Randomized Open Label Clinical Trial Directed to Optimize the Duration of Empirical Antimicrobial Therapy in Haematologic Patients With Febrile Neutropenia
Phase: PHASE4
Conditions: Febrile Neutropenia
Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

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CLINICAL TRIAL PROTOCOL 
 
“OPEN LABEL AND RANDOMISED CLINICAL TRIAL FOR THE OPTIMIZATION OF 
THE DURATION OF EMPIRICAL ANTIMICROBIAL THERAPY IN CNACER 
PATIENTS WITH FEBRILE NEUTROPENIA”. 
 
SPONSOR: Fundación Pública Andaluza para la Gestión de la Investigación en Salud 
se Sevilla (FISEVI) 
 
PROTOCOL CODE: HOWLONG  
EudraCT: 2011-005152-34 
Version: 5.0 February 2, 2015. 

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INDEX 
1. SUMMARY .................................................................................................................5 
1.1 Type of request ........................................................................................................5 
1.2 Sponsor ………………….………...............................................................................5 
1.3 Official title……………………....................................................................................5 
1.4 Protocol code .…………….........................................................................................5 
1.5 Study director.……….……........................................................................................5 
1.6 Paticipating centres...................................................................................................5 
1.7 Ethics committee..……………………………..............................................................5 
1.8 Responsible for monitoring…....................................................................................5 
1.9 Experimental and Control treatments…....................................................................5 
1.10 Clinical trial phase….…………................................................................................5 
1.11 Objectives……….....................................................................................................5 
1.12 Design………….......................................................................................................5 
1.13 Condition on study…………….................................................................................5 
1.14 Outcome measures…………...................................................................................5 
1.15 Study population and total number of patients……….............................................6 
1.16 Treatment duration……………….............................................................................7 
1.17 Schedule and expected study completion date: .....................................................7 
1.18 Investigators…………..............................................................................................7 
2. GENERAL INFORMATION ........................................................................................8 
2.1 Trial identification……………….................................................................................8 
2.2 Type of clinical trial…………......................................................................................8 
2.3 Description of study products………………...............................................................8 
2.4 Promotor data……………………...............................................................................8 
2.5 Principal investigators ………....................................................................................8 
2.6 Person authorized by the promoter ..........................................................................8 
2.7 Responsible for monitoring……………......................................................................8 
2.8 Investigators data……………………………...............................................................8 
2.9 Setting…………………………………………..............................................................8 
3 RATIONALE ……….....................................................................................................9 
4 HYPOTHESIS AND OBJECTIVES…………………...…………..................................11 
5 DESIGN……………………………..............................................................................13 
5.1 Variables description…………….............................................................................13 
5.2 Design and control method……..............................................................................13 
5.3 Patients assignation…………..................................................................................13 
5.4 Trial treatments descripticon…………………..........................................................14 

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5.5 Randomisation codes………..................................................................................15 
5.6 Study organization……………………………………………………………………….15 
5.7 Identification of data to be registered......................................................................15 
5.8 Trial completion.......................................................................................................16 
6 SELECTION AND WITHDRAWAL OF PATIENTS….................................................17 
6.1 Inclusion Criteria………...........................................................................................17 
6.2 Exclusion criteria………….......................................................................................17 
6.3 Criteria for withdrawal of patients……………………………….................................17 
7 TREATMENT OF PATIENTS………….......................................................................19 
7.1 Scheduled of visits and assessments…..................................................................20 
7.2 Assessements for visits...........................................................................................21 
7.3 Follow-up.................................................................................................................21 
7.4 Storage, preservation and dispensing of medication…………….............................22 
8 EFFICACY ASSESSMENT….....................................................................................23 
9 SAFETY ASSESSMENT/ADVERSE EVENTS……………….....................................25 
9.1 Methods for the evaluation of safety……................................................................25 
9.2 Definitions………….................................................................................................25 
9.3 Management of adverse events……..………….......................................................26 
9.4 Discontinuation of study drugs due to adverse events…..…….………………….....29 
10 STATISTICAL ANALYSES.......................................................................................31 
10.1 Statistical methods………......................................................................................31 
10.2 Sample size estimaton……………………..............................................................31 
11 ETHICAL CONSIDERATIONS.................................................................................33 
11.1 Informed consent……………….............................................................................33 
11.2 Data protection………….. .....................................................................................34 
12.3 Acquisition and dispending of study medication………….....................................34 
11.4 Monitoring and audit……………............................................................................34 
11.5 Non-compliance…….............................................................................................35 
11.6 Premature discontinuation…………………………….............................................35 
12 FUNDING SOURCE AND INSURANCE..................................................................36 
12.1 Funding……………................................................................................................36 
12.2 Insurance...............................................................................................................36 
13 PUBLISHING POLICY…………...............................................................................37 
13.1 Publishing conditions……………...........................................................................37 
13.2 Amendments to the protocol…………………………..............................................37 
13.3 Documentation………. ..........................................................................................37 
14 REFERENCES……..................................................................................................38 

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ANNEX 1. PATIENT INFORMATION SHEET...............................................................42 
ANEXO 2. PATIENT WRITTEN INFORMED CONSENT FORM……...……………......47 
ANEXO 3. LEGAL SURROGATES WRITTEN INFORMED CONSENT FORM  
.......................................................................................................................................48 
ANNEX 4. INVESTIGATORS AND PARTICIPATING CENTRES………………………49 

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1. SUMMARY  
1.1. Type of request  
Non-comercial, investigator-driven phase IV clinical trial. 
1.2. Sponsor 
Fundación Pública Andaluza para la Gestión de la Investigación en Salud de 
Sevilla (FISEVI). NIF: G – 41918830. 
University Hospital Virgen del Rocío. Ave. Manuel Siurot, s/n. 41013- Seville. 
1.3. Official title 
Randomized Open Label Clinical Trial Directed to Optimize the Duration of 
Empirical Antimicrobial Therapy in Hematologic Patients With Febrile Neutropenia. 
1.4. Protocol code 
HOWLONG, EudraCT: 2011-005152-34. 
1.5. Study director 
José Miguel Cisneros, PhD. University Hospital Virgen del Rocío, Seville, Spain.  
1.6. Paticipating centres 
Are detailed in Annex 4. 
1.7. Ethics committee 
Clinical Research Andalusian Central Ethics Review Committee. 
1.8. Responsible for monitoring 
Monitor: Fernando Pérez Martínez. 
Coordination: Dr. Clara M. Rosso Fernández. Clinical Trial Unit (CTU). University 
Hospital Virgen del Rocío. General Hospital. Ground floor. Ave. Manuel Siurot, s/n. 
41013- Seville. 
1.9. Experimental and Control treatments 
Experimental Arm: an individualized clinical protocol as the criterion to suspend the 
empirical antimicrobial therapy (EAT). 
 
Assigned intervention: EAT discontinuation will occur when the patient is: 
afebrile, with resolution of signs, symptoms and test abnormalities and 
normalization of vital signs for ≥ 72 h. 
Active Comparator: Control Arm. The recovery of neutropenia (standard) as the 
criterion to suspend the EAT.  
 
Assigned intervention: Standard EAT discontinuation. The EAT discontinuation 
will occur when the neutrophil count is above 0·5x109/L and the patient is 
afebrile, with resolution of signs, symptoms and test abnormalities and 
normalization of vital signs for >72h. 
1.10. 
Clinical trial phase 
Phase IV. 

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1.11. 
Objectives 
 
Primary objective: to establish wether an individualized clinical protocol (ICP) is 
superior to  the standard approach of neutropenia recovery (neutrophil count> 
0·5 x109/L) for determining EAT discontinuation in a haematological patient with 
febrile neutropenia (FN).  
 
Secondary objectives: 
o Demonstrating that ICP is as safe as the standard approach through the 
comparison of crude mortality (all-cause mortality) and the number of 
days of fever (fever duration) within 28 days from the start of EAT.  
o Analyse the relationship between procalcitonin (PCT) levels and the 
appearance of relapsing fever and its potential usefulness as a guide in 
determining EAT length in haematological patients with FN. 
1.12. 
Design 
Prospective, randomised and open clinical trial. 
1.13. 
Condition on study 
Febrile neutropenia without etiologic (microbiological) diagnosis, including clinically 
documented infection or unexplained fever. 
 
Definitions: 
Fever: a single temperature determination > 38.5 ° C, or two or more 
determinations > 38 ° C in the last 12 hours in the absence of another non-
infectious 
cause 
(transfusion 
fever 
among 
the 
most 
common, 
or 
pharmacological, such as cytarabine fever). 
Neutropenia: neutrophil count < 0·5x10E9/L or < 1.0x10E9/L if a rapid reduction 
is expected in 24-48 hours.  
High-risk neutropenia: expected duration of neutropenia < 0·5x10E9/L during 
more than 7 days. 
1.14. 
Outcome measures 
 
Primary Outcome Measures: Number of days on which patient is free of 
antimicrobial treatment [ Time Frame: 28 days following the initiation of empiric 
antibiotic treatment.  
 
Secondary Outcome Measures: 
• 
Crude mortality [ Time Frame: 28 days following the initiation of empiric 
antibiotic treatment. ] 
• 
Number of days of fever [ Time Frame: 28 days following the initiation of 
empiric antibiotic treatment ] 
• 
The PCT cut-off for predicting recurrent fever. 
1.15. 
Study population and total number of patients 

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• 
Adult patients (equal or older than 18 years) of both sexes admitted in the 
Department of Clinical Hematology who develop a FN. Including fever with 
unknown source and fever secondary to infection focus of clinical diagnosis 
without laboratory confirmation. 
• 
The sample size estimated for this study is n=156 patients. 
1.16. 
Treatment duration 
The duration of treatment is one of the variables of this study and will depend on 
the arm to which the patient has been assigned. However the follow-up of patients 
will be performed for 28 days from the beginning of treatment. 
1.17. 
Schedule and expected study completion date 
The total duration of the trial will be more than four years. They include three 
months for project approvals and coordination, an inclusion period of 48 months, 
three more months for laboratory determinations, three more for the final analysis of 
the results and three last months for the publication of the results. 
Initial request to the AEMPS: November 2011 
Approval date: March 2012 
Study start date: April 30, 2012 
Study completion date: May 1, 2016 
1.18. 
Investigators 
Are detailed in Annex 4.  
 
 

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2. GENERAL INFORMATION 
2.1. Trial identification 
Protocol code: HOWLONG. 
Title: Randomized Open Label Clinical Trial Directed to Optimize the Duration of 
Empirical Antimicrobial Therapy in Hematologic Patients With Febrile Neutropenia. 
2.2. Type of clinical trial 
Non-comercial, investigator-driven phase IV clinical trial. 
2.3. Description of study products 
The investigators of the study will prescribe antimicrobial therapy for FN following 
the local guidelines of each participating centre. The following antibacterials or a 
combination of them, among others, will be used: acyclovir, liposomal amphotericin, 
amikacyn, aztreonam, cefepime, ceftazidime, ganciclovir, imipenem, itraconazole, 
levofloxacin or ciprofloxacin, meropenem, piperacilin-tazobactam, posaconazole, 
valacyclovir, valgancyclovir, vancomycin, fluconazole and voriconazole.   
The dose, route and and schedule of administration will be done following the 
technical file of each product.  
The duration of therapy will depend on the assignation arm. 
2.4. Promotor data 
Fundación Pública Andaluza para la Gestión de la Investigación en Salud de 
Sevilla (FISEVI). NIF: G – 41918830. 
University Hospital Virgen del Rocío. Ave. Manuel Siurot, s/n. 41013- Seville. 
2.5. Principal investigators 
Are detailed in Annex 4 . 
2.6. Person authorized by the promoter  
Dr. Clara M. Rosso Fernández.  
2.7. Responsible for monitoring 
Monitor: Fernando Pérez Martínez. 
Coordination: Dr. Clara M. Rosso Fernández. Clinical Trial Unit (CTU). University 
Hospital Virgen del Rocío. General Hospital. Ground floor. Ave. Manuel Siurot, s/n. 
41013- Seville. 
Telephone 0034 955013292 | Fax: 0034 955013292  
2.8. Investigators data 
Are detailed in Annex 4.  
2.9. Setting 
Are detailed in Annex 4.  
 
 

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3. RATIONALE 
The optimal length of empirical antimicrobial therapy (EAT) in haematological patients 
with febrile neutropenia (FN) is still unknown. The Infectious Diseases Society of 
America (IDSA) recommends continuing EAT until neutropenia is recovered up to 
absolute neutrophil count> 0·5 x109/L at least, with questionable scientific evidence [1]. 
This recommendation may prolong EAT in daily clinical practice. For instance, a patient 
with fever with no identified source and no microbiological diagnosis will probably 
receive between two to four weeks of systemic antimicrobial treatment at the onset of 
neutropenia (median length of 2-3 weeks in high risk patients) even in those patients 
that remain afebriles and asymptomatics since the second day of treatment. In two 
large clinical trials involving nearly 2000 haematological patients with NF, the mean 
length of EAT was 15.8 and 18 days, respectively [2,3]. That length of treatment is 
superior to the standard approach used for infections considered more serious such as 
bacteremia and pneumonia and which are treated for a median duration of 7-14 days.  
This probable antimicrobial overtreatment sets a strong contrast with the exhortation 
from the IDSA to the scientific community regarding the urgent need to optimize 
treatments given the growing increase in resistance and the progressive reduction of 
active antimicrobials [4]. However, available information on the discontinuation of EAT 
before recovery from neutropenia is scarce and focuses mainly on pediatric oncology 
patients with short duration neutropenia. Moreover, the criteria definition for treatment 
discontinuation is very heterogeneous. Data from a retrospective study including 84 
episodes of FN (with a mean of 10 days of neutropenia and 3 days of fever) in pediatric 
patients. EAT was discontinued before neutropenia recovery in those patients receiving 
at least 72 hours of intravenous (i.v.) treatment and were afebrile for more than 24 
hours. The discontinuation was effective and safe, only two patients experienced 
recurrence of the fever, there were no re-infections and no deaths or major 
complications [5]. 
The recurrence of the fever is one of the risks associated to EAT discontinuation before 
the recovery of neutropenia. In a pediatric series conducted at the end of the 80s and 
which included 83 episodes of FN, fever episodes recurred in a total of 21% of patients 
during the two weeks following discontinuation: all of them were eventually cured. The 
criterion for discontinuation were: 1) no evidence of infection, 2) baseline cultures 
negative after 48h and 3) apyrexia for 24h [6]. In a more recent pediatric series of 112 
episodes of FN, the frequency of fever recurrence after i.v. therapy discontinuation was 
2%. In this study, criterion for treatment discontinuation was at the discretion of the 
clinician but, in all cases, before recovery from neutropenia [7].  

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Sequential treatment using oral route antimicrobials after discontinuation of i.v. therapy 
has been recommended with a C-III level of evidence [1]. A randomized study carried 
out in low risk pediatric patients demonstrated that it did not reduce the frequency of 
recurrent fever. This study compared the sequential treatment with cloxacilin plus 
cefixime vs. placebo in 73 children. The criteria for the suspension of i.v. EAT before 
recovery of neutropenia was apyrexia for more than 24 hours, negative blood culture 
results at 48 hours, absence of clinical sepsis, cancer in bone marrow remission and 
absence of comorbid conditions. A total of 9% of patients were readmitted due to fever 
and neutropenia, 14% of patients in the experimental group vs. 6% in the placebo 
group (p = ns). All of them were cured after restarting the i.v. treatment [8]. In adults, 
experience in discontinuing EAT before neutropenia recovery is reduced to a pilot 
study of 10 patients with haematological malignancies and FN who, following five days 
of apyrexia, were switched off i.v. EAT to oral ciprofloxacin. Fever recurred in three of 
them [9]. 
Procalcitonin (PCT) is an indicator for bacterial infection superior than C-reactive 
protein [10,11]. Levels of PCT used to guide antibacterial treatment reduces the length 
of treatment duration in patients with respiratory infections and even in patients with 
serious infections admitted to intensive care units [12–14]. In cancer patients, PCT is 
useful in the diagnosis of bacteraemia [15]. It has also been studied in FN. PCT values 
≥ 0.5 ng/mL at the onset of fever have a negative predictive value of 70% for the 
diagnosis of bacterial infection [16] and a sensitivity and specificity of 85 and 50%, 
respectively, in order to distinguish between severe disseminated infection or not [17]. 
In haematopoietic stem cell transplant recipients with FN and with PCT values ≥ 3 
ng/ml, it has been suggested as sign of invasive aspergillosis [18]. 
PCT values can be elevated by non-infectious causes in cancer patients, treatments 
with anti-T cell, alemtuzumab, interleukin1 antibodies and polymorphonuclear (PMN) 
transfusions in graft versus host disease (GVHD) [19,20]. Usefulness of PCT in the 
discontinuation of EAT in FN has not been studied. 
The purpose of this study is to determine the effectiveness and safety of an 
individualized clinical protocol (ICP) to optimize the length of EAT in haematological 
patients with FN. Additionally, the usefulness of PCT determination as a guide for the 
discontinuation of EAT in this syndrome is evaluated. 
 
 

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4. STUDY HYPOTHESIS AND OBJECTIVES  
4.1. Hypothesis 
The hypothesis of the study is that in haematological patients with FN: a) the 
recovery of neutropenia as a criterion to determine EAT discontinuation 
unnecessarily prolongs the length of treatment; b) EAT discontinuation guided by 
an ICP would optimize EAT, reducing its length without negative consequences for 
the patient; c) PCT might be a useful indicator for the discontinuation of EAT.  
4.2. Objectives 
The primary objective of the study is to establish whether an ICP is better than the 
standard approach of neutropenia recovery (neutrophil count> 0·5 x109/L) for 
determining EAT discontinuation in a haematological patient with FN.  
Secondary objectives include demonstrating that ICP is as safe as the standard 
approach through the comparison of crude mortality (all-cause mortality) and the 
number of days of fever (fever duration) within 28 days from the start of EAT. The 
relationship between PCT levels and the appearance of relapsing fever and its 
potential usefulness as a guide in determining EAT length in haematological 
patients with FN is also evaluated. 
The outcome definitions and time frames on which they are measured are the 
following: 
 
 

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Apyrexia 
Body temperature measurements ˂ 
37.5º C 
≥ 72 hours 
Clinical recovery 
Normal vital signs and resolution of 
signs and symptoms suggestive of 
infection 
≥ 72 hours 
Recovery of neutropenia 
Neutrophil count> 0·5 x109/L 
Up to the end of the 
follow-up (28 days) 
Recurrent fever episodes 
New episode of fever after the 
patient is afebrile > 48h and before 
neutrophil count> 0·5 x109/L 
During the follow-up 
Number of days free of ATb 
(i.v.) 
Result of follow-up days less days 
administered i.v. AT 
On day 28 of follow-up 
Number of days free of ATb   
(i.v. + p.o.) 
Result of follow-up days less days 
administered i.v. + p.o. AT 
On day 28 of follow-up 
Number of days free of fever 
Result of follow-up days less days 
with fever during the entire follow-up 
On day 28 of follow-up 
Cut-off procalcitonin value  
Cut-off value for predicting recurrent 
fever 
At the end of the study 
Crude mortality 
Death from any cause 
On day 28 of follow-up 
 
 
 

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5. CLINICAL TRIAL DESIGN 
5.1. Outcome measures 
The primary efficacy endpoint is the number of free-days from antibacterial therapy 
(EAT). This variable is calculated by the difference between the follow-up days (28 
days) and the days of antibacterial treatment administered.  
The secondary safety endpoints are: 1) the crude mortality at 28 days from 
beginning EAT; 2) the number of free-days from fever during follow-up; and 3) the 
PCT cut-off for predicting recurrent fever. Safety of the interventions will be 
evaluated by the assessment of any AE occurring from the informed consent form 
signature up to 28 days after the last dose of the study medication. 
5.2. Design and control method 
The HOWLONG study (No EudraCT: 2011-005152-34) is a randomised (1:1), 
controlled, multicentre and open-labelled phase IV clinical trial designed to prove 
the superiority of an ICP vs. the standard approach of neutropenia recovery to 
decide the discontinuation of EAT. This is a non-commercial investigator-driven 
clinical study funded through a public competitive call by Instituto de Salud Carlos 
III, Spanish Ministry of Economy (PI11/02674). The setting for the study will be 6 
public and academic hospitals with research group members of the Spanish 
Network for Research in Infectious Diseases (REIPI) and/or the Spanish Study 
and/or the Spanish Society of Infectious Diseases and Clinical Microbiology 
(SEIMC). The study is coordinated by investigators from University Hospital Virgen 
del Rocío in Seville, Spain. Sponsorship is carried out by Fundación Pública 
Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI) whose 
scientific responsibilities are delegated to the CTU of the University Hospital Virgen 
del Rocío, Seville, Spain. Other participating centres are: University Hospital of 
Bellvitge, University Hospital Clinic and University Hospital Vall d'Hebron 
(Barcelona, Spain), Hospital de Jerez de la Frontera (Cádiz, Spain) and University 
Hospital de Salamanca (Salamanca, Spain). The number of participating sites is 6. 
5.3. Patients assignments 
Adult (18 years of age or older) haematological patients with FN admitted to one of 
the participating centres are candidates to be included in the study. Eligible patients 
will be selected from the daily review of results of the complete blood count and 
temperature curves.  
At 72 h (±24) from starting EAT, patients are classified according the clinical and 
microbiological data available in one of the following diagnoses: a) patient with 
febrile syndrome with no clinically or microbiologically documented infection; b) 
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diagnosis and c) patients with FN and etiological diagnosis. Those patients with FN 
but without etiological diagnoses (infection or others such as GVHD, etc.) that meet 
all inclusion criteria and no exclusion criteria are eligible for the study. 
A 1:1 randomisation procedure assigns the treatment groups: either ICP or 
standard therapy approach. This randomization is carried out via a list of randomly 
generated numbers on a computer system using the statistic program Epidat 3.1. 
The list is held by the CTU whose staff is responsible for communicating the 
assignment of the study group following verification of the inclusion and exclusion 
criteria for the study. In order to minimize selection bias, the investigator does not 
know the study group assigned until the study inform consent is signed by the 
patient or relative and formal communication to the CTU is complete, even with the 
open-labelled design.  
5.4. Trial treatments description 
Haematological patients with neutropenia receive EAT at the onset of fever, 
following the local guidelines of each participating centre. The following 
antibacterials or a combination of them, among others, will be used: acyclovir, 
liposomal amphotericin, amikacyn, aztreonam, cefepime, ceftazidime, ganciclovir, 
imipenem, itraconazole, levofloxacin or ciprofloxacin, meropenem, piperacilin-
tazobactam, posaconazole, valacyclovir, valgancyclovir, vancomycin, fluconazole 
and voriconazole.   
Each patient included will be randomized to one of the following treatment groups:  
1- Experimental group (EG): the discontinuation of EAT is carried out when the ICP 
criteria are met and regardless of the neutrophil count > 0·5 x109/L. ICP criteria are: 
a) apyrexia; b) resolution of signs, symptoms and alterations in complementary 
tests of the source of infection and c) normal vital signs (blood pressure, heart rate, 
respiratory rate, O2 saturation and daily diuresis), for ≥ 72 h. 
2- Control group (CG): the discontinuation of EAT is carried out when the patient 
meets ICP criteria and neutrophil count> 0·5 x109/L. 
The administration of granulocyte colony stimulating factor (G-CSF) will follow the 
recoomendations of the current protocols of PETHEMA and GELTAMO1 from the 
Spanish Society of Hematology and Hemotherapy, based on the current clinical 
guidelines of the European Organisation for Research and Treatment of Cancer 
(EORTC)1 y la National Comprehensive Cancer Network (NCCN)2. For this reason 
the indication and dosage will be the same in both groups.  
                                                 
1 Aapro MS, Bohlius J, Cameron DA, et al. European Organisation for Research and Treatment of Cancer. Eur J Cancer. 2011 Jan;47(1):8-32. 2010 update of EORTC guidelines for the use of 
granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. 
2 Crawford J, Althaus B, Armitage J, et al. National Comprehensive Cancer Network (NCCN). Myeloid growth factors. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2007 
Feb;5(2):188-202. 
 
 

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Taking into account that all the study drugs are officially approved for EAT in FN in 
Spain, the sponsor will not provide the study drugs; permission for the use of the 
drugs through the normal provision of each Pharmacy Hospital has been obtained 
for every site participating in the study and approved by the Spanish Regulatory 
Agency (AEMPS: Agencia Española del Medicamento y Productos Sanitarios). In 
order to ensure the tracking of the products administered, the lot number and 
expiration dates will be recorded. This is also required by the AEMPS. 
There are no absolute contraindications for the use of any other drugs during the 
study. As such, concomitant medication is permitted in accordance with investigator 
decision. Contraindications, warnings and precautions for their use and possible 
interactions with the study drugs are to be taken into account. Only antimicrobial 
drugs used during the study period will be collected in the study case report form 
(CRF). 
5.5. Randomisation code 
The patients will be identified with a three digit code from 001 to 156. 
5.6. Study organization  
The study coordinating team is formed by the scientific group located in the 
coordinating site (University Hospital Virgen del Rocío) and the CTU whose 
personnel are responsible for entire coordination of the study in the sites involved. 
The CTU personnel will submit administrative authorizations for the study, handle 
regulatory affairs, provide ethics committee contact and response, take up safety 
monitoring and pharmacovigilance responsibilities of the sponsor and provide 
logistical coordination and a contact point for all six participating hospitals. 
Data and safety monitoring 
The quality of all data collected will be carefully supervised by the CTU. Individuals 
responsible for the revision and update of data collection will remain in close 
contact with investigators in order to carry out a close follow-up of study procedures 
via email or phone contact. Beside this, visits will be organized in order to perform 
data source verification according to the monitoring plan. All the antibacterial study 
drugs, as with the rest of concomitant antimicrobial drugs, will be registered in the 
CRF. An independent, objective review of all accumulated data from the clinical trial 
is foreseen.  
5.7. Identification of data to be registered 
The documents that make up the study master file will include what is established 
in the Standards of Good Clinical Practice (CPMP/ICH/135/95). The researcher will 
ensure that all persons involved in the study will respect the confidentiality of any 

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information about the subjects of the trial, as well as the protection of their personal 
data (according to Law 15/1999, of December 13, Protection of Personal Data). 
5.8. Trial completion 
The end of the trial will be considered the day of the final visit of the last patient 
included in the study. 
 
 

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6. SELECTION AND WITHDRAWAL OF PATIENTS 
6.1. Inclusion criteria 
1. Adult (≥18 years) patients of both sex. 
2. Admitted to the Haematology ward of any of the participating centres. 
3. With any of the following diagnoses: acute leukaemia; lymphoproliferative 
disease; multiple myeloma; myelodysplastic syndrome; bone marrow 
aplasia 
and 
autologous 
or 
allogeneic 
haematopoietic 
stem 
cell 
transplantation. 
4. With high risk FN (expected duration of neutropenia ≤ 0·5x10E9/L more 
than 7 days) without etiologic (microbiological) diagnosis, including clinically 
documented infection or unexplained fever. 
5. Signed informed consent form 
6. Patients who have not previously participated in this trial or, if so, whose 
final visit took place at least one month before the new inclusion. 
6.2. Exclusion criteria 
1. Fever with etiological diagnosis including fever due to an infection with 
microbiological diagnosis and fever with non-infectious aetiologies such as 
transfusion or drug related, due to graft versus host disease (GVHD) or due to 
the underlying disease. 
2. History of epilepsy. 
3. History of tendon disorders related to fluoroquinolone administration. 
4. Pregnancy or breastfeeding. 
5. Concomitant HIV infection. 
6. Severe renal impairment (defined as creatinine clearance below 30 ml/ min). 
7. Patients receiving CYP3A4 substrates medication as ergot alkaloids 
(ergotamine and dihydroergotamine), terfenadine, astemizole, cisapride, 
pimozide or quinidine, rifampin, carbamazepine, phenobarbital, high doses of 
ritonavir (400 mg and above, twice daily) St. John's Wort herb. 
6.3. Criteria for withdrawal of patients 
According to the Declaration of Helsinki, patients have the right to withdraw of the 
study at any time and for any reason, and may express it personally or through its 
representative. 
 
Voluntary abandonment of the patient: 
o By efficiency criteria: When the treatment is ineffective for the patient 
and can aggravate their illness. 
o By security criteria: When, for whatever reason, the treatment 
ceases to be safe for the patient. For example, the patient has an 

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allergic reaction to treatment. Or for any other reason that could 
jeopardize the life of the patient or have serious consequences for 
the patient. 
 
For non-compliance or violation of the rules contained in the protocol: When 
the patient fails to comply with any of the regulations or test procedures 
shall be immediately expelled from the test without possibility of accessing it 
on any other occasion. 
 
Follow-up of patients withdrawn from the study: 
If a patient is removed prematurely from the trial, the main reason for the 
suspension will be provided and, as indicated by the PCB rules, the usual 
procedures for the treatment of the pathology will continue. 
 
Premature termination of the study: 
Premature termination of the clinical trial may occur by a decision of the 
regulatory authorities, for a change in the opinion of the Ethics Committee, 
for safety and/or treatment problems or indications of inefficiency. 
The sponsor reserves the right to interrupt the study in any time for 
reasonable medical and/or administrative reasons.  
 
 

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7. TREATMENT OF PATIENTS 
7.1. Scheduled of visits and assessments 

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Visit 
Selection 
0 
1 
2 
3 
4* 
5† 
Final‡ 
Time 
Day 
of 
febrile 
neutropenia onset 
72 h (+/-24) 
of fever onset 
72h. 
Apyrexia 
Clinical 
recovery 
Neutrophil count 
> 0·5 x109/L 
Recurrent 
fever  
Fever after  
neutrophil 
count > 0·5 
x109/L 
+ 28 days 
Procedures and tests 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Informed consent form 
 
X 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
Clinical record 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Antimicrobial therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology 
X 
X 
X 
X 
X 
X 
 
X 
Biochemistry 
X 
X 
X 
X 
X 
X 
 
X 
Procalcitonin 
 
X 
X 
X 
X 
X 
 
X 
Vital signs 
 
X 
X 
X 
X 
X 
 
X 
Physical examination 
 
X 
X 
X 
X 
X 
 
X 
Etiological 
or 
clinical 
diagnosis 
 
 
 
 
 
 
X 
 
Concomitant treatment 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 

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7.2. Assessments for visits 
Follow-up was organized in four planned visits: visit 1 (72 hours after apyrexia), visit 
2 (72 h after clinical recovery), visit 3 (neutrophil count >0·5x10E9/L) and final visit 
(28±2 days from the beginning of EAT). Additionally, data from unplanned visits 
were collected with special consideration given to any episode of recurrent fever 
(visit 4) and any episode of fever or infection following recovery from neutropenia 
until the end of the follow-up. Additionally, data from unplanned visits will be 
collected with special consideration given to any episode of recurrent fever (V4) 
and any episode of fever following recovery from neutropenia. 
The visit schedule is planned in order to obtain: 
-Inclusion/exclusion criteria 
-Consent informed signed 
-Randomisation 
-Demographic data (age, sex, birthdate, inclusion date) 
-Medical history (previous hematopoietic stem cell transplantation, haematological 
disease, current treatment for main disease) 
-Study condition (FN): date of onset of fever, date of onset of neutropenia, probable 
diagnosis (etiological or clinical diagnosis), clinical presentation including severity 
signs.  
-Clinical status including vital signs and physical examination. 
-Biological samples: All the participating sites are asked to process biological 
samples locally (blood chemistry, blood count and microbiological cultures) at the 
times described in the visit schedule using standard techniques. Microbiology 
laboratory departments of each of the participating centres are asked to use the 
SEIMC Quality Control System [21]. Susceptibility tests are to be interpreted 
according to European Committee on antimicrobial Susceptibility Testing 
(EUCAST) version 5.0 (2015) [22] or Clinical Laboratory Standard Institute (CLSI) 
2015 recommendations [23].  
-Antimicrobial therapy. 
-Efficacy and safety variables (including days of EAT administered, days with fever, 
complete blood count, monitoring of renal and liver function) and adverse events. 
Data for all the outcome variables will be gathered in the final evaluation (28 days 
from follow-up). 
7.3. Follow-up 
Patient´s follow-up will be performed daily by research team members and will be 
continued until 28 days from the start of antimicrobial therapy. 

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7.4. Storage, Preservation and Dispensing of Medication 
The drugs that will be used in this study will be those that daily are dispensed in the 
Pharmacy Department of the participating centres. A record of the traceability of the 
products administered will be included in the study documentation, where active 
principle, batch of the product and expiration date will be collected. 
 
 

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8. EFFICACY ASSESSMENT 
Duration of empirical antimicrobial therapy: only antimicrobials administered 
intravenously, excluding oral and prescribed antimicrobials with prophylactic 
indication, will be included.  
Efficacy variable: The efficacy end-point is the number or free-days of EAT. This 
indicator is calculated as the difference between the number of follow-up days (28 
days) and the number of days of antibacterial treatment received by each patient. 
 
 
Fever 
 
 
 
 
 
 
 
Recurrent fever episodes 
Fever: 
a 
single 
temperature 
determination > 38.5 ° C, or two or 
more determinations > 38 ° C in the 
last 12 hours in the absence of 
another 
non-infectious 
cause 
(transfusion fever among the most 
common, or pharmacological, such 
as cytarabine fever) 
 
 
 
New episode of fever after the 
patient is afebrile > 48h and before 
neutrophil count> 0·5 x109/L 
At febrile neutropenia 
onset 
 
 
 
 
 
 
 
During the follow-up 
Number of days free of EAT
(i.v.) 
Result of follow-up days less days 
administered i.v. AT 
On day 28 of follow-up 
Number of days free of EAT   
(i.v. + p.o.) 
Result of follow-up days less days 
administered i.v. + p.o. AT 
On day 28 of follow-up 
Number of days free of fever 
Result of follow-up days less days 
with fever during the entire follow-up 
On day 28 of follow-up 
Infection episodes 
Number and etiology of infections 
During the follow-up 
Cut-off procalcitonin value  
Cut-off value for predicting recurrent 
fever 
At the end of the study 
Crude mortality 
Death from any cause 
On day 28 of follow-up 
 

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Procalcitonin samples: 
PCT samples are to be taken following the study schedule: 1) at randomization time 
(V0); 2) following 72h of apyrexia (V1); 3) at clinical recovery (V2); 4) in case of 
recurrent fever (V4); 5) at neutropenia recovery (V3) and at the end of follow-up (V5). 
These samples will not be used for the management of patients in the study. These 
samples are identified by patient code (in order to ensure that association with personal 
data is not possible) and the visit number for the sample collection. The samples are 
frozen at -80ºC until the end of the inclusion period, after which PCT determinations will 
be made. The methodology used in the coordinator centre is ECLIA with the reagents 
of the commercial house Roche. Thus, if the other centres have the same methodology 
(technical and reagents), PCT will be determined in its laboratory. Participating centres 
in which this technique is not available will store the frozen samples and send them to 
the University Hospital Virgen del Rocío at the end of the inclusion period. 
 
 

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9. SAFETY ASSESSMENT 
9.1. Methods for the evaluation of safety 
Safety will be assessed in all patients participating in the study, which is by 
intention to treat (ITT). All adverse events (AE) occurring since the informed 
consent is signed until the final visit will be collected. 
9.2. Definitions 
Adverse Event (AE): Is any incidence detrimental to health in a patient or subject 
of a clinical trial treated with a drug, even if it does not necessarily have a 
relationship with such treatment. An AE can therefore be any unfavourable sign 
and unintended (including an abnormal laboratory finding), symptom, or disease 
temporarily associated with the use of a medication in research, whether or not it is 
related to the investigational medicinal product. 
Adverse reaction (AR): is considered to be any harmful and unintended reaction 
to a research drug, irrespective of the dose administered. Unlike an AA, in the case 
of an RA there is a suspicion of a causal relationship between the investigational 
drug and the AE. 
Imputability Criteria: the promoter will classify AA, based on their causal 
relationship with the drug, according to the Algorithm of Karch and Lasagna (1977), 
as: 
 
Definite: There is a reasonable temporal sequence between the administration 
of drug and the appearance of AA. This event coincides with the AR described 
for the drug, improves with suppression or reappears after its readministration 
and cannot be explained by alternative causes. 
 
Probable: there is a reasonable temporal sequence between the administration 
of drug and the appearance of AA. This event coincides with the AR described 
for the drug, improves after discontinuation of treatment and cannot be 
explained by other alternatives. 
 
Possible: there is a reasonable time sequence between the administration of 
the drug and the appearance of AA. This event coincides with the AR described 
for the drug but can be explained by alternative causes. 
 
Conditional or improbable: there is a reasonable time sequence between the 
administration of the drug and the appearance of AA. This event does not 
coincide with the RAs described for the drug and can be explained by 
alternative causes. 
 
Not Related: there is no reasonable time sequence between the administration 
of the drug and the appearance of AA. This event does not coincide with the AR 
described for the drug and can be explained by alternative causes. 

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For the purposes of expeditious notification, the categories: definitive, probable and 
possible of the algorithm of Karch and Lasagna (1977) will be considered as related 
and the conditional or unlikely category of said algorithm will be considered as 
unrelated. 
The determination of the possible relationship with the treatment of the study is a 
responsibility of the principal investigator of the research centre or of the person 
designated by the latter. 
Seriousness 
Is considered severe any AE or AR that at any dose: 
- Cause the death of the patient 
- Threatens the life of the patient 
- Require hospitalization or prolongation of patient hospitalization 
- Cause disability or permanent or major disability 
- It results in a congenital anomaly or malformation 
For the purposes of notification, suspicions of AA or AR that are considered to be 
medically important, but not meet the above criteria, including medical events that 
require intervention to prevent any of the consequences described above, will also 
be notified as serious. All suspicions of transmission of an infectious agent through 
a medicine will also be considered serious. 
Do not confuse the concept of "serious", described previously, with "severe" that 
refers to the intensity of AA or AR (mild / moderate / severe). 
Serious and Unexpected Adverse Reaction (SUSAR) 
Any serious AR whose nature, intensity or consequences do not correspond with 
the reference information for the drug. In this study, baseline information for the 
drugs being studied will be the technical file. The unexpected nature of an AR is 
based on the fact that it has not been observed previously and will not be based on 
what could be anticipated based on the Pharmacological properties of the 
medicinal product. 
9.3. Adverse events management 
9.3.1. Adverse events/pregnancy recording 
Crucial data related to the AE are to be included on a specific form provided for 
the study. In order to collect all the information related to possible AE in the 
study, each study team will be trained during the site initiation visit on the 
definitions and rules for communication of an AE. Any AE, whether it is 
connected to the study medication or not, has to be recorded in the CRF which 
contains a specific pharmacovigilance section. Serious adverse events must be 
completed with more detailed information including the event description 

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(according to international guidelines in pharmacovigilance), date of onset and 
resolution, severity, assessment of causality to study medication, action taken 
and other concomitant medication/procedures used for the treatment of the AE. 
Any AE occurring is monitored using initial and follow-up communication until 
resolution. 
 
The severe adverse event (SAE) form is centralized in the CTU and its 
personnel is responsible for reception (by fax or e-mail communication), 
registration and resolution of queries with participating sites. The identification 
of any SUSAR is assessed by a safety medical monitor in order to evaluate if 
information is to be communicated to Regulatory Authorities, Ethics Committees 
and Investigators following Good Clinical Practice (GPC) rules. In such a case, 
communication through the EudraVigilance system is foreseen. The safety 
medical monitor is responsible for any updates in safety information on the 
investigational medicinal product (IMP). 
AA will be collected since the patient signs Informed Consent (CI) up to 28 days 
after administration of the last dose of the drug in investigation and/or last visit. 
All AA/pregnancy should be documented in the clinical history of the patient and 
in the CRF. All AAs should be monitored until their resolution, or at least during 
the 30 days after discontinuation of study drugs (whatever occurs first), until the 
toxicity returns to a degree ≤ 1, or until the toxicity is considered irreversible. 
In the case of collecting a case of pregnancy information will be collected on: 
1. Normal birth, spontaneous or therapeutic abortion (any anomaly congenital 
detected in the aborted fetus must be documented), dead, congenital 
anomaly. 
2. Neonatal deaths occurring within 30 days of birth. 
3. Death of an infant after 30 days if the investigator suspects that he is related 
to intrauterine exposure to study medication. 
4. All infants born after fetal exposure should be followed during the first 12 
months after delivery. 
Lack of efficacy and overdose should be considered as AA and be collected as 
such in the CRF. 
Any exacerbation of a pre-existing disease occurring after initiation of treatment 
of the study is also considered as an AA. 
Any abnormal results in the laboratory tests that the investigator considers 
clinically significant and requiring a dose adjustment of the treatment, the 
transient or permanent interruption of such treatment, or any other type of 

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intervention or diagnostic evaluation to assess the risk associated with patient, 
will be collected as AA, and should be investigated and monitored adequately. 
9.3.2. Adverse effects due to non-investigational medicinal products 
NIMPs are "non-investigational medicinal products (IMPs)" referred in Article 
2(d) of Directive 2001/20/EC, which may be provided to patients participating in 
a clinical trial according to the protocol. For example, some clinical trial 
protocols require the use of pharmaceutical specialties as concomitant 
treatments or rescue due to prophylactic, diagnostic or therapeutic reasons 
and/or for ensure that subjects receive adequate medical care. They may also 
be used, according to the protocol, to induce a physiological response. These 
pharmaceutical specialties are not considered research drugs (IMP) according 
to Directive 2001/20/EC and PCB standards and are classified as "non-
investigational medicinal products" (NIMP). 
Any AA that may result from the administration of a NIMP should be collected in 
the CRF. If an SAE is considered to be related only to the NIMP and not 
relevant to the safety of the study, the investigator is obliged to communicate it, 
by Yellow Card, to the Pharmacovigilance Centre. 
Procedure for notification of SAE/pregnancies 
In the event of an SAE or a pregnancy case is collected, a member of the 
investigating team will complete and sign the notification form and will send it, 
by fax, immediately and always within 24 hours after having knowledge of the 
event to: 
Fax: 0034 954232992 
The CTU staff will review the form received and, if necessary, will request 
additional information from the investigator. When additional information is 
obtained, or it is resolved or unlikely to change, a follow-up report must be 
completed and faxed to the CTU. If there is a suspicion of a SUSAR, the 
investigator must provide the follow-up information requested by the CTU. 
Any SAE occurring more than 30 days after the end of treatment (without a time 
limit) should be reported if the investigator considers AAG to be related to the 
study treatment (i.e, if it is a serious adverse reaction) or if it is medically 
important. 
It is not necessary to notify the CTU of the following SAE: 
- Hospitalization or death due to the progression of haematological disease. 
- Hospitalization for the performance of scheduled tests. 
- Hospitalization to administer the study drug or to provide palliative care, 
terminal care or to perform scheduled surgical interventions. 

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- Hospitalization or prolongation of hospitalization to perform a procedure 
required by the protocol. 
- Hospitalization or prolongation of hospitalization as a part of the routine 
procedure of the centre (for example, removal of a stent after surgery) 
They will be collected in the CRF and in the patient's medical history. 
Expedited notification of SUSARS to Health Authorities 
The CTU will be responsible for notifying all the SUSARS collected in the study 
to the AEMPS, to the CEICs and to the Health Authorities, following the 
procedure indicated in the current legislation. 
9.3.3. Notification deadlines 
The maximum period for notification of an individual SUSAR suspect case shall 
be 15 calendar days from the date on which the promoter has had knowledge of 
it. When SUSAR is suspected of causing death the patient, or endangered his 
life, the promoter will send the information within 7 calendar days from the date 
on which he/she become aware of it.  
9.3.4. Expedited notification of any other relevant safety information 
The CTU will also notify, in an expeditious manner, all information that could 
modify the benefit/risk balance of the investigational medicinal product, or 
determine changes in the administration schedule or in the performance of the 
trial. 
9.3.5. Annual safety reports 
Safety annual reports are issued with all the safety information in the study 
being reported to regulatory Authorities and Ethics Committees. 
9.3.6. Notification to investigators 
The CTU will communicate to the investigators any safety information that may 
affect the safety of the trial subjects as soon as possible. The SUSAR 
information will be sent annually, in an aggregated form, in a list along with a 
brief analysis of the data provided. Throughout the study, the investigator will 
also be informed of any safety aspects that impact the conduct of the clinical 
trial or product development, including interruption of the development program 
or modifications to the protocol related to safety. 
9.4. Discontinuation of study drugs due to adverse events. 
Certain 
events 
or conditions may 
necessitate temporary 
or permanent 
discontinuation of study medication. Patients presenting such events or conditions 
will remain in the study and will be followed until completion. Any patient who 
interrupts the study medication should temporarily restart it as soon as possible. 
Study procedures will be discontinued and will be replaced by out-of-study 

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procedures with continuing the follow-up of patients. If the administered drug is 
permanently discontinued, subsequent therapy is left to the discretion of the 
investigator. 
Temporary discontinuation 
Criteria for temporary discontinuation of study drugs: The development of a toxicity 
that, depending on its nature and severity, requires a temporary discontinuation of 
study medication until the toxicity is resolved, as well as the development of another 
medical condition that would discourage the administration of study drug. The 
decision to temporarily interrupt study medication in this situation will be left to the 
discretion of the investigator. The period during which patient is not taking the study 
medication will be as short as possible. 
Permanent discontinuation 
Criteria for permanent discontinuation of study drugs: Toxicity development requiring 
permanent discontinuation of any study drug, patient refusal to continue treatment, 
when in the opinion of the investigator continuing study therapy is not the best 
option for the patient and completion of the study. 
 
 

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10. STATISTICAL ANALYSES 
10.1. 
Statistical methods 
This clinical trial is designed to demonstrate the superiority of ICP over the standard 
approach in the decision to discontinue EAT. Safety evaluation of is included in a 
non-inferiority assumption. Efficacy analysis will be performed in the entire clinically 
evaluable population (CEP): patients who have completed EAT following the study 
group assigned without protocol deviation during follow-up. The clinical and 
microbiologically evaluable population (CMEP) is defined as the clinically evaluable 
population in which non-infectious diseases of any aetiology were suspected or 
diagnosed and no other antimicrobials than those indicated for the FN episode 
were started during follow-up. The safety analysis will be performed by intention to 
treat (ITT) in all randomized patients.  
The most favourable PCT cut-off level for predicting recurrent fever will be 
determined through analyses of sensitivity, specificity and receiver operating 
characteristic (ROC) curves. 
A descriptive analysis expressing qualitative variables as proportions and 
quantitative variables as median and interquartile range (RIC) or mean (SD). 
(depending on if they follow a normal distribution or not) will be performed. In order 
to compare study groups, the Chi squared test or Fisher’s exact test for qualitative 
variables and t Student’s test or Mann-Whitney U, when necessary, in quantitative 
variables will be used.  
Analysis will be performed using the Statistical Package for Social Sciences (SPSS 
Inc, Chicago III, U.S.A.) v 19.0. 
An interim analysis is planned once 50% of patients will be recruited. 
 
10.2. 
Sample size 
The sample size estimated for this study is n=156 patients. For analysis efficacy, 
designed to determine whether ICP is superior to the standard approach for 
optimizing the length of EAT, the number of EAT free-days is assessed. 
The sample size calculation was performed on the basis of a 90% statistical power 
to detect differences in the contrast of null hypothesis H0: the mean difference is 
equal to the superiority limit, through a T-Student unilateral test (superiority) for two 
independent samples, with a significance level of 5% and assuming that the 
superiority limit is 3 days, a mean EAT free-day number of 12 days in the CG and 
of 18 days in the EG [2], a standard deviation (SD) of 6 days in both groups and a 
proportion of experimental patients of 50% of the total. It will be necessary to 
include 70 patients in the EG and 70 patients in the CG, making a total of 140 

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patients. Taking into account that the expected percentage of patients to withdraw 
from the study will be 10%, it is necessary to recruit 78 patients in each group, 
making a total of 156 patients in the study. 
 
 

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11. ETHICAL CONSIDERATIONS 
HOWLONG will be carried out in accordance with the Declaration of Helsinki 
principles and the legal norm directive 2001/20/EC of the European Parliament and 
of the Council of 4 April 2001 on the approximation of the laws, regulations and 
administrative provisions of Member States relating to the implementation of Good 
Clinical Practice in the conduct of clinical trials on medicinal products for human 
use. Moreover, all local applicable rules such as Spanish Royal Degree 223/2004 
will be considered for development of the study.   
Due to the pragmatic design of the study, similarities to clinical practice mean that 
special ethical considerations are more present than those that are typical for the 
development of a randomized trial. It is not ethical but practical aspects of this 
study which make its organization complex since the intervention itself is not the 
classical administration of a drug, but the comparison of criteria for withdrawal.  
The trial will start after obtaining approval from a Central Ethics Review Committee, 
conformity from the Directors of the Institutions, and the authorization of the 
AEMPS and the local ethic committees at each site participating in the trial. A 
formal contract agreement was signed between each institution and the sponsor of 
the study.  
11.1. 
Informed consent 
The subject of the trial will grant his/she consent after having understood, through a 
previous interview with the investigator, the objectives of the trial, risks and 
drawbacks, as well as the conditions under which it will be carried out, and after 
being informed of their right to withdraw from the trial in any time without causing 
any harm. 
Each study candidate patient will be provided with the corresponding informed 
consent in which the purposes of the research will be explained in addition to the 
procedures to be used, the expected duration of the research and the expected 
benefits to the patient and others.  
Finally, each patient will be informed of the intention of publishing the results of the 
study in a scientific publication. To include a patient in the trial, he/she must give 
his or her informed consent to all assumptions. 
Consent will be documented through an information sheet for the subject (Annex 1) 
and the consent form (Annex 2 and 3).  
When the subject of the trial is unable to giving consent: 
 
If the subject is an adult without the capacity to give informed consent, the 
investigator will obtain the consent of the legal representative, having been 
informed about the possible risks, discomforts and benefits of the trial. The 

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consent shall reflect the alleged wish of the subject and may be withdrawn at 
any time without detriment to him. When the conditions of the subject allows it, 
he/she shall also give its consent to participate in the trial, after having received 
all the relevant information adapted to their level of understanding. In this case, 
the investigator shall take into account the wish of the person unable to 
withdraw from the trial. 
 
 When the subject is not able to make decisions due to physical or psychic state 
and has no legal representative, consent will be provided by individuals linked 
to him for family or de facto reasons. The subject participating in a clinical trial, 
or their legal representative, may revoke their consent at any time, without 
further explanation and without detriment to him. 
11.2. 
Protection of data 
The confidentiality of records which could identify subjects in the HOWLONG study 
will be protected in accordance with the EU Directive 2001/20/EC. All laws on the 
control and protection of personal information will be carefully followed. The identity 
of patients will not be disclosed in the CRF; names will be replaced by an 
alphanumeric code and any material related to the trial such as samples will be 
identified in the same way so that any personal information can be revealed. 
11.3. 
Acquisition and dispensing study medication 
The process of obtaining the medicines will be the usual for the hospital setting. We 
deal with section 30 of the Clarification document on the application of the 
regulation of clinical trials with medicinal products for their use in human of May 1, 
2004 (version no. 6, May 2008) 
Thus, given the non-commercial nature of this study and the characteristics of the 
same, in that the study medication is the same that is usually used, the drugs will 
be in charge of the participating centres. 
11.4. 
Monitoring and audit 
The study will be monitored through local visits, telephone calls and periodic 
inspection of CRF with sufficient frequency to check the following: 
 
Rate of inclusion of patients, compliance with the rules of the protocol 
procedures, data integrity and accuracy, verification with original documents 
and occurrence of EA. 
 
Monitoring visits will be performed by the study monitor. It is understood that 
she/he may access the medical records of the patients after requesting the 
researcher, who will facilitate access to the documentation to authorized 
persons. 

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The study may be audited by an independent organism. Equally, members 
of the local clinical trials Committees of the participating centres may carry 
out "follow-up visits" to it. 
11.5. 
Non-compliance 
Non-compliance with the protocol and/or regulatory requirements from an 
investigator or from the staff members of the promotor should lead to rapid 
intervention by the promotor, to ensure compliance. 
If the monitoring and / or audit identify a serious and / or persistent non-compliance 
on the part of an investigator, the promoter must remove the investigator of the 
study. When the investigator is withdrawn due to noncompliance, it must promptly 
notify to the regulatory authorities. 
 
11.6. 
Premature discontinuation 
If the trial ends prematurely or is suspended, the sponsor must inform authorities of 
the completion or suspension and of the reason for it as specified by the regulatory 
requirements. 
 
 
 

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12. FOUNDING SOURCE AND INSURANCE 
12.1. 
Funding source 
The study has obtained funding by a public Call for Projects Grants of Health 
Research in 2011, promoted by Subdirección General de Evaluación y Fomento de 
la Investigación of Instituto de Salud Carlos III, Spanish Ministry of Economy 
(PI11/02674). 
12.2. 
Insurance 
The study´s sponsor, FISEVI has an insurance policy with the company HDI, policy 
number 30/002/001692 (directive 2001/20/EC of the European Parliament and the 
Council of 4 April 2001 and Royal Decree 223/2004, of February 6, 2004) which will 
provide compensation for impairment of your health or injury occurring in 
connection with the participation in the study. 
 
 

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13. PUBLICATION POLICY 
13.1. 
Publishing policy 
The publishing policy will be in accordance with the provisions of Royal Decree 
223/2004 of February 6, which regulates the Clinical Trials with medicines, article 
38, which includes the next text: 
1. The sponsor is obliged to publish both positive and negative results from 
authorized clinical trials in scientific journals. 
2. The funds and sources of funding obtained will be recorded. 
3. The anonymity of the subjects participating in the program shall be maintained 
4. The results or conclusions of the clinical trials shall be communicated preferably 
in scientific publications before being made available to the public. The effivacy of 
procedures not yet determined or exaggerated will not be spread prematurely. 
5. Advertising of products undergoing clinical research is absolutely prohibited, as 
set forth in Law 34/1998, of November 11, General of Advertising. 
SPIRIT 2013 Explanation and Elaboration paper and SPIRIT statement [24–26] will 
be followed for the reporting of results to any scientific journal or event. 
 
13.2. 
Amendments to the protocol 
To ensure the study conditions and the valid statistical analysis of the data, neither 
the researcher nor the developer can alter the conditions of the agreed upon and 
stipulated in this protocol. Any modification to the protocol which may have an 
impact on the conduct of the study or potential benefit for the patient, or which may 
affect patient safety, including changes in study objectives, study design, patient 
population, sample size, study procedures or significant administrative aspects, 
would require a formal amendment to the protocol. The study coordination team 
and the CTU will agree such an amendment. The amendment will then become an 
integral part of the study protocol. In case the amendments require the approval of 
the ethical committees and/or Authorities, it will be necessary to obtain it. 
13.3. 
Documentation 
Whether the study is completed or terminated prematurely, the promoter must 
ensure that clinical study reports are prepared and provided to the Authorities. 
 
 
 

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14. REFERENCES 
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antimicrobial agents in neutropenic patients with cancer: 2010 update by the 
infectious diseases society of america. Clin Infect Dis Off Publ Infect Dis Soc Am 
2011;52:e56–93. doi:10.1093/cid/cir073 
2  Sanz MA, López J, Lahuerta JJ, et al. Cefepime plus amikacin versus piperacillin-
tazobactam plus amikacin for initial antibiotic therapy in haematology patients with 
febrile neutropenia: results of an open, randomized, multicentre trial. J Antimicrob 
Chemother 2002;50:79–88. 
3  Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal 
amphotericin B for empirical antifungal therapy in patients with persistent fever and 
neutropenia. N Engl J Med 2004;351:1391–402. doi:10.1056/NEJMoa040446 
4  Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America 
and the Society for Healthcare Epidemiology of America guidelines for developing 
an institutional program to enhance antimicrobial stewardship. Clin Infect Dis Off 
Publ Infect Dis Soc Am 2007;44:159–77. doi:10.1086/510393 
5  Lehrnbecher T, Stanescu A, Kühl J. Short courses of intravenous empirical 
antibiotic treatment in selected febrile neutropenic children with cancer. Infection 
2002;30:17–21. 
6  Jones GR, Konsler GK, Dunaway RP, et al. Risk factors for recurrent fever after the 
discontinuation of empiric antibiotic therapy for fever and neutropenia in pediatric 
patients with a malignancy or hematologic condition. J Pediatr 1994;124:703–8. 
7  Hodgson-Viden H, Grundy PE, Robinson JL. Early discontinuation of intravenous 
antimicrobial therapy in pediatric oncology patients with febrile neutropenia. BMC 
Pediatr 2005;5:10. doi:10.1186/1471-2431-5-10 
8  Klaassen RJ, Allen U, Doyle JJ. Randomized placebo-controlled trial of oral 
antibiotics in pediatric oncology patients at low-risk with fever and neutropenia. J 
Pediatr Hematol Oncol 2000;22:405–11. 
9  Horowitz HW, Holmgren D, Seiter K. Stepdown single agent antibiotic therapy for 
the management of the high risk neutropenic adult with hematologic malignancies. 
Leuk Lymphoma 1996;23:159–63. doi:10.3109/10428199609054816 
10  Santolaya ME, Villarroel M, Avendaño LF, et al. Discontinuation of antimicrobial 
therapy for febrile, neutropenic children with cancer: a prospective study. Clin Infect 
Dis Off Publ Infect Dis Soc Am 1997;25:92–7. 
11  Gilbert DN. Use of plasma procalcitonin levels as an adjunct to clinical 
microbiology. J Clin Microbiol 2010;48:2325–9. doi:10.1128/JCM.00655-10 
12  Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic 
therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit 
Care Med 2006;174:84–93. doi:10.1164/rccm.200512-1922OC 
13  Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of 
COPD: a randomized, controlled trial comparing procalcitonin-guidance with 
standard therapy. Chest 2007;131:9–19. doi:10.1378/chest.06-1500 

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14  Bouadma L, Luyt C-E, Tubach F, et al. Use of procalcitonin to reduce patients’ 
exposure to antibiotics in intensive care units (PRORATA trial): a multicentre 
randomised 
controlled 
trial. 
Lancet 
2010;375:463–74. 
doi:10.1016/S0140-
6736(09)61879-1 
15  Aznar-Oroval E, Sánchez-Yepes M, Lorente-Alegre P, et al. [Diagnostic value of 
procalcitonin, interleukin 8, interleukin 6, and C-reactive protein for detecting 
bacteremia and fungemia in cancer patients]. Enfermedades Infecc Microbiol 
Clínica 2010;28:273–7. doi:10.1016/j.eimc.2009.08.001 
16  Bernard L, Ferrière F, Casassus P, et al. Procalcitonin as an early marker of 
bacterial infection in severely neutropenic febrile adults. Clin Infect Dis Off Publ 
Infect Dis Soc Am 1998;27:914–5. 
17  Massaro KSR, Costa SF, Leone C, et al. Procalcitonin (PCT) and C-reactive 
protein (CRP) as severe systemic infection markers in febrile neutropenic adults. 
BMC Infect Dis 2007;7:137. doi:10.1186/1471-2334-7-137 
18  Ortega M, Rovira M, Filella X, et al. Prospective evaluation of procalcitonin in adults 
with febrile neutropenia after haematopoietic stem cell transplantation. Br J 
Haematol 2004;126:372–6. doi:10.1111/j.1365-2141.2004.05053.x 
19  Brodska H, Drabek T, Malickova K, et al. Marked increase of procalcitonin after the 
administration of anti-thymocyte globulin in patients before hematopoietic stem cell 
transplantation does not indicate sepsis: a prospective study. Crit Care Lond Engl 
2009;13:R37. doi:10.1186/cc7749 
20  Dornbusch HJ, Strenger V, Sovinz P, et al. Non-infectious causes of elevated 
procalcitonin and C-reactive protein serum levels in pediatric patients with 
hematologic and oncologic disorders. Support Care Cancer Off J Multinatl Assoc 
Support Care Cancer 2008;16:1035–40. doi:10.1007/s00520-007-0381-1 
21  CCS: 
Control 
de 
Calidad 
de 
la 
SEIMC. 
http://www.seimc.org/controldecalidadseimc/index.php?mn_MP=66&mn_MS=0&m
n_MN=1&expandable=0 (accessed 21 Aug2015). 
22  EUCAST: 
Breakpoint 
table 
v 
5.0 
2015 
published. 
http://www.eucast.org/eucast_news/news_singleview/?tx_ttnews%5Btt_news%5D=
133&cHash=749e80e1fa0e606e85068e15e2f207ba (accessed 21 Aug2015). 
23  CLSI Standards and Guidelines - CLSI Standards Center. http://clsi.org/standards/ 
(accessed 21 Aug2015). 
24  Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining 
standard protocol items for clinical trials. Ann Intern Med 2013;158:200–7. 
doi:10.7326/0003-4819-158-3-201302050-00583 
25  Chan A-W, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and 
elaboration: guidance for protocols of clinical trials. BMJ 2013;346:e7586. 
26  Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013: new guidance for content 
of 
clinical 
trial 
protocols. 
Lancet 
2013;381:91–2. 
doi:10.1016/S0140-
6736(12)62160-6 
27  Link H, Böhme A, Cornely OA, et al. Antimicrobial therapy of unexplained fever in 
neutropenic patients--guidelines of the Infectious Diseases Working Party (AGIHO) 

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of the German Society of Hematology and Oncology (DGHO), Study Group 
Interventional 
Therapy 
of 
Unexplained 
Fever, 
Arbeitsgemeinschaft 
Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft 
(DKG-German Cancer Society). Ann Hematol 2003;82 Suppl 2:S105–17. 
doi:10.1007/s00277-003-0764-4 
28  Averbuch D, Orasch C, Cordonnier C, et al. European guidelines for empirical 
antibacterial therapy for febrile neutropenic patients in the era of growing 
resistance: summary of the 2011 4th European Conference on Infections in 
Leukemia. Haematologica 2013;98:1826–35. doi:10.3324/haematol.2013.091025 
29  Micol J-B, Chahine C, Woerther P-L, et al. Discontinuation of empirical antibiotic 
therapy in neutropenic acute myeloid leukaemia patients with fever of unknown 
origin: is it ethical? Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 
2014;20:O453–5. doi:10.1111/1469-0691.12445 
30  Orasch C, Averbuch D, Mikulska M, et al. Discontinuation of empirical antibiotic 
therapy in neutropenic leukaemia patients with fever of unknown origin is ethical. 
Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 2015;21:e25–7. 
doi:10.1016/j.cmi.2014.10.014 
31  Cherif H, Björkholm M, Engervall P, et al. A prospective, randomized study 
comparing cefepime and imipenem-cilastatin in the empirical treatment of febrile 
neutropenia in patients treated for haematological malignancies. Scand J Infect Dis 
2004;36:593–600. doi:10.1080/00365540410017590 
32  Slobbe L, Waal L van der, Jongman LR, et al. Three-day treatment with imipenem 
for unexplained fever during prolonged neutropaenia in haematology patients 
receiving fluoroquinolone and fluconazole prophylaxis: a prospective observational 
safety 
study. 
Eur 
J 
Cancer 
Oxf 
Engl 
1990 
2009;45:2810–7. 
doi:10.1016/j.ejca.2009.06.025 
33  Pizzo PA, Robichaud KJ, Gill FA, et al. Duration of empiric antibiotic therapy in 
granulocytopenic patients with cancer. Am J Med 1979;67:194–200. 
34  Cornelissen JJ, Rozenberg-Arska M, Dekker AW. Discontinuation of intravenous 
antibiotic therapy during persistent neutropenia in patients receiving prophylaxis 
with oral ciprofloxacin. Clin Infect Dis Off Publ Infect Dis Soc Am 1995;21:1300–2. 
35  Joshi JH, Schimpff SC, Tenney JH, et al. Can antibacterial therapy be discontinued 
in persistently febrile granulocytopenic cancer patients? Am J Med 1984;76:450–7. 
36  Aguilar-Guisado M, Espigado I, Cordero E, et al. Empirical antifungal therapy in 
selected patients with persistent febrile neutropenia. Bone Marrow Transplant 
2010;45:159–64. doi:10.1038/bmt.2009.125 
37  Aguilar-Guisado M, Martín-Peña A, Espigado I, et al. Universal antifungal therapy 
is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic 
approach. Haematologica 2012;97:464–71. doi:10.3324/haematol.2011.049999 
38  Cisneros JM, Espigado I, Rivero A, et al. [Empirical antifungal therapy in selected 
patients with persistent fever and neutropenia]. Enfermedades Infecc Microbiol 
Clínica 2005;23:609–14. 

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39  Martín-Peña A, Gil-Navarro MV, Aguilar-Guisado M, et al. Cost-effectiveness 
analysis comparing two approaches for empirical antifungal therapy in 
hematological patients with persistent febrile neutropenia. Antimicrob Agents 
Chemother 2013;57:4664–72. doi:10.1128/AAC.00723-13 
40  Cisneros JM, Neth O, Gil-Navarro MV, et al. Global impact of an educational 
antimicrobial stewardship programme on prescribing practice in a tertiary hospital 
centre. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 2014;20:82–
8. doi:10.1111/1469-0691.12191 
 

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ANNEX 1: PATIENTS INFORMATION SHEET 
 
STUDY TITLE: Open label and randomised clinical trial for the optimization of the 
duration of empirical antimicrobial therapy in cancer patients with febrile neutropenia. 
TRIAL CODE: HOWLONG (EudraCT: 2011-005152-34) 
PROMOTER: Fundación Pública Andaluza para la Gestión de la Investigación en 
Salud de Sevilla (FISEVI) 
 
INTRODUCTION 
We are writing to you to inform you of a research study in which you are invited to 
participate. The study was approved by the corresponding Clinical Research 
Andalusian Central Ethics Review Committee and the Spanish Agency of Medicines 
and Health Products (AEMPS) in accordance with current legislation (Royal Decree 
223/2004) regulating clinical trials with medication. 
It is our intention to provide you with correct and sufficient information so that you may 
evaluate and judge whether or not to participate in this study. 
 
VOLUNTARY PARTICIPATION 
Participation in this study is entirely voluntary and you will have the right to withdraw 
your consent at any time with no consequences for your future treatment nor any effect 
on your relationship with your doctor or your level of care. Additionally, your doctor will 
have the option of cancelling your participation if he/she believes this is advisable, 
taking into account your clinical evolution. The necessary conditions for this are 
described in the study. 
 
GENERAL STUDY DESCRIPTION 
You have a haematological disease and currently suffer from a complication called 
febrile neutropenia, which may be severe. Febrile neutropenia consist in fever and a 
decrease in the number of neutrophils, a type of white blood cells that defend us from 
infections, usually caused by the treatment with chemotherapy. When it is diagnosed, 
some tests such as blood cultures and the indication of antimicrobial therapy are 
necessary. This treatment is maintained until fever disappears and recovery from 
neutropenia is achieved. Neutropenia usually lasts between two and three weeks and, 
as such, the duration of antibacterial therapy is frequently prolonged and longer than 
the standard duration of 7-10 days employed when treating other serious infections.  
 
SCOPE OF THE STUDY 

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The aim of the study is to improve antibacterial treatment for febrile neutropenia, 
optimizing its duration. Waiting until neutrophil recovery to withdraw antibacterial 
treatment has the risk of unnecessarily prolonging the duration of antibacterial therapy 
with the consequence of exposure to the adverse effects of these drugs and the 
potential emergence of resistant bacterial infections. 
In order to avoid receiving more antibiotics than necessary, in this study we will 
administer antibacterial treatment to patients with febrile neutropenia until fever and 
symptoms and signs of infection have disappeared, regardless of the neutrophil count.  
Regarding to the safety of this study, you will be clinically evaluated daily and the 
diagnostic tests that you would need would be performed.  
Moreover, we will assess the usefulness of procalcitonin (a protein determined by 
means of a blood test) to decide upon antibacterial therapy withdrawal. 
 
STUDY DESIGN 
There are two treatment groups. Patients from both groups will be treated according 
the hospital’s guidelines and using the available antibacterials. 
For patients included in the EG, the antibacterial treatment will be withdrawn when 
patient is afebrile and signs and symptoms of infections (such as cough, abdominal 
pain, diarrhea…) are resolved and vital signs are normal (blood pressure, heart rate, 
respiratory rate, etc.) for at least 72 hours.  
For patients included in the CG, the antibacterial treatment will be withdrawn when 
patient is afebrile and signs and symptoms of infections (such as cough, abdominal 
pain, diarrhea…) are resolved and vital signs are normal (blood pressure, heart rate, 
respiratory rate, etc.) for at least 72 hours and neutrophil count exceeds 0·5x109/L. 
Group allocation is carried out using “randomisation”. The probability of belonging to 
one group or another is equal. However, the doctor will always know which group you 
belong to. If you participate in the study, the duration will be 28 days.  
We will carry out all routine test while you are admitted, the following being carried out 
daily: 
-Vital signs measurements  
-Physical examination 
-Laboratory test: blood count, biochemistry 
Other test performed less frequently during admission: 
-Blood cultures 
-Chest X-ray 
-Other microbiological cultures when necessary 

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In addition, for the purpose of this study, 6 additional blood samples will be taken (a 
total of 60 ml of blood). 
 
BENEFITS AND RISK OF YOUR PARTICIPATION IN THE STUDY 
If our hypothesis is correct, this trial will improve the antibacterial treatment of patients 
who, like you, have fever and neutropenia, avoiding unnecessary prolonged 
antibacterial therapies and subsequent adverse effects and infections due to resistant 
bacteria. Participating in this study may not provide you with any health benefits but the 
results may be useful for futures patients who have febrile neutropenia such as you 
have now. 
All the drugs used in this study have been approved by the Spanish Regulatory Agency 
(AEMPS) and are property commercialized. Given the different infections contemplated 
in this study, depending on the patient and the bacteria causing the infection, one of 
the following antibacterials or a combination of them will be used: acyclovir, liposomal 
amphotericin, amikacyn, aztreonam, cefepime, ceftazidime, ganciclovir, imipenem, 
itraconazole, levofloxacin or ciprofloxacin, meropenem, piperacilin-tazobactam, 
posaconazole, valacyclovir, valgancyclovir, vancomycin, fluconazole and voriconazole.   
Most of these antibiotics have adverse effects, some of which can be life-threatening. 
The adverse affects you may suffer as a result of the administration of these drugs 
include, among others: digestive upset, rash, allergy reactions, muscle pain, blood and 
hepato-biliary disorders, ototoxicity, kidney problems (including renal failure), and 
neurological disorders. However, the risk of suffering from any of these adverse effects 
as a result of your participation in this study is not higher than if receiving the currently 
established treatment for febrile neutropenia. 
All adverse effects or undesirable events occurring during the study will be monitored 
and registered and, as such, we request you to inform your study doctor if you have 
any discomfort or experience any other new issue. 
 
ALTERNATIVE TREATMENTS 
There are other effective alternatives currently available for the treatment of your illness 
and which you may receive if you do not participate in this study. Therefore, if you do 
not wish to participate, the research team will treat you with an alternative empirical 
antimicrobial therapy. 
 
INSURANCE  
In compliance with the law, this study´s sponsor has an insurance policy with the 
company HDI, policy number 30/002/001692 (directive 2001/20/EC of the European 

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Parliament and the Council of 4 April 2001 and Royal Decree 223/2004, of February 6, 
2004) which will provide compensation for impairment of your health or injury occurring 
in connection with your participation in the study. 
 
CONFIDENTIALITY 
The treatment, communication and transfer of personal data from all participating 
subjects shall comply with the provisions  of Law 15/1999, of December 13 on the 
Protection of Personal data, and Royal Decree 1720/2007 of December 21, approving 
the Regulations implementing this law. According to the provisions of that legislation, 
you may exercise your rights of access, rectification, opposition and cancellation of 
data. Such request should be addressed to your study doctor. The data collected for 
the study will be identified using a single  code and only your study doctor/collaborators 
have the code in order to correlate these data with your and your clinical records. 
Therefore, your identity will not be disclosed to any person with exceptions, such as in 
case of medical emergencies or by legal requirement. Access yo your personal 
information is restricted to the study doctor/collaborators, Health Autothorities 
(AEMPS), the Ethics Committee for Clinical Research and persons authorized by the 
sponsor when they need to check the data and study procedures, but always 
maintaining the confidentiality of such data in accordance wiht current legislation.  
Data from this study will be used only for the specific purposes of the study.  
 
OTHER RELEVANT INFORMATION 
Any new information concerning the drugs used in the study found during your 
participation and which could affect your willingness to participate or continue in the 
study will be notified by your study doctor as soon as possible. 
You may abandon the study at any time without further explanation. If you decide to 
withdraw your consent to participate in this study, no new data will be added to the 
database and you may request the destruction of all previously retained identifiable 
samples in order to avoid the implimentation of new analyses. 
You should be made aware thta you may be excluded from the study is the promoter, 
study investigators, health autothorities or AE event related to the study medication or if 
they consider that you are not accomplishing the procedures required for the study. In 
either case, you will receive an adequate explanation of the reasons leading to your 
removal from the study.  
By signing the attached consent form, you agree to comply with the study procedures 
which have been explanied to you. When the participation is complete, you will receive 

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the best treatment available and which your doctor considers the most appropiate for 
your condition. 
The head of the study in your hospital is Dr ______________________ (telephone 
number____________). He/she will be available  for any questions or calirification you 
may need regarding your participation in the study. If you agree, please sign the 
attached consent form. A copy of the signed informed consent is for you. 

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ANNEX 2. WRITTEN PATIENT INFORMED CONSENT 
Open label and randomised clinical trial for the optimization of the duration of 
empirical antimicrobial therapy in cancer patients with febrile neutropenia. 
Trial code: HOWLONG (EudraCT: 2011-005152-34) 
Promoter: Fundación Pública Andaluza para la Gestión de la Investigación en Salud se 
Sevilla (FISEVI) 
I (name and surname)___________________________________________________ 
DECLARE THAT 
I have read the information leaflet provided by the medical team 
I have had the opportunity to express my questions and doubts 
I have received appropiate answers to my questions 
I have received sufficient information on the study 
I HAVE SPOKEN WITH__________________________________________________ 
(name of the researcher) 
I understand that my participation is voluntary 
I understand that I can pull out of the study 
 
1. Whenever I want 
 
2. Without having to give explanations 
 
3. Without this affecting my medical care 
 
THEREFORE, I freely give my conformity: 
 
- To participate in this study. 
 
- To provide additional confidential information required for the control and 
quality guarantee of the study by personnel assigned by the sponsor and competent 
authorities or, if applicable, the Ethics Committee. 
 
- To archive the encoded information within the framework of data 
confidentiality. 
 
Name of the person that gives his/her informed consent_________________________ 
 
Signature of the person that gives his/her informed consent_________Date (dd/mm/yy) 
 
Numer or the researcher_________________________________________________ 
 
Researcher signature______________________________________Date (dd/mm/yy) 
 
 

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ANNEX 3: LEGAL SURROGATES WRITTEN INFORMED CONSENT FORM 
 
LEGAL SURROGATES INFORMED CONSENT 
Open label and randomised clinical trial for the optimization of the duration of 
empirical antimicrobial therapy in cancer patients with febrile neutropenia. 
Trial code: HOWLONG (EudraCT: 2011-005152-34) 
Promoter: Fundación Pública Andaluza para la Gestión de la Investigación en Salud se 
Sevilla (FISEVI) 
I (name and surname)___________________________________________________ 
DECLARE THAT 
I have read the information leaflet provided by the medical team 
I have had the opportunity to express my questions and doubts 
I have received appropiate answers to my questions 
I have received sufficient information on the study 
I HAVE SPOKEN WITH__________________________________________________ 
(name of the researcher) 
I understand that my participation is voluntary 
I understand that I can pull out of the study 
 
1. Whenever I want 
 
2. Without having to give explanations 
 
3. Without this affecting my medical care 
 
THEREFORE, I freely give my conformity: 
 
- To participate in this study. 
 
- To provide additional confidential information required for the control and 
quality guarantee of the study by personnel assigned by the sponsor and competent 
authorities or, if applicable, the Ethics Committee. 
 
- To archive the encoded information within the framework of data 
confidentiality. 
 
Name of the person that gives his/her informed consent_________________________ 
 
Signature of the person that gives his/her informed consent_________Date (dd/mm/yy) 
 
Numer or the researcher_________________________________________________ 
 
Researcher signature______________________________________Date (dd/mm/yy) 

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ANNEX 4. INVESTIGATORS AND PARTICIPATING CENTRES 
Number 
Centre 
City 
Investigators 
Centres from the beginning of the study, protocol version 1.1 
1 
University Hospital 
Virgen del Rocío, 
Institute of 
Biomedicine of 
Seville 
Seville 
PI: Dr. José Miguel Cisneros 
Herreros 
 
Collaborators: 
Dr. Ildefonso Espigado 
Dra. Rocío Parody  
Dr. José González-Campos 
Dr. José Falantes  
Dª. María Rosario López 
Dra. Manuela Aguilar-
Guisado 
Dr. José Molin 
Dra. Clara Mª Rosso-
Fernández 
Lda. Inmaculada 
Domínguez-Pascual 
Dra. Almudena Martín-Peña 
Dra. María Isabel Montero 
Extension to other centres, protocol version 2.0 
 2 
University Hospital 
of Salamanca 
Salamanca 
PI: Lourdes Vázquez-López 
Collaborators: 
Dra. Lucía López Corral 
Dra. Mª Dolores Caballero 
Barrigón 
3 
University Hospital 
Vall d´Hebron-
Universitat 
Autònoma,  
Barcelona 
IP: Dr. Pere Barba-Suñol 
Collaborators: 
Dra. Isabel Ruiz 
Dra. Nerea Castillo Flores 
Dr. David Valcárcel 
4 
University Hospital 
Clinic  
Barcelona 
IP: Dra. Montserrat Rovira 
Tarrats 
Extension to other centres, protocol version 4.1 
5 
Hospital of Jerez de 
la Frontera 
Jerez de la 
Frontera 
PI: Dr. Sebastián Garzón 
López 
Collaborators: 
Dr. Eusebio Martín-Chacon 
Dr. Vicente Rubio-Sánchez 
Dra. Mª. Dolores Madrigal-
Toscano 
Extension to other centre, protocol version 5.0 
6 
University 
Hospital 
of Bellvitge-Institute 
of 
Oncology 
of 
Catalonia (ICO) 
Barcelona 
PI: Dra. Carlota Gudiol 
Collaborators: 
Dra. Carolina García-Vidal 
Dra. Cristina Royo-
Cebrecos 
Dña. Cristina Padilla-
Montero 
PI: principal investigator