Laporte-Amargos et al. Trials (2020) 21:412 https://doi.org/10.1186/s13063-020-04323-0 STUDY PROTOCOL Open Access Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE) J. Laporte-Amargos1, C. Gudiol1,2,3,4*, M. Arnan5, P. Puerta-Alcalde6, F. Carmona-Torre7, M. Huguet8, A. Albasanz-Puig1,3, R. Parody5, C. Garcia-Vidal6, J. L. del Pozo7, M. Batlle8, C. Tebé9, R. Rigo-Bonnin10, C. Muñoz11, A. Padullés12, F. Tubau13, S. Videla14, A. Sureda5 and J. Carratalà1,2,3 Abstract Background: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal β- lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. Methods: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK (Continued on next page) * Correspondence: carlotagudiol@gmail.com 1 Infectious Diseases Department Hospital Universitari Bellvitge, Institut d’Investigació Biomedica de Bellvitge (IDIBELL), Feixa Llarga SN, 08907, L’Hospitalet de Llobregat, Barcelona, Spain 2 University of Barcelona, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Laporte-Amargos et al. Trials (2020) 21:412 Page 2 of 9 (Continued from previous page) model of the BLA studied. Discussion: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. Trial registration: European Clinical Trials Database: EudraCT 2018–001476-37. ClinicalTrials.gov, ID: NCT04233996. Keywords: Febrile neutropaenia, β-lactam antibiotics, Cefepime, Piperacillin-tazobactam, Meropenem, Extended infusion, Randomised controlled trial Background Patients with FN are similar to critically ill patients in Febrile neutropaenia (FN) is a very common complica- terms of the intra- and inter-individual variability of PK tion in patients with haematological diseases and is asso- parameters, mainly due to an increased volume of distri- ciated with considerable morbidity and mortality. bution and an increased renal clearance [13–15]. BLA Neutropaenia increases the susceptibility of patients to PK parameters are widely affected by these pathophysio- infections, which are more frequent and more severe de- logical changes. In fact, it has been suggested that in pa- pending on the degree and duration of the neutropaenia. tients with FN, some BLA administered by II may not However, only 30% of patients with FN develop a clinic- achieve desirable PK/PD parameters [16–18]. Moreover, ally or microbiologically documented infection, and only the PK/PD therapeutic target is still uncertain in neutro- 20% develop bacteraemia. The epidemiology of bacter- paenic patients, and further studies are required to valid- aemia in cancer patients has changed in recent decades, ate the magnitude of the optimal PK/PD index. with an increase in Gram-negative bacilli, and more im- Regarding the clinical impact of optimised BLA, data portantly, an emergence of multidrug antibiotic resist- on neutropaenic patients are limited and restricted to ance among these organisms [1, 2]. This is of particular certain antibiotics. A prospective, randomised pilot study concern because adequate empirical antibiotic treatment that analysed cefepime administered by EI and II found is associated with increased survival rates in patients no significant clinical differences between the two strat- with FN [3]. egies [19]. However, it should be noted that septic pa- β-lactam antibiotics (BLA) are the most widely used tients were excluded from the analysis, despite being the antibiotics in the routine management of FN. Therefore, subgroup that would most benefit from EI. A retrospect- optimising the use of BLA is essential to improve the ive study with 164 patients found clinical efficacy with prognosis of these patients. One way to optimise the use the use of meropenem by EI compared to II [20]. Simi- of these drugs is to administer them by extended infu- larly, a recent single-centre, randomised clinical trial sion (EI) or continuous infusion (CI). This approach al- found that EI was associated with superior treatment lows free (unbound) concentrations of the drug to be outcomes compared with II, and the benefit was greatest maintained above the minimum inhibitory concentration for patients with pneumonia [21]. Nevertheless, the (MIC) of the pathogen during the dosing interval (fT > study had some methodological flaws, and no PK studies MIC) [4, 5]. Studies seem to show improved outcomes were performed to support the clinical results [22]. in terms of microbiological eradication, clinical success In the current era of widespread antimicrobial resist- and mortality when critically ill patients achieve this ance, and due to the lack of new antibiotics, the use of pharmacokinetic/pharmacodynamic (PK/PD) target [6– optimised administration of BLA may play an important 9]. Moreover, two recent meta-analyses have shown an role in the management of infections in cancer patients. association between prolonged infusion of BLA and For instance, it may prevent the emergence of resistance lower mortality rates [10, 11]. Similar results have also [23] and may be a better approach for treating hard-to- been observed in a non-randomised prospective study in treat infections [24]. cirrhotic patients with bloodstream infections, in whom This randomised clinical trial aims to test the hypoth- prolonged infusion of BLA was associated with improved esis that the administration of BLA would be clinically survival [12]. Nevertheless, earlier studies addressing this more effective by EI than by II in haematological pa- issue have mainly focussed on the general non-severely tients with FN. Patients with FN may benefit from the immunocompromised population. clinical impact of this strategy, reducing the duration of Laporte-Amargos et al. Trials (2020) 21:412 Page 3 of 9 fever, the global antibiotic consumption and mortality tazobactam or meropenem, in monotherapy or in com- rates. A PK/PD study will also be performed to assess bination with another antibiotic. the correlation with the clinical results. Exclusion criteria Hypothesis The administration of BLA by EI would be clinically 1. Allergy to the study drugs more effective than by II in haematological patients with 2. Patient receiving systemic antibiotic treatment FN. (except for prophylaxis) at the time of FN onset In haematological patients with FN, the administration 3. Absence of fever of BLA by EI would be superior to II in reaching the 4. Patients with epilepsy PK/PD target, clearing up bacteraemia more quickly and 5. Severe renal impairment (defined as creatinine decreasing inflammatory biomarkers. Both strategies clearance rate by MDRD/CKD-EPI < 30 mL/min) would be equally safe. 6. Previously enrolled patients in whom the time between inclusion and the current episode is less Trial design than 5 weeks The BEATLE study is a phase IV, randomised, multicen- 7. Previously enrolled patients without current tre, open-label, superiority clinical trial to determine the resolution of the first episode clinical superiority of EI versus II administration of BLA Intervention used as empirical treatment in patients with FN. The BLA studied will be cefepime, piperacillin-tazobactam Patients admitted in the haematology wards of the and meropenem. Patients will be randomised (1:1) at FN participating centres, receiving chemotherapy or onset to receive BLA by EI or II. The intervention will HSCT will be followed up daily by the attending phy- last 5 days. sicians. The study investigators will explain the study The manuscript has been prepared in accordance with to the patients who meet the inclusion criteria, and the Standard Protocol Items: Recommendations for will ask them to sign the informed consent. At the Interventional Trials (SPIRIT) [25], Additional file 1. FN onset, patients will be randomised to receive EI The study will be conducted in accordance with Good or II (1:1). The BLA will be chosen according to the Clinical Practice (IVH-E6). clinical criteria of the attending physician. Once ran- domised, the first BLA dose will be administered within 30 min in all patients. The second dose will be Methods administered according to the randomisation group. Setting In the control group (II) the BLA will be adminis- The study will be conducted in four university hospitals in tered within 30 min at the usual doses recommended Spain. The reference site will be Institut Català d’Oncologia for neutropaenic patients (cefepime 2 g/8 h, L’Hospitalet (ICO Hospitalet) – Hospital Universitari Bell- piperacillin-tazobactam 4 g/6 h and meropenem 1 g/8 vitge. The other three participating sites will be Hospital h), adjusted according to renal function (Table 1). In Clinic de Barcelona (Barcelona), Hospital Germans Trias i the study group, the BLA will be administered at the Pujol (Barcelona) and Clínica Universidad de Navarra same doses but by EI (the infusion time will be equal (Pamplona). to half the time of the dosing interval). Episodes of FN will be classified as ‘microbiologically documented Study population and screening of cases for recruitment infection’ (with or without bacteraemia), ‘clinically This study will include adult patients with haemato- documented infection’ (without microbiological isola- logical malignancies admitted to the haematology wards tion), ‘fever of unknown origin’ or ‘non-infectious who are undergoing chemotherapy or haematopoietic fever’. stem-cell transplant (HSCT) and experience FN; partici- Patients will remain in the study until completing a pants will receive empirical antibiotic therapy with one total of 5 days of antibiotic treatment, or until one of the of the BLA studied. following events occur: discontinuation of BLA based on clinical criteria, severe adverse event (SAE) or death. If Inclusion criteria any microorganism is isolated, in vitro susceptibility tests Adult patients (age ≥ 18 years) undergoing chemotherapy will be performed and antibiotic treatment will be tar- or HSCT who present with FN (defined as axillary geted accordingly. If the BLA needs to be switched to temperature ≥ 38.0 °C and < 500 neutrophils/mm3 or < another BLA also included in the study due to a lack of 1000 expected to drop within 24–48 h), and who receive in vitro activity, the patient will remain in the study. empirical antibiotic therapy with cefepime, piperacillin- Measurements and visits will start along with the Laporte-Amargos et al. Trials (2020) 21:412 Page 4 of 9 Table 1 β-lactam antibiotic adjustment in renal impairment β-lactam antibiotic Creatinine clearance Dose Frequency (mL/min) Piperacillin-tazobactam 30-40 4 g/0.5 g Every 8 hours Cefepime 30-50 2g Every 12 hours Meropenem 30-50 1g Every 12 hours initiation of the second BLA. If the targeted therapy is 4) Protocol violation an antibiotic not included in the study, the patient will be withdrawn from the study. All patients will receive In accordance with the current revision of the Declar- follow-up for 30 days after initiation of the antibiotic ation of Helsinki and the applicable regulations, a patient treatment. has the right to withdraw from the study at any time The determination of plasma BLA concentrations will and for any reason, without this adversely affecting the not influence the dosage, indication or duration of the medical care provided by the patient’s physician. The BLA administered during the study in any case. withdrawal of full consent from a study means that the The participant timeline during the study is described patient does not wish to continue participating in the in Table 2. study. Any patient withdrawing their consent will be re- moved from the study treatment and/or observations Discontinuation criteria immediately after the date the patient requests it. 1) Withdrawal of consent Outcome measures 2) Non-compliance with the inclusion or exclusion Primary endpoint criteria The primary study endpoint is clinical efficacy, measured 3) Serious adverse reaction by the time to defervescence and no need for antibiotic Table 2 Participant timeline of the study Laporte-Amargos et al. Trials (2020) 21:412 Page 5 of 9 change. To assess this endpoint the rate of patients with participating investigators. Death by any cause will defervescence with no change to the antibiotic treatment be recorded in the E-CRF within the first 5 days of therapy will be calculated. De- 5. Population PK analysis to characterise cefepime, fervescence will be considered to be an axillary piperacillin-tazobactam and meropenem PKs in temperature < 37.5 °C for 24 h, assessed at three consecu- haematological patients with FN: a population PK tive time points, with no new documented fever. For this model will be developed and validated, using purpose, axillary temperature will be assessed three concentration-time data obtained from the blood times daily by the attending nurse. Time (in hours) to samples of patients at the reference site (ICO defervescence will also be analysed. In addition, pre- Hospitalet). For each antibiotic, a simultaneous scribed antibiotics will be reviewed every day and re- analysis of all concentration-time data will be corded in the Electronic Case Report Form (E-CRF) by performed by the population approach using the the participating investigators at each site to estimate non-linear mixed-effect models implemented in the number of patients who will not require an antibiotic NONMEM 7.4 (Icon development). The model change. will allow us to identify the clinical covariables The primary endpoint will be analysed by an investiga- that modify the PK parameters. Monte-Carlo tor who will be blind to the treatment group of each simulations will be performed to determine the patient. suitability of different dosing regimens assessed by the probability of target attainment. The valid- ation cohort will include data obtained from pa- Secondary endpoints tients at the other sites Secondary endpoints will be assessed as follows: 6. Adverse events (AEs): all AEs considered not related to the haematological disease or its 1. PK targets: number of patients in whom the free- treatment and all SAEs will be recorded in the antibiotic concentration remains above the MIC E-CRF by the participating investigators. AEs will of the suspected or isolated microorganism for be identified and classified according to the se- 50%, 75% and 100% of the dosing interval. The verity and potential relationship with the BLA same target will also be assessed, taking into ac- and assessed during the intervention (until visit count the number of times per patient. Actual 5). Afterwards, any AEs related to BLA adminis- MIC values will be used to assess the PK target in tration and any SAEs until visit 6 (30 days from those patients with an isolated pathogen. Other- the beginning of the intervention) will be wise, a surrogate MIC will be inferred from the recorded EUCAST database as the highest MIC in the sus- ceptible range for Pseudomonas aeruginosa [26]. Data collection and management For this purpose, the nurse in charge of each pa- All data will be collected by the clinical investigators at tient will take blood samples to determine plasma each participating site and entered in the E-CRF. The BLA concentrations at 50 and 100% of the dosing collected data will be age, sex, height, weight, type of interval at visits 1, 2 and 3, and at 75% of the dos- underlying disease, other comorbidities, date of hospital ing interval at visit 2. The samples will be frozen admission and discharge, HSCT, type and date of HSCT, and subsequently analysed in the biochemistry la- immunosuppressive therapy, concomitant medication boratory at the reference site (particularly other systemic antibiotics, prophylactic an- 2. Bacteraemia clearance: time in days until timicrobials, fluids, antipyretics and granulocyte-colony bacteraemia clearance. In patients with bacteraemia, stimulating factor), duration of neutropaenia, vital signs, daily blood cultures will be performed by the nurse duration of fever, clinical examination, blood tests and in charge of each patient until bacteraemia microbiological results. clearance 3. Inflammatory biomarkers: time in days to normalise Microbiological studies or decrease > 50% the peak value of C-reactive pro- Blood cultures will be drawn at the onset of fever. In pa- tein (CRP), and the number of patients who achieve tients with bacteraemia, daily blood cultures will be this objective. Blood samples for CRP determination taken until clearance. Other cultures will be collected ac- will be drawn at visits 0, 1, 2, 3 and 5, and will be cording to the usual practice and clinical criteria. analysed at each site Cultures will be processed in the microbiology la- 4. Overall (30-day) case-fatality rate: all patients in- boratories at each participating site according to the cluded in the study will receive follow-up for 30 usual techniques (BACTEC Becton Dickinson, Bio- days after the end of the intervention by the Merieux, etc.). The microorganisms isolated will be Laporte-Amargos et al. Trials (2020) 21:412 Page 6 of 9 identified according to the usual methods (conven- number of participants is assigned to each treatment, tional method, MALDI-TOF, etc.). Antibiotic suscep- patients will be randomised in blocks. The randomisa- tibility will be studied by the disc-diffusion method tion will be performed in computed-generated vari- and/or by microdilution method. In addition, the able blocks ranging from four to six, and the exact MIC of the antibiotics administered will be de- investigator will be blind to the size of each block. termined by a quantitative method, using E-test and/ The code numbers for eligible patients will be or adequate microdilution plates. assigned in ascending sequential order. The allocation list will be stored at the Biostatistics Department of the reference site. At each participating hospital, pa- Sample collection for PK/PD analysis tients who provide written informed consent and Plasma BLA concentrations will be determined seven meet the study criteria will be randomised by investi- times. At visit 1 (which should be performed between gators, who will obtain the assigned treatment and 12 and 36 h from the start of the study antibiotic code number from the computer-assisted web site. treatment), the concentrations will be analysed pre- dose (through concentrations or Cmin) and then mid- way through the dosing interval (C50). Subsequently, Sample size the Cmin, C50 and the concentration at the 75% of the The sample size calculation is based on determining dosing interval (C75) will be analysed at visit 2 (if not whether the administration of BLA by EI (study group) possible, this will be done at visit 3 or 4). Last, Cmin will be clinically more effective than the administration and C50 will be analysed at visit 3 (or if not possible, of BLA by II (control group), for the treatment of FN in at visit 4 or 5, consecutive to the visit-2 samples). haematological patients. Previous data suggest that the At the reference site, intensive sampling will be carried clinical efficacy rate in the control group is expected to out at visit 2. The schedule according to drug, method be 0.45 [20, 21]. A relevant clinical efficacy rate in the of administration and frequency is explained in Tables 3 study group is expected to be 0.70. Each therapy group and 4. will required 75 participants (total of 150) to detect sta- A 5-mL blood sample will be centrifuged at 2000 g for tistically significant differences in clinical efficacy. An 10 min at 4 °C, and the supernatant will be aliquoted in alpha risk of 0.05 and a beta risk of 0.2 in a bilateral con- 1.5-mL microcentrifuge tubes and and stored at − 80 °C trast are assumed, and the sample size allows up to 20% until analysis. Samples will be sent in dry ice to Bellvitge losses to follow-up. University Hospital for bioanalysis. Total plasma BLA concentrations will be analysed Interim analysis using a previously validated method based on ultra- An interim analysis will be carried out once 50% of the high-performance liquid chromatography coupled to cases of each arm are recruited. This analysis will evalu- tandem mass spectrometry [27]. Protein binding of ate if the estimated sample size is adequate. The results 30%, 19% and 2% will be applied for piperacillin, cefe- will be issued by an independent committee of experts pime and meropenem, respectively, to the concentra- not participating in this study. tions determined to estimate the unbound fraction [28, 29]. Statistical analysis For the primary endpoint, an intention-to-treat analysis Randomisation will be carried out. The number of patients in both ther- Enrolled patients who sign the informed consent will apy groups with defervescence and with no change in be randomised to receive BLA by either EI or II (1:1). the antibiotic treatment will be compared by a chi- A centralised electronic computer randomisation square test. schedule will be developed by the Biostatistics Depart- For the analysis of secondary endpoints, the between- ment of the reference site. To ensure that an equal group difference in the percentage of patients reaching the Table 3 Sampling time in the study group (β-lactam antibiotic administration by extended infusion (EI)) according to the frequency of administration. Time expressed in minutes from the start of drug administration Frequency of administration Cmin Cmax (C50) Cmax + 30 Cmax + 60 C75 EI 6h -10 180 210 240 270 8h -10 240 270 300 360 12h -10 360 390 420 540 Laporte-Amargos et al. Trials (2020) 21:412 Page 7 of 9 Table 4 Sampling time in the control group (β-lactam antibiotic administration by intermittent infusion (II)) according to the frequency of administration. Time expressed in minutes from the start of drug administration PK target will be compared. The secondary endpoints are: reporting of any AEs, and maintenance of patient (a) days until bacteraemia clearance, (b) time until nor- confidentiality. malisation or 50% decrease of the initial value of the CRP, The need for a Data Monitoring Committee was and (c) days until death by any cause within 30 days, and waived by the Ethic Committee because of the low im- the incidence of these events will be estimated in each pact on the safety of the study patients. group. Survival analysis methods will be used to compare them using the log-rank test. In addition, the rate of thera- peutic failure will be compared. Discussion A population PK model will be developed and validated Prolonged infusion of BLA is a simple strategy that has for each BLA studied in haematological patients with FN, proven to improve survival among certain populations, using the concentration-time data obtained from the such as critically ill and cirrhotic patients. Broad- blood samples. The model will allow us to identify the spectrum antipseudomonal BLAs are routinely used to clinical covariates that modify the PK parameters. Monte- treat cancer patients with FN. Optimised use of these Carlo simulations will be performed to determine the suit- antibiotics could improve the outcomes of these pa- ability of different dosing regimens assessed by the prob- tients, who would benefit from faster defervescence and ability of target attainment. microbiological eradication, as well as a decrease in The AEs and SAEs of the study will be described, and overall antibiotic exposure. However, there are few data their rates will be compared for each group. The severity, on the usefulness of this strategy in this high-risk relationship to treatment and resolution will be described. population. An analysis by protocol will also be carried out. All Only three published clinical studies have addressed study variables will be presented for each group, using this issue so far, with contradictory results. A prospect- descriptive statistics according to the type of variable. ive, randomised pilot study compared cefepime adminis- The main analysis will be replicated in the following tration by II to 33 neutropaenic patients with subgroups: patients with ‘microbiologically documented administration by EI to 30 patients. No significant differ- infection’ (with and without bacteraemia), ‘clinically doc- ences were found in the primary endpoint of deferves- umented infection’, ‘fever of unknown origin’ or ‘non-in- cence at 72 h or in the secondary endpoints, such as fectious fever’. clinical success, in-patient mortality, length of hospital Whenever possible, the estimators of a 95% confidence stay or need for additional antibiotics. Although not sta- interval will be included. Statistical significance will be tistically significant, defervescence seemed to be faster in set at a probability level < 0.05. The statistical package patients treated with cefepime by EI [19]. The main limi- used to process the data and carry out the analyses will tation of this study was the exclusion of patients pre- be R, version 3.6.1 or higher for Windows. senting with sepsis. The presence of sepsis in neutropaenic patients is common and contributes sig- nificantly to the pathophysiological changes that com- Monitoring promise the PK/PD parameters of the BLA and its In compliance with the standards of Good Clinical Prac- efficacy. Therefore, patients with FN and sepsis are tice, the sponsor will monitor the study tasks, following probably the patients who could most benefit from this the approved monitoring plan. Among others, the moni- administration strategy. toring tasks will include assessment of the correct appli- A Spanish group compared the clinical efficacy of mer- cation of the inclusion and exclusion criteria, assessment openem by EI versus II in a retrospective observational of the quality of the data collected, development and study involving haematological patients with FN. Data Laporte-Amargos et al. Trials (2020) 21:412 Page 8 of 9 on defervescence, resolution or improvement of signs Publication plan and symptoms of infection, absence of breakthrough The results will be reported at conferences and in peer-reviewed publica- tions. The first publication will be based on data from the participating cen- bacteraemia, and absence of additional antibiotics were tres and will be analysed as stipulated in the protocol with statisticians’ analysed [20]. The administration of meropenem by EI supervision. Any formal presentation or publication of data collected from was found to be clinically more effective, and also this study will be considered as a joint publication by the participating inves- tigators and will follow the recommendations of the International Committee achieved defervescence and a significant decrease of of Medical Journal Editors. CRP more rapidly. The limitations of this study were its All the investigatros will be front-line authors of the resulting publications. retrospective nature, the definition of a combined pri- The use of professional writers will not be considered. mary endpoint using a large number of variables and the Authors’ contributions lack of plasma meropenem determinations. All authors were involved in the study concept. JLA, CG, AP, CM, SV and JC Last, a recent randomised clinical trial reported better were involved in the design of the study. JLA, CG, AAP, PPA, CGV, FCT, JLdP, MH, MB, MA and RP will be responsible for the recruitment and follow-up of clinical outcomes in patients receiving BLA by EI com- the patients as well as data collection. CT was responsible for the creation of pared with II, particularly those with pneumonia [21]. the randomisation list. RBR will be responsible for the plasma BLA concentra- Nevertheless, this study had some limitations. First, it tions’ determination. FT will be responsible for the microbiological assess- ment. JLA, CG and JC drafted and revised the manuscript. All authors was a single-centre study, which may limit extrapolation reviewed and approved the final version of the manuscript. of the results. Second, the definition used for ‘pneumo- nia’ was somewhat imprecise, as it included all patients Funding with inflammatory radiological opacities. This is rele- The BEATLE study is a non-commercial, investigator-driven clinical trial funded by the Instituto de Salud Carlos III, Spanish Ministry of Economy vant, because pneumonia is the second most common (PI17/01372), by the Spanish Network for Research in Infectious Diseases infection reported in this trial. Third, piperacillin- (REIPI RD16/0016/0005; RD16/0016/0010) and co-funded by the European tazobactam was used in > 90% of patients. Therefore, the Development Regional Fund ‘A way to achieve Europe’, Operative Programme Intelligent Growth 2014–2020. The Spanish Clinical Research Net- results should be only interpreted with the use of this work (SCReN) provides clinical trial data monitoring and oversees pharma- antibiotic. Last, no PK/PD determinations were per- covigilance (PT17/0017/0010). formed to support the study’s findings. Availability of data and materials If our randomised, multicentre, phase IV, open-label, All data generated during this study will be included in published article. superiority clinical trial validates the hypothesis that the The datasets will be available from the corresponding author on reasonable administration of BLA by EI is clinically more effective request. than by II in haematological patients with FN, then this Ethics approval and consent to participate could change the daily routine management of these The study protocol was approved by the Clinical Research Ethics Committee high-risk patients and, thus, improve their outcomes. at Bellvitge Hospital (Ref. Number AC007/19), the Spanish Regulatory Agency (AEMPS, Agencia Española del Medicamento y Productos Sanitarios) and the Institutional Review Boards at each participating site. A formal contract Trial status agreement was signed with each of the institutions and with the study sponsor. The current protocol is version 3.2, dated 9 January The study will be conducted in accordance with the protocol and with the 2020. Patient recruitment started on 12 November 2019 principles established in the latest version of the Declaration of Helsinki, with and will be completed by November 2021. the standards of Good Clinical Practice as described in CPMP/ICH/135/95 and with the Royal Decree of Clinical Trials 1090/2015, which regulates clinical trials with medicines in Spain and includes the full text of European Supplementary information Directive 2001/20/EC, relating to the provisions of member states on the Supplementary information accompanies this paper at https://doi.org/10. implementation of Good Clinical Practice in the conduct of clinical trials on 1186/s13063-020-04323-0. medicinal products for human use. The researchers agreed, when signing the protocol, to adhere to the instructions and procedures described therein and thus to follow the Additional file 1. SPIRIT 2013 Checklist: Recommended items to address principles of Good Clinical Practice that they imply. in a clinical trial protocol and related documents. The data will be treated anonymously at all times, identifying each patient with a protocol number. The privacy and confidentiality of all data will be protected. All patients’ personal data will be processed, disclosed and Abbreviations transferred in accordance with Organic Law 3/2018 of 5 December 2018 and AE: Adverse event; BLA: β-lactam antibiotics; CI: Continuous infusion; CRP: C- Regulation (EU) 2016/679 of the European Parliament and of the Council of reactive protein; E-CRF: Electronic Case Report Form; EI: Extended infusion; 27 April 2016. EUCAST: European Society of Clinical Microbiology and Infectious Diseases; All participants will sign the informed consent. Before signing, all patients FN: Febrile neutropaenia; fT > MIC: Time of free drug concentration above will be informed of the study objectives, possible AEs, procedures that they MIC; HSCT: Haematopoietic stem-cell transplant; ICO Hospitalet: Institut will undergo and the process used to assign the intervention. Furthermore, Català d’Oncologia L’Hospitalet; IDIBELL: Institute of Biomedical Research of they will be informed that their data will be treated with strict Bellvitge; II: Intermittent infusion; MIC: Minimum inhibitory concentration; confidentiality. On the consent form, participants will be asked by the PD: Pharmacodynamic; PK: Pharmacokinetic; SAE: Serious adverse event research team if they agree to collect biological specimens. Biological specimens will be blood samples to determine plasma BLA concentrations. Acknowledgements All biological specimens will be destroyed at the end of the study. The authors wish to acknowledge the Research Support Unit of Hospital Universitari Bellvitge and the UICEC (Unitat d’Investigació Clínica en Assaigs Consent for publication Clínics de l’IDIBELL), for their help in the study. Not applicable Laporte-Amargos et al. Trials (2020) 21:412 Page 9 of 9 Competing interests 11. Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged CG has received honoraria for lectures from Pfizer, Gilead Sciences and MSD. versus short-term intravenous infusion of antipseudomonal β-lactams for JC has received honoraria for lectures from Gilead Sciences and MSD. CGV patients with sepsis: a systematic review and meta-analysis of randomised has received honoraria for lectures form Gilead Sciences, Pfizer, Janssen, trials. Lancet Infect Dis. 2018;18(1):13–4. Novartis and Lilly and has received grants and personal fees from Gilead 12. Bartoletti M, et al. Extended infusion of β-lactams for bloodstream infection Sciences and MSD. JLdP has received honoraria for lectures form Pfizer, in patients with liver cirrhosis: an observational multicenter study. Clin Infect Novartis, MSD and Angelini and has received grants from Novartis. All other Dis. 2019;69(1):1731–9. authors report no potential conflicts of interest. 13. Abbott IJ, Roberts JA. Infusional beta-lactam antibiotics in febrile neutropenia: has the time come? Curr Opin Infect Dis. 2012;25(6):619–25. Author details 14. Gonçalves-Pereira J, Póvoa P. Antibiotics in critically ill patients: a systematic 1 Infectious Diseases Department Hospital Universitari Bellvitge, Institut review of the pharmacokinetics of β-lactams. Crit Care. 2011;15(5):R206. d’Investigació Biomedica de Bellvitge (IDIBELL), Feixa Llarga SN, 08907, 15. Pea F, et al. 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