- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02780583
Treatment of Macrophage Activation Syndrome (MAS) With Anakinra (MAS)
Randomized Placebo Controlled Trial of Subcutaneous rhIL-1A (Anakinra) in the Management of Hospitalized Pediatric and Adult Patients With Macrophage Activation Syndrome
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Estimated)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Alabama
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Birmingham, Alabama, United States, 35294
- University of Alabama at Birmingham
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
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:
- Decreased platelet count (≤262 × 109/L)
- Elevated levels of aspartate aminotransferase (>59 U/L)
- Decreased white blood cell count (≤4.0 × 109/L)
- Hypofibrinogenemia (≤2.5 g/L)
- Central nervous system dysfunction (irritability, disorientation, lethargy, seizures, coma)
- Hemorrhages (purpura, easy bruising, mucosal bleeding)
- 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:
Bicytopenia with two of the following:
- Absolute Neutrophil Count < 1,000,
- Platelets < 100, 000/mm3,
- Hemoglobin < 9 mg/dl
- Fasting triglyceride >265 mg/dL
- Splenomegaly
- ALT OR AST > 120 IU/L (or > 2x upper limit of normal)
- Fever with temp ≥ 101° F
Fibrinogen < 1.5 g/L (150 mg/dl) or INR > 1.5 or d-dimer > 500 ng/ml
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Exclusion Criteria:
- Evidence of malignancy
- Culture evidence of systemic bacterial infection at the time of screening
- 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)
- Previous treatment for the current MAS episode with corticosteroids, anakinra, tocilizumab, anti-TNF therapy or cyclosporine
- <1 year of age
- Family history of familial HLH
Evidence of any of the following
- Creatinine at the time of screening > 2X ULN or > twofold increase from patient's baseline creatinine within past 3 months (if known)
- Albumin < 1.5 at the time of screening
- Mechanical ventilation at the time of screening
- Hypotension requiring use of pressors at the time of screening
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: placebo
methylprednisolone intravenously, placebo shots every 6 hours
|
placebo injection administered every 6 hours along with intravenous methylprednisolone
Other Names:
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Experimental: anakinra (Kineret)
methylprednisolone intravenously, anakinra shots every 6 hours
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anakinra administered subcutaneously every 6 hours x 72 hours along with intravenous methylprednisolone
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of acquired infections, deaths in treatment group vs placebo group
Time Frame: within 72 hours after baseline
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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
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within 72 hours after baseline
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Secondary Outcome Measures
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
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baseline to 72 hours after baseline
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Total corticosteroid use and chemotherapy rescue treatment in anakinra treated group vs placebo treated group
Time Frame: 2 years post enrollment
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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.
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2 years post enrollment
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Collaborators and Investigators
Investigators
- 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
General Publications
- Cron RQ, Chatham WW. The Rheumatologist's Role in COVID-19. J Rheumatol. 2020 May 1;47(5):639-642. doi: 10.3899/jrheum.200334. Epub 2020 Mar 24. No abstract available.
- Eloseily EM, Weiser P, Crayne CB, Haines H, Mannion ML, Stoll ML, Beukelman T, Atkinson TP, Cron RQ. Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis. Arthritis Rheumatol. 2020 Feb;72(2):326-334. doi: 10.1002/art.41103. Epub 2019 Dec 26.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID 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)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
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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