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Trial record 56 of 159 for:    Urinary Tract Infections | Recruiting, Not yet recruiting, Available Studies | "Communicable Diseases"

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
Sponsor:
Collaborator:
Spanish Network for Research in Infectious Diseases
Information provided by (Responsible Party):
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Brief Summary:

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

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 198 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Fosfomycin sodium intravenous
4g every 6 hours iv (60 min infusion)
Drug: Fosfomycin sodium intravenous
4g every 6 hours iv (60 min infusion)
Other Names:
  • Generic name: Fosfomycin
  • Pharmaceutical form: solution for infusion
  • ATC code: J01J3

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
Other Names:
  • Generic name: Meropenem
  • Pharmaceutical form: solution for infusion
  • ATC code: J01D5

Ceftriaxone intravenous
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
Other Names:
  • generic name: ceftriaxone
  • Pharmaceutical form: solution for infusion
  • ATC code:J01DA




Primary Outcome Measures :
  1. 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.



Secondary Outcome Measures :
  1. 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

  2. Mortality [ Time Frame: At day 30 of follow-up ]
    Death for any reason.

  3. Length of hospital stay [ Time Frame: At day 30 of follow-up ]
    It is defined as the time from admission to hospital discharge

  4. 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.

  5. 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.


  6. Fosfomycin steady-state plasma concentration [ Time Frame: At 3 days after treatment started ]
    Therapeutic drug monitoring of fosfomycin, basic pharmacokinetic parameters will be determined.

  7. 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)

  8. 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.

  9. Early microbiological response [ Time Frame: within the first 5 days after treatment started ]
    Cultures are negative

  10. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ≥18 years old hospitalized patients
  • Negative pregnancy test in fertile women
  • Episode of clinically-significant monomicrobial urinary BSI due to multidrug-resistant E.coli susceptible to fosfomycin and meropenem or ceftriaxone
  • Urinary sepsis with multidrug resistant E. coli isolation from the blood cultures, requires at least one clinical criteria and one of the following urinalysis criteria:

Clinical criteria

  • UTI symptoms (dysuriac, urgency, suprapubic pain or pollakiuria)
  • Lumbar back pain
  • Cost-vertebral angle tenderness
  • Altered mental status in people up to 70 years old
  • Intermittent or permanent indwelling foley catheter (or withdrawal during 24 hours previous) even without urinary symptoms urinalysis criteria
  • Urine dipstick test positive for either nitrites or leukocyte esterase
  • Positive urine culture - Signed informed consent form (ICF) executed prior to protocol screening assessments

Exclusion Criteria:

  • Polymicrobial bacteremia
  • No drainage of renal abscess or obstructive uropathy unresolved
  • Pregnant or careening women
  • Haematogenous infection
  • Other concomitant infection
  • Renal transplantation recipients
  • Polycystic kidney
  • Hypersensitivity and/or intolerance to meropenem or fosfomycin or ceftriaxone
  • Palliative care or life expectance < 90 days
  • Septic shock at time of randomization
  • New York Heart Association (NYHA) functional Class IV, hepatic cirrhosis or renal impairment receiving dialysis
  • Active empiric treatment >72 hours
  • Late randomization >24 hours after multidrug resistant.coli blood culture´s identification
  • Participation in other clinical trial with active treatment

Information from the National Library of Medicine

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


Contacts
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Contact: Clara M. Rosso Fernández, MD, PhD +34955013414 claram.rosso.sspa@juntadeandalucia.es
Contact: Eva Recio Sánchez, BS,PhD eva.recio.exts@juntadeandalucia.es

Locations
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Spain
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
Alicante, Spain
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
Barcelona, Spain
Principal Investigator: Evelyn Shaw Perujo, MDPhD         
Hospital de Cruces Recruiting
Bilbao, Spain
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
Córdoba, Spain
Contact: Clara Natera, MD, PhD       clrntr@gmail.com   
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    jesodo@hotmail.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
Sponsors and Collaborators
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Spanish Network for Research in Infectious Diseases
Investigators
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Study Chair: JESUS RODRIGUEZ-BAÑO, MD, PhD Spanish Network for Research in Infectious Diseases

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
ClinicalTrials.gov Identifier: NCT02142751     History of Changes
Other Study ID Numbers: FOREST
First Posted: May 20, 2014    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Fundación Pública Andaluza para la gestión de la Investigación en Sevilla:
Urinary tract infection
Bloodstream infection
Escherichia coli
Extended-spectrum β-lactamases (ESBLs)
Bacteremia
Fosfomycin
Meropenem
Pharmacokinetics
intestinal colonization
Recurrence
multidrug resistance E.coli
Ceftriaxone

Additional relevant MeSH terms:
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Infection
Communicable Diseases
Pharmaceutical Solutions
Meropenem
Ceftriaxone
Fosfomycin
Anti-Bacterial Agents
Anti-Infective Agents