Symptomatic Therapy of Uncomplicated Lower Urinary Tract Infections in the Ambulatory Setting.

Symptomatic Therapy of Uncomplicated Lower Urinary Tract Infections in the Ambulatory Setting. A Randomized, Double Blind Trial

We propose to perform a randomized controlled patient and assessor blind trial in women between the ages of 18 to 70 years with acute uncomplicated UTI to evaluate initial symptomatic treatment for 3 days with the non-steroidal anti-inflammatory drug diclofenac (experimental intervention) against immediate antibiotic treatment with norfloxacin for 3 days (control intervention). Both interventions are followed by optional delayed antibiotic treatment with single dose fosfomycin if deemed necessary by the patients. The primary objective is to determine whether initial symptomatic treatment followed by optional delayed antibiotic treatment (experimental intervention) is non-inferior to immediate antibiotic treatment (control intervention) in terms of symptom resolution.

Study Overview

• Status: Terminated
• Conditions: Urinary Tract Infections
• Intervention / Treatment: Drug: Norfloxacin; Drug: Diclofenac

Detailed Description

Background

Urinary tract infection (UTI) is the most frequent bacterial infection diagnosed and treated by general practitioners and accounts for about 15% of antibiotic prescriptions in ambulatory medicine. World-wide raise of antibiotic resistance among uropathogens, most commonly Escherichia coli, threatens treatment of UTI. Uncomplicated UTI, the most frequent manifestation of UTI, is a benign, self-limited disease and the primary goal of treatment is symptom relief not cure. Antibiotic treatment reduces the duration of symptoms by 1-2 days from 5-6 days to 3-4 days. Symptoms of cystitis are the result of an inflammation evoked by bacterial products which stimulate the production of prostaglandins by a cyclooxygenase dependent mechanism. Therefore, we propose that symptom control with a non-steroidal anti-inflammatory drug (NSAID), an inhibitor of cyclooxygenase 1 and 2, may be equally effective for symptom control as standard antibiotic therapy in non-complicated UTI and may therefore help to reduce antibiotic consumption.

Objective

The primary objective is to determine whether initial symptomatic treatment followed by optional delayed antibiotic treatment (experimental intervention) is non-inferior to immediate antibiotic treatment followed by optional delayed antibiotic treatment (control intervention) in terms of symptom resolution.

The secondary objective is to determine whether the experimental intervention is superior to control in reducing the proportion of patients undergoing antibiotic treatment.

Methods

Randomized controlled patient and assessor blind trial performed in general practices. Study population are women between the ages of 18 to 70 years with acute uncomplicated UTI. The experimental intervention will consist of symptomatic treatment with diclofenac 75mg twice daily, followed by optional, delayed antibiotic treatment with single dose of 3g fosfomycin if deemed necessary by the patient. The control intervention will consist of immediate antibiotic treatment with norfloxacin 400mg twice daily for three days, followed by optional, delayed antibiotic treatment with single dose of 3g fosfomycin if deemed necessary by the patient. Patients will use a diary to describe symptoms for 10 days. A follow-up telephone interview will be performed on day 10 and 30.

• Study Type: Interventional
• Enrollment (Actual): 253
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Berne, Switzerland, 3010
    • Institute for Infectious Diseases, University of Berne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Female
• Age between 18 and 70 years
• Written informed consent
• At least one typical symptom of acute, lower urinary tract infection out of dysuria, frequency, macrohaematuria, cloudy or smelly urine or self-diagnosed cystitis
• A urine dipstick test should be indicative of UTI by positive nitrite or leucocyturia

Exclusion Criteria

• Duration of UTI symptoms for more than 7 days before physician's visit
• Clinical signs of invasiveness such as fever (axillary body temperature >38 degrees Celsius), costovertebral pain or tenderness, rigors, nausea or vomiting
• Known or suspicion of anatomical or functional abnormality of the urinary tract
• Vaginal symptoms: discharge, irritation
• Diabetes mellitus
• Immunosuppression (e.g. prednisone equivalent >10mg per day for >14 days, chemotherapy, radiotherapy, immunomodulators, HIV infection, neutropenia)
• Any other serious comorbidity as judged by the treating physician
• Bladder catheter in situ or during the past 30 days
• Pregnancy
• Recurrent urinary tract infection (more than 3 infections during the last 12 months)
• Antibiotic treatment during the last 4 weeks
• Hypersensitivity to one of the study medications
• Psychiatric illness or dementia
• Unable to communicate in German or French language
• Documented coagulopathy (including therapy with coumarine derivatives) or documented history of gastric or duodenal ulcer disease
• Documented renal insufficiency grade III or higher (calculated GFR <60) or known congestive heart failure (NYHA III or higher)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: antibiotic; Norfloxacin for three days, followed by fosfomycin on day 4 if deemed necessary	Drug: Norfloxacin; Norfloxacin 400mg twice daily for 3 days, followed by fosfomycin 3g single dose on day 4 if deemed necessary
Experimental: symptomatic; Diclofenac retard for three days, followed by fosfomycin on day 4 if deemed necessary	Drug: Diclofenac; Diclofenac retard 75mg twice daily for 3 days, followed by fosfomycin 3g single dose on day 4 if deemed necessary

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The proportion of patients with resolution of symptoms on day 4	one month

Secondary Outcome Measures

Outcome Measure	Time Frame
The proportion of patients ever on antibiotics between randomization at day 1 and follow-up at day 30	one month
The proportion of patients using single dose fosfomycin on day 4	one month
The proportion of patients with re-consultations because of UTI within 30 days	one month
The mean composite symptom scores on days 4, 7 and 30	one month
The proportion of patients with resolution of symptoms on day 7	one month
The proportion of patients with complete resolution of symptoms on days 4 and 7	one month
The time until resolution of symptoms	one month
The proportion of patients with adverse events	one month
Mean overall patient stratification	one month
Health-related quality of life on day 4	one month
Number of working days lost	one month

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Collaborators: University of Bern; Clinic for Infectious Diseases, University Hospital Bern, Switzerland
• Investigators: Principal Investigator: Andreas Kronenberg, University of Bern

Publications and helpful links

General Publications

• Kronenberg A, Butikofer L, Odutayo A, Muhlemann K, da Costa BR, Battaglia M, Meli DN, Frey P, Limacher A, Reichenbach S, Juni P. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. BMJ. 2017 Nov 7;359:j4784. doi: 10.1136/bmj.j4784. Erratum In: BMJ. 2017 Nov 13;359:j5268.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: December 24, 2009
• First Submitted That Met QC Criteria: December 24, 2009
• First Posted (Estimate): December 25, 2009

Study Record Updates

• Last Update Posted (Estimate): July 9, 2015
• Last Update Submitted That Met QC Criteria: July 8, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: Anti-bacterial agents; Urinary tract infections
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Infections; Communicable Diseases; Urinary Tract Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Diclofenac; Norfloxacin
• Other Study ID Numbers: 254/09