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Conclusion | necrosis | REMISSION, DISEASE, MEDULLOBLASTOMA, NECROSIS | For patients with medulloblastoma, remission at time of cRIT was associated with significantly improved survival outcomes. Relapses are often multifocal, particularly in the setting of measurable disease at cRIT initiation. EBRT is a promising tool to achieve NED status at cRIT initiation, with no cases of radiation necrosis. | PMC10050019 |
Supplementary Information | The online version contains supplementary material available at 10.1007/s11060-022-04235-w | PMC10050019 |
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Keywords | PMC10050019 |
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Introduction | toxicity, necrosis | PRIMARY TUMORS, RECURRENT DISEASE, REMISSION, MEDULLOBLASTOMA, NECROSIS | Curative treatment options for patients with recurrent primary tumors of the central nervous system (CNS) are limited. Many patients have had previous multimodality therapy, including external beam radiotherapy (EBRT), which introduces the potential for toxicity with additional treatments. For instance, radiation necrosis is a potential toxicity with an incidence of up to 5% [For medulloblastoma, 131-I-3F8 has been shown to be safe and may have clinical utility in maintaining remission in high-risk or recurrent disease [ | PMC10050019 |
Materials and methods | PMC10050019 |
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Eligible patients | medulloblastoma, ependymoma, Cancer | PRIMARY BRAIN TUMORS, MEDULLOBLASTOMA, EPENDYMOMA, CANCER | Patients with recurrent medulloblastoma or ependymoma known to express B7H3 by immunohistochemical staining were eligible to receive cRIT with 131-I-omburtamab at Memorial Sloan Kettering Cancer Center (MSK) on an IRB-approved phase I protocol (NCT# 00089245) from 2004 TO 2019. Patients were eligible for the protocol if they had no rapidly deteriorating neurologic examination or obstructive hydrocephalus, an absolute neutrophil count > 1000/ul, platelet count > 50,000/ul, serum bilirubin < 3.0 mg/dl, and serum creatinine < 2 mg/dl. Ommaya catheter position, patency, and CSF flow were evaluated in all patients before treatment using 111-Indium diethylene triamine pentaacetic acid scintigraphy studies. There was no prior EBRT dose limit and at least a 3-week interval between most recent EBRT and cRIT. Patients and/or guardians provided informed consent for trial enrollment. For the purposes of evaluating patients with recurrent primary brain tumors, patients with recurrent ependymoma or medulloblastoma who received cRIT and at least one imaging response assessment were included. | PMC10050019 |
131-I-omburtamab administration | toxicity | cRIT with 131-I-Omburtamab was delivered as previously described: a test dose (2 milliCurie [mCi]/injection), then if tolerated, followed by 1 or 2 monthly injections (10-70 mCi/injection) with dosing based on a phase I dose-escalation level at the time of patient entry. Clinical status, vital signs and neurologic examination were monitored overnight. Repeat therapy injections were administered in the absence of grade three or four toxicity [ | PMC10050019 |
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Bridging therapies | Bridging therapy was defined as treatment delivered after diagnosis of the most recent relapse prior to initiation of cRIT. Specifically, surgical resection, EBRT (focal and/or CSI), and medical therapy (both systemic and intrathecal chemo- or immunotherapies) at time of most recent relapse prior cRIT were noted. In addition to bridging therapies, treatment details of all EBRT (e.g., receipt of CSI, delivery with protons, dose, and number of treatments) both pre- and post-cRIT were collected. | PMC10050019 |
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Evaluation of response | cavernomas, radionecrosis | EVENTS, RECURRENCE | All patients had conventional MRI of the brain and spine within 3 weeks prior to cRIT and approximately 5 weeks after each therapy administration along with CSF collection. MRIs included sagittal and axial T1-weighted, axial T2-weighted, axial fluid-attenuated inversion recovery (FLAIR), axial diffusion weighted images, apparent diffusion coefficient and exponential maps, and postcontrast T1-weighted sequences in axial, sagittal, and coronal planes [Initial response on the first post-cRIT MRI and later recurrence on future MRIs were assessed by three board-certified radiologists per RANO/RANO-LM guidelines [Patterns of relapse (e.g., intraparenchymal and/or spine, focal or multifocal/diffuse, CSF cytology) were evaluated. Radiologic events (e.g., radionecrosis, cavernomas) were assessed. | PMC10050019 |
Statistics | death | DISEASE, EVENT | Progression-free survival (PFS) was calculated both from time of first 131-I-omburtamab injection and from time of relapse pre-cRIT to progression, relapse, or death. Overall survival (OS) was calculated from time of first 131-I-omburtamab injection and time of pre-cRIT relapse until death. Extent of disease at cRIT initiation (no evidence of radiologic and cytologic disease [NED] v measurable disease [MD]) along with bridging therapies were evaluated as predictors of PFS and OS by Kaplan–Meier analysis with log-rank tests. Median follow-up was calculated using reverse Kaplan–Meier analysis with death as a censoring event. Time-to-event analyses were stratified by primary histology. Two-sided | PMC10050019 |
Results | PMC10050019 |
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External beam radiotherapy prior to 131-I-omburtamab | medulloblastoma, ependymoma | MEDULLOBLASTOMA, EPENDYMOMA | All patients had EBRT at a median time of 0.9 years (range 0.1–5.2) preceding cRIT (Supplemental Table 1). Most patients received CSI (22, 81%), with a median dose of 2340 cGy (range 2300–3960 cGy) with a boost to 5400 cGy (range 5040–6000 cGy). Ten (37%) CSI treatments were delivered with protons, all for patients with medulloblastoma. Most patients (20, 74%) received a focal course of EBRT, five of which were delivered with protons. Among patients with medulloblastoma, the maximum dose of EBRT pre-cRIT ranged from 1800 to 5000 cGy (median 3000 cGy). For ependymoma, the maximum dose of EBRT pre-cRIT ranged from 4720 to 5940 cGy (median 5700 cGy). Prior to cRIT, 15 (56%) medulloblastoma and 6 ependymoma (86%) patients received more than one course of EBRT. None of the patients received multiple courses of CSI pre-cRIT. | PMC10050019 |
Disease response | PMC10050019 |
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Medulloblastoma | medulloblastoma, ependymoma, leptomeningeal disease | RECURRENCES, DISEASE PROGRESSION, EPENDYMOMA, DISEASE, REMISSION, MEDULLOBLASTOMA, EVENTS | All 20 patients received EBRT prior to cRIT at a median time of 0.6 years (range, 0.1–4.9). Most patients (12, 60%) received EBRT as part of bridging therapy, nearly all (11, 92%) of which were re-irradiation and three were with protons (2 CSI, 1 focal; Table Swimmer’s plot demonstrating timing of treatments received and progression events. An arrowhead indicates that the patient was alive at the time of last follow-up. Those without an arrowhead indicate that the patient died at that time. *One patient was lost to follow-up and died of unknown causes. Four patients remain in remission: at cRIT initiation, three had NED and one had multifocal leptomeningeal disease in the spine. Sixteen patients ultimately had disease progression at a median time of 0.8 years (range, 0.2–4.0) after most recent relapse and 0.2 years (range, 0.1–3.4) after cRIT initiation. Half of those who progressed had NED at cRIT initiation: four progressed focally intracranially, two progressed multifocally intracranially, and one had LMD in the spine per outside report (Supplemental Fig. 2). The other half who progressed had MD at cRIT initiation, and these progression patterns were nearly all multifocal and/or diffuse with LMD, with the exception of one patient with isolated cytologic disease at baseline who ultimately developed focal intracranial LMD.Median PFS following cRIT for the medulloblastoma cohort was 0.4 years from cRIT initiation (95% CI 0.1–1.7; Fig. Survival outcomes among patients with medulloblastoma (top) and ependymoma (bottom) calculated from the time of pre-cRIT relapse. Survival outcomes among patients with medulloblastoma based on disease status at cRIT initiation. Among medulloblastoma patients, three underwent additional focal EBRT following cRIT for future recurrences. One patient received partial brain EBRT (2000 cGy), one patient received focal EBRT to the spine (2000 cGy), and one patient received three additional focal EBRT courses to the brain (maximum dose 3000 cGy). No patients received CSI post-cRIT. | PMC10050019 |
Ependymoma | LMD disease, ependymoma | DISEASE, RECURRENCE, EPENDYMOMA | While all the patients with ependymoma had received EBRT at a median time of 1.2 years (range, 0.2–5.2) preceding cRIT, none had received EBRT as a bridge to cRIT after the most recent relapse (Table Five patients ultimately had progression at a median time of 0.4 years (range, 0.2–1.9) after most recent relapse and 0.2 years (range, 0.1–1.4) after cRIT initiation: two who were NED at cRIT initiation ultimately relapsed at or adjacent to the site of initial intraparenchymal disease, one had progression of the pre-cRIT measurable LMD disease in the spine but had PR in the intracranial LMD, one failed both at the measurable pre-cRIT site in the brain as well as developed new LMD in the spine, and one failed in both the brain parenchymal and had LMD in the spine (Supplemental Fig. 1). One patient who had measurable spine LMD at cRIT initiation was lost to follow up after initial post-cRIT MRI showed stable disease and he ultimately died 12.8 years after cRIT initiation (Fig. Three patients underwent additional focal EBRT to the brain following cRIT for progression (one patient received 5940 cGy) or recurrence (one patient received 4 additional courses to multiple sites in the brain with a maximum dose of 5400 cGy, another patient underwent stereotactic radiosurgery of unknown total dose). No patients received CSI post-cRIT. The one patient who is alive at last follow-up without evidence of disease was originally NED at cRIT initiation. Median OS was 7.1 years from pre-cRIT relapse (95% CI 0.5–12.9) and 6.7 years from cRIT initiation (95% CI 0.4–12.9; Fig. | PMC10050019 |
Radiologic events | radionecrosis, AML, infarcts, cavernoma, intramedullary hemorrhage, cerebral aqueduct stenosis, PRES | ACUTE MYELOID LEUKEMIA, INTRAMEDULLARY HEMORRHAGE, EVENT, HYDROCEPHALUS, AML, SECONDARY, SYNDROME, EFFUSIONS, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME | Of the 13 patients who had radiologic findings following cRIT, there were no cases of radionecrosis (Supplemental Table 2). The most common event identified was cavernoma (6, 46%), although all were asymptomatic and none required intervention. Three patients (23%) had hydrocephalus, one of whom was symptomatic secondary to acute cerebral aqueduct stenosis requiring shunt placement. One patient did ultimately develop posterior reversible encephalopathy syndrome (PRES) in the setting of pre-existing infarcts. However, this clinic-radiographic syndrome was diagnosed after the developing acute myeloid leukemia (AML). One patient had had ventricular prominence, one had subdural effusions, and one had intramedullary hemorrhage. | PMC10050019 |
Discussion | death, ependymoma, radionecrosis, toxicity, cancer, AML, medulloblastoma, necrosis, tumors | DISEASE PROGRESSION, EPENDYMOMA, DISEASE COURSE, CANCER, DISEASE, TUMORS, AML, REMISSION, MEDULLOBLASTOMA, NECROSIS, DISEASE, MINIMAL RESIDUAL DISEASE | Patients with recurrent primary CNS tumors unfortunately have few curative treatment options. Here, we demonstrate that long-term survival over two years is possible among patients with recurrent medulloblastoma or ependymoma treated with multimodality therapy at relapse. These patients comprise a heavily treated population at risk of toxicity. With no cases of radionecrosis in this cohort despite all patients having at least one EBRT course pre-cRIT, our findings were consistent with previously published safety data [Patients who had NED at 131-I-omburtamab cRIT initiation had improved survival outcomes. This finding parallels previously published data for medulloblastoma patients who received 131-I-3F8 showing patients treated with cRIT while in remission had a lower risk of death compared to patients who had MD [Disease status at cRIT initiation was significantly associated with PFS for medulloblastoma. Among the patients with medulloblastoma who died, nearly all died of progression or relapse, with one patient ultimately dying of treatment-related AML. Similarly, among ependymoma patients, all but one patient lost to follow-up were confirmed to have died from disease progression, highlighting the importance of achieving disease control for survival. When patients who were NED at cRIT initiation did ultimately fail, the patterns of failure tended to be more unifocal and intracranial, whereas patients with multifocal failures typically had multifocal, measurable disease at the time of cRIT. This phenomenon of achieving remission prior to cRIT parallels the consistent theme in cancer treatment to achieve CR or minimal residual disease to optimize outcomes of consolidative therapies, such autologous stem cell transplant [Despite all patients having received at least one course of EBRT prior to cRIT, 6 patients having received additional EBRT post-cRIT, and 8 patients having previously received cRIT with I-131-3F8, there was no evidence of radiation necrosis on post-cRIT MRIs. Our findings support prior safety data investigating cRIT in combination with EBRT [This study has several limitations. First, this cohort is heterogeneous with different histologies, therapies, and prognoses. Second, while these data on patients who received I-131-omburtamab were prospectively collected, delivery of EBRT and other treatments varied depending on the treating institution. Third, given patients received therapy at different institutions throughout their disease course, there is a possibility of missing records. Fourth, certain treatments included in this analysis are not widely available and may impact generalizability.In conclusion, for patients with recurrent medulloblastoma or ependyma receiving cRIT, disease status at cRIT initiation may be critical. Among patients with medulloblastoma, radiologic and cytologic remission at 131-I-omburtamab initiation was associated with significantly improved survival. Patterns of relapse also demonstrated that patients with measurable disease at cRIT initiation were likely to fail multifocally and diffusely. For patients with the goal of cure, these findings support efforts to achieve remission prior to cRIT initiation using local bridging therapy (e.g., re-irradiation) as these patients can have improved survival outcomes. | PMC10050019 |
Author contributions | OU | KRT, SLW, NKC, BEM, NPT, MS, and KK: contributed to the study design. KRT, SLW, MK, SH, NKC, BEM, MR, NPT, and KK: contributed to experimental implementation. Data analysis was performed by KRT, SLW, MK, SH, LP, OU, and KK. Data interpretation was performed by KRT, SLW, MK, SH, LP, OY, MR, JKB, NKC, MS, EMB, NPT, PBZ, JLM, and KK. The manuscript was written and edited by all authors. | PMC10050019 |
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Funding | Cancer | CANCER | This work has been supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. | PMC10050019 |
Data availability | The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10050019 |
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Declarations | PMC10050019 |
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Conflict of interest | Cancer | CANCER | Both Memorial Sloan Kettering Cancer Center (MSK) and Dr. Cheung have financial interest in Y-mAbs, Abpro-Labs and Eureka Therapeutics. Dr. Cheung also reports receiving commercial research grants from Y-mabs Therapeutics and Abpro-Labs Inc. Dr. Cheung was named as inventor on multiple patents filed by MSK, including naxitamab and omburtamab licensed to Ymabs Therapeutics, and others licensed to Biotec Pharmacon, and Abpro-labs. Dr. Cheung is a SAB member for Eureka Therapeutics. Dr. Modak and Dr. Kramer reports consulting and equity in Ymabs, Therapeutics Inc. Omburtamab was licensed to Y-mAbs Therapeutics in 2015. Dr. Karajannis reports grants from Y-mAbs Therapeutics, Inc. (research support) and personal fees from Bayer AG, AstraZeneca, Inc., QED Therapeutics, Inc., CereXis, Inc., Recursion, Inc., Cardinal Health and Medscape (Medical Advisory Board and/or consultant). | PMC10050019 |
References | PMC10050019 |
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Background | infections, neutropenic, Cancer | INFECTIONS, CANCER | Multidrug-resistant Gram-negative bacterial (MRGNB) infections represent a major public health threat. Cancer patients and, among them, hematological patients are most vulnerable to these infections. Gut colonization by MRGNB is a common phenomenon occurring during hospitalization and chemotherapy exposure. In the neutropenic phase that occurs after chemotherapy, MRGNB translocation occurs increasing patient’s mortality. Fluoroquinolone prophylaxis with ciprofloxacin or levofloxacin efficacy is now being questioned due to the increase of incidence in MRGNB. | PMC10612155 |
Methods | febrile neutropenia, acute leukemia | FEBRILE NEUTROPENIA, ACUTE LEUKEMIA | A phase III randomized, controlled, clinical trial, open-label parallel-group with a 1:1 ratio, aimed to demonstrate the non-inferiority of oral fosfomycin versus oral ciprofloxacin for febrile neutropenia prevention in patients with acute leukemia (AL) or hematopoietic cell transplant (HSC) receptors. Weekly surveillance cultures are planned to detect gut colonization. Changes in fecal microbiome at the beginning and end of prophylaxis will also be analyzed. | PMC10612155 |
Discussion | febrile neutropenia | FEBRILE NEUTROPENIA | This trial will provide evidence of the efficacy of an alternative drug to ciprofloxacin for febrile neutropenia prevention in high-risk hematological patients. The battery of planned microbiological studies will allow us to evaluate prospectively the microbiological safety of both pharmacological strategies in terms of the selection of MRGNB occurring in each arm. In addition, valuable information on the way in which each drug changes the fecal microbiome of the patients throughout the treatment will be generated. | PMC10612155 |
Trial registration | Clinical trials NCT05311254, Registered on 5 April 2022, | PMC10612155 |
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Keywords | PMC10612155 |
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Administrative information | Martorell | DEL | Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see 1. Hematology Department, University Hospital Central of Asturias. Avenida Roma, 33011, Oviedo, Spain2. Instituto de Investigación Sanitaria del Principado de Asturias. Avenida Roma, 33011, Oviedo, Spain.3. Instituto Universitario de Oncología del Principado de Asturias. C/ Fernando Bongera, 33006 Oviedo, Spain.4. Clinical Trials Agency Valdecilla-IDIVAL, Marqués de Valdecilla University Hospital, Av. Valdecilla, 25, 39008 Santander, Cantabria, Spain5. Department of Clinical Pharmacology, Marqués de Valdecilla University Hospital, Av. Valdecilla, 25, 39008 Santander, Cantabria, Spain.6. Hematology Department, Fundación Jiménez Díaz. Av. Reyes Católicos, 28040, Madrid, Spain.7. Hematology Department, San Pedro Alcántara Hospital. C/ Pablo Naranjo Porras, 10003, Cáceres, Spain.8. Hematology Department, University Clinic Hospital San Carlos. C/ Prof. Martín Lagos, 28040, Madrid.9. Hematology Department, Instituto de Investigación, University Hospital La Fe. Avinguda Fernando Abril Martorell, 46026.10. Hematology Department, University Hospital La Paz. Paseo de la Castellana, 28046, Madrid, Spain.11. Hematology Department, University Clinic Hospital of Valencia. Av Blasco Ibañez, 46010, Valencia.12. Hematology Department, University Hospital Morales Messeguer. C/ Marqués de los Vélez, 30008, Murcia.13. Hematology Department, University Hospital Carlos Haya. Av Carlos Haya, 29010, Malaga, Spain.14. Microbiology Department, University Hospital Central of Asturias. Avenida Roma, 33011, Oviedo, Spain.15. CIBER_Enfermedades Respiratorias ISCIII. Av. Monforte de Lemos, 3–5. Pabellón 11. Planta 0 28029 MadridFundación para la Investigación y la innovación (FINBA), Instituto de Investigación sanitaria (ISPA)Faustino Blanco as representative of the [email protected] | PMC10612155 |
Introduction | PMC10612155 |
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Background and rationale {6a} | neutropenia, musculoskeletal and neurological adverse, dermatological infections, infection, hematologic | URINARY TRACT INFECTIONS, NEUTROPENIA, CNS INFECTIONS, INFECTION, EVENTS, GASTROINTESTINAL TRACT INFECTIONS | The use of fluoroquinolones (FQ) ciprofloxacin or levofloxacin is an established practice for the prevention of infectious events in hematologic patients in whom long lasting and profound neutropenia (absolute neutropenia count ≤ 0.1/ × 10The concerns about the increasing incidence of MRGNB and its risks have led to questioning the actual recommendation of FQ prophylaxis, especially in those settings with a baseline resistance rate above 20% [In addition to multidrug resistance associated to FQ, musculoskeletal and neurological adverse events (AEs) related to them represent another problem. For this reason, the European Pharmacovigilance Risk Assessment Committee recommends restricting their use (Finally, another aspect for which FQ may adversely impact the outcome of patients is the modification of the intestinal microbiota. It has been demonstrated that replacement of the normal fecal microbiota with an abnormal one occurs in patients undergoing allogeneic HSCT [All the aforementioned limitations related to FQ prophylaxis have pointed to the urgent need for exploring new prophylactic drugs. In the past decades, other drugs were evaluated without positive results. This is the case of cephalosporins [Fosfomycin is a broad-spectrum bactericidal antibiotic approved for the treatment of uncomplicated urinary tract infections, gastrointestinal tract infections, and dermatological infections caused by microorganisms sensitive to this antibiotic. It has activity against Gram-positive and Gram-negative microorganisms and against extended-spectrum B-lactamase In view of the above, the need of conducting this study is justified. The results could demonstrate the non-inferiority of oral fosfomycin compared to oral ciprofloxacin in preventing infections in patients with neutropenia at high risk of developing infection as well as its effect on the intestinal flora as assessed by surveillance cultures and fecal microbiota analysis. | PMC10612155 |
Choice of comparator {6b} | febrile neutropenia | FEBRILE NEUTROPENIA | The choice of ciprofloxacin over levofloxacin is based on the evidence supporting its superiority in the prevention of febrile neutropenia [ | PMC10612155 |
Objectives {7} | PMC10612155 |
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Hypotheses | neutropenic, fever of infectious | The use of oral fosfomycin is not inferior to oral ciprofloxacin in the prevention of fever of infectious origin in high-risk neutropenic patients. This hypothesis is based not only on the broad-spectrum activity of fosfomycin but also on the low rate of resistance to this drug. In addition, we anticipate that the clinical efficacy of fosfomycin will be accompanied by an acceptable safety profile. Thus, there is potential for fosfomycin to be useful as a prophylactic agent in settings endemic for GNMRB. | PMC10612155 |
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Objective | febrile neutropenia, acute leukemia | FEBRILE NEUTROPENIA, ACUTE LEUKEMIA | The main objective of this clinical trial is to demonstrate non-inferiority in efficacy of oral fosfomycin versus oral ciprofloxacin in preventing febrile neutropenia in patients with acute leukemia treated with intensive chemotherapy and/or recipients of hematopoietic stem cell transplantation. | PMC10612155 |
Trial design {8} | DISEASE, ACUTE LEUKEMIA | The FOVOCIP study is a randomized, open-label, phase III clinical trial with a non-inferiority design, in which patients are randomized in a 1:1 ratio into two parallel, controlled prophylaxis groups: fosfomycin or ciprofloxacin. The groups are stratified by site and by underlying disease (acute leukemia or stem cell transplantation).FOVOCIP is a pragmatic study and very well adapted to the usual clinical practice of the sites of the public health system in Spain. | PMC10612155 |
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Methods: participants, interventions, and outcomes | PMC10612155 |
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Study setting {9} | RECRUITMENT, ACUTE LEUKEMIAS | The sponsor of this study is FINBA and plans to include 156 patients over 2 years; therefore, 11 Spanish national hospitals are needed to achieve the described objective.The hospitals included are:✓ University Hospital Central of Asturias.✓ University Hospital La Paz.✓ University Clinic Hospital San Carlos.✓ Hospital San Pedro of Alcántara.✓ University Hospital Morales Messeguer.✓ University Hospital La Fe.✓ University Clinic Hospital of Valencia.✓ University Hospital of Málaga.✓ University Hospital Fundación Jiménez Díaz.✓ University Clinic Hospital Lozano Blesa.✓ University Hospital of Burgos.✓ These are academic hospital centers with experience in the management of acute leukemias and stem cell transplants. They are located around several regions in Spain. Therefore, they represent a broad spectrum of our country geography. This guarantees the representativeness of the Spanish population and the achievement of the planned recruitment.✓ The Clinical Trials agency and SCReN (Spanish Clinical Research Network) were responsible for obtaining authorization from the local ethics committee (EC) and notifying to the Spanish Agency of Medicines and Medical Devices of the start-up of the study. | PMC10612155 |
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Eligibility criteria {10} | tumor, neoplasia, psychiatric illness, Fever of infectious, infection, leukemic infiltration, mucositis, neoplasm, allogeneic hematopoietic progenitor transplant, Hematopoietic Comorbidity, acute leukemia | TUMOR, NEOPLASIA, LIVER, HYPERSENSITIVITY, INFECTION, MUCOSITIS, NEOPLASM, ONCOLOGY, ACUTE LEUKEMIA | Candidate selection will be performed in 2 different settings depending on the therapeutic procedure:In subjects with a suspected diagnosis of acute leukemia, where the diagnosis of the neoplasm is made as an inpatient, the selection will take place once the diagnosis has been confirmed and prior to the start of intensive chemotherapy.In HSCT recipients, selection will take place on an outpatient basis during the pre-transplant evaluation.
Subjects must meet all of the following inclusion criteria:
Subjects must be able to understand the study procedures, comply with them, and give written informed consent prior to any specific study procedure.Adult subjects 18 years of age who meet one of the following criteria:
Diagnosis of acute leukemia who are to receive a first course of intensive chemotherapy orCandidates to receive a first allogeneic hematopoietic progenitor transplant with myeloablative conditioning orCandidates to receive a first allogeneic hematopoietic progenitor transplant with reduced-intensity conditioning* or an autologous hematopoietic progenitor transplant provided that at least one of the following risk factors for infection is present: Performance status (Eastern Cooperative Oncology Group, ECOG) ≥ 2. Expected grade 3–4 mucositis. Age ≥ 65 years. Hematopoietic Comorbidity Transplant Index (HCTI) ≥ 3. Serum albumin < 35 g/L. Active or refractory neoplasia at the time of stem cell transplantation. Total dose of etoposide > 500 mg/m. Total dose of cytarabine > 1 g/m.
Performance status (Eastern Cooperative Oncology Group, ECOG) 0 to 3.Adequate organ function defined as:Liver: bilirubin, alkaline phosphatase, or SGOT < 3 times the upper limit of normal (unless attributable to tumor activity)Renal: creatinine ≤ 250 μmol/l (2.5 mg/dL) (unless attributable to leukemic infiltration)
Life expectancy greater than 3 monthsWomen of childbearing age must not be pregnant or breastfeeding and must have a negative pregnancy test at the time of screening. Women of childbearing age and men with female partners of childbearing age must agree to practice 2 highly effective contraceptive measures and must agree not to become pregnant or father a child while receiving any study therapy and for at least 3 months after completion of treatment.
Patients who meet any of the following exclusion criteria cannot be included in this study:
Hypersensitivity to fluoroquinolones or fosfomycin.Treatment with broad-spectrum antimicrobial therapy within 4 weeks of the first study treatment.Intensive chemotherapy or prior hematopoietic stem cell transplantation. Treatment with hydroxyurea or corticosteroids used to control white blood cell count is allowed.Fever of infectious origin or documented infection within 4 weeks of the first study treatment.Presence of any serious psychiatric illness or physical condition that, in the judgment of the physicians, contraindicates the patient’s inclusion in the clinical trial. | PMC10612155 |
Who will take informed consent? {26a} | Principal investigators in each site will provide informed consent to patient candidates for participation. The latest version approved of the patient’s information sheet will be signed by all selected subjects before inclusion in the clinical trial.In the case of selected subjects who cannot understand the study or do not have the ability to read or write, the informed consent must be provided by the legal representative before any procedure of the study is carried out. | PMC10612155 |
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Additional consent provisions for collection and use of participant data and biological specimens {26b} | This study complies with the current regulations of Law 14/2007 on biomedical research regarding the protection of the rights of patients who freely wish to participate and the handling of biological samples.No biological samples from patients will be stored after the end of the clinical trial. | PMC10612155 |
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Interventions | PMC10612155 |
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Explanation for the choice of comparators {6b} | PMC10612155 |
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Intervention description {11a} | The description of the interventions and comparators is detailed in Table Intervention description | PMC10612155 |
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Criteria for discontinuing or modifying allocated interventions {11b} | EVENTS, FEBRILE NEUTROPENIA | Treatment will be interrupted when any of the following events occurs first:
Febrile neutropenia requiring antibacterial treatment (main end point of the study).Absolute neutrophil count (ANC) > 0.5 × 10If the subject fails to achieve more than 0.5 × 10Death | PMC10612155 |
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Strategies to improve adherence to interventions {11c} | Study patients will be hospitalized during the period in which they are receiving the study treatment. The investigator of each site will review and record the traceability of the medication administered. | PMC10612155 |
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Relevant concomitant care permitted or prohibited during the trial {11d} | The concomitant medication recommendations listed in the technical data form for ciprofloxacin should be taken into consideration.Special attention should be paid to drugs that prolong the QT interval (class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, and antipsychotics) as well as tizanidine, methotrexate, and theophylline.The concomitant medication recommendations listed in the technical data form for fosfomycin will be taken into consideration. | PMC10612155 |
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Provisions for post-trial care {30} | The health professionals participating in this clinical trial belong to the Spanish National Health System. These are non-commercial studies where the sponsor is a non-profit foundation, FINBA. The trial subjects do not receive any compensation. | PMC10612155 |
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Outcomes {12} | death, fever, febrile neutropenia, infections, infection, Fever | HAND INFECTION, FEBRILE NEUTROPENIA, ADVERSE EVENTS, INFECTIONS, MIXED INFECTION, INFECTION | The primary endpoint is febrile neutropenia requiring antibacterial treatment.Fever is defined as a single oral temperature of 38.3 °C or a temperature of 38 °C sustained over a 1-h period.If the patient is receiving any medication highly likely to induce fever or has previously received a transfusion, at least one positive culture or infectious focus will be required for fever to be attributed to infection.When febrile neutropenia occurs and infection is suspected, prophylactic antibiotics will be discontinued and evaluation and therapy will be administered according to standard and local guidelines.Secondary endpoints are as follows:Documented infections. They will be classified according to Han’s criteria in one of these categories: microbiologically documented infection (bacterial viral or fungal), mixed infection, clinically documented infection, and possible infection (fever of unknown origin).The amount of concomitant antibiotics prescribed in addition to prophylactic drugs will be measured as a ratio of antibiotic days per days of hospitalization. Antibiotics will be classified according to the watch/reserve classification (21).Overall survival will be defined as the time from the day of randomization to the date of death (whatever the cause of death) or to the completion of the study. Fever-free survival will also be determined.Safety will be assessed by the incidence, severity and type of adverse events (AEs), and by the microbiological assessments: | PMC10612155 |
Microbiological assessments |
Rate of patients colonized by GNMRB as determined by surveillance and metagenomic sequencing.Changes in the gut microbiome produced in both groups. | PMC10612155 |
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Participant timeline {13} | The flow chart for the study and the schedule visits and assessments at different points in the study protocol are described in Table Schedule of visits and assessments at different points of the study protocol
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Sample size {14} | infectious fever, thirty-four | The reviewed clinical trials and meta-analyses have consistently shown that 65% of patients receiving prophylactic the fluoroquinolones levofloxacin and ciprofloxacin will develop infectious fever (2,17,18) which is consistent with success rate of 35%. Considering that the actual rate of resistance to fluoroquinolones is established to be around 50%, we anticipate a success rate of 17% and 30% in the active control and active and experimental control arms, respectively.If a non-inferiority margin of 5% is defined, one hundred and thirty-four patients (67 in each arm) will be needed to demonstrate non-inferiority of fosfomycin versus ciprofloxacin with 80% potency and an alpha level of 0.05.Considering that 15% of the enrolled patients will be ineligible or unable to be evaluated, the maximum number of study participants will be 156: 78 patients in each arm. | PMC10612155 |
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Recruitment {15} | acute leukemia | ACUTE LEUKEMIA | There were strategies for achieving adequate participant enrolment to reach the target sample size.Patients who are undergoing HSCT will be previously evaluated in the pre-transplant consultation while patients diagnosed with acute leukemia will be evaluated during the first days of hospitalization. Based on whether they meet the selection criteria of the FOVOCIP study protocol, they will be asked to participate in the study by signing the informed consent form. | PMC10612155 |
Assignment of interventions: allocation | PMC10612155 |
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Sequence generation {16a} | acute leukemia | DISEASE, ACUTE LEUKEMIA | The randomization will be carried out by the electronic clinical registry (eCRF) called MACRO. The management of the electronic tool is carried out by the SCReN clinical research platform work-package.After inclusion, the randomization list included in the eCRF will automatically assign the case to the control or experimental group in 1:1 ratio. Candidates are stratified according to their baseline disease: acute leukemia or HSCT. | PMC10612155 |
Concealment mechanism {16b} | Allocation concealment will be ensured as MACRO will not release the randomization code until the patient has been recruited into the trial. | PMC10612155 |
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Implementation {16c} | CRF | DIAZ, CRF | The patient assignment codes are made up of 4 digits. On the one hand is the hospital number, University Hospital Central of Asturias (number 01), Hospital San Pedro Alcantara (number 2), University Hospital Morales Messeguer (number 03), University Hospital La Paz (number 04), University Hospital Fundación Jimenez Diaz (number 05), University Hospital Clínico San Carlos (number 06), University Clinic Hospital of Valencia (number 07), University Hospital La Fe (number 08), University Hospital of Málaga (number 09), University Hospital Lozano Blesa of Zaragoza (number 10), and University Hospital of Burgos (number 11), and on the other hand is the consecutive number of the new patient included.These codes are assigned by the CRF of the study. | PMC10612155 |
Assignment of interventions: blinding | PMC10612155 |
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Who will be blinded {17a} | The study is open-label. The investigators and the patient are aware of the treatment administered. The project manager only knows the randomization list, so the investigator does not know the treatment that will be assigned to the patient until the candidate is randomized. The assessors and data analysts will be blinded. | PMC10612155 |
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Procedure for unblinding if needed {17b} | The design is open label with only outcome assessors being blinded, so unblinding will not occur. | PMC10612155 |
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Data collection and management | PMC10612155 |
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Plans for assessment and collection of outcomes {18a} | biochemistry and coagulation | SECONDARY | To evaluate the primary and secondary variables of the study, vital signs (blood pressure, heart rate, temperature) will be checked during the physical examination at successive visits. Laboratory tests including blood count, biochemistry and coagulation, electrocardiogram (ECG), microbiological studies, and review of treatment will be performed. | PMC10612155 |
Plans to promote participant retention and complete follow-up {18b} | ADVERSE EFFECTS | An end-of-treatment visit is made to coincide with the last dose of study medication (fosfomycin or ciprofloxacin). And a follow-up visit is scheduled 15 days after the last dose of treatment to perform physical examinations and record adverse effects, ECOG, concomitant treatment, electrocardiogram (ECG), laboratory investigations, and microbiological studies.If the patient is unable to attend the follow-up visit, this can be done by telephone. | PMC10612155 |
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Data management {19} | The MACRO® software is a data collection and study management application that uses a secure web browser. It provides access to clinical study data and management of the clinical study process.The objective is that, at the end of the study, all the available forms are as follows:✓ Completed by the investigator✓ With no queries pending to be solved by the Investigators✓ With no queries pending to be closed by the CRAs/PMs✓ Verified by the CRAs✓ Locked by the PMs | PMC10612155 |
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Confidentiality {27} | Personal data will be processed in accordance with Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of individuals regarding the processing of personal data and on the free movement of such data and the relevant local laws.The data collected for the study will be identified by an alphanumeric code in such a way that it will not be possible to identify the patient. Only the investigator and authorized persons involved in the study will have access to this code and use this information exclusively for the purposes of the study. All the generated data will be recorded in the eCRF in an anonymized form.Members of the Clinical Research Ethics Committee or Health Authorities may have access to this information in compliance with legal requirements. The confidentiality of this data will be preserved, and it will not be linked to personal data, even if the results of the study are published. | PMC10612155 |
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Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} | MDRGN, neutropenic | INFECTIOUS DISEASES | All study subjects will be screened for MDRGN gut colonization by microbiological culture at the first visit and weekly thereafter during the neutropenic period, until study completion. In each participating center, rectal exudates will be collected in ESwab™ (Copan Diagnostics Inc., Murrieta, CA) that will be sent to the microbiology laboratories for culture in selective media for MDRGN, according to the recommendations of the Spanish Society for Infectious Diseases and Clinical Microbiology (SEIMC) (22,23), specifically in CHROMagar™ The clinical trial includes a substudy in a population of 30 subjects, representative of the two treatment arms, both colonized and non-colonized according to the conventional microbiological techniques results. Two samples from each of these subjects will be recovered between those processed for culture (stored at – 80 °C) at the baseline visit and at the end of the study. In these samples, the evolution of the resistome will be investigated using “shotgun” metagenomic sequencing techniques. These results will be compared with those obtained by culture.The patient’s microbiome evolution will be studied by metataxonomic sequencing. For this purpose, a fecal sample will be collected from each study subject at the baseline visit and at the end of the study.Figure Clinical and microbiological study planning | PMC10612155 |
Statistical methods | PMC10612155 |
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Statistical methods for primary and secondary outcomes {20a} | infections, febrile neutropenia, fever | ADVERSE EVENT, NEUTROPENIC FEVER, FEBRILE NEUTROPENIA, ADVERSE EVENT, EVENT, INFECTIONS, SECONDARY, REGRESSION | This phase 3 trial will compare the efficacy of fosfomycin with that of ciprofloxacin in preventing the occurrence of at least one episode of neutropenic fever of infectious origin in a randomized non-inferiority design.The primary endpoint is febrile neutropenia of infectious origin. This analysis will be performed in the intention-to-treat (ITT) and in the per-protocol population (PP). The ITT population is defined as all patients who are eligible and randomized. The PP population consists of all patients who do not have major protocol deviations, as determined by the study PI, and have received prophylactic drugs for at least of 24 h.The rate of febrile neutropenia will be compared between the 2 arms with a chi-square test with 2-sided alpha of 0.05. The difference in the proportion and the associated 95% CIs will be provided. If, within either patient arm, the data suggest a possible difference in baseline incidence between the randomization strata, we will consider Cochran-Mantel–Haenszel test to examine the association between the incidence of febrile neutropenia and the study treatment with adjustment for the randomization strata. Logistic regression models will be performed to evaluate the treatment effect on the incidence of febrile neutropenia adjusting for stratification and other baseline patient characteristics.The analysis of the secondary endpoints will be performed as follows:Rate and type of documented infections with 2-sided alpha of 0.05. Again, logistic regression models will be performed to evaluate the treatment effect on the incidence of each event adjusting for stratification and other baseline patient’s characteristics.Amount of concomitant antibiotic utilization. The analysis will be performed with a 2-sample Survival will be analyzed using the Kaplan–Meier estimate. The K-M survival curves and medians (if estimable) along with their 2-sided 95% CIs will be provided for each treatment arm. The log-rank test will be used to compare treatment arms. Differences in survival without fever will also be assessed with a log-rank test at the 5% significance level.Adverse events. This end point is included in the safety analysis and will be performed in the SP. AE will be categorized as severe and non-severe, as this classification determines the notification procedure. Intensity of AE will be evaluated according to the National Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.034.The microbiological safety assessments will be analyzed as specified in item 33. | PMC10612155 |
Interim analyses {21b} | An interim analysis will be performed by a data and safety monitoring board (DSMB) for the primary outcome measure after the inclusion of 50 patients. O’Brien- Fleming stopping criteria will be used for the primary outcome (24). If the | PMC10612155 |
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Methods for additional analyses (e.g., subgroup analyses) {20b} | There is no planned sub-group analysis. | PMC10612155 |
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Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} | FCS | ACUTE LEUKEMIA | To prevent attrition bias, two types of analysis will be performed: an intention-to-treat analysis, in which all randomized patients will be analyzed according to the group to which they were randomized, regardless they received the assigned treatment or not, and, in addition, a per-protocol analysis will be performed in all randomized patients who finally received the assigned treatment for at least of 24 h (2 doses of ciprofloxacin and 3 doses of fosfomycin).The imputation of missing variables will consider the distribution of the variables, the allocation group, the center, and the baseline condition (acute leukemia or stem cell transplant).The method of fully conditional specification (FCS) using the MI procedure of SAS, version 9.4 (SAS Inc, Cary, NC, USA), will be used [ | PMC10612155 |
Plans to give access to the full protocol, participant-level data, and statistical code {31c} | Dissemination of results directed to patients will be channeled through the Spanish Agency for Medicines and Health Products, and their content will be adapted to patients. | PMC10612155 |
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Oversight and monitoring | PMC10612155 |
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Composition of the coordinating center and trial steering committee {5d} | The The
Finally, PIs in each center are responsible for including identifying potential recruits and taking consent. | PMC10612155 |
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Composition of the data monitoring committee, its role and reporting structure {21a} | A meeting will be held by non-study personnel to evaluate the results of 80 patients. The interim analysis committee will be composed of a hematologist, a microbiologist and a clinical pharmacologist. | PMC10612155 |
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Adverse event reporting and harms {22} | ADVERSE EVENTS, EVENTS, ADVERSE REACTIONS, ADVERSE EVENT | The investigators will be responsible for collecting all the adverse events in the clinical history based on those referred by the patient spontaneously or by interview during the follow-up visits. The causality of the adverse event related to the intervention will be evaluated and recorded in the clinical history and in the eCRF.The investigators will report to the sponsor all serious adverse events occurring to subjects treated in the clinical trial, without undue delay, but not later than within 24 h of obtaining knowledge of the events.The sponsor will report to the Spanish Agency for Medicines and Health Products all relevant information about suspected unexpected serious adverse reactions to investigational medicinal products occurring in this clinical trial. | PMC10612155 |
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Frequency and plans for auditing trial conduct {23} | fever | ADVERSE REACTIONS, EVENTS, SECONDARY, RECRUITMENT | The CRA is a person independent of the research team who is not involved in patient recruitment and follow-up.The local CRA makes a start-up and closing visit to each site. A first visit will take place in each center 30 days after the inclusion of the first patient. Subsequently, 4 to 6 visits will be performed per site, with a frequency of 1 visit every 4 months.During the monitoring visits, 100% of the informed consents form, selection criteria, events and adverse reactions, and main and secondary variables (neutrophil counts, fever, study treatment, stored samples) will be reviewed. The remaining the variables will be reviewed every 5 patients. | PMC10612155 |
Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25} | All notifications defined as relevant or non-relevant amendments will be made to the Spanish Agency for Medicines and Health Products and to the Ethics Committee of reference in accordance with Spanish legislation on clinical trials RD 1090/2015 of December 4. These decrees regulate clinical trials with medicinal products: the Ethics Committees for Research with medicines and the Spanish Registry of Clinical Trials. | PMC10612155 |
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Dissemination plans {31a} | The results of the present project will be communicated to the scientific community through scientific publications. All publications will be open access. It is foreseen that the project will result in at least 2 peer reviews. All generated data will be accessible and stored in open access data repositories. A list of priority conferences to be targeted will be developed, aiming to achieve local, national, and international impact. | PMC10612155 |
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Discussion | neutropenia, febrile neutropenia, fever, infections, transfusional | ACUTE MYELOID LEUKEMIA, NEUTROPENIA, FEBRILE NEUTROPENIA, CNS INFECTIONS, INFECTIONS, GRAM-NEGATIVE BACTERIAL INFECTIONS, DISEASES | The debate on the efficacy of FQ prophylaxis in the era of multidrug resistance is ongoing. Our study will contribute to this debate by comparing the efficacy and safety of ciprofloxacin with fosfomycin in a homogeneous population of patients treated at several centers with different prevalence in MRGNB.The supporters of FQ prophylaxis (either ciprofloxacin or levofloxacin) have reported an increase in the incidence of Gram-negative bacterial infections [The opponents of FQ prophylaxis argue that these drugs are associated with gut colonization by MRGNB. In hematological patients, gut colonization is associated with blood stream infections when neutropenia occurs [Our study will have some limitations: first it will be open, which might favor the early termination of prophylaxis in the fosfomycin arm. However, a strict definition of febrile neutropenia of infectious origin has been specified in the protocol, which excludes transfusional associated fever or fever related to cytarabine (a common chemotherapy drug used in acute myeloid leukemia) or other drugs. Second, this is not a superiority trial, but a non-inferiority one, because it would have been unethical to conduct a trial comparing fosfomycin with placebo. Notwithstanding the limitations of this type of design [In summary, the present project addresses an extremely important health problem by evaluating the efficacy of fosfomycin, a broad-spectrum antibiotic with a better safety profile and a lower potential of resistance induction than ciprofloxacin, in the prevention of infections in hematological patients with high-risk neutropenia. The battery of microbiological studies that will be carried out will allow us to evaluate prospectively, for the first time, the microbiological safety of both pharmacological strategies and the selection of MRGNB in each arm and will generate valuable information on the way in which changes that occur in the fecal microbiome of the patients throughout the treatment modify the evolution of the studied diseases. | PMC10612155 |
Trial status | MAY, RECRUITMENT | Current version of the protocol is 3.0 of 11 of May 2021.Trial is currently recruiting. The first patient was included in March 2021. At the time of submission, 106 patients have been recruited. The recruitment is expected to be completed by March 2024. | PMC10612155 |
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Acknowledgements | Nicolás | DEL | Institutions and investigators participating in the FOVOCIP groupJavier Fernández Domínguez: Microbiology Department, University Hospital Universitario Central of Asturias.Ana Fernández Verdugo: Microbiology Department, University Hospital Central of Asturias.Pilar Lumbreras Iglesias: Instituto de Investigación Biosanitaria del Principado of Asturias.Rosario Rodicio Rodicio: University of Oviedo.Rosaura Rodicio Rodicio: University of Oviedo.Xenia Váquez Sánchez: University of Oviedo.María de Toro Hernando: Centro de Investigaciones Biomédicas Instituto de la Rioja.Laura Solán Blanco: Hematology Department, University Hospital Fundación Jiménez Díaz, Madrid.Marina Médel-Plaza: Microbiology Department, University Hospital Fundación Jiménez Díaz, Madrid.Sara Cáceres Hernández: Hematology Department, Hospital San Pedro Alcántara, Cáceres.María Izquierdo de-Miguel. Microbiology Department, Hospital San Pedro Alcántara, Cáceres.Juan Miguel Bergüa Burgués: Hematology Department, Hospital San Pedro Alcántara, Cáceres.Cristina Muñoz Cuevas: Microbiology Department, Hospital San Pedro Alcántara, Cáceres.Marta Polo Zarzuela: Hematology Department, University Hospital Clínico San Carlos, Madrid.Laura López: Microbiology Department, University Hospital Clínico San Carlos, Madrid.Blanca Boluda: Hematology Department, University Hospital La Fe, Valencia.Eva González-Barberá: Microbiology Department, University Hospital La Fe, Valencia.Karem Humala: Hematology Department, University Hospital La Paz, Madrid.Guillermo Ruiz Carrascoso: Microbiology Department, University Hospital La Paz, Madrid.Maria Luisa Calabuig: Hematology Department, University Hospital Clinic, Valencia.Javier Colomina: Microbiology Department, University Clinic Hospital of Valencia.Mari Luz Amigo Lozano: Hematology Department, University Hospital Morales Messeguer, Murcia.Irene Weber: Microbiology Department, University Hospital Morales Messeguer, Murcia.Marian Cuesta Casas: Hematology Department, University Regional Hospital of Málaga, Málaga.Dolores Rojo Martín: Microbiology Department, University Regional Hospital of Málaga, Málaga.Maria Teresa Olave: Hematology Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza.Jose Ramón Paño Pardo, Microbiology Department, University Clinic Hospital Lozano Blesa, Zaragoza.Jorge Labrador Gómez; Hematology Department, University Hospital of Burgos.Lucía Lavín Alconero: Clinical Trials Agency Valdecilla-IDIVAL.María del Mar García-Saiz: Clinical Trials Agency Valdecilla-IDIVAL, Department of Clinical Pharmacology, Marqués de Valdecilla University Hospital.Ahinoa Fernández Moreno: Hematology Department, Instituto de Investigación Sanitaria del Principado de Asturias, Instituto de Oncología del Principado de Asturias, University Hospital Central of Asturias.Paula López de Ugarriza: Hematology Department, Instituto de Investigación Sanitaria del Principado de Asturias, Instituto de Oncología del Principado de Asturias, University Hospital Central of Asturias.Ana Julia González Huerta: Hematology Department, University Hospital Central of Asturias.Nicolás Díaz Varela; Hematology Department, Instituto de Investigación Sanitaria del Principado de Asturias, Instituto de Oncología del Principado de Asturias, Hospital Universitario Central of Asturias.Teresa Bernal del Castillo; Hematology Department, Instituto de Investigación Sanitaria del Principado de Asturias, Instituto de Oncología del Principado de Asturias, University Hospital Central of Asturias. CIBER_Enfermedades Respiratorias ISCIII.Spanish Clinical Research Network (SCReN): Plataforma del ISCIII para el soporte para la investigación clínica. | PMC10612155 |
Authors’ contributions {31b} | TBC, LLA | TBC | TBC and JFD are the principal investigators of the study. TBC is the clinical coordinator, and JFD coordinates the microbiological part of the study. TBC and JFD have conceived the idea and developed the clinical trial protocol. MGS is responsible for the clinical trial agency at IDIVAL and the SCReN node in Cantabria. LLA is the project manager and coordinates the local monitors belonging to the SCReN network in the participating centers. TBC, JFD, AFM, and LLA wrote the manuscript. All the authors acquired data and read and approved the final manuscript. | PMC10612155 |
Funding {4} | FOUNDER | This trial is an investigator-initiated trial which is funded by a National Health Research Projects with the identifier PI21/01590. The founder did not have any role in the design of the study and will not have any role in collection, analysis, and interpretation of data and in writing the manuscript.The funding period includes 1 January 2022 to 31 December 2024. | PMC10612155 |
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Availability of data and materials {29} | The protocol and the results of the trial will be the exclusive property of the sponsor, who reserves the right to request on its behalf the industrial property rights that may derive from them. There are no agreements with other entities.The principal investigators are responsible for the preparation of the final report and therefore will have access to all available data. The anonymized data and the statistical code used for the analysis will be available from the principal investigators upon reasonable request.Data obtained from genomic studies will be deposited in repositories and databases and international public platforms such as the National Center for Biotechnology Information (NCBI). | PMC10612155 |
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Declarations | PMC10612155 |
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Ethics approval and consent to participate {24} | MAY | Ethical approval for this trial, which is in compliance with the Helsinki Declaration and in agreement with the SPIRIT statement, was obtained for the Ethics Committee of Principado de Asturias dated 26 August 2021 to corresponds to version 2.1 (19 August 2021). The protocol amendment version 3.0 was approved by the AEMPS on 27 May 2022.The subsequent informed consent form will be obtained from all the participants. According with the current legislation regarding to clinical trials (RD 1090/2015), the AEMPS will be notified of the start of the clinical trial. The obtained personal data and biological samples of all patients will be treated with confidentiality and security, in accordance with the regulations based on Regulation (EU) 2016/679 and Law 14/2007 on Biomedical Research.The clinical trial has been classified as a low intervention level clinical trial (ECBNI) and is, therefore, in accordance with the current legislation RD1090/2015, which specifies that low intervention level studies do not need to be covered by an insurance contract or financial guarantee, if they are covered by the individual or collective professional liability insurance or equivalent financial guarantee of the health site where the clinical trial is carried out. This is the responsibility of each site and not of the sponsor. | PMC10612155 |
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Consent for publication {32} | No identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. The participant information materials and informed consent form are available from the corresponding author on request. | PMC10612155 |
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Competing interests {28} | The authors declare that they have no competing interests. | PMC10612155 |
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References | PMC10612155 |
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Objective | People differ in whether they understand graphical or numerical representations of statistical information better. However, assessing these skills is often not feasible when deciding which representation to select or use. This study investigates whether people choose the representation they understand better, whether this choice can improve risk comprehension, and whether results are influenced by participants’ skills (graph literacy and numeracy). | PMC10625725 |
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Methods | GIST | In an experiment, 160 participants received information about the benefits and side effects of painkillers using either a numerical or a graphical representation. In the “no choice” condition, the representation was randomly assigned to each participant. In the “choice” condition, participants could select the representation they would like to receive. The study assessed gist and verbatim knowledge (immediate comprehension and recall), accessibility of the information, attractiveness of the representation, as well as graph literacy and numeracy. | PMC10625725 |
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Results | GIST | In the “choice” condition, most (62.5%) chose the graphical format, yet there was no difference in graph literacy or numeracy (nor age or gender) between people who chose the graphical or the numerical format. Whereas choice slightly increased verbatim knowledge, it did not improve gist or overall knowledge compared with random assignment. However, participants who chose a representation rated the representation as more attractive, and those who chose graphs rated them as more accessible than those without a choice. | PMC10625725 |
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Limitations | The sample consisted of highly educated undergraduate students with higher graph literacy than the general population. The task was inconsequential for participants in terms of their health. | PMC10625725 |
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Conclusions | When people can choose between representations, they fail to identify what they comprehend better but largely base that choice on how attractive the representation is for them. | PMC10625725 |
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Highlights | fits | GIST | People differ systematically in whether they understand graphical or numerical representations of statistical information better. However, assessing these underlying skills to get the right representation to the right people is not feasible in practice. A simple and efficient method to achieve this could be to let people choose among representations themselves.However, our study showed that allowing participants to choose a representation (numerical v. graphical) did not improve overall or gist knowledge compared with determining the representation randomly, even though it did slightly improve verbatim knowledge.Rather, participants largely chose the representation they found more attractive. Most preferred the graphical representation, including those with low graph literacy.It would therefore be important to develop graphical representations that are not only attractive but also comprehensible even for people with low graph literacy.Making informed health decisions requires understanding of basic statistical information about the benefits and side effects of medical treatments and other health-relevant behaviors. It is well documented, however, that understanding statistical information is quite challenging for most people, including for experts.However, while the use of graphical representations is often recommended as an aid for the interpretation of numerical data,The question thus arises how to get the right representation to the right person, that is, a representation (numerical or graphical) that this person understands well. Assessing patients’ graph literacy and numeracy prior to presenting medical information is time-consuming and potentially awkward, so that it is often not feasible in practice. A much simpler and more feasible method consists in letting people choose which representation they would like to receive themselves, rather than deciding it for them. To improve knowledge, this method would require that people are able to identify the representation that they comprehend better, that is, the representation that fits to their graph literacy and numeracy skills. In this study, we therefore investigate whether allowing people to choose a representation of statistical information does indeed improve knowledge and increases the fit to the underlying skills, compared with a situation in which the representation is randomly assigned.To investigate this question, we conducted an experiment in which participants received statistical information about the benefits and side effects of a painkiller medication. The central manipulation was that half of the participants could choose whether they wanted a graphical or a numerical representation of that information, whereas the other half of the participants received 1 of the 2 representations at random. At 2 time points of measurement, we assessed how well they comprehended (T1) and recalled (T2) the statistical information that they received. The 2 time points were primarily used to enhance the sensitivity to detect differences by avoiding potential ceiling effects and to check potential effects for robustness. In line with previous research (e.g., Gaissmaier et al.,Three research questions guided us, which will be described in detail subsequently: 1) Which representation will be chosen predominantly, and who chooses the graphical rather than the numerical representation? 2) Does being able to choose between numerical and graphical representations foster knowledge of statistical information in comparison with random allocation to either graphical or numerical representations? 3) Does choice increase ratings of accessibility and/or attractiveness, suggesting that either of those attributes may play a role in choosing? | PMC10625725 |
What Will Be Chosen Predominantly, and Who Chooses Graphs Rather than Numbers? | fits | Based on the existing literature, we can expect that most people will choose the graphical rather than the numerical representation: graphs are generally preferred,But do people—despite this general preference for graphical representations—choose the representation that fits to their skills such as graph literacy and numeracy, at least to some degree? If this were the case, then people who select graphical rather than numerical representations should have higher graph literacy on average, because research has shown that people with high graph literacy benefit particularly from graphical representations.Conversely, people higher in numeracy prefer to receive numerical instead of verbal information | PMC10625725 |
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Does Being Able to Choose a Representation Foster Knowledge of Statistical Information? | If people who can choose between representations actually succeeded in choosing the representation that they understand better, they should perform better when confronted with knowledge questions compared with people who randomly received either of the representations, and this should hold true for both individuals who choose graphical and individuals who choose numerical representations. Previous research has studied whether people better understand formats they preferred and found mixed results. While some studies found that preferences were unrelated to knowledge,However, all of these conclusions were based on correlational results. In addition, in most studies, participants provided their preference ratings for all representations, these ratings did not have any consequences, and they were provided only after working with multiple different formats. However, letting people work with all representations before choosing would not be a feasible solution for everyday medical decision making. In sum, to the best of our knowledge, there is no study that has directly tested whether providing the opportunity to choose a representation prior to a knowledge task poses a promising approach to improve knowledge of medical information. | PMC10625725 |
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Does Choice Increase Ratings of Accessibility and/or Attractiveness of the Representation? | Subjective ratings of the accessibility of the information as well as of the attractiveness of the representation could yield additional insights into how representations are chosen. As mentioned above, graphical representations have generally been found to be rated as more attractive than numerical ones (e.g., Gaissmaier et al. | PMC10625725 |
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Methods | PMC10625725 |
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