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Anakinra: Efficacy in the Management of Fever During Neutropenia and Mucositis in ASCT - A Randomized Controlled Trial (AFFECT-2)

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ClinicalTrials.gov Identifier: NCT04099901
Recruitment Status : Recruiting
First Posted : September 23, 2019
Last Update Posted : March 19, 2020
Sponsor:
Collaborator:
Dutch Cancer Society
Information provided by (Responsible Party):
Radboud University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Anakinra Drug: Placebos Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind placebo-controlled randomized trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: 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
Actual Study Start Date : November 4, 2019
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : October 2022


Arm Intervention/treatment
Experimental: Anakinra
Dosage form: intravenous. Dosage: 300 mg. Frequency: once daily. Duration: 15 days (day -2 until day +12).
Drug: Anakinra
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).
Other Name: Kineret

Placebo Comparator: Placebo
Dosage form: intravenous. Dosage: not applicable. Frequency: once daily. Duration: 15 days (day -2 until day +12).
Drug: Placebos
Subjects will be treated with a daily dose of placebo, intravenously, starting on day -2, until day +12 (day 0 is day of SCT).




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

Secondary Outcome Measures :
  1. Reduction in incidence of mucositis-related fever [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  2. Daily mean CRP level [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  3. Intestinal mucositis as measured by the area-under-the-curve of reciprocal citrulline levels [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  4. Clinical mucositis as determined by the daily mouth and gut scores [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  5. Days with fever (≥ 38.5° C) [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  6. Incidence of bloodstream infections i.e. bacteremia [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  7. Length of hospital stay in days [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  8. Use of systemic antimicrobial agents (incidence and duration) [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  9. Use of analgesic drugs (incidence and duration) [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  10. Use of total parenteral nutrition (TPN) (incidence and duration) [ Time Frame: Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days). ]
  11. Quality of life according to the EORTC QLQ-C30 [ Time Frame: Baseline, +30 days/discharge (whichever comes first), +100 days, +1 year ]
    Quality of life according to the EORTC QLQ-C30

  12. Fatigue severity according to the FACIT-Fatigue scale [ Time Frame: Baseline, +30 days/discharge (whichever comes first), +100 days, +1 year ]
    Severity of fatigue as the score measured by the validated FACIT-Fatigue scale

  13. Short term overall survival [ Time Frame: +100 days and +1 year ]
  14. Tumor response evaluation [ Time Frame: +100 days and +1 year ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT04099901


Contacts
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Contact: Postbus Trialbureau Hematologie-Oncologie +31243614794 trialbureauhemat-onco@radboudumc.nl

Locations
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Netherlands
Amsterdam UMC, location AMC Not yet recruiting
Amsterdam, Netherlands
Contact: Trialbureau Hematologie AMC    +31-(0)20-5665950    hemat.trial@amc.nl   
University Medical Center Groningen (UMCG) Not yet recruiting
Groningen, Netherlands
Contact: Trialbureau Hematologie UMCG    +31-(0)50-3615410    e.gkoumasi@umcg.nl   
Radboudumc Recruiting
Nijmegen, Netherlands
Contact: Postbus Trialbureau Hematologie-Oncologie    +31243614794    trialbureauhemat-onco@radboudumc.nl   
Sponsors and Collaborators
Radboud University
Dutch Cancer Society
Investigators
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Principal Investigator: Nicole Blijlevens, MD PhD Radboud University
Principal Investigator: Gerwin Huls, MD PhD UMCG
Principal Investigator: Bart Biemond, MD PhD Amsterdam UMC
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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT04099901    
Other Study ID Numbers: HEMSC42
First Posted: September 23, 2019    Key Record Dates
Last Update Posted: March 19, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Radboud University:
Anakinra
Mucositis
Hematopoietic stem cell transplantation
Febrile neutropenia
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Mucositis
Neutropenia
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Mouth Diseases
Stomatognathic Diseases
Agranulocytosis
Leukopenia
Leukocyte Disorders
Interleukin 1 Receptor Antagonist Protein
Antirheumatic Agents