Fosfomycin Versus Meropenem or Ceftriaxone in Bacteriemic Infections Caused by Multidrug Resistance in E.Coli (FOREST)
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|ClinicalTrials.gov Identifier: NCT02142751|
Recruitment Status : Recruiting
First Posted : May 20, 2014
Last Update Posted : October 18, 2018
Enterobacterieaceae (and specially Escherichia coli) showing resistance due to multidrug-resistant Escherichia coli, plasmid mediated AmpC or quinolone resistance caused by chromosomal mechanisms have spread worldwide during the last decades. This is important because many of these isolates are also resistant to other first-line agents such as fluoroquinolones or aminoglycosides, leaving few available options for therapy, and this condition is associated with increased morbidity- mortality and length of hospital stay. While carbapenems are considered the drugs of choice for multidrug-resistant Escherichia coli and AmpC producers, recent data suggests that certain alternatives may be suitable for some types of infections.
At the present time, finding therapeutic alternatives to carbapenems and cephalosporins for the treatment of invasive infections due to multidrug-resistant Escherichia coli is critical. Fosfomycin was discovered more than 40 years ago but was not investigated according to present standards, and thus is not used in clinical practice except in desperate situations. It is one of the so-considered neglected antibiotics with high potential interest for the future.
With the aim of demonstrate the clinical non-inferiority of intravenous fosfomycin compared to meropenem or ceftriaxone in the treatment of bacteraemic urinary tract infections caused by multidrug-resistant Escherichia coli . The investigators propose a "real practise" randomised, controlled, multicentre phase III clinical trial to compare the clinical and microbiological efficacy and safety of intravenous fosfomycin (4 grammes every 6 hours) with meropenem (1 gramme every 8 hours) or ceftriaxone (1 gramme every 24 hours) as targeted therapy of the previously specified infection; change to oral therapy according to predefined options is allowed in both arms after 5 days. Follow-up for the study is planned up to 60 days.
|Condition or disease||Intervention/treatment||Phase|
|Infection Due to ESBL Escherichia Coli||Drug: Fosfomycin sodium intravenous Drug: Meropenem intravenous Drug: Ceftriaxone intravenous||Phase 3|
The FOREST study is a phase 3, randomised, controlled, multicentric, open-label clinical trial to prove the noninferiority of fosfomycin versus meropenem in the targeted treatment of bacteraemic UTI due to ESBL-EC, designed as a real practice trial. It is a non-commercial, investigator-driven clinical study funded through a public competitive call by Instituto de Salud Carlos III, Spanish Ministry of Economy (PI13/01282).
The study is coordinated by investigators from Hospital Universitario Virgen Macarena in Seville, Spain; the sponsorship is performed by Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI), of which the sponsor-scientific responsibilities are delegated to the CTU (Clinical Trial Unit—Hospital Universitario Virgen del Rocío, Seville, Spain). All participating patients or their relatives must give written informed consent before any study procedures occur, including the withdrawal of biological samples for the study.
The hypothesis to test is that intravenous fosfomycin is not inferior to meropenem for the targeted treatment of bacteraemic UTI caused by ESBL-EC in terms of efficacy.
The primary objective of the study is to demonstrate that intravenous fosfomycin is not inferior to meropenem for reaching clinical and microbiological cure 5-7 days after the completion of treatment.
Secondary objectives include comparing the early clinical and microbiological response, 30-day mortality, hospital stay, recurrence rate, safety and impact on intestinal colonisation by MDR Gram-negative bacilli, evaluation of the rate of resistance development to fosfomycin and blood level concentration of fosfomycin.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||198 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase 3, Randomized, Controlled Multicentric, Open-label Clinical Trial to Prove Non-Inferiority of Fosfomycin vs Meropenem or Ceftriaxone in the Treatment of Bacteriemic Urinary Infection Due to Multidrug Resistance in E.Coli|
|Study Start Date :||July 2014|
|Estimated Primary Completion Date :||March 2019|
|Estimated Study Completion Date :||March 2019|
Experimental: Fosfomycin sodium intravenous
4g every 6 hours iv (60 min infusion)
Drug: Fosfomycin sodium intravenous
4g every 6 hours iv (60 min infusion)
Active Comparator: Meropenem intravenous
1g every 8 hours (15-30 min infusion)
Drug: Meropenem intravenous
1g every 8 hours (15-30 min infusion) It depends on strain sensitivity: Strain with resistance to cephalosporins
1g every 24h (2-4 min)
Drug: Ceftriaxone intravenous
1g every 24 hours iv (2-4 min infusion) It depends on strain sensitivity: Strain with resistance to quinolone but sensitivity to cephalosporins
- Clinical and microbiological cure rate [ Time Frame: Day 5-7 after end of treatment (test of cure) ]
Clinical Cure: Complete resolution of infection symptoms (bacteremia and/or urinary tract infection-UTI-), present at the day on which blood culture was drawn.
Microbiological cure: Negative blood culture at day 5-7 after end of treatment. Besides this, if UTI was confirmed with a positive urine culture with the same microorganism than the blood culture, this culture should become negative.
- Early clinical response [ Time Frame: After 5 -7 days of complete treatment (from the first day of study drugs administration) ]The infection was completely resolved after 5-7 days of complete treatment
- Mortality [ Time Frame: At day 30 of follow-up ]Death for any reason.
- Length of hospital stay [ Time Frame: At day 30 of follow-up ]It is defined as the time from admission to hospital discharge
- Safety of intravenous fosfomycin in this indication [ Time Frame: To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration) ]Gathering any related adverse event from the informed consent form signature to the end of follow-up.
- Recurrences (relapse and reinfection) rate [ Time Frame: To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration) ]
Relapse: new symptoms of UTI in patient with previously considered as clinical or microbiological cured in the visit of day 5-7 plus positive urine or blood cultures with the same microorganism isolated than the initial culture.
Re-infection: same definition but with different strain in the culture results.
- Fosfomycin steady-state plasma concentration [ Time Frame: At 3 days after treatment started ]Therapeutic drug monitoring of fosfomycin, basic pharmacokinetic parameters will be determined.
- Microbiota impact of study treatment bacilli [ Time Frame: Screening, day 5-7, day 12 ]Study treatment impact in the gut colonization of MDRGNB (Multi drug resistant Gram negative bacilli)
- Emergence of resistant clinical isolates of Escherichia coli to fosfomycin and meropenem [ Time Frame: participants will be followed for the duration of fosfomycin, an expected average of 14 days ]Frequency of strains that develop resistance and detection of resistance mechanisms in fosfomycin treatment arm.
- Early microbiological response [ Time Frame: within the first 5 days after treatment started ]Cultures are negative
- Safety of intravenous antibiotic administration in this indication [ Time Frame: To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration) ]Gathering any related adverse event from the informed consent form signature to the end of follow-up.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02142751
|Contact: Clara M. Rosso Fernández, MD, PhDfirstname.lastname@example.org|
|Contact: Eva Recio Sánchez, BS,PhDemail@example.com|
|Hospital Mutua de Terrassa||Recruiting|
|Terrassa, Barcelona, Spain, 08221|
|Principal Investigator: Ester Calbo, MDPhD|
|Hospital Universitario de Gran Canaria Dr. Negrín||Recruiting|
|Las Palmas De Gran Canaria, Gran Canarias, Spain, 35010|
|Principal Investigator: Miguel Angel Cárdenas Santana, MDPhD|
|Hospital Arnau de Vilanova||Recruiting|
|Vilanova, Lleida, Spain|
|Principal Investigator: Alfredo Jover, MDPhD|
|Hospital Clínico Universitario Virgen de la Arrixaca||Recruiting|
|El Palmar, Murcia, Spain, 30120|
|Principal Investigator: Alicia Hernández Torres, MDPhD|
|Hospital Universitario de Canarias||Recruiting|
|La Laguna, Tenerife, Spain, 38320|
|Principal Investigator: María Lecuona Fernández, MDPhD|
|Hospital Marina Baixa||Recruiting|
|Alicante, Spain, 03010|
|Principal Investigator: Concepción Amador Prous, MDPhD|
|Hospital General Universitario de Alicante||Recruiting|
|Principal Investigator: Vicente Voix Martínez, MD|
|Hospital Parc Salud Mar||Recruiting|
|Barcelona, Spain, 08003|
|Principal Investigator: María Luisa Sorli Redó, MDPhD|
|Hospital de la Santa Creu i San Pau||Recruiting|
|Barcelona, Spain, 08025|
|Principal Investigator: Virginia Pomar Solchaga, MDPhD|
|Hospital Vall d'Hebron||Recruiting|
|Barcelona, Spain, 08035|
|Principal Investigator: Carlos Pigrau Serrallach, MDPhD|
|Hospital Universitario de Bellvitge||Recruiting|
|Principal Investigator: Evelyn Shaw Perujo, MDPhD|
|Hospital de Cruces||Recruiting|
|Contact: Elena Bereciartua, MD.PhD ELENA.BERECIARTUABASTARRICA@osakidetza.net|
|Principal Investigator: Miguel Montejo, MD.PhD|
|Principal Investigator: Elena ELENA.BERECIARTUABASTARRICA@osakidetza.net, MD, PhD|
|Hospital Universitario de Burgos||Terminated|
|Burgos, Spain, 09006|
|Hospital Universitario Reina Sofía||Recruiting|
|Contact: Clara Natera, MD, PhD firstname.lastname@example.org|
|Principal Investigator: Clara Natera, MD, PhD|
|Hospital Ramón y Cajal||Recruiting|
|Madrid, Spain, 28034|
|Principal Investigator: Vicente Pintado García, MDPhD|
|Hospital Universitario 12 de Octubre||Recruiting|
|Madrid, Spain, 28041|
|Principal Investigator: José Tiago Sequeira López da Silva, MDPhD|
|Hospital Universitario Central de Asturias||Terminated|
|Oviedo, Spain, 33006|
|Hospital Son Espases||Terminated|
|Palma de Mallorca, Spain, 07010|
|Hospital Marqués de Valdecilla||Recruiting|
|Santander, Spain, 39008|
|Principal Investigator: Luis Martínez Martínez, MDPhD|
|Hospital Universitario Virgen Macarena||Recruiting|
|Sevilla, Spain, 41009|
|Contact: Jesús Sojo Dorado, MD +34 955009024 email@example.com|
|Contact: Adoración Valiente|
|Sub-Investigator: Jesús Sojo Dorado, MD|
|Sub-Investigator: Zaira R Palacios Baena, MD|
|Sub-Investigator: Vicente Merino Bohorquez|
|Sub-Investigator: Adoración Valiente, MD|
|Hospital Universitario y Politécnico La Fe||Terminated|
|Valencia, Spain, 46026|
|Hospital Royo Villanova||Terminated|
|Zaragoza, Spain, 50009|
|Study Chair:||JESUS RODRIGUEZ-BAÑO, MD, PhD||Spanish Network for Research in Infectious Diseases|