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

Renal Insufficiency, Chronic Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01663103
• Other study ID #: 12-0586
• Status: Completed
• Phase: Phase 4
• First received: August 7, 2012
• Last updated: March 8, 2016
• Start date: August 2012
• Est. completion date: December 2014

Study information

• Verified date: March 2016
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Kidney Diseases
• Renal Insufficiency
• Renal Insufficiency, Chronic

Intervention

Drug:
• Rilonacept
12 weeks of treatment with rilonacept (subcutaneous injection with a loading dose of 320 mg, followed by 160 mg/wk)
• Placebo
Twelve weeks of treatment with placebo (subcutaneous injection of normal saline with a loading dose of 320 mg, followed by 160 mg/wk)

Locations

Country	Name	City	State
United States	University of Colorado Clinical and Translational Research Center (CTRC) Outpatient Clinic	Aurora	Colorado
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
University of Colorado, Denver

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in circulating oxidative stress	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.	3 months after start of treatment	No
Other	Change in circulating inflammatory markers	Changes in high-sensitivity C-reactive protein (hsCRP), interleukin-1ß (IL-1ß), 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.	3 months after start of treatment	No
Other	Change in vascular oxidative stress	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.	3 months after start of treatment	No
Other	Change in vascular inflammation	Vascular endothelial cells will be collected and assessed for changes in protein expression of the following markers of inflammation: IL-1ß, 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.	3 months after start of treatment	No
Other	Change in vascular endothelial nitric oxide synthase (eNOS) expression	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.	3 months after start of treatment	No
Primary	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. Change in FMD will also be assessed at intermediate time points of 1 and 2 months.	3 months after start of treatment	No
Secondary	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. Change in aPWV will also be assessed at intermediate time points of 1 and 2 months.	3 months after start of treatment	No
Secondary	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. Assessment of these outcomes will also be made at intermediate time points of 1 and 2 months.	3 months after start of treatment	No
Secondary	Change in contribution of oxidative stress to aPWV	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.	3 months after treatment	No