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

This study is currently recruiting participants.
Verified December 2016 by University of Alabama at Birmingham
Sponsor:
ClinicalTrials.gov Identifier:
NCT02780583
First Posted: May 23, 2016
Last Update Posted: December 29, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
University of Alabama at Birmingham
  Purpose
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.

Condition Intervention Phase
Macrophage Activation Syndrome Drug: kineret Drug: placebo Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Randomized Placebo Controlled Trial of Subcutaneous rhIL-1A (Anakinra) in the Management of Hospitalized Pediatric and Adult Patients With Macrophage Activation Syndrome

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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

  • 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.


Estimated Enrollment: 40
Study Start Date: May 2016
Estimated Study Completion Date: October 2019
Estimated Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: placebo
methylprednisolone intravenously, placebo shots every 6 hours
Drug: placebo
placebo injection administered every 6 hours along with intravenous methylprednisolone
Other Name: 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 Name: Anakinra

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02780583


Contacts
Contact: Walter W Chatham, MD (205) 996-5602 wchatham@uabmc.edu
Contact: Angela C Kendrach, RN (205)-975-8091 ext 58091 akendrach@uabmc.edu

Locations
United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
Principal Investigator: Walter W Chatham, MD University of Alabama Hospital
Principal Investigator: Randall Q Cron, MD Children's Hospital of Alabama
  More Information

Responsible Party: University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02780583     History of Changes
Other Study ID Numbers: F151008003
FWA00005960 ( Other Grant/Funding Number: DEPT. HEALTH AND HUMAN SERVICES )
First Submitted: May 11, 2016
First Posted: May 23, 2016
Last Update Posted: December 29, 2016
Last Verified: December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Nurse Study Coordinators will gather and enter data

Additional relevant MeSH terms:
Syndrome
Macrophage Activation Syndrome
Disease
Pathologic Processes
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Interleukin 1 Receptor Antagonist Protein
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antirheumatic Agents