Mechanisms for the Effect of Acetylcysteine on Renal Function After Exposure to Radiographic Contrast Material

NCT00558142 | Completed Phase 4 Results

• 4 other identifiers: NAC0606NRES reference: 07/MRE00/64EudraCT reference: 2006003509-18
• Study Type: interventional
• Target: 107
• Locations: 1 country
• Sites: 1

Brief Summary

Millions of people receive radiographic contrast material for investigations like CT and coronary angiography. While considered safe in healthy patients, it can cause acute renal impairment. This is termed radiocontrast-induced nephropathy (RCIN) and is generally defined as an increase in serum creatinine over baseline of more than 25% or 0.5 mg/dL (44.2 μmol/l) within 48 hrs. RCIN occurs in less than 2% of patients with normal renal function but is more common in patients with pre-existing renal damage. The pathophysiology of RCIN is unclear. Possible mechanisms involve 1) reduced renal blood flow leading to acute tubular necrosis and 2) direct renal tubular injury by oxygen free radicals. Current prevention strategies focus on increasing renal blood flow and reducing oxidative stress. Patients at risk of RCIN currently receive fluids, a low dose of contrast, and variable and unproven doses of acetylcysteine. The evidence for acetylcysteine administration is unclear. A RCIN consensus working group reported in the American Journal of Cardiology in September 2006 that "N-acetylcysteine is not consistently effective in reducing the risk for contrast-induced nephropathy". The perception of a benefit from acetylcysteine administration that is unproven has disadvantages as some clinicians report giving larger amounts of radio-contrast to patients who have received acetylcysteine since they believe that it prevents RCIN. There is a need to determine how acetylcysteine might prevent RCIN and to identify the appropriate dose and route of administration. Since acetylcysteine is a vasodilator as well as an antioxidant, it may work in two distinct ways, by preventing reduction in renal blood flow (RBF) or contrast-induced oxidative damage. Previous studies have used changes in serum creatinine. In addition to being an insensitive marker of altered renal function, if contrast causes renal vasoconstriction and acetylcysteine vasodilatation, changes in serum creatinine will not be the ideal marker of effect. Finally the optimum dose and route of acetylcysteine administration is unclear, as illustrated by studies using a variety of doses and routes. We propose to study the mechanism of effects of acetylcysteine on healthy and diseased kidneys, both unstressed and stressed by radiocontrast administration. We hypothesise that acetylcysteine may exert a renoprotective effect in RCIN by a renal vasodilatation and/or antioxidant mechanism.

Conditions

Radiocontrast-induced Nephropathy

Keywords

contrast nephropathy; radiocontrast-induced nephropathy; chronic kidney disease; acetylcysteine; clinical study

Outcome Measures

Primary Outcomes (1)

• Changes in Renal Blood Flow

  Measurement of change in renal blood flow through para-aminohippuric acid (PAH) elimination

  0, 2, 2.25, 2.5, 4, 6, and 8 hrs

Secondary Outcomes (1)

• Changes in Glomerular Filtration Rate

  0, 2, 2.25, 2.5, 4, 6, and 8 hrs

Study Arms (4)

1

ACTIVE COMPARATOR

Healthy volunteers will be randomised to receive either placebo capsules PO plus an infusion of normal saline, acetylcysteine capsules PO plus an infusion of normal saline or placebo capsules PO plus an IV infusion of acetylcysteine in normal saline

Drug: Acetylcysteine

2

ACTIVE COMPARATOR

Volunteers with CKD III will be randomised to receive either placebo capsules PO plus an infusion of normal saline, acetylcysteine capsules PO plus an infusion of normal saline or placebo capsules PO plus an IV infusion of acetylcysteine in normal saline

Drug: Acetylcysteine

3

ACTIVE COMPARATOR

Healthy volunteers will receive a single IV dose of 100mls Visipaque 320 (iodixanol, equivalent to 320 mg iodine/ml). They will then be randomised to receive either placebo capsules PO plus an infusion of normal saline, acetylcysteine capsules PO plus an infusion of normal saline or placebo capsules PO plus an IV infusion of acetylcysteine in normal saline

Drug: Acetylcysteine; Drug: Visipaque 320

4

ACTIVE COMPARATOR

Volunteers with CKD III will receive Visipaque 320 during coronary angiography. They will have been randomised to receive either placebo capsules PO plus an infusion of normal saline, acetylcysteine capsules PO plus an infusion of normal saline or placebo capsules PO plus an IV infusion of acetylcysteine in normal saline

Drug: Acetylcysteine; Drug: Visipaque 320

Interventions

Acetylcysteine DRUG

Participants will receive packs of either 8 placebo capsules or 8 acetylcysteine (600mg) capsules. They will be asked to take 2 tablets at 08.00 and 22.00 on the day before the study and the day of the study. On the day of the study participants will receive an IV infusion of either normal saline or acetylcysteine (200mg/kg)

Also known as: Parvolex

1; 2; 3; 4

Visipaque 320 DRUG

100mls IV dose as single dose

Also known as: Iodixanol

3

Eligibility Criteria

• Age: 45 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Study 1 and 3: Healthy male volunteers over 45 years of age with BMI between 22 and 40.
• Study 2: Male volunteers with CKD III with BMI between 22 and 40.
• Study 4: Male patients over 45 year of age with stable CKD III and BMI between 22 and 40, undergoing elective coronary angiography.

You may not qualify if:

• Lack of informed consent
• Age \<46 years
• Current involvement in a clinical trial
• Clinically significant co-morbidity: heart failure, hypertension, known hyperlipidaemia, diabetes mellitus, coagulopathy, peripheral vascular disease, or bleeding disorder
• thyroid disease, myasthenia gravis, asthma, atopy, or a history of allergy/sensitivity to acetylcysteine or contrast medium
• current intake of prescription medicines, in particular beta blockers
• recent infective/inflammatory condition
• blood donation during the preceding three months
• Lack of informed consent
• Age \<46 years
• Current involvement in a clinical trial
• Thyroid disease, myasthenia gravis, asthma, atopy, or a history of allergy/sensitivity to acetylcysteine or contrast medium
• Recent infective/inflammatory condition
• Blood donation during the preceding three months

Sponsors & Collaborators

• University of Edinburgh: lead
• NHS Lothian: collaborator

Study Sites (1)

Clinical Research Facility, Royal Infirmary Edinburgh

Edinburgh, Midlothian, EH16 4SA, United Kingdom

Location

Related Publications (6)

• Parfrey P. The clinical epidemiology of contrast-induced nephropathy. Cardiovasc Intervent Radiol. 2005;28 Suppl 2:S3-11. doi: 10.1007/s00270-005-0196-8.

  PMID: 16419277 BACKGROUND

• Gleeson TG, Bulugahapitiya S. Contrast-induced nephropathy. AJR Am J Roentgenol. 2004 Dec;183(6):1673-89. doi: 10.2214/ajr.183.6.01831673. No abstract available.

  PMID: 15547209 BACKGROUND

• Stacul F. Reducing the risks for contrast-induced nephropathy. Cardiovasc Intervent Radiol. 2005;28 Suppl 2:S12-8. doi: 10.1007/s00270-005-0197-7.

  PMID: 16419278 BACKGROUND

• Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi F, Montorsi P, Veglia F, Bartorelli AL. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. 2006 Jun 29;354(26):2773-82. doi: 10.1056/NEJMoa054209.

  PMID: 16807414 BACKGROUND

• Eddleston M, Goddard J, Bateman N. N-acetylcysteine for contrast nephropathy: more clinical science is required. Arch Intern Med. 2006 Aug 14-28;166(15):1668-9; author reply 1669. doi: 10.1001/archinte.166.15.1668-b. No abstract available.

  PMID: 16908804 BACKGROUND

• Sandilands EA, Cameron S, Paterson F, Donaldson S, Briody L, Crowe J, Donnelly J, Thompson A, Johnston NR, Mackenzie I, Uren N, Goddard J, Webb DJ, Megson IL, Bateman N, Eddleston M. Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol. BMC Clin Pharmacol. 2012 Feb 3;12:3. doi: 10.1186/1472-6904-12-3.

  PMID: 22305183 DERIVED

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Interventions

Acetylcysteine; N-monoacetylcystine; iodixanol

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Prof M Eddleston
• Organization: University of Edinburgh

m.eddleston@ed.ac.uk

01312426776

Study Officials

• Michael Eddleston, MA PhD MCRP

  University of Edinburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2007
• First Posted: November 14, 2007
• Study Start: February 1, 2008
• Primary Completion: January 1, 2015
• Study Completion: January 1, 2015
• Last Updated: September 19, 2024
• Results First Posted: September 19, 2024

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)