Treatment of Macrophage Activation Syndrome (MAS) With Anakinra (MAS)

July 30, 2024 updated by: W Winn Chatham, University of Alabama at Birmingham

Randomized Placebo Controlled Trial of Subcutaneous rhIL-1A (Anakinra) in the Management of Hospitalized Pediatric and Adult Patients With Macrophage Activation Syndrome

The primary purpose of this study is to determine whether giving injections of anakinra is a safe and well tolerated treatment to give as an adjunct to standard prescribed treatment for patients who are admitted to the hospital with signs of severe inflammation (macrophage activation syndrome) that is potentially life-threatening. Anakinra is a commercially available product (Kineret™) approved for the treatment of rheumatoid arthritis; it is a replica of a naturally occurring protein called Il-1 receptor antagonist (IL-1ra), made by humans to inhibit and regulate the action of interleukin-1 (IL-1). IL-1 is a mediator of inflammation that when generated in excess amounts by immune system cells can result in severe dysfunction of multiple organs that can be life-threatening. The specific primary objectives of the study are to determine if giving anakinra results in no increased infection complications or mortality. Additional data will be collected to determine whether anakinra administration results in any other unanticipated side effects in this setting, and the effects of anakinra administration on inflammation markers, the overall dose of steroids required to treat the inflammation, and the length of hospital stay.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Macrophage activation syndrome (MAS) is a disorder whereby the immune system generates very high levels of substances (cytokines) that promote inflammation to the extent dysfunction occurs in multiple organ systems which if unchecked, is frequently fatal to the affected individual. This can occur in the setting of a number of different immune system disorders including, systemic lupus, systemic-onset juvenile arthritis, and adult-onset Still's disease. MAS can also occur in response to infection with certain viruses such as Epstein-Barr virus (EBV) and malignancies involving lymphocytes.

Because of the high fatality of MAS (>50%), a number of different treatments have been tried to manage this disorder, including use of high-dose steroids, immune suppressants such as cyclosporine, and cytotoxic chemotherapy treatments (etoposide) with variable success and/or severe complications of immune suppression (as may occur with etoposide). A number of recent case reports and case series have reported success using cytokine-blocking therapies such as anakinra in the treatment of MAS that is associated with systemic-onset juvenile idiopathic arthritis and adult Still's disease. Anakinra is a bio-engineered form of the naturally occurring interleukin-1 receptor antagonist (IL-1ra), that blocks the action of interleukin-1, one of the cytokines that is expressed and present in very high amounts in patients who have MAS. Anakinra/Il-1ra is an attractive treatment for patients presenting with clinical features of MAS because it has a relatively short half-life and is easy to administer by subcutaneous injection. In previous trials of its use in patients with clinical features of bacterial sepsis (fever, elevated heart rate, low/falling blood pressure) , it was shown that anakinra does not have a harmful effect but also did not appear to have any benefit with repect to the defined primary outcome of improved survival. However, a recent re-analysis of the data accumulated in these same previous sepsis trials (for which the primary defined outcome was survival) indicates that survival was actually increased in the subgroup of sepsis patients with features of MAS (ferritin elevations in excess of 2,000 ng/ml, signs of coagulopathy, and liver enzyme elevations) who were randomized to receive anakinra compared to the subgroup of sepsis patients with features of MAS who were randomized to receive placebo.

Previous doses of anakinra up to 3500 mg/day over 72 hours that were employed in the trials of adult patients with sepsis were noted to be well tolerated without increased adverse outcomes compared to patients randomized to placebo. Recent case reports have shown that doses up to 100 mg every 6 hours were efficacious and well tolerated in children with systemic onset juvenile arthritis complicated by refractory macrophage activation syndrome.

This study will be the first controlled study to confirm whether anakinra at dose of 10 mg/kg/day to a maximum of dose of 200 mg/day divided every 12 hours (for children ≤40 kg) or 5 mg/kg/day up to a maximum dose of 400 mg/day divided every 6 hours (children > 40 kg and adults) does not result in increased mortality or infection complications when administered in addition to current UAB standard of care treatment (corticosteroids) to children and adults hospitalized with suspected macrophage activation syndrome.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
9

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama at Birmingham

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

1 year and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:1] Previous diagnosis of systemic juvenile idiopathic arthritis (sJIA) and fulfills the Ravelli criteria (4) for macrophage activation syndrome with either:

two or more Laboratory criteria: 1. Decreased platelet count (≤262 ×10 9/L) 2. Elevated levels of aspartate aminotransferase (>59 U/L) 3. Decreased white blood cell count (≤4.0 × 109/L) 4. Hypofibrinogenemia (≤2.5 g/L) or, three or more combined clinical/laboratory criteria:

  1. Decreased platelet count (≤262 × 109/L)
  2. Elevated levels of aspartate aminotransferase (>59 U/L)
  3. Decreased white blood cell count (≤4.0 × 109/L)
  4. Hypofibrinogenemia (≤2.5 g/L)
  5. Central nervous system dysfunction (irritability, disorientation, lethargy, seizures, coma)
  6. Hemorrhages (purpura, easy bruising, mucosal bleeding)
  7. Hepatomegaly (≥3 cm below the costal margin or confirmed by imaging)

OR

2] No previous diagnosis of sJIA and serum ferritin > 2,000 ng/ml and 3 out of the following:

  1. Bicytopenia with two of the following:

    1. Absolute Neutrophil Count < 1,000,
    2. Platelets < 100, 000/mm3,
    3. Hemoglobin < 9 mg/dl
  2. Fasting triglyceride >265 mg/dL
  3. Splenomegaly
  4. ALT OR AST > 120 IU/L (or > 2x upper limit of normal)
  5. Fever with temp ≥ 101° F

  6. Fibrinogen < 1.5 g/L (150 mg/dl) or INR > 1.5 or d-dimer > 500 ng/ml

    -

Exclusion Criteria:

  1. Evidence of malignancy
  2. Culture evidence of systemic bacterial infection at the time of screening
  3. Known EBV viremia by PCR at time of screening (positive serologies are not an exclusion; results of EBV testing will not be necessary for enrollment, but may be ordered as part of the standard of care assessment to guide future management as results become available)
  4. Previous treatment for the current MAS episode with corticosteroids, anakinra, tocilizumab, anti-TNF therapy or cyclosporine
  5. <1 year of age
  6. Family history of familial HLH

  7. Evidence of any of the following

    1. Creatinine at the time of screening > 2X ULN or > twofold increase from patient's baseline creatinine within past 3 months (if known)
    2. Albumin < 1.5 at the time of screening
    3. Mechanical ventilation at the time of screening
    4. Hypotension requiring use of pressors at the time of screening

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Placebo Comparator: placebo
methylprednisolone intravenously, placebo shots every 6 hours
Drug: placebo
placebo injection administered every 6 hours along with intravenous methylprednisolone
Other Names:
  • normal saline
Experimental: anakinra (Kineret)
methylprednisolone intravenously, anakinra shots every 6 hours
Drug: kineret
anakinra administered subcutaneously every 6 hours x 72 hours along with intravenous methylprednisolone
Other Names:
  • Anakinra

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of acquired infections, deaths in treatment group vs placebo group
Time Frame: within 72 hours after baseline
The primary outcome measure is to determine whether hospital acquired infections or deaths are increased when anakinra is added to corticosteroid use during the first 72 hours of MAS management
within 72 hours after baseline

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Normalization of elevations of MAS activity markers in treatment group vs placebo group
Time Frame: baseline to 72 hours after baseline
Another purpose of this study is to determine whether adding anakinra to corticosteroids in the first 72 hours of MAS treatment results in greater normalization of MAS activity markers including serum ferritin, CRP, LDH, d-dimer/fibrinogen
baseline to 72 hours after baseline
Total corticosteroid use and chemotherapy rescue treatment in anakinra treated group vs placebo treated group
Time Frame: 2 years post enrollment
Determine if treatment anakinra decreases the overall doses of steroids required to effectively manage anakinra, and if treatment with anakinra decreases the need to use chemotherapy drugs (etoposide) to treat MAS.
2 years post enrollment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Alabama at Birmingham

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Walter W Chatham, MD, University of Alabama Hospital
  • Principal Investigator: Randall Q Cron, MD, Children's Hospital of Alabama

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 15, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 31, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 30, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 11, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 18, 2016

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 23, 2016

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 1, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 30, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • F151008003
  • FWA00005960 (Other Grant/Funding Number: DEPT. HEALTH AND HUMAN SERVICES)
  • SOBI_UAB01 (Other Grant/Funding Number: Sweedish Orphan Biovitrum)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Nurse Study Coordinators will gather and enter data

IPD Sharing Time Frame

Dec 31 2020

IPD Sharing Access Criteria

request to investigator

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • CSR

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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