Anakinra: Efficacy in the Management of Fever During Neutropenia and Mucositis in ASCT - A Randomized Controlled Trial

Study Overview
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Brief Summary
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Oral and intestinal mucositis are major risk factors for the occurrence of fever during neutropenia and bloodstream infections after intensive chemo- and radiotherapy. These complications often require dose reductions or cause delay of treatment, and thereby interfere with optimal anticancer treatment. Currently, there are no effective strategies to prevent or treat mucositis and the related complications. The pro-inflammatory cytokine interleukin-1β (IL-1β) has shown to be pivotal in the pathogenesis of mucositis and recently, it has been established in murine models that IL-1 inhibition significantly ameliorates chemotherapy-induced intestinal mucositis. The investigators recently conducted a phase IIa study (AFFECT-1, NCT03233776) studying the safety and maximum tolerated dose of anakinra, a recombinant human IL-1 receptor antagonist in adult patients with multiple myeloma receiving high-dose melphalan (HDM) in the preparation for an autologous hematopoietic stem cell transplantation (ASCT) who are at high risk for experiencing mucositis and fever during neutropenia (FN). Since treatment with anakinra has shown to be safe in this study population, the investigators will continue with a double-blind randomized placebo-controlled multicenter phase IIb trial to establish efficacy in the management of fever during neutropenia and mucositis.

Official Title
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Anakinra: Efficacy of Anakinra for the Management of Fever During Neutropenia and Mucositis in Patients With Multiple Myeloma Receiving an Autologous Hematopoietic Stem Cell Transplantation After High-dose Melphalan - An RCT

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Anakinra
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years Diagnosed with multiple myeloma Scheduled to receive an autologous SCT after myeloablative therapy with high-dose melphalan Managed with a central venous catheter (triple- or quadruple lumen) Is able and willing to participate Has provided written informed consent Has negative serology for active hepatitis B and C Has negative serology for HIV Has no known hypersensitivity to Escherichia coli derived products or any components of anakinra Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation (during treatment with study medication), and for 30 days after the last dose. Exclusion Criteria: Inability to understand the nature and extent of the trial and the procedures required Enrollment in any other investigational treatment study or use of an investigational agent during the stem cell transplantation (this means studies in multiple myeloma regarding induction or maintenance treatment are permitted). Women who are pregnant or nursing Diagnosed with amyloidosis or light-chain deposition disease ALT or AST greater than 2.0 x upper limit of normal (ULN) of the local laboratories values. Bilirubin levels greater than 2.0 x upper limit of normal (ULN) of the local laboratories values, except for benign non-malignant indirect hyperbilirubinemia such as Gilbert syndrome Impaired renal function with eGFR <40 ml/min Received a live vaccine during the 3 months prior to baseline visit Recent use of IL-1 antagonist, such as anakinra, rilonacept or canakinumab, within three months prior to baseline visit Treatment with TNFα inhibiting agents (such as etanercept, adalimumab, infliximab, certolizumab and golimumab). Uncontrolled bacterial or viral infections, or fungal infections, at the start of therapy Colonization with methicillin-resistant Staphylococcus aureus (MRSA), carbapenemase-producing Enterobacteriaceae (CPE) or vancomycin-resistant enterococci (VRE) prior to registration Gram-negative colonization resistant to prophylaxis with ciprofloxacin or colistin/cotrimoxazole Subjects who are not able to receive antibacterial prophylaxis with ciprofloxacin or colistin/cotrimoxazole (because of hypersensitivity or drug interactions) Subjects with an active solid malignancy prior to registration, with the exception of cutaneous basal or squamous cell carcinomas History of mycobacterial infection. Subjects with intrinsic disorders of the gastro-intestinal (GI) tract, including, but not limited to: Crohn's disease, ulcerative colitis, celiac disease, short bowel syndrome. Subject has any concurrent medical or psychiatric condition or disease that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind placebo-controlled randomized trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anakinra<br>Dosage form: intravenous. Dosage: 300 mg. Frequency: once daily. Duration: 15 days (day -2 until day +12). | Drug: Anakinra<br>* Subjects will be treated with a daily dose of 300 mg anakinra, intravenously, starting on day -2, until day +12 (day 0 is day of SCT).<br>* Other names: Kineret;|
| Placebo Comparator: Placebo<br>Dosage form: intravenous. Dosage: not applicable. Frequency: once daily. Duration: 15 days (day -2 until day +12). | Drug: Placebos<br>* Subjects will be treated with a daily dose of placebo, intravenously, starting on day -2, until day +12 (day 0 is day of SCT).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of the incidence of fever during neutropenia |  | Primary outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in incidence of mucositis-related fever |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Daily mean CRP level |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Intestinal mucositis as measured by the area-under-the-curve of reciprocal citrulline levels |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Clinical mucositis as determined by the daily mouth and gut scores |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Days with fever (≥ 38.5° C) |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Incidence of bloodstream infections i.e. bacteremia |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Length of hospital stay in days |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Use of systemic antimicrobial agents (incidence and duration) |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Use of analgesic drugs (incidence and duration) |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Use of total parenteral nutrition (TPN) (incidence and duration) |  | Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). | 
| Quality of life according to the EORTC QLQ-C30 | Quality of life according to the EORTC QLQ-C30 | Baseline, +30 days/discharge (whichever comes first), +100 days, +1 year | 
| Fatigue severity according to the FACIT-Fatigue scale | Severity of fatigue as the score measured by the validated FACIT-Fatigue scale | Baseline, +30 days/discharge (whichever comes first), +100 days, +1 year | 
| Short term overall survival |  | +100 days and +1 year | 
| Tumor response evaluation |  | +100 days and +1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anakinra, Mucositis, Hematopoietic stem cell transplantation, Febrile neutropenia