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

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00420290
• Collaborator: (none)
• Enrollment: 31
• Location: 1
• Arms: 2
• Duration (Months): 28
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
End Stage Renal Disease	Drug: kineret; Drug: placebo	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Inflammation, Proteolysis and IL-1 Beta Receptor Inhibition in Chronic Hemodialysis Patients
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Kineret Interleukin-1 receptor antagonist	Drug: kineret; 100 mg administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks; Other Names: Anakinra
Placebo Comparator: Placebo	Drug: placebo; 100 mg administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks

Outcome Measures

Primary Outcome Measures

1. High Sensitivity C-reactive Protein (hsCRP) [month 1]

   hsCRP is a sensitive laboratory assay for serum levels of C-reactive protein, which is a biomarker of inflammation.

Secondary Outcome Measures

1. Interleukin-6 (IL-6) [month 1]

   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.

2. Serum Prealbumin [month 1]

   Prealbumin is a sensitive laboratory assay for serum levels of prealbumin, which is a biomarker of nutrition.

3. Serum Albumin [month 1]

   Albumin is a sensitive laboratory assay for serum levels of albumin, which is a biomarker of nutrition.

4. Lean Body Mass (LBM) [month 1]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University

Investigators

• Principal Investigator: Adriana Hung, MD, Vanderbilt University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Adriana Hung, Assistant Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00420290
• Other Study ID Numbers: 060661
• First Posted: Jan 11, 2007
• Last Update Posted: Nov 17, 2011
• Last Verified: Oct 1, 2011

• Keywords provided by Adriana Hung, Assistant Professor, Vanderbilt University: inflammation; end stage renal disease
• Additional relevant MeSH terms: Kidney Diseases; Kidney Failure, Chronic; Inflammation; Interleukin 1 Receptor Antagonist Protein

Study Results

Participant Flow

Recruitment Details	This study was conducted at the Vanderbilt University Medical Center and Nashville Veterans Affairs Outpatient Dialysis units between January 2008 and May 2010.
Pre-assignment Detail	There is a 3-month screening period following enrollment to determine level of inflammation. To be eligible to participate in the intervention phase of the study and be assigned to a group, participants must have three consecutive CRP levels > 5 mg/L. Although 31 subjects were enrolled, only 22 were eligible to be assigned to a group.

Arm/Group Title	Kineret	Placebo
Arm/Group Description	100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks	100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
Period Title: Overall Study
STARTED	11	11
COMPLETED	7	7
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Kineret	Placebo	Total
Arm/Group Description	100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks	100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks	Total of all reporting groups
Overall Participants	11	11	22
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45 (10.5)	50 (11.4)	47 (11.1)
Sex: Female, Male (Count of Participants)
Female	2 18.2%	3 27.3%	5 22.7%
Male	9 81.8%	8 72.7%	17 77.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 90.9%	8 72.7%	18 81.8%
White	1 9.1%	3 27.3%	4 18.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	High Sensitivity C-reactive Protein (hsCRP)
Description	hsCRP is a sensitive laboratory assay for serum levels of C-reactive protein, which is a biomarker of inflammation.
Time Frame	month 1

Outcome Measure Data

Analysis Population Description

The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.

Arm/Group Title	Kineret	Placebo
Arm/Group Description	100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks	100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
Measure Participants	7	7
Mean (Standard Deviation) [mg/dl]	4.67 (2.87)	15.11 (10.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kineret, Placebo
	Comments	Using data from 128 CHD patients, CRP data were highly skewed, and data were log transformed to achieve normality. With 14 pts in each group (total of 28), it was predicted the minimum detectable difference between control and intervention would be 15% (1.22 for control group and 1.00 for the intervention group), with an 80% power and an alpha of 0.05 using t test approach. Thus, planned sample size was 30 to complete the study.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	0.031 is the upper level of significance
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Interleukin-6 (IL-6)
Description	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.
Time Frame	month 1

Outcome Measure Data

Analysis Population Description

The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.

Arm/Group Title	Kineret	Placebo
Arm/Group Description	100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks	100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
Measure Participants	7	7
Mean (Standard Deviation) [pg/ml]	3.34 (3.09)	8.14 (6.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kineret, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Serum Prealbumin
Description	Prealbumin is a sensitive laboratory assay for serum levels of prealbumin, which is a biomarker of nutrition.
Time Frame	month 1

Outcome Measure Data

Analysis Population Description

The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.

Arm/Group Title	Kineret	Placebo
Arm/Group Description	100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks	100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
Measure Participants	7	7
Mean (Standard Deviation) [mg/dl]	46.43 (11.27)	33.57 (12.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kineret, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Serum Albumin
Description	Albumin is a sensitive laboratory assay for serum levels of albumin, which is a biomarker of nutrition.
Time Frame	month 1

Outcome Measure Data

Analysis Population Description

The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.

Arm/Group Title	Kineret	Placebo
Arm/Group Description	100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks	100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
Measure Participants	7	7
Mean (Standard Deviation) [g/dl]	4.26 (0.40)	3.95 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kineret, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Lean Body Mass (LBM)
Description	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.
Time Frame	month 1

Outcome Measure Data

Analysis Population Description

The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.

Arm/Group Title	Kineret	Placebo
Arm/Group Description	100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks	100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
Measure Participants	7	7
Mean (Standard Deviation) [kg]	59.13 (8.72)	50.38 (7.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kineret, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	1 month
Arm/Group Title	Kineret		Placebo
Arm/Group Description	100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks		100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
All Cause Mortality
	Kineret		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Kineret		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Kineret		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)		3/7 (42.9%)
Blood and lymphatic system disorders
thrombocytopenia	0/7 (0%)	0	1/7 (14.3%)	1
General disorders
fatigue	1/7 (14.3%)	1	1/7 (14.3%)	1
Infections and infestations
hemodialysis access site infection	1/7 (14.3%)	1	0/7 (0%)	0
Respiratory, thoracic and mediastinal disorders
asthma	0/7 (0%)	0	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
injection site reaction	2/7 (28.6%)	2	0/7 (0%)	0
injection site hematoma	1/7 (14.3%)	1	0/7 (0%)	0

Limitations/Caveats

The sample size is small and the intervention is of short duration. Also, the results cannot be generalized to all CHD patients because our inclusion criteria were stringent.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.