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

NCT00897715 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: CDA-2-031-09S
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 2

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.

Conditions

Chronic Kidney Disease; Cardiovascular Disease

Keywords

CKD; inflammation; CVD

Outcome Measures

Primary Outcomes (1)

• Change in the Concentration of High Sensitivity C-Reactive Protein (hsCRP) From Baseline to 12 Weeks

  hsCRP is a sensitive laboratory assay for serum levels of C-Reactive Protein, which is a biomarker of inflammation

  baseline and 12 weeks

Secondary Outcomes (1)

• Change in Concentration of Interleukin-6 (IL-6) From Baseline to 12 Weeks

  baseline and 12 weeks

Study Arms (2)

Interleukin-1 receptor antagonist

ACTIVE COMPARATOR

active drug

Drug: Rilonacept

Placebo

PLACEBO COMPARATOR

matching placebo

Drug: Placebo

Interventions

Rilonacept DRUG

160 mg of rilonacept administered subcutaneously once a week for 12 weeks

Also known as: Arcalyst

Interleukin-1 receptor antagonist

Placebo DRUG

160 mg of placebo administered subcutaneously once a week for 12 weeks

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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%;

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (2)

Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Nashville, Tennessee, 37212-2637, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Cardiovascular Diseases; Inflammation

Interventions

rilonacept

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

Results Point of Contact

• Title: Adriana Hung
• Organization: VA Tennessee Valley Healthcare System.

adriana.hung@va.gov

615-873-7480

Study Officials

• Adriana M Hung, MD MPH

  Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 8, 2009
• First Posted: May 12, 2009
• Study Start: January 1, 2013
• Primary Completion: February 25, 2015
• Study Completion: May 8, 2015
• Last Updated: October 1, 2019
• Results First Posted: March 17, 2016

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)