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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Colorado, Denver
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01663103
First received: August 7, 2012
Last updated: May 20, 2014
Last verified: May 2014
  Purpose

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 Intervention Phase
Renal Insufficiency, Chronic
Drug: Rilonacept
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Interleukin-1 Trap to Treat Vascular Dysfunction in Chronic Kidney Disease (CKD)

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • Change in flow-mediated dilation (FMD) [ Time Frame: 3 months after start of treatment ] [ Designated as safety issue: No ]
    Change in FMD after 3 months of treatment with rilonacept will be compared to change in the placebo group. Change in FMD will also be assessed at intermediate time points of 1 and 2 months.


Secondary Outcome Measures:
  • Change in aortic pulse-wave velocity (aPWV) [ Time Frame: 3 months after start of treatment ] [ Designated as safety issue: No ]
    Change in aPWV after 3 months of treatment with rilonacept will be compared to change in the placebo group. Change in aPWV will also be assessed at intermediate time points of 1 and 2 months.

  • Change in contribution of oxidative stress to FMD [ Time Frame: 3 months after start of treatment ] [ Designated as safety issue: No ]
    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. Assessment of these outcomes will also be made at intermediate time points of 1 and 2 months.

  • Change in contribution of oxidative stress to aPWV [ Time Frame: 3 months after treatment ] [ Designated as safety issue: No ]
    aPWV will be assessed following acute infusion of ascorbic acid compared to saline. The improvement in aPWV with ascorbic acid reflects the degree of oxidative stress contributing to increase in arterial stiffness. Assessment of these outcomes will also be made at intermediate time points of 1 and 2 months.


Other Outcome Measures:
  • Change in circulating oxidative stress [ Time Frame: 3 months after start of treatment ] [ Designated as safety issue: No ]
    Changes in Oxidized low-density lipoprotein (oxLDL), glutathione peroxidase (GPX) and total antioxidant status (TAS) after 3 months of rilonacept vs. placebo will be assessed as circulating markers of oxidative stress. Assessment of these outcomes will also be made at intermediate time points of 1 and 2 months.

  • Change in circulating inflammatory markers [ Time Frame: 3 months after start of treatment ] [ Designated as safety issue: No ]
    Changes in high-sensitivity C-reactive protein (hsCRP), interleukin-1β (IL-1β), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6) and interleukin-10 (IL-10) after 3 months of rilonacept vs. placebo will be assessed as circulating markers of inflammation. Assessment of these outcomes will also be made at intermediate time points of 1 and 2 months.

  • Change in vascular oxidative stress [ Time Frame: 3 months after start of treatment ] [ Designated as safety issue: No ]
    Vascular endothelial cells will be collected and assessed for changes in protein expression of the following markers of oxidative stress: nitrotyrosine, NADPH p47phox and copper-zinc superoxide dismutase (CuZnSOD) after 3 months of rilonacept vs. placebo. Assessment of these outcomes will also be made at intermediate timepoints of 1 and 2 months.

  • Change in vascular inflammation [ Time Frame: 3 months after start of treatment ] [ Designated as safety issue: No ]
    Vascular endothelial cells will be collected and assessed for changes in protein expression of the following markers of inflammation: IL-1β, IL-1Ra, nuclear factor k B (NFkB), IL-6 and IL-10 after 3 months of rilonacept vs. placebo. Assessment of these outcomes will also be made at intermediate timepoints of 1 and 2 months.

  • Change in vascular endothelial nitric oxide synthase (eNOS) expression [ Time Frame: 3 months after start of treatment ] [ Designated as safety issue: No ]
    Vascular endothelial cells will be collected and assessed for changes in protein expression of eNOS and eNOS phosphorylated at Ser 1177 after 3 months of treatment with rilonacept vs. placebo. Assessment of these outcomes will also be made at intermediate timepoints of 1 and 2 months.


Estimated Enrollment: 38
Study Start Date: August 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rilonacept
12 weeks of treatment with rilonacept (subcutaneous injection with a loading dose of 320 mg, followed by 160 mg/wk)
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 (subcutaneous injection of normal saline with a loading dose of 320 mg, followed by 160 mg/wk)
Drug: Placebo

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01663103

Contacts
Contact: Heather Farmer, B.A. 303-724-7791 Heather.Farmer@ucdenver.edu

Locations
United States, Colorado
University of Colorado Clinical and Translational Research Center (CTRC) Outpatient Clinic Recruiting
Aurora, Colorado, United States, 80045
Contact: Heather Farmer, B.A,    303-724-7791    Heather.Farmer@ucdenver.edu   
Principal Investigator: Kristen L Jablonski Nowak, Ph.D.         
Sponsors and Collaborators
University of Colorado, Denver
Investigators
Principal Investigator: Kristen L Jablonski Nowak, Ph.D. University of Colorado Denver Anschutz Medical Campus
  More Information

No publications provided

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01663103     History of Changes
Other Study ID Numbers: 12-0586
Study First Received: August 7, 2012
Last Updated: May 20, 2014
Health Authority: United States: Institutional Review Board

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
Renal Insufficiency, Chronic
Kidney Failure, Chronic
Urologic Diseases

ClinicalTrials.gov processed this record on July 23, 2014