Inflammation, Proteolysis and IL-1 Beta Receptor Inhibition in Chronic Hemodialysis Patients

End Stage Renal Disease Clinical Trial

Official title:

Inflammation, Proteolysis and IL-1 Beta Receptor Inhibition in Chronic Hemodialysis Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00420290
• Other study ID #: 060661
• Status: Completed
• Phase: N/A
• First received: January 10, 2007
• Last updated: October 10, 2011
• Start date: January 2008
• Est. completion date: May 2010

Study information

• Verified date: October 2011
• Source: Vanderbilt University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Chronic hemodialysis (CHD) patients display multiple metabolic abnormalities related to advanced uremia. Despite vigorous attempts to prevent these abnormalities and their consequences, most CHD patients suffer from a unique form of nutritional derangement, which can be termed as "uremic wasting". Several studies have demonstrated that the presence of uremic wasting, especially the degree of loss of muscle mass, sharply increases mortality and hospitalization rate in CHD patients.

Several factors have been thought to be associated with uremic wasting, including hormonal derangement, anorexia, physical inactivity, and concurrent illnesses. Chronic inflammation, also highly prevalent in these patients, causes muscle catabolism in animal models and certain clinical conditions. Epidemiological studies show an association between chronic inflammation and uremic wasting in hemodialysis patients indicating a possible causal relationship.

The cause for the activated inflammatory state in CHD patients is believed to be multi-factorial. Nevertheless, it is certainly important for the host to limit its biological activity by eliciting a stronger anti-inflammatory response, for example through the production of naturally occurring receptor antagonist. Interleukin 1 beta, one of the major pro-inflammatory cytokines has been shown to be associated with protein catabolism in several chronic disease states, including advanced uremia. A balance between interleukin 1 beta (agonist) and its naturally occurring receptor antagonist IL-1ra may play a pivotal role in controlling the inflammatory response and its consequences in this population.

The overall goal of this particular grant application is to examine the short-term effects of the administration of the recombinant form of IL-1ra on 1) chronic inflammatory state and 2) protein homeostasis in chronically inflamed CHD patients.

We have updated our protocol to perform an interim analysis. The interim analysis will be performed after half of the planned study sample has been enrolled (14 subjects; 7 in each arm). The interim analysis has been approved by the Data Safety Monitoring Board.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: May 2010
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Patients on CHD for more than 3 months;

2. Ability to read and sign the consent form;

3. Have acceptable dialysis adequacy (Kt/V > 1.2);

4. Use biocompatible hemodialysis membrane;

5. Have a patent, well functioning, arteriovenous dialysis access;

6. Signs of chronic inflammation (the average of three consecutive CRP measurements = 5 mg/L).

Exclusion Criteria:

1. Patients with residual renal function > 5 ml/min or urine output > 100 ml/day;

2. Pregnancy;

3. Intolerance to the study medication or contraindication to the study medication:

Hypersensitivity to E. coli-derived proteins, anakinra, or any component of the formulation; patients with active infections (including chronic or local infection);

4. Severe, unstable, active, or chronic inflammatory disease (active infection, active connective tissue disorder, active cancer or cancer history in the prior 5 years, HIV, liver disease including positive test or history of Hepatitis B or C);

5. Hospitalization within 1 month prior to the study;

6. Malfunctioning arterial-venous vascular access [recirculation and/or blood flow < 500 ml/min for an arterial-venous graft (AVG) or < 400 ml/min for an arterial-venous fistula (AVF)];

7. Patients receiving steroids and/or other immunosuppressive agents;

8. Life-expectancy less than 6 months;

9. Age greater than 75 or less than 18 years old;

10. Hypersensitivity to organic nitrates, isosorbide, or nitroglycerin.

11. Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy. Subjects with current active TB, or recent close exposure to an individual with active TB, are excluded from the study.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• End Stage Renal Disease
• Inflammation
• Kidney Diseases
• Kidney Failure, Chronic

Intervention

Drug:
• kineret
100 mg administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
• placebo
100 mg administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University

Country where clinical trial is conducted

United States, 

References & Publications (1)

Hung AM, Ellis CD, Shintani A, Booker C, Ikizler TA. IL-1ß receptor antagonist reduces inflammation in hemodialysis patients. J Am Soc Nephrol. 2011 Mar;22(3):437-42. doi: 10.1681/ASN.2010070760. Epub 2011 Feb 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	High Sensitivity C-reactive Protein (hsCRP)	hsCRP is a sensitive laboratory assay for serum levels of C-reactive protein, which is a biomarker of inflammation.	month 1	No
Secondary	Interleukin-6 (IL-6)	IL-6 is a sensitive laboratory assay for serum levels of interlukin-6, which is a pro-inflammatory cytokine that is used to evaluate the inflammatory response.	month 1	No
Secondary	Serum Prealbumin	Prealbumin is a sensitive laboratory assay for serum levels of prealbumin, which is a biomarker of nutrition.	month 1	No
Secondary	Serum Albumin	Albumin is a sensitive laboratory assay for serum levels of albumin, which is a biomarker of nutrition.	month 1	No
Secondary	Lean Body Mass (LBM)	LBM is a measurement of body composition in terms of lean body mass as determined using Dual Energy X-ray Absorptiometry (DEXA) performed 1 to 2 hours after dialysis.	month 1	No