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Inflammation in Chronic Kidney Disease and Cardiovascular Disease - The Role of Genetics and Interleukin-1 Receptor Antagonist (IL-1ra)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00897715
Recruitment Status : Completed
First Posted : May 12, 2009
Results First Posted : March 17, 2016
Last Update Posted : February 25, 2019
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE May 8, 2009
First Posted Date  ICMJE May 12, 2009
Results First Submitted Date  ICMJE February 18, 2016
Results First Posted Date  ICMJE March 17, 2016
Last Update Posted Date February 25, 2019
Actual Study Start Date  ICMJE January 1, 2013
Actual Primary Completion Date February 25, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2016)
Change in the Concentration of High Sensitivity C-Reactive Protein (hsCRP) From Baseline to 12 Weeks [ Time Frame: baseline and 12 weeks ]
hsCRP is a sensitive laboratory assay for serum levels of C-Reactive Protein, which is a biomarker of inflammation
Original Primary Outcome Measures  ICMJE
 (submitted: May 11, 2009)
Non traditional CV risk factors : Inflammatory Markers, endothelial function, Oxidative stress, insulin resistance and Pulse wave velocity [ Time Frame: 12 weeks ]
Change History Complete list of historical versions of study NCT00897715 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2016)
Change in Concentration of Interleukin-6 (IL-6) From Baseline to 12 Weeks [ Time Frame: baseline and 12 weeks ]
IL-6 is a sensitive laboratory assay for serum levels of Interleukin-6, which is a pro-inflammatory cytokine that is used to evaluate the inflammatory response
Original Secondary Outcome Measures  ICMJE
 (submitted: May 11, 2009)
Renal Outcomes: Urinary Cytokines. Albumin/creatinine Ratio [ Time Frame: 12 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Inflammation in Chronic Kidney Disease and Cardiovascular Disease - The Role of Genetics and Interleukin-1 Receptor Antagonist (IL-1ra)
Official Title  ICMJE Inflammation in CKD and CVD - The Role of Genetics and IL-1ra
Brief Summary

There has been an exponential growth in the number of people with Chronic Kidney Disease (CKD) needing dialysis or transplantation, increasing from 209,000 in 1991 to 472,000 in 2004. This is highly concerning due to both the human cost and the burden that it represents to the health care system. Recent comparison of the NHANES surveys showed that CKD prevalence increased from 10% in 1988-1994 to 13% in 1999-2004. Patients with CKD are more likely to die from premature cardiovascular death than to reach ESRD. In those that reach ESRD, cardiovascular disease (CVD) accounts for over half of the deaths in dialysis. The prevalence of CKD for the VA population is 20%, and 31.6% for diabetics, higher than in the general population. These observations emphasize the need of risk stratification, early detection, and prevention efforts with respect to CKD progression and the CVD burden that afflicts CKD through targeted interventions in high-risk groups (personalized medicine).

CKD is multifactorial, however familial aggregation of end-stage renal disease (ESRD) and CKD have been reported for all types of nephropathy underscoring "kidney disease genetic susceptibility ". Genetic predisposition to ESRD is stronger in African Africans. African Americans with a first-degree relative with ESRD have a 9-fold increase risk of ESRD vs. a 3-5 fold increase in whites.

Studies consistently show that CKD is an inflammatory process and that biomarkers of inflammation increase since early stages of CKD. CVD is also an inflammatory process, and genes that affect inflammation are associated with higher risk of CVD. Since inflammation is a common denominator of both disease processes (CKD and CVD), it is likely that genes that govern inflammation may be involved in both, the predisposition to CKD and the burden of CVD attributable to CKD. Additionally if inflammation plays a central role in the burden of CVD in CKD than drugs that modulate inflammation should impact both: CKD progression and non-traditional CV risk factors and CVD.

The overall goal of this proposal is to study genetic predisposition to CKD, and CVD risk in CKD through inflammatory pathways, and the effect that a potent anti-inflammatory intervention like interleukin 1 receptor antagonist (IL-1ra), will have in inflame patients with CKD stages 3&4. Specific Aims: 1) To determine if specific polymorphism/haplotypes, genotype combinations and gene-environmental interactions that can affect inflammation, available from the Third National Health and Nutrition Examination Survey (DNA data set), specifically in the CRP,IL-1, IL-10 and TNF- genes, are associated with CKD. 2) To determine if the specific polymorphisms and haplotypes studied in Aim 1 are associated with faster CKD progression and CV outcomes in a longitudinal cohort from the African American Study of Kidney Disease. 3)To determine if a targeted anti-inflammatory intervention, an IL-1 receptor antagonist, will modulate systemic inflammation, endothelial function, oxidative stress and urinary cytokines, the proposed surrogate markers of CVD and CKD progression in inflame patients with CKD stages 3&4.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Kidney Disease
  • Cardiovascular Disease
Intervention  ICMJE
  • Drug: Rilonacept
    160 mg of rilonacept administered subcutaneously once a week for 12 weeks
    Other Name: Arcalyst
  • Drug: Placebo
    160 mg of placebo administered subcutaneously once a week for 12 weeks
Study Arms  ICMJE
  • Active Comparator: Interleukin-1 receptor antagonist
    active drug
    Intervention: Drug: Rilonacept
  • Placebo Comparator: Placebo
    matching placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 20, 2015)
Original Estimated Enrollment  ICMJE
 (submitted: May 11, 2009)
Actual Study Completion Date  ICMJE May 8, 2015
Actual Primary Completion Date February 25, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 18 years of age or older;
  • estimated glomerular filtration rate (eGFR) between 15-60 mL/min/1.73m2;
  • Must be on stable regimens of medications that can affect inflammatory axis (Aspirin, Thiazolidinediones, statins);
  • Willing and able to comply with clinic visits and study-related procedures;
  • Provide signed informed consent.

Exclusion Criteria:

  • Recent infection or hospitalization (within one month);
  • History of active or chronic hepatitis B, history of active or chronic hepatitis C, human immunodeficiency virus (HIV), history of tuberculosis (patient must be purified protein derivate negative);
  • Patients taking tumor necrosis factor (TNF) inhibitors, TNF blocker, interleukin-6 (IL-6) blockers or interleukin-1 (IL-1) blocking drugs;
  • Patients on steroids or receiving any other immunosuppressive agent or anti-inflammatory drug (aspirin up to 325 mg a day is allowed) one month prior;
  • Have clinically significant chronic lymphopenia (low white blood cell count);
  • History of malignancy in the prior 5 years. Any history of melanoma or lymphoma;
  • Life expectancy less than six months;
  • Intolerance to the study medication;
  • The use of any other investigational drug 30 days prior to enrollment or within five half-lives of the medication used;
  • Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose;
  • Currently receiving parenteral iron or scheduled to receive parenteral iron during the study;
  • Uncontrolled diabetes mellitus (glycated hemoglobin > 10);
  • high sensitivity c-reactive protein (hsCRP) <2mg/L or >30 mg/L;
  • Body mass index (BMI) > 40;
  • Known diagnosis of severe congestive heart failure with documented ejection fraction (EF) < 35%;
  • Pregnant or breast-feeding women;
  • Sexually active men* or women of childbearing potential** who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device (IUD); bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly).

    • Contraception is not required for men with documented vasectomy. **Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of child bearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00897715
Other Study ID Numbers  ICMJE CDA-2-031-09S
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Adriana M Hung, MD MPH Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
PRS Account VA Office of Research and Development
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP