Interleukin-1 Trap to Treat Vascular Dysfunction in Chronic Kidney Disease (CKD)

Risk of cardiovascular diseases (CVD) is significantly elevated in patients with chronic kidney disease (CKD); however, this increased risk is only partially explained by traditional cardiovascular risk factors. Patients with CKD exhibit chronic inflammation, a key mechanism contributing to vascular dysfunction (i.e., large elastic artery stiffening and endothelial dysfunction). Inhibiting inflammation improves vascular dysfunction in other populations characterized by chronic inflammation. However, it is currently unknown if reducing inflammation with an interleukin-1 (IL-1) blocker enhances vascular function in CKD patients. Aim 1 will assess the efficacy of IL-1 blocking with rilonacept for treating vascular dysfunction in patients with stage III or IV CKD (estimated glomerular filtration rate 15-60 mL/min/1.73 m2). Aim 2 will determine if blocking IL-1 with rilonacept also reduces inflammation and oxidative stress. These studies could shift clinical practice guidelines by establishing a novel therapy for reducing CVD risk in CKD patients not requiring chronic hemodialysis.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency, Chronic
• Intervention / Treatment: Drug: Rilonacept; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Clinical and Translational Research Center (CTRC) Outpatient Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-80 years
• CKD stage III or IV (eGFR with the 4-variable Modified Diet Renal Disease (MDRD) prediction equation: 15-60 mL/min/1.73m2; stable renal function in the past 3 months)
• An elevated high sensitivity C-reactive protein (hs-CRP) of > 2.0 mg/L and <30 mg/L on at least 2 consecutive weekly determinations
• Urine protein excretion < 5.0 g/24h estimated by a spot urine protein/creatinine ratio
• Ability to provide informed consent

Exclusion Criteria:

• Patients with advanced CKD requiring chronic dialysis
• Active infection (chronic or acute (within 3 months) or antibiotic therapy (w/in 1 mo); history of recurrent infection
• Significant co-morbid conditions that lead the investigator to conclude that life expectancy is less than 1 year
• Expected to undergo living related transplant in next 6 months
• History of severe congestive heart failure (i.e., EF < 35%)
• Hospitalization in the past month
• Severe arthritis, lupus, inflammatory bowel disease, asthma or other disease(s) or medical condition(s) that, in the opinion of the investigator, could interfere with hsCRP or immune function
• Immunosuppressant agents such as cyclosporine, tacrolimus, azathioprine, etanercept, infliximab, adalimumab, anakinra or long-term oral glucocorticoids taken in past 12 months
• Known malignancy
• HIV, active, chronic hepatitis B as evidenced by HBsAg positive and HBsAb negative, or hepatitis C positive
• Woman who are pregnant, nursing or planning to become pregnant
• Body mass index (BMI) >40 kg/m2
• Warfarin use (or other cytochrome P (CYP)450 substrates with a narrow therapeutic index) [ok if do not participate in endothelial cell collection]
• Taking medication(s) that interact with agents administered during experimental sessions (e.g., sildenafil interacts with nitroglycerin)
• Currently receiving or planning to receive live or inactivated vaccines
• Alcohol dependence or abuse
• Subjects at risk for tuberculosis (TB). Specifically, subjects with:
• Current clinical, radiographic or laboratory evidence of active TB at screening or latent TB that has not been previously treated
• A history of active TB within the last 3 years even if it was treated.
• A history of active TB greater than 3 years ago unless there is documentation that the prior anti-TB treatment was appropriate in duration and type.
• Therapy for latent TB which has not been completed as per local guidelines.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rilonacept; 12 weeks of treatment with rilonacept	Drug: Rilonacept; 12 weeks of treatment with rilonacept (subcutaneous injection with a loading dose of 320 mg, followed by 160 mg/wk); Other Names: Arcalyst
PLACEBO_COMPARATOR: Placebo; Twelve weeks of treatment with placebo	Drug: Placebo; Twelve weeks of treatment with placebo (subcutaneous injection of normal saline with a loading dose of 320 mg, followed by 160 mg/wk); Other Names: normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Flow-mediated Dilation (FMD)	Change in FMD after 3 months of treatment with rilonacept will be compared to change in the placebo group.	3 months after start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Aortic Pulse-wave Velocity (aPWV)	Change in aPWV after 3 months of treatment with rilonacept will be compared to change in the placebo group.	3 months after start of treatment
Change in Contribution of Oxidative Stress to FMD	FMD will be assessed following acute infusion of ascorbic acid compared to saline. The improvement in FMD with ascorbic acid reflects the degree of oxidative stress contributing to impairment in FMD.	3 months after start of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in High-sensitivity C-reactive Protein (hsCRP)	Change in high-sensitivity C-reactive protein (hsCRP) after 3 months of rilonacept vs. placebo will be assessed as a circulating marker of inflammation.	3 months after start of treatment
Change in Vascular Endothelial NADPH Oxidase Expression	Vascular endothelial cells will be collected and assessed for changes in protein expression of NADPH oxidase after 3 months of treatment with rilonacept vs. placebo. Protein expression is calculated as a ratio of intensity of staining in the patient cells relative to human umbilical vein endothelial cell (HUVEC) control cells. The absolute change in this ratio between baseline and week 12 is reported below.	3 months after start of treatment

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Kristen L Jablonski Nowak, Ph.D., University of Colorado Denver Anschutz Medical Campus

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: August 7, 2012
• First Submitted That Met QC Criteria: August 8, 2012
• First Posted (ESTIMATE): August 13, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): September 12, 2016
• Last Update Submitted That Met QC Criteria: August 2, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Inflammation; Oxidative Stress; Endothelial cells; Vascular Stiffness; Endothelium, Vascular; Interleukin-1
• Additional Relevant MeSH Terms: Urologic Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Anti-Inflammatory Agents; Rilonacept
• Other Study ID Numbers: 12-0586