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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01663103

Enrollment

Registered

2012-08-13

Start date

2012-08-31

Completion date

2014-12-31

Last updated

2016-09-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Renal Insufficiency, Chronic

Keywords

Interleukin-1, Endothelium, Vascular, Vascular Stiffness, Oxidative Stress, Inflammation, Endothelial cells

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.

Interventions

DRUGRilonacept

12 weeks of treatment with rilonacept (subcutaneous injection with a loading dose of 320 mg, followed by 160 mg/wk)

DRUGPlacebo

Twelve weeks of treatment with placebo (subcutaneous injection of normal saline with a loading dose of 320 mg, followed by 160 mg/wk)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Flow-mediated Dilation (FMD)	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

Measure	Time frame	Description
Change in Aortic Pulse-wave Velocity (aPWV)	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	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

Measure	Time frame	Description
Change in High-sensitivity C-reactive Protein (hsCRP)	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	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Rilonacept 12 weeks of treatment with rilonacept Rilonacept: 12 weeks of treatment with rilonacept (subcutaneous injection with a loading dose of 320 mg, followed by 160 mg/wk)	21
Placebo Twelve weeks of treatment with placebo Placebo: Twelve weeks of treatment with placebo (subcutaneous injection of normal saline with a loading dose of 320 mg, followed by 160 mg/wk)	21
Total	42

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0
Overall Study	dog bite	1	0
Overall Study	Withdrawal by Subject	1	2

Baseline characteristics

Characteristic	Rilonacept	Placebo	Total
Age, Continuous	61 years STANDARD_DEVIATION 11	65 years STANDARD_DEVIATION 11	63 years STANDARD_DEVIATION 11
Estimated glomerular filtration rate	38 mL/min/1.73m^2 STANDARD_DEVIATION 14	38 mL/min/1.73m^2 STANDARD_DEVIATION 12	38 mL/min/1.73m^2 STANDARD_DEVIATION 13
Etiology of CKD Autosomal Dominant Polycystic Kidney Disease	1 participants	2 participants	3 participants
Etiology of CKD Focal Segmental Glomerulosclerosis	1 participants	0 participants	1 participants
Etiology of CKD Hypertension	12 participants	10 participants	22 participants
Etiology of CKD Renal Cell Carcinoma	0 participants	3 participants	3 participants
Etiology of CKD Type I DIabetes	1 participants	2 participants	3 participants
Etiology of CKD Type II Diabetes	10 participants	9 participants	19 participants
Race/Ethnicity, Customized African American	5 participants	5 participants	10 participants
Race/Ethnicity, Customized Hispanic	6 participants	6 participants	12 participants
Race/Ethnicity, Customized White	16 participants	16 participants	32 participants
Sex: Female, Male Female	5 Participants	5 Participants	10 Participants
Sex: Female, Male Male	16 Participants	16 Participants	32 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	5 / 21	2 / 21
serious Total, serious adverse events	0 / 21	0 / 21

Outcome results

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.