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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

Tracking Information
First Submitted Date  ICMJE August 7, 2012
First Posted Date  ICMJE August 13, 2012
Results First Submitted Date  ICMJE April 6, 2016
Results First Posted Date  ICMJE September 12, 2016
Last Update Posted Date September 12, 2016
Study Start Date  ICMJE August 2012
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 2, 2016)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 8, 2012)
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. Change in FMD will also be assessed at intermediate time points of 1 and 2 months.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 2, 2016)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 8, 2012)
  • 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. 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 ]
    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 ]
    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.
Current Other Pre-specified Outcome Measures
 (submitted: August 2, 2016)
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: August 8, 2012)
  • Change in circulating oxidative stress [ Time Frame: 3 months after start of treatment ]
    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 ]
    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 ]
    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 ]
    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 ]
    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.
 
Descriptive Information
Brief Title  ICMJE Interleukin-1 Trap to Treat Vascular Dysfunction in Chronic Kidney Disease (CKD)
Official Title  ICMJE Interleukin-1 Trap to Treat Vascular Dysfunction in Chronic Kidney Disease (CKD)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Renal Insufficiency, Chronic
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Experimental: Rilonacept
    12 weeks of treatment with rilonacept
    Intervention: Drug: Rilonacept
  • Placebo Comparator: Placebo
    Twelve weeks of treatment with placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 2, 2016)
42
Original Estimated Enrollment  ICMJE
 (submitted: August 8, 2012)
38
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (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 NCT01663103
Other Study ID Numbers  ICMJE 12-0586
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Colorado, Denver
Study Sponsor  ICMJE University of Colorado, Denver
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kristen L Jablonski Nowak, Ph.D. University of Colorado Denver Anschutz Medical Campus
PRS Account University of Colorado, Denver
Verification Date June 2016

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