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Study Comparing Nitrofurantoin to Fosfomycin for Acute Urinary Tract Infection in Women (AIDA-WP2)

Primary Purpose

Urinary Tract Infections, Cystitis

Status
Unknown status
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
nitrofurantoin
fosfomycin
Sponsored by
University Hospital, Geneva
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Urinary Tract Infections focused on measuring nitrofurantoin, fosfomycin, urinary tract infection, clinical efficacy, bacteriologic response

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Tel Aviv University
  • Lodz University Hospital
  • University Hospitals of Geneva

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

nitrofurantoin

fosfomycin

Arm Description

Nitrofurantoin will be given orally at a dose of 100 mg three times daily for 5 days.

A single 3g dose of oral fosfomycin will be given.

Outcomes

Primary Outcome Measures

Number of participants with clinical cure, clinical failure, or indeterminate clinical response (see description below)
Clinical response is defined as either (1) clinical cure, which in turn is defined as complete resolution of symptoms with no recurrence of symptoms or signs of urinary tract infection; (2) clinical failure, defined as the need for additional, or change in, antibiotic treatment due to a urinary tract infection, OR discontinuation due to lack of efficacy; or (3) indeterminate response, defined as either persistence of symptoms without objective evidence of infection (absence of bacteriuria or pyuria) OR any extenuating circumstances precluding a classification or clinical cure/failure.

Secondary Outcome Measures

Number of participants with bacteriologic cure and with bacteriologic recurrence
Bacteriologic response is defined as either (1) bacteriologic cure, that is, eradication of the infecting strain with no recurrence of bacteriuria (<10x3 cfu/mL) during follow-up; or (2) bacteriologic recurrence, defined as bacteriuria >10x3 cfu/mL. However, bacteriologic recurrence without urinary tract symptoms will be designated asymptomatic bacteriuria and left untreated.

Full Information

First Posted
October 10, 2013
Last Updated
May 1, 2017
Sponsor
University Hospital, Geneva
Collaborators
European Commission
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1. Study Identification

Unique Protocol Identification Number
NCT01966653
Brief Title
Study Comparing Nitrofurantoin to Fosfomycin for Acute Urinary Tract Infection in Women
Acronym
AIDA-WP2
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

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Unknown status
Study Start Date
October 2013 (Actual)
Primary Completion Date
May 2017 (Anticipated)
Study Completion Date
August 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital, Geneva
Collaborators
European Commission

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Urinary Tract Infections, Cystitis
Keywords
nitrofurantoin, fosfomycin, urinary tract infection, clinical efficacy, bacteriologic response

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
600 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
nitrofurantoin
Arm Type
Active Comparator
Arm Description
Nitrofurantoin will be given orally at a dose of 100 mg three times daily for 5 days.
Arm Title
fosfomycin
Arm Type
Active Comparator
Arm Description
A single 3g dose of oral fosfomycin will be given.
Intervention Type
Drug
Intervention Name(s)
nitrofurantoin
Other Intervention Name(s)
Macrodantin, Furadantine
Intervention Description
nitrofurantoin 100 mg po tid for 5 days
Intervention Type
Drug
Intervention Name(s)
fosfomycin
Other Intervention Name(s)
Monuril
Intervention Description
fosfomycin 3g po single dose
Primary Outcome Measure Information:
Title
Number of participants with clinical cure, clinical failure, or indeterminate clinical response (see description below)
Description
Clinical response is defined as either (1) clinical cure, which in turn is defined as complete resolution of symptoms with no recurrence of symptoms or signs of urinary tract infection; (2) clinical failure, defined as the need for additional, or change in, antibiotic treatment due to a urinary tract infection, OR discontinuation due to lack of efficacy; or (3) indeterminate response, defined as either persistence of symptoms without objective evidence of infection (absence of bacteriuria or pyuria) OR any extenuating circumstances precluding a classification or clinical cure/failure.
Time Frame
at 28 days post therapy completion
Secondary Outcome Measure Information:
Title
Number of participants with bacteriologic cure and with bacteriologic recurrence
Description
Bacteriologic response is defined as either (1) bacteriologic cure, that is, eradication of the infecting strain with no recurrence of bacteriuria (<10x3 cfu/mL) during follow-up; or (2) bacteriologic recurrence, defined as bacteriuria >10x3 cfu/mL. However, bacteriologic recurrence without urinary tract symptoms will be designated asymptomatic bacteriuria and left untreated.
Time Frame
at 28 days post therapy completion
Other Pre-specified Outcome Measures:
Title
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Time Frame
within 28 days post therapy completion

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephan Harbarth, MD, MS
Organizational Affiliation
University of Geneva
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tel Aviv University
City
Tel Aviv
Country
Israel
Facility Name
Lodz University Hospital
City
Lodz
Country
Poland
Facility Name
University Hospitals of Geneva
City
Geneva
ZIP/Postal Code
1201
Country
Switzerland

12. IPD Sharing Statement

Citations:
PubMed Identifier
29710295
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.
Results Reference
derived
Links:
URL
http://www.aida-project.eu/
Description
Related info.

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Study Comparing Nitrofurantoin to Fosfomycin for Acute Urinary Tract Infection in Women

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