The primary objective is to evaluate the efficacy of anakinra in patients with multiple myeloma receiving high-dose melphalan (HDM) in the preparation for an autologous hematopoietic stem cell transplantation (SCT). The primary endpoint is the…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
- Gastrointestinal inflammatory conditions
- Body temperature conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
- Reduction of incidence of fever during neutropenia
Secondary outcome
Secondary endpoints:
- Incidence of mucositis-related fever
- Maximum CRP level on day +9-10
- Daily mean CRP level
- Intestinal mucositis as measured by the area-under-the-curve of reciprocal
citrulline levels
- Clinical mucositis as determined by the daily mouth and gut scores
- Days with fever ((>= 38.2° C)
- Days with fever (>= 38.5° C)
- Mean daily morning temperature
- Area under the curve of daily morning temperature
- Incidence of bloodstream infections i.e. bacteremia
- Type of bloodstream infections
- Incidence of persistently positive blood cultures on day +4
- Quality of life according to the EORTC QLQ-C30
- Severity of fatigue as the score measured by the validated FACIT-Fatigue scale
- Tumor response evaluation (100 days and 1 year)
- Short term overall survival (100 days and 1 year)
- Length of hospital stay in days
- Use of systemic antimicrobial agents (incidence and duration)
- Use of analgesic drugs (incidence and duration)
- Use of total parenteral nutrition (TPN) (incidence and duration)
Background summary
Mucosal barrier injury (MBI) of the mouth (oral mucositis) and gut (intestinal
mucositis) is an important side effect of treatment with intensive chemotherapy
and radiotherapy. The occurrence of mucositis is a major risk factor for fever
during neutropenia (febrile neutropenia, FN) and the development of bloodstream
infections (BSI) with microbes residing at the integument. These complications
often require dose reductions or cause delay in and even cessation of
treatment, all precluding optimal treatment for patients with cancer with a
lower chance for cure. Currently, however, there are no effective strategies to
prevent or treat mucositis. Therefore, there is an unmet need for effective
treatment and prevention strategies for mucositis and fever during neutropenia.
Cytokines that belong to the interleukin-1 family are involved in multiple
inflammatory and immune responses, but also play a crucial role in the
pathogenesis of mucositis. Inhibition of the IL-1 pathway has proven to be
effective in a number of IL-1 mediated diseases, such as rheumatoid arthritis
(RA), gout and Cryopyrin-associated Periodic Syndromes (CAPS). Recently,
studies in murine models of chemotherapy-induced mucositis demonstrated that
anakinra, a recombinant human interleukin-1 receptor antagonist, significantly
ameliorated intestinal mucositis. Therefore, we hypothesize that inhibition of
the IL-1 pathway, in patients receiving intensive chemotherapy in the context
of hematopoietic stem cell transplantation, can decrease the incidence of
intestinal mucositis and consequently fever during neutropenia.
Study objective
The primary objective is to evaluate the efficacy of anakinra in patients with
multiple myeloma receiving high-dose melphalan (HDM) in the preparation for an
autologous hematopoietic stem cell transplantation (SCT). The primary endpoint
is the reduction of the incidence of fever during neutropenia. Secondary
objectives are the gathering of blood and microbiota samples for translational
research.
Study design
A multicenter phase IIb double-blind randomized placebo-controlled study.
Intervention
Subjects will be randomized between the intervention group (Arm A: anakinra
intravenously once daily, in dose defined in pilot study AFFECT-1), and the
control group (Arm B: placebo intravenously once daily) with a 1:1 ratio.
Investigators, healthcare providers and subjects will be blinded to both the
randomization schedule and subsequent treatment allocation.
Study burden and risks
Burden associated with participation:
Subjects will receive study treatment with either placebo or anakinra
intravenously once daily. In all subjects, as compared to standard treatment
outside study context, three times a week additional blood tests will be
obtained (total volume 100 mL), as well as stool samples and oral swabs twice a
week. Also, from day +4 until day +12, additional blood cultures will be
obtained (total volume 120 mL). Finally, subjects will be asked to complete a
number of questionnaires (2 questionnaires, both on 4 time points) related to
quality of life and fatigue severity.
Risks associated with the investigated product:
The impact of anakinra on mucositis and therewith the expected reduced
incidence of fever and infections has not been established yet. Being an
anti-inflammatory drug, the signs of infections may be masked and the
immunosuppressive effects may increase the risk for infections. In addition,
neutropenia and headache are documented side effects of anakinra. However, in
previous studies in allogeneic SCT recipients the use of anakinra was not
accompanied by untoward side effects and no detrimental effects of engraftment
post-SCT have occurred. Currently, we are performing the AFFECT-1 study, in
which the safety and maximum tolerated dose (100, 200 or 300 mg) of anakinra is
determined. In this study, so far (actual dose level 300 mg reached), no side
effects related to anakinra have occurred.
Benefits: In murine models of chemotherapy-induced mucositis, treatment with
anakinra was associated with decreased signs and symptoms of mucositis.
Therefore, treatment with anakinra in our study population at high risk for MBI
might result in decreased incidence and severity of mucositis, with possibly a
lower incidence of febrile neutropenia and infections related to MBI. In
addition, patients might experience less pain related to MBI, require less
antibiotics and opioids and have lower symptom scores and better quality of
life. Also, participation in the study may facilitate the development of an
effective drug in the management of fever during neutropenia and mucositis for
future SCT recipients.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
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
- Enrolment 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
- Documented 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-005046-10-NL |
| CCMO | NL66297.091.19 |