End Stage Renal Disease
Conditions
Keywords
inflammation, end stage renal disease
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.
Interventions
DRUGkineret
100 mg administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
DRUGplacebo
100 mg administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks
Sponsors
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Serum Prealbumin | month 1 | Prealbumin is a sensitive laboratory assay for serum levels of prealbumin, which is a biomarker of nutrition. |
| Serum Albumin | month 1 | Albumin is a sensitive laboratory assay for serum levels of albumin, which is a biomarker of nutrition. |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Kineret 100 mg Interleukin-1 receptor antagonist administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks | 11 |
| Placebo 100 mg placebo administered subcutaneously every other day (3 days a week during hemodialysis) for 4 weeks | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | did not meet inclusion/exclusion | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Kineret |
|---|---|---|---|
| Age Continuous | 50 years STANDARD_DEVIATION 11.4 | 47 years STANDARD_DEVIATION 11.1 | 45 years STANDARD_DEVIATION 10.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 18 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Male | 8 Participants | 17 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 7 | 3 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 |
Outcome results
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.
Time frame: month 1
Population: The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kineret | High Sensitivity C-reactive Protein (hsCRP) | 4.67 mg/dl | Standard Deviation 2.87 |
| Placebo | High Sensitivity C-reactive Protein (hsCRP) | 15.11 mg/dl | Standard Deviation 10.18 |
Comparison: 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.p-value: 0.008ANCOVA
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.
Time frame: month 1
Population: The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kineret | Interleukin-6 (IL-6) | 3.34 pg/ml | Standard Deviation 3.09 |
| Placebo | Interleukin-6 (IL-6) | 8.14 pg/ml | Standard Deviation 6.04 |
p-value: 0.03ANCOVA
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.
Time frame: month 1
Population: The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kineret | Lean Body Mass (LBM) | 59.13 kg | Standard Deviation 8.72 |
| Placebo | Lean Body Mass (LBM) | 50.38 kg | Standard Deviation 7.86 |
p-value: >0.05ANCOVA
Secondary
Serum Albumin
Albumin is a sensitive laboratory assay for serum levels of albumin, which is a biomarker of nutrition.
Time frame: month 1
Population: The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kineret | Serum Albumin | 4.26 g/dl | Standard Deviation 0.4 |
| Placebo | Serum Albumin | 3.95 g/dl | Standard Deviation 0.38 |
p-value: >0.05ANCOVA
Secondary
Serum Prealbumin
Prealbumin is a sensitive laboratory assay for serum levels of prealbumin, which is a biomarker of nutrition.
Time frame: month 1
Population: The number of participants for analysis was based on those subjects who completed the 4-week study. The analysis was per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kineret | Serum Prealbumin | 46.43 mg/dl | Standard Deviation 11.27 |
| Placebo | Serum Prealbumin | 33.57 mg/dl | Standard Deviation 12.23 |
p-value: >0.05ANCOVA