Clinical trial NCT01966653: Study Comparing Nitrofurantoin to Fosfomycin for Acute Urinary Tract Infection in Women
Official title: Randomised Clinical Trial Comparing Fosfomycin vs. Nitrofurantoin for Treatment of Uncomplicated Lower Urinary Tract Infection in Female Adults at Increased Risk of Antibiotic-resistant Bacterial Infection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Urinary Tract Infections
Cystitis
Keywords: nitrofurantoin
fosfomycin
urinary tract infection
clinical efficacy
bacteriologic response
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
Collaborators: name: European Commission
First posted: 2013-10-21
Enrollment: 600
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Developed before the establishment of a structured process for drug assessment, nitrofurantoin is now being prescribed frequently given the rise in multi-resistant gram-negative pathogens. Doubts remain regarding fosfomycin's long-term clinical effectiveness. A randomized, controlled trial is needed to explore the clinical effectiveness and better define the side effect profiles of both nitrofurantoin and fosfomycin. This multi-center open trial will randomize 600 non-pregnant women at three international sites (200 each in Poland, Switzerland, and Israel) at increased risk for carriage of resistant uropathogens and with suspicion of uncomplicated lower urinary tract infection to receive either oral nitrofurantoin 100 mg three times daily for 5 days or a single 3g dose of oral fosfomycin. Patients will be followed for clinical and bacteriologic response at days 14 and 28 post therapy completion. The study hypothesis holds that nitrofurantoin will be superior to fosfomycin in clinical efficacy at final follow-up.

Detailed description: Developed before the establishment of a structured process for drug assessment, nitrofurantoin is now being prescribed frequently given the rise in multi-resistant gram-negative pathogens. Doubts remain regarding fosfomycin's long-term clinical effectiveness. A randomized, controlled trial is needed to explore the clinical effectiveness and better define the side effect profiles of both nitrofurantoin and fosfomycin. From autumn 2013 through summer 2016, this multi-center open trial will randomize 600 non-pregnant women at three international sites (200 each in Poland, Switzerland, and Israel) at increased risk for carriage of resistant uropathogens and with suspicion of uncomplicated lower urinary tract infection to receive either oral nitrofurantoin 100 mg three times daily for 5 days or a single 3g dose of oral fosfomycin. Patients will be followed for clinical and bacteriologic response at days 14 and 28 post therapy completion. The study hypothesis holds that nitrofurantoin will be superior to fosfomycin in clinical efficacy at final follow-up.

Eligibility criteria: Inclusion Criteria:

* Female gender
* Age ≥ 18 years
* Written informed consent
* At least one of four key UTI symptoms that could be attributed to an uncomplicated UTI, and no alternative explanation (i.e. symptoms suggestive of STI or vulvo-vaginitis):
* Dysuria
* Urgency (including nocturia)
* Frequency
* Suprapubic tenderness
* Urine dipstick test positive for either nitrites or leukocyte esterase
* Patient is at increased risk for resistant pathogens, e.g., FQ-resistant or ESBL-producing Enterobacteriacae

Exclusion Criteria:

* Male sex
* Pregnancy or planned pregnancy
* Known carriage of nitrofurantoin- or fosfomycin-resistant uropathogens(s)
* Concomitant antimicrobial therapy
* Use of any antibiotics in the past 7 days
* Known or suspected hypersensitivity or allergy to fosfomycin or nitrofurantoin
* History of lung or liver reaction or peripheral neuropathy after use of nitrofurantoin or other nitrofurans in the past
* Pre-existing polyneuropathy
* G6PD deficiency
* Symptoms consistent with UTI in the preceding 4 weeks
* Active upper UTI (e.g. pyelonephritis, urosepsis: fever \> 38.0, flank pain, chills)
* Symptoms/signs suggestive of vaginitis or sexually transmitted infection
* Indwelling catheter, nephrostomy, ureter stent or other foreign material
* Otherwise complicated UTI:
* A history of anatomical or functional abnormalities of the urogenital tract:
* Congenital abnormalities
* Polycystic kidney disease
* Obstruction or stricture of renal pelvis, ureter or urethra
* Kidney stones
* Cystocele
* Cystic diverticulae
* Change of anatomical proportions (e.g. after ureter implantation)
* Chronic vesico-urethral reflux
* Neurogenic bladder
* Severe chronic renal (creatinine clearance \< 30 ml/min) or hepatic dysfunction
* Porphyria
* Immunosuppression:
* Untreated infection with the human immunodeficiency virus (HIV)
* Use of high-dose systemic corticosteroids or other immunosuppressive medication
* Chemotherapy
* Treatment with radiation
* Critical illness requiring intensive care
* Planned surgery within the next 6 weeks
* Inability to take oral drugs
* Participation in another prospective clinical trial
* Previous enrolment in the proposed study
* Inability to understand or to follow the study protocol

Primary outcomes:
measure: Number of participants with clinical cure, clinical failure, or indeterminate clinical response (see description below)
timeFrame: at 28 days post therapy completion
Secondary outcomes:
measure: Number of participants with bacteriologic cure and with bacteriologic recurrence
timeFrame: at 28 days post therapy completion
Other outcomes:
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: within 28 days post therapy completion
Locations:
city: Tel Aviv
country: Israel
facility: Tel Aviv University
city: Lodz
country: Poland
facility: Lodz University Hospital
city: Geneva
country: Switzerland
facility: University Hospitals of Geneva
Study officials:
affiliation: University of Geneva
name: Stephan Harbarth, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huttner A, Kowalczyk A, Turjeman A, Babich T, Brossier C, Eliakim-Raz N, Kosiek K, Martinez de Tejada B, Roux X, Shiber S, Theuretzbacher U, von Dach E, Yahav D, Leibovici L, Godycki-Cwirko M, Mouton JW, Harbarth S. Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial. JAMA. 2018 May 1;319(17):1781-1789. doi: 10.1001/jama.2018.3627.