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Anti-Cytokine Therapy for Hemodialysis InflammatION (ACTION)

Primary Purpose

End-Stage Renal Disease

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Anakinra

Placebo

About this trial

This is an interventional treatment trial for End-Stage Renal Disease focused on measuring ESRD, End-Stage Kidney Disease

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Maintenance hemodialysis therapy 3 times per week for end-stage renal disease
≥6 months since hemodialysis initiation
C-reactive protein measured by high sensitivity assay (hsCRP) ≥2.0 mg/L at screening and within 10 days prior to randomization
Most recent single pool Kt/V > or = 1.2 within 30 days prior to first screening visit
Negative tuberculosis interferon gamma release assay (e.g. Quantiferon-TB Gold) for tuberculosis unless documented treatment for a) positive PPD, b) positive interferon gamma release assay, or c) tuberculosis.
Negative human immunodeficiency virus (HIV) antibody test, negative hepatitis C Ab test unless viral clearance following direct antiviral therapy is documented, and negative hepatitis B surface antigen positivity.
For women of childbearing potential, willingness to use a highly effective method of birth control for up to 4 weeks after the last dose of anakinra.
Ability to provide informed consent

Exclusion Criteria:

Current or anticipated use of a hemodialysis central venous catheter
Acute bacterial infection, including vascular access infection, within 60 days prior to screening unless treated with antibiotics and resolved. Any chronic bacterial infection (e.g., osteomyelitis or bronchiectasis)
Hospitalization within 30 days unless for vascular access procedure
Cirrhosis
Malignancy within the past 5 years with exception of basal or squamous cell carcinoma
Use of an immunosuppressive drug within the past 3 months except low doses of oral corticosteroids (total daily dose ≤10 mg/day of prednisone or equivalent)
Receipt of live vaccine within the past 3 months. Live vaccines include Varicella zoster, measles, oral polio, rotavirus, yellow fever, and the nasal spray influenza vaccine
Absolute neutrophil count (ANC) <2,500 cells/mm3 (2.5 x 109 cells/L)
Platelet count <100,000/mm3 (100 x 109/L)
Known allergy to anakinra
Anticipated kidney transplantation, change to peritoneal dialysis, or transfer to another dialysis unit within 9 months
Expected survival less than 9 months
Pregnancy, anticipated pregnancy, or breastfeeding
Incarceration
Receipt of an investigational drug within the past 30 days
Current or anticipated participation in another intervention study

Sites / Locations

The George Washington University
Brigham & Women's Hospital
Vanderbilt University Medical Center
University of Washington Kidney Research Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Anakinra

Placebo

Arm Description

Anakinra (Kineret®) is a therapeutic agent that blocks the effects of IL-1 alpha and IL-1 beta by competitively binding to the interleukin-1 type I receptor (IL-1RI). Anakinra is a recombinant, non-glycosylated form of the naturally occurring human interleukin-1 receptor antagonist (IL-1Ra). Anakinra will be supplied in pre-filled syringes as a sterile, clear, colorless-to-white, preservative free solution. Each syringe will contain 100 mg in 0.67 ml solution (pH 6.5) containing disodium EDTA (0.12 mg), sodium chloride (5.48 mg), sodium citrate (1.29 mg), and polysorbate 80 (0.70 mg) in Water for Injection, USP.

Saline (0.9%) will be used as the placebo, supplied in pre-filled syringes as a sterile, clear, colorless-to-white, preservative free solution.

Outcomes

Primary Outcome Measures

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis

The primary safety endpoint is serious adverse events per patient-year.

Change in Log-transformed Circulating CRP Concentration After 24 Weeks of Treatment for Patients Receiving Maintenance Hemodialysis

For this outcome, CRP measurements from Baseline and Week 24 were compared.

Secondary Outcome Measures

Number of Participants With Adverse Events That Preclude Further Treatment With the Study Agent

Adverse events were one measure used to assess safety and tolerability of anakinra, for patients receiving maintenance hemodialysis. This measure assessed the number of participants with adverse events that precluded further treatment with the study agent.

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis - Infections

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis - Neutropenia

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis - Thrombocytopenia

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis - Systemic Hypersensitivity Reactions

Change in Markers of Inflammation and Oxidative Stress - IL-1β pg/ml

Change in circulating markers of inflammation and oxidative stress between baseline and end of treatment

Change in Markers of Inflammation and Oxidative Stress - IL-6, pg/mL

Change in Markers of Inflammation and Oxidative Stress - IL-10, pg/mL

Change in Markers of Inflammation and Oxidative Stress - TNF Alpha, pg/ml

Change in Markers of Inflammation and Oxidative Stress - Albumin, g/dL

Change in Patient-reported Indicators of Fatigue After 24 Weeks of Treatment

Change in patient reported outcomes using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale from Baseline to Week 24. To score the FACIT-fatigue, all items are summed to create a single fatigue score with a range from 0 to 52. Items are reverse scored when appropriate to provide a scale in which higher scores represent better functioning or less fatigue. All participants were assessed with the same scoring system.

Change in Patient-reported Indicators of Depression After 24 Weeks of Treatment for Patients Receiving Maintenance Hemodialysis

Change in patient reported outcomes using the Beck Depression Inventory - II (BDI-II) scale at baseline, Weeks 12, 24 and 28. The instrument uses a 21-item self-report inventory measuring the severity of depression in adolescents and adults.The standard cut-offs are as follows: 0-9: indicates minimal depression 10-18: indicates mild depression 19-29: indicates moderate depression 30-63: indicates severe depression. Higher total scores indicate more severe depressive symptoms.

Change in Burden of Patient-reported Symptoms After 24 Weeks of Treatment for Patients Receiving Maintenance Hemodialysis

Mean change in patient reported outcomes using the Dialysis Symptom Index, Burden subscale The DSI is a 30-question instrument assessing whether participants report a particular symptom during the past week and the severity of that symptom. Symptom burden is assessed using 30 "yes/no" questions. The scale is a count of the number of "yes" responses. The minimum is 0. The maximum is 30. The mean change in score after 24 weeks of treatment was measured. A lower score is better as a higher score indicates greater symptom burden.

Change in Severity of Patient-reported Symptoms After 24 Weeks of Treatment for Patients Receiving Maintenance Hemodialysis

Change in patient reported outcomes using the Dialysis Symptom Index, Severity subscale The DSI severity subscale includes 30-questions assessing whether a symptom is present (previous outcome - burden subscale). The severity of each symptom that was reported as being present was assessed by asking patients to rate the degree to which the symptom was bothersome using a five-point Likert scale (1 = "not at all bothersome" to 5 = "bothers very much"). Higher scores indicating greater symptom severity. The minimum score is 30, the maximum score is 150. The mean change was used to measure this outcome.

Change in Patient-reported Indicators of Quality of Life After 24 Weeks of Treatment for Patients Receiving Maintenance Hemodialysis

Change in patient reported outcomes using the Kidney Disease - Quality of Life subscale of the SF-12 (KDQOL SF-12) at baseline, Weeks 12, 24 and 28. A higher score reflects a more favorable health state. The questionnaire consists of 24 questions and the total possible score sum is 0-100. Items in the same scale are averaged to create scale scores.

Change in Measure of Muscle Strength (Hand Grip Strength) After 24 Weeks of Treatment for Patients Receiving Maintenance Hemodialysis

Change in measurement of hand grip strength using a standard dynamometer at baseline, Weeks 12, 24 and 28. This was measured in kg using the dominant hand.

Full Information

NCT ID

NCT03141983

First Posted

April 11, 2017

Last Updated

February 17, 2023

Sponsor

University of Pennsylvania

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

1. Study Identification

Unique Protocol Identification Number

NCT03141983

Brief Title

Anti-Cytokine Therapy for Hemodialysis InflammatION

Acronym

ACTION

Official Title

Anti-Cytokine Therapy for Hemodialysis InflammatION (ACTION): A Phase II Multi-center Study to Evaluate the Safety and Tolerability of Anakinra, an IL-1 Receptor Antagonist, for Patients Treated With Maintenance Hemodialysis

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Completed

Study Start Date

December 15, 2017 (Actual)

Primary Completion Date

September 2, 2021 (Actual)

Study Completion Date

September 2, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Pennsylvania

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Anti-Cytokine Therapy for Hemodialysis InflammatION (ACTION) is a phase II multi-center study to evaluate the safety and tolerability of anakinra, an IL-1 receptor antagonist, for patients treated with maintenance hemodialysis.

Detailed Description

The ACTION Trial will enroll 80 participants being treated with maintenance hemodialysis for end-stage renal disease. Participants will be randomized to receive Anakinra, 100 mg administered intravenously 3 times per week at the end of the hemodialysis session, or matched placebo. The duration of study drug administration is 24 weeks. There will be an additional 24 weeks of follow-up after study drug administration has been completed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

End-Stage Renal Disease

Keywords

ESRD, End-Stage Kidney Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

80 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Anakinra

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Saline (0.9%) will be used as the placebo, supplied in pre-filled syringes as a sterile, clear, colorless-to-white, preservative free solution.

Intervention Type

Drug

Intervention Name(s)

Anakinra

Other Intervention Name(s)

Kineret®

Intervention Description

Anakinra (Kineret®) is a therapeutic agent that blocks the effects of IL-1α and IL-1β by competitively binding to the interleukin-1 type I receptor (IL-1RI). It is a recombinant, non-glycosylated form of the naturally occurring human interleukin-1 receptor antagonist (IL-1Ra) but differs from human IL-1Ra in that it has the addition of a single methionine residue at the amino terminus. It is supplied commercially in single use 1 ml prefilled glass syringes as a sterile, clear, colorless-to-white, preservative free solution. Each syringe contains: 0.67 ml (100 mg) of anakinra in a solution (pH 6.5) containing sodium citrate (1.29 mg), sodium chloride (5.48 mg), disodium EDTA (0.12 mg) and polysorbate 80 (0.70 mg) in Water for Injection, USP.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Saline (0.9%) will be used as the placebo, in single use 1 ml prefilled glass syringes as a sterile, clear, colorless-to-white, preservative free solution.

Primary Outcome Measure Information:

Title

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis

Description

The primary safety endpoint is serious adverse events per patient-year.

Time Frame

48 Weeks (after the 24-week treatment period and the 24-week post-treatment period)

Title

Change in Log-transformed Circulating CRP Concentration After 24 Weeks of Treatment for Patients Receiving Maintenance Hemodialysis

Description

For this outcome, CRP measurements from Baseline and Week 24 were compared.

Time Frame

Change from Baseline to 24 Weeks (end of treatment phase)

Secondary Outcome Measure Information:

Title

Number of Participants With Adverse Events That Preclude Further Treatment With the Study Agent

Description

Time Frame

24-week treatment period

Title

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis - Infections

Time Frame

48 weeks

Title

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis - Neutropenia

Time Frame

48 weeks

Title

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis - Thrombocytopenia

Time Frame

48 weeks

Title

Safety and Tolerability of Anakinra, for Patients Receiving Maintenance Hemodialysis - Systemic Hypersensitivity Reactions

Time Frame

48 weeks

Title

Change in Markers of Inflammation and Oxidative Stress - IL-1β pg/ml

Description

Change in circulating markers of inflammation and oxidative stress between baseline and end of treatment

Time Frame