|Wagenlehner et al., 2018 ||Gágyor et al., 2015 ||Bleidorn et al., 2010 ||Vik et al., 2018 ||Kronenberg et al., 2017 |
|Medication||BNO 1045 vs. fosfomycin (FT)||Ibuprofen vs. fosfomycin||Ibuprofen vs. ciprofloxacin||Ibuprofen vs. pivmecillinam||Diclofenac vs. norfloxacin|
|Study designa||Double-blind, controlled, double-dummy, parallel group, randomized, multicentre, multinational Phase III||Double-blind, randomized, multicentre, comparative effectiveness trial with two parallel active treatment arms||Double-blind, randomized, controlled equivalence trial||Double-blind, randomized, parallel-group, multicentre, non-inferiority trial||Double-blind, randomized, controlled non-inferiority trial|
|Inclusion criteriab||Sum score of the three main uUTI symptoms (dysuria, pollakiuria and urgency) reported on the ACSS-typical domain on Day 1 is ≥6, leukocyturia on Day 1, confirmed by positive dipstick||Dysuria and/or frequency/urgency of micturition, with or without lower abdominal pain||At least one of the main UTI symptoms, dysuria and frequency||Dysuria combined with either increased urinary frequency or urinary urgency, or both, with or without visible haematuria||One or more symptoms of acute lower UTI (dysuria, frequency, macrohaematuria, cloudy or smelly urine) or self-diagnosed symptomatic cystitis in combination with a positive urine dipstick test for nitrite or/and leucocytes|
|Exclusion criteriab||History of recurrent infection of the urinary tract||UTI within the past 2 weeks||UTI within the last 2 weeks||Symptoms of UTI within the last 4 weeks||Recurrent UTI (> 3 infections during the past 12 months)|
|Number of patients||n = 325 (BNO 1045), n = 334 (FT)||n = 241 (ibuprofen), n = 243 (FT)||n = 40 (ibuprofen), n = 39 (ciprofloxacin)||n = 194 (ibuprofen), n = 189 (pivmecillinam)||n = 133 (diclofenac), n = 120 (norfloxacin)|
|Duration in days||1–38||0–28||0–28||0–28||0–30|
|Dosage and duration of administration||BNO 1045, 7 days, 2 tablets TID|
Fosfomycin trometamol (FT), single dose on Day 1 (3 g)
|ibuprofen, 3 days, 1 tablet (400 mg) TID|
fosfomycin trometamol (FT), single dose on Day 1 (3 g)
|ibuprofen, 3 days, 1 tablet (400 mg) TID|
ciprofloxacin, 3 days, 1 tablets (250 mg) BID
|ibuprofen, 3 days, 1 tablet (600 mg) TID|
pivmecillinam, 3 days, 1 tablet (200 mg) TID
|diclofenac, 3 days, 1 tablet (75 mg) BID|
norfloxacin, 3 days, 1 tablet (400 mg) BID
|Paracetamol||Allowed||Not reported||Not reported||At patients’ discretion. There is the possibility that intake of paracetamol may have masked symptomatic progression of upper UTI.||Not reported|
|Visits/calls* (days)||1,4*,8,38||1*,3*,5*,7*,28||0, 4, 7, 28||?||30*|
|Symptom scale||ACSS questionnaire: Mean sum scores of the ACSS-typical domain between Days 1 and 38|
Typical symptoms (n = 6) of lower uUTIs (ACSS-typical), where 0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe symptoms
|Dysuria, frequency/urgency of micturition, and low abdominal pain, each on a five point scale from 0 to 4.||Intensity of main symptoms - dysuria, frequency, low abdominal pain - was recorded, scoring each symptom from 0 (none) to 4 (very strong)||Patient diary for recording daily symptoms, diary was based on a previously validated version||The self-report questionnaire used to ascertain the severity of symptoms was developed based on questionnaires described by Clayson et al. and Little et al.|
Women rated the severity of five UTI symptoms (dysuria, frequency, urgency, abdominal pain when passing urine, pain or tenderness in the lower back or loin) daily from days 0 to 10 in a diary and on day 30 by telephone interview on a Likert scale from 0 to 6, with their composite score ranging from 0 to 30. Symptom resolution was defined as 2 or less points (slight, very slight, or no problems) on all five components. Complete absence of symptoms was defined as 0 points on all components.
|Primary endpoint(s)||Additional antibiotic intake between days 1–38||Total number of courses of antibiotics on days 0–28, burden of symptoms on days 0–7 as area under the curve||Symptom resolution on day 4||Proportion of patients who felt cured by day 4, as assessed based on a patient diary||Resolution of symptoms at day 3 (72 h after randomization and 12 h after intake of the last study drug)|
|Secondary endpointsb||ACSS questionnaire assessments at days 4, 8 and 38||Numbers of adverse events||Burden of symptoms on days 4 and 7 (based on the sum score of all symptoms), symptom resolution on day 7 and frequency of relapses||Proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis||Use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30 (ITT)|
|Statistics||Non-inferiority margin (− 15%)||Superiority in the first and non-inferiority (125%) in the second co-primary endpoint||Rough estimate of equivalence of ibuprofen and ciprofloxacin for uUTI regarding symptom resolution||Non-inferiority margin (−15%)|
|Main Result||Antibiotic Reduction of 85%.|
Clinical benefit on reduction of the main ACSS-typical symptoms was observed after 3 days of treatment.
More cases of pyelonephritis in the non-antibiotic group.
|Fosfomycin: 243 study antibiotic + 34 additional for UTI.|
Ibuprofen: 81 additional for UTI -- > Antibiotic Reduction of 67%.
Symptom burden sum score decreased in both groups (Day 0: 6 -- > Day 7: < 1) -- > non-inferiority margin of 125% exceeded.
Higher burden of symptoms.
More cases of pyelonephritis in the non-antibiotic group.
|Assumption of non-inferiority is supported, but confirmation by further trials needed.||Ibuprofen was inferior to pivmecillinam for treating uUTI, reducing the use of antibiotics came at the cost of stronger symptom burden, longer duration of symptoms, and more complications.||Diclofenac is inferior to norfloxacin for symptomatic relief in UTI and is likely to be associated with an increased risk of pyelonephritis.|
|Symptoms||Symptom decline comparable in both groups (statistical significance in favour of fosfomycin on Day 4)||Symptoms lasted 1 day longer in the ibuprofen group.|
Day 4: 56% in fosfomycin group symptom-free vs. 39% in the ibuprofen group.
|As for symptom resolution, 58.3% of patients in the ibuprofen group and 51.5% in the ciprofloxacin group were completely free of symptoms on Day 4 (difference non-significant). On Day 7, the proportion of symptom-free patients had increased further in both groups, without a significant difference between groups. The course of symptoms in terms of mean symptom sum scores: with respect to Day 4, the difference in total sum scores was − 0.33 score points (95% CI (− 1.13; + 0.47)) in the PP analysis (primary analysis). The corresponding ITT analysis resulted in a difference of 0.50 (95% CI: (− 1.31; + 0.31). With regard to general impairment, there were no significant differences between the ibuprofen and ciprofloxacin groups. In particular, no difference could be shown between groups for the course of dysuria.||Patients in the pivmecillinam group generally felt cured sooner than the patients in the ibuprofen group.|
The median duration of symptoms was 6 days in the ibuprofen group and 3 days in the pivmecillinam group.
|The median time until resolution of symptoms was 4 days in the diclofenac group, compared with 2 days in the norfloxacin group.|
|Safety||5 cases of pyelonephritis (BNO 1045) vs. 1 case (fosfomycin)||5 cases of pyelonephritis (ibuprofen) vs. 1 case (fosfomycin)|
One gastrointestinal haemorrhage in the ibuprofen group
|58 non-serious adverse events (32 ibuprofen, 26 ciprofloxacin)||7 SAEs during the trial, 1 in the pivmecillinam group and 6 in the ibuprofen group. 5 patients developed a febrile UTI and 7 patients developed pyelonephritis, all initially treated with ibuprofen||6 cases of pyelonephritis (diclofenac) vs. 0 (norfloxacin)|
|Recurrence||The AB rates were comparable across the different reasons for additional AB intake during the clinical trial (persistent or worsening symptoms: BNO 1045: 66.0% and FT: 67.7%; recurrent symptoms: BNO 1045: 23.4% and FT: 25.8%; no symptoms reported: BNO 1045: 10.6% and FT: 6.5%).||Comparable in both groups, but significant more recurrences after day 14 in the FT group (11% vs. 6%)||The surprisingly high number of patients presenting again with persistent/recurrent symptoms while taking ciprofloxacin (18%) might indicate that antibiotic treatment takes a few days to resolve symptoms, a fact which may have worried trial patients who did not know which drug they were taking.||Comparing the subgroup with recurrent UTIs (i.e., 3 or more UTIs during the previous 12 months) to the subgroup with 0 ± 2 UTIs within the last 12 months, the highest symptom burden over 6 days was observed in the recurrent UTI patients treated with ibuprofen.|
The difference in symptom burden between the treatment groups was greater for those with recurrent UTIs, but significant in both subgroups.
|Recurrent UTI: 4% diclofenac vs. 3% norfloxacin|
Recurrent UTI was defined as additional visits after day 14 because of recurrent UTI symptoms after symptoms had resolved by day 10, and the physician decided to treat with antibiotics.
|Limitations||Microbiological data (but not mandatory for uUTIs)||Inclusion was biased towards patients with less severe symptoms -- > results only applicable to patients with mild to moderate symptoms, rather than all uUTI|
Neither symptom score or measurement of the area under the curve were validated -- > relevance for affected patients was not formally proved
|Small sample size, pilot trial||High dosage of ibuprofen, low dosage of pivmecillinam||Rescue antibiotic (fosfomycin) could be taken at patients’ discretion after day 3|
Symptom resolution ≠ complete absence of symptoms
|Conclusion||Trial may inform treatment choices and encourage wider adoption of antibiotic alternatives, such as BNO 1045, for the treatment of lower uUTIs in routine clinical practice||Non-inferiority not achieved, no general recommendation of the “ibuprofen first approach”||Results support the assumption of non-inferiority, but further trials or an adequately powered trial is necessary.||Until we can identify those women in need of antibiotic treatment to prevent complications, ibuprofen alone cannot be recommended to women with uUTIs.||Trial failed to detect non-inferiority of NSAIDs compared with antibiotics for symptom control.|
Symptomatic treatment of lower urinary tract infections prolongs symptom duration and is likely to be associated with an increased risk of pyelonephritis.