
clearance to provide sample size estimates for future studies.
2. 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.
3. To determine NAC pharmacology administered IV or IA.
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:
1. To obtain data on changes from baseline serum creatinine and calculated creatinine
clearance to provide sample size estimates for future studies.
2. 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.
3. To determine NAC pharmacology administered IV or IA.
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
We found this trial at
1
site
3181 Southwest Sam Jackson Park Road
Portland, Oregon 97239
Portland, Oregon 97239
503 494-8311
Oregon Health and Science University In 1887, the inaugural class of the University of Oregon...
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