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

Multiple Myeloma Clinical Trial

— AFFECT-2  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04099901
• Other study ID #: HEMSC42
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 4, 2019
• Est. completion date: March 2024

Study information

• Verified date: November 2023
• Source: Radboud University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 88
• Est. completion date: March 2024
• Est. primary completion date: March 14, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 TNFa 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.

Related Conditions & MeSH terms

• Mucositis
• Multiple Myeloma
• Neoplasms, Plasma Cell
• Neutropenia

Intervention

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).
• 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).

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC, location AMC	Amsterdam
Netherlands	University Medical Center Groningen (UMCG)	Groningen
Netherlands	Radboudumc	Nijmegen

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University Medical Center	Dutch Cancer Society

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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).
Secondary	Daily mean CRP level		Outcome will be determined during the period of hospitalization (day of admission [day -3] until discharge, maximum period +30 days).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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
Secondary	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
Secondary	Short term overall survival		+100 days and +1 year
Secondary	Tumor response evaluation		+100 days and +1 year