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

Fosfomycin Versus Meropenem or Ceftriaxone in Bacteriemic Infections Caused by Multidrug Resistance in E.Coli

Sponsors

Lead sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Collaborator: Spanish Network for Research in Infectious Diseases

Source 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.

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.

Overall Status Completed
Start Date July 2014
Completion Date March 2019
Primary Completion Date December 2018
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Clinical and microbiological cure rate Day 5-7 after end of treatment (test of cure)
Secondary Outcome
Measure Time Frame
Early clinical response After 5 -7 days of complete treatment (from the first day of study drugs administration)
Mortality At day 30 of follow-up
Length of hospital stay At day 30 of follow-up
Safety of intravenous fosfomycin in this indication To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
Recurrences (relapse and reinfection) rate To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
Fosfomycin steady-state plasma concentration At 3 days after treatment started
Microbiota impact of study treatment bacilli Screening, day 5-7, day 12
Emergence of resistant clinical isolates of Escherichia coli to fosfomycin and meropenem participants will be followed for the duration of fosfomycin, an expected average of 14 days
Early microbiological response within the first 5 days after treatment started
Safety of intravenous antibiotic administration in this indication To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
Enrollment 161
Condition
Intervention

Intervention type: Drug

Intervention name: Fosfomycin sodium intravenous

Description: 4g every 6 hours iv (60 min infusion)

Arm group label: Fosfomycin sodium intravenous

Intervention type: Drug

Intervention name: Meropenem intravenous

Description: 1g every 8 hours (15-30 min infusion) It depends on strain sensitivity: Strain with resistance to cephalosporins

Arm group label: Meropenem intravenous

Intervention type: Drug

Intervention name: Ceftriaxone intravenous

Description: 1g every 24 hours iv (2-4 min infusion) It depends on strain sensitivity: Strain with resistance to quinolone but sensitivity to cephalosporins

Arm group label: Ceftriaxone intravenous

Eligibility

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

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
JESUS RODRIGUEZ-BAÑO, MD, PhD Study Chair Spanish Network for Research in Infectious Diseases
Location
facility
Hospital Mutua de Terrassa | Terrassa, Barcelona, 08221, Spain
Hospital Universitario de Gran Canaria Dr. Negrín | Las Palmas De Gran Canaria, Gran Canarias, 35010, Spain
Hospital Arnau de Vilanova | Vilanova, Lleida, Spain
Hospital Clínico Universitario Virgen de la Arrixaca | El Palmar, Murcia, 30120, Spain
Hospital Universitario de Canarias | La Laguna, Tenerife, 38320, Spain
Hospital Marina Baixa | Alicante, 03010, Spain
Hospital General Universitario de Alicante | Alicante, Spain
Hospital Parc Salud Mar | Barcelona, 08003, Spain
Hospital de la Santa Creu i San Pau | Barcelona, 08025, Spain
Hospital Vall d'Hebron | Barcelona, 08035, Spain
Hospital Universitario de Bellvitge | Barcelona, Spain
Hospital de Cruces | Bilbao, Spain
Hospital Universitario de Burgos | Burgos, 09006, Spain
Hospital Universitario Reina Sofía | Córdoba, Spain
Hospital Ramón y Cajal | Madrid, 28034, Spain
Hospital Universitario 12 de Octubre | Madrid, 28041, Spain
Hospital Universitario Central de Asturias | Oviedo, 33006, Spain
Hospital Son Espases | Palma de Mallorca, 07010, Spain
Hospital Marqués de Valdecilla | Santander, 39008, Spain
Hospital Universitario Virgen Macarena | Sevilla, 41009, Spain
Hospital Universitario y Politécnico La Fe | Valencia, 46026, Spain
Hospital Royo Villanova | Zaragoza, 50009, Spain
Location Countries

Spain

Verification Date

August 2019

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Arm group label: Fosfomycin sodium intravenous

Arm group type: Experimental

Description: 4g every 6 hours iv (60 min infusion)

Arm group label: Meropenem intravenous

Arm group type: Active Comparator

Description: 1g every 8 hours (15-30 min infusion)

Arm group label: Ceftriaxone intravenous

Arm group type: Other

Description: 1g every 24h (2-4 min)

Acronym FOREST
Patient Data No
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov