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

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ClinicalTrials.gov Identifier: NCT01663103
Recruitment Status : Completed
First Posted : August 13, 2012
Results First Posted : September 12, 2016
Last Update Posted : September 12, 2016
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Renal Insufficiency, Chronic Drug: Rilonacept Drug: Placebo Phase 4

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Interleukin-1 Trap to Treat Vascular Dysfunction in Chronic Kidney Disease (CKD)
Study Start Date : August 2012
Actual Primary Completion Date : December 2014
Actual Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Rilonacept

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 Name: 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 Name: normal saline




Primary Outcome Measures :
  1. Change in Flow-mediated Dilation (FMD) [ Time Frame: 3 months after start of treatment ]
    Change in FMD after 3 months of treatment with rilonacept will be compared to change in the placebo group.


Secondary Outcome Measures :
  1. Change in Aortic Pulse-wave Velocity (aPWV) [ Time Frame: 3 months after start of treatment ]
    Change in aPWV after 3 months of treatment with rilonacept will be compared to change in the placebo group.

  2. Change in Contribution of Oxidative Stress to FMD [ Time Frame: 3 months after start of treatment ]
    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.


Other Outcome Measures:
  1. Change in High-sensitivity C-reactive Protein (hsCRP) [ Time Frame: 3 months after start of treatment ]
    Change in high-sensitivity C-reactive protein (hsCRP) after 3 months of rilonacept vs. placebo will be assessed as a circulating marker of inflammation.

  2. Change in Vascular Endothelial NADPH Oxidase Expression [ Time Frame: 3 months after start of treatment ]
    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.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01663103


Locations
United States, Colorado
University of Colorado Clinical and Translational Research Center (CTRC) Outpatient Clinic
Aurora, Colorado, United States, 80045
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
University of Colorado, Denver
Investigators
Principal Investigator: Kristen L Jablonski Nowak, Ph.D. University of Colorado Denver Anschutz Medical Campus

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01663103     History of Changes
Other Study ID Numbers: 12-0586
First Posted: August 13, 2012    Key Record Dates
Results First Posted: September 12, 2016
Last Update Posted: September 12, 2016
Last Verified: June 2016

Keywords provided by University of Colorado, Denver:
Interleukin-1
Endothelium, Vascular
Vascular Stiffness
Oxidative Stress
Inflammation
Endothelial cells

Additional relevant MeSH terms:
Kidney Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Urologic Diseases