Phase II Clinical Trial to Evaluate an Antibiotic Regimen Pharmacokinetic Applicable to Outpatient Parenteral Antimicrobial Therapy in Enterococcus Faecalis Infective Endocarditis
Phase: PHASE2
Conditions: Infectious Endocarditis
Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

ENDOKINETIC-CEF 
 Versión 1.1 
 11.01.2018 
 
 
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Phase II clinical trial to evaluate an antibiotic regimen pharmacokinetic applicable to 
outpatient parenteral antimicrobial therapy in Enterococcus faecalis infective endocarditis 
 
Eudra TC number: 2017-003127-29 
Protocol ID: ENDOKINETIC-CEF 
Summary of Version 1.1  11 of january 2018 
 
 
 
 
 
Sponsor: Fundación Pública Andaluza para la Gestión de la Investigación en Salud de 
Sevilla. (FISEVI) 
University Hospital Virgen del Rocío. 
 
 
 
 
 
 

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1. Abstract 
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2. Trial identification 
4 
3. Principal investigator 
4 
4. Sponsor identification 
4 
5. Clinical trial site 
4 
6. Ethics committee infotmation 
4 
7. Clinical trial monitor 
4 
8. IMP identification 
4 
9. Trial type and phase 
5 
10. Objectives of the trial 
5 
11. Design of the trial 
5 
12. Disease under investigation 
6 
13. End points 
6 
14. Inclusion and exclusión criteria 
7 
15. Clinical trial duration 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. Abstract 
 
Infective endocarditis (IE) is an uncommon but virulent infection disease. One of the most 
frequent etiology for this infection is Enterococcus faecalis. IE treatment is difficult due to the 
characteristics of the infection itself, the bacterial species and the frequent comorbidities of the 
patients. A bactericidal antimicrobial treatment is mandatory for the resolution of this disease, 
but most antibiotics do not exhibit this effect against E. faecalis and have prompted the 
combination of an aminoglycoside and a cell-wall active agent (generally a β-lactam) as the 
standard treatment. This is a lengthy treatment (4-6 weeks) and its primary side effect is 
nephrotoxicity. Furthermore, aminoglycoside resistant strain’s rates are increasing in USA and 
Europe, getting more complicated to establish an effective antibiotic regimen. Nowadays, 
patients with E. faecalis IE are old and often have significant underlying comorbidities with an 
increased risk of developing nephrotoxicity with aminoglycoside treatment. For this reason, and 
for the relevance of high-level aminoglycoside-resistant strains, some alternatives have been 
explored.  
 
A double β-lactam regimen is an option, despite the intrinsically resistance of E. faecalis to 
cephalosporins. The most studied combination is a regimen based on ampicillin plus ceftriaxone, 
which has shown a synergistic effect in vitro. This combination is as effective as ampicillin plus 
gentamycin, but with lower nephrotoxicity. Those patients need at least 4-6 weeks of treatment 
with a prolonged hospitalization. However, after 2 week of treatment some patients are clinically 
stabilized and could be benefit of an outpatient parenteral antibiotic therapy (OPAT) program. 
For that purpose, it is essential to design a treatment regimen, which ensures the effectiveness 
and safety of the treatment, based on stability and pharmacokinetic and pharmacodynamics 
(PK/PD) studies of the administered drugs. Furthermore, the logistic and schedule should be 
simple enough to enable the inclusion in an OPAT program. In order to design an antibiotic 
regimen suitable for OPAT programs and as effective as the standard therapies for E. faecalis IE, 
we decided to start a project consisting of a phase II clinical trial and a stability study.  
 
The clinical trial is designed as a phase II, crossover clinical trial. It will be carried out in healthy 
volunteers, who will receive two different antibiotic regimen based on ceftriaxone. One of the 
regimens had shown clinical effectiveness in this scenario, but it is not suitable for OPAT 
programs. In the other hand, a new treatment schema useful in OPAT programs is proposed, but 
there is still a lack of pharmacokinetic data to support it. The plasma drug concentrations will be 
measured in both cases, comparing the minimal drug concentration observed and the 
pharmacokinetic profiles of the two regimens. Likewise, the stability study pursuits to establish 
the useful life at room temperature of this antibiotic regimen for an OPAT program. 
 
 
 
 
 

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2. Trial identification 
 
Title: Phase II clinical trial to evaluate an antibiotic regimen pharmacokinetic applicable to 
outpatient parenteral antimicrobial therapy in Enterococcus faecalis infective endocarditis 
Nº Eudra TC: 2017-003127-29 
Versión: 1.1 11 of january 2018 
Código del protocolo: ENDOKINETIC-CEF  
 
3. Investigador principal del ensayo 
 
Dra. María Victoria Gil Navarro. 
Hospital Pharmacy Service 
University Hospital Virgen del Rocío. 
Manuel Siurot Avenue, s/n. 41013. Sevilla. 
Phone.: 955012300. Fax: 955012088. e-mail: mariav.gil.sspa_juntadeandalucia.es 
 
4. Sponsor identification 
 
Fundación pública andaluza para la gestión de la investigación en salud de Sevilla (FISEVI). 
University Hospital Virgen del Rocío. Edificio de laboratorios, 6ª floor. 
Manuel Siurot Avenue, s/n. 41013. Sevilla Teléfono: 955013295 
 
5. Clinical trial site 
 
University Hospital Virgen del Rocío. Manuel Siurot Avenue, s/n. 41013. Sevilla, Spain. 
 
6. Ethics committee infotmation  
 
Comité de Ética de la Investigación provincial. Doctor Fedriani Avenue 3 41009. Sevilla, 
Spain, 
 
7. Clinical trial monitor 
 
University Hospital Virgen del Rocío. Manuel Siurot Avenue, s/n. 41013. Sevilla, Spain. 
 
8. IMP identification 
 
a) 4 grams of ceftriaxone in a single short infusion each 24 hours  
b) 2 grams of ceftriaxone in a single short infusion each 12 hours 
 
 
 

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9. Trial type and phase 
 
A phase II, single-centre, open, non-randomized, cross-over, clinical trial. 
 
10. Objectives of the trial 
 
Main objective 
 
To determinate whether 24 hours after the administration of 4 grams of ceftriaxone in a single 
short infusion, serums levels would be higher than 5 micrograms per mililitre 
 
Secondary objectives 
 
1. To compare the 24 hours area under the curve (AUC) after the administration of 4 grams of 
ceftriaxone in a single short infusion and the administration of 2 grams of ceftriaxone in a two 
short infusions separated for 12 hours.  
2. To determinate all dose-dependants pharmacokinetics parameters after the administration of 4 
grams of ceftriaxone in a single short infusion. 
3. To determinate the safety of the administration of 4 grams of ceftriaxone in a single short 
infusion 
 
11. Design of the trial 
 
A phase II, single-centre, open, non-randomized, cross-over, clinical trial. It is defined as a non-
commercial study with low level of intervention. The study will recruited 12 healthy volunteers. 
The subjects will be identify by an alphanumeric sequential code order by inclusion. Every 
individual will received two cycles of treatment. First, each individual will be administrated 2 
doses of 2 g of ceftriaxone separated for 12 hours. After a wash-out period (5-7 days) the same 
individuals will receive a single dose 4 g of ceftriaxone. In both cycles, plasma drug 
concentrations will be measure during 24 hours. The study will be structured in an initial 
interview, two phases of treatment and two follow-up visits: 
  
1. First visit: It will involve all the procedures before the sign of the informed consent and the 
initial clinical and analytical check.   
 
2. Phase I: 2 doses of 2 g of ceftriaxone will be administrated separated for 12 hours. Plasma 
drug concentration will be measure after 0.5, 1, 2, 3, 6, 8. 10, and 12 hours of each dose.  
 
3. Phase II: A single dose of 4 g of ceftriaxone will be administrated. Plasma drug concentration 
will be measure after 0.5, 1, 2, 3, 6, 8. 10, 12, 16, 20 and 24 hours after the administration. 
 

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4. Follow-up visit: Clinical and analytical check one week after the last dose of ceftriaxone. The 
last follow-up visit will take place by phone, one month after phase II.  
 
Phases I and II will be separated for a wash-out period of 5-7 days. In order to ensure the 
absence of ceftriaxone and analytical variations, one additional blood sample will be extract 
before the beginning phase I and II. Patient follow-up: 1 month. 
 
12. Disease under investigation 
 
Healthy volunteers (Enterococcus faecalis infective endocarditis) 
 
13. End points 
 
Primary end point 
 
Serums levels of ceftriaxone 24 hours after the administration of 4 grams of ceftriaxone in a 
single short infusion. 
 
Secondary end points 
 
1. Serums levels of ceftriaxone 0.5, 1, 2, 3, 6, 8, 10, 12, 16 y 20 and 24 hours after the 
administration of 4 grams of ceftriaxone in a single short infusion. 
2. Dose-dependants pharmacokinetics parameters after the administration of 4 grams of 
ceftriaxone in a single short infusion: plasma clearance and volume of distribution.  
3. Significant differences between serums levels of ceftriaxone 24 hours after the administration 
of 4 grams of ceftriaxone in a single short infusion and serums levels of ceftriaxone 24 hours 
after the administration of 2 grams of ceftriaxone in two short infusion separated for 12 hours. 
4. Number of adverse reactions after the administration of 4 grams of ceftriaxone in a single 
short infusion. 
5. Frequency and importance of adverse reactions. 
 
 
 
 

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14. Inclusion and exclusión criteria 
 
Inclusion criteria 
 
1. Male and female adult subjects. 
2. Weight between 40 and 18 kilograms, both included, and body mass index lower than 34 
kilograms per square meter. 
3. The subject (or his/her "trusted representative") must have given his/her informed and signed 
consent approved by an Ethical Committee. 
4. The subject must have normal analytical values or abnormal without clinical significance of 
biochemical parameters, liver and kidney function panel test, hemogram and album level. A 
medical check will be carry out by workers of Infectious Diseases Department. 
5. The subject must have a normal physical examination or abnormal without clinical 
significance. A medical check will be carry out by workers of Infectious Diseases Department. 
6. The medication taken usually by the subjects will be check by the Pharmacy Department in 
order to find possible interactions with ceftriaxone. 
 
Exclusion criteria 
 
1. Subjects with clinically significant abnormalities in laboratory test or physical exploration. A 
medical check will be carry out by workers of Infectious Diseases Department. 
2. Subjects undergoing an active infection find at the screening. 
3. Subjects with any clinical or surgery condition which contraindicate his/her inclusion, check 
by workers of Infectious Diseases Department. 
4. Subjects who has received treatment with cephalosporins 21 days before the trial starts or 
during the trial (apart from the protocol treatment). 
5. Subjects hypersensitive or allergic to cephalosporins or penicillin. 
6. Subjects undergoing chronic or acute cutaneous diseases which prevent the treatment 
administration. 
7. Subjects not giving his/her informed and signed consent approved by an Ethical Committee. 
 
15. Clinical trial duration 
 
 
Estimated of the duration of the trial: 1 year 
Estimated dates: 26/04/18-26/04/19